CN104606144A - Oral slow-release rotundine preparation - Google Patents
Oral slow-release rotundine preparation Download PDFInfo
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- CN104606144A CN104606144A CN201510038692.3A CN201510038692A CN104606144A CN 104606144 A CN104606144 A CN 104606144A CN 201510038692 A CN201510038692 A CN 201510038692A CN 104606144 A CN104606144 A CN 104606144A
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- rotundine
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Abstract
The invention relates to an oral slow-release rotundine preparation. According to the oral slow-release rotundine preparation, rotundine is taken as a main component, with the combination of multiple principles, that is, the gastric pit 'capture' principle of human bodies, the hollow structure floating principle, the macromolecule swelling and adhesion principle and the stomach emptying action principle, hollow slow-release microspheres which can be retained by gastric pit structures on the surfaces of gastric mucosa are designed, the particle size of the hollow slow-release microspheres is 10-80mu m, and the gastric retention time can be as long as 10 hours. The constitutional materials of the oral slow-release rotundine preparation can be one or more of pharmaceutically acceptable gastric-soluble, enteric-soluble or slight-soluble materials. The preparation method can be an emulsion diffusion-volatilization method, a template method, a spray-freezing drying method, a complex coacervation method, a self-assembling method or a suspension method. The oral slow-release rotundine preparation can be used as a chronic, lasting and non-severe pain long-lasting pain relieving preparation, overcomes the defects that a rotundine tablet or injection in the market is short in action time, needs to be taken frequently and is easy in hypnosis, and is free of dependence addiction and good in market prospect.
Description
[technical field]
The invention belongs to novel pharmaceutical formulation and new technical field, being specifically related to a kind of take rotundine as the design of multiple-unit stomach retention sustained-release (long-acting) preparation of main active.
[background technology]
Rotundine, that is, [(-)-tetrahydropalmatine, Rotundine], chemistry by name 2,3,9,10-tetramethoxy-5,8,13,13a-tetrahydrochysene-6H-dibenzo [a, g] quinolizine, another name has rotundine, rotundin, rotundine, and its character is white extremely micro-yellow, odorless, tasteless, chance light is heated and easily turns yellow.Rotundine is insoluble in water, slightly molten in ethanol or ether, dissolves in chloroform, easily molten in diluted acid.This medicine synthetic, two of Chinese Pharmacopoeia version in 2005,2010 are all recorded, clinical in analgesic, are non-narcotic analgesics, do not belong to antipyretic anti-inflammatory analgesic.Its analgesic activity is weak compared with dolantin, but more general antipyretic analgesic is strong, suitable with tramadol, but the side effect of the Nausea and vomiting caused without tramadol, to Chronic persistent pain and internal organs dull pain effect better, poor to the effect of wound and postoperative pain.Discovered in recent years rotundine, except analgesic activity, still has obvious sedative-hypnotic effect, is therefore applicable to tonicity pain or because of the insomnia patients caused by pain.Its great advantage is that toxicity is low, and safety is large, without additive.Its mechanism of action waits to illustrate, may with by suppressing reticular formation of brain stem ascending activating system, to block the function of dopamine receptor in brain relevant.
The rotundine dosage form used clinically is generally oral tablet and injection, and single dose is 60 ~ 200mg, needs administration 3 ~ 4 times general every day.Test from Mus and rabbit and show, when high dose, rotundine very easily enters cerebral tissue through blood brain barrier (BBB), thus shows quick drowsiness side effect during high dose.This reduces patient's compliance to a certain extent, thus limits its application.Although there is the research report of other dosage forms afterwards successively, as oral cavity disintegration tablet, dispersible tablet, the nasal mist of rapid release, the double-layer tablet, chitosan sustained-release bead etc. of slow release, but no matter simple rapid release or slow releasing preparation all have certain limitation, the drowsiness frequently side effect caused as quick releasing formulation can affect the normal work of patient, and slow releasing preparation can not pain relieving rapidly.
And the floating hollow microsphere of stomach (buoyant microspheres, BM)---on the basis of microencapsulation and floating preparation technology, in recent years intersect the Novel medicine feeding carrier developed, be the floating Novel medicine feeding carrier of multiple-unit stomach that a kind of inside being carrier material is made has hollow-core construction with macromolecule, its particle size range of bibliographical information mostly is 5 ~ 200 μm.
BM utilizes the gastric pits of human body as natural " trap " mechanism, produce and there is the advantage that distribution area is large, the flotation time is long, local irritation is little, the individual variation of emission and absorption is little, overcome that single unit slow-released system distribution area is in vivo little, gastric transit time is not enough to the effective soak time of medicine, " entirely having " or " completely without " release limitation, medicine still there is the prominent shortcoming to release etc., drug bioavailability is improved greatly.And compared to being both the intra-gastric floating microsphere of multiple unit system, hollow microsphere utilizes its distinctive hollow structure, reduce microsphere global density, increase specific surface area, improve its floatability, and hollow microsphere particle diameter is little, be easy to be coated in the gastric pits of body of stomach, utilize the dual function drinking buoyancy of water and gastric emptying, make it more effectively can extend gastric transit time thus the chance of a series of slow controlled release is provided.Therefore rotundine is made the preparation clear curative effect of the floating hollow microsphere of stomach, persistent, side effect is minimum.Thus the Study and Development of the floating hollow microsphere of rotundine stomach is more favored and is paid close attention to.
[summary of the invention]
[key issue that will solve]
The use limitation of BM: can the key of stomach floating forms design success or failure be the floating effect that produce expection at gastric, if can not be floating, then only when in a common slow releasing preparation.And the principle of BM slow releasing preparation effect is the construction features utilizing BM inner hollow, the density after making it oral in gastric juice is less than the density of gastric content thus floats on object gastric juice realizing extending the stomach holdup time.But research shows, unless had a large amount of water at gastric, otherwise low-density medicine-releasing system can not at floating in stomach.Cause the liquid of gastric to be not that the moment is sufficient in BM can be made floating because gastrointestinal tract is emptying with the physiological activity of wriggling etc. and the Individual differences of different patient, therefore related documents is pointed out to allow patient have a drink water to create the environment of floating in stomach every 1h.But for healthy the intestines and stomach, the gastric emptying rate of water is about 5 ~ 10min, is repeatedly drunk water by patient as seen and realize BM slow releasing function and unrealistic, therefore have no its listing.
And the BM of the present invention's design utilizes five restitution reasons first: the gastric pits of human body " catches " principle, hollow structure floatation principle, high molecular swelling and adhesion principles, combine the dual function principle of drinking buoyancy of water and gastric emptying again, the particle diameter of requirement BM is 10 ~ 80 μm, can effectively solve appeal key issue, many-sided machine-processed and secure object completing prolongation gastric transit time can be utilized again.Wherein, the gastric pits that the present invention also proposes human body first " catches " principle, its content is: the particle diameter of control BM, the buoyancy of water utilizing patient to drink and the dual function of gastric emptying, BM is driven more extensively to coat equably in the gastric pits of gastric mucosa layer, thus prolongation gastric transit time, play more lasting effect.
[technology path]
The present invention is by appropriate design, and successfully solve above-mentioned key issue, said preparation formula is as follows:
| Component | Weight ratio (%) |
| Rotundine | 1～50 |
| One or more carrier materials that release allows | 50～99 |
| Emulsifying agent | 0.5～25 |
| Organic solvent | 1～20 |
| Purified water | 10～90 |
Preparation is taked: emulsifying-volatility process.
Wherein, carrier material used is: one or more mixed carrier materials that the releases such as ethyl cellulose, polyvinyl alcohol, acrylic resin, sodium alginate, chitosan, methylcellulose, hydroxypropyl emthylcellulose allow; Described organic solvent is: one or more the mixture in ethanol, ether, acetone, dichloromethane, ethyl acetate etc.; Described emulsifying agent is: the one in polyvinyl alcohol, tween 80, sodium lauryl sulphate.
The preparation method of this rotundine oral slow-releasing preparation is:
A. decentralized photo prepares: the rotundine of above-mentioned recipe quantity, carrier material are put into beaker, adds appropriate organic solvent dissolution, for subsequent use.
B. the preparation of continuous phase: the emulsifying agent getting recipe quantity fully dissolves in purified water, 25 ~ 40 DEG C of insulations are for subsequent use.
C. above-mentioned decentralized photo is slowly instilled in continuous phase under the magnetic agitation of 300 ~ 800rpm, at 25 ~ 40 DEG C continuous stirring 0.5 ~ 2h to organic solvent volatilization completely, microscopy, after microsphere form is qualified, sucking filtration, cold drying in vacuum drying or baking oven.
D. above all operations relating to rotundine are all carried out under the condition of lucifuge.
The advantage of invention formulation product:
1. safety is high: the rotundine intra-gastric floating microsphere preparation designed by the present invention, every day oral need once, accumulated dose is low, avoids that the preparation action time of going on the market is short, medication is frequent and high dose easily causes the shortcomings such as drowsiness; And said preparation belongs to multiple-unit preparation simultaneously, can avoid single unit preparation in gastric emptying process due to " entirely having " or " completely without " individual difference that causes, the burst drug release caused when reducing the local excitation that causes because single unit medicine-releasing system local drug concentration is too high and avoid cellular system to control bad.
2. application is wide: the rotundine oral slow-releasing preparation designed by the present invention is easy to use, side reaction is few, be widely used, be not only applicable to the pain of Encelialgia that digestive system disease causes especially gastric ulcer and duodenal ulcer, also can be used for after general headache, menstrual pain, childbirth chronic, persistence, the non-severe pain such as uterine contraction pain.
3. good development prospect: product of the present invention belongs to the secondary development of ripe medicine, its development & production cost is low, the cycle is short, risk is little, easily go on the market, and by the improvement of technology of preparing, future also can be developed into compound preparation.
[detailed description of the invention]
Example below will be further elaborated formula preparation method of the present invention, but not limit content of the present invention:
[embodiment 1]
Take respectively 30mg rotundine, 0.15g especially strange E, 0.35g ethyl cellulose (EC) in beaker A, after adding 3mL dichloromethane and 2mL ethanol, slowly stir until dissolution of solid with Glass rod.Under 700rpm rotating speed magnetic agitation condition, the liquid of beaker A is slowly added 35mL, 30 DEG C the PVA aqueous solution containing 0.05g beaker B in, continuous stirring 1h makes that it is fully emulsified-diffusion, and microscopy, after balling-up is qualified, sucking filtration, washes with water rapidly to adhesion.The hollow microsphere of preparation is dried as in the baking oven of 40 DEG C, to obtain final product.
[embodiment 2]
Take respectively 30mg rotundine, 0.12g especially strange L30D-55,0.1g ethyl cellulose (EC) in beaker A, after adding 2.5mL dichloromethane and 2.5mL ethanol, slowly stir until dissolution of solid with Glass rod.Under 550rpm rotating speed magnetic agitation condition, the liquid of beaker A is slowly added 40mL, 25 DEG C the PVA aqueous solution containing 0.1g beaker B in, continuous stirring 1.5h makes that it is fully emulsified-diffusion, and microscopy, after balling-up is qualified, sucking filtration, washes with water rapidly to adhesion.The hollow microsphere of preparation is dried as in the baking oven of 40 DEG C, to obtain final product.
[embodiment 3]
Take 30mg rotundine, 0.10g hydroxypropyl emthylcellulose (HPMC) respectively, 0.05g ethyl cellulose (EC), in beaker A, after adding 2.5mL dichloromethane and 2.5mL ethanol, slowly stirs until dissolution of solid with Glass rod.Under 350rpm rotating speed magnetic agitation condition, the liquid of beaker A is slowly added 30mL, 27 DEG C the PVA aqueous solution containing 0.2g beaker B in, continuous stirring 1h makes that it is fully emulsified-diffusion, and microscopy, after balling-up is qualified, sucking filtration, washes with water rapidly to adhesion.The hollow microsphere of preparation is dried as in the baking oven of 45 DEG C, to obtain final product.
[embodiment 4]
Take respectively 30mg rotundine, 0.13g especially strange L100,0.1g ethyl cellulose (EC) in beaker A, after adding 3mL dichloromethane and 2mL ethanol, slowly stir until dissolution of solid with Glass rod.Slowly added by the liquid of beaker A in the beaker B of 25mL, 30 DEG C of PVA aqueous solutions containing 0.075g under 600rpm rotating speed magnetic agitation condition, continuous stirring 1h makes its fully emulsified-diffusion, and microscopy, after balling-up is qualified, sucking filtration, washes with water rapidly to adhesion.The hollow microsphere of preparation is dried as in the baking oven of 55 DEG C, to obtain final product.
[embodiment 5]
Take 30mg rotundine, 0.15g hydroxypropyl emthylcellulose (HPMC) respectively, 0.1g ethyl cellulose (EC), in beaker A, after adding 2mL dichloromethane and 3mL ethanol, slowly stirs until dissolution of solid with Glass rod.Slowly added by the liquid of beaker A in the beaker B of 50mL, 28 DEG C of PVA aqueous solutions containing 0.05g under 350rpm rotating speed magnetic agitation condition, continuous stirring 1h makes its fully emulsified-diffusion, and microscopy, after balling-up is qualified, sucking filtration, washes with water rapidly to adhesion.The hollow microsphere of preparation is dried as in the baking oven of 35 DEG C, to obtain final product.
Claims (6)
1. can retain by the gastric pits structure of gastric mucosa surface (catching) particle size range be the gastric retention hollow sustained-release micro-spheres of 10 ~ 80 μm, it is characterized in that the active component of package-contained is rotundine.
2. " rotundine " in preparation described in claim 1, is characterized in that chemistry by name 2,3,9,10-tetramethoxy-5,8,13,13a-tetrahydrochysene-6H-dibenzo [a, g] quinolizine, that is, Rotundine, (-)-tetrahydropalmatine, another name has rotundine, rotundin, rotundine.
3. microsphere according to claim 1, tool hollow structure, tool floatability in water and simulated gastric fluid, its bulk density, grain density are all less than 1.
4. its gastric transit time scope of microsphere according to claim 1 is 10 ~ 720 minutes.
5. its composition material of sustained-release micro-spheres according to claim 1 can be one or more combinations of acceptable gastric solubility or enteric solubility or slightly solubility material on pharmaceutics.
6. the preparation method of sustained-release micro-spheres according to claim 1 can be emulsifying (diffusion)-volatility process, template, atomizing freeze drying method, complex coacervation, self-assembly method, suspension method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510038692.3A CN104606144A (en) | 2015-01-21 | 2015-01-21 | Oral slow-release rotundine preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510038692.3A CN104606144A (en) | 2015-01-21 | 2015-01-21 | Oral slow-release rotundine preparation |
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| CN104606144A true CN104606144A (en) | 2015-05-13 |
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| CN201510038692.3A Pending CN104606144A (en) | 2015-01-21 | 2015-01-21 | Oral slow-release rotundine preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973568A (en) * | 2020-08-28 | 2020-11-24 | 广东药科大学 | 3D printing-based preparation floatable drug sustained-release carrier with micro air bags and preparation method and application thereof |
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2015
- 2015-01-21 CN CN201510038692.3A patent/CN104606144A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111973568A (en) * | 2020-08-28 | 2020-11-24 | 广东药科大学 | 3D printing-based preparation floatable drug sustained-release carrier with micro air bags and preparation method and application thereof |
| CN111973568B (en) * | 2020-08-28 | 2022-12-02 | 广东药科大学 | 3D printing-based preparation-based floatable drug sustained-release carrier with micro air bags and preparation method and application thereof |
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Application publication date: 20150513 |