CN104138599A - Application of medicinal composition - Google Patents
Application of medicinal composition Download PDFInfo
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- CN104138599A CN104138599A CN201310170815.XA CN201310170815A CN104138599A CN 104138599 A CN104138599 A CN 104138599A CN 201310170815 A CN201310170815 A CN 201310170815A CN 104138599 A CN104138599 A CN 104138599A
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- anisodamine
- pharmaceutical composition
- cholinesterase inhibitor
- neostigmine
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Abstract
The invention discloses an application of a medicinal composition in the preparation of anti-rheumatoid arthritis medicines. The medicinal composition contains a muscarine acceptor blocker and a cholinesterase inhibitor. The medicinal composition has the advantages of strong anti-inflammatory effect, substantial effect, small toxic side effects, and overcoming of side effects caused by present medicines when the medicinal composition is used to treat the rheumatoid arthritis.
Description
Technical field
The present invention relates to a kind of application of pharmaceutical composition.
Background technology
In prior art, the clinical application of M-ChR blocker is as follows: 1, remove smooth muscle spasm: be applicable to various internal organs angor, to gastrointestinal angor, irritation sign of bladder is as better in the curative effect such as frequent micturition, urgent micturition, but poor to biliary colic or Renal Colic, often need share with opium kind analgesics.2, suppress glandular secretion: for administration before general anesthesia, to reduce respiratory tract body of gland and salivary gland secretion, prevent the generation of block of secretion respiratory tract and aspiration pneumonitis, also can be used for serious night sweat and ptyalism.3, ophthalmology: 1) iridocyclitis: 0.5%～1% atropine solution eye drip, can relax iris sphincter muscle and ciliary muscle, make it abundant rest, contributes to inflammation to disappear; Also can prevent iris and lenticular adhesion, still can with miotic alternate application; 2) optometry gets the right lensses for one's eyeglasses: ophthalmic drips and has the paralysis effect of adjusting with atropine, now because crystalline lens is fixed, and can the lenticular diopter of Accurate Determining; But atropine acting duration is longer, can maintain 2～3 days, therefore now use less; While only having child's optometry, still use it, because child's ciliary muscle regulatory function is stronger, need bring into play it with atropine and regulate fully paralysis effect; 3) examination of ocular fundus: utilize its platycoria effect, can carry out examination of ocular fundus; 4) slow arrhythmia: atropine can be used for treating vagus nerve be overexcited due to the slow arrhythmia such as sino atrial block, auriculoventricular block; 5) shock: to patients with septic shock, available large-dose of atropine treatment, can remove vasospasm, and diastole peripheral blood vessel, improves microcirculation; 6) rescue organophosphorus compounds is poisoning.
The clinical application of cholinesterase inhibitor is as follows: 1, myasthenia gravis; 2, postoperative abdomen flatulence and urine retention: the neostigmine excited gastrointestinal smooth muscle of energy and detrusor of bladder, promote aerofluxus and urinate; 3, the excessive poisoning rescue of muscle relaxant: the rescue when as excessive in tubocurarine for nondepolarizing type skeletal muscle relaxant; 4, other application: paroxysmal supraventricular tachycardia, glaucoma.But the use of combining of M-ChR blocker and cholinesterase inhibitor pharmaceutical composition there is not yet report.
Rheumatoid arthritis (RA) is a kind of chronic inflammation disease taking symmetry multi-joint inflammation as main manifestations, has histoorgan outside joint to get involved, and can disable and make quality of life to decline.The method of traditional treatment RA, is mainly the antirheumatic medicine that adopts non-steroidal drug, glucocorticoid and can improve the state of an illness, and side effect is larger.In RA patient's synovium of joint liquid and blood, have cytokine profiles to exist, and proinflammatory cytokine is serving as vital role aspect RA synovioblast invasive growth.Research finds that Anisodamine is by blocking-up M cholinoceptor, make more acetylcholine in body act on macrophage α 7 nicotine receptors, strengthen the activation of acetylcholine to macrophage α 7 nicotine receptors, thereby activated nicotine anti-inflammatory pathway, reached the effect for the treatment of RA.But use separately clinically Anisodamine to exist dosage large, easily produce the shortcoming of atropine-like side effect.
Summary of the invention
Technical problem to be solved by this invention is the problem that lacks clinically effective drugs for rheumatoid arthritis at present in order to overcome, and provides a kind of pharmaceutical composition in the application of preparing in resisting rheumatoid disease arthritis drug.
For solving the problems of the technologies described above, one of technical scheme that the present invention takes is: a kind of pharmaceutical composition is in the application of preparing in resisting rheumatoid disease arthritis drug, and wherein said pharmaceutical composition contains M-ChR blocker and cholinesterase inhibitor.
Wherein said rheumatoid arthritis (Rheumatoid arthritis, RA) is a kind of general autoimmune disease taking chronic aggressivity arthritis as feature.The lesion characteristic of rheumatoid arthritis is synovitis, and the articular cartilage causing thus and bone destruction, finally causes joint deformity.
When the present invention finds that through research combining of M-ChR blocker and cholinesterase inhibitor used treatment rheumatoid arthritis, action effect is remarkable, and the drug dose using is little, effect is strengthened greatly, and overcome M-ChR blocker xerostomia, flushing, slight platycoria, look the side effect such as nearly thing is fuzzy, and use the cholinesterase inhibitor m receptor excitement that can cause to the unify untoward reaction of digestive system of cardiovascular system.
Wherein, the quality ratio of described M-ChR blocker and cholinesterase inhibitor is preferably 2.5 × 10
2～4.0 × 10
3.
Wherein, described M-ChR blocker is the conventional M-ChR blocker that uses in this area, is preferably selected from Anisodamine, containing one or more in plant extract and the atropine of Anisodamine, commercially available obtaining.
As shown in Equation 1, it is the esters being formed by tropic acid and organic base to the structural formula of described Anisodamine, and structure and atropine are similar, on 6 carbon atoms of tropyl, has asymmetric hydroxyl.
Formula 1
Described atropinic structural formula as shown in Equation 2.
Formula 2
Wherein, described cholinesterase inhibitor is the conventional cholinesterase inhibitor using in this area, is preferably one or more in neostigmine, pyridostigmine bromide and physostigmine, commercially available obtaining.
The structural formula of described neostigmine as shown in Equation 3.
Formula 3
The structural formula of described physostigmine as shown in Equation 4.
Formula 4
The structural formula of described pyridostigmine bromide as shown in Equation 5.
Formula 5
In the present invention, described Anisodamine can also extract from plant.Described Anisodamine can extract from plant Radix Anisodi Tangutici, extracting method can list of references " Simultaneous analysis of hyoscyamine, scopolamine, 6 β-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography " (Journal of Chromatography A, 2005,1091 (1-2): 32-39).
A preferred embodiments in the present invention, described M-ChR blocker is Anisodamine, described cholinesterase inhibitor is neostigmine.
In the present invention, described pharmaceutical composition is preferably one of following four kinds of pharmaceutical compositions:
(1) neostigmine: the mass ratio of Anisodamine is 1:500-1:4000;
(2) neostigmine: atropinic mass ratio is 1:250-1:500;
(3) pyridostigmine bromide: the mass ratio of Anisodamine is 1:250-1:500;
(4) pyridostigmine bromide: atropinic mass ratio is 1:500-1:2000.
Described pharmaceutical composition is preferably neostigmine: the mass ratio of Anisodamine is 1:500.
All commercially available obtaining of each raw material of addressing in the present invention or reagent.
The preparation method of pharmaceutical composition of the present invention can be by existing commercially available above-claimed cpd, or the extract containing above-claimed cpd extracting from plant, by proportioning, adopts the conventional method of this area mix and get final product.
Pharmaceutical composition of the present invention also can comprise existing other the medicine for the treatment of rheumatoid arthritis as active constituents of medicine, as long as its not appreciable impact pharmaceutical composition effect of the present invention.
As required, pharmaceutical composition of the present invention also can comprise pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, and wherein, diluent is as starch, Icing Sugar, dextrin, microcrystalline Cellulose, mannitol, lactose and Semen sojae atricolor wet goods; Binding agent is as polyvinylpyrrolidone or hydroxypropyl cellulose etc.; Disintegrating agent is as sodium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose etc.; Lubricant is as magnesium stearate or Pulvis Talci etc.; Stabilizing agent is as sodium carboxymethyl cellulose or cyclodextrin etc.; Antiseptic is as ethylparaben or sodium benzoate etc.In addition, can also in this pharmaceutical composition, add other adjuvant if flavouring agent and/or sweeting agent are as sucrose, fructose and aspartame etc.The active component of this pharmaceutical composition is the M-ChR blocker of the present invention for the treatment of effective dose and the pharmaceutical composition of cholinesterase inhibitor.This pharmaceutical composition can adopt the method for medical domain routine, and described active component and pharmaceutically acceptable carrier are made to various dosage forms.When oral, can be prepared into conventional solid preparation as tablet, capsule, soft capsule, liquid preparation, granule, soft extract, pill, drop pill, suspending agent, dispersant, syrup or suppository etc.; While being used for injecting, can be prepared into injection.Each pharmaceutical composition of the present invention can put on by dosage form the patient who needs this treatment by intravenous injection, subcutaneous injection or oral form.The general dosage that imposes on the patient who needs treatment is that M-ChR blocker is 1-100mg/kg, and cholinesterase inhibitor is 6.25-100 μ g/kg; Preferably dosage M-ChR blocker is 12.5-50mg/kg, and cholinesterase inhibitor is 12.5-50 μ g/kg; Best dosage is Anisodamine 25mg/kg, neostigmine 50 μ g/kg.In concrete use procedure, also can take the circumstances into consideration to change according to patient's age, the state of an illness etc.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition, can combination in any, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the present invention proposes that first M-ChR blocker and this two classes medicine of cholinesterase inhibitor are combined to use (being Compouneded anisodamine) in the proper ratio and carrys out Synergistic treatment rheumatoid arthritis, has obtained the therapeutic combination that a kind of antiphlogistic effects is good and side effect is low.The invention discloses described pharmaceutical composition in the application of preparing in resisting rheumatoid disease arthritis drug, wherein said pharmaceutical composition contains M-ChR blocker and cholinesterase inhibitor.Pharmaceutical composition of the present invention is for the preparation of resisting rheumatoid disease arthritis drug, and gained medicine antiinflammatory action strengthens, and effect is remarkable, and toxic and side effects is little, has overcome the side effect that existing medicine often causes.
Brief description of the drawings
Fig. 1 is mouse arthritis therapeutic outcome figure.Wherein A is mouse arthritis appraisal result figure; B is Mouse Weight result figure; C is mice joint photo.
Fig. 2 is mouse arthritis radiology testing result figure.Wherein A is X-ray check result figure; B is Micro-CT testing result figure; C is radiology appraisal result figure.In Fig. 2 (C), 1 is common mice, and 2 is blank group mice, and 3 is medication therapy groups mice.
Fig. 3 is the result figure of mice joint tissue section HE dyeing.Wherein A is the result figure of HE dyeing; B is HE dyeing appraisal result figure.In Fig. 3 (B), 1 is common mice, and 2 is blank group mice, and 3 is medication therapy groups mice.
Detailed description of the invention
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to conventional method and condition, or selects according to catalogue.
Anisodamine, Hangzhou Fu Ma Chemical Co., Ltd.; Neostigmine, Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd..
Embodiment 1
Mouse arthritis modeling and administration: use cattle II Collagen Type VI (Chondrex, 2002-1) to be dissolved in 0.1M glacial acetic acid solution, concentration is 4mg/ml, and 4 DEG C are spent the night.Get 1.2ml cattle II Collagen Type VI-glacial acetic acid solution and Freund's complete adjuvant (Chondrex, 7001) mixed in equal amounts, emulsifying, low-temperature operation.Inject 100 μ l, immune from mice (male DBA/1 mice, Shanghai Shrek company limited) 1.5cm place of root of the tail portion injection 100 μ l for the first time, tail Intradermal inserting needle, injects 2-3 point.Immunity is for the first time designated as 0 day, and immunity is for the second time the 21st day, Freund's incomplete adjuvant and cattle II Collagen Type VI acetic acid solution mixed in equal amounts emulsifying, and 100 μ l inject in root of the tail portion.Matched group is injecting normal saline.Body weight and the redness and swelling of joints degree of a mice of every two days records after immunity for the second time, immunity abdominal cavity the previous day gives Compouneded anisodamine (Anisodamine dosage is 25mg/kg, and neostigmine dosage is 50 μ g/kg), successive administration ten days for the second time.
Draw materials: test cervical vertebra dislocation in the 35th day and put to death mice, get ankle joint, 4% paraformaldehyde is fixed, 10%EDTA decalcification, conventional dehydration, paraffin embedding, section, HE dyeing, claps X-ray (faxitron x-ray Mx-20) and is Micro-CT(eXplore Locus Micro CT), the detection method explanation that installs instruments operates.
Mouse arthritis scoring: each arthropathy degree is by 5 grades of point systems." 0 ": without red and swollen; " 1 ": the red pneumonedema in joint; " 2 ": joint is slightly red and swollen; " 3 ": joint moderate redness; " 4 ": the red and swollen companion of joint severe dysfunction.Arthritis mark (arthritis score, AS) is the summation of every all pathological changes of mice joint mark, and best result is 16 points.The summation of all mouse arthritis marks of each group, divided by the number of elements of this group mice, is the average arthritis index of this group (mean arthritic index, MAI).
The HE scoring of dyeing: " 0 ": NIP is invaded; " 1 ": extremely light inflammation is invaded; " 2 ": weak inflammation is invaded; " 3 ": the inflammation of moderate is invaded and edema; " 4 ": significant inflammation is invaded and significant edema; " 5 ": serious inflammation is invaded and edema.
Radiology scoring: " 0 ": damage without bone; " 1 ": swollen tissue and edema; " 2 ": junction erosion, corrode; " 3 ": bone corrosion and bone good horse.
Experimental result: compound treatment group mouse arthritis degree obviously alleviates.As a result one: the scoring for the treatment of group mouse arthritis is starkly lower than matched group, the body weight for the treatment of group mice also by treatment higher than matched group, the above results is as shown in Figure 1.As a result two: X-ray check result shows that treatment group bone-loss compared with matched group obviously reduces; The result of Micro-CT shows to be obviously lighter than matched group with the bone corrosion of the scorching mice of compound treatment posterior joint, and the above results as shown in Figure 2.As a result three: the articular morphology that the result of HE dyeing shows treatment group mice relatively completely and synovial membrane erosion degree be also obviously lighter than matched group, shown in the above results Fig. 3.
Should be understood that, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (7)
1. pharmaceutical composition, in an application of preparing in resisting rheumatoid disease arthritis drug, is characterized in that, described pharmaceutical composition contains M-ChR blocker and cholinesterase inhibitor.
2. application as claimed in claim 1, is characterized in that: described M-ChR blocker is selected from Anisodamine, containing one or more in plant extract and the atropine of Anisodamine.
3. application as claimed in claim 1, is characterized in that: described cholinesterase inhibitor is one or more in neostigmine, pyridostigmine bromide and physostigmine.
4. application as claimed in claim 1, is characterized in that: described M-ChR blocker is Anisodamine; Described cholinesterase inhibitor is neostigmine.
5. application as claimed in claim 1, is characterized in that: described M-ChR blocker and the quality ratio of cholinesterase inhibitor are 2.5 × 10
2-4.0 × 10
3.
6. application as claimed in claim 1, is characterized in that, described pharmaceutical composition is the one in following four kinds of pharmaceutical compositions:
(1) neostigmine: the mass ratio of Anisodamine is 1:500-1:4000;
(2) neostigmine: atropinic mass ratio is 1:250-1:500;
(3) pyridostigmine bromide: the mass ratio of Anisodamine is 1:250-1:500;
(4) pyridostigmine bromide: atropinic mass ratio is 1:500-1:2000.
7. application as claimed in claim 1, is characterized in that: described pharmaceutical composition also comprises pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310170815.XA CN104138599A (en) | 2013-05-10 | 2013-05-10 | Application of medicinal composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310170815.XA CN104138599A (en) | 2013-05-10 | 2013-05-10 | Application of medicinal composition |
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|---|---|
| CN104138599A true CN104138599A (en) | 2014-11-12 |
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| CN201310170815.XA Pending CN104138599A (en) | 2013-05-10 | 2013-05-10 | Application of medicinal composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110742889A (en) * | 2019-11-25 | 2020-02-04 | 镇江星盘商务咨询有限公司 | Medicine for treating colitis |
-
2013
- 2013-05-10 CN CN201310170815.XA patent/CN104138599A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| LI SUN ETAL: "Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors", 《ACTA PHARMACOLOGICA SINICA》 * |
| MARJOLEIN A. VAN MAANEN ETAL: "Stimulation of Nicotinic Acetylcholine Receptors Attenuates Collagen-Induced Arthritis in Mice", 《ARTHRITIS & RHEUMATISM》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110742889A (en) * | 2019-11-25 | 2020-02-04 | 镇江星盘商务咨询有限公司 | Medicine for treating colitis |
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Application publication date: 20141112 |