Hydrobromide salt of an anti-HIV compound

Abstract

Solid dispersions and dosage forms comprising the hydrobromide salt of a diarylpyrimidine derivative, useful as an anti-HIV agent.

Claims

1. A solid dispersion comprising a compound of formula (I): ##STR00003## in a water-soluble polymer selected from hydroxypropylmethyl cellulose 2910 5 mPa.Math.s and vitamin E TGPS, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 10:1 or about 9:1.

2. The solid dispersion according to claim 1, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

3. A dosage form comprising the solid dispersion of claim 1.

4. The dosage form of claim 3 wherein the dosage form is selected from a tablet and a capsule.

5. The solid dispersion according to claim 1 obtainable by spray-drying.

6. The solid dispersion according to claim 5, further containing microcrystalline cellulose.

7. The solid dispersion according to claim 1, wherein the water-soluble polymer is hydroxypropylmethyl cellulose 2910 5 mPa.Math.s.

8. The solid dispersion according to claim 1, wherein the water-soluble polymer is vitamin E TGPS.

9. The solid dispersion according to claim 7, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

10. The solid dispersion according to claim 8, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

11. The dosage form of claim 3, wherein the water-soluble polymer is hydroxypropylmethyl cellulose 2910 5 mPa.Math.s.

12. The dosage form of claim 3, wherein the water-soluble polymer is vitamin E TGPS.

13. The dosage form of claim 3, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

14. The dosage form of claim 11, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

15. The dosage form of claim 12, wherein the weight:weight ratio of the water-soluble polymer to the compound of formula (I) is about 9:1.

Description

EXAMPLE 1—PREPARATION OF SALTS OF THE COMPOUND OF FORMULA (A)

(1) The compound of formula (A), that is, 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile, was dissolved in dichloromethane and aqueous hydrobromic acid was added. The mixture was evaporated to dry yielding the hydrobromide salt of (A), i.e. the compound of formula (I). Other addition salts of the compound of formula (A) can be obtained similarly and are shown in the following Table 1.

(2) TABLE-US-00001 Acid Salt of compound of formula (I) obtained Hydrobromic acid Hydrobromide (i.e. compound of formula (I)) Hydrochloric acid Hydrochloride Maleic acid Maleate Methanesulfonic acid Methanesulfonate Fumaric acid Fumarate Sulfuric acid Sulfate

(3) Capsules were filled with the various salts of the compound of formula (I) in the amounts shown in the following Table 2.

(4) TABLE-US-00002 Salt of compound (I) Amount of salt per capsule in mg Hydrobromide 118.6 Hydrochloride 108.4 Maleate 63.3 Methane sulfonate 122.1 Fumarate 63.3 Sulfate 122.5

EXAMPLE 2—IN-VIVO STUDY OF BIOAVAILABILITY IN DOGS OF THE COMPOUND OF FORMULA (I) COMPARED WITH SALTS OF THE COMPOUND OF FORMULA (I)

(5) Four male dogs were used per tested formulation. The animals were randomized over the test groups by a computer-generated random algorithm according to body weight, with all animals within ±20% of the sex mean. A health inspection was performed prior to commencement of treatment to ensure that the animals were in a good state of health. The dogs were subjected to an acclimatization period of at least 5 days before the start of treatment under laboratory conditions. A controlled environment was maintained in the room. The animals were dosed once orally with the formulations of example 1, and blood was collected from all animals under light ether anaesthesia at regular intervals for a period of 12, 24 or 48 hours after dosing.

(6) The mean pharmacokinetic parameters relating to the mean plasma concentration with time of each test formulation are shown in Table 3. The standard deviation, where calculated, is shown between brackets. Analysis of the peak plasma concentration (C.sub.max) and bioavailability in terms of area under the curve (AUC.sub.0-last) shows that the hydrobromide salt of compound (I), that is the compound of formula (I) has advantageously improved bioavailability in dogs compared with other salts of compound (I). t.sub.max is the time taken to reach the peak plasma concentration. t.sub.last is the last time at which the peak plasma concentration was determined.

(7) TABLE-US-00003 Methane- HBr Maleate sulfonate Fumarate Sulfate Parameter salt HCl salt salt salt salt salt t.sub.max (h) 4.5 (2.1) 1.5 (0.7) 2.0 (—) 1.5 (0.7) 2.0 (—) 2.0 (0) t.sub.last (h) 48 (0) 48 (0) 24 (—) 48 (0) 12 (—) 48 (0) AUC.sub.0-last 5855 (1456) 1875 (158.7) 446.5 (—) 3753 (803.3) 102.7 (—) 3143 (794.3) (ng .Math. h/ml) (without dose normalization) C.sub.max (ng/ml) 365.5 (212.8) 222.0 (86.27) 52.00 (—) 409.0 (57.98) 15.2 (—) 294.0 (29.70) (without dose normalization) AUC.sub.0-last 516.1 (83.02) 168.2 (29.43) 77.70 (—) 318.8 (35.56) 20.67 (—) 279.9 (49.45) (ng .Math. h/ml) (dose normalized to 1 mg/kg) C.sub.max (ng/ml) 31.73 (16.05) 20.19 (9.513 9.048 (—) 34.87 (1.337) 3.058 (—) 26.34 (0.6133) (dose normalized to 1 mg/kg)

EXAMPLE 3—SPRAY-DRIED FORMULATION COMPRISING THE COMPOUND OF FORMULA (I)

(8) TABLE-US-00004 Formulation G Compound of formula (I)  59.3 mg HPMC 5 m Pa .Math. s 177.9 mg

(9) To prepare formulation G, the compound of formula (I) was dissolved in a first beaker in methanol/dichloromethane 50/50 v/v % at a concentration of 6.5 g per 750 ml of methanol/dichloromethane. HPMC 2910 5 mPa.Math.s was dissolved in methanol/dichloro-methane 50/50 v/v % in a second beaker. The concentration of HPMC 2910 5 mPa.Math.s in the solution was 6.5 g per 100 ml methanol/dichloromethane.

(10) The two solutions were subsequently mixed and then spray-dried using the following spray-drying operating conditions: Inlet air temperature: 80° C. Outlet air temperature: 40-55° C. Flow rate of the solution: 12 ml/min Air pressure: 1 bar

(11) After spray-drying, the spray dried powder was dried under reduced pressure at 40° C. for 5 days. The resulting formulation was filled into Swedish-orange capsules.

(12) An in-vivo dog study of the bioavailability of capsules comprising formulation G was carried out as described in Example 2. The mean pharmacokinetic parameters are shown in Table 6. The standard deviation, where calculated, is shown between brackets.

(13) TABLE-US-00005 Parameter Formulation G t.sub.max (h)  .sup.  1.0 (1.0-2.0) t.sub.last (h) 48 (0).sup.  AUC.sub.0-last (ng .Math. h/ml) 13752 (2378).sup.  (without dose normalization) C.sub.max (ng/ml) 1263 (165.6) (without dose normalization) AUC.sub.0-last (ng .Math. h/ml) 1179 (293.7) (dose normalized to 1 mg/kg) C.sub.max (ng/ml) 107.0 (15.38)  (dose normalized to 1 mg/kg)

EXAMPLE 5—IN-VIVO STUDY OF BIOAVAILABILITY IN HUMANS OF THE COMPOUND OF FORMULA (I) FORMULATION L

(14) To prepare formulation L, 118.6 mg of the compound of formula (I) was dissolved in a first beaker in methanol/dichloromethane 50/50 v/v % at a concentration of 6.5 g per 750 ml of methanol/dichloromethane In a second beaker, 234.8 mg HPMC 2910 5 mPa.Math.s was dissolved in methanol/dichloromethane 50/50 v/v %. The concentration of HPMC 2910 5 mPa.Math.s in the solution was 6.5 g per 100 ml methanol/dichloromethane. The two solutions were subsequently mixed and then sprayed onto 121 mg of HMPC 5 mPa.Math.s. The resulting powder was filled into Swedish-orange capsules. One capsule of formulation L contained 118.6 mg of the compound of formula (I), which is equivalent to 100 mg of compound (A).

(15) A randomized human bioequivalence trial was carried out to monitor bioavailability in humans of formulation L.

(16) For formulation L, nine subjects were given 800 mg of formulation L twice daily for 13 days, with a single dose on day 14. A 12 h pharmacokinetic profile was determined on day 1 and on day 14. Pre-dose concentrations were determined every other day. The results are listed in the following Table.

(17) TABLE-US-00006 Scheduled Plasma conc. of TMC125 (ng/ml) time Mean ± SD Day 1 0 h Not quantifiable 1 h  35.3 ± 33.1 2 h  638 ± 451 3 h 1220 ± 750 4 h  136 ± 681 6 h 1020 ± 395 8 h  680 ± 285 10 h   476 ± 182 12 h   392 ± 166 Day 3 0 h 1230 ± 341 Day 5 0 h 1630 ± 513 Day 7 0 h 1830 ± 769 Day 9 0 h 1830 ± 720 Day 11 0 h 1940 ± 758 Day 13 0 h 1870 ± 740 Day 14 0 h 1660 ± 578

(18) For formulation L, pre-dose levels reached steady-state between 3 to 5 days. Good bioavailability was observed.