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 powder-form, crosslinked, water-insoluble, low-swelling polyacrylate for use as a disintegrant for solid pharmaceutical dosage forms.

2. The polyacrylate according to claim 1, wherein the polyacrylate is a popcorn polymer.

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

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

5. The polyacrylate according to claim 1, wherein the comonomer structural elements comprise a (meth)acrylic ester.

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

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

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

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

10. The polyacrylate 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. A solid pharmaceutical dosage form comprising a disintegrant, powder-form water-insoluble crosslinked polyacrylate according to claim 1.

12. A process for producing a polyacrylate used according to claim 1 comprising a free-radical polymerization in aqueous medium.

13. The process according to claim 12, wherein the polymerization takes place without addition of a radical initiator.

14. The process according to claim 12, wherein the polymerization takes place in an aqueous medium in the absence of oxygen.

15. The process according to claim 12, wherein the polymerization takes place in an aqueous medium in the presence of a reductant.

16. The polyacrylate of claim 5, 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.

17. The polyacrylate 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.

18. The polyacrylate 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.

Description

[0040] The present invention is accordingly characterized in particular by the following embodiments, with each embodiment encompassing all the features of the embodiments to which it relates.

[0041] Embodiment 1: The use of powder-form, crosslinked, water-insoluble, low-swelling polyacrylates as disintegrants for solid pharmaceutical dosage forms.

[0042] Embodiment 2: The use according to embodiment 1, wherein the polyacrylates are popcorn polymers.

[0043] Embodiment 3: The use according to embodiment 1 or 2, wherein “low-swelling” means that the percent change in the polymer particle size in water compared with the change in particle size in hexadecane is less than 50%.

[0044] Embodiment 4: The use according to any of embodiments 1 to 3, wherein the polyacrylates consist of structural elements of acrylic acid or methacrylic acid or mixtures thereof.

[0045] Embodiment 5: The use according to any of embodiments 1 to 4, wherein the polyacrylates contain up to 20% by weight of comonomer structural elements.

[0046] Embodiment 6: The use according to any of embodiments 1 to 5, wherein the comonomer structural elements are selected from the group consisting of (meth)acrylic esters such as methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate and ethyl acrylate, butyl acrylate, and 2-ethylhexyl acrylate.

[0047] Embodiment 7: The use according to any of embodiments 1 to 6, wherein powder-form polyacrylates having an average particle size within a range from 100 to 200 μm are used.

[0048] Embodiment 8: The use according to any of embodiments 1 to 7, wherein the polyacrylates additionally comprise structural elements from a crosslinker.

[0049] Embodiment 9: The use according to any of embodiments 1 to 8, wherein the crosslinker is selected from the group consisting of methylenebisacrylamide, N,N′-acryloylethylene diamine, ethylene glycol diacrylate, ethylene glycol dimethacrylate, tetraethylene glycol acrylate, tetraethylene glycol dimethacrylate, diethylene glycol acrylate, diethylene glycol methacrylate, butanediol diacrylate, hexanediol dimethacrylate, trimethylolpropane triacrylate, divinyl dimethylmalonate, polyallyl ethers of sucrose, pentaerythritol triallyl ether, and mixtures thereof.

[0050] Embodiment 10: The use according to any of embodiments 1 to 9, wherein the crosslinker is at least trifunctional.

[0051] Embodiment 11: The use according to any of embodiments 1 to 10, wherein the crosslinker is pentaerythritol triallyl ether.

[0052] Embodiment 12: The use according to any of embodiments 1 to 11, wherein the polyacrylates contain 0.1% to 15% by weight, based on the amount of acrylic acid or methacrylic acid, of a crosslinker.

[0053] Embodiment 13: The use according to any of embodiments 1 to 12, wherein the polyacrylates contain 0.5% to 10% by weight, based on the amount of acrylic acid or methacrylic acid, of a crosslinker.

[0054] Embodiment 14: The use according to any of embodiments 1 to 13, wherein the polyacrylates contain 1% to 5% by weight, based on the amount of acrylic acid or methacrylic acid, of a crosslinker.

[0055] Embodiment 15: The use according to any of embodiments 1 to 14, wherein the polyacrylates have a gelation time of less than 30 seconds.

[0056] Embodiment 16: The use according to any of embodiments 1 to 15, wherein the polyacrylates have a gelation time of less than 30 seconds and the gelation time is determined as the time after which the vortex in a test liquid caused by stirring is no longer visible, a 0.9% by weight sodium chloride solution being used as the test liquid.

[0057] Embodiment 17: A solid pharmaceutical dosage form in accordance with the use according to any of embodiments 1 to 16 that comprises, as a disintegrant, powder-form water-insoluble crosslinked polyacrylates.

[0058] Embodiment 18: A solid pharmaceutical dosage form according to embodiment 17 that comprises, as a disintegrant, polyacrylates in amounts of 0.1% to 50% by weight, preferably 0.2% to 20% by weight, more preferably 0.5% to 5% by weight, in particular 0.5% to 2% by weight, based on the total weight of the dosage form.

[0059] Embodiment 19: A process for producing the polyacrylates used according to any of embodiments 1 to 18 through free-radical polymerization in aqueous medium.

[0060] Embodiment 20: The process according to embodiment 19, through free-radical polymerization in aqueous medium, wherein the polymerization takes place without addition of a radical initiator.

[0061] Embodiment 21: The process according to either of embodiments 19 or 20, wherein the polymerization takes place in an aqueous medium in the absence of oxygen.

[0062] Embodiment 22: The process according to any of embodiments 19 to 21, wherein the polymerization takes place in an aqueous medium in the presence of a reductant.

[0063] Embodiment 23: The process according to any of embodiments 19 to 22, wherein the polymerization takes place in an aqueous medium in the presence of a reductant and the reductant is selected from the group consisting of sodium sulfite, sodium pyrosulfite, sodium dithionite, ascorbic acid or mixtures thereof.

[0064] Embodiment 24: The process according to any of embodiments 19 to 23, wherein the polymerization takes place in an aqueous medium in the presence of 0.05% to 1% by weight of a reductant.

[0065] Embodiment 25: The process according to any of embodiments 19 to 24, wherein the polymerization is carried out in the presence of seed material, wherein the seed material used consists of particle fractions of the polyacrylates used according to the invention.

[0066] Embodiment 26: The process according to any of embodiments 19 to 25, wherein the polymerization is carried out in the presence of complexing agents.

[0067] Embodiment 27: The process according to any of embodiments 19 to 26, wherein the polymerization is carried out in the presence of complexing agents such as the sodium salt of ethylenediaminetetraacetic acid or sodium pyrophosphate.

[0068] Embodiment 28: The process according to any of embodiments 19 to 27, wherein the polyacrylates are partially neutralized.

[0069] Embodiment 29: The process according to any of embodiments 19 to 28, wherein the polyacrylates are partially neutralized with aqueous alkali solutions such as sodium hydroxide or potassium hydroxide solution or aqueous ammonia solutions.

[0070] Embodiment 30: The process according to either of embodiments 28 or 29, wherein the polyacrylates are adjusted to a degree of neutralization of up to 80%.

EXAMPLES

[0071] 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%.

[0072] Demin. water=demineralized water

[0073] Production of popcorn polymer A: 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.

[0074] 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 μpm sieve fraction was tested as a disintegrant.

[0075] Production of popcorn polymer B: 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.

[0076] Production of popcorn polymer C: Popcorn polymer C was produced in analogous manner to the production of popcorn polymer

[0077] 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%.

[0078] Production of popcorn polymer D: Popcorn polymer D was produced in analogous manner to the production of popcorn polymer

[0079] 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%.

[0080] Production of popcorn polymer E:

[0081] 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%.

[0082] Production of popcorn polymer F: Popcorn polymer F was produced in analogous manner to the production of popcorn polymer A, but with 4.50 g of the <100 pm 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%.

[0083] Production of popcorn polymer G: 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%.

[0084] Production of popcorn polymer H: 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%.

[0085] Production of popcorn polymer I: 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%.

[0086] Production of popcorn polymer J: 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%.

[0087] Production of popcorn polymer K:

[0088] 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%.

[0089] Production of popcorn polymer L:

[0090] 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. 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%.

[0091] Production of popcorn polymer M: 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%.

[0092] For comparison: Production of gel polymer Cl: 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). Production of placebo tablets

[0093] All disintegration times reported hereinbelow were tested on placebo tablets obtained as follows: Tablet formulation (direct tableting): 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.

[0094] 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.

[0095] Determination of the gelation time The gelation time is determined as described in EP-A 1035196, [0028]. The exact method is described above in the general description.

[0096] Determination of the particle size distribution (PSD) in hexadecane and water

[0097] The measurements were carried out using a Mastersizer 3000 (static light scattering/Fraunhofer diffraction) in accordance with ISO 13320:2009.

[0098] Method 1: aqueous The measurement unit for aqueous samples is the Hydro MV unit: 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: Stirrer speed: 1500 rpm Ultrasound: Without Evaluation model: Fraunhofer Analysis model: Universal

TABLE-US-00001 Medium water Sample Laser obscuration (%) Gel polymer C1 6.49 Polymer M 9.33

[0099] Method 2: in hexadecane The measurement unit for hexadecane is the SV cell unit:

[0100] 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:

[0101] Stirrer speed: 1500 rpm Ultrasound: Without Evaluation model: Fraunhofer Analysis model: Universal

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

[0102] The results are listed in the table below.

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 pH 1.1 time pH 6.8 time Demin. Disintegrant [min:s] [min:s] water [min:s] Ac-Di-Sol 2:56 3:50 2:39 (croscarmellose- Na) Primojel (Na 2:45 3:38 3:32 starch glycolate) Kollidon ® CL 1:15 1:54 1:12 (crospovidone) Polymer M 2:09 2:35 2:12

[0103] 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.

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

[0104] 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.

[0105] 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.

TABLE-US-00005 TABLE 3 Neutralization, pH, and disintegration time: Popcorn vs. Amberlite Neutralization pH Disintegration Disintegration Disintegration [mol % carboxylic (1% in time pH 1.1 time pH 6.8 time Demin. Disintegrant acid groups] water) [min:s] [min:s] water [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)

TABLE-US-00006 TABLE 4 Determination of the disintegration times of tablet formulations at different pH values Disintegration Disintegration Disintegration time pH 1.1 time pH 6.8 time Demin. Polymer [min:s] [min:s] water [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 I 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