MX2009001884A

MX2009001884A - Process for preparing pramipexole dihydrochloride tablets with high storage stability.

Info

Publication number: MX2009001884A
Application number: MX2009001884A
Authority: MX
Inventors: Hans Werner Wernersbach
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2006-08-24
Filing date: 2007-08-22
Publication date: 2009-03-06
Also published as: AR062509A1; AU2007287560A1; CL2007002477A1; WO2008023027A2; KR20090045943A; IL197130A0; BRPI0715835A2; CA2661616A1; JP2010501525A; EP2056795A2; TW200816998A; RU2009110253A; WO2008023027A3

Abstract

The present invention relates to a process for preparing tablets of pramipexole dihydrochloride. In particular, the present invention relates to a process for preparing tablets of pramipexole dihydrochloride wherein the tablets exhibit high storage stability properties.

Description

PROCESS FOR PREPARING PRAMIPEXOL DIHYDROCHLORIDE COMPRESSES WITH HIGH CONSERVATION STABILITY FIELD OF THE INVENTION The present invention relates to a process for preparing tablets of pramipexole dihydrochloride. In particular, the present invention relates to a process for preparing tablets of pramipexole dihydrochloride, in which the tablets show high properties of preservation stability.

BACKGROUND OF THE INVENTION Pramipexole is a known dopamine D2 receptor agonist. It is structurally different from drugs derived from ergot, for example, bromocriptine or pergolide. It is also unique from the pharmacological point of view, because it is a complete agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors. Pramipexole was first described in U.S. Patent Nos. 4,731,374, 4,843,086 and 4,886,812, all of which are incorporated herein by reference.

Pramipexole is indicated chemically as (S) -2-amino- 4, 5, 6, 7-tetrahydro-6- (propylamino) benzothiazole, and has the molecular formula Ci0Hi7N3S and a relative molecular mass of 211.33. The chemical formula is the following: The solvate form that is commonly used is pramipexole dihydrochloride monohydrate (molecular formula C10H21Cl2N3OS, relative molecular mass 302.27). Pramipexole dihydrochloride monohydrate is an insipid crystalline powder, white to whitish in color. It melts in the range of 296 ° C to 301 ° C, with decomposition. Pramipexole is a chiral compound with a chiral center. The pure (S) -enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during the synthesis. Pramipexole dihydrochloride monohydrate is a very soluble compound. The solubility in water is more than 20 mg / ml, and the solubility in a buffer medium is, in general, greater than 10 mg / ml between pH 2 and pH 7.4. Pramipexole dihydrochloride monohydrate is not hygroscopic and has a very crystalline nature. After a grinding, the crystalline modification (monohydrate) does not change. He Pramipexole is very stable in the solid state, but in solution it is sensitive to light. Immediate-release tablets (LI) of pramipexole were first authorized in the USA in 1997, followed, in the following years, by marketing authorizations in the European Union (EU), Switzerland, Canada and South America, as well as in countries of Eastern Europe, Near East and Asia. In the EU and the US, LI pramipexole tablets are indicated for the treatment of signs and symptoms of early Parkinson's disease or advanced Parkinson's disease, along with levodopa. The product is known in the USA with the trademark MIRAPEX *. LI tablets should be taken 3 times daily. The manufacturing process of pramipexole dihydrochloride monohydrate tablets, which were marketed in the USA in 2005 (the package / product to be initialized is hereinafter referred to as the "commercial formulation"), produces a tablet having a relatively stable shelf life, wherein about 95% of the labeled average amount of the active ingredient remains in the tablet after 18 months of storage. However, it is desirable to develop products that have a degradation as close to zero as possible after having been conserved for long periods of time.

The present invention relates to a process for preparing tablets of pramipexole dihydrochloride monohydrate, in which the tablets show high properties of preservation stability.

THE INVENTION For the purposes of this description and invention, hereinafter, the term "pramipexole dihydrochloride" means pramipexole dihydrochloride and its pharmaceutically acceptable solvates, including, in particular, pramipexole dihydrochloride monohydrate.

According to the present invention, there is provided a process for producing pramipexole dihydrochloride tablets, wherein the tablets exhibit high preservation stability properties.

A process for preparing pramipexole dihydrochloride tablets is also provided, wherein the process involves formulating tablets comprising intragranular tablet-forming ingredients, pramipexole dihydrochloride, a binder, and extragranular tablet-forming agents. The process comprises the steps of optionally adjusting the size of the intragranular tablet forming ingredients to form size particles. substantially uniform of the intragranular tablet-forming ingredients, form a premix containing the intragranular tablet-forming ingredients, optionally with a substantially uniform size, the pramipexole dihydrochloride and the binder, granulate the premix and dry said granulated premix to a in final moisture of about 1.5% to about 2.5%, more preferably from 1.0% to about 2.5% to form a dried premix, mix the extragranular tablet forming agents with the dried premix to form a final blend, and compress the final blend to form tablets.

Also provided is a process for preparing pramipexole dihydrochloride tablets comprising intragranular tablet forming ingredients, pramipexole dihydrochloride, a binder, and extragranular tablet forming agents, wherein at least a portion of the process is performed in a system closed, and comprises the stages of: (a) loading particles of the intragranular tablet-forming ingredients into a fluid bed granulator, wherein the size of the particles of the tablet-forming ingredients can optionally be adjusted intragranular before loading them to form particles of substantially uniform size, and mixing the ingredients, (b) dissolving the pramipexole dihydrochloride and povidone in water to form an aqueous solution of pramipexole dihydrochloride, and spraying the solution of pramipexole dihydrochloride onto the particles of the intragranular tablet formation ingredients in the fluid bed granulator, (c) preparing a binder paste and / or pasty suspension and / or suspension, and adding the binder paste and / or pasty suspension and / or suspension to the fluid bed granulator by spraying to form a granulate, (d) drying said granulate mixture to a final moisture content of from about 1.0% to about 2.5%, (e) optionally, passing the dried granulate through a sieve mill to produce the raw granulate, (f) mixing said granulate premixture of step (e) with the extragranular tablet forming agents and mixing to form a mixture final, (g) compressing the final mixture into tablets using a tablet press.

In a preferred embodiment there is provided a process for preparing pramipexole dihydrochloride tablets comprising intragranular tablet-forming ingredients, pramipexole dihydrochloride, a binder, and extragranular tablet-forming agents, wherein at least a portion of the process is performed in a closed system, and comprises the steps of: (Stage 1): loading mannitol, anhydrous colloidal silica and corn starch in a fluid bed granulator, in which the particle size of the ingredients can optionally be adjusted of forming intragranular tablets before loading them to form particles of substantially uniform size, and mixing the ingredients, preferably as a dry mixture, (Step 2): dissolving the pramipexole dihydrochloride in water and povidone to form an aqueous solution of pramipexole dihydrochloride, and spraying the pramipexole dihydrochloride solution onto the particles of the intragranular tablet forming ingredients in the fluid bed granulator, (Step 3): prepare a paste of corn starch suspended in purified water, and add it to the fluid bed granulator to form a granulate (fluid bed granulation), while protecting, preferably, the wet granulate from the light, (Step 4): drying the granulate, preferably while protecting the dried granulate from light, (Step 5): preparing a raw granulate by passing the dried granulate through a sieving mill, (Step 6): mixing the granulate crude with magnesium stearate, anhydrous colloidal silica and corn starch by a diffusion mixer (final mixture), (Step 7): compress the final mixture into tablets of final potency (tablets), for example, approximately 210 mg, (Stage 8): optionally pack. Tablets produced according to the aforementioned process and their embodiments show high conservation stability attributes. Another aspect of the invention includes a process for the manufacture of a pharmaceutical formulation in tablets comprising pramipexole dihydrochloride, in which the average amount of pramipexole dihydrochloride remaining in the tablet after 18 months under 25 ° C preservation conditions. and a relative humidity of 60% is at least about 97% of the labeled quantity. Another aspect of the invention includes a process for the manufacture of a pharmaceutical formulation in tablets comprising pramipexole dihydrochloride, in which the average amount of pramipexole dihydrochloride remaining in the tablet after 24 months under 25 ° C preservation conditions. and a relative humidity of 60% is at least about 95% of the labeled amount and more preferably it can be at least about 97%. Another aspect of the invention includes a process for the manufacture of a pharmaceutical formulation in tablets comprising pramipexole dihydrochloride, in which the average amount of pramipexole dihydrochloride remaining in the tablet after 36 months under 25 ° C preservation conditions. and a relative humidity of 60% is at least about 95% of the labeled amount and more preferably it can be at least about 97%. The term "average amount", as used herein, is calculated by determining the amount of the indicated product (the active ingredient or the degradation product) present in a particulate sample of the product, and then taking the average of the samples of product.

Typically, in the final commercial pramipexole product, the tablets are included as packaged products, and the package may include bottles, blister packs or the like. These and other features, benefits and advantages of the invention will be apparent from the following description.

Brief Description of the Drawings FIG. 1 is a flow diagram showing a process for producing pramipexole dihydrochloride tablets according to one aspect of the invention.

Detailed description of the invention According to the present invention, tablets of pramipexole dihydrochloride showing high preservation stability can be prepared. This is valuable in the pharmaceutical field, since it allows pharmaceutical manufacturers to produce and store the tablets of pramipexole dihydrochloride for long periods of time, thereby reducing the concern about whether the product has expired and must be eliminated. This, in turn, allows pharmacies and, ultimately, consumers, enjoy the benefits of reduced costs associated with the need to control the effectiveness of a product and the need to replenish the supply in the market due to the expiration of the product.

According to the invention, it has been found that by controlling certain parameters during the manufacture of pramipexole dihydrochloride tablets, the resulting tablets show high stability. In particular, mediates the control of the particle size of the intragranular tablet formation ingredients, so that they possess a relative substantial uniformity (optional), the preparation and use of a binder suspension, the performance of the process in a closed system, as well as the control of the moisture content of the product before the formation of the tablets allows the production of a tablet of pramipexole dihydrochloride which has very desirable conservation stability improvements.

According to the above, the pramipexole dihydrochloride tablets of the invention comprise intragranular tablet-forming ingredients, pramipexole dihydrochloride, a binder and extragranular tablet-forming agents. The process of the invention comprises the steps of adjusting the size of the intragranular tablet-forming ingredients to form particles of substantially uniform size of the intragranular tablet-forming ingredients (optional step), form a mixture containing the intragranular tablet-forming ingredients optionally with a uniform size, the pramipexole dihydrochloride and the binder, granulate the mixture and dry said granulated mixture to a final moisture content of about (loss after drying (LOD) at 95-105 ° C, preferably 105 ° C) from about 1.0% to about 2.5%, to form a dried mixture , mixing the extragranular tablet forming agents with the dried mixture to form a final mixture, and compressing the final mixture to form tablets. In another embodiment, the granulated mixture is dried to a final moisture content of about 1.5% to about 2.5%.

Figure 1 shows a process for formulating tablets that can produce commercial pramipexole products with high stability. The process shown in Figure 1 involves a process for preparing pramipexole dihydrochloride tablets comprising intragranular tablet-forming ingredients, pramipexole dihydrochloride, a binder, and extragranular tablet-forming agents, wherein at least a portion of the process is done in a system closed. The process includes the stages of: (a) loading particles of the intragranular tablet-forming ingredients into a fluid bed granulator, in which the size of the particles of the intragranular tablet-forming ingredients can optionally be adjusted before being charged to form size particles substantially uniform, (b) dissolving the pramipexole dihydrochloride and povidone in water to form an aqueous solution of pramipexole dihydrochloride, and spraying the solution of pramipexole dihydrochloride onto the particles of the intragranular tablet formation ingredients in the fluid bed granulator, (c) preparing a binder paste and / or slurry and / or suspension, and adding the binder suspension to the fluid bed granulator by spraying, (d) mixing the particles of the intragranular tablet-forming ingredients, the pramipexole dihydrochloride solution and the binder solution in the fluid bed granulator to form a mixture, (e) granulating said mixture to form a granulated mixture, (f) drying said granulated mixture to a final moisture content of from about 1.0% to about 2.5%, (g) mixing said granulated mixture of step (f) with the extragranular tablet forming agents and mixing to form a final mixture, (h) compressing the final mixture into tablets using a tablet press.

The ingredients of intragranular tablet formation include D-mannitol USP, colloidal silicon dioxide NF, povidone (K25) USP, corn starch NF and purified water USP.

The D-mannitol used as a starting material in the process of the present invention is preferably a mixture of the crystalline delta modification and the beta crystalline modification. Preferably, the weight percent of the crystalline delta modification is greater than the weight percent of the beta crystalline modification. Preferably, the percentage of beta crystalline modification is not greater than 10%, with the remaining 90% being a crystalline delta modification. In a embodiment, the beta content is between 1.0 and 10%, preferably between 1.5 and 10%, more preferably between 2.0 and 10%, and even more preferably between 2.5 and 10% The extragranular tablet forming agents of the present invention include colloidal silicon dioxide NF, corn starch NF and magnesium stearate NF.

With respect to the ingredients of intragranular tablet formation and the extragranular tablet formation ingredients, the following table represents the preferred amounts of tablet-forming ingredients in each tablet, as a percentage of the total amount used in each batch, as well as the amount of API (pramipexole dihydrochloride): Table 1 Ingredient% per batch D-mannitol 50-60 Corn starch 35-45 Colloidal 1-3 silicon dioxide Povidona 1-3 Magnesium stearate 1-3 API * * ** The amount of API (pramipexole dihydrochloride) depends on the desired potential of the tablet.

The powers of the tablet can be 0.125 mg a 2. 5 mg, with typical potencies of 0.125 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1 mg, 1.5 mg and 2.0 mg.

The following table presents various formulations of tablets which are representative examples, but not limiting, of the tablet formulations according to the invention: Table 2 Component mg / tablet API 0.125 0.25 0.5 1.00 1.25 1.5 Mannitol 49,455 61.00 122.0 121.50 162.00 208.5 Corn starch, dried 25,010 30.90 61.8 61.85 82.55 106.0 Corn starch, not dried 7,300 9.00 18.0 18.00 24.00 30.8 Colloidal silicon dioxide 0.940 1.20 2.4 2.30 3.10 4.0 Povidone (K25) 0.940 1.15 2.3 2.35 3.10 4.0 Magnesium stearate 1,230 1.50 3.0 3.00 4.00 5.2 Purified water * * * * * * Tablet weight 85,000 105.00 210.00 210.00 280.00 360.00 * For production, purified water was adapted to the equipment used and does not appear in the final product.

The advantages that are acquired using the processes of the invention to produce pramipexole dihydrochloride tablets of the invention include high preservation stability properties. These high conservation stability properties include, but are not necessarily limited to a high shelf life. The high shelf-life of the pramipexole dihydrochloride tablets prepared according to the processes of the present invention is shown in the capacity of the tablets of maintain a high percentage of active ingredient when they are preserved under certain conditions. In particular, the pramipexole dihydrochloride tablets prepared according to a process of the present invention have an average amount of pramipexole dihydrochloride remaining in the tablet after 18 months under preservation conditions of 25 ° C and a relative humidity of 60%. at least about 97% of the labeled quantity. The commercial formulation preserved under the same conditions has an average lower than 95.8% of the quantity labeled (average amount). The tendency of the amount of active ingredient present in the preserved tablets prepared according to the invention can be projected up to 24 and even 36 months, after which, even at 36 months, more than 95% of the labeled quantity must remain. Of course, it is significant because it allows a high expiration of the product and, therefore, costs are saved to consumers, since the manufacturer should not replace the product so frequently due to the expiration of the unused product retained by the manufacturer, distributorship and / or pharmacist. The following example is representative of the process used to prepare dehydrated pramipexole tablets according to the invention.

Example 2 The following process was used to prepare tablets of 0.5 mg pramipexole dihydrochloride: In a fluid bed granulator, the following intragranular ingredients were dispensed at the same time as they were passed through a comolino (Quadro) having a 1.4 m sieve: D-mannitol: 122,000 g 122,000 g Colloidal silicon dioxide: 1,200 g Corn starch, dried (not dried): 56,000 (58.8) g In a separate stainless steel vessel, 500 g of pramipexole dihydrochloride was dissolved in 20,000 ml of purified water with stirring and then 2,300 g of polyvidone 25 (povidone K25) were added and the solution was completed with stirring. The solution of pramipexole dihydrochloride was then sprayed onto the mixture of intragranular ingredients in the fluid bed granulator. In a separate stainless steel vessel, 5,800 g of non-dried corn starch (6.09 g) were added to 15,000 ml of purified water with stirring, forming a starch paste. The pasta Starch was then added to 38,000 ml of purified water that had been heated to 95 ° C and stirred at a rate of about 350 RPM (agitation can be from about 250 RPM to about 1250 RPM). Then 21,000 ml more of purified water (room temperature) was added and stirred at 350 RPM. The temperature was allowed to cool to about 60 ° C (the temperature may be from about 55 ° C to about 65 ° C at this stage). The starch solution was then sprayed onto the mixture of intragranular ingredients and pramipexole dihydrochloride in the fluid bed granulator. The material in the fluid bed granulator was then granulated and dried to a residual moisture content of 2.3%, and sieved through a sieving mill to form a crude pramipexole granulate. An extragranular mixture of magnesium stearate (3,000 g), colloidal silicon dioxide (1,200 g) and corn starch (18,000 g) was mixed with 187,800 g of pramipexole raw granulate in a diffusion mixer for 30 minutes at 10 RPM for form a final mixture. The final mixture was then compressed into tablets weighing 210 mg and containing 0.5 mg of pramipexole dihydrochloride.

The present invention is not limited in scope by the specific embodiments described herein, considered as point illustrations of aspects Individuals of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. It is intended that these modifications be within the scope of the appended claims.

Claims

1. Process for preparing pramipexole dihydrochloride tablets comprising intragranular tablet forming ingredients, pramipexole dihydrochloride or its pharmaceutically acceptable solvate, a binder and extragranular tablet forming agents, wherein the process is performed in a closed system, and comprises the steps of: (a) loading particles of the intragranular tablet formation ingredients into a fluid bed granulator, (b) dissolving pramipexole dihydrochloride, or its pharmaceutically acceptable solvate, and povidone in water to form an aqueous solution of dihydrochloride of pramipexole, and spraying the solution, of pramipexole dihydrochloride onto the particles of the intragranular tablet formation ingredients in the fluid bed granulator, (c) preparing a solution, suspension or binder paste, and adding the solution, suspension or binder paste to the fluid bed granulator for for sea a granulate, (d) drying said granulated premix to a final moisture content of about 1.0% to about 2.5%, (g) mixing said granulated mixture with the extragranular tablet forming agents and mixing to form a final mix, (f) compress the final mixture in tablets using a tablet press.

2. Process according to claim 1, further comprising the step of adjusting the size of the intragranular tablet forming agents before loading, to a substantially uniform size.

3. Process according to claim 1, wherein pramipexole dihydrochloride monohydrate is used.

4. Process according to claim 1, wherein the binder solution is an aqueous suspension or paste comprising corn starch.

5. Process according to claim 1, wherein the ingredients of intragranular tablet formation comprise D-mannitol, colloidal silicon dioxide, and corn starch.

6. Process according to claim 1, wherein the ingredients of extragranular tablet formation comprise colloidal silicon dioxide, starch, and magnesium stearate.

7. Process according to claim 5, wherein the D-mannitol has no more than 10% of beta modification product present.