CN105769794A - Memantine hydrochloride sustained release micro-pill tablets and preparation method thereof - Google Patents

Abstract

The invention provides a memantine hydrochloride sustained-release pellet tablet and a preparation method thereof. Memantine Hydrochloride Sustained-release Pellets and Tablets are directly compressed from a self-protective multi-layered pellets, without additional tablet auxiliary materials such as fillers and disintegrants. Self-protecting multi-layer pellets are composed of pellet core, drug layer, slow-release layer, protective layer and compressible compound excipient layer, which can withstand a certain degree of compression force, which is conducive to maintaining the sustained release of pellets The integrity of the coating film and good drug sustained release performance. The self-protecting multilayer pellets also have good compressibility, disintegration and lubricity, and can be directly compressed into tablets. The prepared memantine hydrochloride sustained-release pellets and tablets have good drug content uniformity.

Description

A kind of memantine hydrochloride sustained-release pellet tablet and preparation method thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations, and relates to a memantine hydrochloride sustained-release pellet tablet and a preparation method thereof.

Background technique

Memantine hydrochloride is a low-medium affinity, non-competitive, strong voltage-dependent N-methyl-D-aspartate receptor antagonist, which can block over-opening receptors and effectively regulate excitatory transmitters , slows down the neurodegenerative process, and has a therapeutic effect on Alzheimer's disease without the side effects on the central nervous system that other N-methyl-D-aspartate receptors usually have. It is the first FDA-approved The medicine for treating moderate and severe senile dementia has good application prospect.

Since Alzheimer's disease requires long-term medication, making memantine hydrochloride into a sustained-release preparation can reduce the number of doses, facilitate the application of patients, and improve compliance. In June 2010, the US FDA approved the memantine sustained-release capsules (NamendaXR7, 14, 21, 28 mg) of Forest Company for the treatment of moderate and severe AD. The low dose is used for the initial dose and for those with severe renal impairment, the maintenance dose is 28mg. At present, the products that have been approved for marketing in China include memantine hydrochloride tablet and oral solution. Memantine sustained-release capsules have not yet been marketed in China. The currently published patents on the sustained-release preparations of memantine hydrochloride are as follows:

Chinese patent CN103417491A discloses a memantine hydrochloride sustained-release pellet preparation and a preparation method thereof. Patent CN104013592A discloses memantine hydrochloride sustained-release pills and a preparation method thereof. The pills are composed of a blank core, a drug layer, an isolation layer and a sustained-release layer.

Patent CN102552218A discloses memantine hydrochloride sustained-release capsule preparation, which is composed of two kinds of pellets, one is a sustained-release pellet composed of a blank core, a drug layer and a sustained-release layer, and the other is a pellet with a blank core Immediate-release pellets composed of drug layer.

Patent CN103181914A discloses memantine hydrochloride sustained-release capsules and a preparation method thereof. In this invention, drug-containing pellets containing memantine hydrochloride are subjected to sustained-release coating to obtain sustained-release pellets, thereby making sustained-release capsules.

Patent CN103054826A discloses a memantine hydrochloride sustained-release pellet orally disintegrating tablet and its preparation method. The preparation in this patent is obtained by direct compression of drug-containing pellets with sustained-release effect and powder auxiliary materials. The particle size of the pellets is not more than 710 μm, and the prepared tablet can disintegrate rapidly in the oral cavity.

Patent CN19686848A discloses a modified-release preparation of memantine, which provides a pharmaceutical composition administered once a day, which is a matrix-type sustained-release tablet.

The above patents related to memantine sustained-release preparations can be divided into two categories, one is integral matrix sustained-release tablets, and the other is multi-unit (membrane-controlled pellets) sustained-release preparations (including capsules and tablets). Compared with matrix preparations, multi-unit (film-controlled pellets) sustained-release preparations can avoid dose bursts, have better sustained-release controllability, and are conducive to improving drug absorption and drug safety. Multi-unit (film-controlled pellets) sustained-release preparations are mostly made into capsules and tablets. Compared with capsules, the high productivity of tablets is more conducive to low-cost large-scale production. In addition, for drugs that need to be adjusted in dose, compared with the indivisible dose of capsules that need to be produced in multiple specifications, tablets are available because they can Segmentation enables a product of one specification to meet the needs of multiple specifications, simplifying the production process. However, there are still two main problems in the tableting of sustained-release pellets at present. One is that the coating film is easily broken during tableting and the sustained-release performance is lost; the other is that the pellets are easily separated from other powder fillers during tableting. The layer caused the unqualified drug content uniformity. In order to solve these problems, the inventor has tried a variety of methods and found that the sustained-release pellets are wrapped with a protective layer, and the auxiliary materials such as fillers, disintegrants, and lubricants required for the tablet are directly wrapped in the slow-release pellets with a protective layer. Release pellets, and then compressed to obtain tablets with acceptable content uniformity, and can achieve the desired sustained-release effect.

Contents of the invention

There are two main technical problems to be solved by the present invention: (1) the coating film of the sustained-release pellets is broken during tablet compression, resulting in faster and uncontrollable drug release; Pills and other tablet excipients are different in size, shape, density, etc., so it is not easy to mix evenly, and it is easy to produce stratification, which leads to the problem of unqualified drug content uniformity in tablets.

The solution provided by the present invention is to wrap a protective layer and a compressible auxiliary material layer on the basis of the sustained-release pellets coated with a sustained-release layer to make a self-protective type that protects the integrity of the sustained-release coating film. Multi-layer pellets, the pellets also have good compressibility, disintegration and lubricity, and can be directly compressed into tablets without adding fillers, disintegrants, lubricants and other auxiliary materials, which is very good It solves the two technical problems mentioned above. The memantine hydrochloride sustained-release pellets and tablets involved in the present invention have similar sustained-release effects to the original sustained-release pellets with only a sustained-release layer, good drug content uniformity, and can also be divided for use. Maintain the original sustained-release performance.

The memantine hydrochloride sustained-release pellet tablet and its preparation method provided by the present invention are characterized in that the tablet is directly compressed from a self-protective multi-layer pellet without adding fillers, disintegrating pellets, etc. Tablet excipients such as solution. The self-protecting multi-layer micropill is composed of a drug-containing micropill, a slow-release layer, a protective layer and a compressible auxiliary material layer. Wherein said drug-containing pellets contain memantine hydrochloride and pill-forming materials and binder A, said slow-release layer contains slow-release materials, and said protective layer contains lubricant and binder B, said The compressible auxiliary material layer contains a filler, and may also contain a disintegrant, a lubricant and a binder C.

The diameter of the drug-containing pellets is in the range of 100-1000 μm. The pelleting material in the drug-containing pellets contains one of sucrose and microcrystalline cellulose or both are used in combination. The content of the pill-forming material accounts for 40%-85% of the weight of the medicine-containing pellets. The content of memantine hydrochloride in the drug-containing pellets accounts for 3%-40% of the weight of the drug-containing pellets. The drug-containing pellets also contain binder A and anti-sticking agent A, wherein the binder A includes but Not limited to one or more of hypromellose (HPMC), ethyl cellulose (EC), polyethylene glycol (PEG), povidone (PVP), hydroxypropyl cellulose (HPC), viscose The content of the mixture accounts for 0.5%-20% of the weight of the drug-containing pellets; the anti-tack agent A therein includes but is not limited to one or more of talcum powder, micronized silica gel, magnesium stearate and glyceryl monostearate. There are several kinds, and the content of the anti-adhesive agent accounts for 0-15% of the weight of the pellets containing the medicine.

The sustained-release material is one or more of ethyl cellulose, Surelease, Aquacoat, acrylic resin EudragitRL, EudragitRS, EudragitRL30D, EudragitRS30D, EudragitNE30D, KollicoatSR30D, and the content of the sustained-release material accounts for 35% of the sustained-release layer- 100%. Also can contain plasticizer and antisticking agent B in the described sustained-release layer, plasticizer includes but not limited to triethyl citrate, polyethylene glycol, tributyl citrate and dibutyl sebacate One or more of them, the content of the plasticizer accounts for 0-30% of the slow-release layer; the anti-sticking agent includes but not limited to one of talcum powder, micronized silica gel, magnesium stearate and glyceryl monostearate or several kinds, the content of anti-tack agent B accounts for 0-65% of the slow-release layer.

The protective layer contains a lubricant and also contains an adhesive B. Lubricants include, but are not limited to, magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, sucrose fatty acid esters, fatty acid glycerides, polyoxyethylene fatty acid esters, polyoxyethylene fatty acids One or more of alcohol ether, poloxamer, polyethylene glycol, hydrogenated vegetable oil, micronized silica gel, talcum powder, the content of lubricant accounts for 50%-95% of the protective layer. The binder B includes But not limited to one or more of hypromellose (HPMC), ethyl cellulose (EC), povidone (PVP), hydroxypropyl cellulose (HPC), polyethylene glycol, binder The content of B accounts for 5-50% of the protective layer.

The compressible auxiliary material layer contains fillers, lubricants, disintegrants and binders. The fillers include but are not limited to one or a combination of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, and pregelatinized starch, and the content of fillers accounts for 65% of the compressible auxiliary material layer -100%. Adhesive C includes but is not limited to one or more of hypromellose (HPMC), povidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene glycol. The content of agent C accounts for 0%-35% of the compressible auxiliary material layer. Lubricants include but not limited to one of magnesium stearate, sodium stearate fumarate, talcum powder, sodium stearate, stearic acid One or several kinds, the content of the lubricant accounts for 0-15% of the compressible auxiliary material layer. The disintegrating agent is a pharmaceutically acceptable disintegrating agent, including but not limited to cross-linked povidone (PVPP), cross-linked One or more of sodium carboxymethyl cellulose, sodium carboxymethyl starch (CNS-Na), low-substituted hydroxypropyl cellulose (L-HPC), the content of disintegrants accounts for 0% of the compressible auxiliary material layer %-35%.

1. the method for described memantine hydrochloride slow-release pellet tablet, is characterized in that, step is as follows:

(1) Preparation of drug-containing pellets: suspending or dissolving memantine hydrochloride in any proportion of ethanol solution or water containing binder A to make a drug solution containing binder; In the bed coating machine, the pellet core is fluidized and heated to 25°C-50°C, the atomization pressure is controlled at 0.05-0.25MPa, and the above-mentioned drug solution is wrapped on the surface of the pellet core by means of bottom spray, side spray or top spray; After the drug application is completed, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes to prepare pellets containing a drug layer;

(2) Pack the slow-release layer: disperse the slow-release material, plasticizer and anti-sticking agent in water or an organic solvent solution, the organic solvent is one or more of ethanol, acetone, and isopropanol, and stir for 15 minutes Above, make the sustained-release material coating solution; put the drug-containing pellets prepared in (1) into the fluidized bed coating machine, make it fluidized and heated to 24 ° C ~ 55 ° C, control the atomization pressure At 0.05-0.25MPa, use the bottom spray, side spray or top spray method to wrap the above coating solution on the surface of the drug-containing pellets; after the coating is completed, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes , prepared micropills containing sustained-release layer;

(3) Cover the protective layer: dissolve the adhesive B in the protective layer in any proportion of ethanol solution or water, add a lubricant to make it evenly dispersed, and stir for at least 15 minutes to obtain a suspension containing the lubricant; The pellets containing the sustained-release layer obtained in (2) are placed in a fluidized bed coating machine, fluidized and heated to 24°C-55°C, the atomization pressure is controlled at 0.05-0.25MPa, and bottom spray, Wrap the lubricant-containing suspension on the surface of the pellets containing the sustained-release layer by side spraying or top spraying; after coating, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes to obtain Micropellets with a protective layer;

(4) pack compressible auxiliary material layer: the adhesive C in the auxiliary material layer is dissolved in water to make a content of 0-10% adhesive C solution; the filler in the auxiliary material layer, the disintegrating agent and Mix the lubricant powder evenly and use it as the auxiliary material layer powder; put the protective layer-containing pellets prepared in (3) in a side-spray fluidized bed or a centrifugal granulator, make it fluidized and heat it to 15°C-35°C ℃, control the atomization pressure at 0.01-0.2MPa, spray water or the aqueous solution of binder C onto the pellets through the atomization spray gun, wrap the powder of the auxiliary material layer on the surface of the pellets containing the protective layer, and obtain a compressible Self-protecting multilayer pellets with excipient layer.

The isolation layer can also be wrapped before the drug layer, the slow-release coat layer, and the lubricant protective layer. The material of the isolation layer can be selected from one of acrylic resin, hypromellose, hypromellose and povidone or in combination.

For the memantine hydrochloride sustained-release pellets and tablets provided by the invention, the drug cumulative release rate is 5%-35% in 1 hour, 20%-75% in 4 hours, and greater than 70% in 12 hours. The unit dose of memantine hydrochloride is one of 7mg, 14mg, 21mg, and 28mg, and the tablets of the latter three doses can also be divided for use, and the sustained release performance will not be affected after division.

The present invention has the following beneficial effects:

(1) On the basis of the sustained-release pellets coated with a sustained-release layer, a protective layer and a compressible auxiliary material layer are wrapped to obtain a self-protective multi-layer pellet, which can withstand a certain degree of The extrusion of the tableting force is conducive to maintaining the integrity of the sustained-release film of the pellets and good drug sustained-release performance.

(2) The outermost layer of the self-protecting multilayer pellets contains fillers with better compressibility, and also contains disintegrants and lubricants, so the pellets have good compressibility, disintegration and lubricity, It can be directly compressed into tablets without additional fillers, disintegrants, lubricants and other auxiliary materials, which solves the drug-containing tablet caused by uneven mixing of pellets and powder auxiliary materials and easy layering during tablet compression In order to solve the problem of uneven dosage, the memantine hydrochloride sustained-release pellets and tablets involved in the present invention have good drug content uniformity.

(3) The memantine hydrochloride sustained-release pellets and tablets involved in the present invention can be divided and used, and the original sustained-release effect is still maintained after the tablet is divided.

Description of drawings

Fig. 1, the release curve of the memantine hydrochloride sustained-release pellet tablet of embodiment 1, the comparative preparation and the control pellet. The control pellet is the sustained-release pellet that only covers the drug layer and the sustained-release layer in Example 1.

The release measurement method refers to the guideline 9013 for sustained-release, controlled-release and delayed-release preparations in the second part of the Chinese Pharmacopoeia 2015 edition, using 900mL of pH 1.2 hydrochloric acid solution as the release medium, with a speed of 100r/min and a temperature of 37±0.5°C. Sampling is filtered through a 0.45 μm microporous membrane, with reference to the literature (Li Ying. Research on Meclidinium Hydrochloride Sustained Release Tablets [D]. Beijing: Academy of Military Medical Sciences of the Chinese People's Liberation Army, 2005), using gas chromatography to measure and calculate Cumulative drug release.

detailed description

The present invention will be further described below in combination with specific embodiments. It should be understood that the following description is only for explaining the present invention, not limiting its content.

Example 1

The composition of self-protected multi-layer pellets is shown in the following table:

Preparation:

Drug coating layer: dissolve memantine hydrochloride and PVPK30 in 50% ethanol solution to prepare drug solution containing adhesive. Put the sucrose ball core into the fluidized bed coating machine, and wrap the above drug solution on the surface of the ball core by means of bottom spraying. The atomization pressure is controlled at 0.1MPa, the ventilation rate is 50m ³ /h, and the material temperature is 32-38°C. After the drug application is completed, the atomization pressure is turned off and the micropills are kept in a fluidized state for 15 minutes to prepare the micropills containing the drug layer for subsequent use.

Including slow-release layer: disperse Surelease in an appropriate amount of water to make an aqueous dispersion with a solid content of 15%, and stir for more than 15 minutes. The drug-containing pellets are put into a fluidized bed coating machine, and the drug-containing pellets are coated by bottom spraying. The atomization pressure is controlled at 0.1MPa, the ventilation rate is 50m ³ /h, and the material temperature is 35-38°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 15 minutes to prepare the micropills containing the sustained-release layer for subsequent use.

Protective coating layer: dissolve hypromellose E5 in 70% ethanol solution, add magnesium stearate, and stir for at least 15 minutes to prepare a suspension of magnesium stearate. Take the above-mentioned micropellets containing the sustained-release layer and place them in a fluidized bed coating machine, spray and coat the bottom of the micropellets with a suspension of magnesium stearate, control the atomization pressure at 0.1MPa, and ventilate at 50m ³ /h , material temperature 30-35 ℃. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 15 minutes to prepare micropills with a protective layer for subsequent use.

Pack the compressible auxiliary material layer: dissolve a certain amount of PVPK30 in an appropriate amount of water to make a binder solution with a content of 3%; mix the powder of the compressible auxiliary material layer evenly, and place the pellets containing the protective layer prepared above In the fluidized bed, make it fluidized and heated to 20°C, the atomization pressure is controlled at 0.01MPa, the binder solution is sprayed onto the pellets through the atomization spray gun, and the auxiliary material layer powder is wrapped by powder layering On the surface of the micropill with the protective layer, a self-protective multilayer micropill containing a compressible auxiliary material layer is prepared.

Add the above-mentioned self-protective multi-layer pellets into the hopper of the tablet press, directly compress the tablet, control the tablet pressure to make the tablet hardness about 30N, and press it into memantine hydrochloride sustained-release pellets with a tablet weight of 297mg , Each tablet contains 14mg of memantine hydrochloride.

Take 10 tablets of memantine hydrochloride sustained-release pellets, and measure the content uniformity. The results show that the drug content of 10 tablets is in the range of 95%-105% of the labeled amount, with an average value of 98.0%, and a standard deviation of S=1.3 , A+1.8S=4.3<15, the content uniformity inspection is qualified.

Example 2

The composition of self-protected multi-layer pellets is shown in the following table:

Preparation:

Drug coating layer: dissolve memantine hydrochloride and PVPK30 in 50% ethanol solution to prepare drug solution containing adhesive. Put the sucrose ball core into the fluidized bed coating machine, and use the bottom spray method to coat the above drug solution on the surface of the ball core. The atomization pressure is controlled at 0.15MPa, the ventilation rate is 60m ³ /h, and the material temperature is 32-37°C. After the drug application is completed, the atomization pressure is turned off to allow the micropills to continue to maintain the fluidized state for 10 minutes, and the micropills containing the drug layer are prepared for subsequent use.

Including slow-release layer: disperse Surelease in an appropriate amount of water to make an aqueous dispersion with a solid content of 15%, and stir for more than 15 minutes. The drug-containing pellets are put into a fluidized bed coating machine, and the drug-containing pellets are coated by bottom spraying. The atomization pressure is controlled at 0.15MPa, the ventilation rate is 60m ³ /h, and the material temperature is 35-40°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to prepare the micropills containing the sustained-release layer for subsequent use.

Protective coating layer: dissolve hypromellose E5 in 70% ethanol solution, add magnesium stearate, and stir for at least 15 minutes to prepare a suspension of magnesium stearate. Take the above-mentioned micropellets containing the slow-release layer and place them in a fluidized bed coating machine, spray and coat the bottom of the micropellets with a suspension of magnesium stearate, control the atomization pressure at 0.15MPa, and ventilate at 60m ³ /h , material temperature 30-36 ℃. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to prepare micropills with a protective layer for subsequent use.

Pack the compressible auxiliary material layer: dissolve a certain amount of PVPK30 in an appropriate amount of water to make a binder solution with a content of 3%; mix the powder of the compressible auxiliary material layer evenly, and place the pellets containing the protective layer prepared above In the fluidized bed, make it fluidized and heated to 25 ° C, the atomization pressure is controlled at 0.1 MPa, the binder solution is sprayed onto the pellets through the atomization spray gun, and the auxiliary material layer powder is wrapped by powder layering On the surface of the micropill with the protective layer, a self-protective multilayer micropill containing a compressible auxiliary material layer is prepared.

With above-mentioned self-protection type multi-layer micropill, direct tableting, control tableting pressure makes tablet hardness be about 25N, is pressed into the memantine hydrochloride slow-release micropill sheet that sheet weight is 445mg, and each contains memantine hydrochloride 28mg.

Take the memantine hydrochloride sustained-release pellets, break them into half tablets, and measure the drug release curves of the whole tablet and the half tablet. The results show that the similarity between the drug release curves of the half tablet and the whole tablet is higher, and the similarity factor f2=61.

Example 3

The lubricant in the protective layer of the self-protecting multi-layer pellets is selected from sodium stearate fumarate, and the composition of the pellets is shown in the table below.

Preparation:

Drug coating layer: dissolve memantine hydrochloride and PVPK30 in 50% ethanol solution to prepare drug solution containing adhesive. Put the sucrose ball core into a fluidized bed coating machine, and wrap the above drug solution on the surface of the ball core by means of bottom spraying. The atomization pressure is controlled at 0.1MPa, the ventilation rate is 70m ³ /h, and the material temperature is 34-39°C. After the drug application is completed, the atomization pressure is turned off to allow the micropills to continue to maintain the fluidized state for 30 minutes, so as to prepare the micropills containing the drug layer for subsequent use.

Including slow-release layer: disperse Surelease in an appropriate amount of water to make an aqueous dispersion with a solid content of 15%, and stir for more than 15 minutes. The drug-containing pellets are put into a fluidized bed coating machine, and the drug-containing pellets are coated by bottom spraying. The atomization pressure is controlled at 0.1MPa, the ventilation rate is 70m ³ /h, and the material temperature is 35-40°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 30 minutes to prepare the micropills containing the sustained-release layer for subsequent use.

Protective coating layer: dissolve hypromellose E5 in 70% ethanol solution, add magnesium stearate, and stir for at least 15 minutes to prepare a suspension of magnesium stearate. Take the above-mentioned micropellets containing the sustained-release layer and place them in a fluidized bed coating machine, spray and coat the bottom of the micropellets with a suspension of magnesium stearate, control the atomization pressure at 0.1MPa, and the ventilation rate is 70m ³ /h , material temperature 30-36 ℃. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 30 minutes to prepare micropills with a protective layer for subsequent use.

Pack the compressible auxiliary material layer: dissolve a certain amount of PVPK30 in an appropriate amount of water to make a binder solution with a content of 3%; mix the powder of the compressible auxiliary material layer evenly, and place the pellets containing the protective layer prepared above In the fluidized bed, make it fluidized and heated to 30°C, the atomization pressure is controlled at 0.15MPa, the binder solution is sprayed onto the pellets through the atomization spray gun, and the auxiliary material layer powder is wrapped by powder layering On the surface of the micropill with the protective layer, a self-protective multilayer micropill containing a compressible auxiliary material layer is prepared.

The above-mentioned self-protective multilayer pellets were directly compressed into tablets, and the tableting force was controlled so that the tablet hardness was about 40N, and the sustained-release pellets with a tablet weight of 280 mg were pressed into tablets, each containing 14 mg of memantine hydrochloride.

Example 4

The composition of self-protected multi-layer pellets is shown in the following table:

Preparation:

Wrap isolation layer: hypromellose Dissolve in water to make a solution with a concentration of 5%, wrap the isolation layer on the pellet core, control the atomization pressure at 0.1MPa, the ventilation rate 60m ³ /h, and control the material temperature at 40-42°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to obtain a ball core coated with an isolation layer for subsequent use.

Coating the drug layer: Suspend the drug layer memantine hydrochloride in the aqueous solution containing hypromellose, add talcum powder, mix, stir for at least 30 minutes, use the bottom spray to coat the drug layer on the ball core that has been coated with the isolation layer, The atomization pressure is controlled at 0.1MPa, the ventilation rate is 60m ³ /h, and the material temperature is 35-38°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to obtain the micropills containing the drug layer.

Wrapping the slow-release layer: mix the slow-release layers EudragitRS30D and EudragitRL30D, stir evenly, add triethyl citrate, and stir for 30 minutes to prepare a plasticizer-containing slow-release material liquid. Add talc powder to water, stir for 30 minutes to disperse evenly, add it to the above-mentioned sustained-release material liquid, and continue stirring for at least 30 minutes to obtain a sustained-release layer liquid. The pellets containing the drug layer are placed in a fluidized bed coating machine, the atomization pressure is controlled at 0.1MPa, the ventilation rate is 60m ³ /h, and the material temperature is controlled at 23-28°C. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to obtain the micropills containing the sustained-release layer.

Protective coating layer: dissolve hypromellose E5 in 70% ethanol solution, add magnesium stearate, and stir for at least 15 minutes to prepare a suspension of magnesium stearate. Take the above-mentioned micropellets containing the sustained-release layer and place them in a fluidized bed coating machine, spray and coat the micropellets at the bottom with a suspension of magnesium stearate, control the atomization pressure at 0.1MPa, and ventilate at 60m ³ /h , material temperature 35-38 ℃. After the coating was completed, the atomization pressure was turned off to keep the micropills in a fluidized state for 20 minutes to prepare micropills with a protective layer for subsequent use.

Pack the compressible auxiliary material layer: dissolve a certain amount of PVPK30 in an appropriate amount of water to make a binder solution with a content of 3%; mix the powder of the compressible auxiliary material layer evenly, and place the pellets containing the protective layer prepared above In the fluidized bed, make it fluidized and heated to 25°C, the atomization pressure is controlled at 0.05MPa, the binder solution is sprayed onto the pellets through the atomization spray gun, and the auxiliary material layer powder is wrapped by powder layering On the surface of the micropill with the protective layer, a self-protective multilayer micropill containing a compressible auxiliary material layer is prepared.

The above-mentioned self-protective multi-layer pellets were directly compressed into tablets, and the tablet pressure was controlled so that the tablet hardness was about 45N, and the sustained-release pellets with a tablet weight of 382 mg were pressed into tablets, each containing 21 mg of memantine hydrochloride.

comparative example

The sustained-release pellets containing only the drug layer and the sustained-release layer were prepared according to the composition and method of Example 1, and then 52.5% of the total weight of microcrystalline cellulose, 1.8% of magnesium stearate and 7% of crospovin Ketones were mixed and added to the hopper for tableting. The tableting force was controlled to make the hardness of the tablet close to that of Comparative Example 1 to obtain the comparative preparation.

Get 10 tablets of comparative example preparations, carry out the mensuration of content uniformity, the result shows, wherein the drug content of one tablet is 88.7% of the labeled amount, less than 90%, the average content of 10 tablets is 98.1% of the labeled amount, the standard deviation S=8.1, A+1.8S=16.2>15, the content uniformity inspection failed.

Claims (9)

1. A memantine hydrochloride slow-release pellet tablet is characterized in that, the tablet; is formed by direct compression of a self-protective multilayer pellet, and the self-protective multilayer pellet sequentially from the inside to the outside It comprises drug-containing pellets, a sustained-release layer, a protective layer and a compressible auxiliary material layer; wherein the drug-containing pellets contain memantine hydrochloride and pill-forming materials, and the sustained-release layer contains sustained-release materials, and the The protective layer contains lubricant, and the compressible auxiliary material layer contains filler. 2. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, the drug-containing pellet, slow-release layer, protective layer, compressibility in described self-protection type multilayer pellet The mass ratio of each component of the auxiliary material layer is as follows: drug-containing pellets: sustained-release layer = 4:1-18:1, (medicine-containing pellets + sustained-release layer): protective layer = 10:1-25:1 , (medicine-containing pellets+sustained-release layer+protective layer): compressible auxiliary material layer=1:6-1.5:1. 3. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, the diameter scope of described drug-containing pellet is in 100-1000 μ m; The pelleting material in described drug-containing pellet It is one or more of sucrose and microcrystalline cellulose; the content of memantine hydrochloride in the drug-containing pellets accounts for 3%-40% of the weight of the drug-containing pellets; the drug-containing pellets also contain binder A , wherein the binder A is one or more of hypromellose, ethyl cellulose, polyethylene glycol, povidone, and hypromellose, and the content of binder A accounts for 0.5%-20% of the weight of the pill; the drug-containing pellets contain anti-adhesive agent A or do not contain anti-adhesive agent A, wherein the anti-adhesive agent A is talcum powder, micronized silica gel, magnesium stearate and glycerol monostearate One or more of the esters, the content of the anti-sticking agent A accounts for 0-15% of the weight of the medicine pellets. 4. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, described sustained-release material is ethyl cellulose, Surelease, Aquacoat, acrylic resin EudragitRL, EudragitRS, EudragitRL30D, EudragitRS30D, EudragitNE30D , KollicoatSR30D, one or more of them, the content of slow-release material accounts for 35%-100% of the slow-release layer; the slow-release layer contains one or both of plasticizer and anti-sticking agent B, or not Contains plasticizer and anti-sticking agent B; the plasticizer is one or more of triethyl citrate, polyethylene glycol, tributyl citrate and dibutyl sebacate, and the plasticizer accounts for 0-30% of the release layer; the anti-adhesive agent B is one or more of talcum powder, micropowder silica gel, magnesium stearate and glyceryl monostearate, and the B content of the anti-adhesive agent accounts for the weight of the sustained-release layer 0-65%. 5. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, described protective layer contains lubricant, also contains binding agent B; Described lubricant is magnesium stearate, Sodium stearate fumarate, stearic acid, calcium stearate, sucrose fatty acid ester, fatty acid glyceride, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, polyethylene glycol, One or more of hydrogenated vegetable oil, micronized silica gel, talcum powder, the content of lubricant accounts for 50%-95% of the protective layer; the binder B is hypromellose, ethyl cellulose, poly One or a combination of vitamin ketone, hydroxypropyl cellulose and polyethylene glycol, and the content of the binder accounts for 5%-50% of the weight of the protective layer. 6. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, the filler in described compressible auxiliary material layer is microcrystalline cellulose, lactose, mannitol, sorbitol, wood One or more of sugar alcohols and pregelatinized starches, the content of fillers accounts for 65%-100% of the compressible auxiliary material layer; or also includes binder C, disintegrants and lubricants; the described Binder C includes one or more of hypromellose, povidone, hypromellose, polyethylene glycol, and the content of binder C accounts for 0%-35% of the compressible auxiliary material layer ; Described lubricant comprises one or more in magnesium stearate, sodium stearate fumarate, talcum powder, sodium stearate, stearic acid, and the content of lubricant accounts for the compressible auxiliary material layer 0%-15%; the disintegrating agent includes one or more of crospovidone (PVPP), croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose , the content of the disintegrant accounts for 0%-35% of the compressible auxiliary material layer. 7. prepare the method for memantine hydrochloride slow-release pellet tablet as claimed in claim 1, it is characterized in that, step is as follows: (1) Preparation of drug-containing micropills: take the pellet material as the core of the pellet, and wrap the drug layer on the core of the pellet; (2) Wrap the slow-release layer on the drug-containing pellets, the weight gain of the slow-release layer is in the range of 5%-25%, and the weight gain of the slow-release layer=(the quality of the micro-pills behind the bag slow-release layer-the weight of the drug-containing pellets quality)/quality of drug-containing pellets*100%; (3) Wrap the protective layer outside the slow-release layer, the weight gain range of the protective layer is 2%-15%, and the weight gain of the protective layer=(the quality of the micropills behind the package protective layer-the quality of the micropills after the package slow-release layer) /The quality of the pellets after the sustained release layer*100%; (4) Wrap the compressible auxiliary material layer outside the protective layer, the weight gain of the compressible auxiliary material layer is not less than 40%, and the compressible auxiliary material layer weight gain=(the quality of the micropill after the compressible auxiliary material layer-package The quality of the pellets after the protective layer)/the quality of the pellets after the protective layer*100%. The isolation layer is wrapped or not wrapped before the drug layer, slow-release layer, and protective layer; the material of the isolation layer is one or more of acrylic resin, hypromellose, hypromellose, and povidone. 8. prepare the method for the memantine hydrochloride slow-release pellet tablet as described in any one of claim 1-6, it is characterized in that, step is as follows: (1) Preparation of drug-containing pellets: suspending or dissolving memantine hydrochloride in any proportion of ethanol solution or water containing binder A to make a drug solution containing binder; In the bed coating machine, the pellet core is fluidized and heated to 25°C-50°C, the atomization pressure is controlled at 0.05-0.25MPa, and the above-mentioned drug solution is wrapped on the surface of the pellet core by means of bottom spray, side spray or top spray; After the drug application is completed, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes to prepare pellets containing a drug layer; (2) Pack the slow-release layer: disperse the slow-release material, plasticizer and anti-sticking agent in water or an organic solvent solution, the organic solvent is one or more of ethanol, acetone, and isopropanol, and stir for 15 minutes Above, make the sustained-release material coating solution; put the drug-containing pellets prepared in (1) into the fluidized bed coating machine, make it fluidized and heated to 24 ° C ~ 55 ° C, control the atomization pressure At 0.05-0.25MPa, use the bottom spray, side spray or top spray method to wrap the above coating solution on the surface of the drug-containing pellets; after the coating is completed, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes , prepared micropills containing sustained-release layer; (3) Cover the protective layer: dissolve the adhesive B in the protective layer in any proportion of ethanol solution or water, add a lubricant to make it evenly dispersed, and stir for at least 15 minutes to obtain a suspension containing the lubricant; The pellets containing the sustained-release layer obtained in (2) are placed in a fluidized bed coating machine, fluidized and heated to 24°C-55°C, the atomization pressure is controlled at 0.05-0.25MPa, and bottom spray, Wrap the lubricant-containing suspension on the surface of the pellets containing the sustained-release layer by side spraying or top spraying; after coating, turn off the atomization pressure to keep the pellets in a fluidized state for 5-30 minutes to obtain Micropellets with a protective layer; (4) pack compressible auxiliary material layer: the adhesive C in the auxiliary material layer is dissolved in water to make a content of 0-10% adhesive C solution; the filler in the auxiliary material layer, the disintegrating agent and Mix the lubricant powder evenly and use it as the auxiliary material layer powder; put the protective layer-containing pellets prepared in (3) in a side-spray fluidized bed or a centrifugal granulator, make it fluidized and heat it to 15°C-35°C ℃, control the atomization pressure at 0.01-0.2MPa, spray water or the aqueous solution of binder C onto the pellets through the atomization spray gun, wrap the powder of the auxiliary material layer on the surface of the pellets containing the protective layer, and obtain a compressible Self-protecting multilayer pellets with excipient layer. 9. memantine hydrochloride sustained-release pellet tablet according to claim 1, is characterized in that, the unit dose of memantine hydrochloride is one of 7mg, 14mg, 21mg, 28mg, and the tablet of the latter three dosages also Divisible.