WO2019024310A1

WO2019024310A1 - Pramipexole hydrochloride sustained release preparation and preparation method therefor.

Info

Publication number: WO2019024310A1
Application number: PCT/CN2017/110351
Authority: WO
Inventors: 林浩文; 颜携国; 陶安进; 袁建成
Original assignee: 深圳翰宇药业股份有限公司
Priority date: 2017-07-31
Filing date: 2017-11-10
Publication date: 2019-02-07
Also published as: CN109316466A; CN109316466B

Abstract

A pramipexole hydrochloride sustained release preparation and a preparation method therefor. The sustained release preparation comprises first sustained-release pellets and third sustained-release pellets. The first sustained-release pellets comprise pramipexole hydrochloride first medicated pellets, a first coating, and a second coating. The third sustained-release pellets comprise pramipexole hydrochloride third medicated pellets and a third coating. The content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets is 4:1. The burst effect of pramipexole hydrochloride under acidic conditions can be avoided.

Description

Pramipexole hydrochloride sustained-release preparation and preparation method thereof

This application claims the priority of the Chinese Patent Application filed on July 31, 2017, the Chinese Patent Office, the application number is 201710642262.1, the invention is entitled "a pramipexole hydrochloride sustained-release preparation and its preparation method", the entire contents of which are The citations are incorporated herein by reference.

Technical field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pramipexole hydrochloride sustained-release preparation and a preparation method thereof, in particular to a pramipexole hydrochloride sustained-release capsule and a preparation method thereof.

Background technique

Parkinson's disease (Parkinson Sdisease) is a common slow-developing neurodegenerative disease that occurs in middle-aged and elderly people. It is characterized by resting tremor, myotonia and dyskinesia. As the population ages, its prevalence increases year by year, and it has become a common neurological disease after cerebrovascular disease. For a long time, levodopa-based drug replacement therapy is the first choice for the treatment of Parkinson's disease, but the existing treatment measures can not effectively prevent or even slow the progress of the disease. Treatment of early Parkinson's disease For nearly 30 years, levodopa has been the main effective drug for the treatment of Parkinson's disease, but the long-term use will cause fluctuations in the response including "end-of-agent phenomenon" and "switching phenomenon" and sports complications such as dyskinesia Dystonia. The emergence of a new generation of non-ergoline dopamine receptor agonist pramipexole has brought hope to patients with Parkinson's disease.

Pramexole can be used alone in the treatment of Parkinson's disease, reducing the incidence of dyskinesia caused by levodopa treatment, combined with levodopa, can reduce the dose and adverse reactions of levodopa. Early use of pramipexole in the early use of levodopa can delay the onset of these symptoms and improve the quality of life of patients.

Pramipexole hydrochloride was developed by Boehringer Ingelheim and has the structure shown in Formula 1. Pramipex hydrochloride was approved by the US FDA on July 1, 1997, and then approved by EMA on October 14, 1997. It was approved by the Japanese PMDA on December 2, 2003.

Pramipexole hydrochloride is a non-ergoline dopamine agonist with high in vitro relative specificity and complete intrinsic activity with the dopamine receptor D2 subfamily, and higher affinity to D2 or D4 for the dopamine D3 family.

It is used to improve the symptoms and signs of spontaneous Parkinson's (PD) and moderate to severe restless leg syndrome (RLS).

Pramipexole hydrochloride belongs to the third category in the Biopharmaceutical Classification System (BCS), a highly soluble, low-permeability drug under physiological conditions. The sustained-release preparation refers to a preparation which slowly releases the drug at a constant rate in a prescribed release medium as required, and which has a lower frequency of administration and can increase the compliance or efficacy of the patient in comparison with the conventional preparation. When pramipexole hydrochloride is made into sustained-release pellets, the release rate of the active ingredient can be effectively controlled to achieve the effect of prolonging the action time of the drug.

The currently available pramipexole hydrochloride sustained-release dosage form is a tablet, and an extended release tablet comprising pramipexole and a salt thereof disclosed in Chinese Patent No. CN101005831B, which comprises an active ingredient, a pregelatinized starch in an anionic polymer and a Three water-swellable polymers for sustained release. The anionic polymer described therein is selected from the group consisting of acrylic polymers, grade A acrylic copolymers, alginates, carrageenan, gum arabic, xanthan gum, chitosan, sodium carboxymethylcellulose, and added cellulose calcium. . However, the preparation prepared by the above method has a burst effect under acidic conditions, and the burst effect causes a large amount of drug to be released in a short time, so that the blood level in the body is suddenly increased, and the optimal effect of the drug cannot be achieved. Increase the incidence of adverse reactions.

Summary of the invention

In view of this, the object of the present invention is to provide a defect in the prior art. A sustained release preparation of pramipexole hydrochloride and a preparation method thereof. The sustained release preparation of pramipexole hydrochloride of the invention can also be slowly and slowly released under acidic conditions, thereby effectively avoiding the burst effect of pramipexole hydrochloride under acidic conditions and reducing the incidence of adverse reactions.

In order to achieve the object of the present invention, the present invention adopts the following technical solutions:

A sustained release preparation of pramipexole hydrochloride, comprising first sustained release pellets and third sustained release pellets, the first sustained release pellets comprising pramipexole hydrochloride first drug-containing pellets, a first coating and a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and third sustained-release pellets in the first sustained-release pellet The content of pramipexole hydrochloride is 4:1.

In the pramipexole hydrochloride sustained-release preparation of the present invention, the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets is 4:1, that is, the first The sustained-release pellets are high drug-containing sustained-release pellets, and the third sustained-release pellets are low-drug sustained-release pellets. The first sustained release pellets contain two layers of coating, and the third sustained release pellets contain a coating. The first sustained release pellets have a slower release rate, and the third sustained release release rate is relatively fast. The release rate of the released pellets is different, that is, the release rate of the low drug-containing sustained-release pellets is relatively fast, and the release rate of the high drug-containing sustained-release pellets is slow. In the pramipexole hydrochloride sustained-release preparation of the present invention, two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, and the drug released from the early release is mainly composed of a low drug-containing sustained release microparticle. Pills are provided, and in the later stage (after 2h), the release of the drug is mainly provided by the high drug-containing sustained-release pellets, and can also be slowly and slowly released under acidic conditions, which can effectively avoid the burst effect of pramipexole hydrochloride under acidic conditions.

Wherein the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is made of pramipexole hydrochloride, a first medicinal pellet core, a binder and a solvent, the first The coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is made of a second sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent; The third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is made of pramipexole hydrochloride, a third medicinal pellet core, a binder and a solvent, and the third coating It is made of a third sustained release film material, a plasticizer, an anti-adhesive agent and a solvent.

The first sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention The first drug-containing pellet of pramipexole hydrochloride is prepared from the first medicinal pellet core in the presence of a binder and a solvent. The first medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core. In some embodiments, the first medicinal pellet core is a 0.3-0.425 mm sucrose-type medicinal pellet core.

Preferably, the binder in the first drug-containing pellet is povidone K30. More preferably, povidone k30 has a concentration of 8%.

Preferably, the solvent in the first drug-containing pellet is ethanol. More preferably, it is 95% ethanol.

In the pramipexole hydrochloride sustained-release preparation of the present invention, the first drug-containing pellet of pramipexole hydrochloride is sequentially coated twice with the first coating and the second coating. The first coating is an inner layer coating of the first sustained release pellets, and the second coating is an outer coating of the first sustained release pellets. The first coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is composed of a second sustained release coating material, a plasticizer, an anti-adhesive agent, and Made of solvent.

Preferably, the first sustained release coating material is quaternary ammonium methacrylate copolymer type B (RS) and/or quaternary ammonium methacrylate copolymer type A (RL); the second sustained release coating material It is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion ( 30D), at least one of cellulose acetate and methacrylic acid copolymer type B (S-100).

The first slow release coating material, quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL), are insoluble in water and below pH 7.0, different pH values. There is no effect on the dissolution profile, but pores are formed in the coating film through which the drug releases the drug. The second sustained-release coating material is a water-insoluble material, and the formed film can avoid acid degradation, prevent sudden release under gastric acid conditions, and ensure release of pramipexole hydrochloride in the small intestine in the pramipexole hydrochloride sustained-release preparation. .

In some embodiments, the first sustained release coating material is a mixture of a quaternary ammonium methacrylate copolymer type B (RS) and a quaternary ammonium methacrylate copolymer type A (RL) mass ratio of 9:1. The second sustained release coating material is ethyl cellulose (7 cps) and methyl A mixture of acrylic acid copolymer type B mass ratio of 3:7.

In some embodiments, the first sustained release coating material is an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55) and an aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer (30D) a mixture having a mass ratio of 2:1, the second sustained release coating material being a mixture of cellulose acetate and methacrylic acid copolymer type B (S-100) in a mass ratio of 2:3.

The plasticizer in the first coating and the second coating is preferably triethyl citrate.

The coating process of the present invention also includes an anti-adhesive agent. In the coating process, the drug-containing pellets and the coating film material are rubbed in the coating pan to generate static electricity, and the anti-adhesive agent may be added in the coating process to remove static electricity in time to avoid the adhesion of the drug-containing pellets. Preferably, the anti-adhesive agent in the first coating and the second coating of the present invention is talc.

The solvent in the first coating and the second coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.

The third drug-containing pramipexole hydrochloride in the presence of a binder and a solvent in the third sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention, the pramipexole hydrochloride and the third medicinal pellet core Pellet.

The third medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core.

The third medicinal micropellet core of the third sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention may be the same as or different from the first medicinal micropellet core of the first sustained-release pellet. In some embodiments, the third medicinal pellet core is a 0.5-0.7 mm sucrose-type medicinal pellet core.

Preferably, the binder in the third drug-containing pellet is povidone K30.

Preferably, the solvent in the third drug-containing pellet is ethanol. More preferably, it is 95% ethanol.

The third drug-containing pellet of pramipexole hydrochloride in the pramipexole hydrochloride sustained-release preparation of the present invention is subjected to a third coating. The third coating is made of a third sustained release coating material, a plasticizer, an anti-adhesive, and a solvent.

Preferably, the third sustained release coating material is ethyl cellulose (7 cps), methyl propyl Alkenoic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid At least one of copolymer type B (S-100).

In some embodiments, the third sustained release coating material is methacrylic acid copolymer type B (S-100).

Plasticizers and anti-adherents are also included in the third coating. The plasticizer is preferably triethyl citrate; the anti-adhesive agent is talc.

The solvent in the third coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.

The content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet in the pramipexole hydrochloride sustained-release preparation of the present invention, and the first medicinal pellet core, The ratio of the binder to the solvent is 1:41.7: (1 to 2): (11.8 to 23.6). In some embodiments, the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is the same as that of the first medicinal pellet core, binder, solvent The dosage ratio is 1:41.7:1.3:15.3.

The ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the first coating of the first sustained-release pellet is 1 : (0.11 to 0.15): (0.01 to 0.03): (0.025 to 0.035): (1.58 to 2.16). In some embodiments, the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the first coating is 1:0.11: 0.011: 0.031: 1.58.

The ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the second coating is 1:0.06: (0.005 to 0.007): (0.01 to 0.02): (0.075 to 0.088). In some embodiments, the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the second coating is 1:0.06: 0.006:0.015:0.863.

The ratio of the amount of pramipexole hydrochloride to the third medicinal pellet core, the binder and the solvent in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is 1:166.7: 3 to 4): (34.5 to 46.0). In some embodiments, the third of pramipexole hydrochloride The dosage ratio of pramipexole hydrochloride to the third medicinal pellet core, binder and solvent in the drug-containing pellets was 1:166.7:3.33:38.3.

The ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the third coating is 1:0.025: (0.002 to 0.003): (0.005 to 0.0065): 0.475. In some embodiments, the ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the third coating is 1:0.025:0.0025 : 0.00625: 0.475.

In the sustained-release preparation of the present invention, the particle diameter of the first sustained-release pellet and the third sustained-release pellet is preferably 24-40 mesh.

The sustained release preparation of the present invention may be a capsule, and the first sustained release pellet and the third sustained release pellet are mixed according to a certain ratio, and the pramipexole hydrochloride sustained-release capsule can be obtained by filling the pharmaceutical capsule. It is worth noting that the mixing ratio of the first sustained-release pellets and the third sustained-release pellets in the pramipexole hydrochloride sustained-release capsule is not limited as long as the pramipexole hydrochloride and the third in the first sustained-release pellet are ensured. The content ratio of pramipexole hydrochloride in the sustained-release pellets is 4:1.

Preferably, the medicinal capsule is a medicinal gelatin capsule, such as 0# capsule, 1# capsule, 2# capsule, 3# capsule, 4# capsule, 5# capsule, and the like.

The invention also provides a preparation method of the sustained release preparation of pramipexole hydrochloride, comprising the following steps:

1) mixing pramipexole hydrochloride with the first medicinal micropellet core, binder and solvent to prepare the first drug-containing pellet, drying and sieving; pramipexole hydrochloride and the third medicinal pellet core, sticky Mixing the mixture and the solvent to prepare the third drug-containing pellet, drying and sieving;

2) mixing the first sustained release coating material with a plasticizer, an anti-adhesive agent and a solvent to prepare a first coating liquid, coating the first drug-containing pellets to form a first coating, drying and sieving Sustained-release pellet A; mixing the second sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a second coating liquid, and coating the sustained-release pellet A to form a second coating, after drying Screening the first sustained release pellets;

3) mixing the third sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a third coating liquid, and coating the second drug-containing pellet to form a third coating, which is dried and sieved. Third Sustained release pellets;

4) mixing the first sustained-release pellets with the third sustained-release pellets, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets 4:1;

Wherein, the order of step 2) and step 3) is in no particular order.

The pelletizing process has certain requirements on the particle size of the material. Preferably, in the preparation method of the present invention, the pramipexole hydrochloride raw material is subjected to micronization treatment to increase the specific surface area of the raw material, so that the drug in the micropellet administration process can be uniformly distributed on the pellets, and at the same time obtain a circle. Better pellets. In some embodiments, the particle size of the micronized pramipexole hydrochloride is controlled to be less than 20 μm at D(90),

The first drug-containing pellet and the third drug-containing pellet obtained in the above step (1) of the preparation method need to be dried and sieved in time to avoid adhesion of the pellet. Preferably, the dry sieving is dried at 30-40 ° C, and the pellets between 30-60 mesh are collected by sieving.

In the coating process in the above preparation steps 2) and 3), the temperature of the pellets in the fluidized bed should be controlled between 20 and 30 °C. At the beginning of the spray, a lower spray rate should be used to prevent solvent/water from penetrating into the interior of the pellet. After the pellet is coated with a film, the spray rate can be increased.

Residual solvent or water will have the effect of increasing the speed and thus affect the permeability of the film. Therefore, after the completion of the pellet coating, the pellets need to be dried afterwards. Preferably, the drying process is dried at 40 ° C for 24 h.

Preferably, the coating of step 2) and step 3) is sieved to a dry sieve and passed through a 24-40 mesh sieve to collect pellets between 24 and 40 mesh.

According to the above technical solution, the present invention provides a pramipexole hydrochloride sustained-release preparation and a preparation method thereof. The sustained release preparation of pramipexole hydrochloride of the present invention comprises a first sustained release pellet and a third sustained release pellet, the first sustained release pellet comprising pramipexole hydrochloride first drug-containing pellet, first coating And a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and the third sustained release microparticle in the first sustained-release pellet The content of pramipexole hydrochloride in the pellet was 4:1. Hydrochloride in two sustained-release pellets The content ratio of the lacquer is 4:1, while the first sustained-release pellet contains two coats, and the third sustained-release pellet contains a coat, and the release rates of the two sustained-release pellets are different. In the pramipexole hydrochloride sustained-release preparation of the invention, two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, which can be slowly and slowly released under acidic conditions, thereby effectively avoiding hydrochloric acid. The burst effect of pramipexole under acidic conditions. The preparation method of the sustained-release preparation of pramipexole hydrochloride of the invention is simple in operation and suitable for industrialization.

DRAWINGS

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art description will be briefly described below.

Figure 1 shows the release profile of Example 3 in a pH 1.2 medium;

Figure 2 shows the release profile of Example 5 in each dissolution medium.

Detailed ways

The invention discloses a pramipexole hydrochloride sustained-release preparation and a preparation method thereof. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and product of the present invention have been described by the preferred embodiments, and it is obvious that those skilled in the art can change or appropriately modify and combine the methods described herein to implement and apply the present invention without departing from the spirit, scope and scope of the invention. Invention technology.

For a better understanding of the present invention, the embodiments of the present invention will be clearly and completely described in the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, but not all embodiments. . All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

Unless otherwise stated, the reagents involved in the examples of the present invention are all commercially available products, both of which are Can be purchased through commercial channels.

Example 1: Preparation of drug-containing pellets

1. Prescription of high-containing pellets:

2. Prescription of low-containing pellets:

3. Preparation process

3.1 pretreatment of raw materials: pramipexole hydrochloride micronized treatment, particle size control D (90) is less than 20μm;

3.2 Pills: The medicinal pellets are added to the centrifugal granulator for the pellets, and the binder is 8% povidone K30; after the pellets are finished, the pellets are placed at 30- Drying was carried out at 40 °C.

3.3 Screening treatment: The drug-containing pellets are sieved to retain the pellets between 30-60 mesh.

Example 2:

The high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film, and the film material was quaternary ammonium methacrylate copolymer type B (RS), quaternary ammonium methacrylate copolymer type A (RL), and B. Base cellulose (7 cps) and methacrylic acid copolymer type B (S-100) gave high drug-containing sustained release pellets. The prescription is shown in Table 1.

Table 1 High drug-containing sustained-release pellets release film prescription

Preparation Process

1, the first layer of clothing film

1.1, the preparation of coating liquid

(1) dissolving quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL) in 95% ethanol, stirring until completely dissolved;

(2) After completely dissolving, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.

1.2, fluidized bed coating: the pellets are placed in a fluidized bed for coating, the temperature of the pellets in the fluidized bed is controlled between 20-30 °C.

1.3, dry curing:

After the end of the coating, 0.5% talc was added as an anti-adhesive agent, and the pellet was dried at 40 ° C for 24 hours or more. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained release pellets A.

2, the second layer of clothing film

2.1, the preparation of coating liquid

(1) Ethyl cellulose (7 cps) and methacrylic acid copolymer type B (S-100) are dissolved in 95% ethanol and stirred until completely dissolved;

2.2. Fluidized bed coating: The high-medicine sustained-release pellets containing the first layer of the coating film are placed in the second layer of the fluidized bed package, and the operation process is consistent with the first layer of the coating film.

2.3, dry curing:

After coating, the pellets were dried at 40 ° C for more than 24 hours. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are sustained-release pellets B (high drug-containing sustained-release pellets).

Example 3:

The high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film to obtain a high drug-containing sustained-release pellet. The coating film material is methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid copolymer Type B (S-100). The prescription is shown in Table 2.

Table 2 High drug-containing sustained-release pellets release film prescription

The high drug-containing pellets prepared in Example 1 were placed in a fluidized bed for coating.

Preparation Process:

1, the first layer of clothing film

1.1, the preparation of coating liquid

(1) dissolving a methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and a quaternary ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) in purified water, stirring until completely dissolved;

(2) After completely dissolved, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.

1.3, dry curing:

2, the second layer of clothing film

(1) Dissolving cellulose acetate and methacrylic acid copolymer type B (S-100) in 95% ethanol, stirring until completely dissolved;

2.3, dry curing:

After coating, the pellets were dried at 40 ° C for more than 24 hours. The dried pellets pass through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained-release pellets B (high drug-containing buffer) Released Pills).

The cellulose acetate obtained in the sustained release pellet B (high drug-containing sustained-release pellet) is a water-insoluble coating material, an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55), ethyl acrylate- The methyl methacrylate copolymer aqueous dispersion (30D) is insoluble at pH 7.0 or lower, and different pH values have no effect on the dissolution profile, and the drug release is diffused through the pores of the coating film. The release profile of the medium at pH 1.2 is shown in Figure 1.

Example 4

The low drug-containing pellets sustained release coating film prepared in Example 1 was used to obtain a low drug-containing sustained-release pellet, and the coating film material was a methacrylic acid copolymer type B (S-100). The prescription is shown in Table 3.

Table 3 Low drug-containing sustained-release pellets release film prescription

Preparation Process:

1. Preparation of coating liquid

(1) Dissolving methacrylic acid copolymer type B (S-100) in 95% ethanol and stirring until completely dissolved;

2. The low-medication pellets prepared in Example 1 were placed in a fluidized bed for coating treatment, and then the pellets were dried at 40 ° C for 24 hours or more for curing treatment. The temperature of the pellets in the fluidized bed is controlled between 20-30 °C.

The sustained release pellets prepared in the above Example 2, Example 3, and Example 4 were tested for the content of pramipexole hydrochloride, and the amount of the sustained release capsule was calculated based on the content. Listed in Table 4 below It is the content of pramipexole hydrochloride of the sustained release pellets of three specific examples:

Table 4 Example of sustained release pellets of pramipexole hydrochloride

实施例Example	盐酸普拉克索含量(％)Pramipexole hydrochloride content (%)
实施例2Example 2	1.98％1.98%
实施例3Example 3	1.90％1.90%
实施例4Example 4	0.55％0.55%

The high drug-containing sustained-release pellets and the low drug-containing sustained-release pellets are mixed in a certain proportion, wherein the high drug-containing sustained-release pellets comprise 4 parts of pramipexole hydrochloride, and the low drug-containing sustained-release pellets comprise 1 part of pramipexole hydrochloride In order to calculate the amount of the two sustained release pellets.

Example 5

121 mg of the sustained-release pellets prepared in Example 2 and 109 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 3 mg, wherein the high drug-containing microparticles prepared in Example 2 were obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.

The prepared 3 mg pramipexole hydrochloride sustained-release capsules were placed in pH 1.2, pH 4.5, pH 6.8 and water for release experiments, and the preparation of pramipexole hydrochloride sustained-release capsules in each dissolution medium was compared. The effect of the release effect, the results shown in Figure 2.

The release curves of the obtained pramipexole hydrochloride sustained-release capsules in each dissolution medium were compared, and the results showed that the prepared pramipexole hydrochloride sustained-release capsules were slowly released in each dissolution medium, and there was no sudden release phenomenon.

Example 6

126 mg of the sustained-release pellets prepared in Example 3 and 109 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 3 mg, wherein the high-medication micropellets prepared in Example 3 were obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.

Example 7

60.5 mg of the sustained-release pellets prepared in Example 2 and 54.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 1.5 mg, wherein the high content of the preparation of Example 2 was obtained. The ratio of pramipexole hydrochloride in the pellets of the drug pellets to the low-medication pellets prepared in Example 4 was 4:1.

Example 8

63 mg of the sustained-release pellets prepared in Example 3 and 54.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a 1.5 mg-molecular Lactobacillus hydrochloride sustained-release capsule, wherein the high-medication microparticle prepared in Example 3 was obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.

Example 9

181.5 mg of the sustained-release pellets prepared in Example 2 and 163.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 4.5 mg, wherein the high content of the preparation of Example 2 was obtained. The ratio of pramipexole hydrochloride in the pellets of the drug pellets to the low-medication pellets prepared in Example 4 was 4:1.

Example 10

189 mg of the sustained-release pellets prepared in Example 3 and 163.5 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 4.5 mg, wherein the high-medication prepared in Example 3 was obtained. The ratio of pramipexole hydrochloride in the pellets in the pellets to the low-medication pellets prepared in Example 4 was 4:1.

The amounts of the two kinds of pellets in the above Examples 5 to 10 are not a fixed value, and the amount thereof is converted based on the pramipexole hydrochloride content in the two kinds of sustained-release pellets, and the above is one of the embodiments. The ratio of pramipexole hydrochloride to pramipexole hydrochloride in the high drug-containing pellets in each of the above examples was 4:1.

Comparing the release curves of pramipexole hydrochloride sustained-release capsules prepared in Examples 6 to 10 in each dissolution medium, the results showed that the pramipexole hydrochloride sustained-release capsules prepared in Examples 6 to 10 were each dissolved. The medium can also be released slowly without sudden release.

Claims

A sustained release preparation of pramipexole hydrochloride, comprising: first sustained release pellets and third sustained release pellets, wherein the first sustained release pellet comprises pramipexole hydrochloride first drug-containing pellets, a coating and a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexine hydrochloride and the third in the first sustained-release pellet The content ratio of pramipexole hydrochloride in the sustained release pellets was 4:1.
The sustained-release preparation according to claim 1, wherein the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is composed of pramipexole hydrochloride, a first medicinal pellet core, Made of a binder and a solvent, the first coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is composed of a second sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent; the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet comprises pramipexole hydrochloride, a third medicinal pellet core, and a binder The agent is prepared from a third sustained release film material, a plasticizer, an anti-adhesive agent, and a solvent.
The sustained release preparation according to claim 2, wherein the first medicinal pellet core in the first drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type a medicinal micropellet pellet; the first sustained release coating material is a quaternary ammonium methacrylate copolymer type B (RS) and/or a quaternary ammonium methacrylate copolymer type A (RL); the second sustained release The coating material is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer water At least one of the dispersion (30D), cellulose acetate, and methacrylic acid copolymer type B (S-100).
The sustained release preparation according to claim 3, wherein the first medicinal pellet core in the first drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core, and the binder is Povidone K30; the first sustained release coating material is a mixture of quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL) mass ratio of 9:1 or a mixture of an aqueous acrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and an ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) having a mass ratio of 2:1; the second sustained release coating The membrane material is ethyl cellulose (7 cps) and methacrylic acid a mixture having a mass ratio of B:3:7 or a mixture of cellulose acetate and methacrylic acid copolymer type B (S-100) in a mass ratio of 2:3; the plasticizer is triethyl citrate; The anti-adhesive agent is talc; the solvent is 95% ethanol.
The sustained release preparation according to claim 2, wherein the third medicinal pellet core in the third drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type a medicinal micropellet core; the third sustained release film material is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), At least one of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, and methacrylic acid copolymer type B (S-100).
The sustained release preparation according to claim 5, wherein the third medicinal pellet core in the third drug-containing pellet is 0.5-0.7 mm sucrose-type medicinal pellet core, and the binder is Povidone K30; the third sustained release coating material is methacrylic acid copolymer type B (S-100); the plasticizer is triethyl citrate; the anti-adhesive agent is talc; The solvent is 95% ethanol.
The sustained-release preparation according to claim 2, wherein the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is the first medicinal micro-pill The ratio of the core, the binder and the solvent is 1:41.7: (1 to 2): (11.8 to 23.6); the first drug-containing pellet of the pramipexole hydrochloride in the first coating and the first sustained release The ratio of the film material, plasticizer, anti-adhesive agent and solvent is 1: (0.11 - 0.15): (0.01 - 0.03): (0.025 - 0.035): (1.58 - 2.16); The ratio of the first drug-containing pellets of pramipexole hydrochloride to the second sustained-release film material, plasticizer, anti-adhesive agent and solvent is 1:0.06: (0.005-0.007): (0.01-0.02): 0.075 to 0.088);

The ratio of the amount of pramipexole hydrochloride to the third medicinal pellet core, the binder and the solvent in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is 1:166.7: 3 to 4): (34.5 to 46.0); the ratio of the third drug-containing pellets of pramipexole hydrochloride to the third sustained-release film material, plasticizer, anti-adhesive agent and solvent in the third coating It is 1:0.025: (0.002 to 0.003): (0.005 to 0.0065): 0.475.
The sustained release preparation according to claim 1, wherein the preparation is a capsule The agent also includes a medicinal gelatin capsule.
A method for preparing a sustained release preparation of pramipexole hydrochloride according to claim 1, comprising the steps of:

1) mixing pramipexole hydrochloride with the first medicinal micropellet core, binder and solvent to prepare the first drug-containing pellet, drying and sieving; pramipexole hydrochloride and the third medicinal pellet core, sticky Mixing the mixture and the solvent to prepare the third drug-containing pellet, drying and sieving;

2) mixing the first sustained release coating material with a plasticizer, an anti-adhesive agent and a solvent to prepare a first coating liquid, coating the first drug-containing pellets to form a first coating, drying and sieving Sustained-release pellet A; mixing the second sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a second coating liquid, and coating the sustained-release pellet A to form a second coating, after drying Screening the first sustained release pellets;

3) mixing the third sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a third coating liquid, and coating the second drug-containing pellet to form a third coating, which is dried and sieved. Third sustained release pellets;

4) mixing the first sustained-release pellets with the third sustained-release pellets, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets 4:1;

Wherein, the order of step 2) and step 3) is in no particular order.
The preparation method according to claim 9, wherein the step 1) the granule D (90) of pramipexole hydrochloride is less than 20 μm; the step 1) is dried and sieved to dry at 30-40 ° C, The sieve collects the pellets between 30-60 mesh; the coating temperature of step 2) and step 3) is controlled at 20-30 ° C; the drying of the step 2) and the step 3) is carried out at 40 ° C Dry for more than 24 hours, dry and pass through a 24-40 mesh sieve to collect pellets between 24-40 mesh.