阅读说明：本技术 一种用于强直性脊柱炎的药物及制备方法 (Medicine for ankylosing spondylitis and preparation method thereof ) 是由 蔡剑飞 刘伟 于 2021-09-11 设计创作，主要内容包括：本发明公开了一种用于强直性脊柱炎的药物及制备方法,配方包括：双氯芬酸钠、白细胞介素-11、迪高替尼、米诺环素、促渗剂、热熔压敏胶基质、1-十二烷基-氮杂唑-2-酮和柠檬烯,制备方法包括步骤一,称取原料；步骤二,制作药物；步骤三,制作载体；步骤四,制备成品；所述步骤一中,促渗剂选自二甲基亚砜、乙醇、丙二醇、乙二醇、乙氧基二乙二醇、红没药醇、脂质体、角质去除剂、氮酮、油酸、胡椒素中的一种,本发明制备药物的过程中,所使用的是市场常规的试剂,具有较高的安全性；本发明能够明显缩短强直性脊柱炎疾病活动的时间；本发明可以减轻强直性脊柱炎疾病对患者造成的关节疼痛,大大抑制疾病的进展。(The invention discloses a medicament for ankylosing spondylitis and a preparation method thereof, and the formula comprises: diclofenac sodium, interleukin-11, digoxitinib, minocycline, a penetration enhancer, a hot-melt pressure-sensitive adhesive matrix, 1-dodecyl-azazole-2-ketone and limonene, wherein the preparation method comprises the following steps of weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product; in the first step, the penetration enhancer is selected from one of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, cutin remover, azone, oleic acid and piperine; the invention can obviously shorten the time of ankylosing spondylitis disease activity; the invention can relieve the arthralgia of ankylosing spondylitis to patients and greatly inhibit the progress of diseases.)

1. A medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, digoxitinib, minocycline, a penetration enhancer, a hot-melt pressure-sensitive adhesive matrix, 1-dodecyl-azazole-2-ketone and limonene, and is characterized in that: the weight percentage of each component is as follows: 7.5-30% of diclofenac sodium, 0.15-1.5% of interleukin-11, 0.25-2.5% of digotinib, 2-30% of minocycline, 5-25% of a penetration enhancer, 2-60% of a hot-melt pressure-sensitive adhesive matrix, 5-30% of 1-dodecyl-azazole-2-one and 5-22% of limonene.

2. The drug for ankylosing spondylitis according to claim 1, characterized in that: the weight percentage of each component is as follows: 27% of diclofenac sodium, 1.2% of interleukin-11, 1.8% of digoxitinib, 20% of minocycline, 8% of a penetration enhancer, 25% of a hot-melt pressure-sensitive adhesive matrix, 9% of 1-dodecyl-azazol-2-one and 8% of limonene.

3. A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product; the method is characterized in that:

in the first step, the components in percentage by mass are as follows: 7.5-30% of diclofenac sodium, 0.15-1.5% of interleukin-11, 0.25-2.5% of digotinib, 2-30% of minocycline, 5-25% of a penetration enhancer, 2-60% of a hot-melt pressure-sensitive adhesive matrix, 5-30% of 1-dodecyl-azazole-2-one and 5-22% of limonene, and weighing according to the mass percentage sum of 1;

in the second step, the diclofenac sodium, the interleukin-11, the digoxinity and the minocycline in the first step are put into ethanol for extraction and concentration, and then glycerin and purified water are added for uniform mixing to prepare a paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-one and the limonene in the first step are added into the mixed solution containing the hot-melt pressure-sensitive adhesive matrix and are uniformly stirred to prepare a carrier matrix;

and in the fourth step, the paste in the second step is mixed with the substrate in the third step, the mixture is coated on an anti-sticking layer, and the anti-sticking layer is placed in an environment with the temperature of 4-8 ℃ for cooling and cutting to obtain the medicinal patch and is stored.

4. The method for preparing a drug for ankylosing spondylitis according to claim 3, characterized in that: in the first step, the hot-melt pressure-sensitive adhesive substrate is one of a synthetic rubber type pressure-sensitive adhesive and an SBS type hot-melt adhesive.

5. The method for preparing a drug for ankylosing spondylitis according to claim 3, characterized in that: in the first step, the penetration enhancer is one selected from dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, cutin remover, azone, oleic acid and piperine.

6. The method for preparing a drug for ankylosing spondylitis according to claim 4, characterized in that: the synthetic rubber type pressure-sensitive adhesive contains butyl rubber, polyisobutylene, naphthenic oil, paraffin, an antioxidant, an anti-aging agent and the like.

7. The method for preparing a drug for ankylosing spondylitis according to claim 4, characterized in that: the SBS type hot melt adhesive contains SBS rubber, C9 petroleum resin, terpene resin, naphthenic oil antioxidant and the like.

Technical Field

The invention relates to the technical field of medicines, in particular to a medicine for ankylosing spondylitis and a preparation method thereof.

Background

Ankylosing spondylitis is a chronic arthritis, often occurs in the spine, and can also occur in other parts, such AS the hip, the chest, the back or the feet, and often starts to be developed from puberty to 30 years old, so that pain occurs in the waist, the back and the sacral tail, and the waist of a patient can be bent forward and difficult to walk seriously, so that medicines can be used for control clinically, but the existing AS oral medicines have serious risks of digestive tract and cardiovascular, and first-line treatment is mostly injections, which cause great influence on the treatment compliance of the patient.

Disclosure of Invention

The invention aims to provide a medicament for treating ankylosing spondylitis and a preparation method thereof, and aims to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme: a medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, digoxitinib, minocycline, a penetration enhancer, a hot-melt pressure-sensitive adhesive matrix, 1-dodecyl-azazole-2-ketone and limonene, wherein the mass percentage of each component is as follows: 7.5-30% of diclofenac sodium, 0.15-1.5% of interleukin-11, 0.25-2.5% of digotinib, 2-30% of minocycline, 5-25% of a penetration enhancer, 2-60% of a hot-melt pressure-sensitive adhesive matrix, 5-30% of 1-dodecyl-azazole-2-one and 5-22% of limonene.

Preferably, the mass percentage of each component is as follows: 27% of diclofenac sodium, 1.2% of interleukin-11, 1.8% of digoxitinib, 20% of minocycline, 8% of a penetration enhancer, 25% of a hot-melt pressure-sensitive adhesive matrix, 9% of 1-dodecyl-azazol-2-one and 8% of limonene.

A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product;

in the first step, the components in percentage by mass are as follows: 7.5-30% of diclofenac sodium, 0.15-1.5% of interleukin-11, 0.25-2.5% of digotinib, 2-30% of minocycline, 5-25% of a penetration enhancer, 2-60% of a hot-melt pressure-sensitive adhesive matrix, 5-30% of 1-dodecyl-azazole-2-one and 5-22% of limonene, and weighing according to the mass percentage sum of 1;

in the second step, the diclofenac sodium, the interleukin-11, the digoxinity and the minocycline in the first step are put into ethanol for extraction and concentration, and then glycerin and purified water are added for uniform mixing to prepare a paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-one and the limonene in the first step are added into the mixed solution containing the hot-melt pressure-sensitive adhesive matrix and are uniformly stirred to prepare a carrier matrix;

and in the fourth step, the paste in the second step is mixed with the substrate in the third step, the mixture is coated on an anti-sticking layer, and the anti-sticking layer is placed in an environment with the temperature of 4-8 ℃ for cooling and cutting to obtain the medicinal patch and is stored.

Preferably, in the first step, the hot-melt pressure-sensitive adhesive substrate is one of a synthetic rubber type pressure-sensitive adhesive and an SBS type hot-melt adhesive.

Preferably, in the first step, the penetration enhancer is one selected from the group consisting of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxydiglycol, bisabolol, liposome, keratolytic agent, azone, oleic acid, and piperine.

Preferably, the synthetic rubber type pressure sensitive adhesive contains butyl rubber, polyisobutylene, naphthenic oil, paraffin, an antioxidant, an anti-aging agent and the like.

Preferably, the SBS type hot melt adhesive contains SBS rubber, C9 petroleum resin, terpene resin, naphthenic oil antioxidant and the like.

Compared with the prior art, the invention has the beneficial effects that: in the process of preparing the medicament, the conventional reagents in the market are used, so that the safety is high; the invention can obviously shorten the time of ankylosing spondylitis disease activity; the invention can relieve the arthralgia of ankylosing spondylitis to patients and greatly inhibit the progress of diseases.

Drawings

FIG. 1 is a flow chart of a method of the present invention;

figure 2 shows the BASDAI disease activity scores for the transdermal patch group/experimental group for ankylosing spondylitis;

fig. 3 shows the incidence of tuberculosis in the transdermal patch group/experimental group.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Referring to fig. 1-3, a technical solution provided by the present invention is:

example 1:

a medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, digoxitinib, minocycline, a penetration enhancer, a hot-melt pressure-sensitive adhesive matrix, 1-dodecyl-azazole-2-ketone and limonene, wherein the mass percentage of each component is as follows: 27% of diclofenac sodium, 1.2% of interleukin-11, 1.8% of digoxitinib, 20% of minocycline, 8% of a penetration enhancer, 25% of a hot-melt pressure-sensitive adhesive matrix, 9% of 1-dodecyl-azazol-2-one and 8% of limonene.

A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product;

in the first step, the components in percentage by mass are as follows: 27 percent of diclofenac sodium, 1.2 percent of interleukin-11, 1.8 percent of digoxitinib, 20 percent of minocycline, 8 percent of penetration enhancer, 25 percent of hot-melt pressure-sensitive adhesive matrix, 9 percent of 1-dodecyl-azazole-2-ketone and 8 percent of limonene, and weighing according to the mass percentage sum of 1, wherein, the penetration enhancer is selected from one of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, cutin remover, azone, oleic acid and piperine, the pressure-sensitive adhesive matrix is one of synthetic rubber pressure-sensitive adhesive and SBS type hot melt adhesive, the synthetic rubber pressure-sensitive adhesive contains butyl rubber, polyisobutylene, naphthenic oil, paraffin, antioxidant, anti-aging agent and the like, and the SBS type hot melt adhesive contains SBS rubber, C9 petroleum resin, terpene resin, naphthenic oil antioxidant and the like;

in the second step, the diclofenac sodium, the interleukin-11, the digoxinity and the minocycline in the first step are put into ethanol for extraction and concentration, and then glycerin and purified water are added for uniform mixing to prepare a paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-one and the limonene in the first step are added into the mixed solution containing the hot-melt pressure-sensitive adhesive matrix and are uniformly stirred to prepare a carrier matrix;

and in the fourth step, the paste in the second step is mixed with the substrate in the third step, the mixture is coated on an anti-sticking layer, and the anti-sticking layer is placed in an environment with the temperature of 4-8 ℃ for cooling and cutting to obtain the medicinal patch and is stored.

Example 2:

a medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, didotinib, a penetration enhancer, a hot melt pressure sensitive adhesive matrix, 1-dodecyl-azazole-2-ketone and limonene, wherein the mass percent of each component is as follows: 28% of diclofenac sodium, 1.3% of interleukin-11, 1.7% of didotinib, 12% of penetration enhancer, 31% of hot-melt pressure-sensitive adhesive matrix, 10% of 1-dodecyl-azazole-2-ketone and 16% of limonene.

A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product;

in the first step, the components in percentage by mass are as follows: 28% of diclofenac sodium, 1.3% of interleukin-11, 1.7% of didotinib, 12% of penetration enhancer, 31% of hot-melt pressure-sensitive adhesive matrix, 10% of 1-dodecyl-azazole-2-ketone and 16% of limonene, and weighing according to the mass percentage sum of 1, wherein the penetration enhancer is selected from one of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, cutin remover, azone, oleic acid and piperine, the pressure-sensitive adhesive matrix is one of synthetic rubber type pressure-sensitive adhesive and SBS type hot-melt adhesive, the synthetic rubber type pressure-sensitive adhesive contains butyl rubber, polyisobutylene, naphthenic oil, paraffin, antioxidant and the like, and the SBS type hot-melt adhesive contains SBS rubber, C9 petroleum resin, terpene resin, naphthenic oil antioxidant and the like;

in the second step, the diclofenac sodium, the interleukin-11 and the digoxitinib in the first step are taken and put into ethanol for extraction and concentration, and then the glycerol and the purified water are added for uniform mixing to prepare the paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-one and the limonene in the first step are added into the mixed solution containing the hot-melt pressure-sensitive adhesive matrix and are uniformly stirred to prepare a carrier matrix;

and in the fourth step, the paste in the second step is mixed with the substrate in the third step, the mixture is coated on an anti-sticking layer, and the anti-sticking layer is placed in an environment with the temperature of 4-8 ℃ for cooling and cutting to obtain the medicinal patch and is stored.

Comparative example 1:

a medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, digoxitinib, minocycline, a penetration enhancer, 1-dodecyl-azazole-2-ketone and limonene, wherein the mass percent of each component is as follows: 30% of diclofenac sodium, 1.5% of interleukin-11, 2.5% of digoxitinib, 30% of minocycline, 14% of a penetration enhancer, 10% of 1-dodecyl-azazol-2-one and 12% of limonene.

A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product;

in the first step, the components in percentage by mass are as follows: 30% of diclofenac sodium, 1.5% of interleukin-11, 2.5% of digoxitinib, 30% of minocycline, 14% of penetration enhancer, 10% of 1-dodecyl-azazole-2-ketone and 12% of limonene, and weighing according to the mass percentage sum of 1, wherein the penetration enhancer is selected from one of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, cutin remover, azone, oleic acid and piperine;

in the second step, the diclofenac sodium, the interleukin-11, the digoxinity and the minocycline in the first step are put into ethanol for extraction and concentration, and then glycerin and purified water are added for uniform mixing to prepare a paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-ketone and the limonene in the first step are uniformly stirred to prepare a carrier solution;

and in the fourth step, mixing the paste in the second step with the solution in the third step, and cooling in an environment at 4-8 ℃ to obtain the medicinal mouthwash and storing.

Comparative example 2:

a medicine for treating ankylosing spondylitis, which comprises the following components in part by weight: diclofenac sodium, interleukin-11, didotinib, a penetration enhancer, 1-dodecyl-azazole-2-ketone and limonene, wherein the mass percentage of each component is as follows: 30% of diclofenac sodium, 1.5% of interleukin-11, 2.5% of didotinib, 21% of a penetration enhancer, 24% of 1-dodecyl-azazol-2-one and 21% of limonene.

A preparation method of a medicament for treating ankylosing spondylitis comprises the steps of firstly, weighing raw materials; step two, preparing a medicine; step three, manufacturing a carrier; step four, preparing a finished product;

in the first step, the components in percentage by mass are as follows: 30% of diclofenac sodium, 1.5% of interleukin-11, 2.5% of digoxin, 21% of penetration enhancer, 24% of 1-dodecyl-azazole-2-ketone and 21% of limonene, and weighing according to the mass percentage sum of 1, wherein the penetration enhancer is selected from one of dimethyl sulfoxide, ethanol, propylene glycol, ethylene glycol, ethoxy diethylene glycol, bisabolol, liposome, a cutin remover, azone, oleic acid and piperonyl;

in the second step, the diclofenac sodium, the interleukin-11 and the digoxitinib in the first step are taken and put into ethanol for extraction and concentration, and then the glycerol and the purified water are added for uniform mixing to prepare the paste medicine;

in the third step, the penetration enhancer, the 1-dodecyl-azazole-2-ketone and the limonene in the first step are uniformly stirred to prepare a carrier solution;

and in the fourth step, mixing the paste in the second step with the solution in the third step, and cooling in an environment at 4-8 ℃ to obtain the medicinal mouthwash and storing.

The properties of the examples and comparative examples are given in the following table:

experimental example 1:

192 patients diagnosed as ankylosing spondylitis from 5 months in 2019 to 5 months in 2020 are brought into the study, the patients reach the diagnosis standard of the national ankylosing spondylitis diagnosis and treatment guideline, each patient is diagnosed by 2 senior rheumatologists, and the patients are subjected to whole-body examination or screening, including skull Magnetic Resonance Imaging (MRI), chest Computed Tomography (CT), gastrointestinal endoscopy, abdominal ultrasound, vascular ultrasound of important blood vessels, and blood examination including liver, kidney function, glucose, cancer markers, T.SPORT, Hepatitis B Virus (HBV), treponema pallidum, acquired immune deficiency syndrome (HIV), autoantibodies and the like, so as to eliminate internal organ responsible persons and other diseases, such as infection, diabetes, rheumatoid arthritis, cancer, Crohn's disease and ulcerative colitis. All participants had only the manifestation of axial and peripheral joint damage in ankylosing spondylitis, which may be manifested in their history as keratitis, conjunctivitis, anterior uveitis, but posterior uveitis, which may affect vision, was also excluded when intensive therapy was required.

The patients were randomly divided into two groups, namely a control group and a transdermal patch intervention group, wherein the transdermal patch was the drug patch prepared in example 1, before the experiment, the two groups of patients had no difference in sex, age, course of disease and severity of disease condition, 150 patients in the control group had thalidomide 100mg, were taken before sleep, had at least one non-steroidal anti-inflammatory drug and reached the standard dose, the first-line biologic baseline treatment was adjusted according to the disease condition, 192 patients in the treatment group had the same oral drug as the control group, and the two groups of patients had a follow-up visit for 1 year, and the following results were observed:

as shown in FIG. 2, the effect of disease activity (BASDAI) on disease activity in AS patients using the present transdermal patch AS a second-line or at least third-line drug was not significantly different (p < 0.001) compared to treatment with the first-line biologic.

As shown in FIG. 3, patients with AS who used the present transdermal patch AS a second-line or at least third-line drug did not develop tuberculosis infection, (p < 0.001).

Experimental example 2:

the male patient is diagnosed with 24 years old and Zhanjiang in Guangdong, "repeated low back pain 15 years", the patient is diagnosed in most jia hospitals in Guangzhou in the past history of gastric ulcer, takes non-steroidal anti-inflammatory drugs, subcutaneously injects biological agents and the like, the condition control is not good, the gastric ulcer is repeatedly attacked, the patient suffers from repeated attack of the gastric ulcer, the mood is lowered, the diet is reduced, and the biological agent injection treatment cannot be performed in cooperation with doctors.

Auxiliary detection: can be used for treating infectious diseases such as tuberculosis and hepatitis B, and has no obvious abnormality in gastrointestinal endoscope detection and ophthalmoscopy and blood sedimentation of 60 mm/h.

The drug patch prepared in example 1 was administered, and the patient was ordered one patch per day, and the patient was reviewed for 9mm/h on day 14, adjusting the patient's basal antirheumatic drug, and the disease only relapsed 1 time with a follow-up visit of 2 years.

Based on the above, when the medicine patch or mouthwash prepared by the invention is used for treatment, as the prepared reagent is conventionally visible on the market, the safety is guaranteed, and the medicine prepared by the invention can greatly shorten the time of the ankylosing spondylitis attack of a patient, the medicine prepared by the invention can effectively relieve arthralgia caused by ankylosing spondylitis, and can inhibit the progress of diseases; in actual use, if a patient has a topical skin infection, an adjunct solvent agent is added to the transdermal patch to relieve the infection, the concentration of minocycline in the transdermal patch is 10%, and if the patient is free of a topical skin infection, the concentration of minocycline in the mouthwash may be 2%.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.