CN112516135A - Application of ixabelmycin in preparation of anti-arthritis medicine - Google Patents
Application of ixabelmycin in preparation of anti-arthritis medicine Download PDFInfo
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- CN112516135A CN112516135A CN202011383454.3A CN202011383454A CN112516135A CN 112516135 A CN112516135 A CN 112516135A CN 202011383454 A CN202011383454 A CN 202011383454A CN 112516135 A CN112516135 A CN 112516135A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses application of ixabelmycin in preparing an anti-arthritis medicament, wherein the content of the ixabelmycin is more than or equal to 0.1 mu M. The transdermal absorption preparation prepared by taking the ixomycin as the raw material has the characteristic of directly and obviously inhibiting the acute arthritis induced by the carrageenan, has good treatment effect, can effectively slow down the foot swelling of mice, and can be used for treating related diseases such as arthritis. In addition, the preparation can effectively inhibit the expression of inflammatory factors IL-1, IL-6 and TNF-alpha, reduce the content of the inflammatory factors in serum and reduce the occurrence of inflammation. The preparation can be directly applied to affected part, and has convenient application and high use value.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to application of ixabelmycin in preparation of an anti-arthritis medicament.
Background
Arthritis is a common chronic disease, the number of patients is large, the incidence rate can reach 13%, and 1 person can be suffered in every 10 persons on average. Arthritis is an inflammatory disease which occurs in the joints and surrounding tissues of the human body, is caused by inflammation, infection, degeneration, trauma or other factors, and can be divided into dozens of types, such as bone, rheumatoid, ankylosis, reactivity, gout, rheumatism, suppuration and the like. Arthritis has great harm, the disability rate can reach 53 percent, and the harmfulness is great. The severity of pain and dysfunction caused by arthritis can be equal to or even greater than that of cardiovascular and cerebrovascular diseases, and at present, stable, safe and effective anti-arthritis medicines do not exist, and the existing medicines for treating arthritis still have many problems, such as poor selectivity, gastrointestinal discomfort, renal failure and other side effects, so that the continuous research of safe and effective anti-arthritis medicines is urgent.
The ixomycin (Equisetin, yinhitin) is originally discovered in terrestrial fungi, and has a plurality of activities such as antibiosis, anti-AIDS and anticancer. By virtue of specific chemical structure and remarkable biological activity, Equisetin and analogues thereof have attracted extensive attention of chemical and medical researchers, and are mainly used as antibacterial agents for inhibiting gram-positive bacteria at present. However, no use of ixabepilin for other conditions or related aspects has been found.
Disclosure of Invention
The invention aims to provide the application of the ixabelmycin in preparing the medicament for treating the arthritis;
another object of the present invention is to provide a medicament for treating arthritis;
the invention also aims to provide the application of the medicine in preparing the anti-arthritis transdermal absorbent.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
the use of ixomycin in the preparation of a medicament for the treatment of arthritis.
The ixomycin (Equisetin, YINHUICHUANG, FE1) is a metabolite secreted by Fusarium (Fusarium equiseti), and has antibacterial effect.
The chemical structural formula of the ixomycin is shown as the formula (I):
the inventor finds that the ixomycin can effectively inhibit the expression of inflammatory factors IL-1, IL-6 and TNF-alpha in mouse serum, thereby relieving joint swelling caused by arthritis and inhibiting the further development of the arthritis.
Further, the content of the aforementioned ixomycin is 0.1. mu.M or more.
Further, the content of the aforementioned ixomycin is 0.1 to 4. mu.M.
The inventors found that 0.1. mu.M of ixomycin exerts an inflammatory inhibitory effect, whereas a significant inhibitory effect is obtained when the concentration is increased to 1. mu.M, and the effect is comparable to 5. mu.M of BAY.
Further, the arthritis includes non-erosive arthritis, degenerative arthritis, and metabolic arthritis.
Furthermore, the composition or the medicament can be used as an effective substitute of an anti-arthritis medicament such as glucocorticoid or methotrexate, and is used for treating arthritis with the same indication as that of the glucocorticoid or methotrexate serving as the anti-arthritis medicament.
In the present example, the above arthritis was exemplified by a carrageenan-induced mouse arthritis model. Carrageenan can enable mice to have a series of reactions similar to acute inflammation of human bodies, such as local capillary dilatation, increased vascular permeability, exudation, edema and the like, is a common arthritis induction model in the field, and is widely used in evaluation tests of novel drugs related to various inflammations.
Further, the formulation of the above anti-arthritis agent includes a solution, lotion, emulsion, powder, ointment or paste.
Furthermore, the dosage form of the anti-arthritis preparation is ointment.
The anti-arthritis preparation in the embodiment of the invention adopts a transdermal absorption preparation (ointment) for external use, and the preparation can exert the effect by being coated on the affected part, and of course, the skilled person can obtain other preparations by reasonably modifying inactive ingredients in the formula of the anti-arthritis preparation according to actual requirements.
In a second aspect of the present invention, there is provided:
a medicament, the medicament contains ixomycin, the content of the ixomycin is greater than or equal to 0.1 MuM.
Further, the content of the aforementioned ixomycin is 0.1 to 4. mu.M.
Furthermore, the medicine also contains other pharmaceutically acceptable auxiliary agents.
Still further, the above-mentioned other pharmaceutically acceptable adjuvants include paraffin, vaseline and propylene glycol.
Still further, the paraffin wax includes liquid paraffin wax.
Further, the paraffin is liquid paraffin.
Liquid paraffin, also referred to as mineral oil, is insoluble in water and ethanol, and soluble in volatile oil and most of the nonvolatile oils. The liquid paraffin can effectively promote the mixing of the composition with vaseline and propylene glycol so as to avoid the occurrence of uneven mixing.
Furthermore, the contents of the components in the medicine are as follows: 10-15mg of ixomycin, 1200mg of paraffin wax, 90-135mg of vaseline and 150mg of propylene glycol.
Furthermore, the contents of the components in the medicine are as follows: 10mg of ixomycin, 800mg of paraffin, 90mg of vaseline and 100mg of propylene glycol.
In a third aspect of the present invention, there is provided:
the preparation method of the medicine comprises the following steps:
mixing the ixomycin with the paraffin, and adding the vaseline and the propylene glycol to obtain the compound ixabepilone injection.
The ixomycin needs to be put into a mortar to be ground into uniform and fine paste, and then is mixed with the paraffin to accelerate the mixing process and improve the mixing uniformity.
Vaseline and propylene glycol need to be added into the ixomycin paraffin mixture in several times (mixed by an equivalent incremental method) to ensure uniform mixing.
In a fourth aspect of the present invention, there is provided:
the application of the above medicines in preparing transdermal absorbent for resisting arthritis is provided.
The invention has the beneficial effects that:
1. the composition, the medicine and the related preparation containing the ixomycin have the characteristic of directly and obviously inhibiting the acute arthritis induced by the carrageenan, have good treatment effect, can effectively relieve the foot swelling of mice, and can be used for treating the related diseases such as the arthritis.
2. The composition, the medicine and the related preparation containing the ixomycin can effectively inhibit the expression of inflammatory factors IL-1, IL-6 and TNF-alpha, reduce the content of the inflammatory factors in serum and reduce the occurrence of inflammation.
3. The composition, the medicine and the related preparation containing the ixomycin in the embodiment of the invention adopt an external preparation form, are directly applied to the affected part and are convenient to use.
Drawings
Fig. 1 is a graph of the effect of the transdermal formulation of ixomycin on RANKL induced NF- κ B, wherein P <0.05, P <0.01, P <0.001, n-3 compared to the RANKL group;
FIG. 2 is a graph showing the therapeutic effect of each experimental group on carrageenan-induced acute arthritis mice, in which FE1 represents the ixomycin group;
FIG. 3 is a statistical chart of the results of the therapeutic effect of carrageenan-induced acute arthritis mice for each experimental group, A is a statistical chart of the difference in foot thickness (mm) and B is a statistical chart of the difference in foot weight (g) for each experimental group;
FIG. 4 is a graph of the morphological change (fold: x200) of the paw tissue of carrageenan-induced acute arthritic mice for each experimental group, wherein FE1 represents the ixomycin group;
FIG. 5 shows the inhibitory effect of the transdermal absorption preparation of ixomycin on IL-1(A), IL-6(B) and TNF- α (C) which are inflammatory factors in the serum of mice.
Detailed Description
In order to make the objects, technical solutions and technical effects of the present invention more clear, the present invention will be described in further detail with reference to specific embodiments. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The experimental materials and reagents used are, unless otherwise specified, all consumables and reagents which are conventionally available from commercial sources.
Ifumycin drug effective dose testing
The effective dose of the ixabepilin is judged by the activation of NF-kB in the embodiment, and the principle is as follows:
when an inflammatory reaction occurs in an organism, a natural immune response is started, natural immune response cells can release inflammatory factors (such as interleukins IL-1, IL-6, IL-8, reactive oxygen species, cyclooxygenase-2, nitric oxide synthase, growth factors and the like), and the transcription of the cytokines depends on the activation of an NF-kappa B channel, so that whether the inflammatory reaction exists can be judged only by detecting whether the NF-kappa B channel is activated or not.
The method comprises the following specific steps:
the method is characterized in that a RAW264.7 cell strain stably transformed by NF-kB-luc is adopted, RANKL (nuclear factor kB receptor activating factor ligand) is adopted for stimulation, meanwhile, different concentrations of 0.1-4 mu M of ixomycin and a positive control drug (5 mu M BAY, CAS number is 1803274-65-8) are added, the effect of the drug on the transcription expression of NF-kB in cells is observed by detecting the expression of luciferase after 8 hours, and the result is shown in figure 1.
As a result, it was found that 0.1. mu.M of ixomycin exerts an effect of suppressing inflammation, and that a significant suppression effect is produced when the concentration is increased to 1. mu.M, and the effect is comparable to that of 5. mu.M BAY.
Wherein 1 μ M of ixomycin is about 0.373mg/mL of ixomycin.
Preparation of ixomycin transdermal absorption preparation
The formula of the ixabelmycin transdermal absorption preparation is as follows:
10mg of ixomycin, 800mg of liquid paraffin, 90mg of vaseline and 100mg of propylene glycol.
The preparation steps are as follows:
according to the formula content, the ixomycin and the liquid paraffin are put into a mortar for grinding, a small amount of the ixomycin and the liquid paraffin are ground for multiple times to form uniform and fine paste, then the vaseline and the propylene glycol are added for multiple times to full amount, and the mixture is ground uniformly to obtain the ixabepilone.
The ixomycin and the liquid paraffin are fully mixed firstly, so that the subsequent addition of the vaseline can be facilitated, and the uniform mixing can be ensured. The mixing should be done by equal incremental method to ensure uniform mixing.
Preparation of mouse model of carrageenan-induced acute arthritis
(1) Preparation of 1% carrageenan inducer
Taking an autoclaved small mortar, pouring the carrageenan into the small mortar, grinding with a small amount of sterile 0.9% physiological saline, and slowly adding the remaining physiological saline for a plurality of times.
It should be noted that the carrageenan inducer can be formulated 24 hours prior to the experiment and left overnight in a 4 degree freezer.
The carrageenan inducer is used by grinding.
(2) Carrageenan induced acute arthritis in mice
Female C57BL/6 mice, about 6 weeks in size, were placed in a clean animal room to acclimate for one week, and then randomly grouped into 6 mice (Blank group (Blank), Model group (Model), ixomycin group (FE1), and Positive group (Positive)) per group.
The blank group was not smeared with any substance;
the model group was coated with a solvent paste (no ixomycin);
applying 1% of the cutaneous permeable preparation of the ixabelmycin prepared in the above embodiment to the ixabelmycin group;
the positive medicine group is smeared with a butraline emulsion agent.
The corresponding substances were applied to the left and right hind limbs of mice simultaneously, 1 time every 10min, and 6 times consecutively, according to groups. After 30min of administration, the mice were inflamed by injecting 30 μ L of 1% carrageenan inducer subcutaneously into the right hind footpad of the foot. After 5h of injection, the eyeball is removed, blood is taken, the cervical vertebra is removed, the mouse is killed, then the thickness of the left and right toes of the mouse is measured, the feet of the mouse are symmetrically cut off from the ankle joint, the weight difference of the left and right feet is used as the evaluation of the foot swelling degree of the mouse. The left and right toes were then fixed with 10% formaldehyde for 72h, decalcified with 10% EDTA for 2 weeks, processed by routine sectioning, HE stained, and examined for histological changes under a microscope.
It should be noted that toe injection is the key for modeling of inflammation model, and after the mice are anesthetized with ether, the mice are stood on their stomach, and an insulin syringe is used to insert the needle from the distal end of the right hind limb of the mice, and the injection is performed along the midline of the foot by 2 mm. During the injection process, the extremely thin subcutaneous bulge can be seen, and the needle head needs to be rotated when the needle is withdrawn.
Blood samples obtained from mouse eyeballs are centrifuged, supernatant is obtained, and the expression of inflammation-related factors IL-1, IL-6 and TNF-alpha in serum is detected by an ELISA kit.
The results of the mice of each experimental group after being coated with the drug are shown in fig. 2, the mice of the model group have obvious acute joint swelling after being injected with carrageenan, the toe thickness and the left and right foot weight difference of the mice of the experimental group coated with the 1% ivermectin transdermal absorption preparation and the mice of the positive drug (natalin) control group are statistically different from those of the mice of the model group, and the effect of resisting the foot swelling of the mice coated with the 1% ivermectin is better than that of the natalin with the same dose. The inhibition effect of FE1 on the joint swelling is further verified by the thickness difference of the left and right toes of the mouse, the statistical result of the weight difference of the left and right toes and the HE staining result, and the statistics result is shown in figure 3.
In fig. 3, the difference in the left and right toe thicknesses and the difference in the left and right foot weights of the mice in the iximab group were significantly lower than those in the model group, indicating that the iximab could exert significant therapeutic effects. Moreover, as can be seen from the figure, the treatment effect of the ixomycin group is stronger than that of the positive drug group, which indicates that the ixomycin group has the potential of serving as a candidate component for treating acute arthritis.
FIG. 4 shows morphological changes of the paw tissue of the carrageenan-induced acute arthritis mouse in each experimental group, and it can be seen from the figure that the HE staining of the model group shows obvious inflammatory cell infiltration, while the infiltration of the positive drug group and the ixomycin group is obviously reduced compared with the model group.
The inhibition effect of the transdermal absorption preparation of the ixabepilin prepared in the above embodiment on the expression of the inflammatory factors IL-1, IL-6 and TNF-alpha in the serum of the mouse is shown in fig. 5, after the transdermal absorption preparation of the ixabepilin prepared in the above embodiment is coated, the inflammatory factors IL-1, IL-6 and TNF-alpha in the serum of the mouse are remarkably controlled compared with a model group, and the inhibition effect is equivalent to that of a positive drug (nataline).
In conclusion, the transdermal absorption preparation containing the ixomycin can obviously inhibit acute carrageenan-induced arthritis, relieve joint swelling and inhibit the expression of IL-1, IL-6 and TNF-alpha.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The use of ixomycin in the preparation of a medicament for the treatment of arthritis.
2. The use according to claim 1, wherein the content of ixomycin is 0.1 μ M or more; the content of the ixomycin is preferably 0.1-4 mu M.
3. The use of claim 1, wherein the arthritis comprises non-erosive arthritis, degenerative arthritis, and metabolic arthritis.
4. The use according to claim 1, wherein the formulation of the anti-arthritic preparation comprises a solution, lotion, emulsion, powder, ointment or paste; the dosage form of the anti-arthritis preparation is preferably an ointment.
5. A medicament for treating arthritis, which comprises ixomycin.
6. The medicament according to claim 5, wherein the content of the ixomycin in the medicament is more than or equal to 0.1 μ M; the content of the ixomycin is preferably 0.1-4 mu M.
7. The medicament of claim 5, further comprising paraffin, petrolatum, and propylene glycol; wherein the paraffin preferably comprises liquid paraffin.
8. The medicament according to claim 7, wherein the medicament comprises the following components in percentage by weight: 10-15mg of ixomycin, 800-1200mg of paraffin, 90-135mg of vaseline and 100-150mg of propylene glycol.
9. The medicament of claim 5, further comprising other pharmaceutically acceptable adjuvants.
10. Use of the medicament of claim 8 for the manufacture of an antiarthritic transdermal patch.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107802598A (en) * | 2017-11-29 | 2018-03-16 | 中国人民解放军陆军军医大学第三附属医院（野战外科研究所） | A kind of nano medicament carrying system of equisetin and its derivative and preparation method thereof and the application in skin soft-tissue infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107802598A (en) * | 2017-11-29 | 2018-03-16 | 中国人民解放军陆军军医大学第三附属医院（野战外科研究所） | A kind of nano medicament carrying system of equisetin and its derivative and preparation method thereof and the application in skin soft-tissue infection |
Non-Patent Citations (5)
| Title |
|---|
| 上海第一医学院，中山医学院主编: "《内科学 供医学、儿科、口腔、卫生专业用 下》", 30 June 1980, 人民卫生出版社 * |
| 任晓等: "微生物来源的人白细胞弹性蛋白酶抑制剂F01-221A的研究", 《中国抗生素杂志》 * |
| 刘宝生等: "《现代农村疾病诊治手册》", 31 October 2000 * |
| 国家食品药品监督管理局药品审评中心编: "《药品技术评价文集 第1辑》", 31 December 2006, 中国医药科技出版社 * |
| 胡显腾等: "白细胞弹性蛋白酶抑制剂", 《生命的化学》 * |
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