Oral mucosa absorption gargle tablet based on black rhizoma cimicifugae extract

Abstract

The invention discloses an oral mucosa absorption gargle tablet based on black cimicifuga foetida extract, and particularly relates to the field of pharmaceutical preparations, the oral mucosa absorption gargle tablet comprises the following components by weight: 30 wt% of a quick release layer and 70 wt% of a slow release layer; the quick release layer is prepared from black cimicifuga foetida nano-liposome, a disintegrating agent and a penetration enhancer, and the mass ratio of the black cimicifuga foetida nano-liposome to the disintegrating agent to the penetration enhancer in the quick release layer is 4: 1: 1; the slow-release layer is prepared from chitosan, soy isoflavone, a pH sensitive material and a flavoring agent, and the mass ratio of the chitosan to the soy isoflavone to the pH sensitive material to the flavoring agent in the slow-release layer is 2: 3: 1: 2. Through the double-layer structure design of the quick release layer and the slow release layer, quick effect and continuous effect of active ingredients are realized, and the oral preparation is obviously superior to a traditional oral preparation; the black cimicifuga foetida nano-liposome and the menthol-beta-cyclodextrin inclusion compound have a synergistic effect, so that the cumulative infiltration capacity of mucous membranes within 24 hours reaches 82.5%, and the transmembrane absorption efficiency of active ingredients is greatly improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, and more particularly to an oral mucosa absorption gargling tablet based on black cohosh extract. BACKGROUND

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

[0003] Black cohosh, as a traditional medicinal plant, has estrogen-like activity, but its extract (triterpenoid saponin) has low mucosal permeability (only 27.3% for ordinary tablets) due to its large molecular weight and low fat solubility. The existing nanoliposome preparation technology also has the problems of low encapsulation efficiency (< 80%) and uneven particle size (> 200 nm), which limits its application in mucosal drug delivery; therefore, an oral mucosa absorption gargling tablet based on black cohosh extract is proposed to solve the above problems. SUMMARY

[0004] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present application provide an oral mucosa absorption gargling tablet based on black cohosh extract.

[0005] To achieve the above-mentioned purpose, the present application provides the following technical scheme: an oral mucosa absorption gargling tablet based on black cohosh extract, which is composed of the following ingredients by weight percentage: 30wt% of an immediate-release layer and 70wt% of a sustained-release layer.

[0006] The immediate-release layer is composed of black cohosh nanoliposomes, disintegrants and penetration enhancers, wherein the black cohosh nanoliposomes, disintegrants and penetration enhancers in the immediate-release layer are composed of 4:1:1 by mass ratio.

[0007] The sustained-release layer is composed of chitosan, soy isoflavones, pH-sensitive materials and flavoring agents, and the chitosan, soy isoflavones, pH-sensitive materials and flavoring agents in the sustained-release layer are composed of 2:3:1:2 by mass ratio.

[0008] In a preferred embodiment, the disintegrant in the immediate release layer is cross-linked sodium carboxymethyl cellulose, and the penetration enhancer in the immediate release layer is menthol-β-cyclodextrin inclusion compound.

[0009] In a preferred embodiment, the pH-sensitive material in the sustained release layer is Eudragit E100, and the flavoring agent is a mixture of erythritol and natural berry flavor.

[0010] In a preferred embodiment, 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.

[0011] The present application also includes a method for preparing a buccal mucosa absorption gargling tablet based on black cohosh extract, comprising a nanoliposome freeze-drying process and a double-layer tabletting process.

[0012] In a preferred embodiment, the nanoliposome freeze-drying process is as follows: mix black cohosh nanoliposomes with mannitol, and freeze-dry the mixture formed at -45℃ for 24 hours to form porous microparticles.

[0013] In a preferred embodiment, the double-layer tabletting process is as follows: pass the powders of the immediate release layer and the sustained release layer through an 80-mesh sieve, and press them into tablets with a tablet weight of 500 mg and a hardness of 70-90 N using a double-layer tablet press with a pressure of 80-100 kN.

[0014] The present application also includes a method for preparing black cohosh nanoliposomes, with the specific preparation steps being as follows:

[0015] S1: ultrasonically extract black cohosh rhizomes with 70% ethanol and purify the extract with AB-8 resin to obtain an extract with a triterpenoid saponin content ≥10%;

[0016] S2: mix the extract obtained in step S1 with phospholipids (DPPC: cholesterol = 8:2) at a mass ratio of 1:5, and use the film hydration method to prepare liposomes, and then homogenize them at a high pressure (50 MPa) to a particle size ≤100 nm and an encapsulation efficiency ≥90% to obtain a liposome suspension;

[0017] S3: mix the liposome suspension obtained in step S2 with mannitol, and freeze-dry it (-45℃, 24h) into porous microparticles.

[0018] The technical effects and advantages of the present application are as follows:

[0019] 1、The present application realizes rapid onset (10 minutes of hot flashes inhibition) and sustained effect (78% of soy isoflavones released in 8 hours) through the dual-layer structure design of the immediate-release layer (disintegration time ≤5 seconds) and the sustained-release layer (pH≥6.5 triggered release), which is significantly better than the traditional oral preparation (45 minutes of onset, release rate <5% in gastric acid environment);

[0020] 2、The present application breaks through the bioavailability improvement: the synergistic effect of black cohosh nanoliposomes (particle size ≤100 nm, encapsulation efficiency ≥90%) and menthol-β-cyclodextrin inclusion compound makes the 24-hour mucosal cumulative permeation amount reach 82.5% (only 27.3% for ordinary tablets), greatly improving the transmembrane absorption efficiency of the active ingredient;

[0021] 3、The present application realizes targeted delivery and stability optimization: the pH sensitivity of Eudragit E100 in the sustained-release layer ensures that the release rate of the active ingredient is <5% in the gastric acid environment (pH 1.2), avoiding ineffective degradation; precise release in the oral neutral environment (pH 7.0), reducing the risk of systemic exposure;

[0022] 4、The present application enhances safety and compliance: flavoring agents (erythritol + natural berry essence) significantly improve the taste, and the incidence of oral mucosa irritation in clinical trials is 0% (12% for the traditional tablet group), and the patient acceptance is high; animal experiments show that bone density is increased by 18% (p<0.01), and no liver and kidney toxicity is reported;

[0023] 5、The present application has process and cost advantages: the combination of thin film hydration and high-pressure homogenization technology simplifies the nanoliposome preparation process, and freeze-dried porous microparticles guarantee the stability of the preparation; the double-layer tabletting process (80-100 kN pressure) realizes the large-scale production of high-hardness tablets (70-90 N), and the cost is controllable. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present application will be described below in conjunction with the embodiments in the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0025] Example 1:

[0026] The application provides an oral mucosa absorption gargling tablet based on black cohosh extract, wherein the tablet is composed of a quick-release layer and a sustained-release layer in a weight percentage of 30% and 70% respectively, the quick-release layer is composed of black cohosh nanoliposomes, a disintegrant and a penetration enhancer, the black cohosh nanoliposomes, the disintegrant and the penetration enhancer in the quick-release layer are composed of 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, and the chitosan, the soy isoflavones, the pH-sensitive material and the flavoring agent in the sustained-release layer are composed of a mass ratio of 2:3:1:2;

[0027] As a preferred technical solution of the application, the disintegrant in the quick-release layer can be cross-linked sodium carboxymethyl cellulose, and the penetration enhancer in the quick-release layer can be menthol-β-cyclodextrin inclusion compound.

[0028] As a preferred technical solution of the application, 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.

[0029] As a preferred technical solution of the application, the preparation method of the black cohosh nanoliposomes is as follows:

[0030] S1, the rhizome of black cohosh is ultrasonically extracted with 70% ethanol, purified by AB-8 resin, and an extract with a triterpenoid saponin content of greater than or equal to 10% is obtained;

[0031] S2, the extract is mixed with phospholipids (DPPC: cholesterol = 8:2) at a mass ratio of 1:5, and the liposomes are prepared by a film hydration method, and are subjected to high-pressure homogenization (50 MPa) to a particle size of less than or equal to 100 nm and an encapsulation efficiency of greater than or equal to 90%;

[0032] S3, the liposome suspension is mixed with mannitol, and is freeze-dried (-45°C, 24h) into porous microparticles;

[0033] As a preferred technical solution of the application, the disintegration time of the quick-release layer is less than or equal to 5 seconds, and the sustained-release layer continuously releases the active ingredient when the pH is greater than or equal to 6.5.

[0034] As a preferred technical solution of the application, the preparation method of the oral mucosa absorption gargling tablet based on black cohosh extract comprises a nanoliposome freeze-drying process, and the nanoliposome freeze-drying process is that the black cohosh nanoliposomes are mixed with mannitol, and the mixture formed thereby is placed in an environment of -45°C and freeze-dried for 24 hours to form porous microparticles.

[0035] As a preferred technical solution of the application, the preparation method of the oral mucosa absorption gargling tablet based on black cohosh extract further comprises a double-layer tablet pressing process, and the double-layer tablet pressing process is that the quick-release layer and the sustained-release layer powders are respectively passed through an 80-mesh sieve, and are pressed by a double-layer tablet press with a pressure of 80-100 kN to be tablets with a tablet weight of 500 mg and a hardness of 70-90 N.

[0036] Example 2:

[0037] Cimicifuga racemosa extract 100 mg was mixed with phospholipid mixture (DPPC 160 mg + cholesterol 40 mg) in chloroform, rotary evaporated to form a film, and then hydrated and homogenized under high pressure to obtain liposomes with a particle size of (92 ± 15) nm and an encapsulation efficiency of 92.3%;

[0038] Gargling tablet formulation

[0039] Ingredient 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

[0040] Experimental data

[0041] 1. In vitro release and permeation

[0042] Immediate-release layer: 95% Cimicifuga racemosa released in 5 minutes in artificial saliva (HPLC detection);

[0043] Sustained-release layer: 78% soy isoflavones released in 8 hours at pH 7.0, and <5% released in a gastric acid environment (pH 1.2);

[0044] Mucosal permeation: 82.5% permeated in 24 hours (27.3% for ordinary tablets);

[0045]

[0046]

[0047] 2. Animal model (OVX rats)

[0048] Hot flashes were inhibited: 70% reduction in skin temperature fluctuations 10 minutes after sublingual administration of the gargling tablets, significantly faster than oral administration (45 minutes to take effect);

[0049] Bone density: femoral bone density increased by 18% after 12 weeks of treatment (p < 0.01);

[0050]

[0051] 3. Clinical trial (multi-center randomized controlled)

[0052] Subjects: 200 menopausal women (Kupperman score ≥ 25) were divided into a gargling tablet group and a placebo group;

[0053] Results:

[0054] Hot flash frequency decreased by 63% (17% for the placebo group), and insomnia improvement rate was 79% (p < 0.001);

[0055] Salivary estrogen levels were stable (ERβ activation rate increased by 45%).

[0056] The incidence of oral mucosa irritation was 0% (12% for the control group of traditional tablets);

[0057]

[0058]

[0059] Table notes: the data is derived from the experimental verification part of the specific embodiment in the document;

[0060] As can be seen from the above table, the experimental results show that the gargling tablet is significantly better than the traditional oral preparation in terms of rapid effectiveness, bioavailability and safety. Through the double-layer structure design of the rapid-release layer and the sustained-release layer, the rapid onset and sustained effect of the active ingredients are realized, which is significantly better than the traditional oral preparation. The synergistic effect of the black cohosh nanoliposome and the menthol-β-cyclodextrin inclusion compound makes the 24-hour mucosal cumulative permeation amount reach 82.5%, greatly improving the transmembrane absorption efficiency of the active ingredients.

[0061] Finally: the above only describes the preferred embodiments of the present application and is not used to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A mouthwash tablet based on black cohosh extract, characterized in that: It is composed of the following components by weight percentage: 30 wt% immediate-release layer and 70 wt% sustained-release layer; The immediate-release layer is composed of black cohosh nanoliposomes, a disintegrant and a penetration enhancer, wherein the black cohosh nanoliposomes, disintegrant and penetration enhancer in the immediate-release layer are composed of black cohosh nanoliposomes, a disintegrant and a penetration enhancer in a mass ratio of 4:1:

1. The sustained-release layer is composed of chitosan, soy isoflavones, pH-sensitive materials, and flavoring agents, with the chitosan, soy isoflavones, pH-sensitive materials, and flavoring agents arranged in a mass ratio of 2:3:1:

2.

2. The oral mucosal absorbent mouthwash tablet based on black cohosh extract according to claim 1, characterized in that: The disintegrant in the immediate-release layer is croscarmellose sodium carboxymethyl cellulose, and the penetration enhancer in the immediate-release layer is menthol-β-cyclodextrin inclusion complex.

3. The oral mucosal absorbent mouthwash tablet based on black cohosh extract according to claim 1, characterized in that: The pH-sensitive material in the sustained-release layer is Eudragit E100, and the flavoring agent is a mixture of erythritol and natural berry flavoring.

4. A method for preparing an oral mucosal absorbent mouthwash tablet based on black cohosh extract as described in any one of claims 1-3, characterized in that: This includes the lyophilization process for nanoliposomes and the bilayer tableting process.

5. The method for preparing an oral mucosal absorbent mouthwash tablet based on black cohosh extract according to claim 4, characterized in that: The freeze-drying process for the nanoliposomes is as follows: black cohosh nanoliposomes are mixed with mannitol, and the mixture is placed in an environment of -45°C and freeze-dried for 24 hours to form porous microparticles.

6. The method for preparing an oral mucosal absorbent mouthwash tablet based on black cohosh extract according to claim 4, characterized in that: The double-layer tableting process is as follows: the immediate-release layer and the sustained-release layer powder are respectively passed through an 80-mesh sieve and pressed by a double-layer tableting machine with a pressure of 80-100kN to form tablets with a weight of 500mg and a hardness of 70-90N.

7. A method for preparing black cohosh nanoliposomes for use in oral mucosal absorption mouthwash tablets based on black cohosh extract as described in any one of claims 1-3, characterized in that, The specific preparation steps are as follows: S1: Black cohosh rhizomes were extracted with 70% ethanol by ultrasonic extraction and purified with AB-8 resin to obtain an extract with a triterpenoid saponin content ≥10%. S2: The extract obtained in step S1 is mixed with phospholipids at a mass ratio of 1:5, and liposomes are prepared using the thin-film hydration method. The mixture is then homogenized under high pressure until the particle size is ≤100nm and the encapsulation rate is ≥90% to obtain a liposome suspension. S3: Mix the liposome suspension obtained in step S2 with mannitol and freeze-dry it into porous microparticles.

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