Oral mucosa absorption gargle tablet based on black rhizoma cimicifugae extract

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an oral mucosa absorption gargle tablet based on black cimicifuga foetida extract, which is composed of the following components in percentage by mass: 30% of quick release layer and 70% of slow release layer, the quick release layer is composed of black cimicifuga foetida nano-liposome, a disintegrating agent and a penetration enhancer, and the slow release layer is composed of a disintegrating agent and a penetration enhancer. The quick release layer is composed of black cimicifuga foetida nano-liposome, a disintegrating agent and a penetration enhancer according to a mass ratio of 4: 1: 1, and the slow release layer is composed of chitosan, soy isoflavone, a pH sensitive material and a flavoring agent; through the double-layer structure design of the quick release layer (disintegration time is less than or equal to 5 seconds) and the slow release layer (pH is greater than or equal to 6.5 to trigger release), the quick effect (inhibiting hectic fever in 10 minutes) and the continuous effect (releasing 78% of soybean isoflavone in 8 hours) of the active ingredients are realized, and the preparation is obviously superior to the traditional oral preparation (the effect is realized in 45 minutes, and the release rate lt in a gastric acid environment is 5%).

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and specifically to a gargle tablet for oral mucosal absorption based on black cohosh extract. Background Art

[0002] At present, the treatment of menopausal syndrome (such as hot flashes, osteoporosis, etc.) mostly relies on oral or transdermal administration preparations, but these methods have significant limitations. Traditional oral tablets need to be absorbed through the gastrointestinal tract, affected by the first-pass effect, with low bioavailability; and the gastric acid environment (pH 1.2) is easy to destroy active ingredients (such as soy isoflavones), resulting in a decrease in efficacy. Although transdermal patches can avoid the first-pass effect, there are problems such as slow onset and skin irritation. In addition, existing oral mucosal absorption preparations generally have insufficient synergy between rapid release and sustained release: the disintegration time of the rapid release layer is too long (>10 seconds), leading to delayed onset, the sustained release layer lacks pH sensitivity, it is difficult to release precisely in the target area (such as the neutral oral environment), and the taste adjustment technology is single, affecting patient compliance.

[0003] As a traditional medicinal plant, the extract (triterpenoid saponins) of black cohosh has estrogen-like activity, but when directly applied, due to its large molecular weight and low liposolubility, the mucosal permeability is low (only 27.3% for ordinary tablets). Existing nano-liposome preparation technologies also have problems such as low encapsulation efficiency (<80%) and uneven particle size (>200nm), which limit its application in mucosal drug delivery.

[0004] Therefore, we propose a gargle tablet for oral mucosal absorption based on black cohosh extract to solve the above problems. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention discloses a gargle tablet for oral mucosal absorption based on black cohosh extract. The technical solution adopted is that it is composed of the following components by mass percentage: 30% of the rapid release layer and 70% of the sustained release layer. The rapid release layer is composed of black cohosh nano-liposomes, a disintegrant, and a penetration enhancer. In the rapid release layer, the black cohosh nano-liposomes, the disintegrant, and the penetration enhancer are composed according to a mass ratio of 4:1:1. The sustained release layer is composed of chitosan, soy isoflavones, a pH-sensitive material, and a flavoring agent. In the sustained release layer, chitosan, soy isoflavones, the pH-sensitive material, and the flavoring agent are composed according to a mass ratio of 2:3:1:2.

[0006] As a preferred technical solution of the present invention, the disintegrant in the rapid release layer can adopt cross-linked carboxymethyl cellulose sodium, and the penetration enhancer in the rapid release layer can adopt menthol-β-cyclodextrin inclusion complex.

[0007] As a preferred technical solution of the present invention, the pH-sensitive material in the sustained-release layer can be Eudragit E100, and the flavoring agent can be a mixture of erythritol and natural berry essence.

[0008] As a preferred technical solution of the present invention, the preparation method of the black cohosh nano-liposomes is as follows:

[0009] S1. The black cohosh rhizome is ultrasonically extracted with 70% ethanol and purified by AB-8 resin to obtain an extract with a triterpenoid saponin content of ≥10%.

[0010] S2. The extract is mixed with phospholipids (DPPC: cholesterol = 8:2) at a mass ratio of 1:5, and liposomes are prepared by the thin-film hydration method, and then homogenized under high pressure (50 MPa) until the particle size is ≤100 nm and the encapsulation efficiency is ≥90%.

[0011] S3. The liposome suspension is mixed with mannitol and freeze-dried (-45 °C, 24 h) to form porous microparticles.

[0012] As a preferred technical solution of the present invention, the disintegration time of the rapid-release layer is ≤5 seconds, and the sustained-release layer continuously releases the active ingredient at pH ≥6.5.

[0013] As a preferred technical solution of the present invention, the manufacturing method of the buccal mucosa-absorbing gargle tablets based on black cohosh extract includes a nano-liposome freeze-drying process and a double-layer tableting process.

[0014] As a preferred technical solution of the present invention, the nano-liposome freeze-drying process is as follows: The black cohosh nano-liposomes are mixed with mannitol, and the formed mixture is placed in an environment of -45 °C and freeze-dried for 24 hours to form porous microparticles.

[0015] As a preferred technical solution of the present invention, the double-layer tableting process is as follows: The powders of the rapid-release layer and the sustained-release layer are respectively passed through a 80-mesh sieve and pressed by a double-layer tableting machine with a pressure of 80-100 kN to obtain tablets with a tablet weight of 500 mg and a hardness of 70-90 N.

[0016] The beneficial effects of the present invention:

[0017] 1. Synergistic release of rapid effect and long effect: Through the double-layer structure design of the rapid-release layer (disintegration time ≤5 seconds) and the sustained-release layer (triggered release at pH ≥6.5), the rapid onset of the active ingredient (inhibiting hot flashes in 10 minutes) and the continuous action (releasing 78% of soy isoflavones in 8 hours) are realized, which is significantly better than traditional oral preparations (onset in 45 minutes, release rate <5% in the gastric acid environment);

[0018] 2. Breakthrough improvement in bioavailability: The synergistic effect of black cohosh nanoliposomes (particle size ≤ 100 nm, encapsulation efficiency ≥ 90%) and menthol-β-cyclodextrin inclusion complex enables the 24-hour mucosal cumulative penetration amount to reach 82.5% (only 27.3% for ordinary tablets), greatly improving the transmembrane absorption efficiency of active ingredients;

[0019] 3. Targeted delivery and stability optimization: The pH sensitivity of Eudragit E100 in the sustained-release layer ensures that the release rate of active ingredients is < 5% in the gastric acid environment (pH 1.2), avoiding ineffective degradation; it is precisely released in the oral neutral environment (pH 7.0), reducing the risk of systemic exposure;

[0020] 4. Enhanced safety and compliance: The flavoring agent (erythritol + natural berry flavor) significantly improves the taste. The incidence of oral mucosal irritation in clinical trials is 0% (12% in the traditional tablet group), with high patient acceptance; animal experiments confirm a 18% increase in bone density (p < 0.01), and there are no reports of liver and kidney toxicity;

[0021] 5. Process and cost advantages: The thin-film hydration combined with high-pressure homogenization technology simplifies the preparation process of nanoliposomes, and freeze-drying porous microparticles ensures the stability of the preparation; the double-layer tableting process (pressure of 80 - 100 kN) realizes the large-scale production of high-hardness tablets (70 - 90 N), with controllable costs. Detailed implementation manners

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0023] Example 1

[0024] The present invention discloses an oral mucosal absorption gargle tablet based on black cohosh extract, and the adopted technical solution is that it is composed of the following components by mass percentage: 30% of the rapid-release layer and 70% of the sustained-release layer. The rapid-release layer is composed of black cohosh nanoliposomes, a disintegrant, and a penetration enhancer. In the rapid-release layer, the black cohosh nanoliposomes, the disintegrant, and the penetration enhancer are composed according to the mass ratio of 4:1:1. The sustained-release layer is composed of chitosan, soy isoflavones, a pH-sensitive material, and a flavoring agent. In the sustained-release layer, chitosan, soy isoflavones, the pH-sensitive material, and the flavoring agent are composed according to the mass ratio of 2:3:1:2.

[0025] As a preferred technical solution of the present invention, the disintegrant in the rapid-release layer can adopt cross-linked carboxymethyl cellulose sodium, and the penetration enhancer in the rapid-release layer can adopt menthol-β-cyclodextrin inclusion complex.

[0026] As a preferred technical solution of the present invention, the pH-sensitive material in the sustained-release layer can be Eudragit E100, and the flavoring agent can be a mixture of erythritol and natural berry essence.

[0027] As a preferred technical solution of the present invention, the preparation method of the black cohosh nano-liposomes is as follows:

[0028] S1. The black cohosh rhizome is extracted by ultrasonic extraction with 70% ethanol and purified by AB-8 resin to obtain an extract with a triterpenoid saponin content of ≥10%.

[0029] S2. The extract is mixed with phospholipids (DPPC:cholesterol = 8:2) at a mass ratio of 1:5, and liposomes are prepared by the thin-film hydration method, and then homogenized under high pressure (50 MPa) until the particle size is ≤100 nm and the encapsulation efficiency is ≥90%.

[0030] S3. The liposome suspension is mixed with mannitol and freeze-dried (-45°C, 24 h) to form porous microparticles.

[0031] As a preferred technical solution of the present invention, the disintegration time of the rapid-release layer is ≤5 seconds, and the sustained-release layer continuously releases the active ingredient at pH ≥6.5.

[0032] As a preferred technical solution of the present invention, the manufacturing method of the buccal mucosa-absorbing gargle tablets based on black cohosh extract includes a nano-liposome freeze-drying process, and the nano-liposome freeze-drying process is: mixing the black cohosh nano-liposomes with mannitol, and placing the formed mixture in an environment of -45°C and freeze-drying for 24 hours to form porous microparticles.

[0033] As a preferred technical solution of the present invention, the manufacturing method of the buccal mucosa-absorbing gargle tablets based on black cohosh extract further includes a double-layer tableting process, and the double-layer tableting process is: the powders of the rapid-release layer and the sustained-release layer are respectively passed through a 80-mesh sieve, and pressed by a double-layer tableting machine with a pressure of 80-100 kN to form tablets with a tablet weight of 500 mg and a hardness of 70-90 N.

[0034] Example 2

[0035] Take 100 mg of black cohosh extract and dissolve it with a phospholipid mixture (160 mg of DPPC + 40 mg of cholesterol) in chloroform, evaporate to form a film by rotary evaporation, hydrate and then homogenize under high pressure to obtain liposomes with a particle size of (92±15) nm and an encapsulation efficiency of 92.3%.

[0036] Gargle tablet formula

[0037] Ingredients Immediate Release Layer (mg) Sustained Release Layer (mg) Black Cohosh Nanoliposomes 150 - Croscarmellose Sodium 25 - Menthol-β-Cyclodextrin Inclusion Complex 25 - Chitosan - 70 Soy Isoflavones - 105 Eudragit E100 - 35 Erythritol + Berry Flavor - 70 Magnesium Stearate 5 5

[0038] Experimental data

[0039] 1. In vitro release and permeation

[0040] Immediate release layer: 95% of black cohosh is released within 5 minutes in artificial saliva (detected by HPLC).

[0041] Sustained release layer: 78% of soy isoflavones are cumulatively released in 8 hours (pH 7.0), and the release rate is <5% in gastric acid environment (pH 1.2).

[0042] Mucosal permeation amount: The cumulative permeation amount reaches 82.5% in 24 hours (27.3% for ordinary tablets).

[0043] Experiment Type Indicators Results Control Group Data Immediate Release Layer Release Black Cohosh Release Rate in Artificial Saliva at 5 Minutes 95% (Detected by HPLC) - Sustained Release Layer Release Soy Isoflavone Release Rate at pH 7.0 for 8 Hours 78% Ordinary Tablets 27.3% Gastric Acid Stability Soy Isoflavone Release Rate at pH 1.2 <5% - Mucosal Penetration Ability Cumulative Penetration Amount in 24 Hours 82.5% (Nanoliposome Group) Ordinary Tablets 27.3%

[0044] 2. Animal model (OVX rats)

[0045] Hot flash suppression: After sublingual administration of the gargle tablet group for 10 minutes, the skin temperature fluctuation decreased by 70%, significantly faster than the oral group (which takes effect in 45 minutes).

[0046] Bone mineral density: The femoral bone mineral density increased by 18% after 12 weeks of treatment (p<0.01).

[0047] Experiment Type Indicators Results Control Group Data Hot Flash Inhibition Reduction Time of Skin Temperature Fluctuation after Sublingual Administration Onset in 10 Minutes, Inhibition Rate 70% Oral Administration Group Onset in 45 Minutes Bone Density Improvement Change in Femoral Bone Density after 12 Weeks of Treatment Increased by 18% (p < 0.01) -

[0048] 3. Clinical trial (multi - center randomized controlled)

[0049] Subjects: 200 menopausal women (Kupperman score ≥25), divided into the gargle tablet group and the placebo group.

[0050] Results:

[0051] The hot flash frequency decreased by 63% (17% in the placebo group), and the improvement rate of insomnia was 79% (p<0.001).

[0052] The salivary estrogen level was stable (the activation rate of ERβ increased by 45%).

[0053] The incidence of oral mucosal irritation was 0% (12% for traditional tablets in the control group).

[0054] Experiment Type Indicators Results Control Group Data Change in Hot Flash Frequency Lozenges Group vs Placebo Group Decrease by 63% (Placebo Group 17%) - Insomnia Improvement Rate Lozenges Group 79%（p<0.001） - Estrogen Level Salivary ERβ Activation Rate Increase by 45% - Mucosal Irritation Incidence of Oral Mucosal Irritation 0% Traditional Tablets Group 12%

[0055] Table description

[0056] The data are from the experimental verification part of the specific implementation in the document.

[0057] The experimental results show that the gargle tablet is significantly superior to the traditional oral preparation in terms of rapidity, bioavailability and safety.

[0058] The components not detailed in this article are prior art.

[0059] Although the specific embodiments of the present invention have been described in detail above, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those of ordinary skill in the art, various changes can be made without departing from the gist of the present invention, and modifications or variations that do not involve creative labor are still within the scope of protection of the present invention.

Claims

1. An oral mucosa-absorbing gargle tablet based on black cohosh extract, characterized in that, It is composed of the following components by mass percentage : immediate-release layer 30% and sustained-release layer 70%. The immediate-release layer is composed of black cohosh nanoliposomes, disintegrant and penetration enhancer. In the immediate-release layer, the black cohosh nanoliposomes, disintegrant and penetration enhancer are composed according to the mass ratio of 4:1:

1. The sustained-release layer is composed of chitosan, soy isoflavones, pH-sensitive material and flavoring agent. In the sustained-release layer, chitosan, soy isoflavones, pH-sensitive material and flavoring agent are composed according to the mass ratio of 2:3:1:

2.

2. The buccal absorption gargle tablet based on black cohosh extract according to claim 1, characterized in that, The disintegrant in the immediate-release layer can be cross-linked carboxymethyl cellulose sodium, and the penetration enhancer in the immediate-release layer can be menthol-β-cyclodextrin inclusion complex.

3. The buccal absorption gargle tablet based on black cohosh extract according to claim 1, characterized in that, The pH-sensitive material in the sustained-release layer can be Eudragit E100, and the flavoring agent can be a mixture of erythritol and natural berry essence.

4. The buccal absorption gargle tablet based on black cohosh extract according to claim 1, characterized in that, The preparation method of the black cohosh nanoliposomes is as follows : S1. The black cohosh rhizome is extracted by ultrasonic with 70% ethanol and purified by AB-8 resin to obtain an extract with a triterpenoid saponin content of ≥10%; S2. The extract is mixed with phospholipids (DPPC:cholesterol = 8:2) according to a mass ratio of 1:5, and liposomes are prepared by the thin film hydration method and homogenized under high pressure (50 MPa) until the particle size is ≤100 nm and the encapsulation efficiency is ≥90%; S3. The liposome suspension is mixed with mannitol and freeze-dried (-45 °C, 24 h) into porous microparticles.

5. The buccal absorption gargle tablet based on black cohosh extract according to claim 1, characterized in that, The disintegration time of the immediate-release layer is ≤5 seconds, and the sustained-release layer continuously releases the active ingredient at pH ≥6.

5.

6. The buccal absorption gargle tablet based on black cohosh extract according to any one of claims 1-4, characterized in that, The manufacturing method of the oral mucosal absorption gargle tablets based on black cohosh extract includes a nanoliposome freeze-drying process and a double-layer tableting process.

7. The buccal absorption gargle tablet based on black cohosh extract according to claim 6, characterized in that, The nanoliposome freeze-drying process is: mixing the black cohosh nanoliposomes with mannitol, and placing the formed mixture in an environment of -45 °C and freeze-drying for 24 hours to form porous microparticles.

8. The buccal absorption gargle tablet based on black cohosh extract according to claim 6, characterized in that, The double-layer tableting process is: the powders of the immediate-release layer and the sustained-release layer are respectively passed through a 80-mesh sieve and pressed by a double-layer tableting machine with a pressure of 80-100 kN into tablets with a tablet weight of 500 mg and a hardness of 70-90 N.