Poly(meth)acrylic acid popcorn polymerizates as disintegrants for tablets

Abstract

The use of powder-form, crosslinked, water-insoluble, low-swelling polyacrylates as disintegrants for solid pharmaceutical dosage forms.

Claims

1. A solid pharmaceutical dosage form comprising a disintegrant, wherein the disintegrant is a powder-form water-insoluble, low-swelling crosslinked polyacrylate, and wherein the polyacrylate is a popcorn polymer and has a gel time of greater than 30 seconds.

2. The dosage form according to claim 1, wherein the polyacrylate comprises structural elements of acrylic acid or methacrylic acid or mixtures thereof.

3. The dosage form according to claim 1, wherein the polyacrylate contains up to 20% by weight of comonomer structural elements.

4. The dosage form according to claim 1, wherein the comonomer structural elements comprise a (meth)acrylic ester.

5. The dosage form of claim 4, wherein the (meth)acrylic ester is selected from the group consisting of methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate and ethyl acrylate, butyl acrylate, and 2-ethylhexyl acrylate ester.

6. The dosage form according to claim 1, wherein powder-form polyacrylate has an average particle size within a range from 100 to 200 μm.

7. The dosage form according to claim 1, wherein the polyacrylate additionally comprises structural elements from a crosslinker.

8. The dosage form according to claim 7, wherein the crosslinker is at least trifunctional.

9. The dosage form according to claim 8, wherein the crosslinker is pentaerythritol triallyl ether.

10. The dosage form according to claim 8, wherein the polyacrylate comprises 0.1% to 15% by weight, based on the amount of acrylic acid or methacrylic acid, of the trifunctional crosslinker.

11. The dosage form of claim 10, wherein the polyacrylate comprises 0.5% to 10% by weight, based on the amount of acrylic acid or methacrylic acid, of the trifunctional crosslinker.

12. The dosage form of claim 10, wherein the polyacrylate comprises 1% to 5% by weight, based on the amount of acrylic acid or methacrylic acid, of the trifunctional crosslinker.

13. The dosage form of claim 1 wherein the crosslinked polyacrylate is partially neutralized.

14. A solid pharmaceutical dosage form comprising a disintegrant, wherein the disintegrant is a powder-form, water-insoluble, low-swelling crosslinked polyacrylate consisting of (a) structural elements selected from the group consisting of acrylic acid, methacrylic acid, and a mixture thereof; (b) up to 20% by weight of (meth)acrylic ester comonomer structural elements; and (c) 0.5 to 10% by weight, based on the amount of structural elements (a) of a trifunctional crosslinker; wherein the polyacrylate is a popcorn polymer and has a gel time of greater than 30 seconds.

15. The dosage form of claim 14, wherein the (meth)acrylic ester comonomer is selected from the group consisting of methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate and ethyl acrylate, butyl acrylate, and 2-ethylhexyl acrylate ester.

16. The dosage form of claim 14 wherein the trifunctional crosslinker is pentaerythritol triallyl ether.

Description

EXAMPLES

(1) Pentaerythritol triallyl ether (PETAE) is commercially available from Perstorp GmbH. Manufacturer's data: Diallyl ether content: 4.0-16.0%, triallyl ether content: 75.0-84.0%, and tetraallyl ether content: 5.0-12.0%.

(2) Demin. water=demineralized water

(3) Production of Popcorn Polymer A:

(4) A 3-liter glass reactor equipped with a stirrer, a reflux condenser, and metering devices was charged with 1086 g of deionized water, 450 g of acrylic acid, 22.5 g of pentaerythritol triallyl ether (PETAE), and 2.25 g of sodium pyrophosphate and heated to 50° C. with stirring at a stirrer speed of 180 rpm. During the heating period up to the end of the polymerization, nitrogen was passed through the solution, this being introduced into the reaction mixture by means of a tube extending down to the base of the stirring apparatus. The flow rate was 20 L/hour. Once the temperature of the reaction mixture had reached 50° C., 1.04 g of sodium dithionite was added. The mixture was held at 50° C. The first popcorn polymer particles were formed 60 minutes after adding the sodium dithionite, whereupon heat was evolved, which lasted a further 70 minutes. Stirring of the mixture was continued during this time. The aqueous suspension was then stirred for one hour further at 50° C. and filtered off. The polymer was washed with three 2000 ml portions of water to remove contaminants such as soluble polymer and residual monomers. The product was dried under reduced pressure for 12 hours at 75° C. The yield of popcorn polymer was 93%. The popcorn polymer exhibited a very heterogeneous particle size distribution and comprised particles of 5-10 cm in size. The product was milled with a Vorwerk Thermomix for 4 minutes at maximum speed and then sieved. The 100-200 μm sieve fraction was tested as a disintegrant.

(5) Production of Popcorn Polymer B:

(6) Popcorn polymer B was produced in analogous manner to the production of popcorn polymer A, but with 4.50 g of the 100-200 μm sieve fraction of polymer A added as seed to the initial charge. The first popcorn polymer particles were discernible after just 10 minutes. The yield of popcorn polymer was 91%. The use of seed resulted in a distinctly finer product having an average particle size in the region of 1 mm.

(7) Production of Popcorn Polymer C:

(8) Popcorn polymer C was produced in analogous manner to the production of popcorn polymer B, but was produced without the use of 2.25 g of sodium pyrophosphate. The first popcorn polymer particles were discernible after 10 minutes. The yield of popcorn polymer was 88%.

(9) Production of Popcorn Polymer D:

(10) Popcorn polymer D was produced in analogous manner to the production of popcorn polymer A, but with 2.25 g of a 200-500 μm sieve fraction of polymer A added as seed to the initial charge. The first popcorn polymer particles were discernible after 20 minutes. The yield of popcorn polymer was 94%.

(11) Production of Popcorn Polymer E:

(12) Popcorn polymer E was produced in analogous manner to the production of popcorn polymer, but with the reactor initially charged with only 90 g of acrylic acid. The remaining 360 g of acrylic acid was metered in over a two-hour period at a constant addition rate once the first popcorn particles had formed, which occurred 10 minutes after addition of the sodium dithionite. The yield of popcorn polymer was 95%.

(13) Production of Popcorn Polymer F:

(14) Popcorn polymer F was produced in analogous manner to the production of popcorn polymer A, but with 4.50 g of the <100 μm sieve fraction of polymer A added as seed to the initial charge. The first popcorn polymer particles were discernible after 30 minutes. The yield of popcorn polymer was 92%.

(15) Production of Popcorn Polymer G:

(16) Popcorn polymer G was produced in analogous manner to the production of popcorn polymer F, but with partial neutralization of the polymer. Partial neutralization was effected by adding 300 g of a 25% by weight aqueous sodium hydroxide solution to the aqueous suspension after the polymerization, followed by stirring at room temperature for one hour. The first popcorn polymer particles were discernible after 30 minutes. The yield of popcorn polymer was 91%.

(17) Production of Popcorn Polymer H:

(18) Popcorn polymer H was produced in analogous manner to the production of popcorn polymer B, but with 450 g of methacrylic acid used instead of 450 g of acrylic acid. The first popcorn polymer particles were discernible after 23 hours. The reaction mixture was then stirred for 8 hours at 80° C. Filtration, drying, and milling was in accordance with 689. The yield of popcorn polymer was 62%.

(19) Production of Popcorn Polymer I:

(20) Popcorn polymer I was produced in analogous manner to the production of popcorn polymer B, but with partial neutralization of the polymer. Partial neutralization was effected by adding 420 g of a 25% by weight aqueous potassium hydroxide solution to the aqueous suspension after the polymerization, followed by stirring at room temperature for one hour. The first popcorn polymer particles were discernible after 30 minutes. The yield of popcorn polymer was 96%.

(21) Production of Popcorn Polymer J:

(22) Popcorn polymer J was produced in analogous manner to the production of popcorn polymer F, but using the following amounts of starting materials: 1050 g of deionized water, 250 g of acrylic acid, 12.5 g of PETAE, 1.25 of sodium pyrophosphate, 2.50 g of a <100 μm sieve fraction of polymer A as seed, and 0.58 instead sodium dithionite. The first popcorn polymer particles were discernible after 20 minutes. The yield of popcorn polymer was 85%.

(23) Production of Popcorn Polymer K:

(24) Popcorn polymer K was produced in analogous manner to the production of popcorn polymer J, but using 2.50 g of the 100-200 μm sieve fraction of polymer A as seed. The first popcorn polymer particles were discernible after 20 minutes. The yield of popcorn polymer was 76%.

(25) Production of Popcorn Polymer L:

(26) Popcorn polymer L was produced in analogous manner to the production of popcorn polymer B, but using the following amounts of starting materials: 1300 g of deionized water, 300 g of acrylic acid, 15.0 g of PETAE, 1.50 g of sodium pyrophosphate, 3.00 g of the 100-200 μm sieve fraction of polymer A as seed, and 0.69 g of sodium dithionite. The polymer was additionally partially neutralized.

(27) Partial neutralization was effected by adding 200 g of a 25% by weight aqueous potassium hydroxide solution to the aqueous suspension after the polymerization, followed by stirring at room temperature for one hour. The first popcorn polymer particles were discernible after 35 minutes. The yield of popcorn polymer was 85%.

(28) Production of Popcorn Polymer M:

(29) Popcorn polymer M was produced in analogous manner to the production of popcorn polymer J, but using 2.50 g of the <100 μm sieve fraction of polymer A as seed and with partial neutralization of the polymer. Partial neutralization was effected by adding 167 g of a 25% by weight aqueous sodium hydroxide solution to the aqueous suspension after the polymerization, followed by stirring at room temperature for one hour. The first popcorn polymer particles were discernible after 30 minutes. The yield of popcorn polymer was 90%.

(30) For Comparison: Production of Gel Polymer C1:

(31) A 2-liter glass reactor equipped with a stirrer and a reflux condenser was charged at room temperature and under a nitrogen atmosphere with 605 g of deionized water, 400 g of acrylic acid, 20 g of PETAE, and 5 g of a 5% by weight aqueous hydrogen peroxide solution. The mixture was stirred at 180 rpm and heated to 30° C. A 25% by weight aqueous sodium hydroxide solution (266.6 g) was metered in over 20 minutes. This was followed by the addition of 28.2 g of an aqueous L(+)-ascorbic acid solution (0.2 g of L(+)-ascorbic acid in 28 g of water). A very pronounced evolution of heat and increase in viscosity were observed within a few seconds. The stirring speed was reduced to 20 rpm. The viscosity continued to increase and a homogeneous clear gel formed. The gel was stirred for two hours and then removed from the reactor, comminuted, and freeze-dried. The yield of gel polymer was 99%. The product was milled with a Vorwerk Thermomix for 4 minutes at maximum speed and then sieved. The 100-200 μm sieve fraction was tested as a disintegrant (Table 3).

(32) Production of Placebo Tablets

(33) All disintegration times reported hereinbelow were tested on placebo tablets obtained as follows:

(34) Tablet Formulation (Direct Tableting):

(35) 467.50 mg of Ludipress LCE (96.5% lactose monohydrate, 3.5% polyvinylpyrrolidone (Kollidon® 30)), 30 mg of disintegrant (popcorn and gel polymers, Amberlite IRP 88, Ac-Di-Sol, Primojel, Kollidon CL), and 2.50 mg of magnesium stearate. All starting materials were sieved through a 0.8 mm mesh screen and mixed for 10 minutes in a Turbula mixer. Tablets were pressed at 18 kN on a Korsch XP1 eccentric press, at 6 and 12 kN in the case of some of these formulations. Disintegration times were determined using an Erweka ZT 74 (disintegration tester) in 0.08 N HCl (pH 1.1), phosphate buffer (pH 6.8), and demineralized water.

(36) The measurement of the disintegration time with the Erweka ZT 74 was performed according to the following method: Fill a 1000 ml beaker (low-sided form) with 800 ml of the desired test medium (e.g. 0.08 N HCl, phosphate buffer, demineralized water), stand in a water bath, and thermally equilibrate at 36-38° C. Into each of the numbered tubes of the measurement basket is placed a tablet or capsule (sixfold determination per formulation) and the associated disk is laid on top of this. This measurement basket is suspended in the holder over the filled beaker and the measurement is started. The basket is moved up and down until the residual thickness of the tablet is only max. 0.2 mm in all tubes. The sensor issues a signal according to the distance of the inbuilt magnet inside the disk. When the sample has disintegrated, the smallest-possible distance will have been reached and the time is recorded. The end of the test is reached and the disintegration time determined when all the test specimens have disintegrated. The measurement basket then switches off automatically.

(37) Determination of the Gelation Time

(38) The gelation time is determined as described in EP-A 1035196, [0028]. The exact method is described above in the general description.

(39) Determination of the particle size distribution (PSD) in hexadecane and water

(40) The measurements were carried out using a Mastersizer 3000 (static light scattering/Fraunhofer diffraction) in accordance with ISO 13320:2009.

(41) Method 1: Aqueous

(42) The measurement unit for aqueous samples is the Hydro MV unit:

(43) For the measurement in the Hydro unit, after the initialization step and the background measurement, the sample (microspatula) was added directly to the Hydro unit until the optimal laser obscuration of 2-15% had been reached. After addition of the sample, a wait time of approx. 30 seconds to allow the sample to disperse thoroughly was observed before starting the measurement. Parameters for analysis and evaluation in the Hydro MV unit:

(44) Stirrer speed: 1500 rpm

(45) Ultrasound: Without

(46) Evaluation model: Fraunhofer

(47) Analysis model: Universal

(48) TABLE-US-00001 Medium water Sample Laser obscuration (%) Gel polymer C1 6.49 Polymer M 9.33
Method 2: in Hexadecane

(49) The measurement unit for hexadecane is the SV cell unit:

(50) For the measurement in the SV cell unit, after initialization and the background measurement, the sample (homogenize 1 spoon-spatula of sample with hexadecane in a 10 ml screw-cap bottle) was added dropwise until the optimal laser obscuration of 2-15% had been reached. After introducing the cell measurement unit into the instrument, the measurement was started. Parameters for analysis and evaluation in the SV cell unit:

(51) Stirrer speed: 1500 rpm

(52) Ultrasound: Without

(53) Evaluation model: Fraunhofer

(54) Analysis model: Universal

(55) TABLE-US-00002 Hexadecane Sample Laser obscuration (%) Gel polymer C1  6.78 Polymer M 12.50

(56) The results are listed in the table below.

(57) TABLE-US-00003 TABLE 1 Comparison of disintegration times of the tablet formulation of commercial disintegrants with the inventive polymer M Disintegration Disintegration Disintegration time time time pH 1.1 pH 6.8 Demin. water Disintegrant [min:s] [min:s] [min:s] Ac-Di-Sol 2:56 3:50 2:39 (croscarmellose-Na) Primojel 2:45 3:38 3:32 (Na starch glycolate) Kollidon ® CL 1:15 1:54 1:12 (crospovidone) Polymer M 2:09 2:35 2:12

(58) The polyacrylic acid popcorn polymer M performed better than inexpensive disintegrant products such as Ac-Di-Sol and Primojel that are currently on the market.

(59) TABLE-US-00004 TABLE 2 Gelation time, PSD in hexadecane/ water and disintegration time: Popcorn vs. gelpolymerization Change in Disinte- Particle Particle particle gration Gelation size in size in size time time* hexadecane water C.sub.16H.sub.34 .fwdarw. pH 1.1 Disintegrant [min:s] [μm] [μm] H.sub.2O [min:s] Gel polymer C1 <0:10 110 475 +332% 3:18 Polymer M >10:00 124 165 +33% 2:09 *Described in EP1035196 B1 (page 5, [0028])

(60) Although the polymers were produced using identical amounts of monomer and crosslinker, they differed considerably. The results in Table 2 show that the gel polymer swells rapidly and substantially in water. The popcorn polymer swells only little and very slowly, but shows a better disintegrant effect.

(61) In addition, the disintegrant effect of inventive polymers was compared with the disintegrant effect of the commonly used commercial Amberlite™ IRP 88. The results are listed in Table 3.

(62) TABLE-US-00005 TABLE 3 Neutralization, pH, and disintegration time: Popcorn vs. Amberlite Disinte- Neutralization Disinte- Disinte- gration [mol % pH gration gration time carboxylic (1% time time Demin. acid in pH 1.1 pH 6.8 water Disintegrant groups] water) [min:s] [min:s] [min:s] Amberlite IRP 88 60* 9.7 2:25 2:24 2:42 Polymer K  0 3.4 1:54 2:00 1:40 Polymer M 30 7.7 2:09 2:35 2:12 Polymer L 50 9.0 1:14 1:01 0:48 *calculated from determination of the water content and elemental analysis (potassium and oxygen)

(63) TABLE-US-00006 TABLE 4 Determination of the disintegration times of tablet formulations at different pH values Disinte- Disinte- Disinte- gration gration gration time time time Demin, pH 1.1 pH 6.8 water Polymer [min:s] [min:s] [min:s] A 1:34 1:32 1:12 B 1:18 1:42 1:13 C 1:28 1:42 1:21 D 2:33 2:06 1:28 E 2:07 2:12 1:52 F 1:30 1:32 1:13 G 1:54 2:11 1:56 H 3:44 4:30 3:55 1 2:29 1:45 1:52 J 2:00 2:09 1:41 K 1:54 2:00 1:40 L 1:14 1:01 0:48 M 2:09 2:35 2:12