CN113440614A - Composition for treating rheumatoid arthritis and application thereof - Google Patents
Composition for treating rheumatoid arthritis and application thereof Download PDFInfo
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
Abstract
The invention discloses a composition for treating rheumatoid arthritis and application thereof, wherein the composition comprises a component A and a component B, the component A is tofacitinib or pharmaceutically acceptable salt thereof, and the component B is one or/and a plurality of non-steroidal anti-inflammatory drugs (NSAIDs); the weight ratio of the component A to the component B in the composition is 1: 30 to 240. The composition provided by the invention can act on different targets of rheumatoid arthritis through two components, play a role in synergistically treating rheumatoid arthritis, and simultaneously remarkably reduce the dosage of the component B and reduce toxic and side effects. In addition, the component B can reduce adverse reactions caused by taking the component A.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a composition for treating rheumatoid arthritis and application thereof.
Background
Rheumatoid arthritis is a clinically multiple disease condition, the incidence rate is about 1%, the disease involves multiple joints in the whole body, and finally the function of bones and joints is lost, and the life quality of patients is seriously affected. At present, although the clinical treatment can control the disease process, an effective cure means is still lacked, and the used medicines have strong side effects.
Tofacitinib is a Janus kinase (JAK) inhibitor, is approved by the U.S. Food and Drug Administration (FDA) to be on the market in 2012, is mainly used for treating rheumatoid arthritis, but is easy to reduce the immunity of an organism after being taken for a long time to cause serious infection; ibuprofen is one of nonsteroidal anti-inflammatory drugs, has antipyretic and analgesic effects, can be clinically used for treating rheumatoid arthritis, but has a large dosage of 2.4 g/day and large side effect after long-term use.
Research shows that the long-term taking of tofacitinib can cause systemic infection, and ibuprofen can improve cellular immune function and improve anti-infection capacity. The tofacitinib and the ibuprofen are combined, so that the dosage of the ibuprofen can be obviously reduced, the curative effect is kept or improved, and the adverse reaction of the tofacitinib is reduced, which has great significance for patients.
Disclosure of Invention
In view of the above, the main objective of the present invention is to provide a composition for treating rheumatoid arthritis, so as to solve the problems in the prior art.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a composition for the treatment of rheumatoid arthritis, said composition comprising component a and component B, said component a being tofacitinib or a pharmaceutically acceptable salt thereof, said component B being one or/and more of non-steroidal anti-inflammatory drugs (NSAIDs).
Preferably, the component B is one or more of aspirin, acetaminophen, diclofenac, indometacin, ibuprofen, sulindac, naproxen, nabumetone, piroxicam and celecoxib. Further preferably, the component B is ibuprofen.
Preferably, the component A is tofacitinib citrate.
Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals on the cell membrane generated by cytokine or growth factor-receptor interactions to influence cellular processes of hematopoiesis and immune cell function. In the signaling pathway, JAKs phosphorylate and activate signal transducers and transcriptional activators (STATs), which regulate intracellular activities, including gene expression. Tofacitinib inhibits JAK regulatory signaling pathways, thereby preventing phosphorylation and activation of STATs. The JAK enzymes transmit cytokine signals through JAK partners (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK 2). Tofacitinib inhibited the in vitro activity of the JAK1/JAK2, JAK1/JAK3 and JAK2/JAK2 combinations with IC50 of 406, 56 and 1377 nM, respectively.
Ibuprofen inhibits COX-2 activity and blocks prostaglandin (PGE 2) synthesis. Ibuprofen directly inhibits the activation and aggregation of leukocytes and reduces the production of leukotriene B4 (leukocyte chemokines and activators). Ibuprofen can improve cellular immunity and improve anti-infection ability.
In an inflammatory pathway in RA, cytokines induce the enhancement of inflammatory gene expression through JAK pathway conduction, phosphorylated STATs perform gene regulation in cell nucleus, the expression of immune cytokines is up-regulated, inflammation is activated, COX-2 is highly expressed, and the highly expressed COX-2 is combined into a large amount of PGE2 to cause inflammation, edema and pain. Thus, inhibition of the JAK/STATs pathway conduction by inhibiting the JAK pathway at the upstream end, reduces cytokine expression and may interrupt the cycle of leukocyte recruitment, activation and expression of pro-inflammatory cytokines at the site of inflammation. At the downstream end, expression of PGE2 can be reduced by inhibiting COX-2 activity. Therefore, the combined application of tofacitinib and ibuprofen can block the cytokine passage at the upstream end and the downstream end of RA at the same time, and can play a role in synergistic treatment of RA. The synergistic mechanism of the combined use of tofacitinib and ibuprofen is shown in figure 1.
Due to the existence of the synergistic effect, the daily dosage of the ibuprofen can be reduced from 2.4 g/day to below 800 mg/day. Meanwhile, ibuprofen can improve the cellular immune function and improve the anti-infection capability, so that adverse reactions of serious infection caused by long-term administration of tofacitinib are reduced.
Pharmaceutical compositions of tofacitinib and ibuprofen, the route of administration includes, but is not limited to, the following: gastrointestinal administration, e.g., oral administration; parenteral administration, such as intramuscular, intravenous or transdermal administration. In the treatment of rheumatoid arthritis, oral administration is preferred.
The composition for treating rheumatoid arthritis is characterized in that the weight ratio of the component A to the component B is 1: 30 to 240. Preferably, the weight ratio of the component a to the component B is 1: 50 to 200. Further preferably, the weight ratio of the component a to the component B is 1: 60 to 120. Still more preferably, the weight ratio of said component a to said component B is 1: 60-80.
Preferably, in the composition for treating rheumatoid arthritis, the component A is tofacitinib citrate, the component B is ibuprofen, and the weight ratio of tofacitinib citrate (calculated as tofacitinib) to ibuprofen is 1: 40 to 240. Preferably, the weight ratio of tofacitinib citrate (calculated as tofacitinib) to ibuprofen is 1: 50 to 200. Further preferably, the weight ratio of tofacitinib citrate (calculated as tofacitinib) to ibuprofen is 1: 60 to 120. Still more preferably, the weight ratio of tofacitinib citrate (calculated as tofacitinib) to ibuprofen is 1: 60-80.
Wherein the ibuprofen is lower than the single effective dose. By lower than single effective dose is meant a dose of ibuprofen in the combination which is lower than the amount normally expected to produce an effective therapeutic response when the components are administered separately.
The invention also aims to provide application of any one of the compositions in preparing a medicament for treating rheumatoid arthritis.
Alternative dosage forms for oral administration of the composition for the treatment of rheumatoid arthritis include, but are not limited to: tablet, granule, capsule, and solution. Among them, sustained-release capsules are preferable.
The sustained-release capsule consists of particles containing tofacitinib and ibuprofen, wherein the particles can consist of one or/and more of micro-tablets and micro-pills.
The active ingredients of the granules are tofacitinib or/and ibuprofen, and the granules further comprise pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials include but are not limited to: blank pellet core and adhesive.
The blank pill core comprises sucrose pill core, starch pill core, microcrystalline cellulose pill core, tartaric acid pill core, silicon dioxide pill core and mannitol pill core.
The binder comprises polyvidone, hypromellose, and hyprolose.
Preferably, the granules consist of immediate release granules comprising tofacitinib and sustained release granules comprising ibuprofen.
The prescription composition of the immediate-release tofacitinib granules comprises but is not limited to:
and (2) component A: 5 to 20 percent of
A sucrose pellet core: 80 to 95 percent
Polyvidone: 1 to 5 percent
The ibuprofen sustained-release granule prescription comprises but is not limited to:
and (B) component: 70 to 90 percent
A sucrose pellet core: 10 to 30 percent
Polyvidone: 1 to 5 percent
The quick-release particles of tofacitinib can be completely released within 1 hour, and the sustained-release particles of ibuprofen can be continuously released for more than 12 hours.
The ibuprofen sustained release granules do not contain a sustained release material.
Preferably, the extended release capsule consists of the same granulate comprising an immediate release layer comprising tofacitinib and a delayed release layer comprising ibuprofen.
The particle prescription composition includes but is not limited to:
and (2) component A: 0.5 to 5 percent
And (B) component: 65 to 90 percent
A sucrose pellet core: 10 to 30 percent
Polyvidone: 1 to 5 percent
The quick release layer containing tofacitinib in the granules is completely released within 1 hour, and the slow release layer containing ibuprofen can be continuously released for more than 12 hours.
The particles do not contain a slow release material.
The invention has the beneficial effects that:
the invention provides a composition for treating rheumatoid arthritis. The combined use of the tofacitinib and the ibuprofen reduces the dosage of the ibuprofen, increases the curative effect of the medicament, and reduces the toxic and side effects of the medicament, thereby achieving better effect of treating the rheumatoid arthritis.
Drawings
Figure 1 RA pathological process and tofacitinib and ibuprofen points of action.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
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.
Example 1
Preparation of quick-release granules
(1) Prescription
Tofacitinib 5 mg/granule
Sucrose pill core 80 mg/pill
Povidone 1 mg/granule
Purified water proper amount (qs)
(2) Preparation method
Adding the purified water with the prescription amount into a preparation container, slowly adding the povidone by times, stirring to completely dissolve, slowly adding the micronized tofacitinib by times, and uniformly stirring to obtain a suspension. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension, and drying after spraying to obtain the quick-release granules.
Preparation of sustained-release granules
(1) Prescription
Ibuprofen 300 mg/granule
Sucrose pill core 80 mg/pill
Povidone 8 mg/granule
Purified water qs
(2) Preparation method
Adding purified water according to the prescription amount into a preparation container, slowly adding povidone in several times, stirring to completely dissolve, slowly adding micronized ibuprofen in several times, and uniformly stirring to obtain a suspension. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension, and drying after spraying to obtain the slow-release granules.
Preparation of sustained-release capsules
Filling the quick-release granules and the sustained-release granules into the same capsule according to the dose of 5 mg/granule of tofacitinib and the dose of 300 mg/granule of ibuprofen.
Example 2
Preparation of quick-release granules
(1) Prescription
Tofacitinib 5 mg/granule
Sucrose pill core 80 mg/pill
Povidone 1 mg/granule
Purified water qs
(2) Preparation method
Adding the purified water with the prescription amount into a preparation container, slowly adding the povidone by times, stirring to completely dissolve, slowly adding the micronized tofacitinib by times, and uniformly stirring to obtain a suspension. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension, and drying after spraying to obtain the quick-release granules.
Preparation of sustained-release granules
(1) Prescription
Ibuprofen 400 mg/granule
Sucrose pill core 80 mg/pill
Purified water qs
(2) Preparation method
Adding purified water according to the prescription amount into a preparation container, slowly adding povidone in several times, stirring to completely dissolve, slowly adding micronized ibuprofen in several times, and uniformly stirring to obtain a suspension. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension, and drying after spraying to obtain the slow-release granules.
Preparation of sustained-release capsules
Filling the quick-release granules and the sustained-release granules into the same capsule according to the dose of 5 mg/granule of tofacitinib and the dose of 400 mg/granule of ibuprofen.
Example 3
(1) Prescription
Tofacitinib 5 mg/granule
Ibuprofen 300 mg/granule
Sucrose pill core 80 mg/pill
Povidone 8 mg/granule
Purified water qs
(2) Preparation method
Adding a proper amount of purified water into a preparation container 1, slowly adding part of povidone in different times, stirring to completely dissolve, slowly adding micronized tofacitinib in different times, and uniformly stirring to obtain a suspension 1. Adding a proper amount of purified water into the preparation container 2, slowly adding the rest povidone in several times, stirring to completely dissolve, slowly adding the micronized ibuprofen in several times, and uniformly stirring to obtain a suspension 2. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension 2, and drying after spraying is finished to obtain the ibuprofen sustained-release layer granules. And continuously and slowly spraying the ibuprofen slow release layer particles serving as a substrate into the suspension 1, and drying after spraying is finished to obtain the particles simultaneously containing the ibuprofen slow release layer and the tofacitinib quick release layer. Filling the granules into capsules to obtain the sustained-release capsules.
Example 4
(1) Prescription
Tofacitinib 5 mg/granule
Ibuprofen 400 mg/granule
Sucrose pill core 80 mg/pill
Purified water qs
(2) Preparation method
Adding a proper amount of purified water into a preparation container 1, slowly adding part of povidone in different times, stirring to completely dissolve, slowly adding micronized tofacitinib in different times, and uniformly stirring to obtain a suspension 1. Adding a proper amount of purified water into the preparation container 2, slowly adding the rest povidone in several times, stirring to completely dissolve, slowly adding the micronized ibuprofen in several times, and uniformly stirring to obtain a suspension 2. And (3) putting the sucrose pill cores in the coating equipment according to the prescription amount, slowly spraying the suspension 2, and drying after spraying is finished to obtain the ibuprofen sustained-release layer granules. And continuously and slowly spraying the ibuprofen slow release layer particles serving as a substrate into the suspension 1, and drying after spraying is finished to obtain the particles simultaneously containing the ibuprofen slow release layer and the tofacitinib quick release layer. Filling the granules into capsules to obtain the sustained-release capsules.
Example 5
The following experiments demonstrate the beneficial effects of the present invention
(1) Test drug
Tofacitinib citrate (available from Hubei Xinrund); ibuprofen (purchased from Shandong Xinhua pharmaceutical industry).
(2) Animal(s) production
Mouse model of type ii collagen arthritis: 8-week-old DBA/1J male mice were injected subcutaneously with 50. mu.l of 2mg/ml bovine type II collagen and 50. mu.l of 1mg/ml complete Freund's adjuvant in the tail root of the mice on day 0. And injected subcutaneously in the tail root on day 21 with 50. mu.l of 2mg/ml bovine type II collagen and 50. mu.l of incomplete Freund's adjuvant in the form of an emulsifier.
(3) The test animals were grouped by the administered drug:
1) normal group
2) Model group of type II collagen arthritis
3) Tofacitinib citrate (1mg/kg, calculated as tofacitinib, the same below) group
4) Tofacitinib citrate (2 mg/kg) group
5) Ibuprofen (100mg/kg) group
6) Ibuprofen (150mg/kg) group
7) Ibuprofen (200mg/kg) group
8) Tofacitinib citrate (1mg/kg) + ibuprofen (60 mg/kg)
9) Tofacitinib citrate (1mg/kg) + ibuprofen (70mg/kg)
10) Tofacitinib citrate (1mg/kg) + ibuprofen (80 mg/kg).
(4) Dosing regimens
The administration was carried out according to the set drug groups from day 21, all of which were intragastric administration.
(5) Mouse inflammatory lesion score and spleen and thymus tissue index
All mice were sacrificed at day 42 after primary immunization and serum, limb joints, thymus tissue and spleen tissue were removed, respectively. Hind limb joint tissues were fixed with 4% formalin and EDTA solution for decalcification, paraffin embedded, and 4-5 micron thick coronal sections were prepared and stained with hematoxylin-eosin.
1) Histological changes in the joints were scored according to the following criteria
The synovial membrane of the joint is coated with epithelial cells without degeneration and necrosis, fibrous tissue hyperplasia, interstitial congestion and inflammatory cell infiltration. Articular cartilage and bone tissue with or without destruction or fibrosis. According to the degree of pathological changes of each part of the joint, the disease was quantified as "1 point (mild)", "2 points (moderate)", "3 points (severe)", and "4 points (severe)", and the non-diseased tissue was counted as "0 point". And accumulating all the scores to obtain a total score, and calculating the average score of each animal in each group for t test.
The joint tissues of the model animals are found to be degenerated and necrosed by the tissue section examination, the synovial tissues are congested, and the synovial tissues have high inflammatory cell infiltration and fibrous tissue hyperplasia. The articular cartilage and bone tissues are seriously damaged, and the joint cavity disappears due to the proliferation of a large amount of fibrous tissues; and the combination of tofacitinib and ibuprofen can significantly improve local inflammatory reaction of animal inflammation, synovium tissue lesion and cartilage and bone tissue damage after the treatment of the low-dose group. The results of the histological grading of each group are shown in table 1. P <0.05, P <0.01, vs model mice.
TABLE 1 histopathology scores for each group
| Group of | Animals (only) | Lesion score (X + -SD) |
| (1) Normal group | 5 | 0.00±0.00** |
| (2) Model group of type II collagen arthritis | 5 | 10.90±2.65* |
| (3) Tofacitinib citrate (1mg/kg) group | 5 | 6.70±3.02 |
| (4) Tofacitinib citrate (2 mg/kg) group | 5 | 5.20±2.36 |
| (5) Ibuprofen (100mg/kg) group | 5 | 8.40±3.79** |
| (6) Ibuprofen (150mg/kg) group | 5 | 7.90±3.21* |
| (7) Ibuprofen (200mg/kg) group | 5 | 7.50±2.53* |
| (8) Tofacitinib citrate (1mg/kg) + ibuprofen (60 mg/kg) | 5 | 1.50±1.36 |
| (9) Tofacitinib citrate (1mg/kg) + ibuprofen (70mg/kg) | 5 | 1.50±1.86** |
| (10) Tofacitinib citrate (1mg/kg) + ibuprofen (80 mg/kg) | 5 | 1.40±2.33* |
2) Detection of spleen and thymus indices
Taking spleen and thymus tissues of an arthritic mouse, weighing the spleen and thymus tissues respectively, and calculating the spleen and thymus indexes respectively according to the following formulas:
spleen index ═ spleen weight (mg)/body weight (g) × 10
Thymus index is weight (mg)/weight (g) x 10 of thymus
The results of spleen index and thymus index of each group are shown in Table 2. P <0.05vs model mice.
TABLE 2 spleen and thymus indices of the groups
| Group of | Spleen index (mg/10 g weight) | Thymus index (mg/10 mg weight) |
| (1) Normal group | 26.3±3.6** | 12.0±3.2** |
| (2) Model group of type II collagen arthritis | 46.2±3.1** | 11.0±2.2** |
| (3) Tofacitinib citrate (1mg/kg) group | 18.2±2.3* | 8.2±1.5 |
| (4) Tofacitinib citrate (2 mg/kg) group | 15.5±2.9 | 7.5±2.6 |
| (5) Ibuprofen (100mg/kg) group | 45.3±1.8** | 11.2±2.7** |
| (6) Ibuprofen (150mg/kg) group | 43.7±2.3 | 10.1±1.3** |
| (7) Ibuprofen (200mg/kg) group | 42.5±2.3** | 10.6±2.9* |
| (8) Tofacitinib citrate (1mg/kg) + ibuprofen (60 mg/kg) | 24.5±1.5** | 10.8±2.4 |
| (9) Tofacitinib citrate (1mg/kg) + ibuprofen (70mg/kg) | 25.3±1.9** | 11.8±2.6 |
| (10) Tofacitinib citrate (1mg/kg) + ibuprofen (80 mg/kg) | 23.3±2.7 | 10.8±3.0* |
The spleen index and the thymus index of the tofacitinib group in the used dose in the experiment are the lowest, the immunosuppressive action is very strong, and the tofacitinib and ibuprofen are combined without showing obvious toxic and side effects of reducing the spleen and thymus indexes, so that the toxic and side effects of the tofacitinib and ibuprofen can be reduced by the combined application of the tofacitinib and the ibuprofen.
(6) Detection of antibody and cytokine levels in serum
Animal sera were taken and tested for levels of TNF α, IFN γ, IL-2, IL-4, IL-6, IL-10 and IL17A according to the CBA kit instructions and IL-1 β using an ELISA kit and IgG, IgG1, IgG2a, IgG2b, IgG3, IgA and IgM using an immunoglobulin kit. The results for each group of IL-1. beta., IL-6, IgG and IgG2b are shown in Table 3. P <0.05vs model mice.
TABLE 3 expression of antibodies and cytokines in the sera of arthritic mice
| Group of | IgG（OD450mm） | IgG2b（OD450mm） | IL-1β（pg/ml） | IL-6（pg/ml） |
| (1) Normal group | 1.25±0.17* | 0.72±0.26** | 156.2±21.7* | 10.3±1.7** |
| (2) Model group of type II collagen arthritis | 1.42±0.12** | 1.30±0.23* | 436.2±35.5 | 30.5±3.4** |
| (3) Tofacitinib citrate (1mg/kg) group | 1.29±0.21 | 1.21±0.15** | 323.2±45.1 | 22.3±3.4 |
| (4) Tofacitinib citrate (2 mg/kg) group | 1.25±0.23** | 1.19±0.26 | 273.2±29.3* | 18.5±2.5* |
| (5) Ibuprofen (100mg/kg) group | 1.35±0.19* | 1.23±0.16** | 377.2±30.5** | 27.2±1.9** |
| (6) Ibuprofen (150mg/kg) group | 1.29±0.21** | 1.20±0.13** | 368.6±26.4** | 23.1±2.6* |
| (7) Ibuprofen (200mg/kg) group | 1.25±0.22** | 1.12±0.19** | 346.7±29.2** | 21.8±2.7** |
| (8) Tofacitinib citrate (1mg/kg) + ibuprofen (60 mg/kg) | 1.02±0.15* | 0.93±0.15* | 162.6±26.3** | 12.5±3.6 |
| (9) Tofacitinib citrate (1mg/kg) + ibuprofen (70mg/kg) | 1.08±0.16 | 1.01±0.25** | 159.7±30.4* | 13.0±3.1** |
| (10) Tofacitinib citrate (1mg/kg) + ibuprofen (80 mg/kg) | 1.05±0.21* | 1.05±0.22* | 152.2±23.5** | 12.6±2.8** |
The results show that the combined application group of tofacitinib and ibuprofen can reduce the levels of IL-1 beta, IL-6, IgG and IgG2b more obviously than the single drug application group.
In the invention, although both tofacitinib and ibuprofen can be used for treating rheumatoid arthritis, the dosage and the effect of the tofacitinib and ibuprofen are unpredictable, and particularly, the prior art lacks the technical suggestion of predicting the treatment effect after dosage reduction. The invention combines two medicines with lower effective doses than the respective medicines, thereby not only reducing the toxic and side effects of tofacitinib, but also generating the beneficial effect of synergy and providing an important treatment selection for patients with rheumatoid arthritis.
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 (23)
1. A composition for treating rheumatoid arthritis, said composition comprising component a and component B, wherein component a is tofacitinib or a pharmaceutically acceptable salt thereof, and component B is one or more of non-steroidal anti-inflammatory drugs (NSAIDs).
2. The composition according to claim 1, wherein the weight ratio of component a (in tofacitinib) to component B is 1: 30 to 240.
3. The composition according to claim 1, wherein the weight ratio of component a (in tofacitinib) to component B is 1: 60 to 120.
4. The composition according to claim 1, wherein the weight ratio of component a (in tofacitinib) to component B is 1: 60-80.
5. The composition of claim 1, wherein the component B is one or more of aspirin, acetaminophen, diclofenac, indomethacin, ibuprofen, sulindac, naproxen, nabumetone, piroxicam and celecoxib.
6. The composition of claim 1, wherein component a is tofacitinib citrate and component B is ibuprofen.
7. The composition according to claims 1-6, wherein the oral administration form of the composition is tablet, granule, capsule or solution.
8. The composition according to claims 1 to 6, wherein the composition is administered orally, preferably in the form of a slow-release capsule.
9. The composition according to claims 1-6, wherein the component A is tofacitinib citrate, the component B is ibuprofen, and the weight ratio of the component A (calculated as tofacitinib) to the component B is 1: 60-120, and the oral administration dosage form of the composition is a sustained-release capsule.
10. The composition according to claims 1-6, wherein the component A is tofacitinib citrate, the component B is ibuprofen, and the weight ratio of the component A (calculated as tofacitinib) to the component B is 1: 60-80, and the oral administration dosage form of the composition is a sustained-release capsule.
11. The composition according to claims 9-10, wherein the sustained release capsule consists of granules comprising a and comprising B.
12. The composition of claim 11, wherein the particles are composed of one or more of micro-tablets, micro-pellets.
13. The composition of claim 11, wherein the granules consist of one or more of immediate release granules, sustained release granules, or both.
14. A composition according to claims 11-13, wherein the granules consist of immediate release granules comprising a and sustained release granules comprising B.
15. The composition of claim 14, wherein the immediate release granule formulation composition comprises, but is not limited to:
and (2) component A: 5 to 20 percent of
A sucrose pellet core: 80 to 95 percent
Polyvidone: 1 to 5 percent.
16. The composition of claim 14, wherein the sustained release granule formulation comprises but is not limited to:
and (B) component: 70 to 90 percent
A sucrose pellet core: 10 to 30 percent
Polyvidone: 1 to 5 percent.
17. The composition of claim 16, wherein the immediate release granules release completely within 1 hour and the sustained release granules release continuously for more than 12 hours.
18. The composition of claims 9-10, wherein the extended release capsule consists of the same granule comprising an immediate release layer comprising a and an extended release layer comprising B.
19. The composition of claim 18, wherein the particle prescription composition comprises but is not limited to:
and (2) component A: 0.5 to 5 percent
And (B) component: 65 to 90 percent
A sucrose pellet core: 10 to 30 percent
Polyvidone: 1 to 5 percent.
20. The composition of claim 19, wherein the immediate release layer comprising a of the granule is completely released within 1 hour and the sustained release layer comprising B is released over a period of more than 12 hours.
21. The composition of claim 19, wherein the particles do not contain a slow release material.
22. The composition of claim 19, wherein the particle prescription composition comprises but is not limited to:
and (2) component A: 5mg of
And (B) component: 300mg
A sucrose pellet core: 80mg of
Polyvidone: 8 mg.
23. The composition of claim 19, wherein the particle prescription composition comprises but is not limited to:
and (2) component A: 5mg of
And (B) component: 400mg of
A sucrose pellet core: 80mg of
Polyvidone: 10 mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010225900.1A CN113440614A (en) | 2020-03-26 | 2020-03-26 | Composition for treating rheumatoid arthritis and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010225900.1A CN113440614A (en) | 2020-03-26 | 2020-03-26 | Composition for treating rheumatoid arthritis and application thereof |
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| CN106456777A (en) * | 2014-05-27 | 2017-02-22 | 阿尔米雷尔有限公司 | Combination |
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| CN106456777A (en) * | 2014-05-27 | 2017-02-22 | 阿尔米雷尔有限公司 | Combination |
| CN106902119A (en) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | Application of tofacitinib citrate in medicine for treating multiple Takayasu arteritis |
| US20190083609A1 (en) * | 2016-01-18 | 2019-03-21 | Helmoltz Zentrum München - Deutsches Forschungszentrum Für Gesundheit And Umwelt (Gmbh) | Tofacitinib as vaccination immune modulator |
| WO2019038156A1 (en) * | 2017-08-22 | 2019-02-28 | Bayer Pharma Aktiengesellschaft | Use of an ep4 antagonist for the treatment of arthritis |
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