CN120860147A - Atomized inhalation preparation based on traditional Chinese medicine components and application of atomized inhalation preparation in replacing tobacco products - Google Patents

Abstract

The invention discloses an atomized inhalation preparation based on traditional Chinese medicine components and application thereof in replacing tobacco products, wherein the atomized inhalation preparation comprises a lung-clearing group, an air supplementing group, an spleen strengthening and blood activating group, a nerve calming and stabilizing group, an agilawood volatile oil and lily saponin, an atomizing carrier, plant glycerol and propylene glycol, a flavoring agent, menthol and glycyrrhizic acid. The atomized inhalation preparation of the traditional Chinese medicine components and the application thereof in replacing tobacco products provide a natural atomized preparation which has high-efficiency smoking cessation (78% reduction of smoking desire in 24 hours), lung function restoration (42% reduction of IL-6) and good taste acceptance (92% acceptance) through the traditional Chinese medicine compound compatibility and nano-wrapping technology, the lung deposition rate reaches 65% and the stability is excellent, and a safe and effective solution is provided for tobacco replacement.

Description

Atomized inhalation preparation based on traditional Chinese medicine components and application of atomized inhalation preparation in replacing tobacco products

Technical Field

The invention relates to the technical intersection field of traditional Chinese medicine and modern inhalation preparations, in particular to an atomization inhalation preparation based on traditional Chinese medicine components and application thereof in replacing tobacco products.

Background

Pain spots in the prior art;

traditional nicotine replacement therapy (such as patch and chewing gum) has side effects of palpitation, skin allergy, etc., and can not simulate smoking behavior, and has low user compliance.

Electronic cigarettes rely on chemical synthesis components (such as propylene glycol), and long-term use may induce airway inflammation, and flavoring agents present a safety hazard.

The traditional Chinese medicine smoking cessation products are mostly limited to oral administration or patches, have slow effect and low bioavailability, and lack the mechanism design for the cooperative conditioning of lung and kidney.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides an atomized inhalation preparation based on traditional Chinese medicine components and application thereof in replacing tobacco products, and solves the problems that the traditional nicotine replacement therapy (such as patches and chewing gum) has side effects of palpitation, skin allergy and the like, can not simulate smoking behavior, has low user compliance, depends on chemical synthesis components (such as propylene glycol) for electronic cigarettes, can induce respiratory tract inflammation after long-term use, has potential safety hazard, and the traditional Chinese medicine smoking cessation products are mostly limited to oral administration or patches, have slow effect and low bioavailability, and lack the mechanism design for synergetic conditioning of lung and kidney.

The invention aims at realizing the purposes by adopting the following technical scheme that the atomization inhalation preparation based on traditional Chinese medicine components consists of the following raw materials in parts by mass:

the lung-heat clearing group comprises 10-15 parts of cordate houttuynia extract, 5-8 parts of mulberry leaf flavone and 4-6 parts of total anthraquinone of semen cassiae;

the qi tonifying component comprises 5-10 parts of ginseng extract and 2-5 parts of cordycepin;

The kidney tonifying group comprises 3-8 parts of cistanche deserticola polysaccharide and 3-5 parts of eucommia ulmoides total glycosides;

The spleen-invigorating and blood-activating component comprises 5-10 parts of pachymaran and 2-4 parts of tanshinone;

1-3 parts of agilawood volatile oil and 2-4 parts of lily saponin;

The atomizing carrier is 30-50 parts of plant glycerol and 10-20 parts of propylene glycol;

the flavoring agent is menthol 0.5-1 weight portions and glycyrrhizic acid 0.2-0.5 weight portions.

Preferably, the cordate houttuynia extract is prepared by a water extraction method, the total flavone content is more than or equal to 40%, the eucommia ulmoides total glycoside is extracted by 70% ethanol with the assistance of ultrasonic, the glycoside purity is more than or equal to 80%, and the cassia seed total anthraquinone is prepared by an alcohol extraction process, and the anthraquinone content is more than or equal to 60%.

Preferably, the cordycepin and agilawood volatile oil adopt liposome encapsulation technology, wherein the liposome consists of soybean phospholipid and cholesterol according to a mass ratio of 4:1, the particle size is 50-100nm, and the encapsulation rate is more than or equal to 85%;

the mulberry flavone and pachyman are wrapped by chitosan-sodium alginate microspheres, the particle size of the microspheres is 100-200nm, and the slow release time is more than or equal to 6 hours.

Preferably, the mass ratio of the plant glycerol to the propylene glycol of the atomization carrier is 3:1 to 5:1, and the viscosity of the atomization carrier after mixing is 50-80 mPa.s (measured at 25 ℃).

Preferably, the pH value of the preparation is 6.8-7.4, the particle size of the atomized liquid drops is 1-5 mu m, and the lung deposition rate is more than or equal to 65%.

The invention discloses a preparation method of an atomization inhalation preparation, which comprises the following steps:

(1) Sectional extraction, namely extracting herba Houttuyniae, folium Mori and Poria with water at 80deg.C under reflux for 2 times;

extracting semen Cassiae, eucommiae cortex, and Saviae Miltiorrhizae radix with 70% ethanol under ultrasound, extracting lignum Aquilariae Resinatum and Cistanchis herba with supercritical CO 2;

(2) Nanometer coating, wherein the liposoluble components (cordycepin, lignum Aquilariae Resinatum volatile oil) are encapsulated by liposome, and the water-soluble components (folium Mori flavone, pachyman) are encapsulated by chitosan-sodium alginate microsphere;

(3) Mixing and shaping, mixing the above components with atomized carrier and correctant, homogenizing, emulsifying, sterilizing with 0.22 μm filter membrane, and packaging.

Preferably, the supercritical CO2 extraction condition is that the pressure is 25-30MPa, the temperature is 40-45 ℃, the CO2 flow is 20-25L/h, and the extraction time is 2-3 hours.

The invention also discloses application of the aerosol inhalation preparation in replacing tobacco products, wherein the daily inhalation dosage is 0.5-2mL, and the aerosol inhalation preparation is continuously used for 4-8 weeks, and is used for reducing anxiety behavior (the recovery of serum corticosterone to normal level is more than or equal to 90%), inhibiting the expression of lung tissue inflammatory factors IL-6 and TNF-alpha (the reduction of amplitude is more than or equal to 40%), and improving the haemorheology index (the reduction of whole blood viscosity is more than or equal to 15%).

Preferably, the preparation is used in combination with a low-temperature ceramic core atomizing device, and the atomizing temperature is controlled to be 120-150 ℃ so as to avoid pyrolysis of components.

Preferably, the mass ratio of the cordate houttuynia extract to the eucommia total glycosides in the formula is (10-15): 3-5%, and the cordate houttuynia extract and the eucommia total glycosides synergistically reduce the MDA level of lung tissues (the reduction of amplitude is more than or equal to 35%).

The invention provides an aerosol inhalation preparation based on traditional Chinese medicine components and application thereof in replacing tobacco products. Compared with the prior art, the method has the following beneficial effects:

1. The atomized inhalation preparation based on the traditional Chinese medicine components and the application thereof in replacing tobacco products provide a natural atomized preparation which has high-efficiency smoking cessation (78% reduction of smoking desire in 24 hours), lung function restoration (42% reduction of IL-6) and good taste acceptance (92% acceptance) through the traditional Chinese medicine compound compatibility and nano-wrapping technology, and the lung deposition rate reaches 65% and the stability is excellent, so that a safe and effective solution is provided for tobacco replacement.

Drawings

FIG. 1 is a schematic diagram of the triple synergic action mechanism of clearing lung-tonifying kidney-invigorating spleen of the present invention;

FIG. 2 is a schematic diagram of a nanoliposome transmission electron microscope structure according to the present invention;

FIG. 3 is a comparative schematic diagram of the behavior of a rat in the nicotine withdrawal model of the present invention;

FIG. 4 is a graph showing in vitro release profile of the present invention;

FIG. 5 is a schematic diagram of the mass ratio of the core components of the invention.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Referring to fig. 1-5, the embodiment of the invention provides a technical scheme that an atomized inhalation preparation based on traditional Chinese medicine components comprises the following raw materials in parts by mass:

the lung-heat clearing group comprises 10-15 parts of cordate houttuynia extract, 5-8 parts of mulberry leaf flavone and 4-6 parts of total anthraquinone of semen cassiae;

the qi tonifying component comprises 5-10 parts of ginseng extract and 2-5 parts of cordycepin;

The kidney tonifying group comprises 3-8 parts of cistanche deserticola polysaccharide and 3-5 parts of eucommia ulmoides total glycosides;

The spleen-invigorating and blood-activating component comprises 5-10 parts of pachymaran and 2-4 parts of tanshinone;

1-3 parts of agilawood volatile oil and 2-4 parts of lily saponin;

The atomizing carrier is 30-50 parts of plant glycerol and 10-20 parts of propylene glycol;

the flavoring agent is menthol 0.5-1 weight portions and glycyrrhizic acid 0.2-0.5 weight portions.

The application of an aerosol inhalation preparation based on traditional Chinese medicine components in preparing substitute tobacco products delivers medicines in an aerosol inhalation mode, and the daily dosage is 0.5-2mL, and the aerosol inhalation preparation is used for relieving nicotine withdrawal reaction, repairing alveolar epithelial injury, reducing serum inflammatory factor level and improving blood viscosity.

A method for preparing Chinese medicinal components based on atomization inhalation comprises the following steps

Pretreatment of raw materials

Houttuynia cordata extract (Water extraction method)

Pulverizing dried herba Houttuyniae whole herb to 40 mesh, adding pure water at feed-liquid ratio of 1:15, reflux-extracting at 80deg.C for 2 times each for 1.5 hr, mixing filtrates, concentrating under reduced pressure to relative density of 1.25 (60 deg.C), and spray-drying to obtain pale yellow powder (total flavone content not less than 40%).

Mulberry leaf flavone (commercially available standardized extract)

Directly purchasing mulberry leaf total flavone (HPLC detection content is more than or equal to 80%) for standby.

Semen Cassiae total anthraquinone (alcohol extraction method)

Pulverizing semen Cassiae seed to 60 mesh, adding 70% ethanol at a feed-liquid ratio of 1:8, extracting with ultrasonic assistance (power 300W, frequency 40 kHz) for 3 times, each for 30 min, mixing extractive solutions, recovering ethanol under reduced pressure, purifying with macroporous resin (model D101), eluting with 60% ethanol, concentrating and drying to obtain orange red powder (total anthraquinone content not less than 60%).

Ginseng extract (Water extraction method)

Slicing Ginseng radix, adding pure water at a feed-liquid ratio of 1:10, reflux-extracting at 90deg.C for 3 times, each for 2 hr, mixing filtrates, concentrating, and freeze-drying to obtain pale yellow powder (ginsenoside Rg1 content is greater than or equal to 5%).

Cordycepin (liposome package)

Dissolving soybean phospholipid and cholesterol (4:1) in chloroform, adding cordycepin (dissolved in absolute ethanol), rotary evaporating to form film, adding phosphate buffer (pH 7.4), performing ultrasonic treatment (power 200W,5 min) after hydration, and filtering with 0.22 μm filter membrane to obtain liposome with particle diameter of 80+ -10 nm (encapsulation rate not less than 85%).

Cistanche polysaccharide (supercritical CO2 extraction)

Taking dry stems of cistanche deserticola, pulverizing to 30 meshes, extracting for 2 hours in a supercritical CO2 device (the pressure is 25MPa, the temperature is 40 ℃ and the CO2 flow is 20L/h), collecting an extract, and freeze-drying to obtain white polysaccharide powder (the purity is more than or equal to 90%).

Total glycosides of eucommia ulmoides (alcohol extraction method)

Pulverizing cortex Eucommiae to 60 mesh, adding 70% ethanol at a feed-liquid ratio of 1:10, extracting with ultrasonic assistance (power 300W, frequency 40 kHz) for 3 times for 30min each time, mixing extractive solutions, recovering ethanol under reduced pressure, purifying with macroporous resin (model AB-8), eluting with 60% ethanol, concentrating and drying to obtain tan powder (total glycosides content of cortex Eucommiae is more than or equal to 80%).

Pachyman (Water extraction method)

Pulverizing Poria to 40 mesh, adding pure water at a feed-liquid ratio of 1:12, reflux-extracting at 100deg.C for 2 hr each time, mixing filtrates, concentrating, precipitating with ethanol (final concentration of 80%), centrifuging, collecting precipitate, and vacuum drying to obtain white powder (polysaccharide content not less than 85%).

Tanshinone (alcohol extraction method)

Pulverizing radix Salviae Miltiorrhizae into 50 mesh, adding 95% ethanol at a feed-liquid ratio of 1:8, reflux-extracting at 80deg.C for 3 times, each for 1 hr, mixing extractive solutions, concentrating under reduced pressure to obtain paste, and purifying by silica gel column chromatography (eluent: chloroform-methanol=9:1) to obtain red crystal (tanshinone IIA content is not less than 90%).

Agilawood volatile oil (supercritical CO2 extraction)

Extracting lignum Aquilariae Resinatum wood dust in supercritical CO2 device (pressure 30MPa, temperature 45 deg.C, CO2 flow 25L/h) for 3 hr, collecting volatile oil, and dehydrating with anhydrous sodium sulfate to obtain yellowish oily substance (beta-caryophyllene content not less than 70%).

Lily saponin (Water extraction method)

Pulverizing Bulbus Lilii bulb to 40 mesh, adding pure water at a feed-liquid ratio of 1:10, reflux-extracting at 90deg.C for 2 hr for 2 times each time, mixing filtrates, concentrating, purifying with macroporous resin (model HPD-100), eluting with 50% ethanol, and drying to obtain white powder (total saponin content not less than 60%).

Plant glycerol (commercial pharmaceutical grade)

Directly purchasing medicinal plant glycerol (purity is more than or equal to 99.5%) without pretreatment.

Propylene glycol (commercial pharmaceutical grade)

Directly purchasing pharmaceutical grade propylene glycol (purity is more than or equal to 99.9%) for standby.

Menthol (commercially available crystal)

Purchasing menthol crystal (purity is more than or equal to 98%), and crushing to 100 meshes for later use.

Glycyrrhizic acid (alcohol extraction method)

Pulverizing Glycyrrhrizae radix to 50 mesh, adding 50% ethanol at a feed-liquid ratio of 1:8, reflux-extracting at 70deg.C for 3 times each for 1 hr, mixing extractive solutions, concentrating under reduced pressure, adjusting pH to 3.0, precipitating, centrifuging, and drying to obtain glycyrrhizic acid (purity not less than 95%).

2. Preparation technology (complete steps)

Premixing raw materials

Mixing water-soluble components:

Dissolving herba Houttuyniae extract (12 g), folium Mori flavone (6 g), pachyman (8 g), and Ginseng radix extract (8 g) in 40mL plant glycerol, stirring at 60deg.C until completely dissolved;

Alcohol soluble components are mixed:

Mixing semen Cassiae total anthraquinone (5 g), eucommiae cortex total glycoside (4 g), tanshinone (3 g) with 10mL propylene glycol, and ultrasonic dispersing (40 kHz,10 min);

Nano-wrap component integration

Adding cordycepin liposome (3 g) and cistanche deserticola polysaccharide (5 g) into the alcohol-soluble mixed solution, and magnetically stirring for 30 minutes;

Dispersing mulberry leaf flavone (6 g) and chitosan-sodium alginate microspheres (embedded according to a mass ratio of 1:2) in 5mL of pure water, and performing ultrasonic treatment (100W for 5 minutes) to form uniform suspension;

Volatile component addition

Sequentially adding lignum Aquilariae Resinatum volatile oil (2 g), bulbus Lilii saponin (3 g), mentholum (0.8 g), and glycyrrhizic acid (0.3 g), emulsifying with high pressure homogenizer (pressure 100MPa, circulating for 3 times) to form stable emulsion;

Shaping of end products

Sterilizing the mixed solution with 0.22 μm polyether sulfone filter membrane, filling into aluminum aerosol canister under nitrogen protection, sealing under 0.3MPa, and collecting the atomized solution with pH value of 6.8-7.4 and atomized particle diameter of 1-5 μm (measured by laser particle sizer).

Stability test experimental data are shown in table 1 below;

TABLE 1 stability test (25 ℃ C. Storage for 6 months)

3. Key process parameters

Extraction process

The water extraction temperature is 80-100 ℃, so that the high temperature is prevented from damaging thermosensitive components (such as mulberry leaf flavone);

Supercritical CO2 extraction, namely, the pressure is 25-30MPa, the temperature is 40-45 ℃, and the yield of volatile oil is precisely controlled.

Nanometer wrapping technology

The encapsulation rate of the liposome is more than or equal to 85 percent, and the particle size is 50-100nm (verified by a dynamic light scattering method);

the slow release time of the chitosan-sodium alginate microsphere is more than or equal to 6 hours (in vitro release test).

Sterilization and stability

Sterilizing with 0.22 μm filter membrane to avoid degradation of components caused by high temperature sterilization;

The finished product is stored for 6 months at 25 ℃, and the retention rate of the active ingredients is more than or equal to 95 percent (verified by HPLC).

The experimental data for the formulation synergy verification are shown in table 2 below;

TABLE 2 verification of synergistic effect of formulations (in vitro cell model)

The expression shows that p <0.05 and blood viscosity is whole blood high cut viscosity (200 s-1) compared with the single group.

4. Examples and effects verification

EXAMPLE 1 100mL preparation of an atomized liquid

The formula comprises 12g of cordate houttuynia extract, 6g of flavonoids of mulberry leaves, 5g of total anthraquinone of semen cassiae, 8g of ginseng extract, 3g of cordycepin liposome, 5g of cistanche deserticola polysaccharide, 4g of total glycosides of eucommia ulmoides, 8g of pachyman, 3g of tanshinone, 2g of agilawood volatile oil, 3g of lily saponin, 40mL of plant glycerin, 10mL of propylene glycol, 0.8g of menthol and 0.3g of glycyrrhizic acid.

And (3) effect verification:

In vitro release, wherein the release rate of the active ingredient is more than or equal to 90% in 3 hours;

animal experiments show that the anxiety behavior of the rat with nicotine withdrawal is reduced by 68% and the IL-6 in lung tissue is reduced by 42%;

sensory evaluation 89% of users consider the mouthfeel to be close to that of traditional tobacco, without throat irritation.

Experimental data of human sensory test results are shown in table 3 below;

TABLE 3 human sensory test results (n=80)

Test methods double blind randomized trial, subjects inhaled 1mL daily for 7 days.

Animal model experimental data are shown in table 4 below;

TABLE 4 behavioral and biochemical indicators of animal models (nicotine withdrawal rats)

It is stated that p <0.01 (t-test) is shown compared to the model group, and data is collected from test results after 14 days of continuous treatment (n=10).

Results of body sensory testing experimental data are shown in table 5 below;

Table 5 human sensory test results (n=80)

Test methods double blind randomized trial, subjects inhaled 1mL daily for 7 days.

Description of technical advantages

The key active ingredients (such as cordycepin and tanshinone) optimize the delivery efficiency through the nano technology.

Process integrity:

all the component treatment steps are covered in the whole course from raw material pretreatment to final product filling;

Process parameters (such as temperature, pressure, encapsulation efficiency) are specified to ensure batch consistency.

The innovation is as follows:

The limitations of the traditional Chinese medicine preparation are broken through by combining water extraction, alcohol extraction, supercritical extraction and nano technology;

the problem of bitter taste of the traditional Chinese medicine atomized liquid is solved by the synergistic taste correction of glycyrrhizic acid and menthol.

The traditional Chinese medicine atomization inhalation preparation provided by the invention has the following remarkable beneficial effects by scientifically matching 15 traditional Chinese medicine active ingredients such as cordate houttuynia, ginseng, eucommia ulmoides and the like and combining the segmented extraction and nano-encapsulation technology:

the preparation simulates the taste of the traditional smoking (92% of user approval), reduces the smoking desire by 78% within 24 hours, and is obviously superior to the commercial electronic cigarette (45%);

Multi-target treatment, namely synchronously relieving withdrawal symptoms (68% reduction of anxiety behaviors of rats), repairing lung injury (42% reduction of IL-6) and improving metabolism (15% reduction of blood viscosity) through a synergistic mechanism of lung clearing, kidney tonifying and spleen strengthening;

The technology breaks through that the nano liposome technology ensures that the lung deposition rate reaches 65 percent (the traditional preparation is less than or equal to 30 percent), the active ingredient release rate exceeds 90 percent in 3 hours, and the stability retention rate is more than or equal to 95 percent in 6 months;

The safety advantage is that no chemical synthesis addictive component is generated, no adverse reaction such as palpitation or respiratory tract stimulation is reported in clinical test, and the WHO harm reduction strategy is met.

It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (6)

1. An atomized inhalation preparation based on traditional Chinese medicine ingredients is characterized by comprising the following raw materials in parts by mass:

the lung-heat clearing group comprises 10-15 parts of cordate houttuynia extract, 5-8 parts of mulberry leaf flavone and 4-6 parts of total anthraquinone of semen cassiae;

the qi tonifying component comprises 5-10 parts of ginseng extract and 2-5 parts of cordycepin;

The kidney tonifying group comprises 3-8 parts of cistanche deserticola polysaccharide and 3-5 parts of eucommia ulmoides total glycosides;

The spleen-invigorating and blood-activating component comprises 5-10 parts of pachymaran and 2-4 parts of tanshinone;

1-3 parts of agilawood volatile oil and 2-4 parts of lily saponin;

The atomizing carrier is 30-50 parts of plant glycerol and 10-20 parts of propylene glycol;

the flavoring agent is menthol 0.5-1 weight portions and glycyrrhizic acid 0.2-0.5 weight portions.

2. The aerosol inhalation preparation based on traditional Chinese medicine ingredients according to claim 1, wherein the cordycepin and agilawood volatile oil adopt liposome encapsulation technology, the particle size of the liposome is 50-100nm, and the encapsulation rate is more than or equal to 85%.

3. The aerosol inhalation preparation based on traditional Chinese medicine ingredients according to claim 1, wherein the mulberry leaf flavone and pachyman are wrapped by chitosan-sodium alginate microspheres, the microsphere particle size is 100-200nm, and the slow release time is more than or equal to 6 hours.

4. The aerosol inhalation preparation based on traditional Chinese medicine ingredients of claim 1, wherein the houttuynia cordata extract is prepared by a water extraction process, and the total flavone content is more than or equal to 40%.

5. The aerosol inhalation preparation based on traditional Chinese medicine ingredients of claim 1, wherein the total glycosides of eucommia are prepared by alcohol extraction process, and the purity of glycosides is not less than 80%.

6. The use of an aerosol inhalation formulation based on herbal ingredients in the manufacture of a substitute tobacco product according to claim 1, wherein the medicament is delivered by aerosol inhalation at a daily dosage of 0.5-2mL for alleviating nicotine withdrawal, repairing alveolar epithelial lesions, reducing serum inflammatory factor levels and improving blood viscosity.