DISPERSIBLE COMPOSITIONS

Abstract

The present invention is concerned with dispersible compositions comprising rilpivirine or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. Such compositions are useful in the treatment of HIV infection and their dispersibility properties lend themselves to be useful in particular amongst the pediatric or geriatric population.

Claims

1. A dispersible composition comprising E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-benzonitrile (rilpivirine) or a pharmaceutically acceptable acid addition salt thereof, as the active ingredient, wherein said active ingredient is present in the dispersible composition in the form of granules, said granules further comprising a pharmaceutically acceptable excipient; wherein the dispersible composition comprises 2.5 mg base equivalent of E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-benzonitrile; and wherein the dispersible composition further comprises next to the granules, in the extragranular fraction, a non-soluble diluent.

2. The dispersible composition according to claim 1 wherein the pharmaceutically acceptable excipient of the granules comprises a wetting agent.

3. The dispersible composition according to claim 1 wherein the pharmaceutically acceptable excipient of the granules comprises a disintegrant.

4. The dispersible composition according to claim 1 wherein the pharmaceutically acceptable excipient of the granules comprises a diluent.

5.-6. (canceled)

7. The dispersible composition according to claim 1 comprising in the extragranular fraction a wetting agent.

8. The dispersible composition according to claim 1 comprising in the extragranular fraction a disintegrant.

9. The dispersible composition according to claim 1 wherein the composition is a tablet.

10. The dispersible composition according to claim 1 wherein the active ingredient is rilpivirine HCl.

11.-13. (canceled)

14. A combination comprising a dispersible composition according to claim 1 and one or more other therapeutic agents useful in the treatment of HIV infection.

15. A method of treating a patient suffering from HIV infection comprising administering to the patient a therapeutically effective amount of a dispersible composition according to claim 1.

16. The method of claim 15, wherein the dispersible composition is administered in combination with one or more other therapeutic agents useful in the treatment of HIV infection.

17. The method of claim 15, wherein the patient is a pediatric patient or a geriatric patient.

Description

EXPERIMENTAL PART

[0159] The active ingredient, rilpivirine and pharmaceutically acceptable salt thereof, may be prepared for example in accordance with the procedures described in international patent applications WO 03/16306, WO2004/016581 and WO2006/024668.

[0160] 1) Preparation of a Dispersible Composition of the Present Invention

[0161] Rilpivirine HCl 2.75 mg

[0162] Lactose monohydrate

[0163] Croscarmellose sodium

[0164] Polyvinylpyrrolidone (e.g. Povidon K30)

[0165] Polysorbate 20

[0166] Purified water (removed during processing)

[0167] Total: 8.73 mg

[0168] Mannitol

[0169] Microcrystalline cellulose

[0170] Sodium lauryl sulfate

[0171] Croscarmellose sodium

[0172] Sodium stearyl fumarate

[0173] Total: 100 mg

[0174] Rilpivirine HCl granules were prepared by wet granulation. The first 12 portion of lactose monohydrate 200 mesh was charged in a suitable container. Rilpivirine HCl was charged in the suitable container. Croscarmellose sodium was charged in the suitable container. The second 12 portion of lactose monohydrate 200 mesh was charged in the suitable container. The mixture was blended. The binder solution was prepared by charging purified water and povidone in a suitable vessel. Polysorbate 20 was added. The mixture was stirred. Granulation was performed in a fluid bed granulator (Glatt WSG 200). The powder blend was charged under vacuum in the granulator. The binder solution was sprayed onto the mixture. The dried material was discharged from the granulator, milled and charged in a suitable container (step 1). The granules contain 31.48% of rilpivirine HCl.

[0175] The rilpivirine containing granules were co-sifted with mannitol, microcrystalline cellulose, corscarmellose sodium and sodium lauryl sulfate using a suitable sieve and the co-sifted blend was blended using a suitable blender (step 2). Sodium stearyl fumarate was sifted, added to the blend of step 2 and the blend was lubricated using a suitable blender (step 3).

[0176] The blend of step 3 was compressed into tablets using a suitable tablet press. The resulting tablets were packed in suitable containers (e.g. high-density polyethylene (HDPE) bottles e.g. with child resistant polypropylene closure and desiccant (e.g. silica gel 2 g in HDPE pouch).

[0177] 2) Identification and Quantitative Determination of Active Ingredient

[0178] To test the assay (% w/w) of the active ingredient of the composition described in 1), stored under different conditions, the following conditions were used:

[0179] HPLC Operating Conditions:

[0180] Column: Zorbax Extend C18, 100 mm length×4.6 mm i.d., 3.5 μm particle size

[0181] Column Temperature: 45° C.

[0182] Flow Rate: 1 mL/min

[0183] Injection Volume: 10 μL

[0184] Detection: UV at 280 nm

[0185] Mobile Phase: A: 10 mM ammonium acetate buffer in water

[0186] B: Acetonitrile

[0187] Elution Mode: Gradient:

TABLE-US-00001 Time (minute) A (% vol) B (% vol) 0 95 5 30 40 60 31 40 60 32 95 5 37 95 5

[0188] Analysis Time: 37 minutes

[0189] Relative retention Time (minute): 1.0 for rilpivirine HCl.

[0190] Results for assay (% w/w) and total degradation products (% w/w) (study ID 151187: 65 tablets in 40 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00002 Total degradation Storage condition Test interval Assay product Initial 101.7 0.3 ICH light.sup.a unprotected.sup.b 8 hours 103.7 0.7 ICH light.sup.a protected.sup.c 8 hours 100.4 0.3  5° C. 1 month 101.8 0.4 3 months 105.3 0.3 25° C./60% RH 1 month 100.5 0.3 3 months 102.4 0.3 6 months 102.2 0.3 9 months 101.3 0.3 12 months 101.3 0.3 30° C./75% RH 1 month 100.3 0.3 3 months 102.1 0.3 6 months 100.3 0.3 9 months 99.9 0.3 12 months 103.6 0.3 40° C./75% RH 1 month 99.3 0.3 2 months 102.6 0.3 3 months 102.5 0.3 6 months 98.6 0.3 50° C. 1 month 101.8 0.4 .sup.aintegrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.btablets were directly exposed to Light ICH in a petri dish .sup.ctablets were exposed to Light ICH packed in original container

[0191] Results for assay (% w/w) and total degradation products (% w/w) (study ID 151188: 65 tablets in 75 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00003 Total degradation Storage condition Test interval Assay product Initial 103.4 0.3 ICH .sup.a light unprotected.sup.b 8 hours 101.3 0.6 ICH .sup.a light protected .sup.c 8 hours 100.3 0.3  5° C. 1 month 101.9 0.4 3 months 102.6 0.3 25° C./60% RH 1 month 102.0 0.4 3 months 102.0 0.3 6 months 102.0 0.3 9 months 100.2 0.3 12 months 102.0 0.3 30° C./75% RH 1 month 100.6 0.3 3 months 102.1 0.3 6 months 101.5 0.3 9 months 99.6 0.3 12 months 105.5 0.3 40° C./75% RH 1 month 101.2 0.3 2 months 100.9 0.3 3 months 103.5 0.3 6 months 100.4 0.3 50° C. 1 month 100.7 0.3 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.btablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0192] 3) Dissolution Test

[0193] To test the dissolution behavior of the composition described in 1), the following conditions were used:

[0194] Apparatus: Paddle apparatus (USP type 2);

[0195] Dissolution medium: 0.025% (w/v) polysorbate 20 (Tween® 20) in 0.01 M HCl

[0196] Volume: 900 ml

[0197] Temperature: 37° C.;

[0198] Rotation speed: 75 rpm;

[0199] Sampling time: 5, 10, 15, 20, 30, 45 and 60 minutes.

[0200] Rilpivirine HCl was measured by HPLC:

[0201] HPLC Operating Conditions:

[0202] Column: X-terra, RP18, 50 mm×4.6 mm id, 3.5 m particle size or equivalent

[0203] Column Temperature: Elevated or Room temperature, or 35±3° C.

[0204] Flow Rate: 1.2 mL/min

[0205] Injection Volume: 50 μL

[0206] Detection: UV at 280 nm

[0207] Mobile Phase: A: 10 mM ammonium acetate pH4.0 [0208] B: Acetonitrile

[0209] Elution Mode: Isocratic (Mobile phase A: Mobile phase B) (45:55)

[0210] Analysis Time: 2.5 mina .sup.a Retention Time (guide): Approximately 1.7 minutes for rilpivirine HCl

[0211] Results for dissolution at 45 minutes (%) (a % dissolution of at least 80% at 45 minutes was deemed acceptable for clinical testing) (study ID 151187: 65 tablets in 40 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure).

TABLE-US-00004 dissolution at 45 minutes Storage condition Test interval (%) Initial 97 ICH .sup.a light unprotected .sup.b 8 hours 100 ICH .sup.a light protected .sup.c 8 hours 101  5° C. 1 month 101 3 months 101 25° C./60% RH 1 month 100 3 months 102 6 months 100 9 months 101 12 months 102 30° C./75% RH 1 month 100 3 months 97 6 months 99 9 months 100 12 months 103 40° C./75% RH 1 month 99 2 months 99 3 months 102 6 months 98 50° C. 1 month 102 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0212] Results for dissolution at 45 minutes (%) (study ID 151188:65 tablets in 75 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00005 dissolution at 45 minutes Storage condition Test interval (%) Initial 100 ICH .sup.a light unprotected .sup.b 8 hours 101 ICH .sup.a light protected .sup.c 8 hours 98  5° C. 1 month 104 3 months 102 25° C./60% RH 1 month 99 3 months 100 6 months 100 9 months 98 12 months 99 30° C./75% RH 1 month 103 3 months 102 6 months 97 9 months 104 12 months 103 40° C./75% RH 1 month 101 2 months 97 3 months 100 6 months 98 50° C. 1 month 97 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0213] 4) Appearance

[0214] The appearance of the product was also evaluated (visual) and was considered appropriate: white to off-white round tablets.

[0215] 5) Disintegration Time

[0216] The product was evaluated for disintegration in accordance with Ph. Eur.<2.9.1>.

[0217] Results for disintegration time (minutes) (study ID 151187: 65 tablets in 40 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00006 Disintegration time (minutes; 1 means higher than or equal to 30 seconds; 0 means lower Storage condition Test interval than 30 seconds) Initial 1 ICH .sup.a light unprotected .sup.b 8 hours 1 ICH .sup.a light protected .sup.c 8 hours 1  5° C. 1 month 1 3 months 1 25° C./60% RH 1 month 1 3 months 1 6 months 1 9 months 1 12 months 0 30° C./75% RH 1 month 1 3 months 1 6 months 1 9 months 1 12 months 0 40° C./75% RH 1 month 1 2 months 0 3 months 0 6 months 0 50° C. 1 month 1 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0218] Results for disintegration time (minutes) (study ID 151188:65 tablets in 75 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00007 Disintegration time (minutes; 1 means higher than or equal to 30 seconds; 0 means lower Storage condition Test interval than 30 seconds) Initial 1 ICH .sup.a light unprotected .sup.b 8 hours 1 ICH .sup.a light protected .sup.c 8 hours 1  5° C. 1 month 1 3 months 1 25° C./60% RH 1 month 1 3 months 1 6 months 1 9 months 1 12 months 1 30° C./75% RH 1 month 1 3 months 1 6 months 1 9 months 0 12 months 0 40° C./75% RH 1 month 1 2 months 1 3 months 1 6 months 0 50° C. 1 month 1 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0219] 6) Fineness of Dispersion

[0220] The fineness of the dispersion was tested according to Ph.eur.<2.9.1>. The acceptance criteria was passing a sieve of 710 μm.

[0221] The product stored as indicated in the above tables complied to the fineness of dispersion test.

[0222] 7) Water Content

[0223] The water content was determined by Karl fisher in accordance with USP <291> method I/EP<2.5.12>.

[0224] Results for water content (% w/w) (study ID 151187: 65 tablets in 40 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00008 Water content Storage condition Test interval (% w/w) Initial 2.5 ICH .sup.a light unprotected .sup.b 8 hours 2.2 ICH .sup.a light protected .sup.c 8 hours 1.8  5° C. 1 month 2.3 3 months 1.9 25° C./60% RH 1 month 2.5 3 months 1.7 6 months 1.9 9 months 1.7 12 months 1.7 30° C./75% RH 1 month 2.6 3 months 1.9 6 months 1.9 9 months 1.9 12 months 1.9 40° C./75% RH 1 month 2.1 2 months 1.9 3 months 1.8 6 months 2.1 50° C. 1 month 2.0 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0225] Results for water content (% w/w) (study ID 151188: 65 tablets in 75 cc HDPE bottle with 2 g desiccant; child resistant polypropylene closure)

TABLE-US-00009 Water content Storage condition Test interval (% w/w) Initial 2.2 ICH .sup.a light unprotected .sup.b 8 hours 2.3 ICH .sup.a light protected .sup.c 8 hours 1.8  5° C. 1 month 2.2 3 months 1.6 25° C./60% RH 1 month 2.1 3 months 1.7 6 months 1.9 9 months 1.9 12 months 1.7 30° C./75% RH 1 month 2.2 3 months 2.2 6 months 1.9 9 months 1.8 12 months 2.0 40° C./75% RH 1 month 2.2 2 months 1.9 3 months 1.9 6 months 2.3 50° C. 1 month 1.9 .sup.a integrated near UV energy not less than 200 W .Math. h/m.sup.2, overall illumination not less than 1200 klux .Math. hr .sup.b tablets were directly exposed to Light ICH in a petri dish .sup.c tablets were exposed to Light ICH packed in original container

[0226] 8) Content Uniformity

[0227] The content uniformity was determined according to the Ph. Eur. <2.9.40> or USP <905>. The requirements for dosage uniformity were met (acceptance value of the first 10 dosage units less than or equal to L1 (L1: not more than 15.0).

[0228] The composition described in 1) was studied in a phase I, open label, randomized (according to a Williams design), four way cross over trial in healthy HIV-negative adults aged 18-55 years (Study TMC278IFD1008; NCT02561936). In the first part of the study, the dispersible tablets dispersed in water (10 tablets of 2.5 mg rilpivirine base equivalent) were taken following a standard breakfast (treatment C), and compared to the Edurant® reference tablet taken following a standard breakfast (treatment A). In the second part of the study, the dispersible tablets dispersed in water (10 tablets of 2.5 mg rilpivirine base equivalent) were taken following a standard breakfast or in fasted conditions, or dispersed in orange juice (acidic beverage) and taken after a standardized breakfast, or dispersed in water and taken with yoghurt.

[0229] Venous blood samples were collected over 168 hours after dosing for determination of rilpivirine plasma concentrations. Bioanalysis of rilpivirine in plasma was performed using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method, with a lower limit of quantification of 1.0 ng/ml.

[0230] The palatability was assessed using a taste questionnaire rating bitterness, sweetness, and flavor, as well as overall acceptability using a four-point scale, and also overall taste using five point visual hedonic scale.

[0231] Administration of the dispersible tablet was generally safe and well-tolerated, both in fed and fasted conditions. The rilpivirine exposure was higher than with the 25 mg Edurant® reference tablet following a standardized breakfast (treatment C versus treatment A).

[0232] Bioavailability of the dispersible tablet taken in fasted conditions was lower than when taken with a standard breakfast. When taken with only yoghurt, the bioavailability was lower compared with a normal calorie, normal fat breakfast. Dispersion of the tablet in orange juice compared to in water increased the bioavailability. Overall the tablets showed good bioavailability, acceptable palatability, and was well tolerated.

TABLE-US-00010 Treatment A Treatment C C.sub.max (ng/ml) 96.1 (±25.6)  121 (±26.2) AUC.sub.0-last (ng*h per ml) 3592 (±1156) 4310 (±1147) AUC.sub.0-inf (ng*h per ml) 3411 (±1449) 4367 (±1106)