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

Abstract

The invention discloses a huperzine A controlled-release preparation with biphasic drug release behavior. Within a predetermined period of time, the release distribution is in two phases in vivo and in vitro, wherein the first phase is an immediate release phase, and the second phase is a The sustained-release phase, wherein, based on the total weight of the active pharmaceutical ingredient, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredient. The huperzine A controlled-release preparation can take effect quickly after taking; it can be released continuously during the required physiological cycle (daytime), improving the patient's memory, cognition and behavioral functions, and at night when the activity level is low, the plasma drug The concentration can be adjusted accordingly to reduce the occurrence of drug resistance; the gastrointestinal irritation is small, and the patient's compliance is good; on the basis of increasing the dosage, it only needs to be taken once a day to maintain a stable blood concentration and obtain Constant curative effect, lower incidence of adverse reactions, safer medication, more suitable for long-term medication for moderate and severe Alzheimer's patients.

Description

Huperzine A controlled release preparation with biphasic drug release behavior and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a huperzine A controlled-release preparation with biphasic drug release behavior and a preparation method thereof.

technical field

Huperzine A (Huperzine A) is a natural new type of effective monomer of lycopodium alkaloids isolated from Huperziaserrata (commonly known as Melaleuca) in China. active acetylcholinesterase inhibitors. The chemical name is (5R,9R,11E)5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methylenecycloocta(6)pyridine- 2(1H)ketone, molecular formula is C ₁₅ H ₁₈ N ₂ O, molecular weight: 242.32. Huperzine A is optically active and only exists in plants in the form of the left-handed isomer, and in vivo and in vitro experiments have found that (-) huperzine A has a more selective inhibitory effect on cholinesterase than (+) huperzine A Pinetaxel is 50 times stronger.

Huperzine A has a significant effect on the treatment of Alzheimer's disease. In recent years, studies have found that huperzine A also has multiple pharmacological effects: it has neuroprotective effects such as regulating the expression and secretion of nerve growth factors, and resisting glutamate receptors; huperzine A is not only an efficient and highly selective It is a central acetylcholinesterase inhibitor, and also protects cells by resisting excitotoxicity caused by glutamate, anti-oxidative stress, and anti-apoptosis, and has the potential to treat various neurodegenerative diseases.

Alzheimer's disease, also known as Alzheimer's disease, is a chronic degenerative neurological disease characterized by progressive memory and cognitive impairment and involving multiple etiological factors. Short-term memory loss is the most common symptom of Alzheimer's disease, and advanced symptoms include confusion, irritability, mood swings, language breakdown, long-term memory loss, and other generalized withdrawals due to the subject's decline in consciousness. The dysfunction of the cholinergic system in the brain is the earliest evidence to be involved in the pathogenesis of Alzheimer's disease. There are many dysfunctions in the cholinergic nervous system in the brain of patients with Alzheimer's disease, and the cholinergic activity in the brain The reduction was significantly correlated with the degree of cognitive impairment.

At present, cholinesterase inhibitors are considered to be one of the most effective drugs for the treatment of senile dementia. These drugs inhibit the hydrolysis of acetylcholine by inhibiting the activity of cholinesterase, enhance cholinergic function, supplement the precursor of acetylcholine, and increase the Synthesis, thereby exciting cholinergic neurons, increasing the ability of learning and memory.

From a neurochemical perspective, Alzheimer's disease is considered a neurodegenerative disease in which cholinergic deficits lead to loss of acetylcholine levels in the synaptic cleft. Huperzine A is a potent reversible cholinesterase inhibitor, which has a selective inhibitory effect on cholinesterase. Compared with other drugs for the treatment of Alzheimer's disease, Huperzine A has a high Oral absorption and availability, easy to pass through the blood-brain barrier, can selectively inhibit acetylcholinesterase in the brain, and its side effects on the peripheral cholinergic system and dose-dependent liver toxicity are low, it can improve senile memory loss, and can Significantly improves memory, cognition and behavioral function in Alzheimer's patients.

In 1994, Huperzine A Tablets (trade name: Haberin) was approved for the treatment of Alzheimer's disease and benign memory disorders. The efficacy of Huperzine A in the treatment of middle-aged and elderly memory loss and various types of dementia has been confirmed by a large number of domestic clinical studies.

The pharmacokinetic study of rodents showed that the pharmacokinetics of rats after oral or intravenous injection of ³ H-huperzine A was an open two-compartment model. Oral administration of huperzine A is rapidly and completely absorbed, with a bioavailability of 96.9% and a half-life of 9.8 minutes in the distribution phase. It is mainly excreted in the form of prototype and metabolites through urine. After 24 hours of intravenous injection ^{of 3} H-huperzine A, the amount excreted from the urine was 73% of the dose, and the amount of radioactivity excreted from the feces within 24 hours was 2.8% of the dose. The study of mouse autoradiography shows that ³ H-huperzine A is distributed in various brain regions, and the distribution is more concentrated in the cortical frontoparietal cortex, striatum, hippocampus and nucleus accumbens. Pharmacokinetic study of healthy young volunteers shows that after oral administration of huperzine A, it is rapidly absorbed, widely distributed in the body, eliminated from the body at a moderate speed, and the change of plasma concentration conforms to the first-order kinetics of the one-compartment open model.

According to the patent search, the general preparation patents related to Huperzine A include: Huperzine A Orally Disintegrating Tablets (CN1568985), Huperzine A Intravenous Injection (CN101129329), Huperzine A Dropping Pills (CN1493287) , Huperzine A pellet preparation (CN101007002), etc.

At present, the commonly used oral preparations of huperzine A are ordinary tablets or capsules. In the clinical application process, the common preparations of huperzine A still have the following disadvantages: ①Due to the rapid onset of the drug, the blood drug concentration rises rapidly It is highly likely to cause adverse drug reactions (including dizziness, nausea, gastrointestinal discomfort, fatigue and other symptoms), and the duration of the drug effect of ordinary preparations is short. In clinical practice, it usually needs to be taken twice a day, and the blood drug concentration fluctuates greatly. Poor compliance; ②This product is a reversible cholinesterase inhibitor, and its dosage has inter-individual differences. In order to reduce the adverse reactions of patients, the general initial dose should start from a small dose and gradually adjust the dose. Clinical medication has brought certain inconvenience; ③ poor curative effect on moderate and severe Alzheimer's disease patients; ④ common tablets or capsules of huperzine A do not take into account the normal physiological function of acetylcholinesterase in the patient's brain Rhythm, sleep, and the role of learning and memory have design flaws.

Chinese patent CN101485640 discloses a single-layer osmotic pump controlled-release tablet of huperzine A, comprising: a tablet core containing an effective dose of huperzine A and pharmaceutical adjuvants and a semi-permeable coating film wrapping the core, so The coating film is provided with a drug release hole, and it is characterized in that: the tablet core contains huperzine A 0.01%-1.0%, blocker 1.0%-10%, penetration enhancer 1.0%-40%, the coating The weight ratio of polyethylene glycol 6000 to cellulose acetate in the coating liquid is (0.05-0.25): 1, and the weight gain of the coating film accounts for 5%-25% of the weight of the tablet core.

Chinese patent CN101485639 discloses a double-layer osmotic pump controlled-release tablet of huperzine A, comprising: a double-layer tablet core composed of a drug-containing layer and a push layer; and a semi-permeable coating film wrapping the double-layer tablet core, The coating film is provided with a drug-releasing aperture on one side of the drug-containing layer; the drug-containing layer in the tablet core contains effective doses of huperzine A, suspending agents, osmotic pressure active substances and pharmaceutical adjuvants. The push layer contains swelling agent, penetration enhancer and binder; the coating film contains polyethylene glycol as a plasticizer, and the weight gain of the coating film accounts for 8% to 20% of the weight of the tablet core. The diameter of the release hole on the surface of the drug-containing layer is 0.2 to 2.0 mm.

Chinese patent CN101606917 discloses a sustained-release tablet of huperzine A and its derivatives or its salts, which contains 20-50% of the tablet weight sustained-release material hydroxypropyl methylcellulose, hypromellose The base cellulose is a combination of two or more of K4M, K15M and K100M, wherein the weight ratio of K4M and/or K15M to K100M is 3-50:0-1.

Chinese patent CN1682719 discloses an enteric-coated sustained-release tablet containing huperzine A and its preparation method, which uses enteric-coated technology to overcome the adverse effects of lower pH in the stomach on drug diffusion in matrix tablets , to avoid the adverse effects of human gastric juice on the huperzine A matrix tablets released by diffusion, so as to ensure the stable, slow and complete release of the drug. The active drug ingredient contained in the sustained-release tablet is a reversible cholinesterase inhibitor huperzine A, and the matrix sustained-release layer is covered with a layer of enteric polymer film coating layer. The pharmaceutical active ingredient can also be salts of various acids of huperzine A that are acceptable on preparations. The content of huperzine A in the active pharmaceutical ingredients in each tablet is 10-500 μg.

Chinese patent CN1751683 discloses skeleton-type sustained-release tablets of huperzine A and its derivatives or their salts and the preparation process thereof, and specifically relates to new drug preparations of huperzine A and its derivatives. The sustained-release tablets contain an effective amount of Huperzine A and its derivatives or salts thereof, the hydrophilic gel matrix slow-release material accounting for 20-90% of the tablet weight and the filler accounting for 5-75% of the tablet weight overcome the existing slow-release technology The relatively serious defect of medium burst release can maintain the continuous and stable release of the active ingredient huperzine A and its derivatives or its salts, so that the body maintains a certain blood drug concentration for 12 hours, and truly achieves a 12-hour sustained release effect. The invention has the characteristics of high bioavailability, good curative effect, low side effect and simple preparation process.

Chinese patents CN101485640, CN101485639, CN101606917, CN1682719, and CN1751683 realize the delayed or controlled release of the active ingredient huperzine A through osmotic pump tablets, hydrophilic gel matrix tablets, enteric-coated sustained-release tablets, etc. Long-lasting release. However, while the preparations in the above patents achieve long-term release, they cannot achieve rapid drug onset; studies have shown that acetylcholine is one of the five neurotransmitters that play a role in the wakefulness and alertness of animals. There is a circadian rhythm in acetylcholine levels; increases in acetylcholine levels are positively correlated with locomotor activity, maintaining relatively high levels during wakefulness and relatively low levels during sleep. The above-mentioned patents fail to fully consider the circadian rhythm of the level of cholinesterase in the brain, and cannot realize the optimal design of drug efficacy, which has defects.

Research data suggest that low levels of acetylcholine during slow-wave sleep are strongly associated with memory consolidation. The brain regulates the transmission of memory information between the cortex and hippocampus by regulating the level of acetylcholine. When awake, information is transmitted to the hippocampus through the neocortex, where the information is encoded in the hippocampus and then transmitted to the cortical area. In the early stage of memory formation, the hippocampus maintains a high level of acetylcholine, which inhibits the transmission circuit between the hippocampus and the cortex to reduce the interference of previously stored memory information on new information. On the contrary, in the late stage of memory formation (corresponding to the slow wave sleep stage), the low level of acetylcholine in the brain is conducive to the transmission between the hippocampus and the cortex, and promotes the storage of memory information. Compared with the normal rhythm of normal individuals, patients with Alzheimer's disease have spontaneous activity disorder, and the rhythm boundary of circadian activity is not obvious. A considerable number of patients have sleep symptoms during the day and cannot fall asleep at night, and have intermittent sleep. . Researchers believe that abnormal sleep in Alzheimer's disease patients is related to the decline of cognitive function, especially the decline of working memory.

It can be seen that in order to make Huperzine A more effective, reduce adverse reactions after medication, and increase patients' compliance with medication, it is necessary to take into account the circadian rhythm of cholinesterase levels in the brain and rationally Select and optimize the release behavior of drugs to maximize their efficacy.

Contents of the invention

The primary purpose of the present invention is aimed at the physical and chemical properties, stability and biological properties of huperzine A, according to the clinical treatment needs of Alzheimer's disease patients and the requirements of drug compliance, fully considering the cholinesterase in the patient's brain On the basis of the circadian rhythm of the level, design and provide a kind of huperzine A controlled-release preparation with biphasic drug release behavior, within a predetermined period of time, its drug release behavior in vivo and in vitro can be distributed according to the biphasic release, wherein The first phase is an immediate release phase, and the second phase is a sustained release phase.

Another object of the present invention is to provide the prescription and preparation method of the huperzine A controlled release preparation with biphasic drug release behavior.

The invention provides a controlled-release preparation containing huperzine A and its derivatives or salts thereof, characterized in that the controlled-release preparation of huperzine A has a biphasic drug release behavior, within a predetermined period of time, In the release medium conforming to the sink condition, its release behavior follows a two-phase release distribution, wherein the first phase is an immediate-release phase, and the second phase is a sustained-release phase; based on the total weight of the pharmaceutically active ingredients in the preparation, the The immediate-release phase contains 5wt%-50wt% of active pharmaceutical ingredients, and the sustained-release phase contains 50wt%-95wt% of active pharmaceutical ingredients; the active pharmaceutical ingredients are huperzine A and its derivatives or salts thereof.

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the design of the quick-release phase can well ensure the rapid release of the initial drug, meet the demand for rapid onset of the drug, and quickly reach the therapeutic concentration; The release phase design can ensure the steady release of active ingredients in the later stage, ensure the continuous release of active ingredients during the day when the activity level is high, and improve the memory, cognition and behavior functions of Alzheimer's patients, while the activity level is low. At night, the plasma drug concentration can be adjusted accordingly to reduce the occurrence of drug resistance.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that the biphasic release in vitro is carried out in a 0.1M hydrochloric acid solution at 37°C according to the provisions of the Chinese Pharmacopoeia 2010 edition. , Under stirring at a rate of 50rpm or 75rpm, measured with a paddle method or a basket method release measuring device.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that the drug active ingredient in the immediate-release phase meets the sink condition according to the requirements of the Chinese Pharmacopoeia 2010 edition dissolution method. In the release medium, preferably more than 90wt% of the active pharmaceutical ingredient assigned to the immediate release phase is released within 30 minutes, more preferably more than 90wt% of the active pharmaceutical ingredient assigned to the immediate release phase is released within 15 minutes.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that, according to the requirements of the Chinese Pharmacopoeia for the determination of the release rate, in the release medium that meets the conditions of the sink, in the sustained-release phase The time for releasing more than 90wt% of the active ingredient of the medicine is 5-15 hours.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that the release behavior of the active ingredient in the slow-release phase conforms to zero-order, first-order, Higuchi or Ritger-Peppas drug release models , preferably zero-order drug release.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that it contains 0.05 mg to 4 mg of active pharmaceutical ingredient huperzine A and its derivatives or salts thereof. The total weight of the active pharmaceutical ingredients in the huperzine A controlled-release preparation is the sum of the weights of the active pharmaceutical ingredients in the immediate-release phase and the sustained-release phase. According to the specifications of the medicine and the needs of treatment, in the huperzine A controlled-release preparation with biphasic drug-release behavior according to the present invention, the ratio of the medicine in the quick-release phase to the total weight of the active ingredients of the medicine is 5wt% ~ 50wt%, Preferably it is 10wt%~45wt%, more preferably 15wt%~40wt%.

The huperzine A controlled-release preparation with biphasic drug release behavior of the present invention is characterized in that the carrier for the immediate-release phase and the slow-release phase is selected from capsules, tablets, double-layer tablets, and multi-layer tablets. , coated tablets and any combination thereof.

Specifically, the immediate-release phase of the present invention is an immediate-release carrier containing an immediate-release dosage of pharmaceutical active ingredients, and the immediate-release phase is preferably but not limited to immediate-release tablets, immediate-release pills, and immediate Release matrix, immediate-release coating layer wrapped around tablet or pellet core, immediate-release layer matrix incorporated into double-layer tablet, and any combination thereof.

Correspondingly, the sustained-release phase of the present invention is a sustained-release carrier containing a sustained-release dosage of pharmaceutical active ingredients, and the sustained-release phase is preferably but not limited to sustained-release tablets, sustained-release pills, and sustained-release tablets in tablets. Matrix, sustained-release carrier in tablet or pellet core, sustained-release layer matrix incorporated into a bilayer tablet, and combinations thereof in any form.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a capsule, wherein the immediate-release phase can include active pharmaceutical ingredients, diluents and other adjuvants; The sustained-release phase may include pharmaceutical active ingredients, sustained-release matrix matrix, diluent and other auxiliary materials.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a tablet, wherein the immediate-release phase can include pharmaceutical active ingredients, diluents and other auxiliary materials; The sustained-release phase may include pharmaceutical active ingredients, sustained-release matrix matrix, diluent and other auxiliary materials.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a double-layer tablet, a multi-layer tablet, or a chip-coated tablet, wherein the immediate-release phase can contain pharmaceutically active ingredients , film coating material, anti-adhesive agent, diluent and other auxiliary materials; the sustained-release phase may contain pharmaceutically active ingredients, hydrophilic polymers, diluent and other auxiliary materials.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a coated tablet composed of a single-layer osmotic pump controlled-release tablet and an immediate-release coating layer, wherein the The single-layer osmotic pump controlled-release tablet includes a tablet core and a controlled-release coating film wrapping the tablet core. The tablet core may contain pharmaceutical active ingredients, hydrophilic polymers, osmotic pressure enhancers and other auxiliary materials; The coating layer may contain pharmaceutical active ingredients, film coating materials, diluents, anti-adhesive agents and other auxiliary materials.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a coated tablet composed of a double-layer osmotic pump controlled-release tablet and an immediate-release coating layer; wherein, the The double-layer osmotic pump controlled-release tablet comprises a double-layer tablet core composed of a drug-containing layer and a booster layer, and a controlled-release coating film wrapping the double-layer tablet core, wherein the drug-containing layer contains pharmaceutical active ingredients, hydrophilic Polymers, osmotic pressure enhancers and other auxiliary materials; the booster layer comprises permeation-promoting polymers, osmotic pressure enhancers and other auxiliary materials; the immediate-release coating layer may comprise pharmaceutically active ingredients, film coating materials, diluents , anti-sticking agent and other accessories.

In one embodiment of the present invention, the huperzine A controlled-release preparation with biphasic drug release behavior can be a sustained-release tablet with an immediate-release coating layer; wherein, the sustained-release phase can contain pharmaceutical active ingredients , hydrophilic polymers, diluents and other auxiliary materials; the immediate-release coating layer may contain active pharmaceutical ingredients, film coating materials, diluents, anti-adhesive agents and other auxiliary materials.

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, in the above embodiment, the active ingredient of the drug is huperzine A and its derivatives or salts thereof.

The diluent is selected from one or more of microcrystalline cellulose, lactose, sucrose, mannitol, sorbitol, starch, sodium carboxymethyl starch, and pregelatinized starch.

The other auxiliary materials include one or more of lubricants, coloring agents, binders, porogens, and plasticizers; the lubricants are selected from magnesium stearate, stearic acid, hard One or more of fatty sodium fumarate, talcum powder, and micropowdered silica gel; the coloring agent is one or more selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, and titanium dioxide . Described binding agent is selected from one of hydroxypropyl methylcellulose, povidone, copovidone, hydroxypropyl cellulose, cornstarch, gelatin, acacia, sodium carboxymethyl cellulose or Various. The porogen is selected from one or more of polyethylene glycols, glycerin, povidone, copovidone, propylene glycol, water-soluble inorganic salts; the plasticizer is selected from phthalic acid One or more of methyl ester, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glyceryl acetate, castor oil .

The blank pellet core can be used as a component for preparing immediate-release pellets or sustained-release pellets, and the blank pellet core is selected from microcrystalline cellulose, sucrose, and mixtures thereof.

The sustained-release matrix matrix is selected from acrylic resin, ethyl cellulose, cellulose acetate, glyceryl monostearate, and mixtures thereof. Described acrylic resin is selected from methacrylic acid copolymer, methacrylate copolymer (such as Eudragit L100-55, Eudragit L30D-55, Eudragit NE30D, Eudragit RL30D, Eudragit RS30D), aminomethacrylic acid copolymer, o-phthalic One or more of hydroxypropylmethylcellulose diformate, hydroxymethylcellulose acetate succinate, and hydroxypropylmethylcellulose acetate succinate.

The material of the sustained-release coating or controlled-release coating is selected from one of cellulose acetate, ethyl cellulose, acrylic resin, cellulose acetate phthalate, and hydroxypropyl methylcellulose acetate succinate or more.

The film coating material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, povidone, copovidone kind.

The osmotic pressure enhancer can be one or more of sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, and fructose.

The hydrophilic polymer is selected from povidone, copovidone, polyoxyethylene, carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium alginate, One or more of xanthan gum, gum arabic, and chitin.

The permeation-promoting polymer is selected from polyoxyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, povidone one or more of.

Described anti-sticking agent is selected from talcum powder, magnesium stearate, glyceryl monostearate, and their mixtures.

The moisture-proof clothing is made by coating the moisture-proof clothing composition. The composition of the moisture-proof coat layer comprises coating powder for forming a moisture-proof coat, and optionally one or more selected from materials such as coloring agents, plasticizers, opacifiers, and anti-sticking agents. All are routine choices of those skilled in the art. The coating powder used to form the moisture-proof coat is a conventional choice of those skilled in the art, including commercially available products Opadry, Chabinlan and other coating powders that can form the moisture-proof coat.

In order to better understand the above invention, the following narration is a detailed description of the present invention, and does not constitute any limitation to the scope of the present invention:

1. Capsules

The capsule of one of the huperzine A controlled-release preparations with biphasic drug release behavior of the present invention can realize the biphasic drug release behavior of the present invention in the following manner.

(1) Capsules containing immediate-release pills and sustained-release pills

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release pill, and the described sustained-release phase is a sustained-release pill; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

①Preparation of capsules containing immediate-release pills and sustained-release pills by wet granulation

The capsule containing the quick-release pills and the sustained-release pills comprises: a capsule shell, quick-release pills and sustained-release pills.

The active ingredient of the drug, diluent and other excipients are prepared by wet granulation, extrusion spheronization and other conventional methods well known to those skilled in the art to prepare immediate-release pills. Wherein, based on the total weight of the quick-release pills, the quick-release pills contain 0.005-4% by weight of active pharmaceutical ingredients, 50-98% by weight of diluents, and 1-46% by weight of other excipients.

Sustained-release pills are prepared by conventional methods such as wet granulation, extrusion and spheronization, such as active pharmaceutical ingredients, sustained-release matrix matrix, diluent and other excipients. Based on the total weight of the sustained-release pills, the sustained-release pills contain 0.01-5% by weight of active pharmaceutical ingredients, 2-50% by weight of sustained-release matrix matrix, 40-80% by weight of diluents, 0.1-15% by weight of other accessories.

The quick-release pills and sustained-release pills prepared above were weighed, mixed uniformly, and filled into capsules; based on the total weight of the active pharmaceutical ingredients in the capsules, the quick-release pills contained 5wt% to 50wt% active pharmaceutical ingredients.

②Preparation of capsules containing immediate-release pills and sustained-release pills by fluidized bed coating

The capsule containing the quick-release pills and the sustained-release pills comprises: a capsule shell, quick-release pills and sustained-release pills.

The quick-release pills include, from the inside to the outside, a blank pellet core and an immediate-release coating layer; the quick-release pills can be loaded with drug active ingredients, The diluent, film coating material, anti-adhesive agent and other auxiliary materials are dispersed or dissolved in the coating solvent, and loaded on the blank pellet core to form the instant-release pellet. Based on the total weight of the immediate-release coating layer, the immediate-release coating layer comprises 0.01 to 25% by weight of the active pharmaceutical ingredient, 10 to 70% by weight of the film coating material, 1 to 30% by weight of the anti-adherent, 0% by weight ~70% by weight of diluent, and 0~10% by weight of other auxiliary materials.

The sustained-release pellets can be coated with drug-loaded mode in a fluidized bed, and the sustained-release coating material is outsourced to the immediate-release pellet core; based on the total weight of the sustained-release coating, the pore-forming agent will The medium ratio is 0 to 30% by weight.

Weigh the prepared quick-release pills and sustained-release pills, mix them evenly, and fill them into capsules; based on the total weight of the active pharmaceutical ingredients in the capsules, the quick-release pills contain 5wt% to 50wt% active pharmaceutical ingredients.

(2) Capsules prepared from sustained-release granules containing an immediate-release coating layer

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release coating layer, and the sustained-release phase is a sustained-release pellet; Based on the total weight of the active pharmaceutical ingredients, the immediate release phase contains 5wt%-50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg-4mg.

The sustained-release granules containing the immediate-release coating layer comprise from inside to outside in structural composition: immediate-release pellets, sustained-release coating films and immediate-release coating layers; wherein, the preparation of the immediate-release pellets and The coating and composition of the sustained-release coating film have been described above; the described immediate-release coating layer can be loaded by fluidized bed coating, and the pharmaceutical active ingredient, diluent, film coating material and Other auxiliary materials are dispersed or dissolved in the coating solvent, and are loaded on the prepared sustained-release pellets to form the sustained-release granules containing the immediate-release coating layer; based on the total weight of the immediate-release coating layer, the The immediate-release coating layer comprises 0.01-25% by weight of active pharmaceutical ingredient, 10-70% by weight of film coating material, 1-30% by weight of anti-adhesive agent, 0-70% by weight of diluent, and 0-10% by weight of diluent. % of other excipients.

Weigh the prepared sustained-release pellets containing the immediate-release coating layer and fill them into capsules; based on the total weight of the active pharmaceutical ingredient in the capsule, the immediate-release coating layer contains 5wt% to 50wt% of the active pharmaceutical ingredient .

(3) Capsules containing immediate-release tablets and sustained-release tablets

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release tablet, and the described sustained-release phase is a sustained-release tablet; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The immediate-release tablet can be prepared by wet granulation or direct compression of the mixture of active pharmaceutical ingredients, diluents and other auxiliary materials. The selection of these functional excipients and diluents is well known to anyone skilled in the art. Wherein, based on the total weight of the immediate-release tablet, the immediate-release tablet contains 0.005-4% by weight of active pharmaceutical ingredients, 50-98% by weight of diluent, and 1-46% by weight of other excipients.

Matrix-type sustained-release tablets are prepared by conventional methods known to those skilled in the art, such as wet granulation or direct compression, by combining active pharmaceutical ingredients, sustained-release matrix matrices, diluents, and other excipients; wherein, the sustained-release tablet-based In total weight, the sustained-release tablet contains 0.01-5% by weight of active pharmaceutical ingredients, 2-50% by weight of sustained-release matrix matrix, 40-80% by weight of diluent, and 0.1-15% by weight of other excipients.

It is also possible to coat the immediate-release tablet containing the active ingredient of the drug through a coating method well known to those skilled in the art, such as a fluidized bed, a high-efficiency coating pan, etc., and coat the tablet core with a sustained-release film material to form the described Sustained Release Tablets.

The prepared immediate-release tablet and sustained-release tablet were weighed, mixed evenly, and filled into capsules; based on the total weight of the active pharmaceutical ingredient in the capsule, the immediate-release pill contained 5wt% to 50wt% of the active pharmaceutical ingredient.

2. Tablets

The tablet of one of the huperzine A controlled-release preparations with biphasic drug release behavior described in the present invention can realize the drug release behavior described in the present invention in the following manner.

(1) Tablets consisting of immediate-release matrix and sustained-release pellets

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release matrix, and the sustained-release phase is a sustained-release pill; based on the drug The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The tablet composed of the quick-release matrix and the sustained-release pills includes the quick-release matrix and the sustained-release pills in terms of structural composition; the quick-release matrix can be prepared by fully mixing or Prepared by wet granulation. Wherein, based on the total weight of the immediate-release matrix, the immediate-release matrix contains 0.005-4% by weight of active pharmaceutical ingredients, 50-98% by weight of diluent, and 1-46% by weight of other excipients.

The sustained-release pills are prepared in the same way as the above-mentioned sustained-release pills; finally, the quick-release matrix and the sustained-release pills are mixed evenly according to the specification ratio of the active ingredients, and then passed through a tabletting machine with a special stirring function. machine, compressed into tablets. Based on the total weight of the active pharmaceutical ingredients in the tablet, the immediate release matrix contains 5wt% to 50wt% of the active pharmaceutical ingredients.

(2) Tablets consisting of an immediate-release matrix and a sustained-release matrix

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release matrix, and the sustained-release phase is a sustained-release matrix; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The tablet that described quick-release matrix and slow-release matrix is formed comprises quick-release matrix and sustained-release matrix on structural composition; Prepared by mixing or wet granulation; wherein, based on the total weight of the immediate-release matrix, the immediate-release matrix comprises 0.005-4% by weight of the pharmaceutical active ingredient, 50-98% by weight of the diluent, and 1-46% by weight % of other excipients.

The sustained-release matrix is prepared into a sustained-release matrix by conventional methods well known to those skilled in the art, such as wet granulation, by taking active pharmaceutical ingredients, sustained-release matrix matrix, diluent and other auxiliary materials. Based on the total weight of the sustained-release matrix, the sustained-release matrix comprises 0.01 to 5% by weight of active pharmaceutical ingredients, 2 to 50% by weight of sustained-release matrix matrix, 40 to 80% by weight of diluent, 0.1 to 15% by weight of other accessories.

Finally, the immediate-release matrix and the sustained-release matrix are uniformly mixed according to the specifications and ratios of the required active ingredients, and compressed into tablets. Based on the total weight of the active pharmaceutical ingredients in the tablet, the immediate release matrix contains 5wt% to 50wt% of the active pharmaceutical ingredients.

3. Double-layer sheet, multi-layer sheet or package chip

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release layer, and the sustained-release phase is a sustained-release layer; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The double-layer tablet, multi-layer tablet or coated chip of one of the huperzine A controlled-release preparations with biphasic drug release behavior of the present invention can realize the drug release behavior of the present invention in the following manner.

The double-layer tablet or coated chip of the huperzine A controlled-release preparation with biphasic drug release behavior includes an immediate-release matrix and a sustained-release matrix, which are respectively used as the immediate-release layer in the two layers of the double-layer tablet or coated chip and sustained-release layer; wherein the immediate-release matrix can be prepared by fully mixing the pharmaceutical active ingredient, diluent and other excipients or through wet granulation; wherein, based on the total weight of the immediate-release layer, the immediate-release matrix contains 0.005 ~4% by weight of pharmaceutical active ingredient, 50~98% by weight of diluent, and 1~46% by weight of other excipients.

The sustained-release matrix can be prepared by conventional methods well known to those skilled in the art such as wet granulation by active pharmaceutical ingredients, sustained-release matrix matrix, diluent and other auxiliary materials; based on the total weight of the sustained-release layer, the The sustained-release layer contains 0.01-5% by weight of active pharmaceutical ingredients, 2-50% by weight of sustained-release matrix matrix, 40-80% by weight of diluent, and 0.1-15% by weight of other auxiliary materials.

Finally, the immediate-release matrix and the sustained-release matrix are respectively added into the hopper of the tablet press, and compressed into a double-layer tablet or a core-packed tablet. Based on the total weight of the active pharmaceutical ingredients in the tablet, the immediate release matrix contains 5wt% to 50wt% of the active pharmaceutical ingredients.

The described huperzine A multi-layer tablet with biphasic drug release behavior comprises an immediate-release matrix, a sustained-release matrix and/or a blank matrix, and the immediate-release matrix or the sustained-release matrix can be divided into two layers, or can be added without A blank matrix layer containing active ingredients; finally, the immediate-release matrix and sustained-release matrix and/or blank matrix are respectively added into the hopper of the tablet press, and compressed into a multi-layer tablet.

4. Coated tablets

The coated tablet of one of the huperzine A controlled-release preparations with biphasic drug release behavior described in the present invention can realize the drug release behavior described in the present invention in the following manner.

(1) Osmotic pump tablet with immediate release coating layer

Osmotic pump controlled-release tablet is an oral controlled-release drug delivery system based on osmosis, and it is also a general technology for the preparation of sustained/controlled release preparations that is more commonly used so far. U.S. Patent Nos. 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 etc. describe these patents in detail by referring to the technology of osmotic pump control. Osmotic pump controlled-release preparations usually have the following advantages: ①Have preset drug release kinetic behavior characteristics; ②It is less affected by factors such as the pH value of the medium environment, gastrointestinal motility, and food, and has a good in vivo and in vitro correlation; ③Avoid large fluctuations in blood drug concentration caused by common oral preparations; ④Reduce the frequency of medication and improve patient compliance.

In the huperzine A controlled release preparation with biphasic drug release behavior of the present invention, the immediate release phase described in this embodiment is an immediate release layer, and the sustained release phase is an osmotic pump tablet; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The described osmotic pump tablet with an immediate-release coating layer is composed of an osmotic pump tablet and an immediate-release coating layer in terms of structural composition, and a moisture-proof coating layer can be added on this basis; The immediate-release coating layer forms an osmotic pump tablet with an immediate-release coating layer, and the osmotic pump controlled-release tablet can be a single-layer osmotic pump controlled-release tablet, a double-layer osmotic pump controlled-release tablet or a multilayer osmotic pump controlled-release tablet.

The single-layer osmotic pump controlled-release tablet is composed of a single-layer tablet core and a controlled-release film with drug release holes. The single-layer tablet core can be compressed by mixing the prescribed amount of pharmaceutical active ingredients, hydrophilic polymers, osmotic pressure enhancers and other auxiliary materials evenly and then granulating; adopting the suspension coating method well known to those skilled in the art, The tablet core is covered with a controlled-release film material; a laser punching machine is used to punch holes to form the single-layer osmotic pump controlled-release tablet.

In the single-layer osmotic pump controlled-release tablet, based on the total weight of the single-layer tablet core, the single-layer tablet core contains 0.005-5% by weight of active pharmaceutical ingredients, 25-85% by weight of hydrophilic polymer, 10-70% by weight of osmotic pressure enhancer, and 0.2-5% by weight of other auxiliary materials. Based on the total weight of the slow-release coating, the proportion of the porogen in the slow-release coating is 0-30% by weight. Based on the total weight of the single-layer osmotic pump controlled-release tablet, the weight gain of the controlled-release coating film is 3-30% by weight of the single-layer osmotic pump controlled-release tablet.

The double-layer osmotic pump controlled-release tablet comprises a tablet core composed of a drug-containing layer and a booster layer and a controlled-release film with drug-release holes in terms of structural composition. The preparation of the double-layer osmotic pump controlled-release tablet can be prepared by mixing the pharmaceutical active ingredient, hydrophilic polymer, osmotic pressure enhancer and other auxiliary materials uniformly, and then preparing drug-containing layer granules; After the pressure accelerator and other auxiliary materials are uniformly mixed, the booster layer granules are prepared; the drug-containing layer and the booster layer are respectively added to a double-layer tablet press, and the double-layer tablet core is compressed; a suspension coating well known to those skilled in the art is adopted According to the method, the controlled-release film material is coated on the core of the tablet; a laser punching machine is used to punch holes to form the double-layer osmotic pump controlled-release tablet.

In the double-layer osmotic pump controlled-release tablet, based on the total weight of the drug-containing layer, the drug-containing layer includes 0.005-3% by weight of active pharmaceutical ingredients, 70-99.5% by weight of hydrophilic polymer, and 0.2% by weight. ~30% by weight of other auxiliary materials; based on the total weight of the booster layer, the booster layer comprises 45-75% by weight of permeation-promoting polymers and 15-50% by weight of osmotic pressure enhancers, and 3-10% by weight other auxiliary materials; based on the total weight of the sustained-release coating, the proportion of the porogen in the sustained-release coating is 0 to 30% by weight. Based on the total weight of the double-layer osmotic pump controlled-release tablet, the weight gain of the sustained-release coating film is 3-30% by weight of the double-layer osmotic pump controlled-release tablet.

The immediate-release coating layer can be used to provide the immediate-release phase release in the biphasic drug release behavior of the present invention; the immediate-release coating layer includes pharmaceutical active ingredients, film coating materials, anti-sticking agents, diluents and other Accessories. The immediate-release coating layer can disperse or dissolve active pharmaceutical ingredients, film coating materials, anti-adhesive agents, diluents and other adjuvants in the coating layer by means of high-efficiency coating drug loading well known to those skilled in the art. In the coating solvent, it is loaded on the prepared osmotic pump tablet to form the described osmotic pump tablet with an immediate-release coating layer; wherein, based on the total weight of the immediate-release coating layer, the immediate-release coating layer contains 0.01 to 25 % by weight of pharmaceutical active ingredient, 10-70% by weight of film coating material, 1-30% by weight of anti-sticking agent, 0-70% by weight of diluent, and 0-10% by weight of other excipients.

The moisture barrier layer is optional. Its preparation method is the routine choice of those skilled in the art. As an example, the moisture-proof coating layer coating solution can be made by dissolving the moisture-proof coating layer composition in a suitable solvent, and then prepare according to the present invention. The huperzine A controlled-release preparation of drug release behavior is formed after coating and drying.

(2) Sustained-release tablets with an immediate-release coating layer

In the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention, the immediate-release phase described in this embodiment is an immediate-release layer, and the sustained-release phase is a sustained-release tablet; The total weight of the active ingredients, the immediate-release phase contains 5wt% to 50wt% of the active pharmaceutical ingredients; the total weight of the active pharmaceutical ingredients is 0.05mg to 4mg.

The sustained-release tablet with an immediate-release coating layer is structurally composed of a sustained-release tablet and an immediate-release coating layer; the sustained-release tablet can be used to provide sustained release in the biphasic drug release behavior of the present invention. phase release; the active ingredient of the drug, hydrophilic polymer, diluent and other excipients can be prepared by wet granulation through conventional methods well known to those skilled in the art and then compressed or mixed uniformly and then prepared by direct compression. Release tablets (sustained release phase). Based on the total weight of the sustained-release layer, the sustained-release layer contains 0.01-5% by weight of the pharmaceutical active ingredient, 2-50% by weight of the hydrophilic polymer, 40-80% by weight of the diluent, 0.1-15% by weight other accessories.

The immediate-release coating layer can be used to provide the immediate-release phase release in the biphasic drug release behavior of the present invention; the immediate-release coating layer includes pharmaceutical active ingredients, film coating materials, anti-sticking agents, diluents and other Accessories. The immediate-release coating layer can disperse or dissolve active pharmaceutical ingredients, film coating materials, anti-adhesive agents, diluents and other adjuvants in the coating layer by means of high-efficiency coating drug loading well known to those skilled in the art. In the coating solvent, it is loaded on the prepared osmotic pump tablet to form the described osmotic pump tablet with an immediate-release coating layer; wherein, based on the total weight of the immediate-release coating layer, the immediate-release coating layer contains 0.01 to 25 % by weight of pharmaceutical active ingredient, 10-70% by weight of film coating material, 1-30% by weight of anti-sticking agent, 0-70% by weight of diluent, and 0-10% by weight of other excipients.

Beneficial effect

Through the research on the physical and chemical properties, stability and biological properties of huperzine A, according to the needs of clinical treatment and the compliance of patients with medication, we fully consider the circadian rhythm of the level of cholinesterase in the brain of patients. Based on this, a kind of huperzine A controlled-release preparation with biphasic drug release behavior has been designed, which has the following advantages:

1. Compared with ordinary immediate-release preparations

① Long-term drug release can be achieved, the drug effect is long-lasting, and the fluctuation of blood drug concentration is small, which reduces the adverse reactions of patients;

② It can increase the dosage of a single administration, reduce the cumbersome process of dose adjustment in the process of administering common preparations, and make it more convenient for clinical administration;

③Slight gastrointestinal irritation and good patient compliance;

2. Compared with ordinary sustained-release preparations

① It has a biphasic drug release behavior, which better conforms to the circadian rhythm of the cholinesterase level in the brain, and can be released continuously in the required physiological cycle (daytime), improving the memory, cognition and behavior functions of patients, while in the At night when the activity level is low, the plasma drug concentration can be adjusted accordingly to reduce the occurrence of drug resistance;

②The design of the quick-release phase ensures that the drug can take effect quickly after taking it and reach the therapeutic concentration; adverse reactions caused by;

③It only needs to be taken once a day, which is more suitable for long-term medication of moderate and severe Alzheimer's patients;

Visible, the beneficial effect of this preparation is based on the advantage of the drug release behavior of the huperzine A controlled-release preparation with biphasic drug release behavior of the present invention embodies, specifically as follows:

(1) It has a biphasic drug release behavior, and the change of blood drug concentration matches the level of cholinesterase in the body. The design of the immediate release phase can ensure that the drug takes effect quickly after taking it; the design of the slow release phase can make the drug Sustained release during the desired menstrual cycle (daytime), improving memory, cognition, and behavioral function in patients, while plasma drug concentrations can be adjusted accordingly at night when activity levels are lower;

(2) The dose can be increased, eliminating the cumbersome process of dose adjustment, and it only needs to be taken once a day, with little gastrointestinal irritation and good patient compliance;

(3) The blood concentration is more stable, the adverse reactions are less, the medication is safer, and it is more suitable for long-term medication of moderate and severe Alzheimer's patients.

Additional objectives, advantages and novel features of the present invention will become apparent to those skilled in the art through the following description of the embodiments in conjunction with the accompanying drawings, or be understood through the practice of the present invention.

Description of drawings

Fig. 1 is the capsule schematic diagram that contains immediate-release pill and sustained-release pill;

Figure 2 is a schematic diagram of a capsule prepared from several sustained-release granules containing an immediate-release coating layer;

Figure 3 is a schematic diagram of capsules containing immediate-release tablets and sustained-release tablets;

Fig. 4 is the tablet schematic diagram that is made up of immediate-release matrix and sustained-release pill;

Fig. 5 is a schematic diagram of huperzine A double-layer tablet or package chip with biphasic drug release behavior;

Fig. 6 is the schematic diagram of the huperzine A controlled-release coated tablet with biphasic drug release behavior;

Fig. 7 is the drug release curve in vitro of the huperzine A controlled release tablet with biphasic drug release behavior;

Fig. 8 is the blood drug concentration curve in Beagle dogs of huperzine A capsule and biphasic drug release huperzine A preparation;

Figure 9 shows the inhibitory effect of different huperzine A preparations on erythrocyte cholinesterase in Beagle dogs.

Detailed ways

The following examples generally describe exemplary formulations of the invention and methods for their preparation, and all percentages are by weight unless otherwise indicated. The following examples are specific illustrations of the present invention, but should not be considered as limiting the scope of the present invention.

Example 1: Capsules Containing Immediate-Release Pills and Sustained-Release Pills

①Quick-release pills

②Sustained-release pills

Ⅰ) Drug-loaded pellet core

Ⅱ) Pack slow-release coat

The preparation method is as follows:

Immediate-release pills: dissolve or disperse huperzine A, lactose, and hypromellose E5 in an aqueous solution to prepare a drug-loading solution, and spray into the prescribed amount of microcrystalline cellulose by fluidized bed coating On the pellet core, as an immediate release pellet.

Sustained-release pills: First, dissolve or disperse huperzine A, lactose, and hypromellose E5 in an aqueous solution to prepare a drug-loading solution, and spray the prescription amount of microcrystalline On the cellulose pellet core, as the drug-loaded pellet core; dissolve ethyl cellulose and polyethylene glycol 4000 in appropriate amount of ethanol and water, mix well, and use it as a slow-release film coating solution, which is coated with a fluidized bed By way of injection into the drug-loaded pill core to make sustained-release pills.

Capsule filling: The quick-release pills and sustained-release pills prepared above are fully mixed according to the prescription amount, and then filled into capsules.

Release Determination

According to the release assay method (Chinese Pharmacopoeia 2005 edition two appendix X D first method), adopt the dissolution assay method (Chinese Pharmacopoeia 2005 edition two appendix X C second method) device to measure according to the preparation of the present invention has biphasic release The drug release characteristics of the huperzine A controlled-release preparation of drug behavior, the specific steps are as follows:

Take this product, use 500ml of 0.1mol/L hydrochloric acid solution as the release medium, the speed is 50 rpm, operate according to the law, after 0.5h, 2h, 4h, 6h, 8h, 12h, take 5ml of the solution, centrifuge (8000rpm, 15min ), and at the same time replenish the release medium at the same temperature and volume, and take the supernatant as the test solution.

Another appropriate amount of huperzine A reference substance was taken, accurately weighed, dissolved in a dissolution medium and quantitatively diluted to make a solution containing about 0.4 μg of huperzine A per 1 ml, and determined by the same method.

The drug released at each time point was determined by high performance liquid chromatography, using octadecylsilane-bonded silica gel as a filler, using isocratic elution, and using methanol-ammonium acetate buffer (45:55) as mobile phase , detection wavelength 310nm. Precisely measure 20 μl of each of the above-mentioned reference substance and the test solution, inject it into the liquid chromatograph, record the peak area, and calculate the cumulative release amount of each tablet at different times according to the peak area by the external standard method.

The release curve is shown in Figure 7.

Example 2: Capsules prepared from sustained-release granules containing an immediate-release coating layer

①Drug-loaded pill core

② Pack slow-release clothing

③ Pack quick-release clothing

The preparation method is as follows:

Drug loading: First, dissolve or disperse huperzine A, lactose, and hypromellose E5 in an aqueous solution to prepare a drug-loading solution, and spray it into the prescribed amount of sucrose pellet core by fluidized bed coating On, as a drug-loaded pill core;

Slow-release coating: Dissolve ethyl cellulose and polyethylene glycol 4000 in appropriate amount of ethanol and water respectively, mix well, and use fluidized bed coating method to spray into the carrier On the core of the pill, it is made into a slow-release pill.

Immediate-release coating: disperse huperzine A, hydroxypropyl cellulose SSL, lactose, and talc in 50% ethanol solution, mix well, and use fluidized bed coating as an immediate-release coating solution , sprayed onto the sustained-release pellets to make sustained-release granules with an immediate-release coating layer.

Capsule filling: the above prepared sustained-release granules containing the immediate-release coating layer are filled into capsules according to the prescription amount.

The release curve is shown in Figure 7.

Example 3: Capsules containing immediate-release tablets and sustained-release tablets

① Immediate-release tablets

②Sustained-release tablets

The preparation method is as follows:

Immediate-release tablets: Mix huperzine A, pregelatinized starch, and microcrystalline cellulose uniformly by equal volume addition method, then add to fluidized bed; spray 10% povidone K30 aqueous solution to granulate; dry to moisture content Less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix evenly, and use it as an immediate-release matrix for huperzine A; according to the prescription amount, press it into an immediate-release tablet with suitable hardness.

Sustained-release tablets: Mix huperzine A, lactose, and polyoxyethylene WSR301 uniformly by equal volume addition method, then add to the fluidized bed; spray 10% povidone K30 aqueous solution to granulate; dry until the moisture content is less than 3% , pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and use it as a sustained-release matrix for huperzine A; according to the prescription amount, press it into sustained-release tablets with suitable hardness.

Capsule filling: The quick-release tablets and sustained-release tablets prepared above are filled in capsules according to the prescription amount and combination.

The release curve is shown in Figure 7.

Example 4: Tablet consisting of immediate release matrix and sustained release pellets

① Immediate release matrix

②Sustained-release pills

Ⅰ) Drug-loaded pellet core

Ⅱ) Pack slow-release coat

The preparation method is as follows:

Immediate-release matrix: mix huperzine A, mannitol, and microcrystalline cellulose uniformly by an equal-volume incremental method, then add to the fluidized bed; spray 10% povidone K30 aqueous solution to granulate; dry until the water content is less than 3 %, through a 20-mesh sieve, granulated, then added with magnesium stearate, mixed evenly, as a huperzine A quick-release matrix.

Sustained-release pills: first, dissolve or disperse huperzine A, lactose, and hypromellose E5 in an aqueous solution to prepare a drug-loading solution, and spray into the prescribed amount of sucrose pills by fluidized bed coating On the core, as the drug-loaded pill core; disperse the acrylic resin Eudragit RL100, triethyl citrate, and talcum powder in an appropriate amount of ethanol solution, mix well, and use it as a sustained-release film coating solution, which is coated by a fluidized bed By way of injection into the drug-loaded pill core to make sustained-release pills.

Tablet compression: mix the prepared immediate-release matrix and sustained-release pills according to the prescription quantity, and compress them into tablets with suitable hardness.

The release curve is shown in Figure 7.

Example 5: Tablet consisting of an immediate release matrix and a sustained release matrix

① Immediate release matrix

②Sustained-release matrix

The preparation method is as follows:

Immediate-release matrix: mix huperzine A, mannitol, and microcrystalline cellulose uniformly by an equal-volume incremental method, then add to the fluidized bed; spray 10% povidone K30 aqueous solution to granulate; dry until the water content is less than 3 %, through a 20-mesh sieve, granulated, then added with magnesium stearate, mixed evenly, as a huperzine A quick-release matrix.

Sustained-release matrix: Mix huperzine A, lactose, hydroxypropyl cellulose, and glyceryl monostearate uniformly by equal volume addition method, then add to fluidized bed; spray into 10% Eudrgit RL100 ethanol solution to granulate; dry When the water content is less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and use it as a huperzine A sustained-release matrix.

Tablet compression: Mix the prepared immediate-release matrix and sustained-release matrix granules according to the prescription quantity, and press them into tablets with suitable hardness.

The release curve is shown in Figure 7.

Example 6: Double-layer tablet or chip-pack consisting of immediate-release matrix and sustained-release matrix

① Immediate release matrix

②Sustained-release matrix

The preparation method is as follows:

Immediate-release matrix: Mix huperzine A, lactose, and microcrystalline cellulose uniformly by equal volume addition method, then add to fluidized bed; spray into 10% povidone K30 aqueous solution to granulate; dry until the moisture content is less than 3% , pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and use it as an immediate-release base for huperzine A.

Sustained-release matrix: mix huperzine A, lactose, hypromellose K100M, and polyoxyethylene N750 uniformly by equal volume addition method, then add to fluidized bed; spray 10% povidone K30 aqueous solution to granulate; Dry until the water content is less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and use it as a huperzine A sustained-release matrix.

Tablet compression: Press the above prepared immediate-release matrix and sustained-release matrix granules according to the prescription amount, using a double-layer tablet press machine to form double-layer tablets or coated chips with suitable hardness.

The release curve is shown in Figure 7.

Example 7: Coated tablet composed of double-layer osmotic pump tablet and immediate-release coating layer

① Drug-containing layer

②Promotion layer

③Semi-permeable membrane

④ Pack quick-release clothing

⑤ Moisture-proof coating film

The preparation method is as follows:

Preparation of the drug-containing layer: mix huperzine A, copovidone S630, and iron oxide yellow uniformly by an equal-volume incremental method, then add to the fluidized bed; spray 95% ethanol-water solution to granulate; dry to the moisture content Less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and set aside;

Preparation of the propulsion layer: Mix sodium carboxymethyl starch, hydroxypropyl methylcellulose K15M, sodium chloride, copovidone S630 and iron oxide red evenly, add to the fluidized bed, and spray 95% ethanol- Aqueous solution granulation; drying until the moisture content is less than 3%, passing through a 20-mesh sieve, granulating, and then adding magnesium stearate, mixing, and setting aside;

Compression of double-layer tablet: Press the above-mentioned prepared drug-containing layer and push layer granules according to the prescription amount, using a double-layer tablet press machine to form a double-layer tablet core with suitable hardness;

Coating controlled release coating: dissolving cellulose acetate in acetone solution, dissolving polyethylene glycol 4000 in aqueous solution, and mixing the two solutions to prepare a semi-permeable membrane coating solution; In the high-efficiency coating pan, the semi-permeable membrane coating solution is used for coating; the coated product is dried at 45°C for 12 hours to remove excess organic solvent and water;

Punching of coated tablets: A drug release hole with a diameter of 0.9mm is punched on the surface of the drug-containing layer of the tablet by laser drilling;

Immediate-release coating: Prepare an immediate-release coating coating solution according to the prescription of the immediate-release coating, and coat the perforated osmotic pump tablet with an immediate-release coating; dry the coated product at 45°C for 12 hours to remove excess organic solvents and moisture;

Moisture-proof coating: Dissolve and disperse Opadry coating powder in water to prepare a moisture-proof coating solution; then coat the perforated controlled-release tablets with a moisture-proof coating solution; dry at 45°C for 12 Hours, that's it.

The release curve is shown in Figure 7.

Example 7: A coated tablet composed of a single-layer osmotic pump tablet and an immediate-release coating layer

① Chip core

②Semipermeable membrane

③ Pack quick-release clothing

④ Moisture-proof coating film

The preparation method is as follows:

Preparation of tablet cores: Mix huperzine A, povidone K30, sodium chloride, and iron oxide yellow uniformly by equal volume addition method, then add to fluidized bed; spray 95% ethanol-water solution to granulate; dry When the moisture content is less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and set aside;

Tablet compression: Press the above-prepared drug-containing layer granules into a tablet core with suitable hardness according to the prescription amount;

Controlled-release coating: Dissolve cellulose acetate in acetone solution, dissolve polyethylene glycol 4000 in aqueous solution, and mix the two solutions to prepare a semi-permeable membrane coating solution; put the compressed tablet core in a high-efficiency coating pan In the process, the semi-permeable membrane coating solution is used for coating; the coated product is dried at 45°C for 12 hours to remove excess organic solvent and water;

Punching of coated tablets: A drug release hole with a diameter of 0.8mm is punched in the core of the tablet by laser drilling;

Immediate-release coating: Prepare an immediate-release coating coating solution according to the prescription of the immediate-release coating, and coat the perforated osmotic pump tablet with an immediate-release coating; dry the coated product at 45°C for 12 hours to remove excess organic solvents and moisture;

Moisture-proof coating: Dissolve and disperse Opadry coating powder in water to prepare a moisture-proof coating solution; then coat the perforated controlled-release tablets with a moisture-proof coating solution; dry at 45°C for 12 Hours, that's it.

The release curve is shown in Figure 7.

Example 9: Coated tablet composed of sustained-release tablet and immediate-release coating layer

③Preparation of sustained-release tablets

④ Immediate release coating

The preparation method is as follows:

Preparation of Huperzine A Sustained-release Tablets: After mixing Huperzine A, lactose, hypromellose K4M, and copovidone S630 uniformly by equal addition method, add to fluidized bed; spray into 95% ethanol -Aqueous solution granulation; dry until the moisture content is less than 3%, pass through a 20-mesh sieve, granulate, then add magnesium stearate, mix well, and then compress into a sustained-release tablet core with suitable hardness;

Immediate-release coating: Prepare an immediate-release coating coating solution according to the immediate-release coating prescription, put the above-mentioned sustained-release tablets in a high-efficiency coating pan for immediate-release coating; dry at 45°C for 12 hours to remove excess organic solvents and water ;

The release curve is shown in Figure 7.

Example 10:

Six healthy Beagle (Beagle) dogs were randomly divided into two groups, 3 dogs in each group, for a single-dose, double-period, crossover self-controlled test, fasting for 12 hours, and free access to water. 3 Beagle dogs of the first group give reference preparation (common capsule, 0.2mg/ grain/only); , 0.2mg/tablet/only). After a one-week washout period, the second test was carried out, and 1.5ml of forelimb venous blood was collected from each Beagle dog before taking the medicine (0h), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24h after taking the medicine. , and immediately transfer it to a heparin-coated centrifuge tube, centrifuge (3000rpm, 5min), separate the plasma, and store it frozen at -20°C. Pay attention to observation, and record the adverse reactions of each dog during the test.

The plasma concentration of huperzine A in Beagle dogs was determined by LC/MS/MS, and the results are shown in FIG. 8 .

Visible by the blood drug concentration-time curve in the Beagle dog body of Fig. 8, with respect to common capsule, the blood drug concentration of huperzine A controlled-release tablet is stable, and fluctuation is less; The onset of the drug reaches the therapeutic concentration; the design of the slow-release phase ensures the smooth release of the active ingredient in the later stage and reduces the adverse reactions caused by the high blood concentration.

Example 11

12 healthy Beagle dogs, male, were randomly divided into four groups, 3 dogs in each group; the effect of taking different huperzine A preparations on erythrocyte cholinesterase in Beagle dogs was determined, and the time course of the drug effects of different preparations was observed. The specific groups are as follows:

The first group was given commercially available huperzine A preparation (Shuangyiping, 0.05mg/tablet, 4 tablets/piece);

The second group was given Huperzine A Capsules (0.2mg/capsule/capsule);

The third group was given huperzine A sustained double-release controlled-release tablets (prescription in Example 7, 0.2mg/tablet/piece);

The fourth group was given huperzine A solution (0.2 mg/rat).

Beagle dogs were fasted for 12 hours before administration and had free access to water. Each Beagle dog collected 1.5ml of forelimb venous blood before taking the medicine (0h), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours after taking the medicine, which was used for red blood cells to carry out choline Determination of esterase activity (results shown in Figure 9). At the same time, observe the symptoms (including secretions, muscle tremors, vomiting and ataxia, etc.) of Beagle dogs given different huperzine A preparations.

As can be seen from the Beagle canine erythrocyte cholinesterase activity assay results of Figure 9, compared to the other three preparations, the huperzine A sustained double-release controlled-release tablet prepared by the present invention not only has a rapid onset of effect, but also has a long-lasting drug effect and has a bile The inhibitory activity of alkaline esterase lasted more than 12 hours; compared with the other three preparations, Beagle dogs taking huperzine A sustained double-release controlled-release tablets basically had no obvious adverse reactions.

Claims (11)

1. A huperzine A controlled-release preparation with biphasic drug release behavior, characterized in that: according to the requirements of the Chinese Pharmacopoeia release assay method, within a predetermined period of time, in the release medium meeting the sink condition, The huperzine A controlled-release preparation is distributed according to two-phase release, wherein the first phase is an immediate-release phase, and the second phase is a sustained-release phase; wherein, based on the total weight of the pharmaceutically active ingredients in the preparation, the immediate-release phase Containing 5wt%-50wt% of active pharmaceutical ingredients, wherein the active pharmaceutical ingredients are huperzine A and its derivatives or salts thereof. 2. The huperzine A controlled-release preparation according to claim 1, characterized in that: the quick-release phase comprises active pharmaceutical ingredients, diluents and other adjuvants; the sustained-release phase comprises active pharmaceutical ingredients, sustained-release matrix Bases, diluents and other excipients. 3. the huperzine A controlled-release preparation according to claim 1, is characterized in that: the quick-release phase comprises pharmaceutical active ingredient, film coating material, anti-sticking agent, diluent and other auxiliary materials; The phase contains pharmaceutically active ingredients, hydrophilic polymers, osmotic pressure enhancers and other excipients. 4. the huperzine A controlled-release preparation according to claim 1, is characterized in that: the quick-release phase comprises pharmaceutically active ingredients, film coating material, anti-adhesive agent, diluent and other adjuvants; The phase contains pharmaceutically active ingredients, hydrophilic polymers, osmotic pressure enhancers, osmotic enhancing polymers and other excipients. 5. the huperzine A controlled-release preparation according to claim 1, is characterized in that: the quick-release phase comprises pharmaceutically active ingredients, film coating material, anti-tacking agent, diluent and other adjuvants; The phase contains pharmaceutically active ingredients, hydrophilic polymers, diluents and other excipients. 6. according to the huperzine A controlled-release preparation described in any one of claim 2-5, it is characterized in that: The diluent is selected from one or more of microcrystalline cellulose, lactose, sucrose, mannitol, sorbitol, starch, sodium carboxymethyl starch, and pregelatinized starch; The other auxiliary materials include one or more of lubricants, colorants, binders, porogens, and plasticizers; The sustained-release matrix matrix is selected from one or more of acrylic resin, ethyl cellulose, cellulose acetate, and glyceryl monostearate; The film coating material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, povidone, copovidone kind; Described anti-sticking agent is selected from one or more in talcum powder, magnesium stearate, glyceryl monostearate; The hydrophilic polymer is selected from povidone, copovidone, polyoxyethylene, carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium alginate, One or more of xanthan gum, gum arabic, and chitin; The osmotic pressure enhancer is one or more selected from sodium chloride, potassium chloride, lactose, mannitol, sorbitol, glucose, sucrose, and fructose; The permeation-promoting polymer is selected from polyoxyethylene, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, povidone one or more of. 7. The huperzine A controlled-release preparation according to any one of claims 1-5, characterized in that: the quick-release phase releases more than 90wt% of its active pharmaceutical ingredients within 30 minutes; the sustained-release phase More than 90wt% of its pharmaceutical active ingredients are released within 5-15 hours. 8. The huperzine A controlled-release preparation according to any one of claims 1-5, characterized in that: the huperzine A controlled-release preparation contains 0.05 mg to 4 mg of active pharmaceutical ingredients. 9. according to any one of claim 1-5 described huperzine A controlled release preparation, it is characterized in that: described quick-release phase is the quick-release matrix in quick-release tablet, quick-release pill, tablet, package The immediate-release coating layer outside the tablet or pellet core, the immediate-release layer matrix combined into the double-layer tablet, or their combination; the sustained-release phase is the sustained-release tablet, sustained-release pill, and sustained release matrix, a sustained release carrier in a tablet or sphere core, a sustained release layer matrix incorporated into a bilayer tablet, or a combination thereof. 10. according to the described huperzine A controlled release preparation in any one of claim 1-5, it is characterized in that: described huperzine A controlled release preparation is capsule, tablet, bilayer tablet, multilayer tablet , coated tablets or their combination. 11. huperzine A controlled-release preparation according to claim 10, is characterized in that: described huperzine A controlled-release preparation is the capsule that contains quick-release pill and sustained-release pill, contains the slow-release coating layer of quick release. Capsules prepared by releasing granules, capsules containing immediate-release tablets and sustained-release tablets, tablets consisting of immediate-release matrix and sustained-release pellets, tablets consisting of immediate-release matrix and sustained-release matrix, consisting of immediate-release matrix and Double-layer tablets or core-coated tablets composed of sustained-release matrix, multi-layer tablets composed of immediate-release matrix, sustained-release matrix and blank matrix, coated tablets composed of single-layer osmotic pump controlled-release tablets and immediate-release coating layer, composed of A coated tablet composed of a double-layer osmotic pump controlled-release tablet and an immediate-release coating layer, or a coated tablet composed of a sustained-release tablet and an immediate-release coating layer.

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