CN114010700A

CN114010700A - Preparation method and application of noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components

Info

Publication number: CN114010700A
Application number: CN202111392401.2A
Authority: CN
Inventors: 王磊; 刘贵栋; 叶婷; 姜宇
Original assignee: Harbin Vocational and Technical College
Current assignee: Harbin Vocational and Technical College
Priority date: 2021-11-23
Filing date: 2021-11-23
Publication date: 2022-02-08

Abstract

The invention discloses a preparation method and application of a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine active ingredients, wherein the active ingredients of the transdermal absorbent are cortex dictamni, earthworm, nux vomica and datura flower extracts, and are prepared into an absorption transdermal patch.

Description

Preparation method and application of noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components

Technical Field

The invention relates to a traditional Chinese medicine composition and a transdermal absorbent thereof, in particular to a preparation method and application of a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine active ingredients.

Background

Rheumatoid arthritis is a long-term chronic inflammation characterized by synovitis, chronic erosive arthritis, which results in the immune system attacking the joints due to autoimmune disorders. Besides invading the joints of hands and feet, other organs or tissues, such as lungs, hearts, nervous systems and the like can be affected, and the medicine has the characteristics of easy repetition, long disease course, high disability rate and the like, and the life quality of patients is seriously affected because RA has higher disability rate.

At present, the therapeutic drugs aiming at RA mainly comprise non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting antirheumatic drugs (SAARDs), Glucocorticoids (GC), biological agents and traditional Chinese medicine/traditional Chinese medicine preparations, the anti-RA effect of the traditional Chinese medicine is increasingly emphasized by people, the anti-RA effect of the traditional Chinese medicine is obvious, and the traditional Chinese medicine has the effects of anti-inflammatory analgesia, immunoregulation and the like, so that the toxic and side effects of western medicines are avoided, the traditional Chinese medicine is suitable for long-term administration, and the unique advantage of the traditional Chinese medicine in treating RA is displayed. Rheumatoid arthritis belongs to the category of arthralgia syndrome in traditional Chinese medicine, the basic pathogenesis is deficiency and marked excess, namely the basic pathogenesis is that the functions of 3 viscera of lung, spleen and kidney are weakened, and the channel blockage caused by qi stagnation and blood stasis caused by exogenous pathogenic factors such as wind, cold, dampness and phlegm is marked excess.

The flos daturae is pungent and warm in taste, has the effects of removing obstruction in channels, relieving pain, calming, regulating immunity, resisting inflammation, inhibiting proliferation and the like, is one of common medicines for clinically treating rheumatoid arthritis, can effectively relieve the synovial inflammatory reaction of the rheumatoid arthritis, regulates the immune response and prevents the further development of the pathological process.

The earthworm has the functions of promoting blood circulation, removing blood stasis, dredging collaterals, cooling blood and the like, can regulate blood circulation and promote metabolism, is widely applied to analgesia and treatment of skin burns and scalds, and has obvious effect.

Cortex Dictamni Radicis has effects of clearing heat, eliminating dampness, dispelling pathogenic wind and removing toxic substance, and can be used for treating damp-heat sore, yellow water stranguria, eczema, rubella, skin pruritus, scabies, jaundice, acute and chronic hepatitis, etc., and earlier research shows that it has analgesic effect.

The nux vomica is bitter in taste, warm in nature and toxic in property, enters liver and spleen channels, has the effects of dredging collaterals, relieving pain, dissipating stagnation and reducing swelling, is mainly used for treating traumatic injury, rheumatism obstinate arthralgia, fracture swelling and pain, numbness, paralysis, sore throat and other symptoms, can be used for treating diseases such as tumors, myasthenia gravis, peripheral neuropathy, arthritis, spinal cord injury, cerebral infarction, fracture, hyperosteogeny and the like, and has pharmacological activities of regulating immunity, resisting inflammation and the like.

Transdermal Drug Delivery System (TDDS) is the third largest drug delivery system following oral, injection. It can bypass the first pass effect of liver, avoid the damage of medicine in gastrointestinal tract, and has the advantages of less blood medicine concentration fluctuation, less toxic side effect, convenient taking, high patient compliance, etc. It has a long history of application in clinical treatment of traditional Chinese medicine, belongs to external treatment, and can be applied to various diseases. The externally-applied therapy is applied topically to block qi, so that the action of the drug is entered into the skin and muscle pores through the pores, unblocking the meridians, or lifting the drug, or attacking and dispersing the drug, which is stronger than the action of the drug. The external treatment of internal diseases has become a common recognition of the Chinese and Western theories.

The hair follicle and the sebaceous gland also play an important role in a local or transdermal drug delivery system, and the hair follicle is a cavity formed by the epidermis which is sunken inwards until the dermis, so that the actual surface area for absorption is greatly increased. The pilosebaceous pathway is one of the mechanisms of promoting transdermal absorption by the liposome, can promote the transdermal absorption of the medicament, can keep the high concentration of the medicament in the skin, is beneficial to the accumulation of the medicament in the epidermis and the dermis, and has obviously less medicament dosage in other organs. Sebum released from pilosebaceous glands can also affect drug absorption by providing a lipid pathway. Of the three major layers of the follicle, the outer root sheath is most important for drug delivery to the follicle. This layer is connected to the epidermis, which increases the surface area for absorption. The diameter of human hair follicles is 10 to 70 μm depending on the type. Sometimes sebaceous glands and hair follicles coexist, or exist alone, particularly in facial skin. The speed of penetration of the skin through the hair follicle opening agent is significantly higher than the speed of penetration through the cortical layer, especially water-soluble agents, and the hair follicles are distributed over the entire skin surface except for the partial areas of the palms and soles, the lips, and the sexual organs.

The invention has the advantages that: the transdermal absorbent can improve the percutaneous absorption of medicines, slowly release medicines, avoid the first pass effect of liver and the inactivation of medicines in gastrointestinal tracts, maintain constant medicine effect blood concentration and physiological effect through hair follicles or cuticles, select pilosebaceous units as the targets of the medicines and serve as medicine storage reservoirs, the medicines enter the hair follicles from sebaceous ducts through the sebum, and can force a certain-degree lipidated medicine compound to enter the hair follicles, the hair follicles are cavities formed by the epidermis inwards sunken to the dermis, so that the actual surface area of absorption is greatly increased, and the sebum released by the pilosebaceous glands can also influence the absorption of the medicines by providing a lipoid path.

The toxicity of the datura flower and the nux vomica is stronger, the fat solubility of the active ingredients of the medicine is better, the half-life period is short, and the bioavailability is low, and the slow release property and the targeting property of the medicine can be improved by adopting different carriers and optimizing the preparation process, so that the overall toxicity of the medicine is reduced, and the curative effect is enhanced; different penetration enhancers can be used to increase the penetration of the drug and thus enhance the therapeutic effect. The nanoparticles can be used for targeted drug delivery, are beneficial to the absorption and sustained release of drugs, and reduce the dosage and the drug delivery frequency, thereby playing the roles of reducing the toxicity and increasing the compliance of patients.

Disclosure of Invention

The invention aims to provide a preparation method and application of a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine active ingredients.

The specific technical scheme is as follows:

a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components is characterized in that the transdermal absorbent contains active components of cortex dictamni, earthworm, nux vomica and datura flower extract; the mass ratio of the cortex dictamni, the earthworm, the nux vomica and the datura flower is as follows: 2:1: 1:0.5, the main components are dictamnine, strychnine and henbane, and the transdermal absorbent is a hair follicle targeted absorption preparation with the particle size of 5-20 microns.

A preparation method of a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components is characterized by comprising the following steps:

(1) feeding cortex Dictamni Radicis, semen Strychni, and flos Daturae Metelis at a ratio of 2:1:0.5, pulverizing, extracting with 8 times of 50-95% ethanol solution for 1-3 times (each for 1-2 hr), collecting ethanol extractive solution, and concentrating until there is no alcohol smell.

(2) Adding Lumbricus according to the proportion of 1, extracting with 8 times of acid water, adding certain amount of anhydrous ethanol to adjust to 80% ethanol content, precipitating with ethanol, centrifuging, and collecting precipitate.

(3) Mixing the samples obtained in the steps (1) and (2), dissolving the mixture by using methanol, loading the mixture by adopting a wet method, passing the mixture through a silica gel column, and reacting the mixture by using methanol: eluting with water at a ratio of 2:3 and 6bv, collecting the eluent, concentrating, and freeze-drying to obtain freeze-dried powder for later use.

(4) Dissolving the freeze-dried powder in 1.5 times of isopropyl myristate, heating at 40 deg.C until both are completely melted to form eutectic mixture, mixing with polyoxyethylene hydrogenated castor oil and glycerol (2:1), vortex mixing, simultaneously dripping appropriate amount of 40 deg.C warm water, and standing until the solution turns from turbid to clear and transparent.

Further, the preparation method comprises the following step (4): dissolving the freeze-dried powder in PBS (pH 5.0), weighing appropriate amount of lecithin and cholesterol, dissolving with appropriate amount of chloroform-ether (1: 1) mixed solution, adding PBS (pH 5.0) prepared from the freeze-dried powder, performing ultrasonic treatment to obtain uniform emulsion, adding buffer salt solution, performing ultrasonic treatment to obtain W/O/W multiple emulsion, performing rotary evaporation to remove organic solvent, adding a small amount of PBS for hydration, standing, and cooling to obtain liposome.

Preferably, the ratio of lecithin to cholesterol in step (4) of the preparation method is 2:1

Preferably, the pH value of PBS in the step (4) of the preparation method is 4.5

Preferably, the pH value of the acidic water in the step (2) is 5-6.

Preferably, the isopropyl myristate in step (4) may be one of azone, oleic acid and limonene.

Further, the transdermal absorbent is used for treating rheumatoid arthritis.

Detailed Description

As mentioned above, the present invention aims to provide a method for preparing a transdermal absorbent containing effective ingredients of traditional Chinese medicine by noninvasive dermal penetration technology and its application, which will be described in detail with reference to the following embodiments.

It is specifically noted that similar alternatives and modifications will be apparent to those skilled in the art, which are also intended to be included within the present invention. It will be apparent to those skilled in the art that the techniques of the present invention may be implemented and applied by modifying or appropriately combining the methods and applications described herein without departing from the spirit, scope, and content of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention.

If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.

Preparation of intermediates

Example 1:

(1) weighing 50g of cortex dictamni, 25g of nux vomica and 12.5g of datura flower, mixing, crushing, extracting for 3 times with 8 times of 50% ethanol solution for 1 hour each time, collecting ethanol extract, and concentrating until no alcohol smell exists.

(2) Weighing 25g of earthworm, extracting with 8 times of acid water (pH value is 5), adding a certain amount of absolute ethyl alcohol to adjust the content of 80% ethanol, carrying out alcohol precipitation, centrifuging, and taking precipitate.

Example 2

(1) Weighing 50g of cortex dictamni, 25g of nux vomica and 12.5g of datura flower, mixing, crushing, extracting for 1 time with 8 times of 95% ethanol solution for 2 hours each time, collecting ethanol extract, and concentrating until no alcohol smell exists.

Example 3

(1) Weighing 50g of cortex dictamni, 25g of nux vomica and 12.5g of datura flower, mixing, crushing, extracting for 3 times with 8 times of 65% ethanol solution for 2 hours each time, collecting ethanol extract, and concentrating until no alcohol smell exists. (2) Adding Lumbricus according to the proportion of 1, extracting with 8 times of acid water, adding certain amount of anhydrous ethanol to adjust to 80% ethanol content, precipitating with ethanol, centrifuging, and collecting precipitate.

Preparation of the formulations

Example 4

Dissolving the freeze-dried powder obtained in the example 3 in 1.5 times of isopropyl myristate, heating at 40 ℃ until the two are completely melted to form eutectic mixture, uniformly mixing with polyoxyethylene hydrogenated castor oil and glycerol (2:1) in a vortex manner, and simultaneously dropwise adding a proper amount of warm water at 40 ℃ until the solution is clear and transparent from turbidity to obtain the freeze-dried powder.

Example 5

Dissolving the lyophilized powder obtained in example 2 in PBS (phosphate buffer solution) with pH value of 5.0, weighing 10ml of lecithin and 5ml of cholesterol, adding 20ml of chloroform-ethyl ether (1: 1) mixed solution for dissolving, adding PBS (phosphate buffer solution) with pH value of 5.0 prepared from the lyophilized powder, performing ultrasonic treatment to obtain uniform emulsion, adding buffer salt solution for ultrasonic treatment to obtain W/O/W multiple emulsion, performing rotary evaporation to remove organic solvent, adding a small amount of PBS for hydration, standing, and cooling to obtain the final product.

Comparative example 1

The procedure of example 4 was followed except that no dittany bark was added to the formulation.

Comparative example 2

Nux vomica is not added in the formula, and the other preparation method is the same as the example 4.

Comparative example 3

The preparation method is the same as that of example 4 except that datura flower is not added in the formula.

Comparative example 4

The formulation was prepared in the same manner as in example 4, except that no earthworm was added.

Comparative example 5

Mixing 8 parts of sodium carboxymethylcellulose and 10 parts of polyvinylpyrrolidone K30, adding 120 parts of 60 ℃ water, standing for 24 hours, and fully swelling to obtain gel A; taking 10 parts of polyvinyl alcohol, adding 110 parts of water, dissolving in a water bath at 95 ℃, uniformly stirring, ultrasonically degassing, standing for 24 hours, and fully swelling to obtain gel B. Mixing the gel A and the gel B on a water bath at 60 ℃, stirring until the gel is uniformly mixed, adding 20 parts of glycerol, fully stirring, dispersing and soaking the freeze-dried powder obtained in the embodiment 3 by using 4 parts of polyethylene glycol 400, then adding the mixture, stirring until the mixture is fully and uniformly mixed, finally adding 20 parts of azone, fully stirring, coating the mixture on a back lining layer while the mixture is hot, drying, then covering an anti-sticking layer, cutting into a proper size, and packaging to obtain the gel.

Comparative example 6

Dissolving 80 parts of soybean lecithin, 1 part of cholesterol and one part of the freeze-dried powder obtained in the embodiment 3 in a proper amount of ethanol, dissolving 3 parts of ceramide in 10 parts of PBS phosphate buffer solution with the pH value of 7.4, heating to 60 ℃, stirring, slowly dripping the obtained ethanol solution into the obtained phosphate buffer solution, continuously stirring, and volatilizing the ethanol to obtain the compound.

Particle size inspection of the preparation

Example 6

The average particle sizes of examples 4 to 5 and comparative example 6 were measured using a potentiometric particle size analyzer, and the results are shown in the following table.

Sample name	Average particle diameter (nm)
		Example 4	80.23
Example 5	87.19
		Comparative example 6	131.22

Percutaneous absorption and accumulation of hair follicle

Example 7

Taking female Kunming female mice, anesthetizing with 10% chloral hydrate (35mg/kg), taking abdominal skin, depilating with 10% sodium sulfide, cleaning, and storing at-20 deg.C for use. The dermal layer of skin faces the receiving pool, and is fixed in a transdermal experimental instrument, and the effective penetration area of the medicine is 2.9cm². The transdermal agents obtained in example 4 and comparative example 6 were uniformly applied to the skin of a subject using 6mL of methanol-physiological saline (1: 1) as a receiving solution, 1mL was sampled 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours after administration, and simultaneously an equal volume of the receiving solution was added, filtered through a 0.22 μm microporous membrane, and the drug content was measured by HPLC.

The analysis was performed using a C18 column; water (0.1% formic acid, 3% triethylamine): acetonitrile 85: 15; the volume flow is 1.0 ml/min; the detection wavelength is 254 nm; the column temperature is 35 ℃; the amount of the sample was 10. mu.L.

After the transdermal experiment is finished, the skin of a mouse is cut off along the edge of the diffusion cell, 5mL of distilled water is used for washing unabsorbed medicines, the skin is cut into pieces and then is added with methanol, the pieces are transferred into a 10m L measuring flask, the volume of the methanol is constant after ultrasonic treatment for 1h, the filtering is carried out through a 0.22 mu m microporous membrane, and the retention amount of the medicines in the skin is measured through an HPLC method. The analysis was performed using a C18 column; water (0.1% formic acid, 3% triethylamine): acetonitrile 85: 1, preparing a catalyst; the volume flow is 1.0 ml/min; the detection wavelength is 254 nm; the column temperature is 35 ℃; the amount of the sample was 10. mu.L.

The specific test results are shown in the following table:

name of ingredient	Strychnine	Dictamnus dasycarpus	Henbane seed alkali
				Comparative example 6 transdermal amount μ g cm^-2	38.10	55.92	78.43
Comparative example 6 skin accumulating amount μ g cm^-2	3.91	10.29	5.99
				Example 4 transdermal amount. mu.g cm^-2	42.37	79.88	87.02
Example 4 skin accumulation amount. mu.g cm^-2	9.54	13.08	6.21

From the above data, it can be seen that the permeation of the three main components in comparative example 6 is lower than that of the preparation of example 4, and the skin accumulation is lower than that of example 4, which indicates that the transdermal effect and the skin accumulation effect of the main components of the preparation obtained in example 4 are better than those of comparative example 6, and indicates that the drug achieves the purpose of promoting transdermal absorption through the pilosebaceous follicles at the particle size, at which not only the transdermal absorption of the drug can be promoted, but also the high concentration of the drug in the skin can be maintained, which is beneficial to the accumulation of the drug in the epidermis and dermis.

Toxicity test

Example 8

20 healthy mice are selected, the weight is 80-120g, the mice are randomly divided into 2 groups, each male and female half of each group, the back is subjected to depilation treatment, the transdermal absorbents prepared in the examples 3 and 4 are respectively smeared on the back once a day, the continuous observation is carried out for 14d, the mice of each group have no death and abnormal toxic reaction, the diet and the activity are normal, no death occurs, after the administration is carried out for 90 days, the mice of each group have no abnormal expression, the behavior is active, the back hair is smooth, the diet is normal, the hemogram, the biochemical index, the urine conventional index and the organ coefficient have no significant difference.

Animal experiment for analgesia

Example 9

The method comprises the steps of adopting an ICR strain female, weighing 19-21 g, feeding for 7 days, measuring the time of reactions such as foot licking, hoarseness, jumping and the like of the mouse by adopting a hot plate method, placing the mouse on an adjustable constant-temperature hot plate instrument, controlling the temperature to be 50 +/-2 ℃, recording the time(s) from the placement of the mouse on the hot plate to the occurrence of the foot licking as the pain threshold value of the mouse, repeatedly measuring each mouse for 3 times, carrying out half hour interval between the two measurements, taking the average value of the 3 measurement results to represent the pre-drug pain threshold value of the mouse, and discarding the mouse with the jumping frequency exceeding 3 times when the pain threshold value exceeds 30s and is calculated according to 30 s. The pain threshold was determined 2 times in duplicate and the average of the two pain thresholds was taken as the pain threshold before administration to the mice.

Selecting 60 mice with pain threshold values meeting experimental requirements, randomly dividing the mice into 5 groups, wherein each group comprises 10 mice, namely a control group, an observation group 1, an observation group 2 and a blank group, shaving the backs of the mice, smearing related experimental preparations on shaving areas, not smearing the control group, and smearing blank matrixes, wherein each blank matrix is 50 mg; the other groups were coated with the relevant experimental formulations at 50 mg/area of shaved back, wherein the formulation of observation group 1 was obtained in example 4, the formulation of observation group 2 was obtained in example 5, and the comparative groups were coated with the corresponding formulations of each group, respectively, and were replaced once daily for 7 days of continuous administration. And (3) measuring the time for the mouse to lick the foot according to the hot plate method, putting the mouse into a hot plate instrument until the time for the mouse to lick the foot appears, and stopping the test when the time for the mouse to lick the foot does not reach 60s, wherein the time is counted according to 60 s. Statistical software is adopted to compare pain thresholds before and after administration of the rats in each group, t test is adopted for comparison between groups, and P <0.05 is regarded as significant difference.

The results of the measurement of the latent phase of the heat-shrinkable feet before and after administration for each group of rats are shown in the following table:

TABLE 1 comparison of pain threshold in mice before and after dosing

Note: wherein P-value before and after administration: p <0.05, x: p < 0.01;

p value # after dosing compared to control group: p <0.05, # #: p < 0.01;

the results show that the pain threshold values of the control group and the blank group before and after administration are not obviously different, the pain threshold values of the observation group 1 and the observation group 2 after administration are obviously improved relative to the pain threshold values before administration, and the pain threshold values of the control group and the blank group after administration are not obviously different, which indicates that the blank matrix used by the invention has no influence on the pain threshold values of the mice, the pain threshold values of the observation group 1 and the observation group 2 after administration are obviously improved relative to the pain threshold values of the control group after administration, and the pain threshold values of the observation group 1 and the observation group 2 after administration are not obviously different, which indicates that the transdermal absorbent has the pain relieving effect, and can achieve better pain relieving effect under the dosage. The pain threshold value before administration of the comparative examples 1-4 groups is not significantly different from that of the observation groups 1-2, the pain threshold value after administration is obviously lower than that of the observation groups 1-2, and the pain threshold value after administration of the comparative example 1 lacking the cortex dictamni and the comparative example 2 lacking the semen strychni is obviously lower than that of the examples 1-2, so that the cortex dictamni and the semen strychni are main components with the pain relieving effect of the formula, the pain relieving effect of the examples 1-2 is obviously higher than that of the comparative example groups, and the components in the 4 medicinal materials play a synergistic effect on the pain relieving effect and the combined use is obviously better than that of the components used singly or used by default.

Joint deformity animal experiment

Example 10

The total number of SD rats at 4 weeks of age is 70, half of the male and female rats, and the average body weight is 130 +/-20 g. SD rats were randomly divided into a model group (30), an administration group (30) and a control group (10) on the basis of similar body weights, and were allowed to freely ingest and drink water.

Dissolving type II natural collagen in 0.1mol/L acetic acid solution to obtain 4mg/mL solution, and placing in a refrigerator at 4 deg.C overnight. On the day of experiment, volume volumes of Freund's complete adjuvant and collagen II are fully shaken and emulsified on ice to prepare CII emulsion.

The rat needing to be molded is firstly injected with a microinjector at the back of the CIA molded rat for multiple points of subcutaneous injection, the injection amount is 0.2mL of CII emulsion, the same dose of immunogen is used for reinforcing immunization once at the same part after the first stimulation for 7 days, and the paw swelling degree of the two hind paws of the rat is regularly observed and measured.

And (3) observing physical signs: the weight of the SD rat is 1 time before the primary immunization, then the weight of the SD rat is 1 time per week, the ingestion condition, the hair color change and the foot swelling degree of the SD rat are observed and recorded, and the foot swelling degree of the SD rat is measured by a drainage method at the 3 rd week. Assessment by Arthritis Index (AI): no swelling was scored as 0 point, 1 to 2 interphalangeal joint affected points were scored as 1 point, mild swelling of joints and toes was scored as2 points, total swelling of toes and ankle joints was scored as 3 points, and severe arthritis of the whole paw was scored as 4 points. The highest 4 points of each limb are counted, the highest 16 points are counted, and the modeling is successful when the total integration exceeds 6 points.

The specific administration method for each group of animals is as follows: the control group is given 50 mg/blank matrix and smeared on the back of a normal mouse for 1 time per day; the model group is given 50 mg/blank matrix and smeared on the back of a model mouse, and 1 time per day; administration group 50 mg/mouse of the preparation obtained in example 3 was applied to the back of model mice 1 time a day; the administration period is 2 months, and the model rats are observed every day, including the changes of the life habits, the mental states, the swelling degrees of joints and the like of the rats.

Compared with model rats, rheumatoid arthritis model rats treated by the preparation obtained in example 4 have obviously improved symptoms such as lameness, slow movement and the like, and have gradually improved dietary state, mental state and the like, and the joint swelling degree is also obviously reduced, which shows that the preparation can improve the joint swelling and deformation conditions.

Clinical trial

Example 11

All the cases were rheumatoid arthritis patients. The results of 63 male patients and 93 female patients were divided into 4 groups, namely, experimental group 1 (administration in example 4), experimental group 2 (administration in example 5), comparative group (administration in comparative example 5) and conventional treatment group (conventional administration), and the results showed that the 4 groups of patients had no significant difference in sex, age, course of disease, syndrome score of Chinese medicine treatment, laboratory index and the like, and the data were comparable, and the treatment period was 8 weeks in all treatment groups.

Standard of care

Referring to the American college of rheumatology rheumatoid arthritis diagnostic standard, namely: morning stiffness lasting more than 1 hour (6 weeks or more); splenomegaly with 3 or more joints (over 6 weeks); these joints include bilateral proximal interphalangeal joints, metacarpophalangeal joints, wrist joints, knee joints, manic joints, and the pubic joints; swollen wrist, palm or proximal interphalangeal joints (over 6 weeks); swelling of joint symmetry (over 6 weeks); rheumatoid Factor (RF) positive (titers greater than 1: 32); subcutaneous rheumatoid nodules; the posterior anterior X-ray film of the hand and wrist can cause bone erosion or obvious osteoporosis; and the rheumatoid arthritis can be diagnosed by one or more of the seven strips.

Referring to the relevant standards of rheumatism immune system diseases in the guidance principle of clinical research of new traditional Chinese medicines in the year: pregnant or lactating women; severely malformed joints, disabled, lost labor; overlap with other rheumatism etc.; patients with serious primary diseases such as cardiovascular diseases, liver diseases, kidney diseases, hemopoietic systems and the like and psychonoses;

after the treatment scheme of the research is adopted, the immunosuppressant, hormone, non-steroidal anti-inflammatory analgesic and the like which are taken before the treatment are taken continuously, and the medicines influencing the curative effect and safety evaluation are not added.

The treatment is carried out according to the above method, the treatment period of all treatment groups is 8 weeks, each clinical index and physicochemical index of the patients are checked every two weeks, and the clinical efficacy is evaluated according to EULAR efficacy standard DAS 28.

(1) The clinical indexes are as follows: comprises morning stiffness time, joint tenderness number, joint swelling number, self-total evaluation before treatment, and examination record after each 2 weeks

(2) Physical and chemical inspection: the Weishi method, before and after treatment, are recorded once;

TABLE 2 comparison of ESR (mm/h) before and after treatment of patients

TABLE 3 CRP (mg/L) comparison of patients before and after treatment

TABLE 4 morning stiffness time comparison before and after patient treatment

TABLE 5 comparison of joint tenderness before and after treatment

TABLE 6 comparison of swelling of joints before and after treatment of patients

TABLE 7 patient before and after treatment self-assessment values (VAS, 10cm)

Table 8 patient DAS28 score pre-and post-treatment comparisons

Note: DAS28 ═ 0.56 × sqrt (TJC28) +0.28 × sqrt (SJC28) +0.70 × InESR +0.14 × GH. Wherein: TJC28 refers to the number of painful joints in a particular 28 joints, SJC28 refers to the number of swollen joints in a particular 28 joints, ESR is the blood sedimentation, and GH refers to the self-ensemble assessment (VAS, 10cm) for evaluation. The 28 joints include: the total number of proximal interphalangeal joints of each hand is 10, the total number of metacarpophalangeal joints of each hand is 10, the total number of wrist joints is 2, the total number of elbow joints is 2, the total number of shoulder joints is 2, the total number of knee joints is 2, and the total number of 28 joints.

The results show that the experimental group before administration has no significant difference from the conventional treatment group, when the administration is carried out for 1-2 weeks, the administration group of the embodiment, namely the experimental group 1-2 can take effect quickly, and can still maintain a good effect after the administration for 4 weeks, the conventional treatment group and the experimental group after the administration for 2 weeks are improved relative to all indexes before the treatment, the experimental group is slightly superior to the conventional treatment group, the comparative group is equivalent to the conventional treatment group, the conventional treatment group and the experimental group after the treatment for 4 weeks are obviously improved relative to all indexes before the treatment, when the treatment is carried out for 8 weeks, all indexes before the conventional treatment group and the experimental group are obviously improved, and the treatment effect of the experimental group is superior to that of the comparative group and the conventional treatment group. The indexes of 3 groups of patients have no significant difference before treatment, the treatment effect of an experimental group is superior to that of a comparative group and a conventional treatment group at 8 weeks after treatment, and the comparative group and the conventional treatment group have no significant difference, so that the transdermal absorbent disclosed by the invention has the curative effects of rheumatoid arthritis and analgesia.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.

Claims

1. A noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components is characterized in that the transdermal absorbent contains active components of cortex dictamni, earthworm, nux vomica and datura flower extract; the mass ratio of the cortex dictamni, the earthworm, the nux vomica and the datura flower is as follows: 2:1: 1:0.5, the main components are dictamnine, strychnine and henbane.

2. A preparation method of a noninvasive dermal penetration technology transdermal absorbent containing traditional Chinese medicine effective components is characterized by comprising the following steps:

feeding cortex Dictamni Radicis, semen Strychni, and flos Daturae Metelis at a ratio of 2:1:0.5, pulverizing, extracting with 8 times of 50-95% ethanol solution for 1-3 times (each for 1-2 hr), collecting ethanol extractive solution, and concentrating until there is no alcohol smell;

adding Lumbricus according to the proportion of 1, extracting with 8 times of acid water, adding certain amount of anhydrous ethanol to adjust to 80% ethanol content, precipitating with ethanol, centrifuging, and collecting precipitate;

mixing the samples obtained in the steps (1) and (2), dissolving the mixture by using methanol, loading the mixture by adopting a wet method, passing the mixture through a silica gel column, and reacting the mixture by using methanol: eluting with water =2:3 ratio, eluting with 6bv, collecting eluent, concentrating, and freeze-drying to obtain freeze-dried powder for later use;

dissolving the freeze-dried powder in 1.5 times of isopropyl myristate, heating at 40 deg.C until both are completely melted to form eutectic mixture, mixing with polyoxyethylene hydrogenated castor oil and glycerol (2:1), vortex mixing, simultaneously dripping appropriate amount of 40 deg.C warm water, and standing until the solution turns from turbid to clear and transparent.

3. The percutaneous absorption agent for noninvasive dermal penetration technology containing Chinese medicinal effective ingredients according to claim 1, wherein the preparation method comprises the following step (4): dissolving the freeze-dried powder in PBS (pH 5.0), weighing appropriate amount of lecithin and cholesterol, dissolving with appropriate amount of chloroform-ether (1: 1) mixed solution, adding PBS (pH 5.0) prepared from the freeze-dried powder, performing ultrasonic treatment to obtain uniform emulsion, adding buffer salt solution, performing ultrasonic treatment to obtain W/O/W multiple emulsion, performing rotary evaporation to remove organic solvent, adding a small amount of PBS for hydration, standing, and cooling to obtain liposome.

4. The transdermal absorbent for noninvasive dermal penetration technology containing herbal ingredients as claimed in claim 3, wherein the ratio of lecithin to cholesterol in step (4) of the preparation method is 2: 1.

5. The transdermal absorbent for noninvasive dermal penetration technology containing herbal ingredients as claimed in claim 3, wherein the pH of PBS in step (4) of the preparation method is 4.5.

6. The transdermal absorbent for noninvasive dermal penetration technology containing herbal ingredients as claimed in claim 3, wherein the pH of the acidic water in step (2) is 5-6.

7. The transdermal absorbent for noninvasive dermal penetration technology containing herbal ingredients as claimed in claim 3, wherein the isopropyl myristate in step (4) is selected from azone, oleic acid, and limonene.

8. Use of a transdermal absorption agent according to any of claims 1 to 2 for the treatment of rheumatoid arthritis.