Controlled release oral dosage form of beta-adrenergic blocking agents

1. A controlled release pharmaceutical dosage form comprising a plurality of pellets wherein the pellets consists essentially of:

(a) a core consisting essentially of:

(i) propranolol or a pharmaceutically acceptable derivative thereof;

(ii) sugar spheres;

(iii) microcrystalline cellulose; and

(iv) ethylcellulose; and

(b) a coating applied directly to the core consisting essentially of a mixture of:

(i) ethylcellulose;

(ii) hydroxypropyl methylcellulose;

(iii) acetyl tributyl citrate; and

(iv) talc, wherein the viscosity of the core ethylcellulose is 8–12 cps and the viscosity of the coating ethylcellulose is above 8 cps wherein the dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) at 37° C.:

after 2 hours 15–40% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 4 hours 35–65% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 8 hours 40–80% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

not less than 70% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 12 hours; and

not less than 80% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 16 hours.

2. The controlled release pharmaceutical dosage form as defined in claim 1 wherein the core consists essentially of:

30–70% propranolol or a pharmaceutically acceptable derivative thereof;

10–40% microcrystalline cellulose;

1–15% ethylcellulose;

10–35% sugar sphere, wherein the foregoing percentages are based on the total weight of the core; and the coating consists essentially of:

50–90% ethylcellulose;

acetyl tributyl citrate;

1–20% hydroxypropyl methylcellulose; and talc, wherein the foregoing percentages are based on the total weight of the coating.

3. The controlled release pharmaceutical dosage form as defined in claim 2 wherein the core consists essentially of:

50–60% propranolol or a pharmaceutically acceptable derivative thereof;

20–30% microcrystalline cellulose;

3–10% ethylcellulose; and 15–30% inert pellet starting material; and the coating consists essentially of:

60–80% ethylcellulose;

5–10% acetyl tributyl citrate;

5–15% hydroxypropyl methylcellulose; and

5–15% of talc.

4. The controlled release pharmaceutical dosage form as defined in claim 1 that exhibits the following dissolution profile when tested in a USP type II apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 6.8 phosphate buffer) and at 37° C.:

after 2 hours 15–30% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 4 hours 45–60% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 8 hours 55–85% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

not less than 75% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 12 hours; and

not less than 85% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 16 hours.

5. A controlled release pharmaceutical dosage form comprising a plurality of pellets wherein the pellets consists essentially of:

(a) a core consisting essentially of:

(i) propranolol or a pharmaceutically acceptable derivative thereof;

(ii) sugar spheres;

(iii) miuocrystalline cellulose; and

(iv) ethylcellulose; and

(b) a coating applied directly to the core consisting essentially of a mixture of:

(i) ethylcellulose;

(ii) hydroxypropyl methylcellulose;

(iii) acetyl tributyl citrate; and talc, wherein the viscosity of the core ethylcellulose is 8–12 cps and the viscosity of the coating ethylcellulose is above 8 cps wherein the dosage form exhibits the following dissolution profile when tested in a USP type II apparatus at 75 rpm in 900 ml of simulated gastric fluid and at 37° C.:

after 2 hours 10–40% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 4 hours 30–60% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 8 hours 50–80% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

not less than 70% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 12 hours; and

not less than 85% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 20 hours.

6. The controlled release pharmaceutical dosage form as defined in claim 5 that exhibits the following dissolution profile when tested in a USP type II apparatus at 75 rpm in 900 ml of simulated gastric fluid and at 37° C.:

after 2 hours 15–30% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

after 4 hours 45–60% of the propranolol or a pharmaceutically acceptable derivative thereof is released;

not less than 60% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 8 hours;

not less than 75% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 12 hours; and

not less than 90% of the propranolol or a pharmaceutically acceptable derivative thereof is released after 20 hours.

7. The controlled release pharmaceutical dosage form as defined in claim 5 wherein the core consists essentially of:

30–70% propranolol or a pharmaceutically acceptable derivative thereof;

10–40% microcrystalline cellulose;

1–15% ethylcellulose;

10–35% sugar sphere, wherein the foregoing percentages are based on the total weight of the core; and the coating consists essentially of:

50–90% ethylcellulose;

acetyl tributyl citrate;

1–20% hydroxypropyl methylcellulose; and talc, wherein the foregoing percentages are based on the total weight of the coating.

8. The controlled release pharmaceutical dosage form as defined in claim 5 wherein the core consists essentially of:

50–60% propranolol or a pharmaceutically acceptable derivative thereof;

20–30% microcrystalline cellulose;

3–10% ethylcellulose; and

15–30% inert pellet starting material; and the coating consists essentially of:

60–80% ethylcellulose;

5–10% acetyl tributyl citrate;

5–15% hydroxypropyl methylcellulose; and

5–15% of talc.