CN112999226B - Pharmaceutical composition for treating rheumatoid arthritis - Google Patents

Pharmaceutical composition for treating rheumatoid arthritis Download PDF

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CN112999226B
CN112999226B CN202110303904.1A CN202110303904A CN112999226B CN 112999226 B CN112999226 B CN 112999226B CN 202110303904 A CN202110303904 A CN 202110303904A CN 112999226 B CN112999226 B CN 112999226B
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rheumatoid arthritis
pharmaceutical composition
tofacitinib
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葛婷
戴艳萍
邹洪平
张俊华
胡卫林
何敏儿
房思良
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Guangzhou Baiyunshan Guanghua Pharmacy Co ltd
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Abstract

The invention relates to a pharmaceutical composition for treating rheumatoid arthritis. The pharmaceutical composition comprises tofacitinib or a salt thereof, and sinomenine or a salt thereof. The invention discovers for the first time that the tofacitinib and the sinomenine have good synergistic effect with each other when used for treating the rheumatoid arthritis, can obviously improve the abnormal activity of TNF-alpha caused by the rheumatoid arthritis, and effectively reduces the content of the TNF-alpha, thereby blocking inflammatory reaction, improving joint function, delaying the progress of the rheumatoid arthritis and relieving the destructive effect of the rheumatoid arthritis.

Description

Pharmaceutical composition for treating rheumatoid arthritis
Technical Field
The invention relates to the field of medicines, in particular to a pharmaceutical composition for treating rheumatoid arthritis.
Background
Rheumatoid Arthritis (RA) is an autoimmune disease with erosive arthritis as the major clinical manifestation. RA causes joint destruction and deformity, reduces physical functions, life quality and social participation of patients, and brings heavy economic burden to families and society of patients. The pathogenesis of RA is not clear, and may be related to abnormal activation and expression of immune cells, unbalanced cell proliferation and apoptosis, abnormal activation of nuclear factor kappa B, reduced expression of matrix metalloproteinase and the like.
Tofacitinib citrate is a Janus Kinase (JAK) inhibitor, and in the pathological process of RA, after a cytokine receptor is combined with JAK Kinase, the JAK Kinase is activated through conformation and phosphorylation, and simultaneously activates a signal transduction factor and a transcription activator, thereby regulating and controlling the gene expression and release of various inflammatory cytokines. Tofacitinib citrate reduces cytokine signaling, cytokine-induced gene expression and cell activation through inhibiting JAK pathway, thereby reducing various chronic inflammatory reactions. The drug is developed by the company of pharmaceutical giant heady refire (Pfizer) in the united states, is approved by FDA in the united states for treating moderate to severe rheumatoid arthritis on day 11/6 in 2012, and is the first JAK inhibitor approved for treating rheumatoid arthritis worldwide. Tofacitinib has, up to now, been approved for the treatment of moderate to severe rheumatoid arthritis in more than 80 countries worldwide and has been recommended as a priority treatment by several international rheumatoid arthritis treatment guidelines, including the european antirheumatic union, the american college of rheumatology and the asia-pacific college of rheumatology union.
However, there are still situations in which treatment with tofacitinib fails to achieve the target and a poor prognosis occurs for some patients. Common adverse reactions of tofacitinib mainly comprise diarrhea, headache, nasopharyngitis, upper respiratory infection, hypertension and the like. Significantly, severe infections that may result during tofacitinib treatment may lead to hospitalization or death of the patient. Severe, and occasionally fatal, infections caused by bacteria, mycobacteria, invasive fungi, viruses, or other opportunistic pathogens have been reported in tofacitinib-treated rheumatoid arthritis patients.
In the drug alert quick 9 (total 197 th), the U.S. alert of tofacitinib increased risk of thrombosis and high dose mortality. Tofacitinib was first approved for marketing in 2012 and used to treat adult RA that does not respond well to methotrexate, and the FDA required manufacturing companies to develop a post-marketing clinical trial aimed at assessing the risk of adverse events associated with heart, cancer and infection in adult RA as compared to methotrexate. The clinical trial used a TNF blocking agent as a control group to study the safety of two different amounts of tofacitinib (2 times daily, 5mg each time, which is currently approved for the treatment of RA, and higher, 2 times daily, 10mg each time). Interim data analysis on this clinical study showed that the incidence of thrombosis and mortality was increased when given 2 times daily in the 10mg patient treatment group compared to the 2 times daily 5mg tofacitinib treatment group and the TNF blocker treatment group.
Sinomenine (SIN) is derived from dried tubers of caulis Sinomenii and caulis Sinomenii of Menispermaceae, and the existing research finds that sinomenine can improve the ratio of osteoprotegerin to ligand (RANKL) of NF-kB receptor activator, thereby competitively inhibiting the combination of NF-kB receptor activator and RANKL, inhibiting the generation and activation of osteoclast, and achieving the effect of resisting RA. The sinomenine has various pharmacological actions such as analgesia, anti-inflammation, immunosuppression and the like, and has definite curative effect, safety and few side effects when being clinically used for treating RA.
Disclosure of Invention
Based on this, the object of the present invention is to provide a pharmaceutical composition for the treatment of rheumatoid arthritis.
The specific technical scheme is as follows:
a pharmaceutical composition for treating rheumatoid arthritis comprises tofacitinib or a salt thereof, and sinomenine or a salt thereof.
In some embodiments, the pharmaceutical composition comprises tofacitinib citrate and sinomenine hydrochloride.
In some of these embodiments, the weight ratio of tofacitinib, or a salt thereof, to sinomenine, or a salt thereof, is 1: (0.1-20).
In some of these embodiments, the weight ratio of tofacitinib or a salt thereof to sinomenine or a salt thereof is (1.
In some of these embodiments, the weight ratio of tofacitinib, or a salt thereof, to the sinomenine, or a salt thereof, is (1.
The invention also aims to provide a pharmaceutical preparation for treating rheumatoid arthritis, which comprises the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
In some of these embodiments, the excipient comprises at least one of starch, pregelatinized starch, starch slurry, sodium carboxymethyl starch, dextrin, microcrystalline cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, polyethylene glycol, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, mannitol, lactose or hydrates thereof, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, talc, aerosil, sodium lauryl sulfate, sodium bicarbonate, sodium carbonate, opadry, S-Eudragit, and enteric coating powder.
In some embodiments, the dosage form of the pharmaceutical preparation is an oral solid preparation, and further preferably tablets, capsules and granules.
In some of these embodiments, the dosage form of the pharmaceutical formulation is a tablet, which is surface coated.
In some of the embodiments, the excipients used for coating preferably include film coating materials, enteric coating materials or gastric coating materials.
In some of these embodiments, the film coating material comprises opadry and the enteric coating material comprises S-Eudragit.
In some embodiments, the tablet is prepared from the following components in parts by weight:
Figure BDA0002987356300000031
the Opadry powder is used as a coating material, and the coating weight is increased by 2.0-3.0%; further, the tablet is prepared by a process comprising the steps of:
uniformly mixing tofacitinib citrate, sinomenine hydrochloride, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate, adding 6-10 wt% of hydroxypropyl methyl cellulose aqueous solution for granulation, drying, granulating, adding magnesium stearate into the dry granules for uniform mixing, tabletting to obtain plain tablets, and coating the plain tablets with 12-18 wt% of opadry powder aqueous solution to obtain the coated tablets.
In some embodiments, the tablet is prepared from the following components in parts by weight:
Figure BDA0002987356300000041
taking enteric coating material S-Eudragit as coating material, and the weight of the coating is increased by 2.5-3.5%; further, the tablet is prepared by a process comprising the steps of:
mixing tolnaftate citrate, sinomenine hydrochloride, microcrystalline cellulose, lactose monohydrate and sodium dodecyl sulfate uniformly, adding 6-10 wt% of hydroxypropyl methyl cellulose aqueous solution for granulation, drying, granulating, adding sodium carboxymethyl starch, talcum powder and magnesium stearate into dry granules, mixing uniformly, tabletting to obtain plain tablets, and coating the plain tablets by using 16-20wt% of 40-60 v/v% ethanol aqueous solution of S-Eudragit to obtain coated tablets.
In some embodiments, the particles coated by the capsule shell of the capsule are prepared from the following components in parts by weight:
Figure BDA0002987356300000042
further, the capsule is prepared by a method comprising the following steps:
mixing tofacitinib citrate, sinomenine hydrochloride, lactose monohydrate and sodium dodecyl sulfate, adding 8-12 wt% of starch slurry to prepare a soft material, preparing wet granules, drying, finishing granules, adding micro-powder silica gel and magnesium stearate into the dry granules, uniformly mixing, and filling into an empty capsule shell to obtain the capsule.
In some embodiments, the granules are prepared from the following components in parts by weight:
Figure BDA0002987356300000051
further, the granules are prepared by a method comprising the following steps: mixing tofacitinib citrate, sinomenine hydrochloride, dextrin and sodium dodecyl sulfate, adding 30-50 v/v% ethanol water solution to prepare a soft material, preparing wet granules, drying and granulating to obtain the tofacitinib hydrochloride soft capsule.
The invention further aims to provide application of the pharmaceutical composition or the pharmaceutical preparation in preparing a medicament for treating rheumatoid arthritis.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers for the first time that the tofacitinib and the sinomenine have good synergistic effect with each other when used for treating the rheumatoid arthritis, can obviously improve the abnormal activity of TNF-alpha caused by the rheumatoid arthritis, and effectively reduce the content of the TNF-alpha, thereby blocking inflammatory reaction, effectively improving the joint swelling caused by the rheumatoid arthritis, improving the joint function, delaying the progress of the rheumatoid arthritis and relieving the destructive effect of the rheumatoid arthritis.
Detailed Description
Experimental procedures according to the invention, in which no particular conditions are specified in the following examples, are generally carried out under conventional conditions, or under conditions recommended by the manufacturer. The various chemicals used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or apparatus that comprises a list of steps is not limited to only those steps or modules recited, but may alternatively include other steps not recited, or may alternatively include other steps inherent to such process, method, article, or apparatus.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 common tablet preparation of tofacitinib citrate + Sinomenine hydrochloride
Prescription:
Figure BDA0002987356300000062
opadry powder (purchased from kalekang, HPMC-based film coating powder, coating solution prepared with water at a concentration of 15wt% before use), the coating weight is increased by 2.5%.
The preparation process comprises the following steps: sieving tofacitinib citrate and sinomenine hydrochloride with a 100-mesh sieve, sieving microcrystalline cellulose and low-substituted hydroxypropyl cellulose with a 80-mesh sieve, uniformly mixing the microcrystalline cellulose, the low-substituted hydroxypropyl cellulose and sodium dodecyl sulfate, adding 8wt% of hydroxypropyl methyl cellulose solution, granulating, drying at 40 ℃, sieving with a 16-mesh sieve, adding magnesium stearate into the dried granules, uniformly mixing, pressing 1000 tablets to obtain plain tablets, and coating the plain tablets with a coating solution to obtain the coated tablets.
Example 2 preparation of enteric coated tablet of tofacitinib citrate + sinomenine hydrochloride
Prescription:
Figure BDA0002987356300000061
Figure BDA0002987356300000073
enteric coating material S-Eudragit (purchased commercially with 3% coating weight gain)
The preparation process comprises the following steps: sieving tofacitinib citrate and sinomenine hydrochloride with a 100-mesh sieve, sieving microcrystalline cellulose, lactose monohydrate and talcum powder with a 80-mesh sieve, uniformly mixing the microcrystalline cellulose, the lactose monohydrate and the lauryl sodium sulfate, adding 8wt% of hydroxypropyl methyl cellulose aqueous solution for granulation, drying at 40 ℃, granulating with a 16-mesh sieve, adding sodium carboxymethyl starch, the talcum powder and magnesium stearate into the dried granules for uniform mixing, pressing 1000 tablets after mixing to obtain plain tablets, dissolving 16-20 wt% of an enteric coating material S-Eudragit with 50% of ethanol, and then coating a film by adopting a spray method to obtain a coated tablet.
Example 3 preparation of Tofacitinib citrate + Sinomenine hydrochloride capsules
Prescription:
Figure BDA0002987356300000074
the preparation process comprises the following steps: mixing tofacitinib citrate, sinomenine hydrochloride, lactose monohydrate and sodium dodecyl sulfate at room temperature, adding 10wt% of starch slurry to prepare a soft material, sieving with a 18-mesh sieve to prepare wet granules, drying at 60 ℃, sieving dry granules with a 16-mesh sieve to size the granules, adding micropowder silica gel and magnesium stearate into the dry granules, uniformly mixing, and filling the granules into 1000 empty capsule shells to obtain the capsule.
Example 4 preparation of Tofacitinib citrate + Sinomenine hydrochloride granules
Prescription:
Figure BDA0002987356300000081
the preparation process comprises the following steps: mixing tofacitinib citrate, sinomenine hydrochloride, dextrin and sodium dodecyl sulfate at room temperature, adding 40% ethanol to prepare soft material, sieving with a 10-mesh sieve to prepare wet granules, drying at 60 ℃, sieving with a 20-mesh sieve to prepare the dry granules, and granulating to obtain the tofacitinib hydrochloride granules.
Example 5 study of therapeutic action of the Compound pharmaceutical composition of the present invention on Rheumatoid arthritis rats
Rheumatoid Arthritis (RA) is a systemic autoimmune disease, and inflammatory cells and cytokines released by them play an important role in the inflammatory response of joints. Modern medical research has found that T lymphocytes are more abundant than B lymphocytes in inflammatory cells infiltrated by synovium, various cytokines can be detected in joint effusion and synovial tissue at inflammatory sites, and the number of detected cytokines in RA joints is continuously increased along with continuous discovery of new cytokines, such as TNF-alpha, IL-6, IL-8 and the like, wherein the inflammatory reaction mediated by TNF-alpha is the most prominent. It can be seen that the abnormal activation of inflammatory cytokines in the process of RA lesion is well recognized, and particularly, the significant increase of the serum TNF-alpha content of rats is closely related to the disease.
1 materials of the experiment
1.1 drugs and reagents
Tofacitinib citrate, sinomenine hydrochloride, type II collagen, complete Freund's adjuvant (Sigma, USA), rat TNF-alpha enzyme-linked immunoassay kit (R & D, USA), PV-200 toe volume measuring instrument (Chengdutai Union science and technology Co., ltd.).
1.2 Experimental animals
Female SD rats, SPF grade, 8 weeks old, 100, body weight (200 ± 10) g, provided by the medical laboratory animal center in guangdong province (SYXK (yue) 2018-0002). The rats are raised in a secondary laboratory of experimental animals at a temperature of 20-25 ℃ and a relative humidity of 50-70%, and 5 animals are fed with granulated feed, free to eat and drink water. The experiment is started one week after the experimental animals are adapted to the new environment, and an appropriate method is adopted to reduce the harm to the animals in the experimental process.
2. Experimental methods
2.1 establishment of rheumatoid arthritis model
Dissolving type II collagen in 0.lmol/L acetic acid water solution to prepare a solution with the type II collagen concentration of 2mg/mL, and standing overnight at 4 ℃. The following day was mixed with complete freund's adjuvant at 1 volume to make an emulsion. Repeatedly pumping with syringe until the mixture is completely emulsified, and making the emulsion not loose when dropping into water and float in water in drop form. Taking emulsified collagen as a modeling agent of an induced rheumatoid arthritis model (CIA), except a blank group, disinfecting the tail root part, the back part and the toe part of the right hind foot by using 75% alcohol, and then injecting the emulsified collagen into the above 3 points per 0.4mL per skin, so that the round skin dome is swollen, and the injection is successful. The emulsified collagen was injected 1 time more intensively at the above 3 points with 0.4 mL/1 by the same method on the 7 th day after molding. After the injection is strengthened, the rat paw is seriously swelled, the diameter growth amplitude of the trodden joint is more than or equal to 12mm, and the volume growth amplitude of the hind paw is more than or equal to 0.80mL, so that the molding is successful.
2.2 Effect of different dosage of pharmaceutical composition on anti-rheumatic Effect
The rats which are successfully molded are taken and raised in cages, 4 rats are raised in each cage, the room temperature is kept at about 21 ℃, and ventilation is good. The rheumatoid arthritis model rats were randomly grouped into 8 rats each for 16 weeks of intervention treatment. Normal rats of the same age were also used as a blank control group. Administration began on day 14 post-molding.
The method comprises the following specific steps:
(1) Blank control group (group a): normal rats are given physiological saline for intragastric administration with 1ml/1000g body weight;
(2) Model control group (group B): the model rat is administrated with normal saline for intragastric administration at 1ml/1000g body weight;
(3) Tofacitinib group (group C): 2mg of tofacitinib citrate, 1000mL of normal saline is added to prepare a solution, and the solution is administered to a model rat for intragastric administration with 1mL/1000g of body weight;
(4) Sinomenine hydrochloride group (group D): 8mg of sinomenine hydrochloride, adding 1000mL of physiological saline to prepare a suspension, and feeding the suspension into a gastric lavage of a model rat with 1mL/1000g of body weight;
(5) Combined group (group E): mixing 2mg of tofacitinib citrate and 8mg of sinomenine hydrochloride uniformly, adding 1000mL of physiological saline to prepare a solution, and feeding 1mL/1000g of weight of the solution to a model rat;
(6) Treatment 1 group: example 1 tablets (the sample size after grinding is about 2mg of tofacitinib citrate and 8mg of sinomenine hydrochloride), 1000mL of physiological saline is added to prepare a suspension, and the suspension is administered to a model rat for intragastric administration with 1mL/1000g of body weight;
(7) Treatment 2 groups: example 3 capsules 30mg (the sample amount after grinding is about equivalent to 2mg of tofacitinib citrate and 8mg of sinomenine hydrochloride), 1000mL of physiological saline is added to prepare a suspension, and the suspension is administered to a model rat for intragastric administration with 1mL/1000g of body weight;
(8) Treatment 3 groups: example 4 granules 235mg (sample size after grinding is about 2mg of tofacitinib citrate and 8mg of sinomenine hydrochloride), 1000mL of physiological saline is added to prepare a suspension, and the suspension is administered to a model rat for intragastric administration with 1mL/1000g of body weight.
Gavage administration was performed 1 time/day for 21 consecutive days. After anesthetizing a rat by an abdominal cavity, taking about 4ml of blood from a femoral artery, centrifuging at 3000R/min for 20min, sucking serum for later use, and measuring the TNF-alpha of the rat serum according to a method required by a rat TNF-alpha enzyme-linked immunosorbent assay kit (produced by R & D company in America).
2.3 Effect of different pharmaceutical compositions on the degree of swelling of rat joints
After modeling of CIA mice, swelling and inflammation of joint soft tissues gradually started, and the disease condition worsened with the increase of time. The administration method and the dose were the same as above, and the indexes and the methods were measured by capillary amplification measurement on the toes and ankle joint volumes of rats on the 14 th, 17 th, 21 st, 27 th and 34 th days after the molding, respectively, to calculate the swelling rate.
Swelling rate (%) = (volume of toe after molding-volume of toe before molding)/volume of toe before molding × 100%
2.4 statistical methods
Statistical methods were analyzed using SPSS19.0 statistical software. Experimental data are expressed as mean ± sd
Figure BDA0002987356300000101
Formally, comparison of differences between groups was performed using one-way anova, with P <0.05 indicating that the differences were statistically significant.
3. As a result, the
3.1 Effect on TNF-alpha expression levels in rat serum
As shown in Table 1, the serum TNF-. Alpha.of rats in each of the remaining groups was significantly increased (P < 0.05) as compared with the blank control group (group A). Compared with rats in a model group (group B), the serum TNF-alpha of rats in a tofacitinib citrate control group (group C) and a sinomenine hydrochloride control group (group D) has a down-regulation trend, compared with the serum TNF-alpha of rats in groups 1 to 3, the serum TNF-alpha of rats in groups C and D is remarkably reduced (P is less than 0.05), and meanwhile, the expression level of the TNF-alpha in the serum of rats between the treatment groups has no remarkable difference; experimental results show that the tofacitinib citrate and the sinomenine have obvious inhibition effect on rat serum TNF-alpha, the anti-inflammatory effect of the combined medicine is superior to that of single medicine treatment, and meanwhile, the anti-inflammatory effects of different dosage forms have no obvious difference.
Table 1 effect on TNF-alpha expression levels in rat serum (ng/L,
Figure BDA0002987356300000111
n＝8)
group of Number of examples Serum TNF-alpha
Group A 8 140.17±35.23
Group B 8 259.36±41.12 a
Group C 8 203.56±38.43 ab
Group D 8 210.25±40.39 ab
Group E 8 157.31±35.78 abcd
Treatment 1 group 8 158.47±37.64 abcd
Treatment of 2 groups 8 165.58±35.21 abcd
Treatment of 3 groups 8 160.24±39.42 abcd
Note: in comparison to the blank group (group a), a P<0.05; in comparison with the model group (group B), b P<0.05; compared with the tofacitinib citrate control group (group C), c P<0.05; compared with sinomenine hydrochloride control group (group D), d P<0.05。
3.2 Effect on the degree of swelling of rat joints
The swelling thickness of the feet of the rats on day 13 of model control is very obvious, the swelling degree becomes more serious along with the prolonging of time, and the difference has statistical significance compared with a normal control group (P is less than 0.05). The corresponding administration treatment is started on the 14 th day, the increasing amplitude of the foot swelling rate of the rats in the drug treatment group is weakened, and after 21 days, the foot swelling rate of the rats is reduced, which indicates that the inflammatory reaction is weakened. The improvement of ankle and toe swelling thickness of rats in each group is compared with the difference between the model group and the normal group and between the treatment group and the model group. Compared with a model control group, the treatment groups 1 to 3 can obviously inhibit the primary lesion of the rat adjuvant arthritis at all time points, the difference has statistical significance (P is less than 0.05), and meanwhile, the different dosage forms have no obvious difference on the effect of inhibiting the primary lesion of the rat adjuvant arthritis. The positive control group also had better inhibitory effect, and the difference had statistical significance (P < 0.05). The results are shown in Table 2.
TABLE 2 Effect on the swelling degree of rat joints: (
Figure BDA0002987356300000121
％，n＝8)
Figure BDA0002987356300000122
Note: in comparison to the blank group (group a), # P<0.05; compared with the model group (group B), * P<0.05。
4. analysis of combined administration effect of tofacitinib citrate and sinomenine hydrochloride
Based on the Median-effect Principle (middle effect Principle or Chou-Talalay combined index method), combidrug statistical software is used for drawing a dose-effect curve and a combination index curve (fa-C curve) under different effects, and the synergistic, antagonistic or additive relationship between the two medicines is quantitatively evaluated from the relationship between the effect of the combination of the two medicines and the combination index. The method comprises the following specific steps:
drug effect, i.e., inhibition ratio (fa) =1- (test serum TNF- α/model control serum TNF- α) according to middle effect equation fa/fu = (D/Dm) m Taking logarithms lgfa/fu = mlgD-mlgDm at two sides, setting a = -mlgDm, b = m, x = lgD, y = lgfa/fu, and substituting into a medium efficiency equation to obtain y = bx + a; wherein fa is the drug action effect, fu =1-fa, D is the drug concentration, m is the slope, and Dm is the intermediate effect concentration, i.e. the drug concentration at 50% effect. According to the above formula, the effective concentration Dm (lgDm = -a/m) of the two drugs used alone or in combination is calculated, and the concentration [ D = Dm (fa/fu) ] of the drug used alone or in combination is calculated 1/m The combination index [ CI = D1/DX1+ D2/DX2+ alpha (D1D 2)/(DX 1DX 2) at the time of the combination of the two drugs at the time of various effects ], can be calculated, D1 and D2 are the concentrations required by the two drugs respectively when the X effect is generated when the two drugs are combined, and DX1 and DX2 are the concentrations of the two drugs respectively when the X effect is generated when the two drugs are used independently. α =0 is two mutually exclusive drugs, α =1 is two mutually non-exclusive drugs. Because the action mechanisms of tofacitinib citrate and sinomenine hydrochloride are different, alpha =0 is taken in the experiment. When CI is<1, the combined effect of the two medicines is synergy; CI =1, the combined effect of the two drugs adds; CI>1, the combination of the two medicines has antagonistic effect.
Through software analysis, the compound pharmaceutical composition has good synergistic effect, the specific effect is shown in table 3, and the compound pharmaceutical composition has strong synergistic effect (Very string synergy) according to the Principle of evaluating the effect by a Medium-effect prism, namely CI index is less than 0.1; strong synergy at CI indices of 0.1-0.3 (Strong synergy); CI index of 0.3-0.7 has synergistic effect (synergy); CI index of 0.7-0.85 has Moderate synergistic effect (Moderate synergy); the CI index is in the range of 0.85-0.90, and has weak synergistic effect (Slight synergy); the CI index is in the range of 0.90-1.10, and has a near additive effect (near additive); and the CI index is more than 1.10 and has antagonistic effect.
TABLE 3 different combinations of compatibility Effect-combined CI index comparisons
Figure BDA0002987356300000131
As can be seen from Table 3, the combination of tofacitinib citrate and sinomenine hydrochloride has a synergistic effect; especially when tofacitinib citrate: the sinomenine hydrochloride has good synergistic effect when the weight ratio of the sinomenine hydrochloride to the sinomenine hydrochloride is 1- (0.1.
The results show that the Tofacitinib and sinomenine combined treatment on the rheumatoid arthritis can effectively improve the joint swelling caused by the rheumatoid arthritis and obviously reduce the expression level of TNF-alpha, thereby blocking inflammatory reaction, improving joint function, delaying the process of RA and relieving the destructive effect of RA. The embodiment of the invention has obvious treatment effect on RA and provides scientific experimental research evidence for clinical application.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (9)

1. The pharmaceutical composition for treating rheumatoid arthritis is characterized in that the active ingredients comprise tofacitinib citrate and sinomenine hydrochloride,
the weight ratio of the tofacitinib citrate to the sinomenine hydrochloride is 1: (0.1 to 20).
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of tofacitinib citrate to sinomenine hydrochloride is (1.
3. The pharmaceutical composition according to claim 2, wherein the weight ratio of tofacitinib citrate to sinomenine hydrochloride is (1.
4. The pharmaceutical composition of claim 3, wherein the weight ratio of tofacitinib citrate to sinomenine hydrochloride is 1.
5. A pharmaceutical preparation for treating rheumatoid arthritis, which is characterized by comprising the pharmaceutical composition according to any one of claims 1 to 4 and pharmaceutically acceptable auxiliary materials.
6. The pharmaceutical formulation of claim 5, wherein the pharmaceutical formulation is in the form of an oral solid formulation.
7. The pharmaceutical preparation according to claim 5, wherein the pharmaceutical preparation is in the form of tablets, capsules or granules.
8. The pharmaceutical formulation of claim 7, wherein the pharmaceutical formulation is in the form of a tablet, and the tablet is coated with an excipient comprising Opadry or S-Eudragit.
9. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the pharmaceutical preparation according to any one of claims 5 to 8 for the preparation of a medicament for the treatment of rheumatoid arthritis.
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CN106176640B (en) * 2014-11-28 2019-12-20 四川海思科制药有限公司 Pharmaceutical composition containing tofacitinib citrate and preparation method thereof
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