WO2020248361A1 - Pramipexole dihydrochloride sustained release tablet and preparation method therefor - Google Patents

Abstract

Provided is a pramipexole sustained release tablet, wherein same is prepared from the following components, with the sum of the components being 100%: 0.12-0.45％ of pramipexole dihydrochloride, 50-60％ of a filler, 25-35％ of a sustained release matrix, 8-12％ of an adhesive, 0.3-3％ of a glidant, and 0.1-1.0％ of a lubricant. The sustained release matrix is Eudragit RD, hydroxypropyl methylcellulose K100M or a combination thereof, preferably the combination of Eudragit RD and hydroxypropyl methylcellulose K100M. The ratio of the glidant to the lubricant is glidant : lubricant = 0.5 to 10, preferably 0.6 to 8.

Description

Pramipexole hydrochloride sustained-release tablet and preparation method thereof Technical field

The invention relates to a preparation process of pramipexole hydrochloride sustained-release tablets and belongs to the field of pharmaceutical preparations.

Background technique

Parkinson's disease (Parkinson disease, PD) is a chronic progressive disease. Its main pathological feature is the degeneration of dopaminergic neurons in the substantia nigra striatum, leading to a decrease in dopaminergic nerve endings and dopamine in the striatum. The clinical symptoms are tremor Paralysis, rigidity, or movement disorders.

Pramipexole, also known as Mirapa, is a dopamine D2 receptor agonist and an antihistamine. It is mainly used clinically to treat Parkinson's disease and its syndromes. The drug form usually used in pharmacy is pramipexole dihydrochloride monohydrate (molecular formula is C ₁₀ H ₁₇ N ₃ S·2HCl·H ₂ O), which is a highly soluble compound with a water solubility greater than 20 mg/ ml, and the solubility in a buffer medium with a pH of 2 to 7.4 is generally above 10 mg/ml. Pramipexole dihydrochloride monohydrate has very low hygroscopicity and high crystallinity, and its crystal modification will not change in the grinding state. Pramipexole dihydrochloride monohydrate is very stable in the solid state, but has photosensitivity in the solution state.

In 1997, pramipexole immediate-release tablets (IR) were approved to be marketed in the USA, but due to the problem of unstable storage of the tablets, only about 95% of the average labeled active ingredients in the tablets after 18 months of storage, so This affects the efficacy of the drug and increases the cost and safety of manufacturing and patient medication.

In 2010, the US FDA approved the Pramipexole Hydrochloride Sustained Release Tablet Mirapex ER developed by Boehringer Ingelheim Pharmaceutical Co., Ltd. to be taken once a day for the treatment of signs and symptoms of early and advanced Parkinson's patients.

Mirapex ER original manufacturer's patent (CN101005831) adopts the powder direct pressing process. The auxiliary materials include: hypromellose, corn starch, carbomer homopolymer, colloidal silicon dioxide and magnesium stearate. First, the active ingredients are combined with some The excipients are ground together and then mixed with other excipients. Due to the small specifications of pramipexole, there are 0.375mg, 0.75mg, 1.5mg, 2.25mg, 3mg, 3.75mg, 4.5mg. The content of the tablets varies greatly, and the content is uniform. It is difficult to guarantee.

In addition, the release of Mirapex ER, a commercially available formulation, is greatly affected by ionic strength. The release in vitro is relatively high in pH 1.2, pH 4.5, and pH 6.8 media, but the release in water is low, with only about 20% released in 24 hours. Due to the complex changes in ionic strength in the human gastrointestinal tract, it is difficult to control the release of the commercially available Mirapex ER in the body.

Chinese patent CN201210351475.6 discloses a pramipexole hydrochloride sustained-release tablet, the components mainly include pramipexole hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, and its preparation The process adopts a granulation mechanism and is dried after granulation. Due to the ratio of the components and the preparation process, the prepared sustained-release tablets still lack uniformity. In addition, pramipexole hydrochloride is sensitive to moisture and is prone to Degradation, wet granulation cannot guarantee product stability.

Chinese patent CN201310186202.5 discloses a pramipexole hydrochloride sustained-release preparation, the components mainly include pramipexole hydrochloride, hydroxypropylmethyl cellulose, starch, hydroxypropyl cellulose, microparts, magnesium stearate, and the preparation process Using powder to directly compress tablets also has the problem of low uniformity.

Summary of the invention

In order to solve the above technical problems, the present inventors provide a preparation method of pramipexole sustained-release tablets. It is planned to use the powder direct compression method to improve the fluidity of the material by optimizing the ratio of glidant and lubricant, and the obtained particles have good fluidity. , The compressibility is good, the content of the prepared product is uniform, and the content difference is small. By setting the combination ratio of the sustained release matrix, the release rate of the drug from the dosage form is delayed, and the in vitro release is not affected by pH changes.

One aspect of the present invention provides a pramipexole sustained-release tablet, which is made of the following components, and the sum of the components is 100%:

Component	Mass percentage (%)
Pramipexole hydrochloride	0.12-0.45
Filler	50-60
Slow release matrix	25-35
Adhesive	8-12
Glidant	0.3-3
Lubricant	0.1-1.0

Wherein, the sustained-release matrix is Eudragit RD, hypromellose K100M or a combination thereof, preferably a combination of Eudragit RD and hypromellose K100M;

The ratio of glidant to lubricant is glidant: lubricant = 0.5-10, preferably 0.6-8.

In the technical solution of the present invention, the sustained-release matrix is a combination of Eudragit RD and hypromellose K100M; and the mass ratio of Eudragit RD and hypromellose K100M is 1.3-3:1.

In the technical scheme of the present invention, the filler is selected from one or more of microcrystalline cellulose, lactose, anhydrous calcium hydrogen phosphate, and corn starch; preferably, the microcrystalline cellulose is microcrystalline cellulose 102. Microcrystalline cellulose 112 or a combination thereof; more preferably a combination of microcrystalline cellulose and anhydrous calcium hydrogen phosphate.

In the technical scheme of the present invention, the binder is selected from hypromellose K4M, povidone K29/32 or a combination thereof.

In the technical scheme of the present invention, the glidant is selected from sodium stearyl fumarate, talc, micropowder silica gel or a combination thereof.

In the technical scheme of the present invention, the lubricant is selected from magnesium stearate, glyceryl behenate or a combination thereof.

In the technical scheme of the present invention, the pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.12%-0.18%, microcrystalline cellulose 102 33%-36%, anhydrous calcium hydrogen phosphate 22%-24%, Eudragit RD 17%-19%, hypromellose K100M 10%-14%, hypromellose K4M 9-11%, Sodium stearyl fumarate 0.3-0.5%, magnesium stearate 0.2-0.4%.

In the technical scheme of the present invention, the pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.12%-0.18%, microcrystalline cellulose 112 33%-36%, anhydrous calcium hydrogen phosphate 22%-24%, Eudragit RD 20%-22%, hypromellose K100M 6%-8%, povidone K29/32 10%-12% , Sodium stearyl fumarate 0.4%-0.6%, glyceryl behenate 0.7-0.9%.

In the technical scheme of the present invention, the pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.3%-0.5%, microcrystalline cellulose 102 33%-36%, anhydrous calcium hydrogen phosphate 23%-25%, Eudragit RD 20%-22%, hypromellose K100M 6%-9%, hypromellose K4M 9-11%, Talc 0.8-1.2%, magnesium stearate 0.4-0.6%.

In the technical scheme of the present invention, the pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.15%-0.35%, microcrystalline cellulose 102 35%-38%, anhydrous calcium hydrogen phosphate 17%-19%, Eudragit RD 16%-20%, hypromellose K100M 12%-15%, povidone K29/32 10-12%, Sodium stearyl fumarate is 1-3%, magnesium stearate is 0.1-0.5%.

In the technical scheme of the present invention, the pramipexole sustained-release tablet is obtained by a powder direct compression method.

In the technical scheme of the present invention, the powder direct compression method includes the following steps:

Step 1: Take pramipexole hydrochloride and sieve;

Step 2: pramipexole hydrochloride and glidant, sustained-release material obtained in step 1, and 15-35% of the total filler and the filler and mix well;

Step 3: After step 2 is completed, add the binder and the filler which will account for 15-35% of the total filler, and mix well;

Step 4: After step 3 is completed, add the remaining filler and mix well;

Step 5: After step 4 is completed, the lubricant is added and mixed to obtain an intermediate;

Step 6: Press the tablet and get it.

The prior art adopts a powder direct compression process, the content of the tablets varies greatly, the content uniformity is difficult to guarantee, the product release is faster, and the release in the body is difficult to control. Solving the problem of content uniformity in the direct pressure state has always troubled R&D personnel. The technology of the present invention adjusts and optimizes the ratio of glidant and lubricant, and sets the combination ratio of sustained-release matrix, which solves the problem of uneven uniformity of sustained-release preparations in the prior art. At the same time, it delays the release rate of the drug from the dosage form and reduces the body’s absorption rate of the drug, which can maintain a relatively stable blood concentration of the drug in the body, continue to exert the drug effect, reduce the number of administrations, and stabilize the treatment The effect is conducive to improving patient compliance.

Beneficial effect

The sustained-release preparation of the present invention can achieve the purposes of high uniformity and delayed release at the same time, and the direct compression method is adopted to avoid the decomposition of the drug.

Detailed ways

The reagents used in the examples are listed below:

Mirapex ER commercial product: Boehringer Ingelheim (Boehringer Ingelheim)

Pramipexole Hydrochloride: Homemade

Lactose, microcrystalline cellulose 102, microcrystalline cellulose 112: FMC

Anhydrous calcium hydrogen phosphate, carbomer: BASF

Hypromellose K100M, Hypromellose K4M: Dow Chemical

Eudragit RD: Evonik

Sodium stearate fumarate, glyceryl behenate: JRS

Magnesium stearate: Liaocheng, Shandong

In order to further understand the present invention, the present invention will be described in detail below in conjunction with embodiments.

Example 1: Preparation of a sustained-release pramipexole hydrochloride tablet

Prescription: the specification is 0.375mg, the prescription is 2000 tablets

Preparation Process:

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix pramipexole hydrochloride obtained in step 1 with 30% microcrystalline cellulose 102 and sodium stearyl fumarate for 5 minutes; after completion, add Eudragit RD and hypromellose K100M in sequence, and mix for 5 minutes;

Step 3: After step 2 is completed, add hypromellose K4M and the remaining 70% microcrystalline cellulose, and mix for 10 minutes;

Step 4: After step 3 is completed, add anhydrous calcium hydrogen phosphate and mix for 5 minutes;

Step 5: After step 4 is completed, magnesium stearate is added and mixed for 3 minutes to obtain an intermediate;

Step 6: Tableting

Example 2: Preparation of a pramipexole hydrochloride sustained-release tablet

Prescription: the specification is 0.375mg, the prescription is 2000 tablets

Process:

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix pramipexole hydrochloride obtained in step 1 with 30% microcrystalline cellulose 112 and hard sodium fumarate for 5 minutes; after completion, add Eudragit RD and hypromellose K100M in sequence, and mix for 5 minutes;

Step 3: After step 2 is completed, add povidone K29/30 and the remaining 70% microcrystalline cellulose 112, and mix for 10 minutes;

Step 4: After step 3 is completed, add anhydrous calcium hydrogen phosphate and mix for 5 minutes;

Step 5: After step 4 is completed, add glyceryl behenate and mix for 3 minutes to obtain an intermediate;

Step 6: Tableting

Example 3: Preparation of a pramipexole hydrochloride sustained-release tablet

Prescription: Specification 1.5mg, prescription amount 2000 tablets

Process:

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix pramipexole hydrochloride obtained in step 1 with 30% microcrystalline cellulose 102 and sodium stearyl fumarate for 5 minutes; after completion, add Eudragit RD and hypromellose K100M in sequence, and mix for 5 minutes;

Step 3: After step 2 is completed, add hypromellose K4M and the remaining 70% microcrystalline cellulose 102, and mix for 10 minutes;

Step 4: After step 3 is completed, add anhydrous calcium hydrogen phosphate and mix for 5 minutes;

Step 5: After step 4 is completed, magnesium stearate is added and mixed for 3 minutes to obtain an intermediate;

Step 6: Tableting

Example 4: Preparation of a pramipexole hydrochloride sustained-release tablet

Prescription: the specification is 0.75mg, the prescription is 2000 tablets

Process:

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix pramipexole hydrochloride obtained in step 1 with 30% microcrystalline cellulose 102 and sodium stearyl fumarate for 5 minutes; after completion, add Eudragit RD and hypromellose K100M in sequence, and mix for 5 minutes;

Step 3: After step 2 is completed, add povidone K29/32 and the remaining 70% microcrystalline cellulose 102, and mix for 10 minutes;

Step 4: After step 3 is completed, add anhydrous calcium hydrogen phosphate and mix for 5 minutes;

Step 5: After step 4 is completed, magnesium stearate is added and mixed for 3 minutes to obtain an intermediate;

Step 6: Tableting

Comparative Example 5: Prepared according to the original formula

Prescription: the specification is 0.375mg, the prescription is 2000 tablets

ingredient	Prescription 5	Features
Pramipexole hydrochloride	0.15	Active ingredient
Microcrystalline Cellulose 102	49.30	Filler
corn starch	26.50	Filler

Carbomer	22.80	Slow release matrix
Micronized silica gel	0.60	Glidant
Magnesium stearate	0.65	Lubricant

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix pramipexole hydrochloride obtained in step 1 with 30% microcrystalline cellulose 102 and micronized silica gel for 5 minutes; add carbomer after completion and mix for 5 minutes;

Step 3: After step 2 is completed, add the remaining 70% microcrystalline cellulose 102 and mix for 10 minutes;

Step 4: After step 3 is completed, add corn starch and mix for 5 minutes;

Step 5: After step 4 is completed, magnesium stearate is added and mixed for 3 minutes to obtain an intermediate;

Step 6: Tableting

Comparative Example 6-14: Prepared according to the composition of prescription 6-14 in Table 1

Process:

Step 1: Take pramipexole hydrochloride and pass through 80 mesh screen

Step 2: Mix the pramipexole hydrochloride obtained in step 1 with 30% filler and glidant for 5 minutes; after completion, add the sustained-release matrix and mix for 5 minutes;

Step 3: After step 2 is completed, add the adhesive and the remaining 70% filler, and mix for 10 minutes;

Step 4: After the completion of step 4, add lubricant and mix for 3 minutes to prepare intermediate;

Step 5: Press tablets.

It can be seen from the results in Table 2 that the content uniformity A+1.80S values of Examples 1, 2, 3, and 4 are all less than 2.5, and the results are significantly less than the 404649 batches and 603801 batches of the commercially available products, indicating that the relatively original research can be obtained through the process of the invention. The manufacturer's better content uniformity, and in comparison with Example 5, the content uniformity A+1.80S value is significantly greater than that of Examples 1, 2, 3, and 4, indicating that the use of different auxiliary materials will have a significant and significant impact on the content uniformity.

Example 7: Determination of in vitro release

Take 900ml of pH6.8 phosphate buffer as the release medium, rotate at 50 rpm, and sample at 2h, 4h, 6h, 8h, 12h and 24h. The release (%) results of different prescription drugs at different time points are as follows:

The description of the above embodiments is only used to help understand the method and core idea of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (9)

1. A sustained-release pramipexole tablet, which is made of the following components, and the sum of the components is 100%:

   Component Mass percentage (%) Pramipexole hydrochloride 0.12-0.45 Filler 50-60 Slow release matrix 25-35 Adhesive 8-12 Glidant 0.3-3 Lubricant 0.1-1.0

   Wherein, the sustained-release matrix is Eudragit RD, hypromellose K100M or a combination thereof, preferably a combination of Eudragit RD and hypromellose K100M;

   The ratio of glidant to lubricant is glidant: lubricant = 0.5-10, preferably 0.6-8.
2. The pramipexole sustained-release tablet according to claim 1, wherein the sustained-release matrix is a combination of Eudragit RD and hypromellose K100M; and the mass ratio of Eudragit RD and hypromellose K100M is 1.3-3:1.
3. The pramipexole sustained-release tablet according to any one of claims 1-2, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, anhydrous calcium hydrogen phosphate, and corn starch; preferably Ground, the microcrystalline cellulose is microcrystalline cellulose 102, microcrystalline cellulose 112 or a combination thereof; more preferably, it is a combination of microcrystalline cellulose and anhydrous calcium hydrogen phosphate.
4. The pramipexole sustained-release tablet according to any one of claims 1 to 3, wherein the binder is selected from hypromellose K4M, povidone K29/32 or a combination thereof.
5. The pramipexole sustained-release tablet according to any one of claims 1 to 4, wherein the glidant is selected from the group consisting of sodium stearyl fumarate, talc, micro-powder silica gel or a combination thereof.
6. The pramipexole sustained-release tablet according to any one of claims 1 to 5, wherein the lubricant is selected from magnesium stearate, glyceryl behenate or a combination thereof.
7. The pramipexole sustained-release tablet according to any one of claims 1-6, which is obtained by a powder direct compression method.
8. The pramipexole sustained-release tablet according to any one of claims 1-7, the pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride Cable 0.12%-0.18%, microcrystalline cellulose 102 33%-36%, anhydrous calcium hydrogen phosphate 22%-24%, Eudragit RD 17%-19%, hypromellose K100M 10%-14%, Hypromellose K4M 9%-11%, sodium stearyl fumarate 0.3%-0.5%, magnesium stearate 0.2%-0.4%; or,

   The pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.12%-0.18%, microcrystalline cellulose 112 33%-36%, no Water calcium hydrogen phosphate is 22%-24%, Eudragit RD 20%-22%, hypromellose K100M 6%-8%, povidone K29/32 10%-12%, sodium stearyl fumarate 0.4 %-0.6%, glyceryl behenate 0.7-0.9%; or,

   The pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.3%-0.5%, microcrystalline cellulose 102 33%-36%, no Hydrogen calcium phosphate is 23%-25%, Eudragit RD 20%-22%, hypromellose K100M 6%-9%, hypromellose K4M 9%-11%, talc 0.8%-1.2% , Magnesium stearate 0.4%-0.6%; or,

   The pramipexole sustained-release tablet is made of the following components, and the sum of the components is 100%: pramipexole hydrochloride 0.15%-0.35%, microcrystalline cellulose 102 35%-38%, no Water calcium hydrogen phosphate is 17%-19%, Eudragit RD 16%-20%, hypromellose K100M 12%-15%, povidone K29/32 10%-12%, sodium stearyl fumarate 1 %-3%, magnesium stearate 0.1%-0.5%.
9. The method for preparing pramipexole sustained-release tablets according to any one of claims 1-8, wherein the pramipexole sustained-release tablets are prepared by a powder direct compression method, comprising the following steps:

   Step 1: Take pramipexole hydrochloride and sieve;

   Step 2: pramipexole hydrochloride obtained in step 1, glidant, sustained-release material, and 15%-35% of the total filler are mixed;

   Step 3: After step 2 is completed, add the binder and the filler that accounts for 15%-35% of the total filler, and mix them;

   Step 4: After step 3 is completed, add the remaining filler and mix well;

   Step 5: After step 4 is completed, the lubricant is added and mixed to obtain an intermediate;

   Step 6: Press the tablet and get it.