CN111643542A

CN111643542A - External application preparation for treating hydrarthrosis and preparation method thereof

Info

Publication number: CN111643542A
Application number: CN202010723450.9A
Authority: CN
Inventors: 刘国英
Original assignee: Beijing Gulou Research Institute Of Difficult Diseases Co ltd
Current assignee: Beijing Gulou Research Institute Of Difficult Diseases Co ltd
Priority date: 2020-07-24
Filing date: 2020-07-24
Publication date: 2020-09-11

Abstract

The invention relates to the technical field of traditional Chinese medicine external application preparations, in particular to an external application preparation for treating hydrarthrosis and a preparation method thereof, wherein the external application preparation for treating hydrarthrosis comprises active ingredients and auxiliary materials, and the active ingredients are prepared from the following medicines in parts by weight: 9-12 parts of roasted astragalus membranaceus, 3-15 parts of radix bupleuri, 6-15 parts of rhizoma drynariae, 6-15 parts of garden balsam stem, 6-15 parts of poria cocos, 10-20 parts of caulis spatholobi, 10-20 parts of radix achyranthis bidentatae, 1-5 parts of safflower carthamus, 3-12 parts of notopterygium root, 3-12 parts of ligusticum wallichii, 3-12 parts of angelica sinensis, 10-18 parts of eucommia ulmoides, 10-18 parts of codonopsis pilosula, 3-9 parts of mirabilite, 1-3 parts of borneol and 0.1-0.8 part of menthol. The external application preparation provided by the invention can relieve arthralgia and eliminate hydrops through mutual compatibility of medicines, has a remarkable curative effect on treating gonarthritis and the like, avoids the damage influence on organs such as intestines, stomachs, livers and the like caused by oral administration, and has small toxic and side effects.

Description

External application preparation for treating hydrarthrosis and preparation method thereof

Technical Field

The invention relates to the technical field of traditional Chinese medicine external application preparations, in particular to an external application preparation for treating hydrarthrosis and a preparation method thereof.

Background

Knee osteoarthritis refers to chronic and degenerative joint diseases caused by degeneration and hyperosteogeny of knee cartilage. Statistics have shown that 80% of people over the age of 50 have proliferative changes in the knee joint, and about 90% of people over the age of 60 have proliferative changes in the knee joint. Joint effusion is characterized in that when a joint is diseased or has certain systemic diseases, factors such as osteophyte and detached cartilage fragments stimulate to induce synovial inflammatory change, promote synovial hyperplasia and exudation, form joint effusion and secrete media directly or indirectly causing cartilage degradation into joint fluid, and the joint effusion further enables chondrocytes immersed in the joint effusion to swell, necrose and fall off, aggravate primary diseases and form vicious circle.

At present, NSAIDS medicines are commonly adopted to diminish inflammation and relieve pain in the prevention and treatment of knee osteoarthritis and secondary joint effusion thereof in clinical practice, or chondroitin sulfate and glucosamine are adopted to protect articular cartilage medicines, or joint puncture liquid drawing is performed, or transparent sodium hyaluronate, glucocorticoid and the like are injected into joints to improve synovial secretion, however, clinical practice shows that the NSAIDS medicines taken for a long time can cause adverse reactions such as gastrointestinal tract and the like; joint puncture injection belongs to invasive treatment, and repeated injection can increase the probability of joint infection.

In addition, the external application preparation in the prior art has short action time on affected parts and low drug effect.

Disclosure of Invention

The invention aims to overcome the problems in the prior art, and provides an external preparation for treating hydrarthrosis and a preparation method thereof.

In order to achieve the purpose, the invention provides an external application preparation for treating hydrarthrosis, which consists of an active ingredient and auxiliary materials, wherein the active ingredient is prepared from the following medicines in parts by weight:

9-12 parts of roasted astragalus membranaceus, 3-15 parts of radix bupleuri, 6-15 parts of rhizoma drynariae, 6-15 parts of garden balsam stem, 6-15 parts of poria cocos, 10-20 parts of caulis spatholobi, 10-20 parts of radix achyranthis bidentatae, 1-5 parts of safflower carthamus, 3-12 parts of notopterygium root, 3-12 parts of ligusticum wallichii, 3-12 parts of angelica sinensis, 10-18 parts of eucommia ulmoides, 10-18 parts of codonopsis pilosula, 3-9 parts of mirabilite, 1-3 parts of borneol and 0.1-0.8 part of menthol.

The external application preparation provided by the invention is applied to the affected part to implement the drug effect, has the effects of promoting diuresis and excreting dampness, promoting blood circulation and removing blood stasis, dredging channels and collaterals, removing dampness and dredging arthralgia, tonifying kidney and strengthening tendons by mutual compatibility of the medicines, can diminish inflammation, relieve pain, promote blood circulation and remove blood stasis, open orifices and penetrate bones and promote local blood circulation when being applied to the affected part, thereby relieving arthralgia, eliminating hydrops, having remarkable curative effect on treating gonarthritis and the like, avoiding the injury influence on organs such as intestines, stomach, liver and kidney and the like caused by oral administration, and having small toxic and side effects.

Preferably, the active ingredients are prepared from the following medicines in parts by weight:

10 parts of radix astragali preparata, 12 parts of radix bupleuri, 9 parts of rhizoma drynariae, 9 parts of garden balsam stem, 9 parts of poria cocos, 15 parts of caulis spatholobi, 15 parts of radix achyranthis bidentatae, 3 parts of safflower, 8 parts of notopterygium root, 8 parts of ligusticum wallichii, 8 parts of angelica sinensis, 12 parts of eucommia ulmoides, 12 parts of codonopsis pilosula, 6 parts of mirabilite, 2 parts of borneol and 0.2 part of menthol.

In order to prolong the drug effect, the auxiliary materials preferably comprise: 50-80 parts of polyethylene glycol, 10-20 parts of glycerol, 5-8 parts of vegetable oil, 3-15 parts of a filler and 8-30 parts of modified chitosan.

The polyethylene glycol in the auxiliary materials is mixed with the glycerol to form a gelatinous medicine at a lesion part, and the gelatinous medicine can cover the lesion part for a long time and treat the lesion part; in addition, the polyethylene glycol can also slowly release the active ingredients, so that discomfort caused by overhigh drug concentration of a lesion part during initial dropping of the nasal drops can be avoided, and the drug can be released for a long time to achieve the effect of long-acting treatment.

In order to further improve the sustained release effect of the drug and prolong the drug effect, the polyethylene glycol is preferably selected from at least one of PEG200, PEG400, PEG800 and PEG2000, and more preferably, the polyethylene glycol consists of PEG400 and PEG2000 in a weight ratio of 1: 0.3-0.8.

In order to further improve the slow release effect of the medicament and prolong the medicament effect, the filling agent is at least one selected from methylcellulose, sodium carboxymethylcellulose, sodium alginate, agar, Arabic gum, xanthan gum, pectin and bentonite.

In order to promote drug absorption, it is preferable that the vegetable oil is at least one selected from the group consisting of tea oil, olive oil, cottonseed oil, and castor oil.

The invention also provides a method for preparing the external application preparation, which comprises the following steps:

(1) cleaning radix astragali Preparata, bupleuri radix, rhizoma Drynariae, caulis et folium Gaultheriae Yunnanensis, Poria, caulis Spatholobi, Achyranthis radix, Carthami flos, Notopterygii rhizoma, rhizoma Ligustici Chuanxiong, radix Angelicae sinensis, Eucommiae cortex, and radix Codonopsis, grinding into Chinese medicinal powder, soaking the Chinese medicinal powder in 2-3 times volume of water at 40-60 deg.C for 1-2 hr, decocting at 100-120 deg.C for 0.5-2 hr, and cooling to obtain Chinese medicinal composition;

(2) stirring and dissolving chitosan and acid anhydride in ethyl acetate, then adjusting the pH value of the system to 4-5, then carrying out ultrasonic dispersion treatment for 1-2h at the temperature of 40-50 ℃, wherein the ultrasonic frequency is 22-30KHz, adding elementary iodine into the solution, heating to 120-130 ℃, and carrying out reflux reaction for 3-5h to obtain an intermediate;

uniformly dispersing the intermediate, alkyl glycoside and silane coupling agent in ethanol, and then performing ultrasonic dispersion for 2-3h at the temperature of 100-150 ℃ in an inert gas atmosphere to obtain modified chitosan;

(3) mixing the modified chitosan and the Chinese medicinal composition, adding Natrii sulfas, Borneolum Syntheticum and menthol, mixing, and adding polyethylene glycol, glycerol, vegetable oil, filler and modified chitosan to obtain topical preparation for treating hydrarthrosis.

The long-chain branch of the chitosan and the molecular chain of the alkyl glycoside are mutually crosslinked, so that the effective components in the medicament can be locked in the molecular chain to achieve the effect of slowly releasing the medicament, and the action time of the medicament is prolonged. By modifying chitosan, hydrophilic groups and hydrophobic groups are introduced on chitosan molecules, so that molecular bonds can be fully formed with various active ingredients in the traditional Chinese medicine compound, active ingredients are adsorbed as much as possible, and the medicine is slowly released in the later use process, thereby prolonging the action time of the medicine. In addition, the alkyl glycoside in the molecular chain can promote the absorption of the medicine, thereby improving the medicine effect.

Preferably, the acid anhydride is at least one selected from maleic anhydride and acetic anhydride.

Preferably, the alkyl glycoside is at least one selected from the group consisting of C8-C16 alkyl glycosides.

Through the technical scheme, the invention has the following technical effects:

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

Example 1

An external preparation for treating hydrarthrosis comprises active ingredients and auxiliary materials, wherein the active ingredients are prepared from the following medicines in parts by weight:

100g of radix astragali preparata, 120g of radix bupleuri, 90g of rhizoma drynariae, 90g of garden balsam stem, 90g of tuckahoe, 150g of suberect spatholobus stem, 150g of achyranthes root, 30g of safflower, 80g of notopterygium root, 80g of szechuan lovage rhizome, 80g of Chinese angelica, 120g of eucommia bark, 120g of codonopsis pilosula, 60g of mirabilite, 20g of borneol and 0.20g of menthol.

The auxiliary materials comprise: PEG 400400 g, PEG 2000200 g, glycerol 150g, olive oil 60g, Arabic gum 120g and modified chitosan 200 g.

The preparation method of the external application preparation comprises the following steps:

(1) cleaning radix astragali Preparata, bupleuri radix, rhizoma Drynariae, caulis et folium Gaultheriae Yunnanensis, Poria, caulis Spatholobi, Achyranthis radix, Carthami flos, Notopterygii rhizoma, rhizoma Ligustici Chuanxiong, radix Angelicae sinensis, Eucommiae cortex and radix Codonopsis, grinding into Chinese medicinal powder, soaking the Chinese medicinal powder in 2-3 times volume of water at 50 deg.C for 1.5 hr, decocting at 120 deg.C for 1 hr, and cooling to obtain Chinese medicinal composition;

(2) stirring and dissolving chitosan and acid anhydride in ethyl acetate, then adjusting the pH value of a system to 4-5, then performing ultrasonic dispersion treatment for 1.5h at 45 ℃, wherein the ultrasonic frequency is 25KHz, adding elemental iodine into the solution, heating to 125 ℃, and performing reflux reaction for 4h to obtain an intermediate;

uniformly dispersing the intermediate, alkyl glycoside and silane coupling agent in ethanol, then performing ultrasonic dispersion for 2.5h at 120 ℃ in an inert gas atmosphere at the ultrasonic frequency of 25KHz, removing the solvent from the solution, adding 300mL of distilled water into the concentrate, placing the concentrate into a dialysis bag, and performing dialysis to remove impurities to obtain modified chitosan;

(3) mixing the modified chitosan and the Chinese medicinal composition uniformly, adding Natrii sulfas, Borneolum Syntheticum and menthol, mixing uniformly, adding polyethylene glycol, glycerol, oleum Olivarum, acacia and modified chitosan, and obtaining the external application preparation for treating hydrarthrosis.

Example 2

90g of radix astragali Preparata, 30g of radix bupleuri, 150g of rhizoma drynariae, 150g of garden balsam stem, 150g of tuckahoe, 200g of caulis spatholobi, 200g of radix achyranthis bidentatae, 50g of safflower, 120g of notopterygium root, 120g of ligusticum wallichii, 120g of angelica, 100g of eucommia bark, 100g of radix codonopsitis, 30g of mirabilite, 10g of borneol and 0.10g of menthol.

The auxiliary materials comprise: PEG 400450 g, PEG 2000350 g, glycerol 100g, olive oil 50g, sodium carboxymethylcellulose 150g and modified chitosan 80 g.

(1) cleaning radix astragali Preparata, bupleuri radix, rhizoma Drynariae, caulis et folium Gaultheriae Yunnanensis, Poria, caulis Spatholobi, Achyranthis radix, Carthami flos, Notopterygii rhizoma, rhizoma Ligustici Chuanxiong, radix Angelicae sinensis, Eucommiae cortex and radix Codonopsis, grinding into Chinese medicinal powder, soaking the Chinese medicinal powder in 2-3 times volume of water at 60 deg.C for 1 hr, decocting at 120 deg.C for 0.5 hr, and cooling to obtain Chinese medicinal composition;

(2) stirring and dissolving chitosan and acid anhydride in ethyl acetate, then adjusting the pH value of a system to 4-5, then performing ultrasonic dispersion treatment for 2 hours at 50 ℃, wherein the ultrasonic frequency is 22-30KHz, adding elementary iodine into the solution, heating to 130 ℃, and performing reflux reaction for 3 hours to obtain an intermediate;

uniformly dispersing the intermediate, alkyl glycoside and silane coupling agent in ethanol, then performing ultrasonic dispersion for 2 hours at 100 ℃ in an inert gas atmosphere, wherein the ultrasonic frequency is 25KHz, removing the solvent from the solution, adding 300mL of distilled water into the concentrate, placing the concentrate into a dialysis bag, and performing dialysis to remove impurities to obtain modified chitosan;

(3) mixing the modified chitosan and the Chinese medicinal composition uniformly, adding Natrii sulfas, Borneolum Syntheticum and menthol, mixing uniformly, adding polyethylene glycol, glycerol, olive oil, sodium carboxymethylcellulose and modified chitosan, and obtaining the external application preparation for treating hydrarthrosis.

Example 3

120g of radix astragali preparata, 150g of radix bupleuri, 60g of rhizoma drynariae, 60g of garden balsam stem, 150g of tuckahoe, 100g of suberect spatholobus stem, 100g of achyranthes root, 10g of safflower, 30g of notopterygium root, 30g of szechuan lovage rhizome, 30g of Chinese angelica, 180g of eucommia bark, 180g of codonopsis pilosula, 90g of mirabilite, 30g of borneol and 0.80g of menthol.

The auxiliary materials comprise: PEG 400380 g, PEG 2000120 g, glycerin 200g, tea oil 80g, sodium carboxymethylcellulose 30g and modified chitosan-300 g.

(1) cleaning radix astragali Preparata, bupleuri radix, rhizoma Drynariae, caulis et folium Gaultheriae Yunnanensis, Poria, caulis Spatholobi, Achyranthis radix, Carthami flos, Notopterygii rhizoma, rhizoma Ligustici Chuanxiong, radix Angelicae sinensis, Eucommiae cortex and radix Codonopsis, grinding into Chinese medicinal powder, soaking the Chinese medicinal powder in 2-3 times volume of water at 40 deg.C for 2 hr, decocting at 100 deg.C for 2 hr, and cooling to obtain Chinese medicinal composition;

(2) stirring and dissolving chitosan and acid anhydride in ethyl acetate, then adjusting the pH value of a system to 4-5, then performing ultrasonic dispersion treatment for 1h at 40 ℃, wherein the ultrasonic frequency is 22-30KHz, adding elementary iodine into the solution, heating to 120 ℃, and performing reflux reaction for 5h to obtain an intermediate;

uniformly dispersing the intermediate, alkyl glycoside and silane coupling agent in ethanol, then performing ultrasonic dispersion for 3 hours at 150 ℃ in an inert gas atmosphere, wherein the ultrasonic frequency is 25KHz, removing the solvent from the solution, adding 300mL of distilled water into the concentrate, placing the concentrate into a dialysis bag, and performing dialysis to remove impurities to obtain modified chitosan;

(3) mixing the modified chitosan and the Chinese medicinal composition uniformly, adding Natrii sulfas, Borneolum Syntheticum and menthol, mixing uniformly, adding polyethylene glycol, glycerol, tea oil, sodium carboxymethylcellulose and modified chitosan, and obtaining the external application preparation for treating hydrarthrosis.

Example 4

The process of example 1 was followed except that: polyethylene glycol is not included.

Example 5

The process of example 1 was followed except that: does not contain vegetable oil.

Comparative example 1

The process of example 1 was followed except that: the chitosan was not modified.

(2) mixing chitosan and Chinese medicinal composition, adding Natrii sulfas, Borneolum Syntheticum, and menthol, mixing, adding polyethylene glycol, glycerol, oleum Olivarum, acacia, and modified chitosan, and making into topical preparation for treating hydrarthrosis.

Comparative example 2

The process of example 1 was followed except that: the chitosan is not modified by acid anhydride.

(2) uniformly dispersing chitosan, alkyl glycoside and silane coupling agent in ethanol, then performing ultrasonic dispersion for 2.5h at 120 ℃ in an inert gas atmosphere, wherein the ultrasonic frequency is 25KHz, removing the solvent from the solution, adding 300mL of distilled water into the concentrate, placing the concentrate into a dialysis bag, and performing dialysis to remove impurities to obtain modified chitosan;

Comparative example 3

The process of example 1 was followed except that: the chitosan is not modified with alkyl glycoside.

(2) stirring and dissolving chitosan and acid anhydride in ethyl acetate, then adjusting the pH value of a system to 4-5, then performing ultrasonic dispersion treatment for 1.5h at 45 ℃, wherein the ultrasonic frequency is 25KHz, adding elementary iodine into the solution, heating to 125 ℃, and performing reflux reaction for 4h to obtain modified chitosan;

Test examples

Action of external application preparation on hydrarthrosis of rats

(1) 3-month-old SPF-grade SD rats, female, 200 rats, and a weight range of 280-320g (Beijing Wittiulihua laboratory animal technology Co., Ltd.) were selected. The animals are raised in cages and freely eat and drink water, the room temperature of the animal room is controlled to be 25 +/-2 ℃, the relative humidity is controlled to be 35-50%, and the animals can freely eat and drink water. Three days after adaptive feeding, the divided dosing was started.

(2) The rats were randomly divided into 10 groups: blank group, control group, and medicine group, each group contains 20. Animals were acclimatized for one week.

Rats in a control group and rats in a drug group are respectively anesthetized by 3% pentobarbital sodium intraperitoneal injection, knee joints on both sides are preserved, the rats are disinfected by 75% alcohol conventionally, 2% sodium iodoacetate 0.05mL is sequentially injected into the knee joints, the opposite side bulge of a joint capsule is taken as an injection standard, gouty arthritis is induced, obvious effusion and fiber exudation of a large amount of inflammatory cell infiltration mainly comprising neutrophil granulocytes appear after sodium iodoacetate is injected into the joint cavity, the tissues are seriously edematous, and the synovial membrane and surrounding tissues also have a large amount of inflammatory cell infiltration. At 4h after model induction, each group of drugs or physiological saline is injected with 0.05 mL.

The blank rats are anesthetized by 3% sodium pentobarbital intraperitoneal injection, the knee joints on both sides are preserved, the rats are disinfected by conventional 75% alcohol, and the knee joints are sequentially injected with 0.05mL of physiological saline.

(3) The external preparations of examples 1 to 5 and comparative examples 1 to 3 were applied to the affected parts of rats of experimental groups, respectively, at a thickness of 2mm 2 times a day;

control rats were not coated with any drug;

(4) swelling degree of joints: the thickness of the right ankle joint of rats before and after the inflammatory disease, 1d, 7d and 30d, respectively, was measured by a vernier caliper, and the difference between before and after the inflammatory disease divided by the thickness before the inflammatory disease x 100% was used as the swelling degree of the gouty arthritis, and the experimental results are shown in table 1;

② the influence on IL-1 beta in the rat joint and peripheral soft tissue: and (3) after 30d of inflammation, killing the animal, taking the synovial membrane of the joint and surrounding soft tissues, weighing the synovial membrane and the surrounding soft tissues, preparing homogenate in an ice bath, adding normal saline for dilution according to the proportion of 1: 20, centrifuging for 5min at 4000r/min, taking supernate, subpackaging in Ep tubes, storing in a refrigerator at the temperature of-80 ℃, and carrying out IL-1 beta quantitative detection according to the specification of a double-antibody sandwich ELISA kit, wherein the experimental results are shown in Table 1.

TABLE 1

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims

1. The externally applied preparation for treating hydrarthrosis is characterized by comprising active ingredients and auxiliary materials, wherein the active ingredients are prepared from the following medicines in parts by weight:

2. The external preparation according to claim 1, wherein the active ingredient is prepared from the following drugs in parts by weight:

3. The formulation for external application according to claim 1, wherein the adjuvant comprises: 50-80 parts of polyethylene glycol, 10-20 parts of glycerol, 5-8 parts of vegetable oil, 3-15 parts of a filler and 8-30 parts of modified chitosan.

4. The formulation for external application according to claim 3, wherein the polyethylene glycol is at least one selected from the group consisting of PEG200, PEG400, PEG800 and PEG 2000.

5. The external preparation according to claim 4, wherein the polyethylene glycol consists of PEG400 and PEG2000 in a weight ratio of 1: 0.3-0.8.

6. The formulation for external application according to claim 3, wherein the filler is selected from at least one of methylcellulose, sodium carboxymethylcellulose, sodium alginate, agar, gum arabic, xanthan gum, pectin, bentonite; and/or

The vegetable oil is at least one selected from tea oil, olive oil, cottonseed oil and castor oil.

7. A process for preparing the formulation for external application of any one of claims 1 to 6, comprising the steps of:

8. The process of claim 7, wherein the anhydride is selected from at least one of maleic anhydride and acetic anhydride.

9. The method according to claim 7, wherein the alkyl glycoside is at least one member selected from the group consisting of C8-C16 alkyl glycosides.