CN101991859A - Beta-cyclodextrin inclusion compound of huperzine A, and preparation method and preparation thereof - Google Patents
Beta-cyclodextrin inclusion compound of huperzine A, and preparation method and preparation thereof Download PDFInfo
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Abstract
The invention discloses a beta-cyclodextrin inclusion compound of huperzine A, and a preparation method and preparations thereof. The beta-cyclodextrin inclusion compound of the huperzine A consists of 2.5 to 9.5 weight percent of huperzine A and 97.5 to 90.5 weight percent of beta-cyclodextrin. The preparation method comprises the following steps of: a) dissolving the huperzine A in an pharmaceutically acceptable organic solvent to prepare solution A, and heating and dissolving the beta-cyclodextrin in water to prepare solution B; and b) slowly adding the solution A into the solution B with stirring, and continuing to perform stirring until the mixed solution is uniform to prepare the beta-cyclodextrin inclusion compound of the huperzine A. The beta-cyclodextrin inclusion compound of the huperzine A further can be mixed with water-soluble carriers with viscosity, such as starch and the like, and then is pelletized, tabletted or filled into capsules with substrates. In the method, an extremely small amount of water-insoluble huperzine A is fully, effectively and uniformly dispersed, so the dissolution rate of the huperzine A is increased and the stability of the huperzine A is improved. The provided beta-cyclodextrin inclusion compound of the huperzine A can be used for preparing solid preparations and liquid preparations, operating steps are reduced and the production cost is remarkably reduced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly Benexate Hydrochloride of a kind of huperzine A and preparation method thereof and preparation.
Background technology
Huperzine A (Huperzine A), the another name Huperzine A-Zhulin Antun, chemical name: (5R, 9R, 11E)-and 5-amino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (b) pyridine-2 (1H) ketone also; Molecular formula: C
15H
18N
2O; Molecular weight: 242.32; Structural formula:
Huperzine A is the crystalline powder of white or off-white color; Odorless, mildly bitter flavor; Have draw moist.Fusing point: 230 ℃, optical rotation :-150.4 °, easily molten in methanol, in ethanol, dissolve, insoluble in water; Slightly soluble in the 0.01mol/L hydrochloric acid solution.
Huperzine A is that China extracts a kind of alkaloid that obtains the earliest from natural plants Herba Lycopodii serrati [Huperzinaserrata (Thumb.) Trev], has tangible anticholinesterase activity, true cholinesterase is had optionally inhibitory action, is a potent acetylcholine esterase reversible inhibitor.Discovering all over the world, huperzine A to hypermnesis, improve memory impairment, improve mental activity efficient, senile amnesia and degenerative brain disorder, adolescents with learning obstacle and hypermnesia and all improve significantly, China's Ministry of Public Health approved is the new drug of treatment degenerative brain disorder.Be applicable to benign memory deficits, cerebrovascular disease, brain trauma, organic mental disorders, peripheral blood vessel occlusive disease, diabetic neuropathy, acute and chronic heel string pain, exercise-induced muscular wound.The clinical myasthenia gravis that is used for the treatment of, effective percentage reaches 99%.Be a class therapeutic index height, the new chemical compound that toxicity is little.
The therapeutic dose of huperzine A is minimum, general oral one time 100～200 μ g, and one day 2 times, a staggering amount is no more than 450 μ g (or following the doctor's advice) at most, so the amount of contained huperzine A also is few in the general preparation.Current edition Chinese Pharmacopoeia regulation: huperzine A sheet, capsule specification are 50 μ g.General, small dimension tablet or capsule, sheet weigh or grain heavily is about 100mg.If huperzine A sheet and capsule monolithic (grain) weight are decided to be 100mg, then principal agent only accounts for 0.05% (wt) of whole weight of formulation, and visible content is very low.Therefore, when solid preparations such as huperzine A tablet and capsule are produced, all exist the uneven problem of content, for this reason, the current edition Chinese Pharmacopoeia to huperzine A tablet and capsule special provision the uniformity of dosage units standard.
The dispersing uniformity problem that the low dose of solid preparation uniformity of dosage units of solution is a crude drug in the production, prior art generally all adopts the equivalent method of progressively increasing to be tackled, promptly earlier crude drug (huperzine A) is added in the dispersant (adjuvant) of equivalent, behind the mix homogeneously, the adjuvant that adds equivalent again mixes once more, to be mixed evenly after, add the equivalent adjuvant once more, according to preceding method operation, reach the regulation requirement until supplementary material mix homogeneously, total amount.But this method is used for the huperzine-A solid preparation when producing, because of crude drug quantity very little, the ratio of supplementary material weight differs too big, needs blended number of times too many, is difficult to guarantee that crude drug can disperse mix homogeneously, reaches the uniformity of dosage units standard of regulation; In addition, this method labor intensity is very big, and loss is a lot, and during actual production, output and quality all can not get guaranteeing.Because the huperzine A consumption really very little and water insoluble, slightly soluble or in the part organic solvent, dissolve in the acid of low concentration only, so prior art is when adopting the equivalent method of progressively increasing to solve the scattering problem of huperzine A, carried out partly improving, promptly earlier make the huperzine A salify water-soluble or make its dissolving, add again and carry out the equivalent mixing of progressively increasing in the adjuvant with organic solvent with the acid of low concentration.This method has solved the problems of dissolution and the part scattering problem of huperzine A when producing, but because introduce diluted acid production equipment has been produced corrosion, and a large amount of uses of organic solvent exist potential safety hazard in the married operation process.
Because huperzine A is to light and damp and hot instability, and and most of adjuvants incompatibility is arranged, the huperzine-A solid preparation of conventional method preparation is easily degraded in storage.For overcoming above-mentioned deficiency, in the public technology, the existing freeze-drying that adopts prepares the production method (patent application: 200710093156.9) that huperzine A lyophilizing dispersion is carried out solid preparation.Yet, the outstanding problem that this method exists is, first, calculate by actual specification, its dispersion that makes also must could satisfy the requirement of tabletting or capsule fill with after appropriate amount of auxiliary materials is mixed, and has the mixing of a solid material in its preparation process again, essence still is the equivalent mixing method of progressively increasing, and a mixing uniformity problem is arranged equally; The second, this method is actual, and what solve only is to avoid the damp and hot negative effect that huperzine A is produced in the production process, does not fundamentally solve the problem that influences that huperzine A is subjected to illumination etc., more not have the incompatibility problem between solution and the adjuvant; In addition, the producing cost of freeze-drying itself is higher, adopts this method to produce, and product cost will raise.
Summary of the invention
Therefore, the technical problem to be solved in the present invention be exactly at existing huperzine-A solid preparation have that huperzine A content is inhomogeneous, preparation process is loaded down with trivial details, cost is higher, product yield and quality all can not get the defective that guarantees, a kind of huperzine A preparation and preparation method thereof is provided, this huperzine A preparation active component huperzine A content is even, the stable difficult degraded of huperzine A; This preparation method step is simple, and material loss reduces, and cost reduces, and process stabilizing is reliable, suitable commercial production in enormous quantities.
The inventor, adds in the beta-schardinger dextrin-solution after discovery is dissolved in organic solvent with water-fast huperzine A through deep research and test repeatedly, can make the Benexate Hydrochloride of huperzine A; The preparation process of this clathrate can make huperzine A obtain full and uniform dispersion, thereby guarantees that huperzine A is uniformly dispersed in whole material system, and uniformity of dosage units is significantly better than required standard; The inventor finds that also huperzine A is wrapped in after the beta-schardinger dextrin-, has changed the solubility property of huperzine A, has become that insoluble matter is soluble substance in the water in the water, for preparation water-soluble liquid preparation provides may; This clathrate is with after a certain amount of adjuvant cooperates, the dissolution of the solid preparation of making in simulated gastric fluid is greatly improved, thereby has improved human body to the absorbing of medicine, and has improved curative effect; The inventor further finds, huperzine A is wrapped in after the beta-schardinger dextrin-, completely cut off and the contacting directly of environment, thereby illumination, damp and hot etc. influence have been reduced, and fundamentally solved and adjuvant between the incompatibility problem, reduced because the risk that the influence of environment and adjuvant causes huperzine A to decompose is decomposed the related substance that produces by huperzine A and can be controlled at below 1%, the product that makes is more reliable and more stable, and quality is improved significantly.On this basis, the inventor further is scattered in starch etc. with the Benexate Hydrochloride of this huperzine A to have in the water-solubility carrier of viscosity, forms a kind of slurry with viscosity, conveniently is used to prepare the solid preparation of various huperzine As.The inventor also further will comprise the viscosity slurry of huperzine A and the base material of pharmaceutic adjuvant composition is made granule, and this granule can further be made tablet, capsule etc. with conventional method, has finally finished the present invention.
Therefore, the present invention solves the problems of the technologies described above one of technical scheme of being adopted: a kind of Benexate Hydrochloride of huperzine A, by percentage by weight is that 2.5～9.5% huperzine A and 97.5～90.5% beta-schardinger dextrin-are formed, preferable is 5% huperzine A and 95% beta-schardinger dextrin-.The Benexate Hydrochloride of this huperzine A can further be made liquid preparations such as injection, oral liquid, has solved because of huperzine A is insoluble in water and can't make the water-soluble liquid preparation, has limited the problem of huperzine A route of administration; Also can cooperate and make oral solid formulation with acceptable auxiliary on the pharmaceutics.
The present invention solves the problems of the technologies described above two of the technical scheme that adopted: a kind of preparation method of Benexate Hydrochloride of huperzine A may further comprise the steps:
A) huperzine A is dissolved on the pharmaceutics in the acceptable organic solvent, solution A; With beta-schardinger dextrin-heating for dissolving in water, get solution B;
B) under stirring, solution A is slowly added in the solution B, continue to be stirred to evenly, get the Benexate Hydrochloride solution of huperzine A.
Among the present invention, in the described solution A of step a), acceptable organic solvent is to dissolve alkaloidal organic solvent on the described pharmaceutics, can limit the organic solvent of use such as version Chinese Pharmacopoeia in 2005 and medicine GMP regulation, preferable be selected from methanol, ethanol, acetone and the chloroform one or more, best is ethanol.Huperzine A and described organic solvent volume ratio by weight are 1: 10～1: 50, are preferably 1: 25～1: 45, and the best is 1: 40.Huperzine A is dissolved in the described organic solvent, can reaches and make huperzine A dispersion and uniform distribution and be the purpose of unimolecule free state fully.In the described solution B of step a), the concentration expressed in percentage by weight of beta-schardinger dextrin-is 1～3%, is preferably 1.8～2.2%, and the best is 2%.With beta-schardinger dextrin-heating for dissolving in water, can earlier beta-schardinger dextrin-be put into water, be heated to 80 ℃, just can guarantee that beta-schardinger dextrin-dissolves fully, obtain finely dispersed solution.With the solution B of beta-schardinger dextrin-dissolving back gained, preferable be cooled to 30 ℃ standby, can not separate out to guarantee beta-schardinger dextrin-because temperature is too low.
Among the present invention, step b) is the routine operation of Benexate Hydrochloride preparation, detailed consults relevant beta-cyclodextrin inclusion compound technology, preferable is under stirring, solution A is slowly added in the solution B, continue to be stirred to evenly, promptly get the Benexate Hydrochloride solution of huperzine A.Wherein, speed and mixing speed, solution quantity that solution A slowly adds in the solution B is relevant, general, and control solid do not occur and separates out and get final product.Because beta-schardinger dextrin-is a hydrophilic substance, and is insoluble in organic solvent, if solution B is joined in the solution A, beta-schardinger dextrin-can be separated out immediately, can not carry out effective enclose to the huperzine A in the solution A and form clathrate, therefore, must adopt solution A is slowly joined method in the solution B.When solution A joins in the solution B, the huperzine A in the solution A enters when separating out in the cavity of beta-schardinger dextrin-and is formed the clathrate molecule by enclose.Because huperzine A by beta-cyclodextrin inclusion compound, is separated out so the huperzine A molecule can't be assembled the formation crystal, finally show as the clathrate form and be dissolved in the water, insoluble matter is solute in the water in the change water.Because enclose is physical process, not as the inorganic chemistry reaction so rapid, so need slowly to add, otherwise can because of the huperzine A molecule separate out in a large number cause molecular aggregates to form crystal can not be by beta-schardinger dextrin-institute enclose.Described continuation is stirred and is preferably 15 minutes, and the best is 30 minutes.In the Benexate Hydrochloride of the huperzine A of gained, the molecular amounts of huperzine A and beta-schardinger dextrin-ratio is 1: 2～1: 8, is preferably 1: 4, and the best is 1: 8; Weight ratio is 1: 10～1: 40, is preferably 1: 20, and the best is 1: 40.Step b) has formed the Benexate Hydrochloride of huperzine A, and makes huperzine A be able to abundant dispersion.Because beta-schardinger dextrin-can be dissolved in water, make that water-fast huperzine A bag is embedded in beta-schardinger dextrin-after, also can be water-soluble, thus make the Benexate Hydrochloride of the huperzine A of gained can further make water preparations such as injection, oral liquid.The Benexate Hydrochloride solution of the huperzine A of step b) gained, behind acceptable auxiliary compatibility on the pharmaceutics, can be directly used in the various solid preparations of preparation, and needn't earlier the Benexate Hydrochloride of huperzine A be separated from solution with methods such as filtrations, can reduce operating procedure like this.
The present invention solves the problems of the technologies described above three of the technical scheme that adopted: a kind of compositions that contains huperzine A, composed of the following components: available on the Benexate Hydrochloride of aforesaid huperzine A, the pharmaceutics have the water-solubility carrier material of viscosity and a base material of being made up of pharmaceutic adjuvant, wherein the weight ratio of available water-solubility carrier material is 1: 20～1: 100 on huperzine A and the pharmaceutics, and huperzine A is 1: 1000～4000 with the base material weight ratio of being made up of pharmaceutic adjuvant.
Wherein, available water-solubility carrier material with viscosity can be an available water miscible material with viscosity on the pharmaceutics on the described pharmaceutics, preferable in starch, dextrin, hydroxypropyl cellulose (HPMC), polyvinylpyrrolidone and the hypromellose one or more, the first-selected starch of being selected from.Described pharmaceutic adjuvant comprises filler and/or disintegrating agent commonly used in the pharmaceutics, comprise starch, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose (LS-HPC), crospolyvinylpyrrolidone (PVPP) and cross-linking sodium carboxymethyl cellulose (CCMC-Na), preferable is made up of starch and lactose, the weight ratio of starch and lactose, be preferably 1: 1～1: 1.5, the best is 1: 1.5.The weight ratio of huperzine A and water-solubility carrier material is 1: 20～1: 100, is preferably 1: 25, and the best is 1: 40.Huperzine A is 1: 1000～1: 4000 with the base material weight ratio of being made up of pharmaceutic adjuvant, preferably 1: 2000.This compositions that contains huperzine A can further be made powder, granule, perhaps through granulation, granulate, add lubricant, total mixing after, compacting in flakes or irritate into capsule is made tablet or capsule.
The present invention solves the problems of the technologies described above four of the technical scheme that adopted: a kind of aforesaid preparation of compositions method that contains huperzine A may further comprise the steps:
1) available water-solubility carrier with viscosity on the pharmaceutics is dissolved in the water, gets viscosity solution C;
2) with the solution of the Benexate Hydrochloride of aforesaid huperzine A and the viscosity solution C mix homogeneously of step 1) gained, 25～50 ℃ of temperature controls, a slurry;
3) with step 2) slurry that obtains and the base material mixing of forming by pharmaceutic adjuvant, granulation gets granule.
Among the present invention, step 1) is: available water-solubility carrier with viscosity on the pharmaceutics is dissolved in the water, gets viscosity solution C.Wherein, available water-solubility carrier material with viscosity as mentioned above on the described pharmaceutics, it can be available water miscible material on the pharmaceutics with viscosity, preferable in starch, dextrin, hydroxypropyl cellulose (HPMC), polyvinylpyrrolidone and the hypromellose one or more, the first-selected starch of being selected from.Described use starch prepares the routine operation that is operating as starch slurry preparation of viscosity solution C, and is preferable, earlier with a small amount of cold water with the starch moistening and stir, add hot water again and become pasty state; Better, starch is added after a small amount of cold water stirs, add the cold water of ormal weight again, under stirring, be heated to more than 80 ℃ and make it gelatinizing, be cooled to 40 ℃ standby.Among the viscosity solution C of gained, the weight percent concentration with Water-solubility Material of viscosity is 3～10%, is preferably 8%.Water-solubility Material with viscosity is with the further homodisperse of the Benexate Hydrochloride of huperzine A.Especially, because step 2) slurry that obtains has suitable viscosity, make the Benexate Hydrochloride molecule of huperzine A wherein and gelatinizing starch molecule deadlocked mutually, cause all molecules in the whole solution system to keep stable homogeneously dispersed state.Because step 2) slurry that obtains has viscosity, can be used as the adhesive in the operation of granulating, and is used for further granulating operation.
Among the present invention, step 2) be: with the solution of the Benexate Hydrochloride of aforesaid huperzine A and the viscosity solution C mix homogeneously of step 1) gained, 25～50 ℃ of temperature controls, a slurry.Wherein, the solution of the Benexate Hydrochloride of aforesaid huperzine A is the Benexate Hydrochloride solution of the huperzine A of step b) gained preferably, temperature must be controlled at 25～50 ℃, the best is 40 ℃, main cause is that the dissolubility of beta-schardinger dextrin-is relevant with temperature, temperature is too low, and the Benexate Hydrochloride of huperzine A can be separated out from solution.Aforesaid slurry, temperature also must be controlled at 25～50 ℃, the best is 40 ℃, because the viscosity of slurry and temperature also have relation, the slurry viscosity can reduce and increase by Yin Wendu, and the viscosity increase is unfavorable for the Benexate Hydrochloride solution of huperzine A and the uniform mixing of solution C, and in addition, the slurry viscosity also is unfavorable for the granulation operation of back too greatly.Step 2) formed stable clathrate slurry, promptly the Benexate Hydrochloride of huperzine A/water-solubility carrier is starched, and this operation makes huperzine A be able to fully disperse once more.The weight ratio of huperzine A and water-solubility carrier material is 1: 20～1: 100, is preferably 1: 25, and the best is 1: 40.
Among the present invention, step 3) is: with step 2) slurry that obtains and the base material mixing of forming by pharmaceutic adjuvant, granulation gets granule.Wherein, described pharmaceutic adjuvant comprises filler and/or disintegrating agent commonly used in the pharmaceutics as mentioned above, and preferable is made up of starch and lactose.Huperzine A and base material weight ratio are 1: 1000～4000, preferably 1: 2000.The method of described granulation can be the method for granulating of this area routine, comprises waving granulating and boiling granulating, preferably boiling granulating.In the boiling granulating, what boiling temperature was preferable is 40～65 ℃, is more preferred from 55 ℃, and the best is 60 ℃.Granulation can reach the degree of scatter of technological requirement like this, and makes granule.
The present invention solves the problems of the technologies described above five of the technical scheme that adopted: a kind of huperzine A tablet or capsule, get by the method preparation that may further comprise the steps: according to a conventional method, with aforesaid huperzine A granule granulate, add lubricant, after total mixing, carry out tabletting or fill capsule, promptly.Wherein, preferable usefulness 16～20 mesh sieve granulate of described granulate.Best 18 mesh sieves of using of tabletting; Capsule is best with 18～20 mesh sieves.Described lubricant adopts pharmaceutics lubricant commonly used, preferable is selected from magnesium stearate, Pulvis Talci, Polyethylene Glycol-6000 (PEG-6000) and the micropowder silica gel one or more.The preferred magnesium stearate of the lubricant of tablet wherein; Capsular lubricant preferably talc powder.The consumption of the lubricant preferably lubricant percentage by weight that accounts for the solid material gross weight is 0.5～1.5%, is more preferred from 1.0%.Total dried granule that mixes gained is preferable carries out analysis of medium, carries out tabletting or fill capsule again according to analysis result.Preferable contains 50 μ g huperzine As calculating sheets (grain) heavily by every (grain).Described tabletting or fill capsule adopt the method for this area routine promptly to carry out tabletting or capsule fill with tablet machine or fully-automatic capsule filling machine.The huperzine A tablet or the capsule of gained can be packed, product inspection, and warehouse-in is sold.
A preferred embodiment of the present invention is as follows:
1. with an amount of medicinal alcohol dissolving huperzine A, promptly get solution A, standby.Wherein, w/v, huperzine A: medicinal alcohol=1: 10～50, be preferably 25, the best is 40.It is free fully that this step reaches the huperzine A molecule, is dispersed in purpose in the whole solution system with the unimolecule form.
2. get an amount of beta-schardinger dextrin-, add purified water, heated and stirred is made beta-schardinger dextrin-solution, is cooled to 30 ℃, promptly gets solution B.Wherein, the consumption of beta-schardinger dextrin-by weight percentage, above-mentioned huperzine A 2.5～9.5%, beta-schardinger dextrin-is 97.5～90.5%, and is preferable, is 5% huperzine A and 95% beta-schardinger dextrin-.In the solution B, by weight percentage, it is 1～3% that solution contains beta-schardinger dextrin-, is preferably 1.8%, and the best is 2%.
3. under stirring, the solution A of gained slowly is added in the solution B, continue to stir a period of time, be preferably 15 minutes, the best is 30 minutes.This step forms the Benexate Hydrochloride solution of huperzine A, wherein, each huperzine A molecule is embedded in the void structure of beta-schardinger dextrin-by bag, form and divide ascus, isolate with external environment effectively, be dispersed in simultaneously in the whole aqueous solution, make huperzine A be able to abundant dispersion, and become soluble substance in the water.
4. get appropriate amount of starch, after adding low amounts of water and disperseing, add hot water and stir into slurry, be cooled to 30 ℃, promptly get solution C.Wherein, the consumption of starch is by weight: huperzine A: starch=1: 20～100, be preferably 25, and the best is 40.In the solution C, starch concentration is 3～10%, is preferably 5%, and the best is 8%.Starch can be substituted first-selected starch by dextrin, hydroxypropyl cellulose (HPMC), polyvinylpyrrolidone or hypromellose.
5. the solution of step 3 is poured in the solution C under stirring, become the farinaceous size of the Benexate Hydrochloride of huperzine A, 25～40 ℃ of temperature controls, the best is 30 ℃.The serosity that this step forms, because of the sticky effect of starch slurry makes all the material molecules in the whole system become homodisperse mixing thick liquid, not only make huperzine A obtain fully disperseing once more, and guaranteed whole system not Yin Wendu etc. variation and produce phenomenons such as precipitation, make whole system be in steady statue.
6. the slurry that step 5 is obtained sprays into boiling granulating in the base material of being made up of starch and lactose.The consumption of starch and lactose is by weight: starch: lactose=1: 2; Be preferably 1: 1; The best is 1: 1.5.Described base material or independent microcrystalline Cellulose, low-substituted hydroxypropyl cellulose (LS-HPC), crospolyvinylpyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (CCMC-Na) also can be two or more mixture of above-mentioned material.40～65 ℃ of the boiling temperatures of boiling granulating are preferably 55 ℃, and the best is 60 ℃.This step reaches the degree of scatter of technological requirement, but but and makes tabletting or the capsular granule of fill.
7. with 16～20 mesh sieve granulate (best 18 orders of tabletting, best 20 orders of capsule), add lubricant.The addition of described lubricant is by weight, lubricant: solid material total amount=0.5～1.5%, be preferably 0.75%, and the best is 1.0%.Described lubricant is preferred magnesium stearate when the preparation tablet, preferably talc powder when the preparation capsule.
8. total mixing can be used various mixing apparatus.
9. dried granule carries out analysis of medium, and it is heavy to contain 50 μ g huperzine As calculating sheets (grain) by every (grain), and is in blocks by the tablet machine compacting, or is filled to capsule through capsule filling machine with the glue shell.General filled capsules granule can carry out granulate with 18 or 20 eye mesh screens.Packing, after product inspection was qualified, warehouse-in was sold.
The present invention is except that specifying, used percentage ratio all is weight percentage.
Supplementary material of the present invention all is pharmaceutically useful supplementary material.Except that specifying, used raw material or adjuvant or reagent are all commercially available to be got.
Than prior art, beneficial effect summation of the present invention is as follows:
(1) dissolves dispersive method with huperzine A and substituted traditional process for dispersing that equivalent is progressively increased, significantly reduced operating procedure, improved dispersion efficiency, improved dispersion effect, reduced labor intensity, reduced the loss of raw material; Because the improvement of dispersion effect, the solid preparation product dispersing uniformity that further prepares is thus greatly improved, and shows that uniformity of dosage units is significantly improved, thereby has guaranteed product quality, has promoted drug safety.
(2) the present invention prepares the Benexate Hydrochloride of the huperzine A of gained, changed the solubility property of huperzine A fully, insoluble huperzine A in the water is transformed into dissolved clathrate in the water, show that dissolution is significantly increased in the water of the solid preparation product that further prepares thus, provide assurance for improving bioavailability, strengthened curative effect.Because the Benexate Hydrochloride of huperzine A can dissolve in water, so be not limited to prepare oral solid formulation, also can prepare various water-soluble liquid preparations, thereby expand formulation art, has increased route of administration.
(3) since huperzine A by beta-cyclodextrin inclusion compound, isolate with external environment effectively, the solid preparation that makes thus is difficult for affected by environment, more stable quality, storage period is longer, the difficult degraded, and fundamentally solved incompatibility problem between huperzine A and the adjuvant, reduced because the risk that the influence of environment and adjuvant causes huperzine A to decompose, the content of related substance that shows prepared preparation is lower, can not produce because degraded causes problems such as related substance index exceeding standard, greatly reducing huperzine A is producing, the risk of degrading in storage and the material compatibility process, the product that makes is more reliable and more stable, and quality is improved significantly, for the patient provides safer, effective and stable product.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition operation, or according to the working condition of pharmaceutical production GMP regulation." room temperature " described in the embodiment is meant the temperature of the operation room of testing to be generally 25 ℃.
Embodiment 1
Get the 0.5g huperzine A, use 20.0ml 95% medicinal alcohol its whole dissolvings.Other gets beta-schardinger dextrin-10.0g, add the 50ml purified water, be heated with stirring to 80 ℃ and make its whole dissolvings, be cooled to 40 ℃, gently in 15 minutes, add above-mentioned huperzine A/alcoholic solution under the stirring, continue to stir 30 minutes, be cooled to 0 ℃, cold preservation 12 hours, filter with filter cloth, dry, get the Benexate Hydrochloride 9.85g of huperzine A, average yield counts 98.5% with beta-schardinger dextrin-weight.The huperzine A average recovery rate is 98%.
Computing formula:
Average yield=clathrate weight ÷ beta-schardinger dextrin-weight * 100% that feeds intake.
Huperzine A weight percentage ÷ huperzine A weight * 100% that feeds intake in average recovery rate=clathrate weight * clathrate.
" clathrate " described in this two formula is meant " Benexate Hydrochloride of huperzine A ".
Embodiment 2
Get the 0.5g huperzine A, use 20.0ml 95% medicinal alcohol its whole dissolvings.Other gets beta-schardinger dextrin-10.0g, adds the 50ml purified water, is heated with stirring to 80 ℃ and makes its whole dissolvings, is cooled to 40 ℃, gently adds above-mentioned huperzine A/alcoholic solution under the stirring in 20 minutes, continues to stir 30 minutes.Other gets 20g starch, add the 230g aqueous dispersion after, be heated to 80 ℃ and stir pulpings, be cooled to 40 ℃, under stirring, mixes spray drying, Benexate Hydrochloride/starch mixture 29.55g that must huperzine A with the beta-schardinger dextrin-solution of huperzine A.Average yield (in the weight of beta-schardinger dextrin-and starch sum) is 98.5%.The huperzine A average recovery rate is 98.5%.
Computing formula:
Average yield=mixture weight ÷ (beta-schardinger dextrin-weight+starch weight) * 100%.
Huperzine A weight percentage ÷ huperzine A inventory * 100% in average recovery rate=mixture weight * mixture.
" mixture " described in this two formula is meant " Benexate Hydrochloride/starch mixture of huperzine A ".
Embodiment 3
Prescription: the medicinal 0.5g of huperzine A
The medicinal 20.0ml of 95% ethanol
The medicinal 10.0g of beta-schardinger dextrin-
The medicinal 250g of 8% starch slurry (starch 20g)
The medicinal 379.5g of starch
The medicinal 580.0g of lactose
The medicinal 10.0g of magnesium stearate
Technology: by the prescription, get huperzine A, with 95% medicinal alcohol with its whole dissolvings.Other gets beta-schardinger dextrin-, adds the 50ml purified water, is heated with stirring to 80 ℃ and makes its whole dissolvings, is cooled to 40 ℃, and stirring adds huperzine A/alcoholic solution down, continues to stir 30 minutes, gets the Benexate Hydrochloride solution of huperzine A.Other gets 20g starch, after adding the 230g purified water and disperseing, is heated to 80 ℃ and stirs pulpings, is cooled to 40 ℃, mixes with the Benexate Hydrochloride solution of huperzine A under stirring, must slurry.Boiling granulating, the control inlet temperature is 60 ℃, slurry is sprayed into to be mixed in the boiling granulating machine of base material by starch, lactose granulate, and material spray finishes, and control moisture is 3% left and right sides discharging.With 18 mesh sieve granulate, add after the magnesium stearate and in V-Mixer, always mix.According to " analysis of medium is carried out in two regulation samplings of Chinese pharmacopoeia (version in 2005), and it is heavy to contain huperzine A 50 μ g calculating sheet by every, is pressed into 10000 with tablet machine.Sheet is heavy: 97.5～102.5mg/ sheet.
Embodiment 4
Prescription: the medicinal 0.5g of huperzine A
The medicinal 20.0ml of 95% ethanol
The medicinal 10.0g of beta-schardinger dextrin-
The medicinal 250g of 8% starch slurry (starch 20g)
The medicinal 379.5g of starch
The medicinal 380.0g of lactose
The medicinal 10.0g of Pulvis Talci
Technology: by the prescription, get huperzine A, with 95% medicinal alcohol with its whole dissolvings.Other gets beta-schardinger dextrin-, adds the 50ml purified water, is heated with stirring to 80 ℃ of its whole dissolvings, is cooled to 40 ℃, and stirring adds huperzine A/alcoholic solution down, continues to stir 30 minutes, gets the Benexate Hydrochloride solution of huperzine A.Other gets starch, after adding the 230g purified water and disperseing, is heated to 80 ℃ and stirs pulpings; be cooled to 40 ℃; under stirring, mix with the Benexate Hydrochloride solution of huperzine A, slurry, pour into by starch, lactose and be mixed in the trough-type mixture machine of base material; mix; wave granulation with 20 mesh sieves on the granulator waving, wet granular is put into baking oven, 60 ℃ of dryings; when treating that pellet moisture is 3% left and right sides, discharging.With 20 mesh sieve granulate, add behind the Pulvis Talci and in V-Mixer, always mix.According to " analysis of medium is carried out in the sampling of two of Chinese pharmacopoeia (version in 2005) regulation, and containing huperzine A 50 μ g by every, to calculate grain heavy, on capsule filling machine with 4
#The fill of glue shell becomes 10000 capsules.Grain weighs 78.0～82.0mg/ grain.
Embodiment 5～8
The prescription of table 1. embodiment 5～8
Technology: carry out following operation by the prescription of table 1 and the technological parameter of table 2.Get huperzine A, with solvent it all being dissolved becomes solution A.Other gets beta-schardinger dextrin-, adds purified water, is heated with stirring to 80 ℃ and makes its whole dissolvings, is cooled to the temperature required solution B that becomes.Stirring adds huperzine A/solvent solution down, continues to stir 30 minutes, gets the Benexate Hydrochloride solution of huperzine A.Other solubleness carrier material of fetching water after adding purified water and disperseing, is heated to 80 ℃ and stirs pulpings, is cooled to temperature requiredly, keeps this temperature to become solution C.Under stirring, mix, get slurry with the Benexate Hydrochloride solution of huperzine A.Boiling granulating, the control inlet temperature sprays into slurry in the boiling granulating machine of built-in base material and granulates, and material spray finishes, control moisture, discharging.With the sieve granulate, add behind the lubricant and in V-Mixer, always mix.According to " analysis of medium is carried out in the sampling of two of Chinese pharmacopoeia (version in 2005) regulation, and containing huperzine A 50 μ g by every (grain), to calculate sheet heavy or grain is heavy, suppresses in blocks or fill becomes capsule.
The technological parameter of table 2. embodiment 5～8
Further specify beneficial effect of the present invention below by effect embodiment.
Effect embodiment 1
Product is examined situation entirely: according to " quality standard and the inspection method thereof of Chinese pharmacopoeia (version in 2005) two ones " huperzine A sheets " and " huperzine A capsule " are carried out quality inspection.
Checked object: respectively by three batches of tablets (lot number 090101,090102,090103) of embodiment 3 preparations and three batches of capsules (lot number 090101,090102,090103) sample of embodiment 4 preparations; Wherein, the huperzine A reference substance is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Assay is as follows:
(1) tablet:
(2) capsule:
Conclusion: all indexs of product all meet national standard.
Effect embodiment 2
Product stability test: according to " quality standard and the inspection method thereof of Chinese pharmacopoeia (version in 2005) two ones " huperzine A sheets " and " huperzine A capsule " are carried out quality inspection.
Checked object: respectively by three batches of tablets (lot number 090101,090102,090103) of embodiment 3 preparations and three batches of capsules (lot number 090101,090102,090103) sample of embodiment 4 preparations; Wherein, the huperzine A reference substance is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Assay is as follows:
1. influence factor's test
(1) strong illumination experiment: get huperzine A sheet and capsule sample, spread out on culture dish, placing illumination is in the illumination apparatus of 4500lx ± 500lx, shines respectively 1 day, 3 days, tests after 5 days and 10 days.
The result is as follows:
(2) hot test: get huperzine A sheet and capsule, put in the airtight glass dish, be positioned over respectively in the calorstat of 40 ℃, 60 ℃ and 80 ℃, in 1,3,5,10 day sample analysis, the result was as follows:
1. .40 ℃ of high temperature:
2. .60 ℃ of high temperature
3. .80 ℃ of high temperature
(3) high wet test: get huperzine A sheet and capsule, spread out in culture dish, place the bottom to have NaCl, KNO respectively
3In the exsiccator of saturated solution, exsiccator places in 25 ℃ of constant temperature ovens, sample analysis after 1,3,5,10 day, and the result is as follows:
1.. relative humidity 75% (NaCl saturated solution):
2.. relative humidity 92.5% (KNO
3Saturated solution):
(4) dew is put test in the air: get huperzine A sheet and capsule, in air, reveal and put 5 and 10 days, and sampling and measuring, the result is as follows:
2. accelerated test
Get huperzine A sheet and capsule sample, routinely after the packing, put in 40 ℃, the climatic chamber of relative humidity 75% and store, after January, February, March and June, sample analysis, the result is as follows:
3. room temperature reserved sample observing
Get huperzine A sheet and capsule sample, room temperature is placed, the mensuration of regularly taking a sample to check, and the result is as follows:
Conclusion: by products made thereby of the present invention, through above-mentioned every test, all indexs all meet national standard.So product of the present invention promptly seals under the situation of shady and cool drying place's preservation in generic condition, has the advantage that stability is high, uniformity of dosage units is good, and difficult the generation degraded and caused the related substance index exceeding standard.
Effect embodiment 3
The product dissolution detects: by " Chinese pharmacopoeia (2005 editions second one) the appendix XC dissolution method three therapeutic methods of traditional Chinese medicine is operated, and rotating speed is 100rpm.The simulated gastric fluid 100ml that the degassing of learning from else's experience is handled, put in each stripping rotor, heat, treat that the dissolution medium temperature constant is at 37 ± 0.5 ℃, get test sample, be divided into 6 parts, 1 every part, drop into respectively in 6 stripping rotors, timing immediately, after 30 minutes, sampling, after No. 4 sintered filter funnels filtrations, reuse 0.22 μ m filtering with microporous membrane is with reference to " dissolution study of huperzine A capsule agent and tablet " (Zhou Zhifang, the red Zhejiang Academy of Medical Sciences of Lin Zhi journal in JIUYUE, 1997) literary composition adopts the HPLC method to measure the dissolution of huperzine A in the dissolution fluid, wherein, the huperzine A reference substance is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Checked object: be test sample by three batches of tablets (lot number 090101,090102,090103) of embodiment 3 preparations and three batches of capsules (lot number 090101,090102,090103) of embodiment 4 preparations respectively.
Assay is as follows:
The average dissolution of different batches huperzine A sheet and huperzine A capsule
Conclusion: by the said determination result as seen, the said goods that the present invention makes all has dissolution preferably.Do not stipulate the dissolution specific requirement in the existing national standard of the said goods, but investigate present commercially available Related product, the stripping situation is all not so good in the simulated gastric fluid, some in addition do not have stripping, greatly influenced absorbing of medicine, but the huperzine A sheet and the huperzine A capsule of the present invention preparation have improved stripping greatly, for effective utilization of medicine provides prerequisite.
Claims (11)
1. the Benexate Hydrochloride of a huperzine A is characterized in that, is that 2.5～9.5% huperzine A and 90.5～97.5% beta-schardinger dextrin-are formed by percentage by weight.
2. the preparation method of the Benexate Hydrochloride of a huperzine A as claimed in claim 1 is characterized in that, may further comprise the steps:
A) huperzine A is dissolved on the pharmaceutics in the acceptable organic solvent, solution A; With beta-schardinger dextrin-heating for dissolving in water, get solution B;
B) under stirring, solution A is slowly added in the solution B, continue to be stirred to evenly, get the Benexate Hydrochloride solution of huperzine A.
3. preparation method as claimed in claim 2 is characterized in that, in the step a), acceptable organic solvent is selected from one or more in methanol, ethanol, acetone and the chloroform on the described pharmaceutics; Huperzine A and described organic solvent volume ratio by weight are 1: 10～1: 50.
4. preparation method as claimed in claim 2 is characterized in that, in the solution B described in the step a), the concentration expressed in percentage by weight of beta-schardinger dextrin-is 1～3%.
5. compositions that contains huperzine A, composed of the following components: available on the Benexate Hydrochloride of huperzine A as claimed in claim 1, the pharmaceutics have the water-solubility carrier material of viscosity and a base material of being made up of pharmaceutic adjuvant, wherein the weight ratio of huperzine A and water-solubility carrier material is 1: 20～1: 100, and huperzine A is 1: 1000～1: 4000 with the base material weight ratio of being made up of pharmaceutic adjuvant.
6. the compositions that contains huperzine A as claimed in claim 5, it is characterized in that available water-solubility carrier material with viscosity is selected from one or more in starch, dextrin, hydroxypropyl cellulose, polyvinylpyrrolidone, the hypromellose on the described pharmaceutics; Described pharmaceutic adjuvant is selected from one or more in starch, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone and the cross-linking sodium carboxymethyl cellulose.
7. the compositions that contains huperzine A as claimed in claim 5 is characterized in that described pharmaceutic adjuvant is made up of starch and lactose, and the weight ratio of starch and lactose is 1: 1～1: 1.5.
8. one kind as each described preparation of compositions method that contains huperzine A of claim 5～7, it is characterized in that, may further comprise the steps:
1) available water-solubility carrier with viscosity on the pharmaceutics is dissolved in the water, gets viscosity solution C;
2) with the solution of the Benexate Hydrochloride of huperzine A as claimed in claim 1 and the viscosity solution C mix homogeneously of step 1) gained, 25～50 ℃ of temperature controls, a slurry;
3) with step 2) slurry that obtains and the base material mixing of forming by pharmaceutic adjuvant, granulation gets granule.
9. preparation method as claimed in claim 8 is characterized in that, among the viscosity solution C of step 1) gained, available concentration with water-solubility carrier of viscosity is 3～10% on the pharmaceutics, and percentage ratio is weight percentage; Granulation described in the step 3) is a boiling granulating, and the boiling temperature of boiling granulating is 40～65 ℃.
10. huperzine A tablet or capsule is characterized in that, by the method preparation that may further comprise the steps and get: according to a conventional method, will be as each described compositions granulate that contains huperzine A of claim 5～7, add lubricant, after total mixing, carry out tabletting or fill capsule, promptly.
11. huperzine A tablet as claimed in claim 10 or capsule, it is characterized in that, described granulate is with 16～20 mesh sieve granulate, described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, Polyethylene Glycol-6000 and the micropowder silica gel, and the consumption of lubricant is that to account for solid material total amount percentage by weight be 0.5～1.5% to lubricant.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108096584A (en) * | 2018-01-30 | 2018-06-01 | 内蒙古工业大学 | Utilize supercritical CO2Tosufloxacin tosilate/cyclodextrin inclusion compound prepared by technology and preparation method thereof and oral formulations |
| EP3446688A1 (en) * | 2011-10-31 | 2019-02-27 | Commissariat à l'Energie Atomique et aux Energies Alternatives | Use of anti-connexin agents for enhancing the therapeutic effect of acetylcholinesterase inhibitors |
| CN114796132A (en) * | 2022-05-13 | 2022-07-29 | 海南灵康制药有限公司 | Lyophilized powder injection of huperzine A and its preparation method |
-
2009
- 2009-10-27 CN CN2009101977107A patent/CN101991859A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3446688A1 (en) * | 2011-10-31 | 2019-02-27 | Commissariat à l'Energie Atomique et aux Energies Alternatives | Use of anti-connexin agents for enhancing the therapeutic effect of acetylcholinesterase inhibitors |
| US10765670B2 (en) | 2011-10-31 | 2020-09-08 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Use of anti-connexin agents for enhancing the therapeutic effect of acetylcholinesterase inhibitors |
| CN108096584A (en) * | 2018-01-30 | 2018-06-01 | 内蒙古工业大学 | Utilize supercritical CO2Tosufloxacin tosilate/cyclodextrin inclusion compound prepared by technology and preparation method thereof and oral formulations |
| CN108096584B (en) * | 2018-01-30 | 2021-02-05 | 内蒙古工业大学 | By using supercritical CO2Tosufloxacin tosylate/cyclodextrin inclusion compound prepared by technology, preparation method and oral preparation thereof |
| CN114796132A (en) * | 2022-05-13 | 2022-07-29 | 海南灵康制药有限公司 | Lyophilized powder injection of huperzine A and its preparation method |
| CN114796132B (en) * | 2022-05-13 | 2023-08-22 | 海南灵康制药有限公司 | Huperzine A freeze-dried powder injection and preparation method thereof |
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Application publication date: 20110330 |