CN114699439B

CN114699439B - Five-flavor mannose self-heating gel patch with anti-inflammatory effect and preparation method thereof

Info

Publication number: CN114699439B
Application number: CN202210348145.5A
Authority: CN
Inventors: 邱丽颖; 朱雪锐; 侯豹; 文嫄媛; 戚梦婷; 蔡维维; 张建峰; 宗咏花; 于晓依; 米玛
Original assignee: Jiangnan University
Current assignee: Jiangnan University
Priority date: 2022-04-01
Filing date: 2022-04-01
Publication date: 2023-08-08
Anticipated expiration: 2042-04-01
Also published as: CN114699439A

Abstract

The invention discloses a five-flavor mannose self-heating gel patch with an anti-inflammatory effect and a preparation method thereof, belonging to the field of pharmaceutical preparations. The formula of the matrix of the self-heating gel patch is as follows: 7.5% of sodium polyacrylate NP800,0.33% of Gan Qiangji aluminum, 0.05% of diethylamine tetraacetic acid, 4.6% of talcum powder, 0.38% of titanium dioxide, 37.52% of glycerol, 1.13% of carboxymethyl cellulose (2200), 4.69% of tween, 0.28% of tartaric acid, and the content of the manna gel plaster for each patch is 2.5%. And the combined application of the gel patch and the warm patch is provided for the first time, so that the condition that a user is stressed due to supercooling of muscles when using the gel patch can be effectively alleviated. The self-heating gel paste has the advantages of luster, small exudation degree of non-woven fabrics, strong skin affinity, aromatic smell, repeated uncovering and pasting and no pollutant residue. Has remarkable therapeutic effect on the auricle swelling inflammation model of mice.

Description

Five-flavor mannose self-heating gel patch with anti-inflammatory effect and preparation method thereof

Technical Field

The invention relates to a five-flavor mannose self-heating gel patch with an anti-inflammatory effect and a preparation method thereof, belonging to the field of biological medicine preparations.

Background

The five-flavor sweet dew is a classical prescription recorded in the Tibetan medicine classic "four-part medical dictionary", and has the main efficacy of treating diseases within the scope of 'long' diseases prescribed by Tibetan medicine such as rheumatoid arthritis. The compound prescription mainly comprises five medicines of ephedra herb, juniper, tarragon, water cypress branch and azalea. Most of the literature reports that the chemical components of the compound medicine mainly contain artemisinin, kaempferide, quercetin, ephedrine hydrochloride and the like.

The five-flavor manna medicated bath is a prescription frequently used by Tibetan medicines, and the defects that the use mode is limited by conditions and the Chinese medicinal bath is not easy to carry are gradually revealed along with the gradual simplification of modern life. However, five-flavor manna has very abundant pharmacological activity and very great research value, and no effective medicine for rheumatic and rheumatoid arthritis appears in the existing market. Therefore, the five-flavor manna medicated bath preparation is prepared into the five-flavor manna self-heating gel patch, which is convenient for patients with rheumatic and rheumatoid arthritis to use, and solves the problem that the current rheumatic and rheumatoid arthritis has no special medicine. The gel emplastrum can accommodate traditional Chinese medicine powder and extract, and has the advantages of relatively simple preparation process, short production period and the like. Spontaneous heating has effects of promoting drug permeation and improving drug effect.

Disclosure of Invention

In order to solve the problem that the use mode of the existing five-flavor mannose as a medicated bath is limited by conditions, the invention firstly provides the five-flavor mannose self-heating gel patch with anti-inflammatory effect, which consists of five-flavor mannose gel and self-heating patch; the five-flavor manna gel comprises the following components: 7.5% of sodium polyacrylate NP800,0.33% of Gan Qiangji aluminum, 0.05% of diethylamine tetraacetic acid, 4.6% of talcum powder, 0.38% of titanium dioxide, 37.52% of glycerol, 1.13% of carboxymethyl cellulose (2200), 4.69% of tween, 0.28% of tartaric acid and self-heating patches, wherein the content of medicinal powder in each patch of five-component manna gel patches is 2.5%.

In one embodiment of the invention, the five-flavor manna powder is prepared by taking 60g of rhododendron anthopogonoides, water cypress branches, juniper, sweet wormwood and Tibetan ephedra, respectively, extracting for 2 times under the water bath of 60 ℃, extracting for two hours in a material-liquid ratio of 1:10, combining the extracting solutions, filtering, decompressing, steaming and drying in a rotary way to obtain the five-flavor manna powder.

The invention also provides a preparation method of the five-flavor mannose self-heating gel patch, which comprises the following steps: gel paste is prepared according to the optimal proportion of matrix auxiliary materials, phase A (sodium polyacrylate NP800, aluminum glycollate, sodium diethylamine tetraacetate, talcum powder, titanium dioxide, glycerol and hydroxymethyl cellulose) and phase B (five-flavor mannite powder, water and tween) are respectively prepared into uniform suspension, phase C (water and tartaric acid) is added into phase C, phase B is added, the mixture is uniformly mixed (quick mixing), the mixture is coated (the coating is sealed to avoid air flow), and the mixture is left for 12 hours to solidify.

The invention also provides a five-flavor mannose self-heating gel patch, wherein the drug loading rate is 2.5%.

The invention also provides the combined application of the five-flavor mannose self-heating gel patch by using the self-heating patch and the gel patch.

The invention also provides application of the five-flavor manna gel patch in preparation of medicines with anti-inflammatory effect.

In one embodiment of the invention, the anti-inflammatory effect is preferably anti-rheumatic and rheumatoid arthritis.

The invention also provides a pharmaceutical composition comprising the five-flavor mannose self-heating gel patch.

The beneficial effects of the invention are that

The invention prepares the five-flavor mannose aqueous extract into the gel patch, is convenient for patients to use and carry at any time, evaluates the drug effect of the five-flavor mannose self-heating gel patch through a mouse auricle swelling model experiment, and the test result shows that the five-flavor mannose self-heating gel patch has remarkable treatment effect on the mouse auricle swelling inflammation model.

Drawings

FIG. 1 five-component mannose self-heating gel paste process flow diagram

FIG. 2 skin response of New Zealand rabbits at the site of administration

Detailed Description

Five-ingredient mannose self-heating gel patch appearance property scoring: according to the evaluation index of the hydrogel patch of the 2015 edition of Chinese pharmacopoeia, the appearance property grading index of the hydrogel patch comprises paste gloss, pollution, exudation degree of non-woven fabrics, skin affinity and smell.

Five-ingredient mannose self-heating gel paste excipient test: according to the method of the fourth part 0122 of the 2015 edition of Chinese pharmacopoeia, 3 pieces of five-flavor manna gel paste are taken, and after the five-flavor manna gel paste is placed for 24 hours, if no flow phenomenon exists on the paste surface, the paste surface meets the pharmacopoeia standard.

Measurement of initial adhesion of five-flavor mannose self-heating gel patches: according to the first method under the fourth part 0952 of the 2015 edition of the Chinese pharmacopoeia. The sample (together with the packaging material) should be left for more than 2 hours at 18-25 ℃ and 40% -70% relative humidity prior to testing. The surfaces of the inclined plate and the stainless steel ball are scrubbed by wiping materials dipped with absolute ethyl alcohol, and are carefully scrubbed by clean dust-free cloth, and the inclined plate and the stainless steel ball are repeatedly cleaned for more than 3 times until the surfaces of the inclined plate and the stainless steel ball are clean through visual inspection. The inclined plate is adjusted according to the inclined angle of 15 degrees, and the horizontal state of the bottom of the experimental device is kept. And 3 pieces of test sample are taken, the back lining of the test sample is respectively fixed on the inclined plate by using a double-sided adhesive tape, wherein the upper end of the test sample is positioned at the horizontal line-down position of the inclined plate, and the test sample is flatly attached to the plate. After removing the cover lining of the test sample, finishing the test as soon as possible, reserving 5cm on the middle paste surface, sequentially placing steel balls with different numbers on an initial line, enabling the distance between the steel balls and the paste to be 1cm, freely falling from the top end of the inclined surface, and recording the maximum number of steel balls capable of being stuck, wherein the number of steel balls with the number of 8 or more can be stuck.

Five-ingredient mannose self-heating gel patch containing paste measurement standard: taking 8 pieces of test sample, removing the cover liner, precisely weighing, and placing in a beaker. Adding appropriate amount of water, heating and boiling to separate the backing from the paste, taking out the backing, washing with water until the backing has no residual paste, and air drying. Drying at 105deg.C for 30min, transferring to a dryer, cooling for 30min, weighing, and removing weight to obtain ointment. According to a second method for determining the paste content in the four parts 0122 of 2015 of Chinese pharmacopoeia, the average paste content of each tablet is about 10.0g, and the paste content is 85% -115% of the marked paste content. Namely converted into 100cm according to the marked quantity ² Is added to the paste.

Five-ingredient mannose self-heating gel patch cumulative transdermal rate experiment: and (3) measuring the transdermal content of flavonoid, saponins and polysaccharide substances in the five-flavor manna gel patch by adopting a transdermal diffusion cell. The temperature of the transdermal diffusion tester is controlled to be 37+/-0.1 ℃, and the rotating speed of the magnetic stirrer is controlled to be 180+/-1.0 r2min- ¹ . The volume of the receiving tank is 8mL, and the diffusion area is 1.77cm ² . The magnetic stirrer is placed in a receiving tank, and the prepared in-vitro mouse skin (1.77 cm) ² ) The upper end of the receiving tank is horizontally placed, the stratum corneum is upwards, and then the releasing tank is fixed on the receiving tank by a clip. Removing the anti-adhesive layer, tightly adhering to the skin of mice, removing air bubbles between the plaster and skin, fixing between the diffusion chamber and the receiving chamber of the diffusion cell, facing the receiving chamber, adding physiological saline solution as receiving solution to scale line via sampling tube by syringe, stirring at constant speed (180 r ² min ^-1 ) 8mL of the receiving solution was extracted at 0.5, 1, 1.5, 2, 4, and 6 hours, respectively, and 8mL of fresh receiving solution was added.

The received solution was filtered with a 0.45 μm filter membrane, and the cumulative transdermal rate (%) was calculated by the following formula:

L _n ＝Q _n /W×100

Q _n to accumulate transdermal flux, C _n For the concentration of the sample at the nth time point, V is the receiving pool volume, C _i For the concentration of the sample at the ith time point, V ₀ For each sampled volume, L _n For accumulating the transdermal rate, W is the content of flavonoids, saponins and polysaccharides in the five-flavor manna gel patch.

Five-ingredient mannose self-heating gel patch irritation experiment: the skin irritation of the self-heating water gel patch is examined by referring to the related requirements of the traditional Chinese medicine natural medicine local irritation and hemolysis research technical guidelines. 6 New Zealand rabbits were selected, and half of the male and female rabbits were removed from the two sides of the spinal column 24 hours before administration, taking care that the epidermis was not damaged. Self-heating hydrogel patch and blank patch (3 cm×3cm) are applied to rabbit hair removal area skin, covered with cellophane, and fixed with medical adhesive tape. Removing the patch 24h after administration, removing residual matrix, observing skin reaction at the administration position at 1, 24, 48 and 72h, and scoring according to the guideline rule, wherein the score is 0 score without erythema, 0 score without oedema and 0-0.49.

Five-flavor manna water extract: reflux extracting 60g of Rhododendron anthoxylum, herba Selaginellae, juniper, herba Artemisiae Annuae and herba Ephedrae respectively in water bath at 60deg.C for 2 times with a feed-liquid ratio of 1:10, extracting for two hours each time, mixing extractive solutions, filtering, and vacuum rotary evaporating to dry to obtain fructus Schisandrae chinensis water extract dry powder.

The present invention is further described below with reference to examples, but embodiments of the present invention are not limited thereto.

Example 1: five-ingredient mannose self-heating gel patch drug-loading quantity screening test

The five-flavor manna self-heating hydrogel patch drug-loading rate is screened by a rat joint inflammation model. Firstly, acute joint inflammation of rats is induced by carrageenan, then the rats are randomly divided into three groups, marked at the ankle joints of the rats, and the foot volume of the rats is measured by using a drainage method. The center of the foot palm of the rat is subcutaneously injected with carrageenan in a telecentric direction, the right foot of each group of rats is coated with five flavors Gan Zhiji with different concentrations, and the left is a blank control group. The ankle volumes of the rats were measured at 2h, 4h, 6h, and 24h, respectively, and the swelling degree and swelling inhibition rate were calculated. Swelling inhibition = control swelling degree-dosing swelling degree)/control swelling degree.

TABLE 1 five-ingredient manna formulations with different concentrations have remarkable inhibiting effect on rat plantar swelling

Note that: p <0.05 compared to the blank; * P <0.01.

As can be seen from table 1, the five-ingredient manna preparation with the mass percentage of 2.5% has a remarkable inhibiting effect on the plantar swelling of rats and has a remarkable treatment effect on the arthritis of rats. Therefore, the five-flavor mannose self-heating gel paste is kept to contain 2.5% of five-flavor mannose powder, and then the mixture ratio of auxiliary materials is changed to screen the final five-flavor mannose self-heating gel paste formula.

Example 2 five-ingredient manna self-heating gel paste process flow and matrix screening

In order to make the medicine in the paste permeate human skin to the maximum extent, be convenient to use and effectively store, the gel plaster is divided into 3 layers, namely a backing layer: the non-woven fabric is mainly used as a carrier of the paste; paste layer: is a main component of the gel emplastrum, contains water molecules and water-soluble polymer skeleton structures of medicines, and generates viscosity in the use process so as to be closely attached to the skin; anti-sticking layer: protecting the paste layer and selecting a polypropylene film by using release paper. The process flow diagram is shown in figure 1.

The proportion of the matrix is the core of the gel patch research, and the selection of the matrix raw materials has great influence on the formation of the gel patch matrix. The matrix of the gel patch mainly comprises: thickening agent, humectant, filler, crosslinking agent, surfactant, antiseptic, and antioxidant can be added as required. The matrix should have no influence on the main drug components, and should not cause injury to human body, and also have suitable viscoelasticity. The study uses the mixing difficulty, coating difficulty, pH value and strength analysis of the basic formula as evaluation indexes of the five-flavor mannose gel patch to determine the dosage of each matrix in the five-flavor mannose basic formula.

From the previous laboratory study and related literature, the following materials were selected as matrix materials for the five-flavor manna gel patch as shown in table 2.

Table 2 matrix material and action of five-ingredient manna gel patch

Matrix material	Action
		Sodium polyacrylate NP800	Thickening agent
Gan Qiangji aluminum	Crosslinking agent
		Diethylamine tetraacetic acid sodium salt	Complexing agent
Talc powder	Filler (B)
		TiO2	Crosslinking agent
Glycerol	Humectant type
		Carboxymethyl cellulose (2200)	Adhesion promoters
Tartaric acid	PH regulator

Example 3 five-ingredient manna self-heating gel paste matrix proportion screening and specific flow

Gan Qiangji aluminium proportional screening

As shown in Table 3, aluminum glycinate was the single variable, and Gan Qiangji aluminum was the variable, with the amounts of other materials remaining unchanged. The content of the aluminum glycinate in the prescription 1 is 0.188 percent, and the content of the aluminum glycinate in the prescription 2 is 0.328 percent.

Table 3 comparison of matrix ratios of recipe 1 and recipe 2

As shown in table 4, prescription 2, which was moderately strong and had a higher pH, was selected for further optimization based on the intensity analysis.

Table 4 comparison of ease of mixing, ease of coating, pH and strength analysis for prescriptions 1 and 2

Tween factor screening

Tween is a single variable, and the phase B main medicine is considered to be difficult to mix with water, so that 4.7% tween is added as prescription 3 on the basis of prescription 2.

Table 5 comparison of matrix ratios of recipe 2 and recipe 3

As shown in table 6. Formula 3 adds 4.7% tween based on formula 2, which can accelerate the B-phase mixing speed.

Table 6 comparison of ease of mixing, ease of coating, pH and strength analysis for prescriptions 2 and 3

Hydroxymethyl cellulose factor screening

As shown in table 7, the hydroxymethyl cellulose in the C phase was transferred to the a phase for mixing, considering that the C phase was uniformly mixed for a long time.

Table 7 comparison of matrix ratios of recipe 2 and recipe 4

As shown in Table 8, after the hydroxymethyl cellulose in phase C is transferred to phase A, the mixing time of phase C is shortened, and the operation time is reduced.

Table 8 comparison of ease of mixing, ease of coating, pH and strength analysis for prescriptions 2 and 4

As shown in Table 9, in the case of coating in the formulations 1 to 4, the paste was easily left on the backing due to the long coagulation time and small cohesion, and the content of the hydroxymethyl cellulose was increased from 0.56% to 1.13% and 2.81%.

Table 9 comparison of matrix ratios for prescriptions 4, 5 and 6

As shown in table 10, by comparison, when the hydroxymethyl cellulose content was 1.13%, the cohesion of the paste was moderate, the coating was easy, and the uniformity was good.

Table 10 comparison of the ease of mixing, ease of coating, pH and strength analysis for prescriptions 4, 5 and 6

According to the optimized result, the optimal matrix of the five-flavor manna gel patch is selected and the ratio is shown in table 11:

table 11 five-ingredient manna gel patch optimal matrix proportion

Example 4 five-ingredient manna self-heating gel patch evaluation of efficacy by mouse auricle swelling model experiment

Modeling of mouse auricle swelling due to xylene: the right ear of the mouse is coated with 100 mu l of dimethylbenzene (50 mu l/surface), the left ear is not treated, after 30min of inflammation, the thickness of the ears of the mouse is measured, the mouse is killed by neck removal, the ear disc is taken out from the same part of the left ear and the right ear by an 8mm puncher, the weight of the ear disc is weighed, and the ear swelling degree is calculated.

The mouse auricle swelling model is divided into four groups: model group, model+shizandra manna self-heating patch gel, model+shizandra manna gel, model+heating patch. After xylene inflammation is coated, the model group is not treated, and three groups of horses are attached with five-flavor manna self-heating paste gel, five-flavor manna gel and a heating paste. After 30min, the thickness of the ears of the mice is measured, the mice are killed by cervical removal, the ear discs are taken from the same positions of the left ear and the right ear by using an 8mm puncher, the weight of the ear discs is weighed, and the ear swelling degree is calculated.

Table 12 mouse auricle swelling model experiment swelling degree and swelling inhibition rate

The results in Table 12 show that the five-flavor mannose self-heating gel patch has remarkable treatment effect on the auricle swelling inflammation model of the mice.

Three batches of five-flavor mannose self-heating gel patches are prepared according to the optimal matrix proportion, and the physical and chemical properties of the five-flavor mannose self-heating gel patches are detected, so that the results show that:

gel patch appearance: the five-flavor mannose self-heating gel paste has the advantages of luster, small exudation degree of non-woven fabrics, strong skin affinity, aromatic smell, repeated uncovering and pasting, no pollutant residue and accordance with pharmacopoeia standards.

Gel paste shaping properties: 3 pieces of five-flavor manna self-heating hydrogel paste are taken, and after the paste is placed for 24 hours, the paste surface has no flowing phenomenon and meets the pharmacopoeia standard.

Gel paste primary adhesion: the five-flavor manna gel paste can be maximally stuck to the 11 # ball by the measurement of a CYZ-G tester. Meets the standards of Chinese pharmacopoeia.

Gel patch contains the following components: according to a second method for determining the paste content in the four parts 0122 of 2015 of Chinese pharmacopoeia, the average paste content of each tablet is about 10.0g, and the paste content is 85% -115% of the marked paste content. Namely, the paste content is converted into 100cm2 according to the marked amount. The gel patch contains 8.58-11.29 g of paste and accords with the standards of Chinese pharmacopoeia.

Gel patch 6h cumulative transdermal rate of active substance: the accumulated transdermal rate of flavonoid substances is 23.01%, the accumulated transdermal rate of saponins substances is 16.4%, and the accumulated transdermal rate of glucose substances is 21.25%.

Gel patch irritation experiment: results figure 2 shows that 6 rabbits showed no erythema and edema after 24 hours of administration of the self-heating gel blank patch and the self-heating hydrogel patch, with a total score of 0 points, indicating that the self-heating hydrogel patch was non-irritating. Meets the pharmacopoeia standard.

Example 5 pharmaceutical composition comprising five-ingredient manna self-heating gel patch

In order to further expand the application prospect of the five-flavor mannose self-heating gel patch, other acceptable pharmaceutical compositions can be prepared by matching other auxiliary materials and carriers, including a mode of combined use with other medicines.

While the invention has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A preparation method of five-flavor mannose self-heating gel paste with anti-inflammatory effect is characterized in that the five-flavor mannose self-heating gel paste consists of five-flavor mannose gel paste and self-heating paste; the five-flavor mannose gel patch is divided into 3 layers, namely a back lining layer, a paste layer and an anti-sticking layer, wherein the back lining layer is made of non-woven fabrics, and the anti-sticking layer is made of polypropylene films; the five-flavor manna gel paste body composition comprises the following components: 7.5% of sodium polyacrylate NP800,0.33% of Gan Qiangji aluminum, 0.05% of sodium diethylamine tetraacetate, 4.6% of talcum powder, 0.38% of titanium dioxide, 37.52% of glycerol, 1.13% of carboxymethyl cellulose 2200,4.69% of tween, 0.28% of tartaric acid, 2.5% of shizandra berry mannose powder and the balance of water;

the five-flavor mannose powder is obtained by the following method: reflux extracting Rhododendron anthoxylum, herba Sambuci Chiensis branch, juniper, herba Artemisiae Annuae and herba Ephedrae respectively at 60g in water bath at 60deg.C for 2 times with a feed-liquid ratio of 1:10, each time for two hours, mixing extractive solutions, filtering, and steaming under reduced pressure to obtain five-flavor manna powder;

the preparation method of the five-flavor mannose self-heating gel paste layer comprises the following steps:

phase a: sodium polyacrylate NP800, aluminum glycinate, sodium diethylamine tetraacetate, talcum powder, titanium dioxide, glycerol and hydroxymethyl cellulose, phase B: five-flavor manna powder, water, tween and phase C: preparing water and tartaric acid into uniform suspension respectively, adding phase A into phase C, adding phase B, mixing, coating, and standing for 12 hr for solidification.

2. According to claim 1The preparation method of the gel patch is characterized in that the five-flavor mannose self-heating gel patch has the paste content of 8.58g/100 cm ² -11.29g/100 cm ² 。

3. The method of claim 1, wherein the post-coating seal prevents air flow.

4. The use of five-ingredient manna self-heating gel patch prepared by the method of claim 1 in the preparation of a medicament with anti-inflammatory effect.

5. The five-flavor mannose self-heating gel patch prepared by the preparation method of claim 1.