NOVEL POLYURETHANES AND THEIR USE IN PHARMACEUTICAL DOSAGE FORMS

Abstract

The present invention relates to novel polyurethanes based on a diisocyanate, a carboxylic acid functionalized diol and an acid-free diol, their use as pharmaceutical excipients for improving gastrointestinal absorption, the respective pharmaceutical dosage forms and methods for making the polyurethanes.

Claims

1. An isocyanate free polyurethane comprising components A to D with 45-70 wt% of at least one diisocyanate A with at least one ring in the molecular structure between the two isocyanate groups; with 15-40 wt% of at least one component B with i) two primary hydroxy groups, ii) one secondary or tertiary carboxylic acid group iii) a molecular weight between 100 and 250 g/mol and iv) no additional group reactive towards an isocyanate; with 5-30 wt% of at least one component C with i) at least two hydroxy groups, ii) a molecular weight between 60 and 250 g/mol, iii) no acid group and iv) no primary or secondary amine or thiol group and optionally with 0-5 wt% of one or more components D which i) contain one or two groups reactive toward isocyanate groups and ii) maximum one of these reactive groups is a hydroxy group, whereby a total amount of incorporated components A to D adds up to 100% by weight.

2. The polyurethane according to claim 1, wherein the diisocyanate A is isophorone diisocyanate.

3. The polyurethane according to claim 1, wherein the component B is 2,2-bis(hydroxymethyl)butyric acid.

4. The polyurethane according to claim 1, wherein the component B is 2,2-bis(hydroxymethyl)propionic acid.

5. The polyurethane according to claim 1 wherein the component C is 1,4-cyclohexane dimethanol.

6. The polyurethane according to claim 1, wherein the component C is neopentyl glycol.

7. The polyurethane according to claim 1, wherein the component C is isosorbide.

8. The polyurethane according to claim 1, wherein the component C is 2,5-dimethyl-2,5-hexanediol.

9. The polyurethane according to claim 1, wherein the component C is 2,2-diethyl-1,3-propanediol.

10. (canceled)

11. The polyurethane according to claim 1, wherein a weight average molecular weight of the polyurethane is in the range of 2,000 to 100,000 g/mol.

12. The polyurethane according to claim 1, wherein at least 25% of the carboxylic acid groups of component B are neutralized.

13. An isocyanate free polyurethane comprising components A to C with 50-65 wt% of isophorone diisocyanate as A; with 20-35 wt% of at least one component B selected from the group consisting of 2,2-bis(hydroxymethyl)butyric acid and 2,2-bis(hydroxymethyl)propionic acid, and with 5-30 wt% of at least one component C selected from the group consisting of 1,4-cyclohexane dimethanol, 1,3-cyclohexane dimethanol, 2,2-diethyl-1,3-propanediol, 2,5-dimethyl-2,5-hexanediol, isosorbide, and neopentyl glycol, whereby the total amount of incorporated components A to C adds up to 100% by weight.

14. The polyurethane according to claim 13, wherein at least 25% of the carboxylic acid groups of component B) are neutralized.

15. The polyurethane according to claim 13, wherein a ratio between isocyanate groups of diisocyanate A and sum of primary and secondary alcohol groups of B and C is 1.1:1 to 0.9:1.

16. The polyurethane according to claim 13, wherein a weight average molecular weight of the polyurethane is in the range of 4,000 to 60,000 g/mol.

17. A pharmaceutical dosage form, comprising a polyurethane according to claim 1 and an active pharmaceutical ingredient with a solubility in water at standard conditions of less than 0.1 % by weight, wherein the active ingredient is present in an amorphous form.

18. A method for inhibiting recrystallization of an active ingredient in a pharmaceutical dosage form in an aqueous environment of a human or animal body, wherein the active ingredienthas a solubility in water at standard conditions of less than 0.1 % by weight, and wherein the active ingredient is present in the pharmaceutical dosage form in the amorphous form comprising adding a polyurethane according to claim 1 to the pharmaceutical dosage form.

19. A method for inhibiting recrystallization of an agricultural active ingredient in an agricultural dosage form in soil, whereby the active ingredient has a solubility in water at standard conditions of less than 0.1 % by weight, and wherein the active ingredient is present in the agricultural dosage forms in the amorphous form comprising adding a polyurethane according to claim 1 to the agricultural dosage form.

Description

EXAMPLES

Synthesis Procedure for Inventive Polyurethane IP1

[0046] A two-liter glass reactor, equipped with a mechanical stirrer, a condenser, a nitrogen sweep, a thermometer and inlets for the addition of starting materials, was charged with 400 grams of butanone (MEK), 61.7 grams of 2,2-bis(hydroxymethyl)butanoic acid (417 mmol) as component B and 30.0 grams of 1,4-cyclohexane dimethanol (208 mmol) as component C. The resulting mixture was stirred at 100 rpm and heated to 80° C. under a nitrogen atmosphere. Isophorone diisocyanate (138.9 grams, 625 mmol), used as component A, was added within 20 minutes through a dropping funnel. The dropping funnel was rinsed with 50 grams of MEK which was then also added to the reaction mixture. The reaction mixture was stirred for 24 hours at 80° C. under a nitrogen atmosphere. After this, 100 g of water was added, and the resulting mixture was stirred at 70° C. for one hour to hydrolyze residual isocyanate groups. After cooling to ambient temperature, the carboxylic acid groups in the product mixture were neutralized by the addition of 60 grams of a 25% aqueous sodium hydroxide solution (380 mmol). Volatiles were removed and the polymer product was subsequently dried overnight in a vacuum oven at 75° C. at 0.02 MPa.

TABLE-US-00001 Monomers used for polyurethane synthesis Monomer CAS Abbreviation Component MW (g/mol) Isophorone diisocyanate 4098-71-9 IPDI A 222.3 Tetramethylxylene diisocyanate 2778-42-9 TMXDI A 244.3 Hexamethylene diisocyanate (not according to the invention) 822-06-0 HMDI Non-cyclic diisocyanate 168.2 L-Lysine ethyl ester, diisocya-nate (not according to the invention) 45172-15-4 LEED Non-cyclic diisocyanate 226.2 2,2-Bis(hydroxymethyl)butyric acid 10097-02-6 DMBA B 148.2 2,2-Bis(hydroxymethyl)propionic acid 4767-03-7 DMPA B 134.1 1,4-Cyclohexane dimethanol 105-05-8 CHDM C 144.2 2,2-Diethyl-1,3-propanediol 115-76-4 DEPD C 132.2 2,5-Dimethyl-2,5-hexanediol 110-03-2 DMHD C 146.2 Isosorbide 652-67-5 IS C 146.1 Fructose 57-48-7 FT C 180.2 Xylitol 87-99-0 XL C 152.1 Neopentyl glycol 126-30-7 NPG C 104.2 Polyethylene glycol 25322-68-3 PEG 400 Polymericdiol 400 MW = molecular weight.

[0047] The other polymers were synthesized by using variations of this procedure. Table 2 describes the differences between the polymerization recipes. Numbers in brackets refer to the used amounts in gram. For the synthesis of IP3, only half the amounts of MEK and water were used. CP2 was prepared using, 140 and 20 grams MEK in the pre-feeding charge and to rinse the dropping funnel respectively, and 35 grams of water to hydrolyze residual isocyanates. In the other cases, the used amounts of solvent and water were identical to the amounts given for the synthesis of IP1. Also reaction times, the temperature during the residual isocyanate hydrolysis and the drying procedure were as described above. In all cases, 90% of the carboxylic acid groups of B were neutralized with a base, after the polymerization and the hydrolysis of residual isocyanate groups. In case of IP6, the polymer was neutralized with triethanolamine instead of an aqueous sodium hydroxide solution.

TABLE-US-00002 Polymer synthesis Polymer Diisocyanate (Component A) Carboxylic acid diol (Component B) Component C Poly. Temp. (°C) Solvent Base used for neutralization IP1 IPDI (138.9) DMBA (61.7) CHDM (30.0) 80 MEK 25% aq. NaOH (60) IP2 IPDI (138.9) DMPA (55.9) CHDM (30.0) 80 MEK 25% aq. NaOH (60) IP3 IPDI (69.5) DMBA (30.9) IS (15.3) 80 MEK 25% aq. NaOH (30) IP4 IPDI (138.9) DMBA (61.7) CHDM (30.0) 100 Dioxane 25% aq. NaOH (60) IP5 IPDI (138.9) DMBA (61.7) DMHD (31.4) 80 MEK 25% aq. NaOH (60) IP6 IPDI (138.9) DMBA (61.7) CHDM (30.0) 80 MEK Triethanolamine (28) IP7 IPDI (138.9) DMBA (46.3) XL (47.6) 80 MEK 25% aq. NaOH (45) IP8 IPDI (138.9) DMBA (46.3) FT (56.3) 65 THF 25% aq. NaOH (45) IP9 IPDI (138.9) DMBA (61.7) DEPD (27.8) 80 MEK 25% aq. NaOH (60) IP10 TMXDI (140.2) DMBA (61.7) CHDM (30.0) 80 Dioxane 25% aq. NaOH (60) IP11 IPDI (138.9) DMBA (68.0) CHDM (23.9) 80 Dioxane 25% aq. NaOH (60) IP12 IPDI (138.9) DMBA (61.7) NPG (21.7) 80 Dioxane 25% aq. NaOH (60) IP13 IPDI (138.9) DMBA (72.0) CHDM (20.1) 80 Dioxane 25% aq. NaOH (70) CP1 HMDI (105.2) DMBA (61.7) CHDM (30.0) 80 MEK 25% aq. NaOH (60) CP2 LEED (49.0) DMBA (18.7) CHDM (13.0) 80 MEK 25% aq. NaOH (18) CP3 IPDI (138.9) DMPA (41.9) PEG 400 (125.0) 80 MEK 25% aq. NaOH (45) CP4 IPDI (138.9) DMBA (92.6) - 80 MEK 25% aq. NaOH (60) CP5 HMDI (105.2) DMBA (52.6) CHDM (39.0) 80 Dioxane 25% aq. NaOH (60) MEK = Butanone.

GPC-Method

[0048] Polymer molecular weights were determined by size exclusion chromatography (SEC) at 35° C., using: hexafluoro-2-propanol containing 0.05 wt% of the potassium salt of trifluoroacetic as eluent, narrow molecular weight distribution poly(methyl methacrylate) standards (commercially available from PSS Polymer Standard Solutions GmbH with molecular weights in the range from M = 800 to M = 2,200,000) and a differential refractive index (DRI) detector.

Preparation of Amorphous Solid Dispersions Via Spray Drying

[0049] Danazol-polymer formulations (10 wt% drug loading): Solid dispersions were composed of polymer and danazol. To prepare the formulations, 1.5 g of danazol and 13.5 g of polymer were dissolved in 285 g of methanol (5 wt% solids content). Spray drying was performed on a Büchi Mini Spray Dryer B-290 equipped with a 0.7 mm two-fluid nozzle under the following conditions:

TABLE-US-00003 Nitrogen flow rate 35 m.sup.3/h Inlet temperature 85 - 105° C. Outlet temperature 50 - 70° C. Atomizing pressure 0.7 MPa Liquid flow rate 300 g/h

[0050] The product was collected using a cyclone. The drug content of the spray-dried formulations was determined by measuring the UV absorbance at 286 nm; the solid-state properties were analyzed using powder X-ray diffraction (PXRD):

TABLE-US-00004 Drug content (UV spectroscopy) 9.4 - 10.8 wt% Solid-state properties (PXRD) X-ray amorphous

[0051] Amorphous solid dispersions of other drugs were prepared under the same conditions, but in these cases, a 25 wt% drug loading was employed. The drug content in the amorphous solid dispersion was determined by UV spectroscopy by measuring the absorbance at the wave lengths listed in Table 3, and was found to lay between 24.6 and 27.5 wt% in all cases.

TABLE-US-00005 Wavelenghts at which drug absorbance was measured Drug Wavelength (nm) Drug Wavelength (nm) Felodipine 360 Celecoxib 252 Gefitinib 250 Telmisartan 296 Itraconazole 262 Fenofibrate 287 Probucol 242 Nifedipine 360

Preparation of Fasted State Simulated Intestinal Fluid (FaSSIF)

[0052] To prepare 1 L of FaSSIF solution, 0.42 g of sodium hydroxide was placed in a volumetric flask and dissolved in approximately 900 mL of water. Then, 3.95 g of sodium dihydrogen phosphate, 6.19 g of sodium chloride, and 2.24 g of FaSSIF/FeSSIF/FaSSGF powder (Biorelevant.com Ltd., London, United Kingdom) were added. The solution was diluted with water to 1 L, the pH was adjusted to 6.8 using 1 molar aqueous sodium hydroxide solution and allowed to stand for 2 h.

Dissolution Testing

[0053] In vitro dissolution tests were done to quantify the drug release and measure the maintenance of supersaturation. To this end, 300 ml FaSSIF were filled into the dissolution vessels of an ERWEKA dissolution tester with mini glass vessels (stirring speed approximately 75 rpm). After a temperature of 37° C. had been reached, a defined amount of the spray-dried formulation (equivalent to a drug concentration of 0.14 mg/ml) was added. Samples of 3 mL were withdrawn after 5 min, 15 min, 30 min, 60 min, 90 min, 120 min, 180 min, 240 min, 300 min and 360 min. All samples were filtered through 0.45 .Math.m PVDF syringe filters and diluted with methanol or methanol/water (1:4 or 1:10, depending on the drug concentration). The concentration of the drug in solution was determined by UV spectroscopy using a calibration curve of the pure drug in methanol. To evaluate the performance of the polymer, the area under the concentration-time curve (AUC) was calculated as follows:

[00001]$AU{C}_{0.fwdarw.t_n}=\frac{1}{2}{\displaystyle {.Math.}_{i=1}^{n-1}\left(C_{t_i}+C_{t_{i+1}}\right)}\cdot \left(t_{i+1}-t_i\right)$

[00002]${\text{C}}_{\text{t}}=\text{Concentration at time t in}\text{mg}/\text{mL}\text{, t=}\text{Time in min}$

[0054] The AUC value was used to calculate active pharmaceutical ingredient (API) release as a percentage value of maximum possible API release. Maximum release meaning complete dissolution of the used amount of API for the entire duration of the 6 hours (360 minutes) dissolution experiment.

[00003]$\text{API release =}\frac{AUC\left(mg/ml\cdot min\right)}{360\left(min\right)\cdot Cmax\left(ma/ml\right)}\cdot 100\%$

[0055] The results summarized in Table 4 and 5 show that the inventive polymers IP are effective crystallization inhibitors.

TABLE-US-00006 Crystallization inhibition performance of synthesized polymers Polymer M.sub.n (g/mol)* M.sub.w (g/mol)* Danazol release (%) IP1 4 060 12 600 94 IP2 4 310 12 300 99 IP3 3 140 8 490 76 IP4 5 700 22 700 84 IP5 4 030 10 500 96 IP6 3 570 8 410 96 IP7 4 010 32 200 76 IP8 4 080 19 200 84 IP9 3 650 9 770 85 IP10 4 110 10 900 68 IP11 5 700 22 700 93 IP12 5 630 16 000 82 IP13 6 970 20 300 82 CP1 4 420 16 500 24 CP2 3 990 15 200 20 CP3 25 500 65 700 14 CP4 4 860 13 900 20 CP5 5 380 22 300 33 *Determined by GPC.

TABLE-US-00007 Release of other drugs in combination with inventive polyurethanes Drug Polyurethane Drug release (%) Felodipine IP1 94 Gefitinib IP13 100 Itraconazole IP1 51 Probucol IP13 100 Celecoxib IP1 95 Telmisartan IP1 98 Fenofibrate IP1 54 Nifedipine IP1 96