CN111671717A

CN111671717A - Temperature-sensitive type particulate matter adsorption gel and preparation method and application thereof

Info

Publication number: CN111671717A
Application number: CN202010541296.3A
Authority: CN
Inventors: 孙春萌; 涂家生; 李紫璇; 葛立琛; 丁源
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2020-06-15
Filing date: 2020-06-15
Publication date: 2020-09-18
Anticipated expiration: 2040-06-15
Also published as: CN111671717B

Abstract

The invention discloses a temperature-sensitive particulate adsorption gel and a preparation method and application thereof. The temperature-sensitive particulate adsorption gel is prepared by mixing temperature-sensitive hydrophilic gel material poloxamer, water, cationic polymer or anionic polymer. The adsorption gel is liquid below 25 deg.C (room temperature), and can be converted into gel with appropriate strength at 28-35 deg.C (nasal cavity), so as to effectively prevent particulate pollutants from entering respiratory tract and lung.

Description

Temperature-sensitive type particulate matter adsorption gel and preparation method and application thereof

Technical Field

The invention belongs to the technical field of daily necessities, and particularly relates to a temperature-sensitive particulate adsorption gel and a preparation method and application thereof.

Background

The compendium conference of the health China 2030 indicates that the healthy Chinese construction is promoted, the prevention is mainly adhered to, the healthy and civilized life style is promoted, the green and safe healthy environment is created, and the occurrence of diseases is reduced. Haze, which is composed of tiny particles suspended in the air, has become a big problem to people as the main pollutant of the air. In recent years, the area affected by haze in China occupies one fourth of the territory area of China, and the number of affected people is increasing continuously. Researches show that the long-term exposure to the environment polluted by particles can destroy the defense function of respiratory tracts, so that diseases such as chronic bronchitis, emphysema and bronchial asthma can occur, and diseases such as cardiovascular systems and reproductive systems can be caused, so that the enhancement of respiratory protection is particularly important at the present day when the haze is increasingly serious.

At present, the air purifier and the wearable mask which are commonly used as breathing protection means are limited by the use environment, the use is convenient, the development of new products with good haze prevention effect is realized, the social requirement is met, and the sound of the health industry is met.

Disclosure of Invention

Aiming at the defects of the existing haze-preventing product, the invention aims to provide a temperature-sensitive particulate adsorption gel, which applies a temperature-sensitive gel technology, adds a cationic polymer or an anionic polymer at the same time, and can effectively prevent particulate pollutants from entering respiratory tracts and lungs after being sprayed into nasal cavities.

The invention also aims to provide a preparation method of the temperature-sensitive particulate adsorption gel.

In order to achieve the above object, the present invention adopts the following technical means:

a temperature-sensitive particulate adsorption gel comprises the following raw materials: a temperature-sensitive hydrophilic gel material, a polymer and water;

the temperature-sensitive hydrophilic gel material is poloxamer, and the polymer is a cationic polymer or an anionic polymer.

Further, the temperature-sensitive hydrophilic gel material is poloxamer 407.

Further, the temperature-sensitive hydrophilic gel material is a mixture of poloxamer 407 and poloxamer 188.

Further, the anionic polymer is sodium hyaluronate, and the cationic polymer is polylysine.

Further, the temperature-sensitive particulate adsorption gel comprises the following raw materials in percentage by weight: poloxamer 40714-20%, poloxamer 1880-2%, cationic polymer or anionic polymer 0.5-1.5%, and water; the weight percentage of all raw materials is 100 percent.

Furthermore, the raw materials of the temperature-sensitive particulate adsorption gel also comprise other pharmaceutically acceptable auxiliary materials, including a humectant, a gel strength regulator, a surfactant, a bacteriostatic agent and a mixture thereof.

The preparation method of the temperature-sensitive particle adsorption gel comprises the steps of taking the water-soluble components in the prescription, adding the water in the prescription amount into the water in the prescription amount, stirring to dissolve, cooling, weighing the poloxamer in the prescription amount, adding the poloxamer into the cooled solution, and standing at a low temperature to fully dissolve until a clear bubble-free solution is formed.

The temperature-sensitive particulate adsorption gel prepared by the invention can be smoothly extruded by using the existing device, is smeared on a nasal cavity, is converted into a gel state after contacting nasal mucosa, and keeps the particulate adsorption effect within a certain time. It can also be used in air purification products or mask products to adsorb particulate matter.

Compared with the prior art, the invention has the following beneficial effects:

1. by adopting a temperature-sensitive gel technology, the product is in a liquid state at normal temperature (25 ℃), and is changed into a gel state along with the temperature difference between the human body temperature and the environment after being smeared or sprayed on the nasal cavity.

2. Poloxamer is used as a basic material, the compatibility with human bodies is good, and the ionic groups such as sodium hyaluronate and polylysine are added, so that the adsorption or repulsion effect on particles can be generated, and the harm to the human bodies can be avoided.

3. The prepared particulate adsorption gel can be designed by adopting an inclined duckbill pump bottle, and the product is easy to be smeared in a nasal cavity and has no foreign body sensation. The package is small and exquisite, conveniently carries and uses.

4. The prepared particulate matter has long gel adsorption time, and can be used for daily going out by combining the gel adsorption time with a human body comfortable interval.

5. The product can be matched with a cleaning agent to be prepared into the nasal cavity anti-haze gel for use, and can also be used for daily cleaning of the nasal cavity.

6. The antibacterial agent can inhibit the growth of microorganisms.

7. The phase change of the gel has reversibility, namely when the environmental temperature is reduced to be lower than the phase change temperature from higher than the phase change temperature, the gel in the gel state can be converted into viscous state again, therefore, the gel applied or sprayed in the nasal cavity can be cleaned by using media such as cold water, and the method is simple and easy.

Drawings

FIG. 1 shows the results of the rheological oscillation temperature-rising scan of the temperature-sensitive particulate adsorption gel of example 4.

FIG. 2 is a graph showing the effect of continuous adsorption and adhesion of the gel to the fine carbon powder in adsorption effect experiment 1.

FIG. 3 shows the adsorption effect of the gel on the fine carbon powder in the adsorption effect experiment 2.

Fig. 4 is a schematic view of the apparatus used in the adsorption effect experiment 3.

Fig. 5 is a graph of adsorption amount of gel to fine particle contaminants versus time in adsorption effect experiment 3.

FIG. 6 shows the safety test results of temperature-sensitive particle adsorption gel in mucosal toxicity test.

Detailed Description

The invention provides a temperature-sensitive type particle adsorption gel, which is prepared by applying a temperature-sensitive gel technology, adding a cationic polymer or an anionic polymer into poloxamer serving as a temperature-sensitive type hydrophilic gel material, and spraying the temperature-sensitive type hydrophilic gel material into a nasal cavity to effectively prevent particle pollutants from entering respiratory tracts and lungs.

The core technology of the invention is temperature-sensitive gel technology. Since 2010, the temperature-sensitive gel is taken as an important soft and wet material, and the research work mainly focuses on cavity administration, transdermal administration, ocular administration, rectal administration and the like. The development of the temperature-sensitive gel gradually matures to form a system, but the application of the technology is still concentrated in the field of medicines at present, and the invention applies the technology to the field of daily consumer products for the first time and is a great innovation in technical application.

Poloxamer high polymer is a thermo-sensitive gel which is most widely researched and applied, and the structure of the poloxamer high polymer is polyoxyethylene-polyoxypropylene copolymer, and the structural formula is as follows:

because the polyoxyethylene and the polyoxypropylene which form the poloxamer block have different physical and chemical properties, when the temperature is increased, the hydrophobicity of the polyoxypropylene block is entwined by the relatively hydrophilic polyoxyethylene, and a micelle structure which has different shapes and sizes but similar compositions is formed on the whole. At a certain temperature, when the concentration of the solution is more than a certain value, poloxamer molecules are further tangled, stacked and aggregated by various acting forces among the micelles, and at the moment, the temperature is continuously increased, and gelation can occur.

In the invention, poloxamer is mainly poloxamer 407 and poloxamer 188, both are polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, but the block ratio of polyoxyethylene to polyoxypropylene is different, poloxamer 407 is the main gel material of the invention, the gelling temperature of the gel material has concentration dependence, and a small amount of poloxamer 188 is added, so that the gelling temperature of the poloxamer 407 solution can be adjusted to be more in line with the physiological temperature of the nasal cavity. Specifically, in the present invention, poloxamer 407 is present in an amount of 14-20 wt.%, and poloxamer 188 is present in an amount of 0-2 wt.%.

In order to further enhance the adsorbability of the poloxamer to haze particles, the invention also adds a cationic polymer or an anionic polymer to the poloxamer. The structure of the cationic polymer contains negatively charged groups, and the positively charged particles can be prevented from entering respiratory tracts and lungs by electrostatic adsorption; the structure of the anionic polymer contains positively charged groups, and the positively charged particles can be repelled by static electricity to prevent the positively charged particles from entering respiratory tracts and lungs. Specifically, in the invention, the anionic polymer is used as a particle adsorption type ionic group additive, and sodium hyaluronate can be selected; the cationic polymer is used as a particle exclusion type ionic group additive, and polylysine can be selected. The gel property of poloxamer is not damaged, and the good particle adsorption property is also needed, and the dosage of the cationic polymer or the anionic polymer is 0-5 wt.%.

Hyaluronic acid, also known as hyaluronic acid, is a macromolecular polysaccharide substance composed of D-glucuronic acid and N-acetylglucosamine disaccharide units, and has the following structural formula:

hyaluronic acid molecules can carry more than 500 times of water, are the best moisturizing components recognized at present, and are widely applied to maintenance products and cosmetics. In addition, it has good biocompatibility and safety, and can be co-dissolved in water with poloxamer. And because the gel has certain biological adhesiveness, the gel can help the gel system to adhere to the nasal cavity and is not easy to be cleared by the nasal cilia. The structure molecule has carboxyl and negative electricity, so that the adsorption effect on positively charged particles is achieved. Therefore, bioadhesion and haze adsorption can be exerted.

Polylysine is a linear polymer of lysine, and the structural formula of the polylysine is shown as follows:

polylysine is rich in cations, so that the polylysine has a rejection effect on positively charged particles and can prevent the particles from entering a nasal cavity, and meanwhile, polylysine is polypeptide with a bacteriostatic effect and can play a role in corrosion prevention and bacteriostasis.

The temperature-sensitive particle adsorption gel disclosed by the invention is in a liquid form at low-temperature refrigeration (4 ℃) and room temperature (25 ℃), the viscosity is gradually increased along with the temperature rise, the phase transition from a liquid state to a gel state occurs at the critical temperature (namely, the gelation temperature), the gelation transition of the gel at the nasal cavity temperature (28-35 ℃) is ensured, the gel is not viscous and can not be sprayed out at the room temperature, the gelation temperature of the gel is lower than the lower limit of the nasal cavity temperature range, but is higher than the room temperature (25 ℃) as much as possible, and the gelation temperature of the gel is comprehensively considered to be controlled to be 28-35 ℃.

The invention also provides a preparation method of the temperature-sensitive particulate adsorption gel, which comprises the following specific steps:

considering that the poloxamer has a high dissolving speed in a low-temperature environment, particularly at 4 ℃, respectively weighing water-soluble components in a prescription, including a particulate adsorption type ionic group additive or a particulate rejection type ionic group additive, a humectant, a gel strength regulator, a surfactant and a bacteriostatic agent, adding the components into the prescription amount of water, stirring to dissolve, cooling, weighing the prescription amount of poloxamer, adding the poloxamer into the cooled solution, and placing at a low temperature to fully dissolve until a clear bubble-free solution is formed, thus obtaining the poloxamer-containing water-soluble humectant.

The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.

Example 1

0.5g of sodium hyaluronate (MW 10000Da) is weighed, added into 83mL of ultrapure water while stirring, dissolved and then cooled at 4 ℃, 16.5g of poloxamer 407 is weighed, added into the cooled solution, placed at 4 ℃ for full dissolution and then kept stand until a clear bubble-free solution is formed. The temperature-sensitive gel is liquid at normal temperature and becomes a semisolid gel state at the temperature of 32 +/-1 ℃.

The prescription composition is as follows:

example 2

0.5g of sodium hyaluronate (MW 10000Da) is weighed, added into 63.25mL of ultrapure water while stirring, dissolved and then cooled at 4 ℃, 15g of poloxamer 407 and 1.25g of poloxamer 188 are weighed, added into the cooled solution, placed at 4 ℃ for full dissolution, 20g of glycerol is added while stirring, and the solution is kept stand until clear and bubble-free solution is formed. The temperature-sensitive gel is liquid at normal temperature and becomes a semisolid gel state at the temperature of 32 +/-1 ℃.

The prescription composition is as follows:

example 3

Weighing 0.5g of polylysine, adding the polylysine into 63.25mL of ultrapure water while stirring, dissolving, cooling at 4 ℃, weighing 15g of poloxamer 407 and 1.25g of poloxamer 188, adding the poloxamer 188 into the cooled solution, placing the solution into the cooled solution at 4 ℃ for full dissolution, adding 20g of glycerol while stirring, and standing until a clear bubble-free solution is formed. The temperature-sensitive gel is liquid at normal temperature and becomes a semisolid gel state at the temperature of 32 +/-1 ℃.

The prescription composition is as follows:

example 4

Weighing 0.5g of sodium hyaluronate (MW 10000Da), adding the sodium hyaluronate into 73.5mL of ultrapure water while stirring, cooling at 4 ℃ after dissolving, weighing 15.5g of poloxamer 407 and 0.5g of poloxamer 188, adding the poloxamer 188 into the cooled solution, placing the solution at 4 ℃ for full dissolution, adding 10g of glycerol while stirring, and standing until a clear and bubble-free solution is formed. The temperature-sensitive gel is liquid at normal temperature and changes into a semisolid gel state at the temperature of 30 +/-1 ℃.

The prescription composition is as follows:

the temperature-sensitive gel is accompanied by the increase and mutation of the elastic modulus in the process of increasing the temperature to change from the solution state to the gel state, and the temperature of the mutation is close to the gel transition temperature. The elastic modulus of the temperature-sensitive gel of the present example was measured by a rheometer, with strain set to 0.05%, frequency set to 0.1Hz, gap set to 500 μm, temperature range set to 20-40 deg.C, heating rate 1 deg.C/min, and the temperature scan results were measured, and the sample was equilibrated at 20 deg.C for 4min before measurement, and measured in parallel for 3 times. As shown in FIG. 1, the elastic modulus of the temperature-sensitive gel of this example is mutated at 30 ℃. + -. 1 ℃.

Example 5

0.5g of sodium hyaluronate (MW 10000Da) is weighed, added into 82.49mL of ultrapure water while stirring, dissolved and then cooled at 4 ℃, 17g of poloxamer 407 and 0.5g of poloxamer 188 are weighed, added into the cooled solution, placed at 4 ℃ for full dissolution, 0.01g of potassium sorbate is added while stirring, and the solution is kept stand until clear and bubble-free solution is formed. The temperature-sensitive gel is liquid at normal temperature and becomes a semisolid gel state at 29 +/-1 ℃.

The prescription composition is as follows:

test example 1 adsorption Effect test

1. The L-shaped right-angle pipeline is designed to simulate the breathing and the inspiration of the nasal cavity, carbon powder is used to simulate fine particle pollutants, a blower is used to blow air at one end of the right-angle pipeline, so that the carbon powder is blown up and enters the right-angle pipeline, meanwhile, a trapping net is arranged at the other end of the right-angle pipeline, water or the adsorption gel of the invention is respectively sprayed on the net surface (the adsorption gel is operated under an infrared lamp, so that the adsorption gel is changed from a liquid state to a semi-solid state at a certain temperature), and the adsorption effect of the adsorption gel of the invention is proved by observing the amount of the carbon powder on the trapping. The samples of examples 2-5 were used as the absorbent gel.

Taking five same interception nets No. 1-5, spraying water on the net surface No. 1 when the experiment starting time is 0 hour, spraying gel on the net surfaces No. 2-5, and carrying out carbon powder adsorption and adhesion experiments by using the experiment method, wherein the net surfaces No. 1 and No. 2 are respectively 0 hour water and gel adsorption effect graphs; and in the experiment for 1 hour, taking the No. 3-5 net surface to perform the carbon powder adsorption and adhesion experiment again, taking the No. 4-5 net surface to perform the same operation in the experiment for 2 hours, taking the No. 5 net surface to adhere again in the experiment for 3 hours, and comparing whether the carbon powder on the net surface is increased or not. The mesh surfaces 3 to 5 can be marked as effect graphs for adsorbing carbon powder for 1, 2 and 3 hours respectively.

As can be directly seen from the experimental results in FIG. 2, the amount of the carbon powder intercepted by the control group of the water spraying net surface is less, while the experimental group, i.e. the net surface sprayed with the adsorption gel, is adhered with more carbon powder. When the infrared lamp is operated, a large amount of carbon powder is sprayed out of the water spraying net surface group, and the interception capability of the net surface is poor. The comparison of the control group and the experimental group can show that after a certain amount of adsorption gel is sprayed, the carbon powder has obvious adsorption and retention capacity at the place where the gel is sprayed. Specifically, the 0 hour gel has a stronger retention of carbon powder than water. Experiments show that the amount of the carbon powder on No. 2-5 mesh surfaces is gradually increased and the color is gradually darkened every 1 hour after 1-5 hours of experiments, which indicates that the gel has a continuous adhesion effect on the carbon powder within 3 hours.

2. The diameter of the curved pipeline close to that of the nasal cavity is adopted to simulate the nasal cavity, the gel and distilled water in example 4 are respectively sprayed into a straw to serve as an experimental group and a control group, and the adsorption effect of the gel is verified by quantitatively blowing fine carbon powder and quantitatively detecting. As shown in FIG. 3, the gel of the present invention has an adsorption effect on fine particles, and the adsorption efficiency can reach more than 70%.

3. The built volume is 0.027m³The opening at the two ends of the system is connected with a PVC pipe, a fan is arranged at the pipe orifice to drive the air flow to circulate, and the PM2.5 detector is placed in the center of the system. Drawing (A)4 is the device schematic diagram, and 1 is transparent closed system, and 2 is PM2.5 granule filling hole, can completely seal after PM2.5 granule is poured into and is accomplished, and 3 is the fan, drives the interior air current circulation of closed system, and 4 are the blank section of PVC pipe, and 5 are PVC pipe gel coating section, and 6 are the fan, prevent PM2.5 granule natural settling, and 7 are PM2.5 detector. 1mL of the gel of example 4 was coated with a syringe in a 5-PVC tube to a length of 3 cm. Simulating PM2.5 by using cigarette smoke, and adjusting the initial concentration to be 300-305 mu g/m³In between, the concentration change was recorded every five minutes. The control group was coated with physiological saline and the procedure was the same. And calculating the adsorption accumulation mass, and making an adsorption quantity-time diagram. As shown in FIG. 5, the gel was saturated in 50min and had an adsorption effect.

Test example 2 mucosal toxicity test

Using in vivo toad palate model method, after destroying brain and marrow with marrow destroying needle, supine fixation on frog plate, respectively coating the gel of example 5, normal saline (negative control) and ciliated toxic 1% sodium deoxycholate (positive control) on the mucosa part of the toad palate of 3 groups, making the palate completely immersed, after contacting for 30min, washing the gel with normal saline, separating the mucosa of the palate with surgical scissors, immediately washing blood and impurities with normal saline, spreading the mucosa face upwards on a glass slide, dropping normal saline, lightly covering the glass slide, observing the shape and movement condition of the mucosa under 40 × 10 times optical microscope.

The experimental results are shown in fig. 6, the cilia on the mucous membrane of the toad palate of the negative control normal saline group are densely distributed and closely and orderly arranged, and the cilia can be observed to swing in the same direction at a certain frequency under a microscope, while the cilia of the positive control group given with 1% sodium deoxycholate solution drop, and the swinging cilia are not found in the visual field, which indicates that the 1% sodium deoxycholate solution has serious cilia toxicity. The cilia of the toad palatal mucosa adsorbing the gel are complete and closely arranged, the phenomenon of lodging or falling is avoided, the swing frequency is consistent with that of a normal saline group, and the cilia of the mucosa are not obviously damaged. The experimental result shows that the poloxamer solution used by the adsorption gel has no cilium toxicity and does not damage the organism in the using process.

Claims

1. A temperature-sensitive particulate adsorption gel is characterized in that: the raw materials comprise: a temperature-sensitive hydrophilic gel material, a polymer and water;

2. The absorbent gel of claim 1, wherein: the temperature-sensitive hydrophilic gel material is poloxamer 407.

3. The absorbent gel of claim 1, wherein: the temperature-sensitive hydrophilic gel material is a mixture of poloxamer 407 and poloxamer 188.

4. The absorbent gel of claim 1, wherein: the anionic polymer is sodium hyaluronate, and the cationic polymer is polylysine.

5. The absorbent gel of claim 1, wherein: the raw materials comprise the following components in percentage by weight: poloxamer 40714-20%, poloxamer 1880-2%, cationic polymer or anionic polymer 0.5-1.5%, and water; the weight percentage of all raw materials is 100 percent.

6. The absorbent gel of claim 1, wherein: and other pharmaceutically acceptable adjuvants including humectant, gel strength regulator, surfactant, bacteriostatic agent and their mixture.

7. The method for preparing the temperature-sensitive particulate adsorption gel according to claim 1, wherein the method comprises the following steps: taking water-soluble components in the prescription, adding the water in the prescription amount, stirring to dissolve, cooling, weighing the poloxamer in the prescription amount, adding the poloxamer into the cooled solution, and standing at low temperature to fully dissolve until a clear bubble-free solution is formed.

8. Use of the temperature-sensitive particulate adsorption gel of claim 1 in the preparation of a nasal anti-haze product.

9. Use of the temperature sensitive particulate adsorption gel of claim 1 in the preparation of an air purifier.

10. Use of the temperature sensitive particulate adsorption gel of claim 1 in the manufacture of a mask article.