CN103417505A

CN103417505A - Huperzine A controlled release preparation having biphasic release behavior, and preparation method thereof

Info

Publication number: CN103417505A
Application number: CN2012101666078A
Authority: CN
Inventors: 唐希灿; 朱春柳; 章海燕; 甘勇; 朱全垒
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Wanbond Pharmaceutical Group Co., Ltd; Shanghai Institute of Materia Medica of CAS
Priority date: 2012-05-24
Filing date: 2012-05-24
Publication date: 2013-12-04
Anticipated expiration: 2032-05-24
Also published as: CN103417505B

Abstract

The invention discloses a huperzine A controlled release preparation having a biphasic release behavior. The in-vivo and in-vitro biphasic release distribution of the huperzine A controlled release preparation is carried out within a predetermined time quantum, wherein a first phase is a rapid release phase, a second phase is a slow release phase, and the rapid release phase contains 5-50wt% of a drug active component. The huperzine A controlled release preparation rapidly takes effect after the preparation is taken; the preparation is continuously released within a needed physiologic period (daytime) and improves the memory, cognition and behavior functions of patients, the plasma drug concentration can be correspondingly adjusted at low-activity-level night to reduce the appearance of the drug resistance; the preparation has small excitation to the stomach and intestine, and has a good patient compliance; and the preparation is taken once every day on the basis of an increased administration dose, so a stable blood drug concentration is maintained, a constant curative effect can be realized, the incidence rate of untoward effects is reduced, the drug use is safe, and the preparation is more suitable for the long-term use of moderate and severe Alzheimer's disease patients.

Description

There is huperzine A controlled release preparation of two-phase drug release behavior and preparation method thereof

Technical field

The present invention relates to field of pharmaceutical preparations, particularly, the present invention relates to a kind of huperzine A controlled release preparation with two-phase drug release behavior and preparation method thereof.

Technical field

Huperzine A (Huperzine A), being to separate a kind of natural novel lycopods alkaloid effective monomer obtained from Chinese Huperziaceae stone araucaria feet added to a snake by an ignorant artist China firs (Huperzia serrata) (being commonly called as Herba Lycopodii serrati), is acetylcholinesterase inhibitor efficient, high selectivity.Chemistry (5R, 9R, 11E) 5-amino by name-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is (6) pyridine-2 (1H) ketone also, and molecular formula is C ₁₅H ₁₈N ₂O, molecular weight: 242.32.Huperzine A has optical activity and only is present in the middle of plant with the form of laevoisomer, and vivo and vitro experimental studies have found that (-) huperzine A is stronger 50 times than (+) huperzine A to the selective inhibitory of cholinesterase.

Huperzine A has significant curative effect in the treatment of Alzheimer's disease (Alzheimer ' s disease).Recent study finds, huperzine A also has multiple pharmacological action: it has the neuroprotectives such as expression and secretion, antiglutamic acid receptor of regulation and control nerve growth factor; Huperzine A is not only a kind of intracerebroventricuacetylcholine acetylcholine esterase inhibitor of efficient high selectivity; but also the approach such as the exitotoxicity by antiglutamic acid is caused, anti-oxidation stress, anti-apoptotic; cell is produced to protection, there is the latent effect of the multiple neurodegenerative diseases for the treatment of.

Alzheimer's disease claims again presenile dementia, is the chronic degenerative nervous system disease that the carrying out property memory and cognition function damage multi-pathogenesis factor that is feature participates in.Impermanent memory loss is the most common symptom of Alzheimer's disease, and late period, symptom comprised confusion of consciousness, angry, emotion change, language collapse, longterm memory loss and other generals of causing due to the consciousness of object decline are retired.Brain Cholinergic systemic-function obstacle is to be proved the earliest the pathogenesis that participates in Alzheimer thatch disease, there is many-sided dysfunction in Alzheimer Disease patient brain Cholinergic nervous system, and the reduction of brain Cholinergic activity and cognitive dysfunction degree have significant correlation.

At present, cholinesterase inhibitor is considered to treat senile dementia one of the most effective medicine, thereby this class medicine suppresses acetylcholine hydrolyzation by suppressing activity of cholinesterase, and enhancing cholinergic function, supplement the acetylcholine precursor, increase the synthetic of acetylcholine, thereby excited cholinergic neuron increases ability of learning and memory.

From the angle of neuro chemistry, Alzheimer's disease is considered to the damaged neurodegenerative diseases that then causes synaptic space levels of acetylcholine disappearance of a kind of cholinergic function.Huperzine A is a kind of potent reversibility cholinesterase inhibitor, to the selective inhibitory action of acetylcholine esterase, comparing, other treats the medicine of Alzheimer's disease, huperzine A has very high oral absorption availability, easily see through blood brain barrier, can suppress acetylcholinesterase in brain by selectivity, and it is lower to the side effect of periphery cholinergic system and dose-dependent hepatotoxicity, it can improve senile memory function and go down, and can significantly improve memory, cognition and the behavioral function of Alzheimer Disease patient.

1994, Huperzine-A Tablets, Tests for Uniformity (trade name: the Huperzine A-Zhulin Antun) diseases such as Alzheimer's disease and benign memory deficits that go through to be applied to treat.Huperzine A is confirmed by domestic a large amount of clinical research in the curative effect aspect the treatment of person in middle and old age's hypomnesis and all kinds dementia.

The pharmacokinetic study of rodent shows, Oral Administration in Rats or intravenous injection ³Pharmacokinetics after the H-huperzine A is opening two chamber models.Oral huperzine A absorbs rapidly and fully, and bioavailability is 96.9%, and the distribution phase half-life is 9.8 minutes, mainly by urine, with prototype and metabolite form, excretes.Intravenous injection ³After H-huperzine A 24 hours, the amount that output is dosage radioactivity is discharged from feces in 73%, 24 hour from urine is dosage 2.8%.The autoradiographic research of mice shows, ³The H-huperzine A is distributed in each brain district, in cortex volume top, striatum, Hippocampus and nucleus accumbens septi brain district, distributes comparatively concentrated.Healthy Youth volunteer's pharmacokinetic shows, after oral huperzine A, absorbs rapidly, widely distributed in vivo, with the medium speed, in body, eliminates, and plasma concentration changes the first order kinetics that meets one compartment open model.

Through patent retrieval, the ordinary preparation patent relevant with huperzine A comprises: huperzine-A oral cavity disintegration tablet (CN1568985), the injection for vein (CN101129329) of huperzine A, huperzine dropping pills (CN1493287), huperzine A pellets preparation (CN101007002) etc.

At present, huperzine A oral formulation commonly used is common tablet or capsule, in the clinical application process, the ordinary preparation of huperzine A still has the following disadvantages: 1. due to the rapid onset of medicine, the rapid rising of blood drug level easily causes bad kickback of using medicine (comprise dizziness, feel sick, gastrointestinal upset, the symptom such as weak), and the ordinary preparation duration of efficacy is short simultaneously, usually needs clinically 2 medications every day, the fluctuation of blood drug level is larger, patient's poor compliance; 2. this product is the reversibility cholinesterase inhibitor, there is interindividual variation in its consumption, and for reducing the untoward reaction of patient's medication, general initial dose should be from low dose, adjust gradually dosage, loaded down with trivial details dose titration process has been brought certain inconvenience to clinical application; 3. the curative effect of the Alzheimer Disease patient of alignment degree and severe is not good enough; 4. the tablet of common huperzine A or capsule are not considered the effect of acetylcholinesterase in the normal physiological rhythm and pace of moving things, sleep and learning and memory in patient's brain, have design defect.

Chinese patent CN101485640 discloses a kind of huperzine A mono-layer osmotic pump controlled release tablets, comprise: containing huperzine A and the label of pharmaceutic adjuvant and the semi-transparent coating membrane of the described label of parcel of effective dosage, described coating membrane is provided with a drug release hole, it is characterized in that: described label is containing huperzine A 0.01%-1.0%, blocker 1.0%-10%, penetrating agent 1.0%-40%, in described coating solution, the weight ratio of polyethylene glycol 6000 and cellulose acetate is (0.05～0.25): 1, and the weightening finish of clothing film accounts for label weight 5%-25%.

Chinese patent CN101485639 discloses a kind of huperzine A double-layer osmotic pump controlled release tablets, comprising: the double-deck label be comprised of medicated layer and push layer; And the semi-transparent coating membrane that wraps up described double-deck label, described coating membrane is provided with a small delivery aperture in medicated layer one side; The huperzine A that in described label, medicated layer contains effective dose, suspending agent, osmotic pressure active substance and pharmaceutic adjuvant, contain extender, penetrating agent, binding agent in described push layer; Described coating membrane contains the Polyethylene Glycol as plasticizer, and the coating membrane weightening finish accounts for 8% to 20% of label weight, and coating membrane is 0.2 to 2.0 millimeter in the drug release hole aperture on medicated layer surface.

Chinese patent CN101606917 discloses the slow releasing tablet of a kind of huperzine A and derivant or its salt, 20～50% the slow-release material hydroxypropyl methylcellulose that this slow releasing tablet contains tablet weight, hydroxypropyl methylcellulose is selected two or more the combination in K4M, K15M and K100M, wherein K4M and/or K15M, with the weight ratio of K100M be 3～50: 0～1.

Chinese patent CN1682719 discloses a kind of enteric soluble coating slow releasing tablet that contains huperzine A and preparation method thereof, it adopts the enteric coating technology to overcome the harmful effect of low pH value to the diffusion of matrix tablet Chinese medicine in stomach, avoid the harmful effect of human gastric juice to the huperzine A matrix tablet that discharges with diffusion way, guarantee that medicine realizes stable, slowly, discharge completely.The active pharmaceutical ingredient contained in this slow releasing tablet is reversibility cholinesterase inhibitor huperzine A, and the skeleton slow release layer is surrounded by the macromolecule membrane clothing layer of one deck enteric solubility outward.Active constituents of medicine can also be the salt of the various acid of acceptable huperzine A on preparation.In every middle active pharmaceutical ingredient, the content of huperzine A is 10～500 μ g.

Chinese patent CN1751683 discloses matrix sustained release tablet and the preparation technology thereof of huperzine A and derivant or its salt, be specifically related to the medicine novel formulation of huperzine A and derivant thereof, this slow releasing tablet is containing huperzine A and derivant or its salt of effective dose, account for the hydrophilic gel skeleton slow-release material and the filler that accounts for tablet weight 5-75% of tablet weight 20-90%, overcome in existing slow release method and dashed forward and release comparatively serious defect, can keep active component huperzine A and derivant thereof or its salt to continue to discharge stably, make to keep in body 12 hours certain blood drug level, really reached the slow release effect of 12 hours, there is bioavailability high, good effect, the characteristics that side effect is low, and preparation technology is simple.

Chinese patent CN101485640, CN101485639, CN101606917, CN1682719, CN1751683 are slow by osmotic pump tablet, hydrogel matrix tablet, enteric soluble coating slow releasing sheet etc., the controlled release preparation means, have realized time delay or the long-acting release of active component huperzine A.But the preparation in above-mentioned patent, when realizing long-acting release, but can't be realized the rapid onset of medicine; Studies show that, acetylcholine is one of five kinds of neurotransmitteies that the awakening of animal and alertness are worked, and there is physiological rhythm in the synapse levels of acetylcholine; Increase and the spontaneous activity of levels of acetylcholine present positive correlation, and in clear-headed, acetylcholine maintains relatively high level, and in sleep, acetylcholine is in relatively low level.Above-mentioned patent all fails to take into full account the physiological rhythm of acetylcholine esterase level in brain, can't realize the optimized design of drug effect, has defect.

The data prompting, low-level acetylcholine and the consolidation of memory in S sleep stage are closely related.Brain is by regulating the transmission of horizontal adjustment recall info between cortex-Hippocampus of acetylcholine.In clear-headed, information exchange is crossed neopallium and is delivered to Hippocampus, in hippocampus information, is encoded and is delivered to the cortex zone again.The commitment formed in memory, hippocampus maintains the levels of acetylcholine of higher level, has suppressed the transmission loop between Hippocampus-cortex, the interference of the recall info in the past stored with minimizing to fresh information.Contrary, in the late period (corresponding to the S sleep stage) formed in memory, the low-level acetylcholine in brain is conducive to the transmission between Hippocampus-cortex, promotes the storage of recall info.Normal rhythm than normal individual, the phenomenon of spontaneous activity disorder has appearred in Alzheimer Disease patient, the rhythm and pace of moving things boundary of patient's diel movement is not obvious, and quite a few patient occurs by day sleeping symptom and can't fall asleep at night, the discontinuity sleep occurs.Researcher thinks, the fail decline of working memory especially of the parahypnosis that Alzheimer Disease patient occurs and its cognitive function is relevant.

Visible, can bring into play better drug effect in order to make huperzine A, untoward reaction after the minimizing medication, increase the compliance that the patient takes medicine, need to be in taking into full account brain on the basis of the horizontal physiological rhythm of acetylcholine esterase, reasonably the release behavior of choice and optimization medicine, make medicine bring into play maximum effect.

Summary of the invention

Primary and foremost purpose of the present invention is physicochemical property, stability and the biological property for huperzine A, according to Alzheimer Disease patient, clinical treatment needs and the demand of medication compliance, in taking into full account patient's brain on the basis of the physiological rhythm of acetylcholine esterase level, design and provide a kind of huperzine A controlled release preparation with two-phase drug release behavior, in the predetermined time section, its inside and outside drug release behavior can be according to biphase release profile, wherein first-phase is the rapid release phase, and second-phase is the slow release phase.

Another purpose of the present invention is to provide this prescription and preparation method with huperzine A controlled release preparation of two-phase drug release behavior.

The invention provides a kind of controlled release preparation containing huperzine A and derivant or its salt, it is characterized in that described huperzine A controlled release preparation has the two-phase drug release behavior, in the predetermined time section, in meeting the release medium of sink conditions, its release behavior is according to biphase release profile, wherein first-phase is the rapid release phase, and second-phase is the slow release phase; Gross weight based on said preparation Chinese medicine active component, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually, and slow release contains the active constituents of medicine of 50wt% ~ 95wt% mutually; Described active constituents of medicine is huperzine A and derivant or its salt.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, the design of rapid release phase can guarantee the rapid release of initial stage medicine well, meets the demand of the rapid onset of medicine, reaches fast treatment concentration; The design of slow release phase can guarantee again the steady release of later stage active component, guarantee the daytime active component sustained release higher in level of activation, improve memory, cognition and the behavioral function of Alzheimer Disease patient, and in level of activation lower night, plasma drug level can be adjusted accordingly, reduces the generation of drug resistance.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, it is characterized in that, described external biphase release is the regulation according to Chinese Pharmacopoeia 2010 editions, in the hydrochloric acid solution of the 0.1M of 37 ℃, under the stirring that is 50rpm or 75rpm in speed, with oar method or basket method drug release determination device, measure.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, it is characterized in that, the active constituents of medicine of rapid release in mutually, requirement according to 2010 editions dissolution methods of Chinese Pharmacopoeia, in meeting the release medium of sink conditions, preferably in 30 minutes, there is the active constituents of medicine of rapid release in mutually that be assigned to over 90wt% to discharge, more preferably in 15 minutes, have the active constituents of medicine of rapid release in mutually that be assigned to over 90wt% to discharge.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, it is characterized in that, according to the requirement of Chinese Pharmacopoeia drug release determination method, in meeting the release medium of sink conditions, it is 5 ~ 15 hours that described slow release phase Chinese medicine active component discharges the above time of 90wt%.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, is characterized in that, the release behavior of the active constituents of medicine of slow release in mutually meets zero level, one-level, Higuchi or Ritger-Peppas release model, is preferably zero-order release.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention, is characterized in that, the active constituents of medicine huperzine A that contains 0.05mg ~ 4mg and derivant thereof or its salt.The gross weight of the active constituents of medicine in the huperzine A controlled release preparation is the summation of rapid release phase and slow release phase Chinese medicine active component weight.According to the specification of medicine and the demand for the treatment of, huperzine A controlled release preparation with two-phase drug release behavior of the present invention, the ratio that the medicine of rapid release in mutually accounts for the active constituents of medicine gross weight is 5wt% ~ 50wt%, is preferably 10wt% ~ 45wt%, more preferably 15wt% ~ 40wt%.

Huperzine A controlled release preparation with two-phase drug release behavior of the present invention is characterized in that the enforcement carrier of rapid release phase and slow release phase, be selected from the combination of capsule, tablet, double-layer tablet, multilayer tablet, coated tablet and arbitrary form thereof.

Particularly, rapid release of the present invention is a kind of rapid-release vehicle that contains rapid release dose drug active component mutually, and described rapid release mutually preferably but be not limited to rapid release substrate in fast-release tablet, rapid release ball, tablet, be wrapped in tablet or the outer rapid release coatings of ball core, be attached to release layer substrate in double-layer tablet and the combination of arbitrary form thereof.

Correspondingly, slow release of the present invention is a kind of slow-released carrier that contains the sustained-release dosage active constituents of medicine mutually, and described slow release mutually preferably but be not limited to slow-released carrier in sustained-release matrix, tablet or the ball core in slow releasing tablet, slow release ball, tablet, be attached to slow release layer substrate in double-layer tablet and the combination of arbitrary form thereof.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be capsule, and wherein, described rapid release can comprise active constituents of medicine, diluent and other adjuvants mutually; Described slow release can comprise active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants mutually.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be tablet, and wherein, described rapid release can comprise active constituents of medicine, diluent and other adjuvants mutually; Described slow release can comprise active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants mutually.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be double-layer tablet, multilayer tablet or clad sheet, wherein, described rapid release can comprise active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants mutually; Described slow release can comprise active constituents of medicine, hydrophilic polymer, diluent and other adjuvants mutually.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be the coated tablet of mono-layer osmotic pump controlled release tablets and rapid release coatings composition, wherein, the clothing film that described mono-layer osmotic pump controlled release tablets comprises label and wraps up described label, described label can comprise active constituents of medicine, hydrophilic polymer, osmotic pressure promoter and other adjuvants; Described rapid release coatings can comprise active constituents of medicine, thin film coating material, diluent, antiplastering aid and other adjuvants.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be the coated tablet of double-layer osmotic pump controlled-release tablet and rapid release coatings composition; Wherein, described double-layer osmotic pump controlled-release tablet comprises the double-deck label that medicated layer and boosting layer form and the clothing film that wraps up described double-deck label, and wherein, described medicated layer comprises active constituents of medicine, hydrophilic polymer, osmotic pressure promoter and other adjuvants; Described boosting layer comprises short osmopolymer, osmotic pressure promoter and other adjuvants; Described rapid release coatings can comprise active constituents of medicine, thin film coating material, diluent, antiplastering aid and other adjuvants.

In an embodiment of the invention, the described huperzine A controlled release preparation with two-phase drug release behavior can be the slow releasing tablet with rapid release coatings; Wherein, described slow release can comprise active constituents of medicine, hydrophilic polymer, diluent and other adjuvants mutually; Described rapid release coatings can comprise active constituents of medicine, thin film coating material, diluent, antiplastering aid and other adjuvants.

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, in the above-described embodiment, described active constituents of medicine is huperzine A and derivant or its salt.

Described diluent is selected from one or more in microcrystalline Cellulose, lactose, sucrose, mannitol, sorbitol, starch, carboxymethyl starch sodium, pregelatinized Starch.

Described other adjuvants, comprise one or more in lubricant, coloring agent, binding agent, porogen, plasticizer; Described lubricant is to be selected from one or more in magnesium stearate, stearic acid, sodium stearyl fumarate, Pulvis Talci and micropowder silica gel; Described coloring agent is to be selected from one or more in iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide.Described binding agent is to be selected from one or more in hydroxypropyl emthylcellulose, polyvidone, copolyvidone, hydroxypropyl cellulose, corn starch, gelatin, arabic gum, sodium carboxymethyl cellulose.Described porogen is selected from one or more in polyethylene glycols, glycerol, polyvidone, copolyvidone, propylene glycol, water-soluble inorganic salt; Described plasticizer is selected from one or more in Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, citroflex A-4, glycerol acetate, Oleum Ricini.

Celphere can be used as the component for preparing rapid release ball or slow release ball, and described celphere is selected from microcrystalline Cellulose, sucrose, and their mixture.

Described sustained-release matrix substrate, be selected from acrylic resin, ethyl cellulose, cellulose acetate, glyceryl monostearate, and their mixture.Described acrylic resin is selected from methacrylic acid copolymer, methacrylate copolymer is (as Eudragit L100-55, Eudragit L30D-55, Eudragit NE30D, Eudragit RL30D, Eudragit RS30D), the amino methyl acrylic copolymer, Hydroxypropyl Methylcellulose Phathalate, succinic acid acetic acid hydroxy methocel, one or more in succinic acid acetic acid hydroxypropyl methylcellulose.

Described extended release coatings film or clothing film material are selected from one or more in cellulose acetate, ethyl cellulose, acrylic resin, cellulose acetate-phthalate, HPMCAS.

Described thin film coating material is selected from one or more in hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, polyvidone, copolyvidone.

Described osmotic pressure promoter can adopt one or more in sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose.

Described hydrophilic polymer is to be selected from one or more in polyvidone, copolyvidone, polyoxyethylene, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium alginate, xanthan gum, arabic gum, chitin.

Described short osmopolymer is to be selected from one or more in polyoxyethylene, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvidone.

Described antiplastering aid is selected from Pulvis Talci, magnesium stearate, glyceryl monostearate, and their mixture.

Moistureproof clothing is by coated the making of moistureproof clothing compositions.Described moistureproof clothing layer composition comprises the coating powder that is used to form moistureproof clothing and nonessentially is selected from one or several in the materials such as coloring agent, plasticizer, opacifier, antiplastering aid, and their consumption is those skilled in the art's routine and selects.The routine that the described coating powder that is used to form moistureproof clothing is those skilled in the art is selected, and comprises that commercially available prod Opadry, color orchid in riotous profusion and other can form the coating powder of described moistureproof clothing.

In order to understand better foregoing invention, narration hereinafter is for detailed description of the present invention, and scope of the present invention is not constituted any limitation:

1. capsule

The capsule of one of huperzine A controlled release preparation with two-phase drug release behavior of the present invention can in the following manner, be realized two-phase drug release behavior of the present invention.

(1) capsule that contains rapid release ball and slow release ball

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is the rapid release ball mutually in the present embodiment, and described slow release is the slow release ball mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

1. the capsule that the wet granulation process preparation contains rapid release ball and slow release ball

The described capsule that contains rapid release ball and slow release ball forms and comprises: capsule shells, rapid release ball and slow release ball.

By active constituents of medicine and diluent and other adjuvants etc., by wet granulation, extrude the conventional method well-known to those skilled in the art such as round as a ball and prepare the rapid release ball.Wherein, the gross weight based on the rapid release ball, the active constituents of medicine that described rapid release ball comprises 0.005 ~ 4 % by weight, the diluent of 50 ~ 98 % by weight, and other adjuvants of 1 ~ 46 % by weight.

By active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants etc., by wet granulation, extrude the conventional method well-known to those skilled in the art such as round as a ball and prepare the slow release ball.Gross weight based on the slow release ball, the diluent of the active constituents of medicine that described slow release ball comprises 0.01～5 % by weight, the sustained-release matrix substrate of 2～50 % by weight, 40～80 % by weight, other adjuvants of 0.1～15 % by weight.

Take the above-mentioned rapid release ball prepared and slow release ball, mix homogeneously, carry out the capsule fill; Gross weight based on Traditional Chinese medicine capsule thing active component, the active constituents of medicine that contains 5wt% ~ 50wt% in described rapid release ball.

2. the capsule that the fluidized bed coating preparation contains rapid release ball and slow release ball

Described rapid release ball comprises from the inside to the outside: celphere and rapid release coatings on structure forms; Described rapid release ball can pass through the mode of fluidized bed coating medicine carrying, and active constituents of medicine, diluent, thin film coating material, antiplastering aid and other adjuvants are dispersed or dissolved in the coating solvent, and bag is stated from celphere, forms described rapid release ball.Gross weight based on the rapid release coatings, the active constituents of medicine that described rapid release coatings comprises 0.01 ~ 25 % by weight, 10 ~ 70 % by weight thin film coating materials, the antiplastering aid of 1 ~ 30 % by weight, the diluent of 0～70 % by weight, and other adjuvants of 0 ~ 10 % by weight.

Described slow release ball can pass through the mode of fluidized bed coating medicine carrying, at rapid release ball core outsourcing extended release coatings membrane material; Gross weight based on the extended release coatings film, porogen ratio in described extended release coatings film is 0 ~ 30 % by weight.

Take the above-mentioned rapid release ball prepared and slow release ball, mix homogeneously, carry out the capsule fill; Gross weight based on Traditional Chinese medicine capsule thing active component, the active constituents of medicine that described rapid release ball contains 5wt% ~ 50wt%.

(2) capsule prepared by the slow-releasing granules that contains the rapid release coatings

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is the rapid release coatings mutually in the present embodiment, and described slow release is the slow release ball mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

The described slow-releasing granules that contains the rapid release coatings comprises from the inside to the outside: rapid release ball, extended release coatings film and rapid release coatings on structure forms; Wherein, the coated and composition of the preparation of described rapid release ball and extended release coatings film is described in the above; Described rapid release coatings can be passed through the mode of fluidized bed coating medicine carrying, active constituents of medicine, diluent, thin film coating material and other adjuvants are dispersed or dissolved in the coating solvent, bag is stated from the slow release ball prepared, and forms the described slow-releasing granules that contains the rapid release coatings; Gross weight based on the rapid release coatings, the active constituents of medicine that described rapid release coatings comprises 0.01 ~ 25 % by weight, 10 ~ 70 % by weight thin film coating materials, the antiplastering aid of 1 ~ 30 % by weight, the diluent of 0～70 % by weight, and other adjuvants of 0 ~ 10 % by weight.

Take the above-mentioned slow-release pill that contains the rapid release coatings prepared, carry out the capsule fill; Gross weight based on Traditional Chinese medicine capsule thing active component, the active constituents of medicine that described rapid release coatings contains 5wt% ~ 50wt%.

(3) contain the capsule that fast-release tablet and slow releasing tablet form

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is fast-release tablet mutually in the present embodiment, and described slow release is slow releasing tablet mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

Described fast-release tablet can pass through the mixture of active constituents of medicine, diluent and other adjuvants, wet granulation or direct compression preparation.Any technical staff in this area all knows the selection to these functional adjuvants and diluent.Wherein, the gross weight based on fast-release tablet, the active constituents of medicine that described fast-release tablet comprises 0.005 ~ 4 % by weight, the diluent of 50 ~ 98 % by weight, and other adjuvants of 1 ~ 46 % by weight.

By by active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants etc., by conventional methods well-known to those skilled in the art such as wet granulation or direct compressions, prepare matrix sustained release tablet; Wherein, the gross weight based on slow releasing tablet, other adjuvants of the sustained-release matrix substrate of the active constituents of medicine that described slow releasing tablet comprises 0.01～5 % by weight, 2～50 % by weight, the diluent of 40～80 % by weight, 0.1～15 % by weight.

The coating mode that also can know by this area staff such as fluid bed, high-efficiency coating pots, carry out coating to the fast-release tablet that contains active constituents of medicine, at label expoeridium extended release coatings membrane material, forms described slow releasing tablet.

Take the above-mentioned fast-release tablet prepared and slow releasing tablet, mix homogeneously, carry out the capsule fill; Gross weight based on Traditional Chinese medicine capsule thing active component, the active constituents of medicine that described rapid release ball contains 5wt% ~ 50wt%.

2. tablet

The tablet of one of huperzine A controlled release preparation with two-phase drug release behavior of the present invention, can in the following manner, realize drug release behavior of the present invention.

(1) tablet formed by rapid release substrate and slow release ball

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is rapid release substrate mutually in the present embodiment, and described slow release is the slow release ball mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

The tablet that described rapid release substrate and slow release ball form comprises rapid release substrate and slow release ball on structure forms; Described rapid release substrate can be prepared from by the abundant mixing by active constituents of medicine, diluent and other adjuvants or through wet granulation.Wherein, the gross weight based on rapid release substrate, the active constituents of medicine that described rapid release substrate comprises 0.005 ~ 4 % by weight, the diluent of 50 ~ 98 % by weight, and other adjuvants of 1 ~ 46 % by weight.

Described slow release ball is consistent with slow release ball preparation method above; Finally, by described rapid release substrate and slow release ball, according to the specification ratio mix homogeneously of active component, then, by the tablet machine with special agitating function, be pressed into tablet.Gross weight based on the tablet Chinese traditional medicine active component, the active constituents of medicine that contains 5wt% ~ 50wt% in described rapid release substrate.

(2) by rapid release substrate and the substrate composed tablet of slow release

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is rapid release substrate mutually in the present embodiment, and described slow release is sustained-release matrix mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

Described rapid release substrate and the substrate composed tablet of slow release comprise rapid release substrate and sustained-release matrix on structure forms; Rapid release substrate of the present invention can be prepared from by the abundant mixing by active constituents of medicine, diluent and other adjuvants or through wet granulation; Wherein, the gross weight based on rapid release substrate, the active constituents of medicine that described rapid release substrate comprises 0.005 ~ 4 % by weight, the diluent of 50 ~ 98 % by weight, and other adjuvants of 1 ~ 46 % by weight.

Described sustained-release matrix, by by active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants etc., is prepared into sustained-release matrix by conventional methods well-known to those skilled in the art such as wet granulations.Gross weight based on sustained-release matrix, other adjuvants of the sustained-release matrix substrate of the active constituents of medicine that described sustained-release matrix comprises 0.01～5 % by weight, 2～50 % by weight, the diluent of 40～80 % by weight, 0.1～15 % by weight.

Finally, by described rapid release substrate and sustained-release matrix, the specification ratio mix homogeneously according to required active component, be pressed into tablet.Gross weight based on the tablet Chinese traditional medicine active component, the active constituents of medicine that contains 5wt% ~ 50wt% in described rapid release substrate.

3. double-layer tablet, multilayer tablet or clad sheet

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is release layer mutually in the present embodiment, and described slow release is slow release layer mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

Double-layer tablet, multilayer tablet or the clad sheet of one of huperzine A controlled release preparation with two-phase drug release behavior of the present invention can in the following manner, be realized drug release behavior of the present invention.

Described double-layer tablet or clad sheet with huperzine A controlled release preparation of two-phase drug release behavior, comprise rapid release substrate and sustained-release matrix, respectively as release layer and slow release layer in double-layer tablet or clad sheet two-layer; Rapid release substrate wherein can be by fully mixing active constituents of medicine, diluent and other adjuvants or being prepared from through wet granulation; Wherein, the gross weight based on release layer, the active constituents of medicine that described rapid release substrate comprises 0.005 ~ 4 % by weight, the diluent of 50 ~ 98 % by weight, and other adjuvants of 1 ~ 46 % by weight.

Sustained-release matrix can, by by active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants etc., be prepared from by conventional methods well-known to those skilled in the art such as wet granulations; Gross weight based on slow release layer, other adjuvants of the sustained-release matrix substrate of the active constituents of medicine that described slow release layer comprises 0.01～5 % by weight, 2～50 % by weight, the diluent of 40～80 % by weight, 0.1～15 % by weight.

Finally, by described rapid release substrate and sustained-release matrix, add respectively in the hopper of tablet machine, be pressed into double-layer tablet or clad sheet.Gross weight based on the tablet Chinese traditional medicine active component, the active constituents of medicine that contains 5wt% ~ 50wt% in described rapid release substrate.

The described huperzine A multilayer tablet with two-phase drug release behavior, comprise rapid release substrate, sustained-release matrix and/or blank substrate, can be by rapid release substrate or sustained-release matrix, be divided into two-layerly, and also can increase not the blank hypothallus containing active component; Finally, by described rapid release substrate and sustained-release matrix and/or blank substrate, add respectively in the hopper of tablet machine, be pressed into multilayer tablet.

4. coated tablet

The coated tablet of one of huperzine A controlled release preparation with two-phase drug release behavior of the present invention can in the following manner, be realized drug release behavior of the present invention.

(1) there is the osmotic pump tablet of rapid release coatings

Osmotic pump controlled release tablet is a kind of based on chemosmotic oral controlled-release drug delivery system, is also current techique prepared by a kind of slow/controlled release preparation of comparatively commonly using so far.United States Patent (USP) 3,845,770,3,916,899,3,995,631,4,008,719,4,160,020,4,034,758,4,327,725,4,578,075,4,681,583,4,783,337,5,019,397,5,156,850 grades are described the osmotic pump controlled-releasing technology in detail, and these patent documentations are by reference to being incorporated herein.Controlled releasing penetrant pump has advantages of as follows usually: 1. have default Drug Release Kinetics behavior characteristics; 2. be subject to the impact of the factors such as media environment pH value, gastrointestinal peristalsis and food little, there is inside and outside dependency preferably; 3. the phenomenon that the blood concentration fluctuation of avoiding common oral preparation to cause is larger; 4. reduce medicining times, improve patient's compliance.

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is release layer mutually in the present embodiment, and described slow release is osmotic pump tablet mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

The described osmotic pump tablet with rapid release coatings is comprised of osmotic pump tablet and rapid release clothing layer on structure forms, and can add moistureproof clothing layer on this basis again; Can be by form the osmotic pump tablet with rapid release coatings at osmotic pump controlled release tablet expoeridium rapid release clothing layer, described osmotic pump controlled release tablet can be mono-layer osmotic pump controlled release tablets, double-layer osmotic pump controlled-release tablet or Multi-layered osmotic pump controlled-releasing tablet.

Described mono-layer osmotic pump controlled release tablets is comprised of monolayer label and the clothing film with drug release hole on structure forms.Can after mix homogeneously, granulate by by the active constituents of medicine of recipe quantity, hydrophilic polymer, osmotic pressure promoter and other adjuvants, the compressed single label; Adopt suspension coating method well-known to those skilled in the art, at label expoeridium clothing film material; Adopt laser-beam drilling machine to be punched, form described mono-layer osmotic pump controlled release tablets.

In described mono-layer osmotic pump controlled release tablets, gross weight based on the monolayer label, the osmotic pressure promoter of the active constituents of medicine that described monolayer label comprises 0.005 ~ 5 % by weight, the hydrophilic polymer of 25 ~ 85 % by weight, 10 ~ 70 % by weight, and other adjuvants of 0.2 ~ 5 % by weight.Gross weight based on the extended release coatings film, porogen ratio in described extended release coatings film is 0 ~ 30 % by weight.Gross weight based on mono-layer osmotic pump controlled release tablets, described clothing film weightening finish is 3 ~ 30 % by weight of mono-layer osmotic pump controlled release tablets.

Described double-layer osmotic pump controlled-release tablet comprises medicated layer and boosting the layer label formed and the clothing film with drug release hole on structure forms.The preparation of described double-layer osmotic pump controlled-release tablet can, by by active constituents of medicine, hydrophilic polymer, osmotic pressure promoter and other adjuvants, after mix homogeneously, prepare the medicated layer granule; To urge osmopolymer, osmotic pressure promoter and other adjuvants, after mix homogeneously, preparation boosting layer granule; Medicated layer and boosting layer are added respectively to bi-layer tablet press, suppress double-deck label; Adopt suspension coating method well-known to those skilled in the art, at label expoeridium clothing film material; Adopt laser-beam drilling machine to be punched, form described double-layer osmotic pump controlled-release tablet.

In described double-layer osmotic pump controlled-release tablet, the gross weight based on medicated layer, the hydrophilic polymer of the active constituents of medicine that described medicated layer comprises 0.005 ~ 3 % by weight, 70 ~ 99.5 % by weight and other adjuvants of 0.2 ~ 30 % by weight; Gross weight based on the boosting layer, the short osmopolymer that described boosting layer comprises 45～75 % by weight and the osmotic pressure promoter of 15～50 % by weight, and other adjuvants of 3 ~ 10 % by weight; Gross weight based on the extended release coatings film, porogen ratio in described extended release coatings film is 0 ~ 30 % by weight.Gross weight based on double-layer osmotic pump controlled-release tablet, described extended release coatings film weightening finish is 3 ~ 30 % by weight of double-layer osmotic pump controlled-release tablet.

Described rapid release clothing layer can be used for providing rapid release in two-phase drug release behavior of the present invention to discharge mutually; Described rapid release coatings comprises active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants.Described rapid release coatings can be passed through the mode of the known high-efficiency coating medicine carrying of those skilled in the art, active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants are dispersed or dissolved in the coating solvent, bag is stated from the osmotic pump tablet prepared, and forms the described osmotic pump tablet with rapid release coatings; Wherein, the gross weight based on rapid release clothing layer, the active constituents of medicine that described rapid release clothing layer comprises 0.01 ~ 25 % by weight, 10 ~ 70 % by weight thin film coating materials, the antiplastering aid of 1 ~ 30 % by weight, the diluent of 0～70 % by weight, and other adjuvants of 0 ~ 10 % by weight.

Described moistureproof clothing layer is nonessential.The routine that its preparation method is those skilled in the art is selected, as an example, can make moistureproof clothing layer coating solution by moistureproof clothing layer composition is dissolved in suitable solvent, then the huperzine A controlled release preparation with two-phase drug release behavior prepared in accordance with the present invention is carried out to coating, dry rear formation.

(2) there is the slow releasing tablet of rapid release coatings

In huperzine A controlled release preparation with two-phase drug release behavior of the present invention, described rapid release is release layer mutually in the present embodiment, and described slow release is slow releasing tablet mutually; Gross weight based on active constituents of medicine, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually; Described active constituents of medicine gross weight is 0.05mg ~ 4mg.

The described slow releasing tablet with rapid release coatings is comprised of slow releasing tablet and rapid release clothing layer on structure forms; Described slow releasing tablet can be used for providing the release of slow release phase in two-phase drug release behavior of the present invention; Can, by by active constituents of medicine, hydrophilic polymer, diluent and other adjuvants etc., by adopting direct compression after tabletting or mix homogeneously after conventional method wet granulation well-known to those skilled in the art, prepare slow releasing tablet (slow release phase).Gross weight based on slow release layer, other adjuvants of the hydrophilic polymer of the active constituents of medicine that described slow release layer comprises 0.01～5 % by weight, 2～50 % by weight, the diluent of 40～80 % by weight, 0.1～15 % by weight.

Beneficial effect

We are by the research of physicochemical property, stability and biological property to huperzine A, according to clinical treatment, need and the demand of the compliance of patient's medication, in taking into full account patient's brain on the basis of the physiological rhythm of acetylcholine esterase level, design a kind of huperzine A controlled release preparation with two-phase drug release behavior, there is following advantage:

1. with common quick releasing formulation, compare

1. can realize the long-acting release of medicine, lasting medicine, the fluctuation of blood drug level is little, has reduced the untoward reaction of patient's medication;

2. single-dose dosage be can improve, the complicated processes of dose titration, convenient clinical application reduced in ordinary preparation medication process;

3. GI irritation is little, and patient's compliance is good;

2. with common slow releasing preparation, compare

1. there is the two-phase drug release behavior, the physiological rhythm that meets better acetylcholine esterase level in brain, can be in the physiological period of needs (daytime) sustained release, improve patient's memory, cognition and behavioral function, and in level of activation lower night, plasma drug level can be adjusted accordingly, reduces the generation of drug resistance;

2. the design of rapid release phase has guaranteed onset rapidly after drug administration, reach treatment concentration, the design of slow release phase can guarantee again the steady release of later stage active component, keeps relatively constant blood drug level, reduces the untoward reaction caused because blood drug level is too high;

3. only need take once every day, be more suitable for the Alzheimer Disease patient long-term prescription of moderate and severe;

Visible, the beneficial effect of this preparation is based on the advantage applies of the drug release behavior of the huperzine A controlled release preparation with two-phase drug release behavior of the present invention, is embodied in:

(1) there is the two-phase drug release behavior, blood drug level change with body in the acetylcholine esterase level be complementary, the design of rapid release phase, can guarantee onset rapidly after drug administration; The design of slow release phase, can make medicine (daytime) sustained release in the physiological period of needs, improves patient's memory, cognition and behavioral function, and in level of activation lower night, plasma drug level can be adjusted accordingly;

(2) can improve dosage, remove the complicated processes of dose titration from, only need take once every day, and gastrointestinal irritation is little, good patient compliance;

(3) blood drug level is more steady, and untoward reaction is few, and medication is safer, is more suitable for the Alzheimer Disease patient long-term prescription of moderate and severe.

By the description to embodiment below in conjunction with accompanying drawing, another object of the present invention, advantage and novel feature will become apparent those skilled in the art, or understand by practice of the present invention.

The accompanying drawing explanation

Fig. 1 is the capsule schematic diagram that contains rapid release ball and slow release ball;

Fig. 2 capsule schematic diagram that several prepare containing slow-releasing granules of rapid release coatings of serving as reasons;

Fig. 3 is the capsule schematic diagram that contains fast-release tablet and slow releasing tablet composition;

Fig. 4 is the tablet schematic diagram be comprised of rapid release substrate and slow release ball;

Fig. 5 is huperzine A double-layer sheet or the clad sheet schematic diagram with two-phase drug release behavior;

Fig. 6 is the huperzine A controlled release coat sheet schematic diagram with two-phase drug release behavior;

Fig. 7 is the huperzine A controlled release tablet tablets in vitro curve with two-phase drug release behavior;

Fig. 8 is huperzine A capsule and two-phase release huperzine A preparation plasma concentration curve in the body of Beagle dog;

Fig. 9 is the different huperzine A preparation inhibitory action to Beagle dog Erythrocytes-cholinesterase.

The specific embodiment

Following examples have been put down in writing exemplary formulation of the present invention and preparation method thereof in general manner, and unless otherwise, all percentage ratios all are weight percentage.Following examples are to illustrate of the present invention, and should not be considered as, limit the scope of the present invention.

Embodiment 1: the capsule that contains rapid release ball and slow release ball

1. rapid release ball

2. slow release ball

I) carry pill core

II) bag extended release coatings

Preparation method is as follows:

Rapid release ball: by huperzine A and lactose, hypromellose E5, be dissolved or dispersed in aqueous solution, be mixed with medicine carrying solution, adopt the mode of fluidized bed coating, spray on the microcrystalline Cellulose ball core of recipe quantity, as the rapid release ball.

Slow release ball: at first, by huperzine A and lactose, hypromellose E5, be dissolved or dispersed in aqueous solution, be mixed with medicine carrying solution, adopt the mode of fluidized bed coating, spray on the microcrystalline Cellulose ball core of recipe quantity, as carrying a pill core; Ethyl cellulose and Macrogol 4000 are dissolved in respectively in appropriate ethanol and water, mix, as extended release coatings film coating solution, adopt the mode of fluidized bed coating, be injected to and carry on pill core, make the slow release ball.

The capsule fill: the rapid release ball that above-mentioned preparation is completed and slow release ball according to recipe quantity, fully mix after, carry out the capsule fill.

Drug release determination

According to drug release determination method (two appendix X D first methods of Chinese Pharmacopoeia version in 2005), adopt dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2005) the measurement device drug release characteristics with huperzine A controlled release preparation of two-phase drug release behavior prepared in accordance with the present invention, concrete steps are as follows:

Get this product, the 0.1mol/L hydrochloric acid solution 500ml of take is release medium, rotating speed is per minute 50 to turn, operation, when 0.5h, 2h, 4h, 6h, 8h, 12h, get solution 5ml in accordance with the law, centrifugal (8000rpm, 15min), supplement the release medium of uniform temp, equal volume simultaneously, get supernatant as need testing solution.

Separately get the huperzine A reference substance appropriate, accurately weighed, dissolve and quantitatively dilute with dissolution medium and make every 1ml approximately containing the solution of huperzine A 0.4 μ g, be measured in the same method.

The medicine discharged by each time point of high-performance liquid chromatography method, take octadecylsilane chemically bonded silica as filler, adopts the mode of isocratic elution, and the methanol-ammonium acetate buffer (45:55) of take is mobile phase, detects wavelength 310nm.Precision measures above-mentioned reference substance and each 20 μ l of need testing solution, and the injection liquid chromatography, record peak area, by external standard method, with calculated by peak area, goes out the every amount of the cumulative release at different time.

Release profiles is shown in Fig. 7.

Embodiment 2: the capsule prepared containing the slow-releasing granules of rapid release coatings

1. carry pill core

2. wrap extended release coatings

3. wrap the rapid release clothing

Preparation method is as follows:

Medicine carrying: at first, by huperzine A and lactose, hypromellose E5, be dissolved or dispersed in aqueous solution, be mixed with medicine carrying solution, adopt the mode of fluidized bed coating, spray on the sucrose ball core of recipe quantity, as carrying a pill core;

Bag extended release coatings: ethyl cellulose and Macrogol 4000 are dissolved in respectively in appropriate ethanol and water, mix, as extended release coatings film coating solution, adopt the mode of fluidized bed coating, be injected to and carry on pill core, make the slow release ball.

Bag rapid release clothing: by huperzine A and hyprolose SSL, lactose, Pulvis Talci, be scattered in respectively in 50% alcoholic solution, mix, as rapid release clothing coating solution, adopt the mode of fluidized bed coating, be injected on the slow release ball, make the slow-releasing granules that contains the rapid release coatings.

The capsule fill: the slow-releasing granules that contains the rapid release coatings that above-mentioned preparation is completed, carry out the capsule fill according to recipe quantity.

Release profiles is shown in Fig. 7.

Embodiment 3: contain the capsule that fast-release tablet and slow releasing tablet form

1. fast-release tablet

2. slow releasing tablet

Preparation method is as follows:

Fast-release tablet: by huperzine A and pregelatinized Starch, microcrystalline Cellulose, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10% PVP K30 aqueous solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as huperzine A rapid release substrate; According to recipe quantity, be pressed into the fast-release tablet that hardness is suitable.

Slow releasing tablet: by huperzine A and lactose, polyoxyethylene WSR301, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10% PVP K30 aqueous solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as the huperzine A sustained-release matrix; According to recipe quantity, be pressed into the slow releasing tablet that hardness is suitable.

The capsule fill: the fast-release tablet that above-mentioned preparation is completed and slow releasing tablet, according to recipe quantity, combination, are carried out the capsule fill.

Release profiles is shown in Fig. 7.

Embodiment 4: the tablet be comprised of rapid release substrate and slow release ball

1. rapid release substrate

2. slow release ball

I) carry pill core

II) bag extended release coatings

Preparation method is as follows:

Rapid release substrate: by huperzine A and mannitol, microcrystalline Cellulose, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10% PVP K30 aqueous solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as huperzine A rapid release substrate.

Slow release ball: at first, by huperzine A and lactose, hypromellose E5, be dissolved or dispersed in aqueous solution, be mixed with medicine carrying solution, adopt the mode of fluidized bed coating, spray on the sucrose ball core of recipe quantity, as carrying a pill core; Eudragit E udragit RL100, triethyl citrate, Pulvis Talci are scattered in respectively in appropriate alcoholic solution, mix, as extended release coatings film coating solution, adopt the mode of fluidized bed coating, be injected to and carry on pill core, make the slow release ball.

Tabletting: the rapid release substrate that above-mentioned preparation is completed, slow release ball, according to the recipe quantity mix homogeneously, are pressed into the tablet that hardness is suitable.

Release profiles is shown in Fig. 7.

Embodiment 5: by rapid release substrate and the substrate composed tablet of slow release

1. rapid release substrate

2. sustained-release matrix

Preparation method is as follows:

Sustained-release matrix: by huperzine A and lactose, hyprolose, glyceryl monostearate, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10%Eudrgit RL100 alcoholic solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as the huperzine A sustained-release matrix.

Tabletting: the rapid release substrate that above-mentioned preparation is completed, sustained-release matrix granule, according to the recipe quantity mix homogeneously, are pressed into the tablet that hardness is suitable.

Release profiles is shown in Fig. 7.

Embodiment 6: the substrate composed double-layer tablet of rapid release substrate and slow release or clad sheet

1. rapid release substrate

2. sustained-release matrix

Preparation method is as follows:

Rapid release substrate: by huperzine A and lactose, microcrystalline Cellulose, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10% PVP K30 aqueous solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as huperzine A rapid release substrate.

Sustained-release matrix: by huperzine A and lactose, hypromellose K100M, polyoxyethylene N750, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spraying into 10% PVP K30 aqueous solution granulates; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, as the huperzine A sustained-release matrix.

Tabletting: the rapid release substrate that above-mentioned preparation is completed, sustained-release matrix granule, according to recipe quantity, adopt bi-layer tablet press to be pressed into double-layer tablet or the clad sheet that hardness is suitable.

Release profiles is shown in Fig. 7.

Embodiment 7: the coated tablet that double-layer osmotic pump tablet and rapid release coatings form

1. medicated layer

2. promoting layer

3. semi-transparent clothing film

4. wrap the rapid release clothing

5. moistureproof clothing film

Preparation method is as follows:

The preparation of medicated layer: by huperzine A and copolyvidone S630, iron oxide yellow, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spray into 95% ethanol-water solution granulation; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, standby;

The preparation of promoting layer: by carboxymethyl starch sodium, hydroxypropyl emthylcellulose K15M, sodium chloride, copolyvidone S630 and iron oxide red, after mix homogeneously, add fluid bed, spray into 95% ethanol-water solution granulation; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, subsequently, add magnesium stearate, mixes, standby;

The compacting of double-layer tablet: the medicated layer that above-mentioned preparation is completed, promoting layer granule, according to recipe quantity, adopt bi-layer tablet press to be pressed into the double-deck label that hardness is suitable;

Bag controlled release clothing: cellulose acetate is dissolved in acetone soln, and by the water-soluble solution of Macrogol 4000, two kinds of solution are hybridly prepared into the semipermeable membrane coating solution; By the above-mentioned double-deck label be up to the standards, set high in the effect coating pan, adopt the semipermeable membrane coating solution to carry out coating; Product after coating, under 45 ℃ of conditions, dry 12 hours, is removed unnecessary organic solvent and moisture;

The punching of coated tablet: adopt the mode of laser boring, on the medicated layer surface of tablet, break into the drug release hole that a diameter is 0.9mm;

Bag rapid release clothing: according to rapid release clothing prescription preparation rapid release clothing coating solution, the osmotic pump tablet after above-mentioned punching is carried out to rapid release clothing coating; Product after coating, under 45 ℃ of conditions, dry 12 hours, is removed unnecessary organic solvent and moisture;

Wrap moistureproof clothing: by the Opadry coating powder, be dissolved in and be scattered in water, be mixed with moistureproof clothing coating solution; Then adopt moistureproof clothing coating solution to carry out coating the controlled release tablet after punching; Under 45 ℃ of conditions, dry 12 hours, obtain.

Release profiles is shown in Fig. 7.

Embodiment 7: the coated tablet that mono-layer osmotic pump sheet and rapid release coatings form

1. label

2. semi-transparent clothing film

3. wrap the rapid release clothing

4. moistureproof clothing film

Preparation method is as follows:

The preparation of label: by huperzine A and PVP K30, sodium chloride, iron oxide yellow, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spray into 95% ethanol-water solution granulation; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, standby;

Tabletting: the medicated layer granule that above-mentioned preparation is completed, according to recipe quantity, adopts and is pressed into the label that hardness is suitable;

Bag controlled release clothing: cellulose acetate is dissolved in acetone soln, and by the water-soluble solution of Macrogol 4000, two kinds of solution are hybridly prepared into the semipermeable membrane coating solution; The label suppressed is set high in the effect coating pan, adopt the semipermeable membrane coating solution to carry out coating; Product after coating, under 45 ℃ of conditions, dry 12 hours, is removed unnecessary organic solvent and moisture;

The punching of coated tablet: adopt the mode of laser boring, at the label of tablet, break into the drug release hole that a diameter is 0.8mm;

Release profiles is shown in Fig. 7.

Embodiment 9: the coated tablet that slow releasing tablet and rapid release coatings form

3. the preparation of slow releasing tablet

4. rapid release coating

Preparation method is as follows:

The preparation of properties of huperzine A sustained release tablets: by huperzine A and lactose, HPMC K4M, copolyvidone S630, adopt equivalent to progressively increase after the method mix homogeneously, add fluid bed; Spray into 95% ethanol-water solution granulation; Be dried to moisture and be less than 3%, cross 20 mesh sieves, granulate, then add magnesium stearate, mixes, and then is pressed into the slow releasing tablet label that hardness is suitable;

Bag rapid release clothing: according to rapid release clothing prescription preparation rapid release clothing coating solution, above-mentioned slow releasing tablet is set high in the effect coating pan and carries out rapid release clothing coating; Under 45 ℃ of conditions, dry 12 hours, remove unnecessary organic solvent and moisture;

Release profiles is shown in Fig. 7.

Embodiment 10:

6 of healthy Beagle (than lattice) dogs, be divided into two groups at random, and 3 every group, carry out single dose, binary cycle, the test of intersection own control, fasting 12h, freely fetch water.First group of 3 Beagle dog give reference preparation (conventional capsule, 0.2mg/ grain/only); Second group of 3 Beagle dog are subject to test preparation (two-phase release huperzine A controlled release tablet, embodiment 7 prescriptions, 0.2mg/ sheet/only).One week eluting after date, test for the second time, every Beagle dog before taking medicine (0h), take medicine after 0.25,0.5,1,2,4,6,8,10,24h, gather respectively forelimb venous blood 1.5ml, existing side by side is about to it and transfers in the centrifuge tube that scribbles heparin, centrifugal (3000rpm, 5min), isolate blood plasma, under-20 ℃ of conditions, freezing preservation.Note observing, and record the untoward reaction of each dog at duration of test.

Adopt LC/MS/MS to measure huperzine A blood drug level in the body of Beagle dog, the results are shown in Figure 8.

From blood drug level-time graph in the Beagle dog body of Fig. 8, with respect to conventional capsule, the blood drug level of huperzine A controlled release tablet is steady, fluctuates less; The design of rapid release phase of the present invention has guaranteed onset rapidly after drug administration, reaches treatment concentration; The design of slow release phase has guaranteed the steady release of later stage active component, has reduced the untoward reaction caused because blood drug level is too high.

Embodiment 11

Healthy Beagle dog, 12, male, be divided at random four groups, 3 every group; Mensuration is taken the effect of different huperzine A preparations to Beagle dog Erythrocytes-cholinesterase, the drug effect time-histories of observing different preparations.Specifically be grouped as follows:

First group, give commercially available huperzine A preparation (huperzine A, 0.05mg/ sheet, 4 /);

Second group, give huperzine A capsule (0.2mg/ grain/only);

The 3rd group, give huperzine A speed slow two controlled release tablet (embodiment 7 prescriptions, 0.2mg/ sheet/only) of releasing;

The 4th group, give huperzine A solution (0.2mg/ only).

Fasting 12h before the administration of Beagle dog, freely fetch water.Every Beagle dog respectively before taking medicine (0h), take medicine after 0.25,0.5,1,2,4,6,8,10,12 and 24 hour, gather respectively forelimb venous blood 1.5ml, carry out cholinesterase activity mensuration (the results are shown in Figure 9) for carrying out erythrocyte.Simultaneously, observe the symptom (comprising secretions, amyostasia, vomiting and ataxia etc.) after the Beagle dog gives different huperzine A preparations.

From the Beagle dog Erythrocytes-cholinesterase vitality test result of Fig. 9, with respect to other three kinds of preparations, slow pair of huperzine A speed prepared by the present invention is released controlled release tablet, and not only onset is rapid, the while lasting medicine, and the inhibition of acetylcholine esterase is active in 12 hours; With respect to other three kinds of preparations, take the slow two Beagle dogs of releasing controlled release tablet of huperzine A speed, substantially have no obvious adverse reaction.

Claims

1. the huperzine A controlled release preparation with two-phase drug release behavior, it is characterized in that: according to the requirement of Chinese Pharmacopoeia drug release determination method, in the predetermined time section, in meeting the release medium of sink conditions, described huperzine A controlled release preparation is according to biphase release profile, wherein first-phase is the rapid release phase, and second-phase is the slow release phase; Wherein, the gross weight based on said preparation Chinese medicine active component, described rapid release contains the active constituents of medicine of 5wt% ~ 50wt% mutually, and wherein, described active constituents of medicine is huperzine A and derivant or its salt.

2. huperzine A controlled release preparation according to claim 1, it is characterized in that: described rapid release comprises active constituents of medicine, diluent and other adjuvants mutually; Described slow release comprises active constituents of medicine, sustained-release matrix substrate, diluent and other adjuvants mutually.

3. huperzine A controlled release preparation according to claim 1, it is characterized in that: described rapid release comprises active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants mutually; Described slow release comprises active constituents of medicine, hydrophilic polymer, osmotic pressure promoter and other adjuvants mutually.

4. huperzine A controlled release preparation according to claim 1, it is characterized in that: described rapid release comprises active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants mutually; Described slow release comprises active constituents of medicine, hydrophilic polymer, osmotic pressure promoter, short osmopolymer and other adjuvants mutually.

5. huperzine A controlled release preparation according to claim 1, it is characterized in that: described rapid release comprises active constituents of medicine, thin film coating material, antiplastering aid, diluent and other adjuvants mutually; Described slow release comprises active constituents of medicine, hydrophilic polymer, diluent and other adjuvants mutually.

6. according to the described huperzine A controlled release preparation of any one in claim 2-5, it is characterized in that:

Described diluent is selected from one or more in microcrystalline Cellulose, lactose, sucrose, mannitol, sorbitol, starch, carboxymethyl starch sodium, pregelatinized Starch;

Described other adjuvants comprise one or more in lubricant, coloring agent, binding agent, porogen, plasticizer;

Described sustained-release matrix substrate is selected from one or more in acrylic resin, ethyl cellulose, cellulose acetate, glyceryl monostearate;

Described thin film coating material is selected from one or more in hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, polyvidone, copolyvidone;

Described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, glyceryl monostearate;

Described hydrophilic polymer is to be selected from one or more in polyvidone, copolyvidone, polyoxyethylene, carbomer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium alginate, xanthan gum, arabic gum, chitin;

Described osmotic pressure promoter being is selected from one or more in sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, fructose;

7. according to the described huperzine A controlled release preparation of any one in claim 1-5, it is characterized in that: more than described rapid release discharged its active constituents of medicine 90wt% in 30 minutes; More than described slow release discharged the 90wt% of its active constituents of medicine in 5 ~ 15 hours.

8. according to the described huperzine A controlled release preparation of any one in claim 1-5, it is characterized in that: the active constituents of medicine that described huperzine A controlled release preparation contains 0.05mg ~ 4mg.

9. according to the described huperzine A controlled release preparation of any one in claim 1-5, it is characterized in that: described rapid release mutually for the rapid release substrate in fast-release tablet, rapid release ball, tablet, be wrapped in tablet or the outer rapid release coatings of ball core, be attached to release layer substrate in double-layer tablet or their combination; Described slow release mutually for the slow-released carrier in sustained-release matrix, tablet or ball core in slow releasing tablet, slow release ball, tablet, be attached to slow release layer substrate in double-layer tablet or their combination.

10. according to the described huperzine A controlled release preparation of any one in claim 1-5, it is characterized in that: described huperzine A controlled release preparation is capsule, tablet, double-layer tablet, multilayer tablet, coated tablet or their combination.

11. huperzine A controlled release preparation according to claim 10, it is characterized in that: described huperzine A controlled release preparation is the capsule that contains rapid release ball and slow release ball, capsule prepared by the slow-releasing granules that contains the rapid release coatings, the capsule that contains fast-release tablet and slow releasing tablet, the tablet formed by rapid release substrate and slow release ball, by rapid release substrate and the substrate composed tablet of slow release, by rapid release substrate and the substrate composed double-layer tablet of slow release or clad sheet, by rapid release substrate, sustained-release matrix and blank substrate composed multilayer tablet, the coated tablet formed by mono-layer osmotic pump controlled release tablets and rapid release coatings, the coated tablet formed by double-layer osmotic pump controlled-release tablet and rapid release coatings, or the coated tablet of slow releasing tablet and rapid release coatings composition.