TW200816998A - Process for preparing pramipexole dihydrochloride tablets - Google Patents

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

200816998 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION This description relates to a method of preparing a pramipex〇le dihydrochloride tablet. In particular, the present invention relates to a process for preparing a pluconin dihydrochloride tablet wherein the tablets exhibit high storage stability. [Prior Art]

Jinlaqin is a known dopamine 02 receptor agonist. It is structurally different from the drug derived from ergot (for example, bromocriptine or pergolide). It is also pharmacologically unique because it is a fully agonist and has receptor selectivity for the dopamine receptor dopamine family. Plaques are disclosed in U.S. Patent Nos. 4,731,374, 4, the disclosures of which are incorporated herein by reference. Chemically named plucometer as P von (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, and 右 right 八一There are knife type C丨oHnls^S and relative molecular Bailey 2 1 1 · 3 3 . The chemical formula is as follows:

〇 The form of the solvate usually used is 八工m U feiqi eric acid dihydrochloride monohydrate (knife type CioHnChNgOs; relative gossip + - gas servant mouth mouth P person pair knife set 302.27) . The pramid- sulphide early hydrate is a white 5 巳 to an off-white, odorless crystalline powder. In the range of 296 C to 301 C, it melts and melts at the same time. Pula 123707.doc 200816998 Is a compound with a pair of palms. The pure (8)·enantiomer system self-synthesis method is obtained by performing palmar recrystallization on one of the intermediates during the synthesis. Plasmin dihydrochloride monohydrate is a highly soluble compound. The water solubility is greater than 2 Gmg/mL, and the solubility in the buffer medium f is generally between 1 and 77. Plazisine dichloride chloride monohydrate is not hygroscopic and has high crystallinity. In the grinding I, the crystal modification (monohydrate) did not change. Plasm is very stable in the solid state, but it is photosensitive in the solution state. The Plaques immediate release (IR) lozenges were first approved in the USA in 1997 and subsequently approved for marketing in the European Union (EU), Switzerland, Canada and South America, as well as in Eastern Europe, Near East and Asia. In EU and US, the Plaques IR lozenge is used in combination with Levodopa to treat signs and symptoms of early Parkinsin's disease, or late Parkinson's disease. This product is known under the trade name MIRAPEX® in us A. Indications to take IR tablets three times a day. The manufacturing method of the Platinol dihydrochloride monohydrate spinner (hereinafter referred to as the "packaged product/product called "commodity formulation") marketed in the USA in 2005 produces a tablet having a relatively stable shelf life, wherein Storage: Approximately 95% of the indicated average amount of active ingredient is still present in the tablet after 8 months. However, it is necessary to develop a product that is as close as possible to zero degradation after a long period of storage. The present invention relates to a preparation A method of lacrin dihydrochloride monohydrate tablet wherein the tablet exhibits high storage stability. 123707.doc 200816998 SUMMARY OF THE INVENTION To achieve the present disclosure and (4) of the present invention, the term "Plack" The squirrel chloride is a sulphate dihydrochloride and a pharmaceutically acceptable solvate thereof, and particularly includes prasin dihydrochloride monohydrate. According to the present invention, there is provided a method of producing a pramin dihydrochloride tablet wherein the tablets exhibit high storage stability. Further provided is a method for preparing a plucometer dihydrochloride tablet, wherein the method comprises formulating H comprising an intragranular tableting component, a plucometer dihydrochloride: a binder, an extragranular tableting agent, and the method comprises The following steps: Depending on the U condition, the intra-granular red component is sized to form granules of substantially uniform size in the granules, forming an intragranular tablet containing substantially uniform size, Pre-mixing of the plucan dihydrochloride and the binder', the premix is granulated, and the granulated premix is dried to about 1.5% to about 2.5%, more preferably 〇% to about 2 An end point moisture content of 5% to form a dry premix, the extragranular tableting agent is mixed with the dry premix to form the final blend, and the final blend is compressed into a tablet. Further provided is a method for preparing a plucometer dihydrochloride spinning agent comprising an intragranular tableting component, a plucometer dihydrochloride, a binder, and an extragranular tableting agent, wherein at least a portion of the method is The closed system is carried out and comprises the following steps: (a) loading the granules of the granulated tablet component into a fluidized bed granulator, wherein the granules of the granulated tablet component are optionally sorted by size before being charged to form Particles of substantially uniform size and mixing of the ingredients, 123707.doc 200816998 (b) Dissolving plucan dihydrochloride and polyvinylpyrrolidone in water to form an aqueous solution of plucan dihydrochloride, and Spraying the plucometer dihydrochloride solution onto the granules of the granules in the fluidized bed granulator, (c) preparing a binder paste and/or a paste suspension and/or suspension And adding the binder paste and/or paste suspension and/or suspension to the fluidized bed granulator by spraying to form granules, (d) drying the granulated mixture to about 1 Torr. % to about 2.5% of the endpoint moisture content, (e) as appropriate The dried granules are passed through a sieving mill to form raw material granules, (1) the granulated premix of step (4) is mixed with an extragranular bonding agent, and blended to form a final blend, (g) using a tablet machine The final blend is compressed into a tablet. In a preferred embodiment, a method for preparing a plucometer dihydrochloride tablet containing an intragranular bond component, a plucometer dihydrochloride, a binder, and an extragranular It agent is provided. Table, Gans ^ & Μ your method, wherein at least part of the method is carried out in a closed system and comprises the following steps: (Step D = mannitol, anhydrous gelatinous dioxygen cut and corn powder into two In a chemical granulator, the granules of the granules in the granules can be sorted according to the size of the granules to form substantially uniform granules, and the components are mixed, preferably a dry mixture, (step 2 Dissolving the pus-mouse compound in water and polyvinylpyrrolidone 123707.doc 200816998 to form an aqueous solution of plucan dihydrochloride, and spraying the plucometer-hydrochloride solution on the stream On the intragranular tablet component particles in the chemical granulator, (Step 3) prepare a corn starch paste of the county method, the heart, and the water, and add the paste to the fluidization. In a bed granulator to form granules (fluidized bed granulation), the same Preferably, the wet granules are protected from light. (v. 4) The granules are preferably 'while keeping the dry granules away from light. (Step 5) The raw granules are prepared by drying the granules by a sieving mill; (Father 1) By: The raw material granules are mixed with magnesium stearate, anhydrous colloidal oxidized sulphuric acid and corn house powder in a diffusion mixer (final blend). Step 7) Pressing the final blend into an ingot having a final strength The agent (tablet), for example, is about 21 mg. (Step 8) Pack as appropriate. The key agent produced according to the above method and its embodiment exhibits a high storage stability property. Another aspect of the invention includes a method of making a formulation comprising a plucometer dihydrochlorination = lozenge formulation, wherein it is still present in the bonding agent at 18 months of hunger and 6% relative humidity = storage conditions The average amount of plucan dihydrochloride is at least about 97 °/ of the indicated amount. . Another aspect of the invention includes a method of making a formulation comprising a plucometer dichlorochloride, wherein the inhibition is 6 ()% relative humidity: no part: 24 months still present in the tablet The average amount of plucan dihydrogen chloride is at least about 95% of the indicated amount, and may be at least about 97%. 123707.doc 200816998 Another aspect of the invention includes a method of making a pharmaceutical (4) 1 formulation comprising pramidin dihydrochloride, which is still present in money under 36 months of hunger and (four) relative thirst storage conditions Plasmidine dinitrochloride

The average amount of the compound is about 95% of the Q of the labeled amount, and may additionally be at least about 97%. As used herein, the term "average amount" is calculated by determining the amount of a specified product (active ingredient or degradation product) present in a particular product sample and then taking the average of the sample of the product. Typically in the final plucani commercial product, the tablet is included in the form of a packaged product, and the package may comprise a bottle, a blister pack or the like. These and other features, advantages and advantages of the present invention will be apparent from the <RTIgt; [Embodiment] According to the present invention, it is possible to prepare a plucometer dichloride chloride (IV) exhibiting high storage stability. This is valuable in the pharmaceutical industry because it enables the manufacturer to produce pramidin dihydrogenate. Lozenges and their long-term storage' thus reduce concerns about whether the product has exceeded its expiration date and whether it needs to be disposed of. This in turn allows the pharmacy and ultimately the consumer to enjoy the benefits of having to monitor the efficacy of the drug and the need to supplement the market due to product expiration: According to the present invention, it has been found that the resulting tablet exhibits high stability by controlling certain parameters during the manufacture of the plucometer dihydrochloride tablet. In particular, the particle size of the ingot component is controlled to be relatively large and uniform, the preparation and use of the binder suspension, the method of the 123707.doc 200816998 and the method before the ingot preparation are carried out. Controlling the moisture content of the product enables the production of a plucometer dihydrochloride tablet having an extremely desirable increase in storage stability. According to the above, the plucometer dihydrochloride tablet of the present invention comprises an intragranular tableting component, a plucometer dihydrochloride, a binder, and an extragranular bond. The method of the present invention comprises the following steps: Ingredients in the ingots are divided into the size of the size of the X. The size of the ingots is generally uniform. The ingot particles (optional step) 'formation &amp; Mixture of dihydrogen compound and binder 'This pellet is granulated and the (4) large mixture is dried to about! 〇% to about 25% of the endpoint moisture content (dry weight loss (LOD), at 95-l〇5 ° C, preferably at 1〇5〇c) to form a dry mixture, the extragranular tableting agent Mixing with the dry mixture to form the final blend' and (iv) final blending is compressed into a bonding agent. &amp; In another embodiment, the particulate mixture is dried to an endpoint moisture content of from about 15% to about 25%. Figure 1 illustrates a method of formulating a tablet which produces a high stability #曰拉克素商 σ mouth. The method illustrated in Figure 1 relates to a method of preparing a plucometer dihydrochloride tablet comprising an intragranular I, a sulphate dihydrochloride, a binder, and an extragranular spirulina, wherein At least one of the methods is performed in a closed system. The method comprises the following steps: U) granules! In the granule-loaded fluidized bed granulator, the granules of the granules in the granules may be sorted by size before being charged to form granules of substantially uniform size. (1) The ruthenium-hydrochloride And the polyethylene, the ketone is dissolved in water XH laccase-hydrogenated water solution, and the pramin II 123707.doc 200816998 hydrochloride solution is sprayed into the fluidized bed granulator On the granules, (0) prepare a binder paste and/or a paste suspension and/or suspension, and add the binder suspension to the fluidized bed granulator by spraying, (d) in the fluidization In the bed granulator, the intragranular tablet component particles, the plucometer-hydrochloride solution and the binder solution are mixed to form a mixture, 0) the mixture is granulated to form a granulated mixture, (f) the granule The mixture is dried to an endpoint moisture content of from about 1.0% to about 2.5%, (g) the particulate mixture of step (f) is mixed with the extragranular tableting agent, and the mixture is recombined to form the final blend, ( h) Compressing the final blend into a tablet using a tablet machine. Intragranular red components include mannitol USP, colloidal silica dioxide NF, polyvinylpyrrolidone (K25) USP, corn starch, NF and pure water usp. The mannitol_D used as a starting material in the process of the invention is preferably a mixture of a delta crystalline acceptor and a beta crystalline variant. Preferably, the weight percentage of the g crystal modification is greater than the weight percentage of the beta crystal modification. Preferably, the percentage of beta crystal modifications is no more than 10% and the remaining 90% is a delta crystalline variant. In one embodiment, 'β δ is between 1·0% and 10%, preferably between 1.7 % and 1%, more preferably between 2.0% and 10%, and even more Good between 25% and 1%. The extragranular tableting agent of the present invention comprises colloidal cerium oxide NF 'Yuqiudian powder NF and magnesium stearate NF. For the intragranular tablet component and the extragranular tablet component, the following table gives the preferred amount of the tablet component in each tablet as a percentage of the total amount used in each batch to 123707.doc -12- 200816998 And API (Zilacin dihydrochloride) scale 1 ingredient mannitol corn stearin j|

API ________^_ * * A PI (遂' i 曰 曰 氲 氲 氲 氲 氲 之 之 i i i i i i i i 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋 旋, 125 § 0 25 叫, G.5G mg, G·75 mg, 1 mg, ι·5 mg, and 2·〇mg 〇 The following table gives the formulation of the lozenge formulation, which is the tablet formulation of the present invention. Representative examples of non-limiting examples: Table 2 Components

API 亳克/录: agent 0.125 corn house powder, dried corn house powder, undried gelatinous cerium oxide 49.455 ^-_-25. 〇1 〇 7.300 polyethylene 吼 g g (Kj^ magnesium stearate 0.940 1.230 1.15 L50 2.3 2,35 3.10 4.00 4.0

The pure water system is adapted according to the equipment used, and does not produce 123707.doc mannitol 0.940 0,25 61.00 30.90 9.00 1.20 0.5 1.00 1.25 122.0 61.8 18.0 2.4 121.50 61.85 18.00 2.30 162.00 82.55 24.00 3.10 1.5 208.5 106.0 30.8 4.0 -13 - 200816998 Now in the final product. Key: = Hairpin method to produce the pramin dihydrochloride of the present invention The β U potential includes 2 storage stability. High storage includes, but is not limited to, long shelf life. ~ The expiration of the plucometer dihydrochloride tablet prepared according to the method of the present invention is exhibited by the ability of the tablet to maintain a high content when stored under specific conditions. / Tongue rumors 'The plucan dihydrogenate tablets prepared according to the method of the present invention are still present in 18 families under the condition of 25 ° C and 60% phase 斟, month L emulsifier The average amount of prasin dichloride is less than about the amount indicated. I: The average value of the commodity formulation under the same conditions is less than the labeled amount w, 95:8/〇 in the sentence:). The time trend (4) of the activity f generated in the storage agent prepared according to the present invention can be expected to be 24 months and even 36 months, and the call in the pot will still exist even at 36 months. More than 95% of the indicated amount. The reason for this is that the vocal vocal 1B field is significant because the product allows for long storage of the product and therefore saves the consumer because the product does not have to be too frequent due to expiration of unused products stored by the manufacturer and/or pharmacist. The ground is replaced by a clothing manufacturer. The following examples are representative methods for preparing a plucometer dehydrating agent in accordance with the present invention. Example 2 The underarm method was used to prepare a 〇·5 mg pramin dihydrochloride tablet: ^Minaizhi was dispensed into a fluidized bed granulator while passing through a coil (Qiiadro) with a sieve: 123707.doc 200816998 Mannitol-D: 122,000 g (4) Dioxide Day: 1,200 g Corn House Powder 'Dryed (not dried) · · 565000 (58,800) g Friends in a separate stainless steel container, under stirring 500 g of pramidin dihydrochloride monohydrate was dissolved in 2G, such as pure water, and then 2,300 g of poly (iv) (polyethylene Dfcn each ketone κ25) was added and allowed to dissolve to completion. The plucometer dihydrochloride solution is then sprayed onto the intragranular component mixture in the fluid bed granulator. In a separate stainless steel container, 5,800 g of dry; ^ corn house powder (not dried (10) 〇 heart added to ' 〇 ml, ' '屯 water' to form a starch paste. Then the starch paste Add to the 38, _ m丨 pure water that has been heated to 95t, and at a rate from the state of the state (four) ((4) can be about (four) qing to about 125G RPM) e then 1 force another 21,000 ml of pure water (room Warm), and 35 〇 drop. Allow the temperature to cool to about 6 generations (the temperature can be about hunger to about hunger at this stage). The intragranular composition of the starch solution sprayed in the fluidized bed granulator A mixture of laccase dihydrochloride. The material in the fluidized bed granulator is then made into I pellets and dried to a residual moisture content of 2.3% and sieved through a sieve mill to form a pramin material. Granules. Extragranular blends of magnesium stearate (3, g), colloidal: oxygen cut U, g) and corn starch: (1) paste g) at 10 RPM in a diffusion mixer with 187, _ § Plaques raw material pellets for 30 minutes to form the final blend. The final blend was then compressed to a weight of 210 mg and containing 0.55 mg of palladium dihydrochloride. The present invention is not limited by the specific examples described herein, which are intended to be purely illustrative of the individual aspects of the present invention, and functionally equivalent methods and 123707.doc 200816998 components are within the scope of the present invention. In fact, various modifications of the invention in addition to those which are shown and described herein will be apparent. Such modifications are intended to fall within the scope of the accompanying claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a flow chart showing a method of a lozenge according to the present invention. Production of plucan dihydrochlorination

123707.doc -16-

Claims (1)

200816998 X. Patent Application Scope 1 · A method for preparing a pramipexole dihydrochloride tablet, wherein the tablet comprises an intragranular tableting component, a plucometer dihydrochloride or a medicinal Acceptable solvates, binders and extragranular tablets, which are carried out in a closed system and comprise the following steps: (a) loading the granules of the granules into a first-class bed In the granulator, (b) dissolving the plucan dihydrochloride or a pharmaceutically acceptable solvate thereof and polyvinylpyrrolidone in water to form a plucan dihydrochloride aqueous solution, and The laccase dihydrochloride solution is sprayed onto the intragranular tablet component particles in the fluidized bed granulator, (4) preparing a binder solution, a suspension or a paste, and the binder/liquid mixture , a suspension or paste is added to the fluidized bed granulator to form granules, (d) drying the granular premix to an endpoint moisture content of from about 1% to about 2.5%, (4) mixing the particulate mixture of step (4) with the extragranular bonding agent, and blending Forming the final blend, (f) compressing the final blend into a tablet using a tablet machine. 2) The method of item 1, wherein the step of sorting the intragranular tableting agents into substantially uniform sizes prior to loading. Wherein, plucan dihydrochloride monohydrate is used. 3. The solvate of the method of claim 1. The method of the method of the invention, wherein the binder solution is a suspension or paste comprising corn starch. The method of the invention, wherein the intragranular ingredients comprise bismuth dioxide and corn starch. 6. The method of claim 1, wherein the extragranular granules in λ comprise colloidal dioxins and stearic acid. The method of claim 5 wherein there is no more than 1% of the beta variant product in the mannitol. 4 · If the request item is water-suspended 5 · As requested, alcohol-D, gelatin 123707.doc