CN111346066A - Sustained release preparation containing piracetam - Google Patents

Abstract

The invention relates to a sustained-release preparation containing piracetam or medicinal derivatives thereof, which can achieve the effect of sustained release after an effective dose is given in the form of a sustained-release preparation, and also relates to a preparation method of the sustained-release preparation containing piracetam or medicinal derivatives thereof. The sustained release preparation containing the piracetam or the medicinal derivatives thereof has the advantages of long-term maintenance of stable blood concentration, convenient administration, good patient compliance and few adverse reactions, and is suitable for large-scale popularization and application.

Description

Sustained release preparation containing piracetam

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a sustained-release preparation containing piracetam or medicinal derivatives thereof and a preparation method thereof.

Background

Piracetam belongs to α -amino acid cyclized derivatives, has the effects of resisting brain function damage caused by physical factors and chemical factors, improving learning, memory and recall abilities, and improving retrograde amnesia caused by anoxia.

The approved dosage forms for the market are piracetam tablets, capsules and injections, which are all quick-release preparations. Although the common tablets and capsules are convenient to take, the administration frequency is high, 0.8-1.6 g (2-4 tablets) is needed each time, 3 times a day, and when a patient suffering from retrograde amnesia caused by brain function damage or hypoxia due to physical factors and chemical factors is treated, repeated administration or forgetting administration is easily caused by multiple administrations. Although the injection has quick response, the carrying and the use are inconvenient.

Piracetam tablets and capsules sold in the market are quickly absorbed in the gastrointestinal tract after being taken, the peak value of the blood concentration can be reached within 30-45 minutes, the obtained blood concentration is periodic, and the low valley of the blood concentration appears before the next administration, which is shown in figure 1. For the brain dysfunction caused by acute and chronic cerebrovascular diseases, brain trauma, various toxic encephalopathies and the like, the disease condition may be aggravated by blood and drug troughs, so that the mild blood and drug concentration is needed, the lasting drug effect is ensured, and the drug administration frequency is reduced. At present, the development of a sustained-release preparation containing piracetam or medicinal derivatives thereof is urgently needed, so that the stable release of the medicine is ensured, the compliance of patients is improved, and the like.

Disclosure of Invention

The invention provides a sustained release formulation containing piracetam or a pharmaceutically acceptable derivative thereof, wherein the sustained release formulation has an in vitro cumulative dissolution release profile, 35-65% of piracetam is released from the formulation within 2-8 hours, and substantially all of piracetam or a pharmaceutically acceptable derivative thereof is released from the formulation within 10-16 hours.

As used herein, "pharmaceutically acceptable derivative" refers to salts and esters, and when administered to a human body to obtain piracetam or its active metabolite, preferred salts are inorganic acid salts such as hydrochloride, hydrobromide, phosphate, or the like, or organic acid salts such as acetate, fumarate, tartrate, fumarate, or the like. By "substantially all" is meant here more than 85%, preferably more than 90%.

The sustained release preparation according to the present invention has an in vitro dissolution profile in which 30 to 65%, preferably 35 to 65%, more preferably 40 to 60% of piracetam or a pharmaceutically acceptable derivative thereof is dissolved within 2 to 8 hours, more preferably within 4 to 6 hours, and 90% or more of piracetam is dissolved within 1 to 20 hours, preferably within 6 to 16 hours, more preferably within 10 to 16 hours.

The invention provides a sustained-release preparation containing piracetam or a medicinal derivative thereof, which can obtain a stable blood concentration curve after multiple administrations, wherein the specification of the piracetam or the medicinal derivative thereof is 200-1500mg, preferably 400-1300 mg.

Preferably, the sustained release formulation comprises piracetam or a pharmaceutically acceptable derivative thereof selected from 400mg, 600mg, 800mg, 1000mg or 1200 mg.

Preferably, the sustained release formulation is sufficient to meet a controlled dosage regimen for all suitable patients.

Preferably, the dosage regimen is administered once a day.

Preferably, one or more doses are administered per administration.

Preferably, the molecular weight of the delayed release polymer used is 10000-120000, more preferably 20000-100000.

A preferred delayed release polymer is hydroxypropyl methylcellulose.

Polymers that can be used include Methocel E4M, Methocel E10M, Methocel K100LV, Methocel K100M, Methocel K4M, Methocel K15M, or mixtures thereof.

The sustained-release preparation further comprises a diluent such as lactose, microcrystalline cellulose, monocalcium phosphate, mannitol, a compressible starch, and a lubricant such as magnesium stearate, silicon dioxide, sodium stearyl fumarate, and stearic acid. Typically, sustained release formulations comprise:

a) 20-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 10-60% by weight of hydroxypropyl methylcellulose;

c) 0-60% of a diluent;

d) 0.1-2.5% of lubricant.

In a preferred embodiment, the sustained release formulation comprises:

a) 35-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 20-55% by weight of hydroxypropylmethylcellulose or a mixture thereof;

c) 0-40% lactose;

d) 0.1-1.5% of lubricant.

In a more preferred embodiment, the sustained release formulation comprises:

a) 40-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 20-50% by weight of hydroxypropylmethylcellulose E4M, K100LV, K100M, K4M or a mixture;

c) 0-30% lactose;

d) 0.5-1.2% magnesium stearate;

e) and an outer coating layer comprising a polymer of 0.05mm to 0.30 mm.

The coating layer of the sustained-release preparation is a film coating layer and can also be a semi-permeable film, and the drug release is controlled by a water-insoluble polymer or a part of water-soluble polymer. Or the film coating layer may control the solvent rate. Preferably, the film coating is considered to be a functional coating tablet.

The polymer contained in the film coating layer comprises acrylate, methacrylate, cellulose or its derivatives such as ethyl cellulose, polyvinyl alcohol, etc.

The water insoluble or partially water soluble polymer for the film coating layer comprises hypromellose such as E4M, K100LV, K100M, eudragit, an aqueous ethylcellulose dispersion, or mixtures thereof. In addition, an aqueous dispersion of ethyl cellulose (sulci) or opadry may be used, using a range of 3% to 8% of the tablet weight.

Typically, embodiments have a film coating layer comprising 60% to 90% by weight ethylcellulose dispersion and 10% to 40% opadry film coating.

The invention relates to a sustained release formulation containing piracetam or a pharmaceutically acceptable derivative thereof, wherein the release rate of the piracetam or the pharmaceutically acceptable derivative thereof exists in two stages, the release rate of the first stage is slower than that of the second stage, preferably, the release rate of the first stage is lower than 20% of that of the piracetam or the pharmaceutically acceptable derivative thereof, and basically the residual piracetam or the pharmaceutically acceptable derivative thereof is released in the second stage. The first phase is mainly released in the stomach and the second phase is mainly released in the intestine.

The invention relates to a sustained-release preparation, which comprises: the tablet comprises a tablet core containing piracetam or medicinal derivatives thereof and an outer coating layer coating the tablet core, wherein the thickness of the outer coating layer can be adjusted, so that external fluid is prevented from permeating into the tablet core. Typically, the outer coating layer may dissolve from 0.5 to 6 hours after administration, or may dissolve in a liquid environment at a pH greater than 5.

In general, the thickness of the outer coating layer is preferably in the range of 0.1 to 0.5mm, more preferably 0.15 to 0.3 mm.

The surface of the sustained release preparation containing piracetam or the medicinal derivative thereof contains holes which are one or two holes, preferably two holes, and the holes are preferably arranged on two sides of the tablet.

The sustained-release preparation related to the invention has the shape of a round, oval, key or capsule, a double-convex shape, preferably a round and standard double-lug.

The invention has the beneficial effects that:

1. the invention solves the practical problem of the piracetam sustained-release preparation, has high curative effect, good administration compliance and less adverse reaction, can quickly take effect and maintain stable blood concentration for a long time.

2. The sustained release tablet composed of the sustained release matrix tablet and the insoluble polymer material is prepared according to the pharmacokinetics characteristic of piracetam and the 'double drug release' principle of first sustained release and then quick release, and has the obvious advantages of improving the dissolution rate of piracetam and realizing the effect of stable and slow drug release.

3. The invention provides a feasible preparation method of the piracetam sustained-release preparation, which is easy to prepare, has good stability and reproducibility and is suitable for large-scale popularization and application.

Drawings

FIG. 1: a simulated pharmacokinetic profile of 800mg piracetam tablets administered 3 times daily;

FIG. 2: example 1 dissolution profile of sustained release tablets;

FIG. 3: example 2 release profile of the extended release tablet;

FIG. 4: blood concentration-time curve of oral administration of piracetam sustained release tablets and reference preparation for beagle dogs.

Detailed Description

Example 1 preparation of sustained Release tablets of different specifications

Weighing piracetam, hydroxypropyl methylcellulose K100LV and lactose according to the formula, placing into a wet granulator, starting a stirring paddle and a shearing paddle, mixing at low speed for 10min, adding purified water for wet granulation, placing into a fluidized bed, drying to control the water content to be not more than 3.0%, granulating with 20 meshes, adding magnesium stearate into dry granules, and tabletting by using a rotary tablet press. And (3) performing film coating on the tablets in a high-efficiency coating machine, wherein the coating liquid is ethyl cellulose aqueous dispersion (Stichil) coating, and the weight gain of the coating is 3-6%. Punching on the surface of the sheet, and packaging to obtain the finished product.

EXAMPLE 2 preparation of sustained Release tablets with different Polymer ratios

Weighing piracetam, hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose E4M and lactose according to the formula, placing the weighed materials into a wet granulator, starting a stirring paddle and a shearing paddle to be low-speed, mixing for 10min, adding purified water for wet granulation, then placing the mixture into a fluidized bed for drying to control the water content to be not more than 3.0%, granulating by a 20-mesh sieve, adding magnesium stearate into dry granules, and tabletting by using a rotary tablet press. The tablets are subjected to film coating in a high-efficiency coating machine, coating liquid is ethyl cellulose aqueous dispersion (Sulisi) and opadry which are mixed according to the proportion of 70/30, and the weight of the coating is increased by about 5 percent. Punching holes on two sides of the slice, and packaging to obtain the finished product.

The punching in example 1 and example 2 is the following process steps:

the coated tablet is mechanically perforated. The tablets were mounted on a height bracket and a hole was drilled in the center of the tablet face until the film coating was chiseled through. The tablets were then turned over and a hole was punched in the center. The depth of the holes, the hole edge regularity and the appearance were examined.

Example 3: in vivo pharmacokinetics study of Beagle dogs

6 healthy Beagle dogs, 3 males and 3 females, with the weight range of 8-10 kg, are randomly divided into two groups, each group comprises 3 dogs, one group is subjected to a single-dose administration test of a released preparation (self-tabletting in example 1, the specification is 1.2 g/tablet, and 1 tablet in total), and the dose of the preparation is 1.2 g/dog; and the other group carries out a plurality of dosing tests of reference preparations (reference preparation manufacturers: Lepu pharmaceutical industry (Beijing) LLC company, the name of piracetam tablet, the specification: 0.4 g/tablet, 3 tablets in total), wherein the dosing is carried out once every 6 hours for 3 times, the dosage is 0.4 g/dose, and the total dosage is 1.2 g/dose. Taking 2ml of blood from one forelimb vein of each Beagle dog before administration (0h), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24 and 48 hours after administration, placing the blood into a heparinized test tube, centrifuging (5000rpm, 10min), separating out plasma, and freezing at-20 ℃ for later use;

the concentration of piracetam in plasma is determined by liquid chromatography-tandem mass spectrometry, and the results of the in vivo blood concentration-time curve are shown in figure 4. The results show that the prescription well ensures the rapid release of the initial drug and meets the requirement of the rapid onset of the drug; the slow release is carried out for 6 to 12 hours in the later period, the relatively stable blood concentration is maintained, the fluctuation of the blood concentration is avoided, and the clinical use is safer and more effective; the product can improve the single administration dosage of the piracetam and provide a novel sustained-release preparation which has good compliance, less adverse reaction, quick response and long-term maintenance of effective blood concentration on the basis of enhancing the treatment effect.

In conclusion, the piracetam sustained-release preparation disclosed by the invention is convenient to use, high in drug curative effect, good in taking compliance, less in adverse reaction, capable of quickly taking effect, capable of maintaining stable and effective blood concentration for a long time, easy to prepare, good in stability and reproducibility, and suitable for large-scale popularization and application.

It will thus be seen that the objects of the invention have been fully and effectively accomplished. The functional and resulting principles of the present invention have been shown and described in embodiments, which can be modified at will without departing from such principles. Therefore, this invention includes all modifications encompassed within the spirit and scope of the claims.

Claims (10)

1. A sustained release preparation containing piracetam or a medicinal derivative thereof is characterized by consisting of piracetam or a medicinal derivative thereof, hydroxypropyl methylcellulose, a diluent and a lubricant.

2. The sustained-release preparation according to claim 1, which is administered 1 time per 1 day.

3. The sustained release formulation of claims 1-2, wherein the formulation is a functional coated tablet, a delayed release tablet or a caplet matrix sustained release tablet, an osmotic pump device, or a combination thereof, wherein the functional coated tablet comprises a waxy matrix tablet or a polymer.

4. A sustained release formulation as claimed in claims 1 to 3 wherein the core is a matrix tablet comprising the compound piracetam or a pharmaceutically acceptable salt or derivative thereof and one or more release retarding polymers.

5. A sustained release formulation as claimed in claims 3 to 4 wherein the release retarding polymer contained in the core is hydroxypropylmethylcellulose.

6. The sustained release formulation of claims 1-5, wherein the formulation comprises:

a) 20-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 10-60% by weight of hydroxypropyl methylcellulose;

c) 0-60% of a diluent;

d) 0.1-2.5% of lubricant.

7. The sustained release formulation of claims 1-6 wherein the formulation comprises:

a) 35-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 20-55% by weight of hydroxypropylmethylcellulose CR Grade, E4M, E10M, K100LV or a mixture thereof;

c) 0-40% lactose;

d) 0.1-1.5% of lubricant.

8. The sustained release formulation of claims 1-7, comprising:

a) a tablet core comprising piracetam or a pharmaceutically acceptable derivative thereof;

b) the outer coating layer for coating the tablet core is mainly used for preventing environmental fluid from penetrating into the tablet core by controlling the thickness of the outer coating layer;

c) said outer coating layer comprises one or more holes which pass substantially completely through said outer coating layer but do not penetrate said core and allow for the release of piracetam or a pharmaceutically acceptable derivative thereof from the core, the area or total area of said holes representing about 20-60% of the total area of the front side of the formulation, wherein the release of piracetam or a pharmaceutically acceptable derivative thereof occurs substantially through said holes.

9. The sustained-release preparation according to claims 1 to 8, wherein the outer coating layer is soluble at 0.3 to 6 hours after administration or when the surrounding pH exceeds 5.

10. The sustained release formulation of any one of claims 6 to 9 wherein the formulation comprises a tablet core comprising:

a) 40-70% by weight of piracetam and pharmaceutically acceptable derivatives thereof;

b) 20-50% by weight of hydroxypropyl methylcellulose or a mixture thereof of different types;

c) 0-30% of a diluent;

d) 0.5-1.2% of a lubricant;

e) and an outer coating layer comprising a polymer of 0.05mm to 0.30 mm.

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