CN111686152A

CN111686152A - External composition and gel for treating lymphedema and preparation method thereof

Info

Publication number: CN111686152A
Application number: CN202010670409.XA
Authority: CN
Inventors: 陈勇
Original assignee: Beijing Underproved Medical Technology Co ltd
Current assignee: Beijing Underproved Medical Technology Co ltd
Priority date: 2020-07-13
Filing date: 2020-07-13
Publication date: 2020-09-22

Abstract

The invention relates to the technical field of external preparations for lymphedema, in particular to an external composition and a gel for treating lymphedema and a preparation method thereof. The external composition provided by the invention comprises a rhubarb extract, a polyporus extract, a folium artemisiae argyi extract, a saffron extract, panax notoginseng saponins, bisabolol, glycyrrhetinic acid and menthol. The composition has synergistic effect of all components, and has excellent effects of inducing diuresis to alleviate edema, promoting blood circulation to arrest pain, resisting inflammation and inhibiting bacteria, preventing skin tissue infection, and promoting skin wound healing. The gel provided by the invention comprises the external composition, the multifunctional transdermal absorption enhancer and the matrix auxiliary material, wherein the multifunctional transdermal absorption enhancer can effectively promote the transdermal absorption and the effective utilization of active ingredients in the external composition, can play a role in assisting in treating lymphedema, is complementary with the external composition, and improves the treatment effect of the lymphedema. The gel has simple application method and low cost, and can be carried about and used at any time.

Description

External composition and gel for treating lymphedema and preparation method thereof

Technical Field

The invention relates to the technical field of external preparations for lymphedema, in particular to an external composition for treating lymphedema, a gel containing the external composition and a preparation method thereof.

Background

Lymphedema is a disease caused by lymphatic circulation disorder and continuous accumulation of interstitial fluid rich in protein, and often occurs in the lower leg, upper arm, genitals, face and the like, and may be accompanied by stump. Lymph, as interstitial fluid within the intercellular spaces, flows back into the veins, mainly through the lymphatic vessels. Congenital dysplasia of lymphatic system and certain reasons generate occlusion and damage, the reflux of distal lymph of the lymphatic system is obstructed, and the reflux of interstitial lymph fluid of tissues is abnormally increased. Lymph fluid under the assistance of compensatory mechanisms can drain, and the compensatory mechanisms comprise other stored lymphatic vessels, smooth branches and the like, but once an impairment-compensatory mechanism appears, the lymph fluid can compensate or increase a lymph load factor through drainage, and is very easy to generate lymphedema.

The lymphedema is clinically classified into primary lymphedema and secondary lymphedema, wherein the primary lymphedema is mainly caused by hereditary diseases, and the secondary lymphedema is mainly caused by tumor radiotherapy and chemotherapy, surgical trauma, infection, lymphatic vessel blockage and other causes. The primary lymphedema is mainly caused by pathological changes of dermal reticular layers and subcutaneous tissues, more lymph fluid exists in interstitial spaces of the tissues, and collagen fibers at the part of dermal papilla are in transparent degeneration. Lymphocyte infiltration with different degrees is generated around blood vessels, inflammatory cell infiltration exists in the early stage of secondary lymphedema, and tissue fibrosis in the later stage is achieved. At present, clinically, the mammary cancer-related lymphedema is particularly common, and according to literature reports, the postoperative lymphedema of mammary cancer reaches the morbidity of 25-50%. The lymphedema after the breast cancer operation is mainly caused by postoperative tumor lymphatic metastasis, upper arm lymphatic reflux blockage and large amount of protein-rich lymph fluid accumulated in the interstitial space of tissues.

Currently, lymphedema is clinically divided into three stages, namely early stage, middle stage and late stage. Lymphedema is different in the early, middle and late stages of the disease course, but is related to each other and continues before and after. The early lesion of the lymphedema has soft skin, and can present obvious concave indentation when being pressed by fingers, and the swelling can disappear or be reduced after the affected part is lifted or the patient is in bed for rest. Fibrous connective tissue hyperplasia occurs to subcutaneous tissue after a long-term illness, limbs become thick, swollen and hard, skin thickens, elasticity disappears, depressed pits are not obvious when finger pressure is performed, and swelling cannot be reduced when the affected part is rested or lifted.

As a disease in which the lymphatic circulation of a patient is disturbed due to various complex causes, the cure rate of lymphedema is low at present, and there is no established treatment. The current clinical treatments include surgical, pharmaceutical and physical treatments.

The surgical treatment comprises lymph-lymph anastomosis, lymph-vein anastomosis, omentum majus transplantation and the most widely applied Charles surgical modes, and a plurality of similar surgical modes are derived according to the principle, the surgical treatment is concentrated on patients with late lymphedema, particularly patients losing mobility due to lymphedema, the risk of secondary trauma of the surgical treatment is high, and the risks of infection and scarring are easily increased.

Diuretic drugs (including western drugs and traditional Chinese medicine diuretics) are mainly used for drug therapy, and although the drugs can achieve the effect of detumescence in a short time, adverse reactions such as hypotension and electrolyte disorder may be caused if patients take the drugs for a long time, for example: diosmin tablets often cause varying degrees of gastrointestinal reactions; intravenous drip of beta-aescine sodium or interferon is easy to cause phlebitis, rash and the like.

Therefore, the current physiotherapy is most commonly used in early lymphedema, and the early lymphedema penetrates through the development process of the whole disease, mainly achieves the traction effect of the capillary lymph vessel wall by massaging, pressing and other modes through instruments, so that tissue fluid enters into a lymph vessel cavity, the local infection is effectively eliminated, and the edema is relieved. For example: in the Manual Lymphatic Drainage (MLD), a professional massage physical therapist needs to apply a gentle massage pressure to the affected limb by hand, so as to reduce the volume of the affected limb, but the improvement of subjective symptoms or limb functions is not obvious. The periodic intermittent air wave pressure therapeutic instrument is sequentially inflated and deflated through multi-cavity equipment to simulate manual massage, so that the dependence on a massager is avoided, and the detumescence effect is expected to be achieved. Physical heat energy such as microwave, infrared ray, far infrared ray and the like is utilized to expand blood vessels, promote stasis proteolysis and delay fibrosis, and mainly comprises microwave or far infrared baking and binding therapy and low-level laser therapy (LLLT). Composite therapeutic treatment (CDT) including fine and personalized skin care (clinical skin care), MLD, compression therapy (compression therapy) and exercise (exercises) is the most effective physical therapy combination scheme at present, has a good effect on patients with early or mild symptoms and a certain curative effect on patients with late tumors, but has a complex process and high price.

The traditional Chinese medicine has certain effect on treating the lymphedema, is mainly used for treating the lymphedema by utilizing certain medicines for inducing diuresis to alleviate edema, promoting blood circulation and removing obstruction in channels, and is mainly orally taken in a drug administration mode. For example: patent CN201410241168.1 (a traditional Chinese medicine for treating upper limb lymphedema after breast cancer operation and a preparation method thereof), CN201510554500.4 (a traditional Chinese medicine composition for efficiently treating elephantiasis after breast cancer operation and a preparation method thereof), CN201410736112.3 (a traditional Chinese medicine for treating upper limb lymphedema after breast cancer operation) and the like are all prepared by using a plurality of traditional Chinese medicines, and are orally taken, however, oral administration not only increases the burden of intestines and stomach of patients, but also easily causes systemic adverse reactions, and is easy to generate toxicity after long-term administration, patent CN201510002446.2 (a traditional Chinese medicine fumigation and washing agent for treating upper limb lymphedema after breast cancer operation and a nursing method) discloses a traditional Chinese medicine lotion, namely, after being decocted, the lotion is used for washing affected parts of lymphedema, and soaked, patent CN201510022660.4 (a traditional Chinese medicine external application agent for treating upper limb lymphedema after breast cancer operation and a nursing method) discloses a method for mixing the traditional Chinese medicine with water, the preparation process of the medicine is long, the use is inconvenient, and the medicine takes effect slowly, the medicine effect is not lasting, and the appearance is influenced.

Disclosure of Invention

An object of the present invention is to provide a composition for external use for treating lymphedema; another object of the present invention is to provide a gel containing the composition for external use and a method for preparing the same.

In order to achieve the purpose, the invention carries out long-term and intensive research on the occurrence and development of lymphedema and the action mode and mechanism of an external preparation in the lymphedema occurrence and development process, and in the research process, the invention discovers that a plurality of traditional Chinese medicine components with better oral administration effect can not play better effect when being used externally, and even if some traditional Chinese medicine components are used with larger dosage or are used together with a plurality of components, the ideal effect of relieving lymphedema when being used externally is difficult to achieve. Through a large number of researches, the invention obtains the composition which is externally used for treating lymphedema and has excellent treatment effect.

The invention firstly provides an external composition for treating lymphedema, which comprises the following components in percentage by mass (1-25): 1, further comprises one or more selected from folium artemisiae argyi extract, saffron extract and panax notoginseng saponins, and one or more selected from bisabolol, glycyrrhetinic acid and menthol.

The rhubarb extract is the extract of dried roots and rhizomes of rhubarb palmate L, rhubarb officinal Baill and Tanggute rhubarb, and has the efficacies of clearing heat and purging fire, cooling blood and detoxifying, removing stasis and dredging channels, promoting diuresis and removing jaundice for external use, and is used for swelling and carbuncle, furuncle, traumatic injury, damp-heat dysentery, dark urine, stranguria, edema, burn and scald, and the like.

Polyporus umbellatus extract is derived from sclerotium of Polyporus umbellatus (Pers.) Fries of Polyporaceae, has effects of promoting diuresis and eliminating dampness, and can be used for treating dysuresia, edema, diarrhea, stranguria with turbid urine, leukorrhagia, etc.

The invention surprisingly discovers that the compatibility mode of the traditional Chinese medicine composition is different from that of an orally-administrated traditional Chinese medicine composition, when the traditional Chinese medicine composition is externally used for lymphedema, the rheum officinale extract and the polyporus umbellatus extract are used in a compatible mode according to the proportion, the efficacies of the rheum officinale extract and the polyporus umbellatus extract can be mutually promoted, the synergistic effect is exerted, and the excellent effect of inducing diuresis to alleviate edema is generated.

The invention further carries out the intensive research on the active ingredients in the grifola extract and the rhubarb extract. The grifola in the Chinese medicine pharmacopoeia uses ergosterol as a quality marker, but in fact, the ergosterol has almost no biological activity and has no obvious effect on lymphedema. The invention discovers that ergosta-4, 6, 8(14), 22-tetraene-3-ketone in the grifola extract can be synergistically acted with anthraquinone substances in rheum officinale, and the external application has better effect of inducing diuresis and reducing edema. Therefore, the grifola extract of the present invention uses ergosta-4, 6, 8(14), 22-tetraen-3-one as a quality control marker. The content of the grifola extract is controlled to be 0.10% or more, and the content of the total anthraquinone in the rhubarb extract is controlled to be 80% or more, so that the grifola extract and the rhubarb extract can fully play a synergistic effect, and the effect of inducing diuresis to alleviate edema is obviously improved.

In the above composition, it is preferable that the ergosta-4, 6, 8(14), 22-tetraen-3-one content of the polyporus umbellatus extract is not less than 0.10%, and the total anthraquinone content of the rhubarb extract is not less than 80%.

The rhubarb extract and the grifola extract of the present invention can be obtained commercially or prepared by conventional extraction methods in the art.

Preferably, the rhubarb extract and the grifola extract are alcohol extracts, and are preferably obtained by ethanol extraction. The rhubarb extract used in the invention can be prepared by the following method: crushing rhubarb, performing reflux extraction for 2-5 times by using 60-90% ethanol, performing reflux extraction for 0.5-2 hours each time, filtering, combining filtrates, performing reduced pressure concentration, adding an alkali solution to adjust the pH to be strong alkaline, filtering, adding an acid to adjust the pH to be 2-4, standing for 6-16 hours, performing suction filtration, precipitating to obtain a solid, and drying.

The grifola extract can be prepared by the following method: crushing the polyporus umbellatus, performing reflux extraction for 2-5 times by using 60-90% ethanol for 0.5-2 hours each time, filtering, combining filtrates, performing reduced pressure concentration, performing extraction for 2-5 times by using petroleum ether, combining extract liquor, performing reduced pressure concentration, and drying.

In the prior art, the idea of the prescription for treating edema is to use single medicines with the effects of inducing diuresis and reducing edema in a compatible way, however, the invention discovers that the effect of inducing diuresis and reducing edema of the compound prepared by compounding the rhubarb extract and the polyporus umbellatus extract and the single medicine or the compound (especially the folium artemisiae argyi extract, the saffron extract and the panax notoginseng saponins) with the effects of promoting blood circulation and relieving pain can be obviously improved, edema can be effectively relieved, pain can be relieved, and the excellent effect of relieving lymphedema can be realized.

The blood circulation-promoting and pain-relieving component compounded on the basis of the rhubarb extract and the polyporus umbellatus extract preferably comprises a folium artemisiae argyi extract, wherein the mass ratio of the folium artemisiae argyi extract to the rhubarb extract is (1-3): 1.

the folium Artemisiae Argyi extract has effects of warming channels, stopping bleeding, dispelling cold, relieving pain, eliminating dampness, and relieving itching. The invention discovers that the folium artemisiae argyi extract and the rheum officinale extract can act synergistically to produce better effects of inducing diuresis and reducing edema.

Preferably, the folium artemisiae argyi extract contains not less than 10% of eucalyptol and not less than 50% of total flavonoids. By controlling the content of eucalyptol and total flavonoids in the folium artemisiae argyi extract, the folium artemisiae argyi extract can be better matched with other components (especially rhubarb extract) in the composition, and the effect of inducing diuresis to alleviate edema of the composition is improved.

The stigma croci Sativi extract has effects of promoting blood circulation, removing blood stasis, cooling blood, removing toxic substance, resolving stagnation, and tranquilizing.

The Notoginseng radix total saponin has effects of stopping bleeding, removing blood stasis, relieving swelling and relieving pain, and can be used for treating traumatic hemorrhage, swelling and pain. The invention discovers that the panax notoginseng saponins directly added into the composition for external use on lymphedema, which contains the rhubarb extract and the polyporus umbellatus extract, have better effect, and the panax notoginseng saponins with high content of the panax notoginseng saponins can not achieve the treatment effect of adding the panax notoginseng saponins even if the same adding amount of the panax notoginseng saponins is achieved.

The folium artemisiae argyi extract, the saffron extract and the panax notoginseng saponins are compounded (the blood circulation promoting and pain relieving active composition), so that a better blood circulation promoting and pain relieving effect can be obtained, and meanwhile, the folium artemisiae argyi extract, the saffron extract and the polyporus umbellatus extract can interact to generate an excellent lymphedema treatment effect.

In the active monomer components introduced by the invention, the menthol has cool and pleasant mint characteristic fragrance, acts on skin or mucous membrane, has the effects of cooling and relieving itching, and has the effects of sterilization and antisepsis. Menthol also has the function of promoting the transdermal absorption of the medicine. The bisabolol has obvious anti-inflammatory, antibacterial and antispasmodic effects, and can reduce skin inflammation, relieve skin acne, prevent acne generation, resist allergy, and improve skin anti-irritation capability; meanwhile, the skin repairing agent has a repairing effect and can repair skin with inflammation injury; and also to increase SPF values in sunscreen products. The bisabolol has good stability and skin compatibility, can protect and care allergic skin, and has the function of increasing skin penetrability of effective components. The glycyrrhetinic acid has the effects of resisting bacteria, diminishing inflammation, resisting oxidation, resisting aging, absorbing ultraviolet rays, whitening and brightening skin, removing freckles and the like; can regulate skin immunity, enhance skin disease resistance, eliminate inflammation, prevent allergy, clean skin, and prevent melanin precipitation. Moreover, glycyrrhetinic acid has obvious diuretic effect and can eliminate edema.

The external composition provided by the invention can comprise the following components in parts by weight: 3-8 parts of rhubarb extract, 0.3-3 parts of grifola extract, 3-7 parts of folium artemisiae argyi extract, 0.3-3 parts of saffron extract, 0.2-3 parts of panax notoginseng saponins and 0.1-1 part of bisabolol. Or, the composition comprises the following components in parts by weight: 3-8 parts of rhubarb extract, 0.3-3 parts of grifola extract, 3-7 parts of folium artemisiae argyi extract, 0.3-3 parts of saffron extract, 0.2-3 parts of panax notoginseng saponins, 0.1-0.5 part of glycyrrhetinic acid and 0.5-1 part of menthol. Or, the composition comprises the following components in parts by weight: 3-8 parts of rhubarb extract, 0.3-3 parts of grifola extract, 3-7 parts of folium artemisiae argyi extract, 0.3-3 parts of saffron extract, 0.2-3 parts of panax notoginseng saponins, 0.1-1 part of bisabolol and 0.5-1 part of menthol.

The invention creatively discovers that the bisabolol, the glycyrrhetinic acid and the menthol are simultaneously introduced into the formula, the components in the formula can perform synergistic action, the high-efficiency diuresis inducing and swelling reducing effects are exerted, meanwhile, the transdermal absorbability of active ingredients is improved, and the excellent lymphedema treatment effect can be realized.

Preferably, the composition comprises the following components in parts by weight: 3-8 parts of rhubarb extract, 0.3-3 parts of grifola extract, 3-7 parts of folium artemisiae argyi extract, 0.3-3 parts of saffron extract, 0.2-3 parts of panax notoginseng saponins, 0.1-0.5 part of bisabolol, 0.1-0.5 part of glycyrrhetinic acid and 0.5-1 part of menthol. The components in the formula have synergistic effect, have no mutual inhibition and opposite effect, and have excellent effects of inducing diuresis to alleviate edema, promoting blood circulation and relieving pain when being externally used for lymphedema.

In the above composition, crocin-I (C) is contained in stigma croci Sativi extract₄₄H₆₄O₂₄) And crocin-II (C)₃₈H₅₄O₁₉) The total amount of the components is not less than 60 percent.

The folium artemisiae argyi extract and the saffron extract can be obtained by commercial purchase or preparation by adopting a conventional extraction method in the field.

For example: the folium Artemisiae Argyi extract can be CO₂Extracting with supercritical fluid, and extracting with ethanol as cosolvent; the stigma croci Sativi extract can be obtained by defatting with petroleum ether under reflux, and extracting with ethanol under reflux.

Specifically, the folium artemisiae argyi extract can be prepared by the following method: CO treatment with ethanol as cosolvent₂Supercritical fluid extraction, CO₂The flow rate of the extraction liquid is 30-60L/h, the extraction pressure is 20-30 MPa, the extraction temperature is 35-45 ℃, the separation temperature is 45-55 ℃, and the separation pressure is 4-8 MPa.

The saffron extract is prepared by the following method: defatting stigma croci with petroleum ether under reflux, filtering, and drying. Extracting with 60-70% ethanol under reflux for 2-5 times, mixing filtrates, concentrating under reduced pressure, purifying with macroporous adsorbent resin, concentrating, and drying.

The invention further provides application of the external composition in preparing a preparation for treating lymphedema.

The invention provides a preparation for treating lymphedema, which comprises the external composition.

The invention also provides a gel for treating lymphedema, which comprises the external composition.

Specifically, the gel comprises the following components: 10-30 parts of an external composition, 10-40 parts of a multifunctional transdermal absorption enhancer and 30-80 parts of a matrix auxiliary material.

The multifunctional transdermal absorption enhancer preferably comprises the following components in parts by weight: 0.01-0.2 part of ginger essential oil, 0.01-0.2 part of tea tree essential oil, 5-10 parts of glycerol, 5-7 parts of propylene glycol, 5-10 parts of butanediol, 0.3-1 part of 1, 2-hexanediol and 1-5 parts of ethanol.

The formula of the multifunctional transdermal absorption enhancer is specially developed aiming at the components of the external composition and the transdermal absorption characteristics of the external composition, and can better act with the external composition, effectively promote the skin absorption of the effective components of the external composition, and better play the role of treating lymphedema by external application. In addition, different from the common transdermal absorption enhancer, the multifunctional transdermal absorption enhancer disclosed by the invention not only has the effect of promoting the transdermal absorption of the active ingredients of the medicine, but also has the functions of resisting bacteria, diminishing inflammation, reducing swelling, relieving pain, promoting wound healing, keeping skin moist, preventing the chapping and inhibiting the formation of wrinkles aiming at skin chapping and opening easily generated by a lymphedema patient. The tea tree essential oil has the effects of sterilizing, diminishing inflammation, relieving swelling and pain and astringing pores, can treat suppurative wounds, burns, sunburn and other skin problems, and has the effects of refreshing brain, recovering vitality, resisting depression and the like. The ginger essential oil has effects of eliminating blood stasis, treating wound, improving body moisture, eliminating phlegm, relieving fever, reducing weight, promoting blood circulation, warming body, promoting perspiration, and relieving edema. The compounding of the tea tree essential oil and the ginger essential oil can promote skin microcirculation, sterilize and relieve pain, not only has the effect of promoting the transdermal absorption of effective components in the external composition, but also has the effect of assisting the external composition in treating lymphedema.

The matrix auxiliary material preferably comprises the following components in parts by weight: 0.2-2 parts of gel matrix, 2-5 parts of isononyl isononanoate, 2-3 parts of glyceryl polyether-261 and 2-2 parts of PE90100.5, and alkaline auxiliary materials are used for adjusting the pH of the gel matrix to be neutral and quantitative.

Preferably, the gel matrix is one or more selected from carbomer, poloxamer, sodium carboxymethyl cellulose and hydroxyethyl cellulose; the alkaline auxiliary material is one or more selected from sodium hydroxide and triethanolamine.

More preferably, the matrix auxiliary material comprises the following components in parts by weight: 2-5 parts of isononyl isononanoate, 261-3 parts of glycerol polyether, 0.3-1 part of carbomer, 90100.5-2 parts of PE, 0-1 part of triethanolamine, 0-1 part of sodium carboxymethylcellulose, 0-1 part of hydroxyethyl cellulose, 0-1 part of sodium hydroxide and 30-75 parts of water.

The invention also provides a preparation method of the gel, which comprises the following steps:

(1) respectively dissolving the gel matrix in the matrix auxiliary materials in water, adding an alkaline auxiliary material to adjust the pH to be neutral, and then mixing to obtain a solution A;

(2) uniformly mixing all components in the multifunctional transdermal absorption enhancer to obtain a solution B;

(3) respectively dissolving radix et rhizoma Rhei extract, folium Artemisiae Argyi extract, Polyporus extract, stigma croci Sativi extract and Notoginseng radix total saponin in water, and mixing to obtain solution C;

(4) dissolving bisabolol, glycyrrhetinic acid and menthol in the solution B, adding matrix adjuvants except the gel matrix, and mixing to obtain solution D;

(5) adding B, C and D into A, mixing well, adding the rest water, mixing well.

The invention also provides application of the gel in treating lymphedema.

The invention has the beneficial effects that:

(1) the components in the external composition provided by the invention have synergistic effect, and have excellent effects of inducing diuresis to alleviate edema, promoting blood circulation to arrest pain, resisting inflammation and inhibiting bacteria, preventing skin tissue infection and promoting skin wound healing.

(2) In the external gel provided by the invention, the multifunctional transdermal absorption enhancer can effectively promote the transdermal absorption and the effective utilization of active ingredients in the external composition, can play a role in assisting in treating lymphedema, is complementary with the external composition, and improves the curative effect. The external gel has the advantages of quick absorption, quick response, obvious effect and lasting drug effect, can relieve edema, prevent skin tissue infection, relieve pain and promote skin trauma healing, can also preserve moisture, moisten skin and prevent skin and subcutaneous tissue hyperplasia and fibrosis complications, and can be used for treating various types of lymphedema caused by various causes; it can also be used for treating lymphedema in early, middle and late stages.

(3) The gel provided by the invention is an external preparation, can reduce the burden of gastrointestinal tract caused by oral administration, and can directly act on the focus part to take effect without causing systemic adverse reaction.

(4) The gel provided by the invention is simple in preparation method and use method, can exert the effect of treating lymphedema without the cooperation of professional massagers and instruments, and is low in price; the gel can be carried about by patients, and can be applied to the affected part at any time, with convenient application.

Drawings

FIG. 1 is a Q-t curve showing the cumulative amount of emodin released in Experimental example 3 of the present invention.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

The experimental procedures used in the following examples are conventional unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

In the following examples, the preparation method of each herbal extract is as follows:

the rhubarb extract is prepared by the following method: pulverizing radix et rhizoma Rhei, sieving with 20 mesh sieve, weighing sieved powder 100g, placing in 2L round bottom flask, adding 1.0L 75% ethanol, reflux extracting for 3 times, each for 1 hr, filtering, mixing filtrates, and concentrating under reduced pressure until no alcohol smell exists. Adding 10% NaOH solution while stirring, adjusting pH to 12, filtering, and removing insoluble substances. The filtrate was adjusted to pH 3 with hydrochloric acid and left overnight at 4 ℃. Filtering, precipitating to obtain yellow solid, and vacuum drying to obtain radix et rhizoma Rhei extract. Wherein, the content of the total anthraquinone in the rhubarb is 83.3 percent by taking the emodin as a standard substance.

The grifola extract is prepared by the following method: pulverizing Polyporus umbellatus, sieving with 20 mesh sieve, weighing sieved medicinal powder 100g, placing in 2L round bottom flask, adding 1.0L 75% ethanol, reflux extracting for 3 times, each for 1 hr, filtering, mixing filtrates, and concentrating under reduced pressure until no alcohol smell is produced. Adding water to the extract to about 50mL, adding petroleum ether of the same amount, extracting for 3 times, mixing extractive solutions, concentrating under reduced pressure, and drying to obtain Polyporus umbellatus extract. The content of ergosta-4, 6, 8(14), 22-tetraen-3-one in the extract is 0.12 percent by HPLC method.

The folium artemisiae argyi extract is prepared by the following method: CO 2₂Supercritical fluid extraction with extraction tank of 1L for 2h, particle size of 40 mesh, cosolvent of ethanol, medicinal material content of 100g, and CO₂The flow rate of the extraction is 50L/h, the extraction pressure is 25MPa, the extraction temperature is 40 ℃, the separation temperature is 50 ℃, and the separation pressure is 6 MPa. Detecting the content of eucalyptol by HPLC method, and detecting the content of total flavone by ultraviolet spectrophotometry (with rutin as standard). Wherein, the content of eucalyptol is 10.6 percent, and the content of total flavone is 51.9 percent.

The saffron extract is prepared by the following method: weighing 50g of saffron crocus, placing the saffron crocus in a round-bottom flask, carrying out reflux degreasing for 1h by using petroleum ether, filtering, and airing the medicinal materials. Reflux-extracting the dried materials with 65% ethanol solution for 3 times (1 hr for the first time, 0.5 hr for the second time and the third time), filtering, mixing filtrates, and concentrating under reduced pressure. Purifying the concentrate with D101 macroporous adsorbent resin, eluting with 70% ethanol, concentrating, and drying to obtain stigma croci Sativi extract. The total amount of crocin-I and crocin-II was 61.8% as determined by UV spectrophotometry using crocin-I as a standard.

Example 1

This example provides a composition for external use, which comprises the following components in parts by weight:

example 2

example 3

example 4

The embodiment provides an external gel, which consists of the following components in percentage by mass:

the embodiment also provides a preparation method of the gel, which comprises the following specific steps:

(1) weighing gel matrix carbomer in the matrix auxiliary materials, dissolving the gel matrix carbomer in water, and adjusting the pH value of the carbomer and triethanolamine to be neutral to obtain gel A;

(2) weighing the ginger essential oil, the tea tree essential oil, the glycerol, the propylene glycol, the butanediol, the 1,2 hexanediol and the ethanol according to the prescription amount, and uniformly mixing to obtain a solution B;

(3) weighing the rhubarb extract, the argyi leaf extract, the grifola extract, the saffron extract and the panax notoginseng saponins in the formula amount, respectively dissolving in water (a proper amount of solution B can be added for assisting dissolution), and then uniformly mixing to obtain a solution C;

(4) weighing bisabolol, glycyrrhetinic acid and menthol according to the prescription amount, dissolving in the solution B, adding isononyl isononanoate, glyceryl polyether-26 and PE9010 according to the prescription amount, and uniformly mixing to obtain a solution D;

(5) and (3) pouring B, C and D into A, mixing uniformly, adding the balance of water, and mixing uniformly to obtain the gel.

Example 5

(1) weighing gel matrix carbomer in the matrix auxiliary materials, dissolving the gel matrix carbomer in water, and adding triethanolamine to adjust the pH to be neutral to obtain a solution A;

(3) weighing radix et rhizoma Rhei extract, folium Artemisiae Argyi extract, Polyporus extract, stigma croci Sativi extract, and Notoginseng radix total saponin, and dissolving in water (optionally adding appropriate amount of solution B for dissolving) to obtain solution C;

Example 6

(1) weighing gel matrix carbomer, sodium carboxymethylcellulose and hydroxyethyl cellulose in the matrix auxiliary material composition, respectively dissolving in water, respectively adding NaOH to adjust pH to be neutral, and mixing to obtain solution A;

(3) weighing and dissolving the rhubarb extract, the argyi leaf extract, the grifola extract, the saffron extract and the panax notoginseng saponins in water (a proper amount of solution B can be added for assisting dissolution) according to the prescription amount to obtain solution C;

Comparative example 1

The comparative example provides an external gel which comprises the following components in percentage by mass:

the preparation method of the external gel comprises the following steps:

(1) weighing gel matrix carbomer in the matrix auxiliary materials, dissolving in water, adding triethanolamine to adjust pH to be neutral, and obtaining gel A;

(3) weighing the rhubarb extract and the grifola extract according to the prescription amount, respectively dissolving the rhubarb extract and the grifola extract in water (a proper amount of solution B can be added for assisting dissolution), and then uniformly mixing to obtain solution C;

Comparative example 2

the preparation method of the external gel comprises the following steps:

(3) weighing folium Artemisiae Argyi extract, stigma croci Sativi extract, and Notoginseng radix total saponin, respectively dissolving in water (optionally adding appropriate amount of solution B for helping dissolution), and mixing to obtain solution C;

Comparative example 3

the preparation method of the external gel comprises the following steps:

(3) weighing the rhubarb extract, the argyi leaf extract, the grifola extract, the saffron extract and the panax notoginseng saponins in the formula amount, respectively dissolving in water (a proper amount of solution B can be added for assisting dissolution), and then uniformly mixing; adding isononyl isononanoate, glyceryl polyether-26 and PE9010 in a prescribed amount, and uniformly mixing to obtain a solution C;

(4) and (3) pouring B, C into the solution A, mixing uniformly, adding the balance of water, and mixing uniformly to obtain the gel.

Comparative example 4

This comparative example provides an external gel, which is different from example 1 only in that the artemisia argyi extract is replaced with the ligusticum wallichii extract.

Comparative example 5

This comparative example provides an external gel which is different from example 1 only in that the rhubarb extract is replaced with the poria cocos extract.

Comparative example 6

the preparation method of the gel comprises the following steps:

(2) measuring the azone and the glycerol according to the prescription amount, and uniformly mixing to obtain a solution B;

Experimental example 1 clinical test of topical gel

Clinical experiments were conducted on the topical gel of example 4, as follows:

1. clinical data and methods

1.1 general data

Selecting 65 patients with affected limb lymphedema after breast cancer operation in outpatient clinics and institutions of residence of the mammary gland department, randomly dividing the patients into 32 treatment groups and 33 control groups, wherein the patients are female, the age of the treatment groups is 36-58 years, the average age is 46 +/-5.3 years, the age of the control groups is 35-57 years, the average age is 44 +/-6.1 years, the average lymph node metastasis number of the treatment groups is 3.6 +/-2.8, and the average lymph node metastasis number of the control groups is 3.2 +/-2.7; the mean course of disease was 32 + -22.5 days in the treatment group and 34 + -26.3 days in the control group. The general data of age, number of lymph node metastases and course of disease are similar in two groups, and the two groups are comparable. In 65 patients, the affected axillary lymph node cleaning operation was performed, wherein the treatment group was subjected to the breast cancer improvement radical operation of 19 cases and the breast protection operation of 8 cases, the control group was subjected to the breast cancer improvement radical operation of 20 cases and the breast protection operation of 7 cases, the treatment group was subjected to the radiotherapy of 22 cases and the control group was subjected to the radiotherapy of 24 cases; in the treatment group, the affected limb matched with the daily dominant limb for 14 cases, and the control group matched with 16 cases; the two groups of patients have comparability in aspects of operation type, postoperative radiotherapy, daily dominant limbs and the like (p is more than 0.05).

Before treatment, the edema degree of the patient is graded, mild edema is that the difference between the circumferences of the affected limb and the healthy limb is less than 3cm, and the edema range is only limited to the proximal end of the upper arm, the forearm or the palm part; moderate edema is that the difference between the circumferences of the affected limb and the healthy limb is 3-6cm, and the range of edema affects the whole upper limb, including the forearm and the back of the hand; severe edema is characterized by the difference between the circumference of the affected limb and the healthy limb of more than 6cm, hard and tough skin, and the edema affecting the whole upper limb including fingers, so that the movement of the whole upper arm and shoulder joint of the patient is severely limited. The difference in the degree of edema before treatment was not statistically significant in both groups (see Table 1), and the two groups were comparable (p > 0.05).

TABLE 1 comparison of edema levels before treatment in two groups of patients

Group/number of cases	Treatment group	Control group
			Mild edema	23	21
Moderate edema	7	9
			Severe edema	2	3

1.2 inclusion and exclusion criteria

1.2.1 inclusion criteria

(1) Patients with upper limb edema after surgical breast cancer surgery: complaints of discomfort such as swelling, soreness and heaviness of the affected limb are reported, and the swelling and thickening of the healthy side of the affected limb (0.2 cm) is measured; (2) the local dialectical syndrome belongs to a patient with yin swelling (swelling of affected limbs, pale and lusterless skin, depression due to soft and tough pressed skin, no red local skin color, low skin temperature and pain accompanying or not); (3) karnofsky score is greater than 60 points, and compliance is good.

1.2.2 exclusion criteria

(1) The affected limb is diagnosed as a patient with acute lymphangitis, and is accompanied with the symptoms of acute infection such as the rise of white blood cells; (2) patients with stage IV breast cancer with distant metastasis; (3) patients with serious organic disease, difficult follow-up and poor compliance with a score of less than 60 points; (4) the postoperative axillary tumor tissue residue or the postoperative tumor relapse, metastasis and compression cause the upper limb edema.

1.3 methods of investigation

1.3.1 methods of treatment

The gel of the invention in example 4 is applied to the affected limb 1 time in the morning, in the middle of the day and in the evening, and is used in combination with physical therapy. The physical therapy comprises the combination of lifting the affected limb, massage by manipulation, functional exercise, elastic oversleeve, limb pneumatic therapeutic apparatus, etc. The control group was treated with physical therapy alone in the same way as the treatment group, and the treatment time was 4 weeks for both groups.

1.3.2 Observation index

The circumference of the affected upper limb and the circumference of the healthy upper limb (measuring the arm circumference at 10cm positions above and below the olecranon by using a flexible rule) before and after treatment, subjective symptoms (mainly taking the degree of limb pain as a main observation index) before and after treatment, and the degree of subjective pain and the degree of edema are evaluated once every week for 4 times with four weeks as a treatment course.

1.3.3 evaluation of therapeutic Effect

Degree of improvement of edema of affected limb: the circumference of the affected limb after treatment is compared with the circumference of the affected limb before treatment, and effective index is calculated (if edema reaches the whole upper limb, the effective index of the upper arm and the effective index of the forearm are calculated respectively, and the average value is taken as the whole effective index). The effective index is more than 90 percent of the effective index is significant, the effective index is 10 to 90 percent of the effective index, and the effective index is less than 10 percent of the effective index and is ineffective. The effective index is (arm circumference of affected limb before treatment-arm circumference of affected limb after treatment)/(arm circumference of affected limb before treatment-arm circumference of healthy limb before treatment) x 100%.

Pain relief degree of affected limb: grading the pain degree of the affected limb before treatment, wherein the pain degree is no pain in grade 0; intermittent pain at level 1, no medication; grade 2, continuous pain, affecting rest, requiring pain-relieving herbs; grade 3 indicates persistent pain with changes in blood pressure and pulse. Pain relief after treatment was 1 grade or more, effective, and the time to complete pain relief was recorded; pain was not relieved or exacerbated and was not effective.

1.4 statistical methods

All data were processed with statistical software, sps 10.0. The baseline comparison counting data adopts t test, the metering data adopts chi fang test, the affected limb effective index group comparison adopts nonparametric rank sum test, the pain relieving degree group comparison adopts chi fang test, and the pain relieving time group comparison adopts t test.

2. Results

2.1 degree of edema improvement in affected limbs

After 1 treatment course (4 weeks), the treatment group has 29 cases of effectiveness, 3 cases of effectiveness and 0 case of ineffectiveness; the significant efficiency is 90.6 percent, and the total effective rate (significant efficiency and effective) is 100 percent; the control group shows that the effective rate is 18.8% and the total effective rate is 78.8% in the effective case 6, the effective case 20 and the ineffective case 7; the difference in total efficacy between the treatment and control groups was statistically significant (p < 0.05).

2.2 pain relief of affected limbs

Of the 65 patients with edema of the upper limbs, 39 were associated with pain discomfort of the affected limb, and the pain level was rated as grade 1, wherein 20 of the treatment groups with pain of the affected limb, 19 of the control group, and 2 of the groups before the treatment had comparable pain levels and numbers (p > 0.05). After 1 course of treatment, the limb pain of 39 patients can be completely relieved, and the effective rate is 100%. The average relieving time of the two groups is different, the average relieving time of the pain of the treatment group is 6.5 days, the average relieving time of the pain of the control group is 14.2 days, and the difference has statistical significance (p is less than 0.05), which indicates that the effect of the treatment group is obviously better than that of the control group in the aspect of relieving the pain.

The results of the tests of the external gels of examples 5 and 6, which were carried out in the same manner as described above, show that the external gels of examples 5 and 6 can achieve a therapeutic effect equivalent to that of example 4.

Experimental example 2 animal experiments with topical gels

1. Experimental methods

1.1 Experimental animals

70 New Zealand white rabbits have the weight of about 2.5kg (2.0-3.0 kg), and the male and female rabbits are not limited. The groups were randomly divided into 7 groups of 10 individuals. The right hind limb of the experimental rabbit was used as the experimental limb and the left hind limb as the control.

1.2 preparation of edema model

New Zealand white rabbits were anesthetized with 2.5% sodium pentobarbital at a dose of about 1ml/kg body weight, and the anesthetic dose was adjusted according to corneal reflex and the reaction of the rabbit limbs to exogenic hyperextension movements and the depth and amplitude of respiration. After the anesthesia was successful, the lower limb operating area (approximately 6cm area distal to the groin) was cut and further depilated with a depilatory. The skin of the dorsum toe web of the right lower limb is treated by the same method, and 0.5ml of 10% methylene blue injection is injected into the skin after disinfection. Sterilizing the operation area, spreading sterile hole towel, taking an annular incision at the position of about 1cm far away from the inguinal region, dissociating and cutting skin and subcutaneous tissues with the width of 3cm far away to reach muscles, scratching the wound surface with an operation knife to thoroughly remove model tissues, cleaning lymph nodes in the inguinal region, separating deep lymphatic vessels accompanying femoral blood vessels and nerves under an operation microscope, ligating two ends, and cutting the middle part by about 4 cm. The femoral blood vessel is covered by the nearby muscle, the incisal margins of the upper end and the lower end of the skin are turned inwards (vital) and sewed on the muscle, and the erythromycin ointment is coated outside and packed aseptically. Penicillin was administered in 80 million units per rabbit post-operatively as a bolus injection for 3 consecutive days. The wound surface is periodically given for dressing change to heal the scar.

Anesthetizing the animal after 3 days, fixing on a wooden fixing frame, extending right lower limb slightly, and using⁶⁰Co irradiation instrument, irradiation field is 4cm × 3cm, 2000c Gry dose is given once to irradiate operation field, and after breeding is continued for 4.5 months, the model is successfully made.

1.3 methods of treatment

The test rabbits were depilated from both legs and further depilated. The affected limb of the rabbit of the experimental group is evenly smeared with the external gel of the example 4 three times a day in the morning, in the middle and in the evening; uniformly coating the external gel of the comparative examples 1,2, 3, 4 and 5 on the rabbits of 5 comparison groups three times a day in the morning, in the middle and in the evening respectively; the control group was not treated. The treatment time is 4 weeks, the affected limb and the leg circumference of the control limb of each group of rabbits are measured every week, and the cure rate is calculated according to the following formula:

2. results of the experiment

TABLE 20-4 leg circumference data of experimental rabbits in each week

As can be seen from table 2, the cure rate of the external gel of example 4 reaches 75%, while the cure rates of comparative example 1 (no diuretic and repercussive active composition), comparative example 2 (no blood circulation-promoting and analgesic active composition), comparative example 3 (no monomer component composition), comparative example 4 (replacing the artemisia leaf extract with the ligusticum wallichii extract) and comparative example 5 (replacing the rhubarb extract with the poria cocos extract) are 20%, 25%, 23%, 36% and 31%, respectively, which indicates that the cure effect of the external gel of example 4 is far greater than that of comparative examples 1,2, 3, 4 and 5, and also indicates that the components of the external composition of the present invention have synergistic effect and the synergistic effect is obvious.

The same animal experiment as above was conducted to test the external gels of examples 5 and 6, and the results showed that the external gels of examples 5 and 6 could achieve a cure rate comparable to that of example 4.

Experimental example 3 in vitro skin permeability test experiment of external gel

The external gels of example 4 and comparative example 6 were subjected to an in vitro skin permeability test using a Franz transdermal diffusion apparatus.

1. Experimental methods

1.1 preparation of Ex vivo skin

Shaving off the hair on the abdomen of Kunming mouse, killing by cervical dislocation, rapidly cutting off the skin on the abdomen, carefully removing the subcutaneous mucosa and adipose tissue, repeatedly washing with normal saline until no turbidity exists, and storing in refrigerator at-20 deg.C for use.

1.2 transdermal absorption test method

The experiments were divided into two groups and the gels of example 4 (n-3) and comparative example 6 (n-3) were tested separately.

Taking the skin of a mouse stored at a low temperature, naturally thawing, washing with normal saline, fixing between a dosing chamber and a receiving chamber, adding 30% ethanol normal saline 8m L into the receiving chamber as a receiving solution, removing bubbles to ensure good contact between the receiving solution and the mouse skin, stirring at a speed of 200r/min, keeping the temperature of a water bath at (37 +/-1) DEG C for 30min, and pouring out the receiving solution; about 200mg of each of example 4 and comparative example 6 was applied to the skin surface, and 8m L of a new receiving solution was added, and after 2, 4, 6, 8, 10, 12, and 24 hours, the receiving solution 5m L was aspirated, and the same volume of receiving solution was added.

1.3 method for determining emodin in receiving liquid

1.3.1 control solution preparation emodin control 10.0mg was weighed accurately into a 10m L measuring flask, dissolved by adding methanol, diluted to the scale and shaken well; precisely sucking 5m L into a 50m L volume flask, adding methanol to a constant volume, and shaking up to obtain a mixed control solution containing 100 μ g/m L of emodin.

1.3.2 preparation of test solution the receiving solutions taken out of the experimental groups were combined into 1 part per 3 parts, evaporated to dryness in a water bath at 60 ℃, dissolved in methanol to a volume of 2m L, and filtered through a 0.22 μm microporous membrane to obtain the final product.

1.3.3 chromatographic conditions the column was an Xtimate C18 column (250mm x 4.6mm, 5 μm), mobile phase acetonitrile-0.1% phosphoric acid solution, gradient elution, elution procedure:

0-15 min, 15% -20% acetonitrile;

15-25 min, 20% -30% acetonitrile;

25-40 min, 30-50% acetonitrile;

40-41 min, 50% -70% acetonitrile;

41-51 min, 70% -80% acetonitrile;

51-60 min, 80% acetonitrile.

The volume flow rate is 1.0m L/min; the detection wavelength is 286 nm; the column temperature is 30 ℃; the amount of the sample was 10. mu.L.

1.3.4 Linear Range inspection

Precisely sucking emodin standard solution 0.125, 0.25, 0.5, 1,2, 4, 8m L, placing in a 20m L volume flask, adding methanol to dilute to scale, shaking, measuring according to chromatographic conditions, and drawing a standard curve with mass concentration (C) as abscissa and peak area (A) as ordinate. The results show that the standard curve equation of the emodin is A which is 17.3685C-0.9821 and r which is 0.9998; emodin 0.5-40 μ g/m L shows good linear relationship.

1.4 calculation method

The emodin cumulative permeation (Qn) is calculated as follows:

a is the effective diffusion area (3.46 cm)²)；

V is the total volume of the receiving solution;

C_nthe mass concentration of the drug in the receiving liquid at the nth sampling;

C_ithe mass concentration of the drug in the receiving liquid at the ith sampling;

V_iis the sample volume.

2. Results of the experiment

With emodinQn (μ g/cm)²) The percutaneous absorption Q-t curve was plotted against the sampling time t (h) (FIG. 1). As can be seen from FIG. 1, the release rate of emodin as the external gel of example 4 is much higher than that of comparative example 6, indicating that the penetration-promoting effect of the multifunctional transdermal absorption composition of the present invention is stronger than that of azone and glycerin used in comparative example 6; in addition, the azone in the comparative example 6 has stronger greasy feeling, and the external gel of the example 4 is more refreshing and has better use feeling.

The in vitro skin permeability test of the external gels of examples 5 and 6 was carried out in the same manner as described above, and the results showed that the external gels of examples 5 and 6 could achieve skin permeability comparable to that of example 4.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A topical composition for treating lymphedema is characterized by comprising the following components in percentage by mass (1-25): 1, further comprises one or more selected from folium artemisiae argyi extract, saffron extract and panax notoginseng saponins, and one or more selected from bisabolol, glycyrrhetinic acid and menthol.

2. The composition of claim 1, wherein said grifola extract has an ergosta-4, 6, 8(14), 22-tetraen-3-one content of not less than 0.10%; the content of total anthraquinone in the rhubarb extract is not less than 80%.

3. The composition according to claim 1 or 2, wherein the composition comprises rhubarb extract, polyporus umbellatus extract and folium artemisiae argyi extract and one or more of bisabolol, glycyrrhetinic acid and menthol, and the mass ratio of the folium artemisiae argyi extract to the rhubarb extract is (1-3): 1.

4. the composition according to any one of claims 1 to 3, wherein the folium artemisiae argyi extract contains eucalyptol not less than 10% and total flavonoids not less than 50%.

5. The composition as claimed in any one of claims 1 to 4, wherein the composition comprises the following components in parts by weight: 3-8 parts of rhubarb extract, 0.3-3 parts of grifola extract, 3-7 parts of folium artemisiae argyi extract, 0.3-3 parts of saffron extract, 0.2-3 parts of panax notoginseng saponins, 0.1-0.5 part of bisabolol, 0.1-0.5 part of glycyrrhetinic acid and 0.5-1 part of menthol.

6. The composition according to claim 5, characterized in that said saffron extract has a total content of crocin-I and crocin-II not lower than 60%.

7. Use of a composition according to any one of claims 1 to 6 in the preparation of a formulation for the treatment of lymphedema.

8. A gel for the treatment of lymphedema, comprising a composition according to any one of claims 1 to 6;

preferably, the gelling agent comprises the following components: 10-30 parts of the composition as claimed in any one of claims 1-6, 10-40 parts of multifunctional transdermal absorption enhancer and 30-80 parts of matrix auxiliary material;

more preferably, the multifunctional transdermal absorption enhancer comprises the following components in parts by weight: 0.01-0.2 part of ginger essential oil, 0.01-0.2 part of tea tree essential oil, 5-10 parts of glycerol, 5-7 parts of propylene glycol, 5-10 parts of butanediol, 0.3-1 part of 1, 2-hexanediol and 1-5 parts of ethanol.

9. The gel of claim 8, wherein the matrix adjuvant comprises the following components in parts by weight: 0.2-2 parts of gel matrix, 2-5 parts of isononyl isononanoate, 261-3 parts of glycerol polyether and 90100.5-2 parts of alkaline auxiliary materials for adjusting the pH of the gel matrix to be neutral and quantitative;

preferably, the gel matrix is one or more selected from carbomer, poloxamer, sodium carboxymethyl cellulose and hydroxyethyl cellulose; and/or the alkaline auxiliary material is selected from one or more of sodium hydroxide and triethanolamine;

10. A process for the preparation of the gel of claim 8 or 9, comprising the steps of:

(5) adding B, C and D into A, mixing well, adding the rest water, mixing well.