CN110251473B - Oral slow-release preparation of oxypiperone - Google Patents

Abstract

The invention discloses an oral sustained-release preparation of oxypeperisone, which comprises the following components: hydroxypyrazine or a pharmaceutically acceptable salt thereof; one or more pharmaceutically acceptable excipients; contains at least one polymer with slow-release function. The invention selects medicinal high molecular material as slow release material, the in vitro release degree test result shows that the provided oxypiperone slow release tablet gradually releases the medicament within 8-24 hours, thereby reducing the peak valley phenomenon of medicament absorption and maintaining the blood concentration required by treatment, and compared with the common tablet, the invention can achieve the purposes of reducing the taking times, having lasting effect and convenient taking, and is more beneficial to the treatment of diseases.

Description

Oral slow-release preparation of oxypiperone

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an oral sustained-release preparation of hydroxypiperidone.

Background

Depression is a syndrome with persistent depressed mood, loss of interest, thought retardation, etc. as main clinical features caused by various reasons, and seriously harms human physical and mental health due to its high incidence, high suicide, high recurrence, high disability rate, and low recognition, low diagnosis, low treatment rate, etc. With the continuous acceleration of the pace of life, the mental pressure of people is gradually increased, depression becomes a common disease and a frequently encountered disease in modern society, and the incidence rate of depression is rising year by year.

Currently, drug therapy is one of the major means for the treatment of depression. Clinically common antidepressant drugs, including 5-HT reuptake inhibitors (SSRIs, such as fluoxetine), 5-HT/NE dual reuptake inhibitors (SNRIs, such as duloxetine) and the like have the serious defects of delayed onset (2-6 weeks), obvious toxic and side effects, low effective rate (50-70%), sexual dysfunction, suicide tendency and the like. The usual antidepressants (e.g. 5-HT reuptake inhibitors) increase the level of 5-HT in the synaptic cleft within hours, but simultaneously activate the presynaptic membrane 5-HT_1AThe autoreceptor generates negative feedback inhibition effect, and reduces synthesis and release of 5-HT. 5-HT 2-4 weeks after administration_1ADesensitizing the autoreceptors to produce an antidepressant effect, 5-HT_1AThe negative feedback inhibition caused by the activation of the autoreceptors is considered to play a key role in delaying the onset of antidepressant drugs. Reported, 5-HT_1AReceptor agonists are also capable of causing neuronal presynaptic membrane 5-HT_1AAuto-receptor desensitization, and antidepressant action, delayed onset of action of about 3-7 weeks. It has been shown that 5-HT reuptake inhibitors and 5-HT_1AThe combined application of the receptor partial agonist can enhance the antidepressant effect of the 5-HT reuptake inhibitor and shorten the onset time. It is possible that the two drugs act synergistically to induce presynaptic membrane 5-HT_1AAutoreceptor desensitization, while enhancing postsynaptic membrane nerve conduction function. The compounds have rapid onset of action and may be more potent than 5-HT reuptake inhibitors or 5-HT inhibitors alone_1AThe receptor agonist is stronger. Thus, there is a combination of 5-HT reuptake inhibition and 5-HT_1AThe receptor-excited double-target active drug becomes a representative direction for the research of novel characteristic antidepressant drugs.

5-HT based on an "optimized monoamine strategy" in recent years_1AReceptor partial agonism and selective 5-HT reuptake inhibition targetsThe marked antidepressants (serotonin partial agonist and reuptake inhibitors, SPARIs) have become the representative direction of novel drugs due to the characteristics of strong effect, quick action, potential low suicide tendency and the like, and the advantage of low incidence of adverse reactions (including sexual dysfunction, weight gain and the like). SPARIs-specific acceleration of presynaptic Membrane 5-HT_1ADesensitizing the autoreceptor to achieve the purposes of accelerating the effect, enhancing the curative effect and reducing the toxicity. The FDA approved a novel antidepressant drug Vilazodone (Vilazodane, Viibryd) in 2011^TM) Is commercially available and used for treating depression. The medicine has ideal antidepressant effect, and has the advantages of high safety, fast acting (1 week acting), high efficiency, less side effect, etc. The chemical structure of the oxypipexolone is completely new (non-me-to and me-beter structures), is completely different from the structural formula of the vilazodone, has simpler structure and similar action mechanism to the vilazodone, and is an innovative medicine of the chemical 1.1 class.

The hydroxypiperone is a new antidepressant drug, and has 5-hydroxytryptamine 1A (5-HT)_1A) The active compound with double targets of receptor agonism and 5-HT reuptake inhibition (SSRI) has the characteristics of definite anti-depression and anti-anxiety effects, cognitive promoting activity, strong effect, quick response, low suicide tendency, low adverse reaction incidence and the like, and can be used for preventing or treating depression, anxiety, cognitive deficiency, mania, schizophrenia, pain, various mental stress, sleep disorder and the like.

The chemical name of the oxypipexolone is 1- [ (4-hydroxypiperidin-4 yl) methyl ] pyridine-2 (1H) -ketone, and the structural formula is shown as the following formula:

since the half-life of oxypipexolone in humans is only 3 to 4 hours, the frequency of administration of immediate release formulations of the drug is designed to be 2 to 3 times a day. The patient takes the medicine orally more times every day, the taking is troublesome, the missing taking and the interval time of taking the medicine at night are easy to appear, the effective blood concentration can not be maintained, the continuous treatment effect can not be exerted, and the blind area in treatment can appear.

Disclosure of Invention

The invention aims to provide an oral sustained-release preparation of hydroxypyrazine, which prolongs the action time of the medicine in vivo, reduces the medicine taking times, reduces the side effect of the medicine and improves the long-term medication compliance of patients.

The novel, convenient and effective oral drug release system with long action cycle provided by the invention can continuously, stably and quantitatively release drugs in a longer time range, and can avoid the generation of the adverse factors. The invention ensures that the patient only needs to take the medicine once every day, thereby improving the compliance of the patient and further achieving better treatment effect.

The technical scheme provided by the invention is as follows:

an oral sustained release formulation of hydroxypyrazine, comprising:

hydroxypyrazine or a pharmaceutically acceptable salt thereof;

one or more pharmaceutically acceptable excipients;

contains at least one polymer with slow-release function.

Preferably, the oral sustained-release preparation further comprises a barrier layer, wherein the barrier layer is prepared from the following components in percentage by weight:

preferably, the sustained release formulation exhibits an in vitro release rate of oxycodone of not more than 40% at the 1 hour time point and of not more than 80% at the 6 hour time point. The detection conditions of the in vitro release rate of the oxypiperone are as follows:

adopts Chinese pharmacopoeia II method, rotating speed 50 turns, and 1000ml deionized water is used as solvent.

Preferably, the dosage form is a sustained release tablet, and a drug layer of the sustained release tablet is prepared from the following components in percentage by weight:

5-20% of the hydroxypyrapone or the pharmaceutically acceptable salt thereof, 5-70% of the framework material, and the balance of the pharmaceutically acceptable excipient to 100%.

Preferably, the sustained release tablet further comprises a barrier layer, wherein the barrier layer is prepared from the following components in percentage by weight:

20-70% of the framework material, and the rest of the framework material is complemented to 100% by the medicinal excipient.

Preferably, the sustained-release tablet is a single-layer framework sustained-release tablet consisting of only a drug layer,

or the like, or, alternatively,

the sustained-release tablet is a multi-layer skeleton sustained-release tablet containing a drug layer and a barrier layer.

Preferably, the unit dosage form of the sustained release tablet comprises 5mg to 50mg of the oxypiperazine, and further preferably, the unit dosage form of the sustained release tablet is 10mg to 40 mg.

Preferably, the drug layer and the barrier layer comprise a matrix material comprising:

one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and sodium salt thereof, sodium alginate, methyl cellulose, ethyl cellulose, polyacrylic resins, polyvinyl acetate, carbomer, polyoxyethylene, stearic acid, glyceryl behenate, glyceryl monostearate, hydrogenated castor oil, beeswax, paraffin, white wax, carnauba wax, microcrystalline wax and octadecanol.

Further, preferably, the drug layer comprises a framework material comprising: a combination of hydroxypropyl methylcellulose and sodium carboxymethylcellulose or a combination of hydroxypropyl methylcellulose, sodium carboxymethylcellulose and glyceryl behenate.

Preferably, the pharmaceutically acceptable excipients of the sustained release tablet include:

fillers, binders, glidants and lubricants.

Further, preferably, the filler includes: one or more of starch, lactose, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, starch lactose mixture, and mannitol starch mixture.

The adhesive comprises: one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose and hydroxypropyl methylcellulose.

The glidant comprises: one or the combination of two of micropowder silica gel and talcum powder.

The lubricant comprises: one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearate fumarate, stearic acid and polyethylene glycol.

The invention also provides a preparation method of the sustained-release tablet of the oxypiperazine, which comprises the following steps:

(1) medicine layer: putting the oxypiperone and other components (except the lubricant) of the drug layer into a wet granulator, uniformly mixing, adding the adhesive in the amount of the prescription, uniformly mixing, sieving, preparing wet granules, drying, granulating, adding the lubricant in the amount of the prescription, and uniformly mixing;

(2) barrier layer: putting all the components (except the lubricant) into a wet granulator, uniformly mixing, adding a prescribed amount of adhesive, uniformly mixing, sieving, preparing wet granules, drying, finishing granules, adding a prescribed amount of lubricant, and uniformly mixing;

(3) pressing the medicine layer particles prepared in the above steps into a single layer tablet to obtain a single layer skeleton sustained release tablet; or pressing the medicine layer particles and the barrier layer particles prepared in the above steps together into a double-layer tablet or a three-layer tablet (the medicine layer is the middle layer), and obtaining the double-layer skeleton sustained release tablet or the three-layer skeleton sustained release tablet.

Preferably, the dosage form of the oral sustained-release preparation of oxypiperone further comprises: a sustained release pellet comprising:

a drug-containing pellet core comprising hydroxypyrazine or a pharmaceutically acceptable salt thereof and a sustained-release coating layer comprising a coating material.

Preferably, the coating material is one of acrylic resin, polyvinyl acetate or ethyl cellulose.

In the technical scheme, the sustained-release pellet is prepared by coating a sustained-release coating film on a drug-containing quick-release pellet core, wherein the drug-containing pellet core is composed of hydroxypyrapone or a pharmaceutically acceptable salt thereof and auxiliary materials, and the auxiliary materials comprise: blank pellet cores (such as sucrose pellet cores, microcrystalline cellulose pellet cores and the like), binders (such as povidone, HPMC and the like), antisticking agents (such as talcum powder, titanium dioxide and the like) and other auxiliary materials.

The coating material comprises a slow release material and other auxiliary materials;

the slow release material is one of acrylic resin, polyvinyl acetate or ethyl cellulose.

Preferably, the dosage form is an osmotic pump tablet comprising:

a tablet core comprising hydroxypipropidone or a pharmaceutically acceptable salt thereof and a semipermeable membrane coating comprising a coating material.

Preferably, the semi-permeable membrane coating comprises:

water insoluble polymers and water soluble polymers.

Preferably, the core of the osmotic pump tablet further comprises:

penetration enhancer, swelling agent.

In the technical scheme, the osmotic pump tablet is prepared by wrapping a semipermeable membrane with a medicine-containing tablet core, wherein the medicine-containing tablet core comprises the oxypiperazine or a pharmaceutically acceptable salt thereof and auxiliary materials;

the auxiliary materials comprise: penetration enhancer (such as sorbitol, mannitol, lactose, etc.), bulking agent (such as polyoxyethylene, hydroxyethyl cellulose, crospovidone, croscarmellose sodium, etc.), and other adjuvants.

The semipermeable membrane coating material comprises a slow release material and other auxiliary materials;

the sustained-release material includes a water-insoluble polymer (e.g., cellulose acetate) and a water-soluble polymer (e.g., polyethylene glycol, hydroxypropyl cellulose).

The preparation method of the sustained-release tablet can be dry granulation, wet granulation, fusion granulation or direct tabletting. The preparation method of the quick-release pill core containing the medicine can be hot-melt extrusion, extrusion rounding or fluidized bed coating medicine application. The preparation process of the semipermeable membrane coated with the drug-containing tablet core can be coating by a coating pan or fluidized bed.

The oral sustained-release preparation of the hydroxypiperidone provided by the invention can bring the following beneficial effects:

1. the invention provides an oral slow-release preparation of oxypeperisone, which prolongs the action time, reduces the times of taking medicine, reduces the side effect of the medicine and improves the medication compliance of patients.

2. The invention selects medicinal high molecular material as slow release material, the in vitro release degree test result shows that the provided oxypiperone slow release tablet gradually releases the medicament within 8-24 hours, thereby reducing the peak valley phenomenon of medicament absorption and maintaining the blood concentration required by treatment, and compared with the common quick release tablet, the invention can achieve the purposes of reducing the taking times, having lasting effect and convenient taking, and is more beneficial to the treatment of diseases.

3. The slow release materials of the hydroxypyrazine slow release tablet are hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose or the combination of hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and glyceryl behenate, which can meet the requirement of approaching zero-order release rate and achieve ideal slow release effect.

4. The hydroxypyrazine sustained-release tablet can be realized by a single-layer framework sustained-release tablet, and the surface area of the drug-containing layer contacting with the outside can be reduced by adding one barrier layer or two barrier layers on the basis of the single-layer framework sustained-release tablet, so that zero-order or near zero-order release is achieved. Wherein, the drug layer consists of the oxypeperisone, the slow release material and other accessories, and the barrier layer consists of the slow release material and other accessories.

5. The invention also provides other sustained-release formulations of the hydroxypipropyrrolone, including sustained-release pellets and osmotic pump tablets, which can meet the sustained-release effect.

Drawings

The above features, technical features, advantages and modes of realisation of the present invention will be further described in the following detailed description of preferred embodiments thereof, which is to be read in connection with the accompanying drawings.

Fig. 1 is a graph showing the release rate of the sustained-release tablet having a single-layered structure according to example 1 of the present invention.

Fig. 2 is a graph showing the release rate of the sustained-release tablet having a double-layered structure according to example 2 of the present invention.

FIG. 3 is a graph of the release rate of the tri-layer matrix sustained release tablets of different amounts of HPMC K100M in example 3 of the present invention.

Fig. 4 is a graph of the release rate of sustained release pellets in example 4 of the present invention.

Fig. 5 is a graph of the release rate of osmotic pump tablets weighted with different amounts of coating according to example 5 of the present invention.

FIG. 6 is a graph of the release rates of the different dosages of hydroxypiprepine hydrochloride of example 8 of the present invention.

Detailed Description

The following representative examples are intended to aid in the illustration of the present invention and should not be construed as limiting the scope of the present invention. Indeed, the entire contents of the documents in this invention, including examples in accordance with the scientific literature and patents cited herein, as well as various modifications and numerous further variations thereof, will be readily apparent to those skilled in the art, except to those shown and described herein. The following examples contain important supplementary information, examples and guidance, and are adaptable to various variations and the like in the present invention.

Example 1 (Single layer matrix sustained release tablet)

The present embodiment is a general single-layer skeleton slow-release tablet of oxypiperidone, the composition and content of the drug layer are shown in table 1:

TABLE 1

The preparation process comprises the following steps:

1. uniformly mixing the formula amount of hydroxypiperonate hydrochloride, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose and pregelatinized starch;

2. preparing soft material with 5% PVPK30 water solution, and sieving with 2.0mm sieve to obtain wet granule;

3. the resulting wet granules were dried in a fluid bed to a moisture content of less than 2%.

4. The dry granules are sieved by a sieve with the diameter of 1.2mm, granulated, mixed with magnesium stearate with the prescription amount, and tabletted, wherein the theoretical weight of the tablet is 150 mg.

The release rate test adopts Chinese pharmacopoeia II method (slurry method) and 50 revolutions, uses 1000ml of deionized water as solvent, and measures the release rate of the sample, and the release curve of the sample is shown in figure 1.

As shown in figure 1, in the single-layer framework sustained-release tablet, 20% of HPMC K100M and 10% of sodium carboxymethylcellulose are combined, so that the sustained-release effect of releasing no more than 40% in 1 hour and releasing more than 80% in 8 hours can be achieved.

Example 2 (double layer matrix sustained release tablet)

The present embodiment is an oxypiperidone double-layer skeleton sustained-release tablet, and the composition and content of the drug layer are shown in table 2:

TABLE 2

The composition and content of the barrier layer of the oxypiperone double-layer skeleton sustained-release tablet are shown in table 3:

TABLE 3

Components	Dosage (mg)
		Lactose monohydrate	47.7
Yellow iron oxide	0.3
		Hydroxypropyl methylcellulose (HPMC, K4M)	60
Glyceryl behenate	37.5
		Polyvinyl pyrrolidone (PVP, K30)	3
Magnesium stearate	1.5
		Total amount of	150

The preparation process of the drug layer of the oxypiperone double-layer skeleton sustained-release tablet comprises the following steps:

1. uniformly mixing the formula amounts of hydroxypiperidone hydrochloride, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, lactose monohydrate and glyceryl behenate;

2. preparing soft material with 5% PVPK30 water solution, and sieving with 2.0mm sieve to obtain wet granule;

3. the resulting wet granules are dried in a fluid bed to a moisture content of less than 2%.

4. The dry granules are sieved by a sieve with the diameter of 1.2mm, and then are evenly mixed with magnesium stearate with the prescription amount.

The preparation process of the barrier layer of the oxypiperone double-layer skeleton sustained-release tablet comprises the following steps:

1. uniformly mixing the lactose monohydrate, the yellow iron oxide (sieved by a 80-mesh sieve), the hydroxypropyl methylcellulose and the glyceryl behenate according to the prescription amount;

2. preparing soft material with 5% polyvidone K30 water solution, and sieving with 2.0mm sieve to obtain wet granule;

3. the resulting wet granules are dried in a fluid bed to a moisture content of less than 2%.

4. The dry granules are sieved by a sieve with the diameter of 1.2mm, and then are evenly mixed with magnesium stearate with the prescription amount.

Tabletting:

the prepared drug layer granules and barrier layer granules were compressed into a bilayer tablet, wherein the drug layer weight was 150mg and the barrier layer weight was 150 mg.

The release rate test adopts Chinese pharmacopoeia II method (slurry method) and 50 revolutions, uses 1000ml of deionized water as solvent, and measures the release rate of the sample, and the release curve of the sample is shown in figure 2.

As shown in figure 2, in the double-layer skeleton sustained-release tablet, 40% of HPMC K100M, 10% of sodium carboxymethylcellulose and 10% of glyceryl behenate are used in a medicine-containing layer in combination, so that the sustained-release effect that the release is not more than 40% within 1 hour and more than 80% within 20 hours can be achieved.

Example 3 (three-layer matrix sustained-release tablet)

The present embodiment is an oxypiperone three-layer skeleton sustained release tablet with different hydroxypropyl methylcellulose contents, wherein the composition and content of the drug layer are shown in table 4:

TABLE 4

The preparation process of the drug layer of the oxypiperone three-layer skeleton sustained release tablet comprises the following steps: the same as in example 2.

The composition and preparation process of the barrier layer of the oxypiperidone three-layer skeleton sustained-release tablet are as follows: the same as in example 2.

Tabletting:

the drug layer particles prepared above were laminated to barrier layer particles in a three-layer tablet, the first layer consisting of 150mg of the barrier layer, the second layer consisting of 150mg of the drug layer containing 20mg of oxyphenopidine, and the third layer consisting of 150mg of the barrier layer.

Coating:

and coating the tablets with hydroxypropyl cellulose coating solution until the weight is increased by about 3 percent to obtain the hydroxypyrapone three-layer skeleton sustained-release tablets.

The hydroxypyrazine three-layer skeleton sustained release tablet obtained in example 3 was subjected to a release degree test, the release degree of the sample was measured by using the Chinese pharmacopoeia II method (slurry method) at a rotation speed of 50 rpm and using 1000ml of deionized water as a solvent, and the release curve of the sample is shown in FIG. 3.

The experimental results show that different drug release curves can be obtained by using different amounts of hydroxypropyl cellulose (HPMC K100M) in the drug layer, the release rate of the drug is faster when the amount of HPMC K100M is less, 5% -40% of HPMC K100M can respectively obtain the release results that the release is not more than 40% in 1 hour and 80% in 8-24 hours, and the ideal sustained release effect is achieved.

Example 4 (sustained Release pellet)

The present embodiment is an oxypiperone sustained release pellet, the composition and content of which are shown in table 5:

TABLE 5

The sustained-release pellet adopts a coating process, the hydroxypipropyrone hydrochloride, the hydroxypropyl methylcellulose and the talcum powder are prepared into a medicine layer solution, the sugar pellet is coated with a medicine layer in a fluidized bed, then a sustained-release coating film is coated on a medicine pellet core until the weight of the coating is increased by 25%, and the sustained-release pellet is continuously dried in the fluidized bed until the water content is less than 2% to prepare the hydroxypipropyrone sustained-release pellet.

The release degree test of the oxypiperone sustained release pellet obtained in example 4 is carried out by adopting the Chinese pharmacopoeia II method (slurry method) and 50 revolutions, taking 1000ml of distilled water as a solvent, and measuring the release degree of a sample, wherein the release curve of the sample is shown in figure 4.

As can be seen from FIG. 4, when Kollicoat SR 30D is used as the sustained-release coating material, the weight of the coating is increased by about 25%, and the sustained-release effect of not more than 40% in 1 hour and more than 80% in 8 hours can be achieved.

Example 5 (osmotic pump tablets)

This example is an oxypiperone osmotic pump tablet, the composition and content of which are shown in table 6:

TABLE 6

The tablet core adopts a direct tabletting process, the pressed tablet core is coated with a semipermeable membrane coating solution until the coating weight is increased by 8-10%, then the tablet is removed from a coating pan and dried in an oven at 45 ℃ for 24 hours. A single hole was drilled at the end of the tablet surface and the diameter of the hole was 0.6 mm.

The hydroxypiperone osmotic pump tablet obtained in example 5 was subjected to a release rate test using the Chinese pharmacopoeia II method (slurry method) at a rotation speed of 50 rpm and 1000ml of distilled water as a solvent to determine the release rate of the sample, and the release curve of the sample is shown in FIG. 5.

As can be seen from fig. 5, when cellulose acetate is used as a slow-release coating material, the weight of the coating is increased by about 8-10%, and the slow-release effect that the release is not more than 40% in 1 hour and more than 80% in 18-24 hours can be achieved.

Example 6

In order to verify whether the prepared piroctone olamine sustained-release tablets meet the sustained-release requirement, the pharmacokinetic study was carried out on the piroctone olamine three-layer skeleton sustained-release tablets in the group 3 in the example 3, and the absorption rate and the absorption degree of the quick-release tablets and the sustained-release tablets in vivo under the same dose were compared.

The composition of the immediate release tablet of hydroxypiperidone is shown in Table 7: the preparation process is wet granulation, and the obtained granules are mixed with magnesium stearate and then tabletted. The dissolution rate of the sample is determined by adopting a Chinese pharmacopoeia II method (slurry method) and a rotating speed of 50 revolutions and taking 1000ml of deionized water as a solvent, and the result shows that the dissolution rate of the quick-release tablet in 5 minutes reaches more than 95 percent.

TABLE 7

Components	Dosage (mg)
		Hydroxypiperone hydrochloride	20
Lactose monohydrate	180
		Microcrystalline cellulose	60
Hydroxypropyl methylcellulose (E5)	5
		Low substituted hydroxypropyl cellulose (L-HPC)	40
Magnesium stearate	3
		Total amount of	308

The composition of the three-layer matrix sustained-release tablet is shown in table 8, and the preparation process is the same as that of example 3. The Chinese pharmacopoeia II method (slurry method) is adopted, the rotating speed is 50 revolutions, the volume of the solution is 1000ml, the release degrees of the samples are respectively measured in deionized water, buffer solutions with the pH value of 1.2, the pH value of 4.5 and the pH value of 6.8, and the results show that the release curves of the three-layer framework sustained-release tablets in different solvents are similar, and no obvious difference exists among the release curves.

TABLE 8

Pharmacokinetic experimental design: beagle dogs (male and female halves) were 6, randomized into 2 groups of 3 dogs each. The administration time before the experiment is 12h, the patient is free to drink water, the first group is administered with the rapid-release tablet of the oxyphenirazone (one tablet per day), the second group is administered with the sustained-release tablet of the oxyphenirazone three-layer framework (one tablet per day), and the administration is carried out alternately after one week. The dose administered was 20 mg/tablet/mouse. Blood was collected from the left forelimb femoral vein after dosing.

Quick-release tablets: blank blood is collected before administration, and blood samples are collected 10 mm, 20min, 40min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h and 24h after administration. The plasma was separated by centrifugation at 3000rpm for 10 min.

Sustained release tablets: blank blood is collected before administration, and blood samples are collected 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 12h, 24h and 30h after administration. The plasma was separated by centrifugation at 3000rpm for 10 min.

As a result: t of quick-release tablet of hydroxypiprpirone after oral administration of 20 mg/tablet/quick-release tablet and sustained-release tablet of hydroxypiprpirone to Beagle dog_maxIs 0.87 plus or minus 0.18 h; t of oxypiperonate sustained release tablet_maxThe time is 5.17 +/-2.48 h. Wherein T is_maxExpressed as the time required to reach the drug peak concentration after administration, this parameter reflects the rate of entry of the drug into the body, with a fast absorption rate leading to a short peak time.

Oxopiperazone quick-release tablet C_max543.6 + -127.4 ng/ml; hydroxypiperone slow release tablet C_max122.3 + -84.9 ng/ml. Wherein, C_maxThe highest value of the blood concentration after administration is an important index reflecting the absorption rate and the absorption degree of the drug in vivo.

AUC of oxypiperonate quick release tablet_0-24h1634.7 +/-787.8 ng.h/ml; AUC of oxypiperone sustained release tablet_0-24hThe concentration is 1119.7 +/-775.2 ng.h/ml. Wherein, AUC_0-24hExpressed as the area enclosed by the plasma concentration curve versus the time axis. The parameter is an important index for evaluating the absorption degree of the drug and reflects the exposure characteristic of the drug in vivo.

Compared with the quick release tablet of the oxyphenirazone, the oxyphenirazone sustained release tablet of the invention has good bioavailability and the time to peak T_maxSignificant delay, peak concentration C_maxObviously reduces the absorption in vivo, is similar to the absorption in the body of the common tablet, and proves that the oxyphenirazone sustained-release tablet achieves good sustained-release effect, thereby further highlighting the creativity of the invention.

Example 7

The specific embodiment screens the sustained-release materials in the single-layer framework sustained-release tablets respectively. The compositions are shown in Table 9.

TABLE 9

The release test is performed by using the chinese pharmacopoeia II method (slurry method) and a rotation speed of 50 revolutions, using 1000ml of deionized water as a solvent, to measure the release of the sample, wherein the sampling time points are 1, 2, 4, 6, 8, 10, 14, 16, 20, and 24 hours, and the obtained test results are shown in table 10.

Watch 10

As can be seen from Table 10, since the solubility of the hydroxypeppirone hydrochloride is about 240mg/ml, the hydroxypeppirone hydrochloride belongs to high-solubility drugs, the single use of the hydroxypropyl methylcellulose is difficult to achieve the ideal release effect, the release rate of the hydroxypropyl methylcellulose reaches more than 80% already after 6 hours, and the combination of the hydroxypropyl methylcellulose and the ionic sodium carboxymethylcellulose can meet the release result of more than 80% after 8 hours, because the ionic sodium carboxymethylcellulose and the hydroxypropyl methylcellulose interact with each other, the hydration and the expansion rate of the hydroxypropyl methylcellulose are synergistically promoted, so that the gel strength is higher, the release rate of the highly water-soluble hydroxypeppirone hydrochloride is reduced, and the zero-order drug release is achieved. Meanwhile, the invention discovers that after the lipophilic sustained-release material glyceryl behenate is added in the formula 3, the release result of more than 80% can be satisfied after 10 hours of release, so that the release curve is closer to zero-order release compared with the release curve without the lipophilic sustained-release material, and an ideal sustained-release effect is achieved. Therefore, the combination of the hydroxypropyl methyl cellulose, the sodium carboxymethyl cellulose and the glyceryl behenate has an advantage in the sustained-release effect of the drug.

In order to further improve the slow release effect, the invention also provides a slow release mechanism, namely, a barrier layer or two barrier layers are added on the basis of the single-layer framework slow release tablet, and the surface area of the medicine-containing layer contacting with the outside is reduced to achieve a more ideal zero-order release effect. The compositions of the drug-containing and barrier layers are shown in Table 11.

TABLE 11

The two-layer or three-layer tablets were compressed according to the above-mentioned formulation, and the release test was conducted as described above, and the test results are shown in Table 12.

TABLE 12

It can be seen from table 12 that the two-layer or three-layer sustained release tablets can further improve the sustained release effect on the release rate of the single-layer sustained release tablet, meet the release condition that the release is not more than 40% in 1 hour and reaches 80% in 20-24 hours, and achieve the sustained release effect closer to zero-order release.

Example 8

The specific embodiment discloses the content of each component of the oxypiperazine hydrochloride in a sustained release preparation of 10-40mg, as shown in Table 13:

watch 13

The preparation process is the same as example 3, the Chinese pharmacopoeia II method (slurry method) is adopted, the rotating speed is 50 revolutions, 1000ml of deionized water is taken as a solvent, the release degree of the sample is measured, and the release curve of the sample is shown in figure 6.

As can be seen from FIG. 6, the sustained release effect of the hydroxypiperone hydrochloride is equivalent when the dosage is between 10 and 40mg, and the sustained release effect of releasing no more than 40% in 1 hour and more than 80% in 14 hours can be achieved.

Finally, while the invention has been described in detail with reference to preferred embodiments, it will be understood by those skilled in the art that the invention is not limited to these embodiments and the methods of preparation used. Furthermore, those skilled in the art can make equivalent substitutions, combinations, improvements or modifications to the technical solution of the present invention based on the description of the present invention without departing from the spirit and scope of the technical solution of the present invention, which is covered by the claims of the present invention.

Claims (2)

1. An oral sustained release formulation of hydroxypyrazine, comprising:

hydroxypyrazine or a pharmaceutically acceptable salt thereof;

one or more pharmaceutically acceptable excipients;

at least contains a polymer with slow release function, and the polymer with slow release function is a framework material;

the sustained-release tablet is a sustained-release tablet, the sustained-release tablet is a multilayer skeleton sustained-release tablet containing a drug layer and a barrier layer, and the drug layer of the sustained-release tablet is prepared from the following components in percentage by weight: 5 to 20 percent of hydroxypropyl methylcellulose, 10 percent of sodium carboxymethylcellulose, 10 percent of glyceryl behenate, 23.67 to 43.67 percent of filling agent, 2 percent of adhesive and 1 percent of lubricant.

2. The oral sustained release formulation of hydroxypiperone of claim 1, wherein:

the sustained release formulation exhibits an in vitro release rate of oxycodone of not more than 40% at the 1 hour time point and of not more than 80% at the 6 hour time point;

the detection conditions of the in vitro release rate of the oxypiperone are as follows:

adopts Chinese pharmacopoeia II method, rotating speed 50 turns, and 1000ml deionized water is used as solvent.

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