CN115252626B - Pharmaceutical composition containing glucocorticoid and application thereof - Google Patents
Pharmaceutical composition containing glucocorticoid and application thereof Download PDFInfo
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- CN115252626B CN115252626B CN202210992088.4A CN202210992088A CN115252626B CN 115252626 B CN115252626 B CN 115252626B CN 202210992088 A CN202210992088 A CN 202210992088A CN 115252626 B CN115252626 B CN 115252626B
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- triptolide
- pharmaceutical composition
- poloxamer
- gel
- methylprednisolone aceponate
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 239000003862 glucocorticoid Substances 0.000 title abstract description 17
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 claims abstract description 62
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 claims abstract description 62
- DALKLAYLIPSCQL-YPYQNWSCSA-N methylprednisolone aceponate Chemical compound C1([C@@H](C)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CC)[C@@]2(C)C[C@@H]1O DALKLAYLIPSCQL-YPYQNWSCSA-N 0.000 claims abstract description 40
- 229960002037 methylprednisolone aceponate Drugs 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 24
- 241000830536 Tripterygium wilfordii Species 0.000 claims abstract description 19
- 235000015398 thunder god vine Nutrition 0.000 claims abstract description 19
- 229930014626 natural product Natural products 0.000 claims abstract description 13
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 26
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- 230000000694 effects Effects 0.000 abstract description 10
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 abstract description 4
- 229960004584 methylprednisolone Drugs 0.000 abstract description 4
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 8
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
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- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010047124 Vasculitis necrotising Diseases 0.000 description 1
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- 230000003213 activating effect Effects 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 230000000241 respiratory effect Effects 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition for treating rheumatoid arthritis, wherein the weight ratio of active ingredients of glucocorticoid to natural products of tripterygium wilfordii is 1: (1-5), wherein the glucocorticoid is methylprednisolone or methylprednisolone aceponate, and the natural product of the tripterygium wilfordii is one or more of triptolide, triptolide and triptolide. The medicine composition provided by the invention has the advantages of simple preparation method and stable quality, and various active ingredients can be used for synergistically treating the rheumatoid arthritis while respective effects are exerted.
Description
Technical Field
The invention relates to the field of medicines, in particular to a pharmaceutical composition containing glucocorticoid.
Background
Rheumatoid arthritis is a chronic autoimmune disease characterized by destructive and symmetrical arthropathy and arthromeningitis, and mainly comprises symptoms such as joint deformity, morning stiffness, ankle temporomandibular arthritis and the like, and can not only reduce the exercise function of a patient, but also accumulate respiratory, renal, cardiac and other systems, so that the life and work of the patient are seriously affected. If the illness state of the patient is not controlled effectively in time, complications such as sicca syndrome, pericarditis, anemia, necrotizing vasculitis and the like can be caused, and the life safety of the patient is threatened.
At present, the pathogenesis of the rheumatoid arthritis is still in a research stage in the medical field, but students consider genetic and environmental factors to be main factors for causing the rheumatoid arthritis, and meanwhile, more immune cells, immune molecules and other substances exist in synovial tissues and synovial fluid of patients, which indicates that the occurrence of the rheumatoid arthritis possibly has correlation with the activation or release of the substances or accelerates the progress of the disease of the patients under the action of the substances.
Methylprednisolone is an artificially synthesized halogen-free intermediate glucocorticoid, and the structural characteristics of unsaturated double bonds increase the fat solubility of the intermediate glucocorticoid, so that the intermediate glucocorticoid is easier to penetrate through a lipid barrier to reach target organs rapidly, and therefore, the intermediate glucocorticoid has the advantages of rapid effect, better tissue penetrability, long biological half-life, long acting time, low protein binding rate, large distribution volume, strong anti-inflammatory effect, weak salt-skin hormone effect, small influence on water-sodium slip and weak HPA axis inhibition effect.
Methylprednisolone aceponate is a fourth generation glucocorticoid drug developed by Schering AG, germany, and has a trade name of Advantan, and is marketed in Germany in 1992, and then in more than ten countries such as Italy, korea, etc. Methylprednisolone aceponate is a white or off-white crystalline powder in appearance, which is extremely soluble in methylene chloride, readily soluble in methanol, ethanol and acetone, and practically insoluble in water. Compared with prednisolone, the modified methylprednisolone aceponate is introduced with propionate and acetate groups, so that the lipophilicity of the methylprednisolone aceponate is greatly improved, the medicine molecules can rapidly and effectively penetrate through the stratum corneum, the effective concentration at a treatment position is ensured, and meanwhile, the methylprednisolone aceponate cannot reach high concentration in blood, so that the systemic side effect is reduced.
As a traditional Chinese medicine, the tripterygium wilfordii has bitter taste and has the effects of activating blood circulation to dissipate blood stasis, clearing heat and detoxicating, detumescence and resolving masses, killing parasites and stopping bleeding and the like. The root, stem and leaf of Tripterygium wilfordii can be used as medicines, but the main clinical medicinal part is the root at present. Pharmacological and clinical studies prove that more than 200 monomer compounds can be separated from the tripterygium wilfordii, wherein tripterygium wilfordii polyglycoside is a main active ingredient of the tripterygium wilfordii. Tripterygium wilfordii has antiinflammatory, antitumor, immunoregulatory and fertility resisting properties, and can be widely used for treating various autoimmune diseases such as rheumatoid arthritis, glomerulonephritis and lupus erythematosus.
At present, the literature of combining glucocorticoid and natural product of tripterygium wilfordii for treating rheumatoid arthritis has not been reported.
Disclosure of Invention
The invention aims to solve the technical problem of providing a pharmaceutical composition which can effectively treat rheumatoid arthritis and has natural source of main active ingredients.
The technical scheme adopted by the invention for solving the problems is to provide a pharmaceutical composition for treating rheumatoid arthritis, wherein the weight ratio of the glucocorticoid serving as an active ingredient to the natural product of tripterygium wilfordii is 1: (1-5).
Preferably, the glucocorticoid is methylprednisolone or methylprednisolone aceponate. More preferably, the glucocorticoid is methylprednisolone aceponate.
Preferably, the natural product of Tripterygium wilfordii is selected from one or more of triptolide, and triptolide. More preferably, the natural product of Tripterygium wilfordii is selected from one or more of triptolide and triptolide. Most preferably, the natural product of Tripterygium wilfordii is a combination of triptolide and triptolide.
Preferably, in the pharmaceutical composition, the weight ratio of methylprednisolone aceponate, triptolide and triptolide is 1: (1-2): (1-2).
Preferably, in the pharmaceutical composition, the weight ratio of methylprednisolone aceponate, triptolide and triptolide is 1:2:2.
preferably, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutical composition is an external preparation.
Preferably, the pharmaceutical composition is a patch, a film, an ointment or a gel. More preferably, the pharmaceutical composition is a gel.
Preferably, the gel comprises a gel matrix, a humectant, a solubilizer and a solvent.
Preferably, the gel matrix is poloxamer 407 and/or poloxamer 188; more preferably, the gel matrix is a composition of poloxamer 407 and poloxamer 188, and the weight ratio of poloxamer 407 to poloxamer 188 is (1-5): 1, a step of; most preferably, the gel matrix is a composition of poloxamer 407 and poloxamer 188 in a weight ratio of 3:1.
Preferably, the humectant is glycerin, the solubilizer is tween 80, and the solvent is distilled water.
Preferably, the gel comprises poloxamer 407, poloxamer 188, glycerin, tween 80 and distilled water.
More preferably, the gel is prepared from the following components in percentage by weight: methylprednisolone aceponate 0.2%, triptolide 0.4%, poloxamer 407 9%, poloxamer 188 3%, glycerol 14%, tween 80 3% and distilled water 70%.
The second aspect of the present invention provides a method for preparing the above pharmaceutical composition, comprising the steps of:
(1) Uniformly mixing glucocorticoid, natural product of radix Tripterygii Wilfordii and solubilizer to obtain medicinal liquid;
(2) Adding a humectant into the gel matrix, uniformly mixing the mixture and the liquid medicine prepared in the step (1);
(3) Adding a solvent into the solution obtained in the step (2), stirring and swelling, and standing for 24 hours to obtain the product.
The third aspect of the invention also provides application of the pharmaceutical composition in preparing medicines for treating rheumatoid arthritis.
The fourth aspect of the invention also provides the use of the above pharmaceutical composition for the preparation of a medicament for reducing the level of one or more of TNF-alpha, IL-1 beta and INF-gamma in serum.
Preferably, the invention also provides application of the pharmaceutical composition in preparing medicines for simultaneously reducing the contents of TNF-alpha, IL-1 beta and INF-gamma in serum.
The fifth aspect of the invention also provides the use of a gel matrix, which is a combination of poloxamer 407 and poloxamer 188, for improving the chemical stability of natural products of tripterygium wilfordii in the pharmaceutical composition.
Preferably, the gel matrix is prepared from the following components in percentage by weight (1-5): 1 and poloxamer 407 and poloxamer 188; more preferably, the gel matrix is a composition of poloxamer 407 and poloxamer 188 in a weight ratio of 3:1.
Preferably, the invention also provides application of the gel matrix in improving the chemical stability of triptolide and triptolide in the pharmaceutical composition, wherein the gel matrix is a composition of poloxamer 407 and poloxamer 188 in a weight ratio of 3:1.
The invention has the positive beneficial effects that:
the inventor of the invention unexpectedly discovers that when the glucocorticoid methylprednisolone aceponate is combined with the natural products of tripterygium wilfordii selected from triptolide, triptolide and triptolide, the glucocorticoid methylprednisolone has unexpected excellent effect on treating rheumatoid arthritis, and a plurality of active ingredients can cooperatively treat the rheumatoid arthritis while exerting respective effects. In addition, the invention obtains the gel preparation with obviously improved chemical stability of the natural product of the tripterygium wilfordii through optimizing the types of gel matrixes (poloxamer 407 and poloxamer 188), which is beneficial to the quality control and long-term storage of the pharmaceutical preparation.
Detailed Description
The present invention will be further described with reference to examples, but the embodiments of the present invention are not limited thereto. The experimental methods used in the following examples are conventional methods unless otherwise specified.
Example 1 gel preparation F1 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 0.4g of triptolide with 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F1.
Example 2 gel formulation F2 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.2g of triptolide and 0.6g of triptolide with 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F2.
Example 3 gel formulation F3 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.6g of triptolide and 0.2g of triptolide with 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F3.
Example 4 gel formulation F4 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 0.4g of triptolide with 3g of tween 80 to obtain a liquid medicine; 14g of glycerin is added into a mixture of 6g of poloxamer 407 and 6g of poloxamer 188, and the mixture is uniformly mixed with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F4.
Example 5 gel formulation F5 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 0.4g of triptolide with 3g of tween 80 to obtain a liquid medicine; 14g of glycerin is added into a mixture of 11g of poloxamer 407 and 1g of poloxamer 188, and the mixture is uniformly mixed with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F5.
Example 6 gel formulation F6 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation F6.
Comparative example 1 gel preparation C1 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.8g of triptolide and 3g of tween 80 to obtain liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain a gel preparation C1.
Comparative example 2 gel preparation C2 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.8g of triptolide and 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation C2.
Comparative example 3 gel preparation C3 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.8g of triptolide and 3g of tween 80 to obtain liquid medicine; adding 14g of glycerin into a mixture of 9g of poloxamer 407 and 3g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation C3.
Comparative example 4 gel preparation C4 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 0.4g of triptolide with 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into 12g of poloxamer 407, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation C4.
Comparative example 5 gel preparation C5 containing methylprednisolone aceponate
Uniformly mixing 0.2g of methylprednisolone aceponate, 0.4g of triptolide and 0.4g of triptolide with 3g of tween 80 to obtain a liquid medicine; adding 14g of glycerin into 12g of poloxamer 188, uniformly mixing, and uniformly mixing with the liquid medicine; adding 70g of distilled water, stirring and swelling, and standing for 24 hours to obtain gel preparation C5.
Test example 1 therapeutic effects of the pharmaceutical composition of the present invention on Rheumatoid Arthritis (RA) model rats
1. Test method
RA rat model was established using Freund's Complete Adjuvant (FCA) induction, specific methods: the left hind plantar region was injected with 0.1mL of complete freund's adjuvant, and on day 1 of injection, rat body weight and left hind sole volume were recorded, followed by measurement of non-injected sole volume with a plethysmograph. The secondary connective tissue was re-weighed on day 21 and was observed and rated for severe swelling of connective tissue on a score scale, 1 point. (3) Tail: no knots are arranged, and 0 minutes is counted; the number of knots is 1 minute. (4) Front claw: no inflammation appearance of joints, counting 0 points; at least one joint exhibits an inflammatory manifestation, counting 1 minute. (5) Rear claw: no inflammation appearance of joints, counting 0 points; joints showed mild inflammation, counting 1 minute; moderate inflammation, count 2 points; severe inflammation, counted 3 points. And when the secondary reaction reaches a peak value, evaluating each group of rats according to the grading method, comparing and analyzing grading results by adopting a double-sample heteroscedastic t test, and indicating successful modeling when the grading of each part of the rats shows a significant difference. The 80 rats selected for successful molding were randomly divided into 8 groups, namely, a model group, examples 1-3, 6 groups of the present invention and comparative examples 1-3 groups of 10 each. Another 10 non-model rats were taken as a blank group.
On day 2 after successful molding, the gel formulations prepared in examples 1-3, 6 and comparative examples 1-3 were applied to the molding site at a dose of 0.1g/kg body weight, 2 times daily, once a day and 4 weeks in succession, and the blank and model groups were each applied with an equivalent dose of a blank gel matrix containing no active ingredient (matrix formulation same as in example 1). On day 2 after the end of the drug treatment period, 5mL of tail venous blood of the rats of each test group was collected using an anticoagulant tube, centrifuged at 3500r/min for 15min, and serum was isolated. ELISA method for determining TNF-alpha, IL-1 beta and INF-gamma content in rat serum
2. Test results
The effect of each of the test groups according to the invention on TNF- α, IL-1β and INF- γ in serum of RA model rats is shown in Table 1 below.
TABLE 1 therapeutic effects of the pharmaceutical compositions of the invention on RA-model rats
Group of | TNF-α(ng/L) | IL-1β(ng/L) | INF-γ(ng/L) |
Blank group | 21.38±2.56 | 8.51±1.34 | 212.36±25.41 |
Model group | 82.04±6.14 | 62.92±5.20 | 551.91±48.09 |
Example 1 | 23.97±3.39 | 10.04±1.51 | 246.31±29.80 |
Example 2 | 36.28±3.45 | 19.13±2.36 | 329.41±35.82 |
Example 3 | 40.92±3.28 | 22.54±3.08 | 342.19±32.05 |
Example 6 | 50.29±4.07 | 32.09±3.37 | 387.62±41.26 |
Comparative example 1 | 63.26±5.50 | 48.05±4.16 | 436.19±43.81 |
Comparative example 2 | 60.07±4.48 | 49.74±5.87 | 451.28±47.25 |
Comparative example 3 | 58.25±4.96 | 50.01±5.51 | 430.92±45.74 |
Studies have reported that IL-1 beta, TNF-alpha play a more direct role in the sustained cellular infiltration and induction of tissue destruction at the site of joint inflammation in rheumatoid arthritis patients and are considered to be the major inflammatory cytokines that undergo bone resorption, destruction and articular cartilage damage, with a more intimate effect with IL-1 beta. Thus, blocking IL-1 beta, TNF-alpha, and IFN-gamma inflammatory factors is critical for controlling joint damage and is a good therapeutic target for rheumatoid arthritis.
The test results in Table 1 above show that the levels of TNF-alpha, IL-1β and INF- γ in serum of RA model rats treated with the gel formulations of examples 1-3 and 6 of the present invention are significantly less than those in the model group (there are significant differences compared to the model group), suggesting that the pharmaceutical compositions of the present invention may be used for the treatment of rheumatoid arthritis, and that the mechanism of action thereof is associated with the reduction of the levels of inflammatory factors TNF-alpha, IL-1β and IFN- γ. In addition, the therapeutic effect of the above examples is also superior to that of comparative examples 1 to 3, and it was confirmed that the combination of the three active ingredients of the present invention is significantly superior to the combination of the two active ingredients in the treatment of rheumatoid arthritis on the basis of the unchanged total amount of the active ingredients, indicating that the three active ingredients produce a synergistic effect, resulting in an unexpected excellent effect.
Experimental example 2 study of chemical stability of pharmaceutical compositions of the present invention
1. Test method
The test set was 5 test groups, wherein test groups 1-3 used the methylprednisolone aceponate-containing gel formulations of the present invention prepared in examples 1 and 4-5, respectively, and test groups 4-5 used the methylprednisolone aceponate-containing gel formulations prepared in comparative examples 4-5, and 3 samples were repeated for each test group. And (3) respectively storing the 5 test groups at 40 ℃ and 75% RH for 6 months, taking out, respectively measuring the content of triptolide and triptolide in each test group preparation, and calculating the average value of the content of triptolide and triptolide in each test group after the triptolide and the triptolide are placed.
2. Test results
The average levels of triptolide and triptolide in each test group are shown in table 2 below.
Table 2 the pharmaceutical composition of the present invention contains triptolide and triptolide at high temperature/high humidity
Test group | Tripterygium wilfordii level (%) | Triptolide content (%) |
Test group 1 | 97.66% | 98.23% |
Test group 2 | 95.29% | 95.32% |
Test group 3 | 95.81% | 95.01% |
Test group 4 | 91.50% | 91.33% |
Test group 5 | 91.07% | 90.28% |
As can be seen from the above table of active ingredient content data, the gel formulations of test groups 1-3 (examples 1 and 4-5) showed no significant decrease in the levels of triptolide and triptolide, and the active ingredient content was maintained at above 95% after storage at high temperature and high humidity. In contrast, poloxamer 188 was omitted in test group 4 (comparative example 4), poloxamer 407 was omitted in test group 5 (comparative example 5), and the content of triptolide and triptolide in the gel preparation after storage was less than 92%, indicating that a large amount of impurities were generated from both active ingredients during storage, and that the chemical stability was poor. The comparison test results show that the gel matrix selected by the invention can effectively inhibit the generation of triptolide and triptolide impurities, and the stability of the compound of the pharmaceutical composition is expected to be good.
Claims (7)
1. The medicine composition for treating the rheumatoid arthritis is characterized in that the weight ratio of the active components methylprednisolone aceponate, triptolide and triptolide in the medicine composition is 1: (1-2): (1-2).
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises methylprednisolone aceponate, triptolide and triptolide in a weight ratio of 1:2:2.
3. the pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a gel.
4. A pharmaceutical composition according to claim 3, wherein the gel comprises a gel matrix, a humectant, a solubiliser and a solvent.
5. A method of preparing the pharmaceutical composition of claim 4, comprising the steps of:
(1) Uniformly mixing methylprednisolone aceponate, triptolide B, triptolide A and a solubilizer to obtain a liquid medicine;
(2) Adding a humectant into the gel matrix, uniformly mixing the mixture and the liquid medicine prepared in the step (1);
(3) Adding a solvent into the solution obtained in the step (2), stirring and swelling, and standing for 24 hours to obtain the product.
6. Use of a pharmaceutical composition according to any one of claims 1-4 for the preparation of a medicament for the treatment of rheumatoid arthritis.
7. Use of a gel matrix for improving the chemical stability of natural products of tripterygium wilfordii in a pharmaceutical composition according to any one of claims 1 to 4, characterized in that the gel matrix is a composition of poloxamer 407 and poloxamer 188, the weight ratio of poloxamer 407 to poloxamer 188 being (1 to 5): 1, the natural products of the tripterygium wilfordii are triptolide B and triptolide A.
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