CN107260732B - A kind of tetrad depot drug product composition and its application in pain is treated - Google Patents
A kind of tetrad depot drug product composition and its application in pain is treated Download PDFInfo
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- CN107260732B CN107260732B CN201710594462.4A CN201710594462A CN107260732B CN 107260732 B CN107260732 B CN 107260732B CN 201710594462 A CN201710594462 A CN 201710594462A CN 107260732 B CN107260732 B CN 107260732B
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- pain
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- lappaconitine
- tetrahydropalmatine
- tetrad
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Classifications
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- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The present invention relates to a kind of tetrad depot drug product composition and its applications in pain is treated, more particularly to a kind of tetrad depot drug product composition, which includes lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid for the treatment of and/or prevention effective dose as active ingredient.The composition that tetrad depot drug product composition of the present invention is formed compared with one-component, two kinds of components or three kinds of components, has the characteristics that good water solubility, good effect, toxic side effect are low.Tetrad depot drug product composition of the present invention can be used for preventing and/or treating pain related disorders, and the pain includes the intractable pain of pain and unknown cause caused by the pain, arthralgia, trauma pain, postoperative pain, inflammatory pain, drug rehabilitation or the drug addiction that are generated after relaxing tumor pain, chemotherapy.In addition, tetrad depot drug product composition of the present invention can be additionally used in calmness, hypnosis, collaboration anesthesia, anti-arrhythmia etc..
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of tetrad depot drug product composition and its answering in pain is treated
With.
Background technology
Lappaconitine also known as Lappaconitine are from the high rhizome of Chinese monkshood Aconitum sinomontanum of ranunculaceae plant
A kind of Diterpenoid Alkaloids extracted in Nakai roots.The high rhizome of Chinese monkshood also known as the Herba Andrographitis rhizome of Chinese monkshood, for Ranunculaceae aconitum plant, property
Temperature, it is bitterly, there is dispelling wind and eliminating dampness, regulating qi-flowing for relieving pain, activating blood circulation and reducing swelling and other effects, be mainly used for arthralgia pain due to rheumatism, painful swelling of joints, stomach
Bitterly, traumatic injury etc..Active ingredient of the lappaconitine as high aconitum analgesia, for the non-addicted analgesics that China initiates, medicine
Reason research is proved it with stronger analgesia, anti-inflammatory, local anaesthesia and antiarrhythmic effect, to cancer pain and other intractables
Pain effect is especially pronounced.The hydrobromate of lappaconitine is clinically often used, for the treatment of moderate more than pain.Corydalis tuber
B prime is the drying from papaveraceae plant corydalis Corydalis yanhusuo W.T.Wang ex Z.Y.Su et C.Y.Wu
A kind of alkaloid extracted in stem tuber is lacked with multiple pharmacological action such as analgesia, anti-cerebral ischemia, anti-arrhythmia, anti-cardiac muscle
The effects that blood, is widely used in clinical practice always for a long time.Fumaric acid also known as fumaric acid, corydalis acid or lichenic acid,
That is fumaric acid is simplest unsaturated dicarboxylic acid, is found earliest from corydalis tuber.Succinic acid also known as succinic acid are used
In flavoring agent, acid, buffer, preservative can be used as, pH adjusting agent and prepares five-ring heterocycles chemical combination at cosolvent
The important industrial chemicals of object.
Chinese patent (application number：200910119610.2) in disclose the lappaconitine and corydalis tuber of a kind of anti-inflammatory and antalgic
B prime pharmaceutical composition, and patch agent for providing the pharmaceutical composition and preparation method thereof.But above-mentioned patent only provides
A kind of dosage form of the pharmaceutical composition, i.e. patch agent, the pharmaceutical composition there are certain toxic side effect, poorly water-soluble, and
Its anti-inflammatory pain-stopping effect is not so good as Meloxicam.Therefore, it is long-acting to develop that a kind of toxic side effect is small, dissolubility is good, analgesic effect is good
Analgesic composition becomes field of medicaments urgent need to solve the problem.
The content of the invention
The present invention provides a kind of tetrad depot drug product composition, which includes treatment and/or prevention effective dose
Lappaconitine, tetrahydropalmatine, fumaric acid and succinic acid as active ingredient.The pharmaceutical composition may also include suitable
Pharmaceutically acceptable pharmaceutic adjuvant (such as pharmaceutically acceptable carrier, diluent or excipient, including solubilizer, surface
Activating agent, film forming agent, antioxidant, stabilizer, adhesive, lubricant etc.)
Above-mentioned tetrad depot drug product composition by weight, preferably comprises 1-5 parts of lappaconitine, tetrahydropalmatine 1-5
Part, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
The dosage form of pharmaceutical composition of the present invention can be solid pharmaceutical preparation, liquid preparation or semisolid preparation, preferably
Tablet, capsule, injection, film preparation, emulsifiable paste or spray, including sustained-release tablet, spansule, slow-release injected.
Another embodiment of the present invention provides aforementioned pharmaceutical compositions as prevention and/or treats answering for pain medication
Prevent and/or treat the application in pain medication with and preparation.The pain includes relaxing tumor pain, chemotherapy
Pain and unknown original caused by the pain, arthralgia, trauma pain, postoperative pain, inflammatory pain, drug rehabilitation or the drug addiction that generate afterwards
The intractable pain of cause.
Another embodiment of the present invention provides aforementioned pharmaceutical compositions and is preparing calmness, hypnosis, collaboration anesthesia, the anti-rhythm of the heart
Application in arrhythmic agents.
Lappaconitine in aforementioned pharmaceutical compositions of the present invention includes lappaconitine and pharmaceutically acceptable high Wu Jia
Plain salt；Tetrahydropalmatine includes tetrahydropalmatine and pharmaceutically acceptable tetrahydropalmatine salt.
The general preparative methods of aforementioned pharmaceutical compositions of the present invention and application, it is as follows：
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Preparation】Using medicinal slow well known to (such as pharmacopeia, textbook, reference book, periodical or patent etc.) in the prior art
Release, form a film, emulsifying, the auxiliary materials such as Transdermal absorption, figuration and solubilizer and general such as tabletting, capsule filling, film and freezing it is dry
It is dry to wait technology and methods, above-mentioned active ingredient can be respectively prepared into suitable for clinical practice according to treatment and/or prevention effective dose
Tetrad durable action composition preparation, preparation can be solid pharmaceutical preparation, liquid preparation or semisolid preparation, include but not limited to piece
The preparations such as agent, capsule, injection, film preparation, emulsifiable paste or spray, above-mentioned preparation can be slow-release controlled-release preparations.
【Using】Pharmaceutical composition of the present invention is suitable for preventing, treat, alleviate, mitigating various pain in clinic, including but
Be not limited to the pain generated after relaxing tumor pain, chemotherapy, arthralgia, trauma pain, postoperative pain, inflammatory pain,
The intractable pain of pain and unknown cause caused by drug rehabilitation or drug addiction；Also calmness, hypnosis, collaboration anesthesia, the rhythm of the heart can be used for lose
The treatment often waited.
【Preparation method】
Involved auxiliary material, the equal foundation of the detection method of pharmaceutical preparation in pharmaceutical preparation preparation process《Chinese Pharmacopoeia》
The regulation of (publication of 2015 Nian Bansibu Chinese Medicines publishing houses) related preparations guideline.
Compared with prior art, the advantage of the invention is that：(1) tetrad depot drug product composition material medicine of the present invention prolongs recklessly
Rope acid forming salt or other complex compounds or is carried between succinic acid and lappaconitine, tetrahydropalmatine by other intermolecular interactions
High lappaconitine and tetrahydropalmatine solubility in water reduce toxic side effect simultaneously；(2) tetrad long-acting drug of the present invention
There are certain synergistic effects between compositions to make its analgesic effect better than the group that one-component, two kinds of components or three kinds of components are formed
Close object；(3) tetrad depot drug product composition of the present invention not only has better analgesic effect, while has calmness, hypnosis, collaboration
The effects that anesthesia, anti-arrhythmia.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments only are not used for limiting the scope of the present invention or implementation principle, reality of the invention for being better understood from inventing
The mode of applying is not limited to herein below.
The preparation example of 1 sustained release preparation of embodiment, ejection preparation, film preparation, spray formulation, tablet, capsule etc.
Sustained release preparation
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】Slow-release material, adhesive, lubricant, common carrier auxiliary material etc..
【Concept and principle】Sustained release preparation means that in defined dissolution medium slowly non-constant velocity discharges one on request
Object, compared with corresponding ordinary preparation, administration frequency reduces one times than ordinary preparation or is reduced, and can dramatically increase patient
The preparation of compliance；Main effect drug ingedient is wrapped up using inorganic material as wall material, through dissolving, emulsifying, the series reactions such as adsorbing
Active drug ingredient is obtained as core, inorganic salts are sustained raw material for the Nano capsule of capsule material, and can be pressed respectively according to design requirement
Piece is filling into capsule preparations.
【Preparating example】It presses【Active ingredient】Content weighs each active ingredient respectively, is provided with the industry in major auxiliary burden
The solubilizer (such as Tween-80) measured below additive amount is allowed to mix, suitable quantity of water is added to make after fully dissolving, sequentially adds emulsifier
And ethyl orthosilicate, it is thoroughly mixed and is formed uniformly mixed solution A, then (stir solution A addition reaction unit equipped with electromagnetism
Mix device, thermometer, condensation reflux unit and dropping funel), (500 revs/min) stirrings at a high speed are sheared 10 minutes, form clear oil
Colostrum at ambient temperature (25 DEG C), gelatin solution is progressively added dropwise into reaction unit, main effect component is under stirring
O/W type droplets are formed, are wrapped in inside emulsifier micella, 2h is reacted, calcium chloride is added dropwise after ethyl orthosilicate is fully hydrolyzed
Solution forms active ingredient Nano capsule after emulsifier micellar surface reaction precipitation, package, curing, is obtained after the reaction was complete
The Nano capsule that active ingredient is capsule-core, calcium silicates is cyst wall adds in the amount of ethyl orthosilicate and calcium chloride by adjusting, and prepares
Not same core wall than active ingredient Nano capsule sustained release preparation to get.
Ejection preparation
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】Solubilizer, excipient, surfactant etc..
【Concept and principle】Injection mean active ingredient or with suitable auxiliary material made of for the sterile system that is injected in vivo
Agent；Injection can be prepared into parenteral solution, injection sterile powder etc. according to actual needs.
【Preparating example】It presses【Active ingredient】Content weighs each active ingredient respectively, is provided with the industry in major auxiliary burden
After solubilizer, excipient, surfactant for being measured below additive amount etc., mixing plus suitable quantity of water is allowed to make fully dissolving, filtration,
Degerming, packing, is freeze-dried to get injection sterile powder.
Film preparation
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】Film forming agent, penetrating agent and solubilizer etc..
【Concept and principle】Film means active ingredient and the processed manufactured film-like preparation of suitable filmogen, for
Oral or mucous membrane application.
【Preparating example】It presses【Active ingredient】Content weighs each active ingredient respectively, is provided with the industry in major auxiliary burden
The solubilizer measured below additive amount is allowed to mix, suitable quantity of water is added to make after fully dissolving, sequentially adds film forming agent such as polyvinyl alcohol, third
One kind in the combination of one or more of the high molecular materials such as olefin(e) acid resinae, cellulose, penetrating agent such as azone, propylene glycol
Or several combinations, be uniformly mixed, form a film to get.
Spray formulation
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】The additives such as solvent, cosolvent, antioxidant, bacteriostatic agent, surfactant and solubilizer.
【Concept and principle】Spray means active ingredient or is filled in proper auxiliary materials in special device, and when use borrows
Pressure, gases at high pressure, ultrasonic vibration or the other methods that assistant moves pump disengage content in spray, for lung sucking or
Directly it is sprayed onto cavity.
【Preparating example】It presses【Active ingredient】Content weighs each active ingredient respectively, is provided with the industry in major auxiliary burden
The solubilizer measured below additive amount is allowed to mix, is separately added into solvent, cosolvent, antioxidant, bacteriostatic agent, surfactant, is mixed
Close it is uniform, it is filling to get.
Sub-micellar emulsion
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】Oil, emulsifier, stabilizer, antioxidant, osmotic pressure regulator, water.
【Concept and principle】Submicron Emulsion (submicro emulsion) is using vegetable oil as matrix, by oil phase, emulsifier
O/W type dispersion of the grain size in the stabilization of 100-1000nm scopes is mutually made in (phosphatide), water.Drug can be encapsulated in oil phase and phosphorus
In fat interfacial film, appearance is in opaque muddiness or emulsus.As a kind of newtype drug movement system, it is optionally accumulated
In target site, medicine is made to exceed the several times of conventional formulation to hundreds times in target area concentration, hence it is evident that improve curative effect.It simultaneously can
Extend the half-life period of drug, reduce drug in normal structure abundance, mitigation adverse reaction achievees the effect that high-efficiency low-toxicity.
【Preparating example】It presses【Active ingredient】Content weighs each active ingredient and is added in together with emulsifier in oil, stirred respectively
Mixing makes its dissolving, as oil phase；Stabilizer, osmotic pressure regulator and antioxidant are added to the water, stirred to dissolve, is made
For water phase；Oil phase is added in water phase, high speed shear is disperseed, and forms colostrum；Colostrum tune pH to 6.0-7.5, it is high-pressure homogenising, it obtains smart
Breast is to get sub-micellar emulsion.
Tablet
【Active ingredient】Treatment and/or lappaconitine, tetrahydropalmatine, fumaric acid and the succinic acid of prevention effective dose；
By weight, preferably lappaconitine 1-5 parts, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
【Major auxiliary burden】Filler or diluent, including starch, Icing Sugar, dextrin, milk extract, amylum pregelatinisatum, microcrystalline cellulose
Element, inorganic salts；Binder and lubrication and agent, including distilled water, ethyl alcohol, starch slurry, sodium carboxymethylcellulose, hydroxy propyl cellulose
Element, methylcellulose and ethyl cellulose, hydroxypropyl methyl cellulose；Disintegrant, including dried starch, sodium carboxymethyl starch, low
Substituent group hydroxypropyl cellulose；Lubricant, including magnesium stearate, superfine silica gel powder, talcum powder, hydrogenated vegetable oil, polyethylene glycols
And magnesium laurylsulfate.
【Preparating example】It presses【Active ingredient】Content weighs one or more of each active ingredient and major auxiliary burden respectively
Tablet is made according to common process in mixing.
Embodiment 2
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 2 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 20g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, Nano capsule sustained release preparation can be prepared into.
Embodiment 3
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 2 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 20g, succinic acid 70g are taken, it is and appropriate
Conventional pharmaceutical adjuvants (preferably carboxymethyl cellulose sodium, magnesium stearate), tablet is made according to common process in mixing.
Embodiment 4
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 7 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 70g, succinic acid 20g are taken, it is and appropriate
Conventional pharmaceutical adjuvants (preferably 1% Tween-80, polyethylene glycol 400), mixing, add suitable quantity of water make fully dissolving after, filtration, remove
Bacterium, packing, is freeze-dried to get injection sterile powder.
Embodiment 5
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 7 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 70g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, film preparation can be prepared into.
Embodiment 6
Bulk pharmaceutical chemicals：1 part of lappaconitine, 5 parts of tetrahydropalmatine, 2 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 50g, fumaric acid 20g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, spray formulation can be prepared into.
Embodiment 7
Bulk pharmaceutical chemicals：1 part of lappaconitine, 5 parts of tetrahydropalmatine, 2 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 50g, fumaric acid 20g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, sub-micellar emulsion can be prepared into.
Embodiment 8
Bulk pharmaceutical chemicals：1 part of lappaconitine, 5 parts of tetrahydropalmatine, 7 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 50g, fumaric acid 70g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, Nano capsule sustained release preparation can be prepared into.
Embodiment 9
Bulk pharmaceutical chemicals：1 part of lappaconitine, 5 parts of tetrahydropalmatine, 7 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 50g, fumaric acid 70g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, sub-micellar emulsion can be prepared into.
Embodiment 10
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 2 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 20g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, spray formulation can be prepared into.
Embodiment 11
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 7 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 70g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, injecting fluid preparation can be prepared into.
Embodiment 12
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 2 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 20g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, film preparation can be prepared into.
Embodiment 13
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 7 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 70g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, tablet can be prepared into.
Embodiment 14
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 1 part of tetrahydropalmatine, 2 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 10g, fumaric acid 20g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, injecting fluid preparation can be prepared into.
Embodiment 15
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 1 part of tetrahydropalmatine, 7 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 10g, fumaric acid 70g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, capsule sustained release preparation can be prepared into.
Embodiment 16
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 1 part of tetrahydropalmatine, 2 parts of fumaric acid, 7 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 10g, fumaric acid 20g, succinic acid 70g, according to reality are taken
The preparation example method described in example 1 is applied, film can be prepared into.
Embodiment 17
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 1 part of tetrahydropalmatine, 7 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 10g, fumaric acid 70g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, tablet can be prepared into.
Embodiment 18
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 1 part of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 10g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, Nano capsule sustained release preparation can be prepared into.
Embodiment 19
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 2 parts of fumaric acid, 1 part of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 20g, succinic acid 10g, according to reality are taken
The preparation example method described in example 1 is applied, Nano capsule sustained release preparation can be prepared into.
Embodiment 20
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 8 parts of fumaric acid, 2 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 80g, succinic acid 20g, according to reality are taken
The preparation example method described in example 1 is applied, tablet can be prepared into.
Embodiment 21
Bulk pharmaceutical chemicals：5 parts of lappaconitine, 5 parts of tetrahydropalmatine, 2 parts of fumaric acid, 8 parts of succinic acid
By above-mentioned parts by weight, lappaconitine 50g, tetrahydropalmatine 50g, fumaric acid 20g, succinic acid 80g, according to reality are taken
The preparation example method described in example 1 is applied, tablet can be prepared into.
Embodiment 22
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 1 part of fumaric acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, fumaric acid 10g are taken, according to remembering in embodiment 1
The preparation example method of load, can be prepared into Nano capsule sustained release preparation.
Embodiment 23
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine, 1 part of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g, succinic acid 10g, according to described in embodiment 1 are taken
Preparation example method, Nano capsule sustained release preparation can be prepared into.
Embodiment 24
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of fumaric acid, 1 part of succinic acid
By above-mentioned parts by weight, lappaconitine 10g, fumaric acid 10g, succinic acid 10g, according to described in embodiment 1 are taken
Preparation example method can be prepared into Nano capsule sustained release preparation.
Embodiment 25
Bulk pharmaceutical chemicals：1 part of lappaconitine, 1 part of tetrahydropalmatine
By above-mentioned parts by weight, lappaconitine 10g, tetrahydropalmatine 10g are taken, according to the preparation example side described in embodiment 1
Method can be prepared into tablet.
Embodiment 26
According to Chinese patent (application number：200910119610.2) in embodiment 3 record method (bulk pharmaceutical chemicals：High Wu Jia
Plain 1.8kg, tetrahydropalmatine 0.5kg, auxiliary material：Propylene glycol 1.8kg, silicone PSA 4kg) prepare lappaconitine and Yan Hu
Suo Yi promotor composition percutaneous plasters.
According to the method that the embodiment of the present invention 1 is recorded, by above-mentioned raw materials medicine：Lappaconitine 1.8kg, tetrahydropalmatine
0.5kg, with suitable conventional pharmaceutical adjuvants (preferably carboxymethyl cellulose sodium, magnesium stearate), mixing is made according to common process
Tablet.
The analgesia of 27 tetrad depot drug product composition of the present invention of embodiment, the pharmacological activity experiment of tranquilizing soporific
Materials and methods
1st, animal：Kunming mice 1400, male, 6 week old, weight 20-24g；By in The Fourth Military Medical University experimental animal
The heart provides, and produces quality certification number：Scxk (army) word the 2012-0007th.
2nd, reagent and instrument：Lappaconitine (content 98.7%, lot number 201611022), tetrahydropalmatine (content
99.1%, lot number 201611011), fumaric acid (content 98.9%, lot number 201610012), succinic acid (content 99.2%, batch
Number 201610021) it is purchased from time bio tech ltd of Baoji, Shaanxi province city；Morphine hydrochloride injection (is made in Shenyang first
Pharmaceutical factory), specification：10mg/mL, lot number：20161102；0.6% acetum (takes glacial acetic acid 1.2mL to add distilled water extremely before use
200mL)；Tween-80 (content 98.5%, lot number 2016051701) is purchased from Jiangsu Hai'an Petrochemical Plant；Estazolam piece
(Tianjin Pacific Pharmaceutical Co., Ltd.), specification：1mg/ pieces, lot number：20160304；Yellow Jackets (two factory of Shanghai reagent),
6mg/mL is made into physiological saline with preceding.
3rd, method and result
(1) in the present composition active ingredient (i.e. bulk pharmaceutical chemicals) intragastric administration on mice acute toxicity test
By test product：Embodiment 2-6 bulk pharmaceutical chemicals, 25 bulk pharmaceutical chemicals of embodiment, are made solution or suspension with 0.5%CMC before use
Liquid is for examination.
Experimental method：Take healthy kunming mice 456, half male and half female is divided into 38 groups according to gender weight, each group mouse with
0.4ml/10g weight gavages are above-mentioned by test product, and the behavior of 7 days mouse is observed continuously in close observation each group reaction of animals after administration
Activity, fur gloss, diet, weight and death condition, dead mouse, which is dissected, during observation finds no main organs naked eyes sight
The pathology observed sexually revises.Main organs pathological section, which has no, to be substantially change.The situation of each group animal dead is as shown in table 1.
The death condition of 1 each group animal of table
The intragastric administration on mice of 2-6 of embodiment of the present invention pharmaceutical composition bulk pharmaceutical chemicals is anxious it can be seen from the experimental result in table 1
Property toxicity LD50It is all higher than or equal to 250mg/kg, and 25 bulk pharmaceutical chemicals (lappaconitine of embodiment：Prolong Hu Yisu=1: 1, each 10g)
LD50Less than 150mg/kg, it is seen then that the toxic side effect of bulk pharmaceutical chemicals is less than lappaconitine and corydalis tuber in pharmaceutical composition of the present invention
The bulk pharmaceutical chemicals of the composition of B prime (1: 1) two kinds of components.Reason may be fumaric acid, succinic acid in pharmaceutical composition of the present invention
Forming salt or other complex compounds or lappaconitine is reduced between lappaconitine, tetrahydropalmatine by other intermolecular interactions
With the toxicity of tetrahydropalmatine.
(2) in the present composition in active ingredient (i.e. bulk pharmaceutical chemicals) and active ingredient one-component analgesic test
Writhing method：According to the prior art (such as CHEN Q.The Book of Technology on Pharmcology
of Materia Medica[M].Beijing:People’s Medical Publishing House,1996:360) in
Method, 372 mouse are randomly divided into morphine group (dosage 50mg/kg, intraperitoneal injection are ip), embodiment 2-26 group (dosage
100mg/kg, gavage, that is, ig), lappaconitine group (dosage 100mg/kg, gavage, that is, ig), tetrahydropalmatine group (dosage 100mg/
Kg, gavage, that is, ig), fumaric acid group (dosage 100mg/kg, gavage, that is, ig), (dosage 100mg/kg, gavage are succinic acid group
Ig), control group (isometric physiological saline, ig), every group 12；Mouse successive administration 3 days, 30 minutes each groups are small after the last administration
0.6% acetum 10ml/kg of mouse ip are observed after ip and are occurred writhing occur in the time (incubation period) and 15 minutes of writhing (stretching
Hind leg is opened up, abdomen shrinks indent, and buttocks is raised) number；It the results are shown in Table 2.
Hot plate method：Mouse 372, the measure mice pain reaction time, (mouse put heat on 55 DEG C of hot plate before experiment
Plate is to starting to lick the metapedes time), mouse of the pain reaction time at 13~30 seconds is selected, is randomly divided into according to the pain reaction time
31 groups (specific grouping, dosage and the same writhing methods of medication).Each group mouse was put into heat again in 30 minutes after the last administration
Plate observes the pain reaction time of mouse, more than 60 seconds based on 60 seconds；It the results are shown in Table 3.
Active ingredient (i.e. bulk pharmaceutical chemicals), lappaconitine group, tetrahydropalmatine in 2 present composition embodiment 2-26 of table
Group, fumaric acid group, succinic acid group, control group and morphine group are to the analgesic activity (writhing method) of mouse
Compared with the control group：*P<0.05,**P<0.01；Compared with embodiment 26 and 25：ΔP<0.05,ΔΔP<0.01；With
Coffee group compares：δP<0.05,δδP<0.01。
Active ingredient (i.e. bulk pharmaceutical chemicals), lappaconitine group, tetrahydropalmatine in 3 present composition embodiment 2-26 of table
Group, fumaric acid group, succinic acid group, control group and morphine group are to the analgesic activity (hot plate method) of mouse
Compared with the control group：*P<0.05,**P<0.01；Compared with embodiment 26 and 25：ΔP<0.05,ΔΔP<0.01；With
Coffee group compares：δP<0.05,δδP<0.01。
Table 2-3 the result shows that, tetrad depot drug product composition (embodiment 2-21 bulk pharmaceutical chemicals) successive administration of the present invention 3 days,
The mouse writhing number caused by ip acetic acid can be substantially reduced, significantly extend the pain reaction time (second), show tetrad of the present invention
Depot drug product composition can be used for preventing and/or treating pain related disorders.Wherein, the active ingredient of embodiment 2-17 is (former
Expect medicine) analgesic activity it is most strong, embodiment 18-21 takes second place, and the analgesic activity of embodiment 22-26 is slightly weak with respect to embodiment 2-21；
The analgesic activity of tetrad depot drug product composition of the present invention is significantly stronger than one-component in composition and (such as lappaconitine group, prolongs
Hu Suo Yisu groups, fumaric acid group, succinic acid group), the combination (embodiment 22-26) of two kinds of components or three kinds of components, reason can
Can be shown there may be certain synergistic effect between lappaconitine-tetrahydropalmatine-fumaric acid-succinic acid tetrad composition
Write the analgesic activity of enhancing composition.
(3) present composition different dosage forms are to the analgesic activity of mouse
Writhing method：According to method of the prior art, 48 mouse be randomly divided into morphine group (dosage 50mg/kg, ip),
Composition tablet group (dosage 150mg/kg, ig, by taking tablet prepared by embodiment 3 as an example), composition injection group (dosage
50mg/kg, ip, by taking injection prepared by embodiment 11 as an example) and control group (the isometric physiological saline of gavage), successive administration 3
My god, there is writhing after observing ip in 30 minutes each group mouse peritoneal injection (ip) 0.6% acetum 10ml/kg after the last administration
Time (incubation period) and 15 minutes in there is writhing (stretching, extension hind leg, abdomen shrink indent, and buttocks raises) number；It the results are shown in Table
4。
4 composition different dosage forms of table are to the analgesic activity (acetic acid writhing test) of mouse
Compared with the control group：**P<0.01。
Hot plate method：Mouse 48, the measure mice pain reaction time, (mouse put hot plate on 55 DEG C of hot plate before experiment
To starting to lick the metapedes time), mouse of the pain reaction time at 13~30 seconds is selected, 4 are randomly divided into according to the pain reaction time
Group (specific grouping, dosage and the same writhing method of medication).Each group mouse was put into hot plate again in 30 minutes after the last administration,
The pain reaction time of mouse is observed, more than 60 seconds based on 60 seconds；It the results are shown in Table 5.
5 composition different dosage forms of table are to the analgesic activity (hot plate method) of mouse
Compared with the control group：**P<0.01。
As a result, it was confirmed that present composition different dosage forms successive administration 3 days, the mouse caused by substantially reducing ip acetic acid is turned round
Body number extends the mice pain reaction time (second), illustrates that the tablet of the present composition and injection have significantly analgesia to make
With analgesic effect is suitable with positive control drug morphine.
(4) synergistic effect that the present composition anaesthetizes yellow Jackets：Mouse 70 is only randomly divided into control group, Ai Si
Azoles logical sequence piece group (dosage 2mg/kg, ig), composition injection group (dosage 50mg/kg, ip, using embodiment 4 prepare injection as
Example) and composition tablet group (dosage 150mg/kg, ig, by taking tablet prepared by embodiment 17 as an example), it is every group 15,10 remaining
For the prerun of the length of one's sleep dosage of yellow Jackets.The continuous ig of each group mouse 3 days, control group ig same volume physiological saline.
Before anaesthesia experiment, yellow Jackets anesthesia duration prerun is first carried out, chooses anesthesia duration (time of righting reflex loss) 30
The yellow Jackets dosage of or so second.Through prerun under this experiment condition, the suitable dose of ip yellow Jackets is 47mg/kg.End
30 minutes ip 4.8mg/mL yellow Jackets normal saline solution 10ml/kg after secondary administration observe mouse righting reflex loss
Start timing (including 1min) after more than 1min, the time recovered to righting reflex；It the results are shown in Table 6.The result shows that of the present invention group
Closing composition injection and tablet for administration has the length of one's sleep for significantly extending yellow Jackets for 3 days, illustrates that the present composition has
Sedative-hypnotic effect.
The synergistic effect that 6 composition different dosage forms of table anaesthetize yellow Jackets
Compared with the control group：**P<0.01。
The solubility test of 28 tetrad depot drug product composition active ingredient (bulk pharmaceutical chemicals) of the present invention of embodiment
According to method of the prior art (such as " static method and dynamic method measure the discussion of solubility in drug water ", Yuan
Fly, etc., ACAD J GCP, the dynamic method described in the 5th the 462-465 pages of the phase of volume 26 in 2010) measure the present invention in fact
Apply the solubility of the bulk pharmaceutical chemicals of a 2-17,22,23,25, the results showed that, 25 bulk pharmaceutical chemicals (lappaconitine of embodiment：Prolong Hu Yisu=1:
1, each 10g) solubility (in 100g water) be less than 10mg, embodiment 22, the solubility of 23 bulk pharmaceutical chemicals are less than (in 100g water)
100mg, the solubility of embodiment 2-17 bulk pharmaceutical chemicals are more than 1g, compared with the solubility of 25 bulk pharmaceutical chemicals of embodiment, improve 100 times with
On, reason may be fumaric acid in pharmaceutical composition of the present invention, be formed between succinic acid and lappaconitine, tetrahydropalmatine
Salt or other complex compounds improve lappaconitine and the solubility of tetrahydropalmatine in water by other intermolecular interactions.
Claims (9)
1. a kind of tetrad depot drug product composition, it is characterised in that by weight, the pharmaceutical composition is by following active ingredient
Composition：1-5 parts of lappaconitine, 1-5 parts of tetrahydropalmatine, 2-7 parts of fumaric acid, 2-7 parts of succinic acid.
2. pharmaceutical composition described in claim 1, it is characterised in that the pharmaceutical composition also includes pharmaceutically acceptable medicine
Use auxiliary material.
3. the pharmaceutical composition described in claim 2, it is characterised in that the pharmaceutic adjuvant be selected from pharmaceutically acceptable carrier,
Diluent or excipient.
4. claim 1-3 any one of them pharmaceutical compositions, it is characterised in that the dosage form of described pharmaceutical composition is selected from solid
Body preparation, liquid preparation or semisolid preparation.
5. claim 1-3 any one of them pharmaceutical compositions, it is characterised in that the dosage form of described pharmaceutical composition is selected from piece
Agent, capsule, injection, film preparation, emulsifiable paste or spray.
6. claim 1-3 any one of them pharmaceutical compositions, it is characterised in that the dosage form of described pharmaceutical composition is selected from slow
It is release tablet formulations, spansule, slow-release injected.
7. application of the claim 1-6 any one of them pharmaceutical composition in prevention and/or treatment pain medication is prepared.
8. the application described in claim 7, it is characterised in that the pain generated after relaxing tumor pain, chemotherapy
Pain, arthralgia, trauma pain, postoperative pain, inflammatory pain, drug rehabilitation or pain caused by drug addiction and the stubbornness of unknown cause
Property pain.
9. application of the claim 1-6 any one of them pharmaceutical composition in calmness, hypnosis, collaboration anaesthetic is prepared.
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