CN104095867B - Oral preparation for analgesia, and preparation method of oral preparation - Google Patents
Oral preparation for analgesia, and preparation method of oral preparation Download PDFInfo
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- CN104095867B CN104095867B CN201410342879.8A CN201410342879A CN104095867B CN 104095867 B CN104095867 B CN 104095867B CN 201410342879 A CN201410342879 A CN 201410342879A CN 104095867 B CN104095867 B CN 104095867B
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- oral formulations
- pharmaceutical composition
- adjuvant
- sodium
- analgesic
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 230000036592 analgesia Effects 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 22
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 claims abstract description 21
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 claims abstract description 11
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 claims abstract description 11
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 claims abstract description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 10
- 229930195725 Mannitol Natural products 0.000 claims abstract description 10
- 239000000594 mannitol Substances 0.000 claims abstract description 10
- 235000010355 mannitol Nutrition 0.000 claims abstract description 10
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 10
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- AEQDJSLRWYMAQI-UHFFFAOYSA-N Tetrahydropalmatine Natural products C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960001193 diclofenac sodium Drugs 0.000 claims abstract description 9
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims abstract description 9
- AEQDJSLRWYMAQI-KRWDZBQOSA-N tetrahydropalmatine Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3C[C@H]2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-KRWDZBQOSA-N 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
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- 229960003438 aspartame Drugs 0.000 claims abstract description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims abstract description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
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- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of medicines, in particular to an oral preparation for analgesia, and a preparation method of the oral preparation. The oral preparation comprises a medicine composition and auxiliary materials, wherein the medicine composition comprises rosmarinic acid, tetrahydropalmatine, mangiferin and diclofenac sodium at a weight ratio of (2-4):(5-8):(3-6):(2-4); the auxiliary materials are preferably methyl cellulose, mannitol, aerosil and aspartame at a weight ratio of (200-400):(30-80):(30-60):(1-3); and a weight ratio of the medicine composition to the auxiliary materials is 1:(15-30).
Description
Technical field
The present invention relates to drug world is and in particular to a kind of be used for analgesic oral formulations and preparation method thereof.
Background technology
Pain is a kind of protection mechanism, and warning body requirement medicine helps.But, chronic pain loses Protection significance and but weighs
The life of impact people.Clinically at least half of patient is because that pain is sought medical advice.Existing analgesic or drug effect are failed to understand
Aobvious, or the untoward reaction that easy generation is serious, or both have.For example, opium can cause addiction, constipation and respiration inhibition
Deng；The generation of possible opium abuse and drug dependence limits the use of this kind of medicine.NSAID (non-steroidal anti-inflammatory drug), cox-2 suppression
The analgesic effects such as preparation are not good enough, and limit its application because of many fatal and nonfatal untoward reaction.Therefore, develop one
Plant with peripheral acceptor as target spot, analgesic potency is relatively strong but does not affect the medicine of other physiological actions (not having side effects)
Thing is very necessary, also very urgent.
The analgesic clinically commonly used is generally divided into two big class, acts on narcosis analgesic and the work of central nervous system
Non-steroidal anti-inflammatory analgesics (nsaid) for peripheral-system, central analgesicses have very strong analgesic activity, but because its pair is made
With big, especially easily additive and limit its application.Non-steroidal anti-inflammatory analgesics are that a class has antipyretic, analgesia and antiinflammatory is made
Medicine, is the essential drugses for the treatment of pain, analgesic activity is weaker than the former, but side effect is relatively small, treatment slight and in
Etc. being considered as a line choice drug in degree pain.But non-steroidal anti-inflammatory class medicine and opioid drug life-time service can draw
Play serious gastrointestinal reaction and have additive.
Content of the invention
It is an object of the present invention to provide a kind of have synergistic oral formulations containing for analgesia, it is by medicine
Compositionss and adjuvant composition, described pharmaceutical composition is made up of rosmarinic acid, tetrahydropalmatine, chimonin and diclofenac sodium.
Described oral formulations are selected from tablet, capsule, slow releasing tablet, pill, granule, dispersible tablet, powder, preferably piece
Agent.
Adjuvant selected by described oral formulations is selected from starch, Pregelatinized Starch, starch slurry, beta-schardinger dextrin-, Carbomer, micro-
Crystalline cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, Polyethylene Glycol (peg), carboxylic
Sodium carboxymethylcellulose pyce, methylcellulose, ethyl cellulose, Mannitol, sodium lauryl sulphate, cross-linking sodium carboxymethyl cellulose,
Lactose, Polyvinylpyrrolidone (pvp), crospolyvinylpyrrolidone, magnesium stearate, Pulvis Talci, micropowder silica gel, A Siba
Sweet, one or more of orange flavor, sodium bicarbonate, sodium carbonate, enteric coating powder.
Described adjuvant is preferably methylcellulose, Mannitol, micropowder silica gel and aspartame.Between four, weight ratio is successively
For: 200～400:30～80:30～60:1～3.
Weight between described pharmaceutical composition and adjuvant is than for 1:15～30, preferably 1:20.
In one embodiment of the invention, described rosmarinic acid, tetrahydropalmatine, chimonin and diclofenac sodium
Weight is than for 1～10:1～10:1～10:1～10；
Described weight than more preferably 2～4:5～8:3～6:2～4, more preferably 3:6:5:3 or 4:
7:4:2.
Further object is that providing a kind of preparation side for analgesia with synergistic oral formulations
Method, specifically comprises the following steps that
1) pharmaceutical composition and adjuvant were pulverized 80 mesh sieves respectively, by pharmaceutical composition, methylcellulose and Mannitol
It is sufficiently mixed,
2) 50% ethanol soft material, 18 mesh sieves are pelletized, and are dried, 16 mesh sieve granulate at 60 DEG C, add micropowder silica gel, mix,
Tabletting, obtains final product.
Another object of the present invention also resides in the application providing above-mentioned oral formulations in preparation treatment pain medication.
Described pain is preferably the pain that cancer or dysmenorrhes lead to.
Rosmarinic acid (rosmarinicacid) is a kind of natural and multi-functional phenolic acid compound.Rosmarinic acid has suppression
Bacterium, antiinflammatory, antiviral, antitumor, antiallergic, antioxidation, antithrombotic antiplatelet aggregation, radioprotective and immunosuppressive action,
Rosmarinic acid has angst resistance effect to nervous system, has protective effect to cell injury, and concrete structure is as follows:
Chimonin, also known as mangiferin, mangiferin.Light lark acicular crystal (50% ethanol).267～272 DEG C of fusing point
(decomposition).+ 43.3 ° of optical rotation (c=0.9, pyridine), 32 ° (ethanol).Be slightly soluble in methanol, ethanol, water, dissolve in hot dilute methanol,
Hot Diluted Alcohol, insoluble in non-polar solven.Be present in the fruit of Anacardiaceae plant Fructus Mangifera Indicae (mangifera indica l.), leaf,
Bark, the rhizome of the liliaceous plant Rhizoma Anemarrhenae (anemarrhena asphodeloides bge.), aerial partss, irides
In the plants such as the flower of Rhizoma Belamcandae [belamcanda chinensis (l.) dc.], leaf.It has suppression central nervous system, antiinflammatory,
Antibacterial, anti-herpes simplex virus hsv-2, function of gallbladder promoting and immunization, alleviate the sacrum nerve root disease that hsv-2 virus causes: performance
For buttocks or thigh pain or paraesthesia, urine retention, it also has proctitis, urethritiss syndrome etc. with disease.Concrete structure
As follows:
Tetrahydropalmatine derives from papaveraceae plant corydalis (Rhizoma Corydalis) corydalis yanhusuo w.t.wang block
Stem, modern pharmacology shows that its Central nervous system and cardiovascular system have extensive effect, and its concrete structure is as follows:
Diclofenac sodium is one kind of non_steroidal anti_inflammatory drug, and it passes through to suppress cyclooxygenase thus reducing prostaglandin
Synthesis, and to a certain extent suppression lipoxygenase and reduce the generation of the products such as leukotriene, Kallidin I and play antipyretic-antalgic
And antiinflammatory action, concrete structure is as follows:
After technique scheme, the present invention has one of at least following beneficial effect:
Compared with prior art, in pharmaceutical preparation of the present invention pharmaceutical composition treatment pain in terms of have as follows project
Advantage: the pharmaceutical composition Dichlorodiphenyl Acetate induced mice writhing model of the present invention and hot plate induced pain mouse model have good treatment
Effect, and shows good synergism, analgesic effect strong hence it is evident that reducing the consumption of each monomer medicine, thus significantly
Reduce toxic and side effects, reduce untoward reaction and occur.And the present invention carries out science according to the feature of pharmaceutical composition to adjuvant and joins
Put, thus greatly improving the stability of described oral formulations.
Specific embodiment
Below will the further for example bright present invention.It is pointed out that following explanation is only will to the present invention
Ask the illustration of the technical scheme of protection, not any restriction to these technical schemes.Protection scope of the present invention is with institute
The content that attached claims are recorded is defined.
The impact of the mouse writhing number of times that embodiment 1 pharmaceutical composition Dichlorodiphenyl Acetate causes
Male icr mice (20 ± 2) g, by body weight random packet, every group 10, each group gives to treat by gavage respectively
Medicine.Model group gavage gives equal-volume normal saline.Mouse peritoneal injection acetic acid, causes abdominal cavity large area and more lasting
Pain stimulation, cause mice produce writhing response.After each dosage group administration 1h, lumbar injection 0.7% acetic acid physiology salt is water-soluble
Liquid 0.1ml/10g, record, from injecting the writhing response number of times that after acetic acid induced pain, every mice occurs in 20min, calculates and respectively gives
The inhibitory rate of medicine group.
Inhibitory rate=[(matched group writhing number of times-medicine group writhing number of times)/matched group writhing number of times] × 100%
In administration group between monomer medicine weight than referring to following table:
| Rosmarinic acid | Tetrahydropalmatine | Chimonin | Diclofenac sodium | |
| Administration group 1 | 3 | 6 | 5 | 3 |
| Administration group 2 | 4 | 7 | 4 | 2 |
| Administration group 3 | 1 | 5 | 10 | 10 |
Result of the test
The impact of the mouse writhing number of times that pharmaceutical composition Dichlorodiphenyl Acetate causes
| Packet | Dosage (mg/kg) | Writhing number of times | Suppression ratio (%) |
| Model group | Normal saline | 41.3±6.7 | — |
| Rosmarinic acid | 25 | 42.5±7.8 | -2.9 |
| Tetrahydropalmatine | 25 | 35.7±6.6 | 13.5 |
| Chimonin | 25 | 37.9±7.2 | 8.2 |
| Diclofenac sodium | 25 | 32.3±8.1 | 21.7 |
| Administration group 1 | 25 | 14.3±7.2 | 65.3 |
| Administration group 2 | 25 | 11.8±6.3 | 71.4 |
| Administration group 3 | 25 | 18.6±5.9 | 54.9 |
The impact that embodiment 2 pharmaceutical composition reacts to mouse hot-plate induced pain
Put female icr mice (20 ± 2) g on 55 ± 0.5 DEG C of intelligent hot-plate instrument, record mice vola contact hot plate
It is pain indicator to the incubation period (s) occurring licking metapedes reaction, reject the mice of response latency ＜ 5s or ＞ 30s or jump.
Choose qualified mice in 10～30s for 140 response latencies, according to the front threshold of pain of medicine and body weight random packet, gastric infusion；
Model group: isopyknic normal saline,
Compositionss group: 50mg/kg, ig
Continuous gavage is administered 5 days, 30 after last dose, 60,90,120min when measure the pain of each administration group mice respectively
Threshold 1 time, pain threshold is calculated with 60s more than 60s person.
Data withRepresent, variance analyses are carried out using spss15.0 software.
Concrete outcome is as follows:
The impact that pharmaceutical composition reacts to mouse hot-plate induced pain
Embodiment 3 tablet
Prescription
Preparation technology: 1) pharmaceutical composition and adjuvant were pulverized 80 mesh sieves respectively, by pharmaceutical composition, methylcellulose
It is sufficiently mixed with Mannitol, 2) 50% ethanol soft material, 18 mesh sieves are pelletized, and are dried, 16 mesh sieve granulate at 60 DEG C, add micropowder silicon
Glue, mixes, tabletting, obtains final product, piece weight 400mg, and pharmaceutical composition proportioning is administration group 2 in embodiment 1.
Embodiment 4 tablet
Prescription
Preparation technology: 1) pharmaceutical composition and adjuvant were pulverized 80 mesh sieves respectively, by pharmaceutical composition, methylcellulose
It is sufficiently mixed with Mannitol, 2) 50% ethanol soft material, 18 mesh sieves are pelletized, and are dried, 16 mesh sieve granulate at 60 DEG C, add micropowder silicon
Glue, mixes, tabletting, obtains final product, piece weight 400mg, and pharmaceutical composition proportioning is administration group 2 in embodiment 1.
The study on the stability of embodiment 5 tablet
Stability guideline according to 2010 editions two annex of Chinese Pharmacopoeia investigates correlated sampless stability, investigates respectively
Place the medicine stability of 36 months at 25 DEG C.Rosmarinic acid, tetrahydropalmatine, chimonin in tablet is measured using hplc method
Content with diclofenac sodium.
25 DEG C place 36 months after each group Effective Component of Chinese Medicine content
Present invention merely illustrates some claimed specific embodiments, one of or more skills
In art scheme, described technical characteristic can be combined with arbitrarily one or more technical schemes, and these are combined and obtain
Technical scheme also in the application protection domain, just as obtained from these are combined, technical scheme is open in the present invention
In content, concrete record is the same.
Claims (7)
1. one kind is used for analgesic oral formulations it is characterised in that it is made up of pharmaceutical composition and adjuvant, described drug regimen
Thing is made up of rosmarinic acid, tetrahydropalmatine, chimonin and diclofenac sodium.
2. according to claim 1 for analgesic oral formulations it is characterised in that fan in described pharmaceutical composition
Repeatedly fragrant acid, the weight of tetrahydropalmatine, chimonin and diclofenac sodium are than about 2～4:5～8:3～6:2～4.
3. according to claim 1 or 2 for analgesic oral formulations it is characterised in that selected by described oral formulations
Adjuvant is selected from starch, Pregelatinized Starch, starch slurry, β-cyclodextrin, Carbomer, Microcrystalline Cellulose, hydroxypropyl methyl fiber
Element, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, Polyethylene Glycol (peg), sodium carboxymethyl cellulose, methylcellulose,
Ethyl cellulose, Mannitol, sodium lauryl sulphate, cross-linking sodium carboxymethyl cellulose, Lactose, Polyvinylpyrrolidone (pvp),
Crospolyvinylpyrrolidone, magnesium stearate, Pulvis Talci, micropowder silica gel, aspartame, orange flavor, sodium bicarbonate, carbonic acid
One or more of sodium, enteric coating powder.
4. according to claim 3 for analgesic oral formulations it is characterised in that described oral formulations be tablet, institute
Stating adjuvant is methylcellulose, Mannitol and micropowder silica gel.
5. according to claim 3 for analgesic oral formulations it is characterised in that described oral formulations be tablet, institute
Stating adjuvant is methylcellulose, Mannitol, micropowder silica gel and aspartame；Between four, weight ratio is followed successively by: 200～400:30
～80:30～60:1～3；Weight between described pharmaceutical composition and adjuvant is than for 1:15～30.
6. a kind of preparation method for analgesic oral formulations prepared described in claim 4 is it is characterised in that concrete steps
As follows:
1) pharmaceutical composition and adjuvant were pulverized 80 mesh sieves respectively, pharmaceutical composition, methylcellulose and Mannitol were filled
Divide mixing,
2) 50% ethanol soft material, 18 mesh sieves are pelletized, and are dried, 16 mesh sieve granulate at 60 DEG C, add micropowder silica gel, mix, pressure
Piece, obtains final product.
7. the oral formulations described in any one of claim 1-4 are used for the application in the medicine treating pain in preparation.
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