Patent Application
20140161880
The present invention relates to a sustained release tablet having two-phase release-controlling system, which consists of a first release-controlling phase comprising pregabalin or its salt and hydroxypropyl methylcellulose; and a second release-controlling phase comprising polyethylene oxide as a swelling polymer, the first release-controlling phase being homogeneously dispersed in the second release-controlling phase.
Pregabalin, chemically known as (S)-(+)-3-aminomethyl-5-methylhexanoic acid, binds to the alpha-2-delta subunit of calcium channels and is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin is useful for treating epilepsy, neuropathic pain, fibromyalgia, etc. Pregabalin is being marketed as an immediate release (IR) formulation, e.g., capsules containing 75 mg, 150 mg, or 300 mg and is usually administered to patients twice a day.
The conversion of drugs administered more than twice a day into a form for once-a-day administration can improve patients' drug compliance; reduce any side effects originated from maximum blood concentration exceeding the desired effective blood concentration and/or sudden increase of blood concentration; and increase the maintenance time of effective blood concentration, thereby increasing pharmacological effects. However, there are some problems in designing a pregabalin-containing formulation for once a day administration. Because pregabalin is absorbed through L-amino acid transport system, it does not exhibit uniform gastrointestinal absorptions. And also, because the absorption of pregabalin takes place in the upper small intestine where most of L-amino acid transporters reside, an average absorption window thereof is less than 6 hours (Su T-Z, Feng M R, Weber M L: Mediation of highly concentrative uptake of pregabalin by L-type amino acid transport in Chinese hamster ovary and Caco-2 cells. J Pharmacol Exp Ther 2005, 313:1406-1415). Therefore, it is very difficult to design pregabalin-containing formulations for once-a-day administration, which can show a release profile equivalent to the formulation for twice-a-day administration, according to conventional technologies for sustained release formations.
Gastro-retentive drug delivery systems may be considered as one of the methods for designing a sustained release formulation for pregabalin. The gastro-retentive drug delivery systems are classified into three systems, i.e., an expansion-by-swelling system, a floating or buoyant system, and a bioadhesive system. As a gastro-retentive drug delivery system, WO 2007/052125 has disclosed a sustained release formulation for once daily oral administration comprising pregabalin, a matrix forming agent, and a swelling agent. However, since the formulation disclosed in WO 2007/052125 is designed for inducing the gastro-retention by simple swelling, individual variations in the absorption of pregabalin (especially, time to reach maximum plasma concentration, Tmax) is very high according to patients' respective gastrointestinal conditions, e.g., according to patients' respective gastrointestinal motilities. And also, there cannot be excluded the possibility to pass through the pylorus depending on patients' gastrointestinal conditions, thereby resulting in not showing sustained release patterns. In addition, there is a disadvantage that matrix hardness of the formulation becomes decreased at the time of about 24 hours.
WO 2006/078811 has been disclosed a controlled release formulation of gabapentin and pregabalin, comprising an immediate release component, a sustained release component, and a delayed release component. However, since the formulation is not a gastro-retentive form, there is a problem that it releases pregabalin not only in the upper small intestine (major absorption site of pregabalin), but also in other gastrointestinal sites such as the stomach and the lower small intestine.
The present inventors performed various researches for developing a sustained release formulation comprising pregabalin having limited absorption window as an active ingredient. Especially, the present inventors carried out various researches for designing a sustained release formulation in a gastro-retentive form, which exhibits a controlled release profile capable of minimizing individual variations. We newly designed a two-phase release-controlling system, in which a first release-controlling phase for both controlling the release of pregabalin and promoting floatability is homogeneously dispersed in a second release-controlling phase having both swellability and floatability. We found that the two-phase release-controlling system can stably show both ‘swellability’ and ‘floatability’; and thus accomplish effective gastro-retention, which make it possible to minimize the individual variations originated from e.g., different gastrointestinal motilities.
Therefore, it is an object of the present invention to provide a sustained release formulation comprising pregabalin or its salt through two-phase release-controlling system.
In accordance with an aspect of the present invention, there is provided a sustained release tablet having two-phase release-controlling system, which consists of a first release-controlling phase comprising pregabalin or its salt and hydroxypropyl methylcellulose; and a second release-controlling phase comprising polyethylene oxide as a swelling polymer, the first release-controlling phase being homogeneously dispersed in the second release-controlling phase.
In the first release-controlling phase, the polyethylene oxide may have an average molecular weight ranging from 100,000 to 7,000,000; and be present in an amount ranging from 10 to 70% by weight, based on the total weight of the tablet.
In the first release-controlling phase, the hydroxypropyl methylcellulose may have a viscosity ranging from 100 to 150,000 centipoises; and be present in an amount ranging from 5 to 40% by weight, based on the total weight of the tablet.
The first release-controlling phase may further comprise hydroxypropyl cellulose as a binder; and the second release-controlling phase may further comprise crospovidone or sodium starch glycolate as a supplemental floating agent.
In an embodiment, a time to reach maximum plasma concentration (Tmax) may range from 4 to 8 hours after oral administration of the sustained release tablet of the present invention. In another embodiment, the sustained release tablet of the present invention may be magnified to 12 mm of size when contacting with water. In still another embodiment, the sustained release tablet of the present invention may be floated within 30 minutes after contact with water and the resultant floating state may be maintained for at least 12 hours.
In accordance with another of the present invention, there is provided a process for preparing a sustained release tablet having two-phase release-controlling system, the process comprising (a) granulating a mixture of pregabalin or its salt and hydroxypropyl methylcellulose; and (b) mixing the granules obtained in the step (a) with polyethylene oxide and a pharmaceutically acceptable excipient, followed by compressing the resulting mixture.
In the process of the present invention, the granulating may be performed using a binder solution.
The sustained release tablet according to the present invention can effectively control the release of pregabalin along with showing controlled and prolonged release profiles (i.e., without showing initial sudden release thereof) at the time of oral administration. In the sustained release tablet of the present invention, the release of pregabalin is controlled in the first release-controlling phase; and then the released pregabalin from the first release-controlling phase is further controlled during the pass through the second release-controlling phase. That is, in the sustained release tablet of the present invention, the release of pregabalin is controlled by two phase release-controlling system. The sustained release tablet according to the present invention may be administered once a day by controlling the release mechanism of pregabalin having limited absorption window. Especially, the polymer in the first release-controlling phase can enhance floatability effectively and thus ensure both ‘swellability’ and ‘floatability’, which increases the shape-maintenance time as well as floating-maintenance time after contact with water, thereby minimizing individual variations in the absorption of pregabalin (especially, time to reach maximum plasma concentration, Tmax) originated from different gastrointestinal motilities. And also, it is possible to control a maximum blood concentration (Cmax) and a bioavailability by controlling the release time and/or the gastro-retentive characteristics through varying amounts of the polymer in the first and/or second release-controlling phase(s).
The present invention provides a sustained release tablet having two-phase release-controlling system, which consists of a first release-controlling phase comprising pregabalin or its salt and hydroxypropyl methylcellulose; and a second release-controlling phase comprising polyethylene oxide as a swelling polymer, the first release-controlling phase being homogeneously dispersed in the second release-controlling phase.
The sustained release tablet according to the present invention is a gastro-retentive drug delivery system, wherein the drug (i.e., pregabalin) is continuously released while it is staying in the stomach for a predetermined time after oral administration, thereby maximizing the absorption of pregabalin in the upper small intestine. In the sustained release tablet of the present invention, the release of pregabalin is controlled in the first release-controlling phase; and then the released pregabalin from the first release-controlling phase is further controlled during the pass through the second release-controlling phase. That is, in the sustained release tablet of the present invention, the release of pregabalin is controlled by two phase release-controlling system. And also, the polymer in the first release-controlling phase can enhance floatability effectively and thus ensure both ‘swellability’ and ‘floatability’, which increases the shape-maintenance time as well as floating-maintenance time after contact with water, thereby minimizing individual variations in the absorption of pregabalin (especially, time to reach maximum plasma concentration, Tmax) originated from different gastrointestinal motilities. In addition, it is possible to control a maximum blood concentration (Cmax) and a bioavailability by controlling the release time and/or the gastro-retentive characteristics through varying amounts of the polymer in the first and/or second release-controlling phase(s). Therefore, the sustained release tablet according to the present invention may be administered once a day by controlling the release mechanism of pregabalin having limited absorption window.
The first release-controlling phase comprises hydroxypropyl methylcellulose, so as to control the release of pregabalin and improve floatability. The hydroxypropyl methylcellulose expands on contact with water to form a matrix, thereby controlling the release of pregabalin; and improves floatability based on its own low density. The hydroxypropyl methylcellulose used in the sustained release tablet of the present invention may have a viscosity ranging from 100 to 150,000 centipoises, preferably 400 to 100,000 centipoises. The hydroxypropyl methylcellulose may be present in an amount ranging from 10 to 70% by weight, based on the total weight of the tablet. When the hydroxypropyl methylcellulose is used in an amount below 10%, dissolution of the active ingredient may be too fast to show a desired sustained release pattern. When the hydroxypropyl methylcellulose is used in an amount above 70%, dissolution of the active ingredient may become slow due to thick matrix formation, which results in showing a drug concentration below an appropriate therapeutic concentration. The first release-controlling phase may further comprise a binder conventionally used in the field of pharmaceutics, preferably hydroxypropyl cellulose. An amount of the binder is not limited. That is, the binder may be used in an amount sufficient for forming the first release-controlling phase, for example the first release-controlling phase in a granular form.
The second release-controlling phase comprises polyethylene oxide as a swelling polymer, so as to improve both swellability and floatability for increasing the gastro-retention time. The polyethylene oxide may have an average molecular weight ranging from 100,000 to 7,000,000, preferably 4,000,000 to 7,000,000. The polyethylene oxide may be present in an amount ranging from 5 to 40% by weight, based on the total weight of the tablet. When the polyethylene oxide is used in an amount below 5%, sufficient swelling may not be shown. When the polyethylene oxide is used in an amount above 40%, it may be difficult to control a release of the drug.
The second release-controlling phase may comprise one or more excipient conventionally used in the field of pharmaceutics, such as a diluent, a lubricant, etc. For example, the diluent includes microcrystalline cellulose, lactose, etc.; and the lubricant includes magnesium stearate, zinc stearate, colloidal silicon dioxide, etc. And also, the second release-controlling phase may further comprise crospovidone or sodium starch glycolate as a supplemental floating agent. If necessary, the second release-controlling phase may further comprise hydroxypropyl methylcellulose as an erosion-preventing agent, in order to prevent potential erosion after swelling.
The sustained release tablet according to the present invention may be coated with a conventional film coating agent.
In an embodiment, a time to reach maximum plasma concentration (Tmax) may range from 4 to 8 hours after oral administration of the sustained release tablet of the present invention. In another embodiment, the sustained release tablet of the present invention may be magnified to 12 mm of size when contacting with water. In still another embodiment, the sustained release tablet of the present invention may be floated within 30 minutes after contact with water and the resultant floating state may be maintained for at least 12 hours. In still another embodiment, when an in vitro dissolution test of the sustained release tablet of the present invention is carried out according to the Korean Pharmacopeia or the US Pharmacopeia, the active ingredient (i.e., pregabalin) is released in an amount below 30% within 1 hour, in an amount (cumulative dissolution rate) ranging 20 to 75% within 4 to 6 hours; and an amount (cumulative dissolution rate) above 75% within 12 hours.
The present invention also provides a process for preparing a sustained release tablet having two-phase release-controlling system. The sustained release tablet having two-phase release-controlling system according to the present invention may be prepared by providing a first release-controlling phase, typically a first release-controlling phase in a granular form, and then compressing the first release-controlling phase with the remaining components. For example, the process for preparing a sustained release tablet having two-phase release-controlling system may comprise (a) granulating a mixture of pregabalin or its salt and hydroxypropyl methylcellulose; and (b) mixing the granules obtained in the step (a) with polyethylene oxide and a pharmaceutically acceptable excipient, followed by compressing the resulting mixture.
The granulating may be performed using a binder solution. In an embodiment, the step (a) may be performed by granulating a mixture of pregabalin (or its salt) and hydroxypropyl methylcellulose in a wet granulator (e.g., High Shear Mixer or One-pot), using a binder solution (e.g., an aqueous ethanol solution of hydroxypropyl cellulose), to form a first release-controlling phase. The obtained first release-controlling phase is mixed with components of the second release-controlling phase, i.e., polyethylene oxide and a pharmaceutically acceptable excipient, followed by compressing the resulting mixture. The pharmaceutically acceptable excipient includes a diluent, a lubricant (such as magnesium stearate, zinc stearate, colloidal silicon dioxide, etc.), etc. And also, the components of the second release-controlling phase may further comprise crospovidone or sodium starch glycolate as a supplemental floating agent; and/or hydroxypropyl methylcellulose as an erosion-preventing agent. The process of the present invention may further comprise coating with a conventional film coating agent.
The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Sustained release tablets were prepared according to the components and amounts shown in Tables 1 to 5. The amounts of Tables 1 to 5 represent the weight (mg) of each component per one tablet. Pregabalin and hydroxypropyl methylcellulose (Metolose™ 90SH-100,000 cps SR, Shinetsu) were charged in a high speed mixer and then a binder solution (prepared by dissolving hydroxypropyl cellulose (HPC JF) in a 50% ethanol solution) was added thereto. The mixer was rotated at 250 rpm for 3 minutes to give granules. The resulting granules were dried and then sieved with a milling machine. The obtained granules were mixed with polyethylene oxide (Polyox 301 and/or Polyox 303), along with a supplementary floating agent (crospovidone or sodium starch glycolate), a diluent (hydroxypropyl cellulose or microcrystalline cellulose), or a lubricant (colloidal silicon dioxide) for 5 minutes. Magnesium stearate was additionally mixed with the mixture for 3 minutes, followed by compressing to obtain sustained release tablets.
Pregabalin (300 g), Kollidon SR (256 g), Plasdone XL (280 g), Polyox N60K NF (224 g), and Carbopol 71G (56.5 g) were mixed for 5 minutes. Magnesium stearate (5.5 g) was additionally mixed with the mixture for 3 minutes, followed by compressing to obtain tablets.
The dissolution tests of the tablets prepared in Examples 1 to 34 were performed according to the ‘Dissolution Test 2 (Paddle Method)’ of the Korean Pharmacopeia. 900 ml of a 0.06N HCl solution was used as a dissolution medium and the dissolution test was performed at 37±0.5° C. and at the paddle rotation speed of 50 rpm. An aliquot was taken from the dissolution medium at the time of 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 minutes, respectively. Each aliquot was analyzed with HPLC (at 210 nm) to calculate the dissolution rates. The results are presented in Tables 6 to 10. As shown in Tables 6 to 10, the tablets prepared according to the present invention showed excellent sustained release dissolution patterns.
The dissolution tests of the tablets prepared in the above Examples were performed according to the ‘Dissolution Test 2 (Paddle Method)’ of the Korean Pharmacopeia. 900 ml of a 0.06N HCl solution was used as a dissolution medium and the dissolution test was performed at 37±0.5° C. and at the paddle rotation speed of 50 rpm. The floating lag times were measured and then the floating-maintenance times were measured until 24 hours. The results are presented in Tables 11 to 13. As shown in Tables 11 to 13, the tablets prepared according to the present invention initiated floating within 30 minutes; and each floating was maintained for at least 24 hours.
The dissolution tests of the tablets prepared in the above Examples were performed according to the ‘Dissolution Test 2 (Paddle Method)’ of the Korean Pharmacopeia. 900 ml of a 0.06N HCl solution was used as a dissolution medium and the dissolution test was performed at 37±0.5° C. and at the paddle rotation speed of 50 rpm. Each tablet was recovered 24 hours after initiating the dissolution test and then the size thereof was measured. The results are presented in Tables 14 to 16. As shown in Tables 14 to 16, the sizes of the tablets prepared according to the present invention were increased to above 12 mm, the size of which allows for gastro-retention.
The dissolution tests of the tablets prepared in Examples 5, 13, 20, and Comparative Example 1 were performed according to the ‘Dissolution Test 2 (Paddle Method)’ of the Korean Pharmacopeia. 900 ml of a 0.06N HCl solution was used as a dissolution medium and the dissolution test was performed at 37±0.5° C. and at the paddle rotation speed of 50 rpm. Each tablet was recovered 6 hours after initiating the dissolution test and then the picture was taken. And also, each tablet was recovered 2, 6, and 24 hours after initiating the dissolution test and then the dissolution medium was removed for about 1 minute. Each size change was measured and each weigh change was obtained by measuring the water content thereof. The results are presented in able 17.
As shown in Table 17, the tablets prepared in Examples 5, 13, and 20 showed more excellent properties in size change and water contents, in comparison with the tablet of Comparative Example 1. These results shows that the tablets of the present invention can increase the gastro-retention time and thus effectively control the drug release. And also, as shown in
The dissolution tests of the tablets prepared in Example 5 and Comparative Example 1 were performed according to the ‘Dissolution Test 2 (Paddle Method)’ of the Korean Pharmacopeia. 900 ml of a 0.06N HCl solution was used as a dissolution medium and the dissolution test was performed at 37±0.5° C. and at the paddle rotation speeds of 50 rpm and 200 rpm, respectively. An aliquot was taken from the dissolution medium at the time of 1, 2, 3, 4, and 6 hours, respectively. Each aliquot was analyzed with HPLC (at 210 nm) to calculate the dissolution rates. The results are presented in Table 18.
As shown in Table 18, the tablet of Example 5 showed small differences in the dissolution rate when the rotation speed of the paddle was increased. In contrast, the dissolution rate, especially the initial dissolution rate, was remarkably increased in the tablet of Comparative Example 1, when the rotation speed of the paddle was increased. These results show that the tablets of the present invention is less affected by the rotation speed of the paddle than the sustained release tablet known in the prior art; and thus that the tablets of the present invention is less affected by gastrointestinal motility, thereby minimizing individual variations.
The comparative pharmacokinetic evaluations on the tablets prepared in Example 5 and Comparative Example 1 were performed using beagle dogs. Beagle dogs (body weight: about 10 kg) fasted for 12 hours were divided into 2 groups, each group having 4 dogs (i.e. n=4). The dogs were provided with a single mixed feed consisting of solid food and liquid nutrients. 1 hour after the feeding, the dogs of each group were orally administered with the tablet of Example 5 and the tablet of Comparative Example 1, respectively. The blood (about 0.5 mL) was collected using a heparin-treated injector, at the time of 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after the administration. The collected blood was centrifuged at 10,000 rpm for 1 minutes, and then the separated serum was stored at −20° C. for analysis. The concentration of pregabalin in the serum was analyzed with LC/MS/MS. The pharmacokinetic parameters obtained from the blood concentration profiles are presented in Table 19 below.
As shown in Table 19, the tablet of Comparative Example 1 showed larger variations than the tablet of Example 5. Especially, the time to reach maximum plasma concentration (Tmax) of the tablet of Example 5 was only from 4 to 8 hours, while Tmax of the tablet of Comparative Example 1 was from 1.5 to 12 hours. These results show that the tablet of the present invention is less affected by gastrointestinal motility, thereby minimizing individual variations.
The pharmacokinetic studies on the tablets prepared in Examples 5, 13, 20, 23, 28, and 31 were performed using beagle dogs, according to the same method as in Example 6. The commercially available Lyrica™ Capsule 150 mg (Pfizer Inc.) and Lyrica™ Capsule 75 mg (Pfizer Inc.) were used as a comparative formulation. The concentration of pregabalin in the serum was analyzed with LC/MS/MS. The blood concentration profiles are shown in
As shown in
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2011-0074011 | Jul 2011 | KR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/KR2012/005831 | 7/20/2012 | WO | 00 | 1/22/2014 |
