Controlled release hydromorphone composition

A solid controlled release, oral dosage form, the dosage form comprising a therapeutically effective amount of hydromorphone or a salt thereof in a matrix wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method of 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. is between 12.5% and 42.5% (by weight) hydromorphone released after 1 hour, between 25% and 55% (by weight) hydromorphone released after 2 hours, between 45% and 75% (by weight) hydromorphone released after 4 hours and between 55% and 85% (by weight) hydromorphone released after 6 hours, the in vitro release rate being independent of pH between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in vivo occurs between 2 and 4 hours after administration of the dosage form.

EXAMPLE 1 
Hydromorphone hydrochloride (4.0 gm) was wet granulated with lactose 
monohydrate (167.0 gm) and hydroxyethyl cellulose (40.0 gm., Natrosol 250 
HX, Trade Mark) and the granules were sieved through a 12 mesh screen. The 
granules were then dried in a Fluid Bed Dryer at 50.degree. C. and passed 
through a 16 mesh screen. 
To the warmed hydromorphone containing granules was added molten 
cetostearyl alcohol (120.0 gm) and the whole was mixed thoroughly. The 
mixture was allowed to cool in the air, regranulated and sieved through a 
16 mesh screen. 
Purified Talc (6.0 gm) and magnesium stearate (3.0 gm) were then added and 
mixed with the granules. The granules were then compressed into 1000 
tablets each containing, 
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mg/tablet 
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Hydromorphone Hydrochloride 
4.0 
Lactose Monohydrate 167.0 
Hydroxyethylcellulose 
40.0 
Cetostearyl alcohol 120.0 
Purified Talc 6.0 
Magnesium stearate 3.0 
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EXAMPLE 2 
The procedure of Example 1 was followed, but with reduced quantities of 
cellulose and fatty alcohol, to give 1000 tablets each containing, 
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mg/tablet 
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Hydromorphone Hydrochloride 
4.0 
Anhydrous Lactose 167.0 
Hydroxyethylcellulose 
30.0 
Cetostearyl Alcohol 90.0 
Purified Talc 6.0 
Magnesium Stearate 3.0 
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EXAMPLE 3 
Hydromorphone hydrochloride (4.0 gm) was wet granulated with lactose 
monohydrate (30.0 gm) hydroxyethyl cellulose (10.0 gm; Natrosol 250 HX, 
Trade Mark) and methacrylic acid copolymer (3.0 gm, Eudragit L-100-55., 
Trade Mark) and the granules were sieved through a 12 mesh screen. The 
granules were then dried in a Fluid Bed Dryer at 50.degree. C. and passed 
through a 16 mesh screen. 
To the warmed hydromorphone containing granules was added molten 
cetostearyl alcohol (30.0 gm) and the whole was mixed thoroughly. The 
mixture was allowed to cool in the air, regranulated and sieved through a 
16 mesh screen. 
The granules were then compressed into 1000 tablets each containing, 
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mg/tablet 
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Hydromorphone Hydrochloride 
4.0 
Lactose Monohydrate 30.0 
Hydroxyethylcellulose 
10.0 
Methacrylic Acid Copolymer 
30.0 
Cetostearyl alcohol 30.0 
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EXAMPLE 4 
Hydromorphone hydrochloride (50 g) microcrystalline cellulose (Avicel 
PHI01, 440 g) and hydroxypropylmethyl cellulose (Methocel E15, 10 g) were 
dry mixed. Water (350 ml) was then added and the mixture was granulated. 
The granulated mass was extruded through a 1 mm cylinder and the extrudate 
was spheronised. The resultant spheroids were dried at 60.degree. C. in a 
fluid bed drier. The moisture content of the dried spheroids was found to 
be 4.3% w/w (Karl-Fischer). The dried spheroids were then sieved and the 
sieve fraction between 1.0 mm and 1.4 mm was retained. 
The spheroids were coated with a film coat, having the formulation given 
below, to a level of 15% w/w. 
Film Coat Formulation 
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Ethylcellulose N10 4.0% w/v 
Hydroxypropylmethylcellulose 
1.0% w/v 
(Methocel E15) 
Propylene glycol BP 
0.5% w/v 
Opaspray K-1-4132 3.0% w/v 
Methanol 60.0% v/v 
Dichloromethane to 100.0% v/v 
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Vitro Dissolution Studies 
In vitro dissolution studies were conducted on tablets prepared as 
described in Example 1. The dissolution method was the USP Paddle Method 
described in US Pharmacopoeia XXI (1985). The paddle speed was 100 rpm, 
the temperature was 37.degree. C. and the medium was 900 ml water. Results 
are given in Table 1. 
TABLE 1 
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Time (hr) wt. % Hydromorphone released 
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1 28.3 
2 41.8 
3 51.5 
4 59.5 
5 65.5 
6 70.0 
7 75.0 
8 80.0 
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In vitro dissolution studies were conducted on tablets prepared as 
described in Example 2. The dissolution method was the USP Paddle Method 
described in US Pharmacopoeia XXI (1985). The paddle speed was 100 rpm, 
the temperature was 37.degree. C. and the medium was an aqueous buffer (pH 
6.5). 
Results are given in Table 2. 
TABLE 2 
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Time (hr) wt. % Hydromorphone released 
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1 26 
2 41 
3 52 
4 60 
5 67 
6 74 
7 79 
8 83 
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In vitro dissolution studies were conducted on tablets prepared as 
described in Example 3. The dissolution method was the USP Paddle Method 
described in US Pharmacopoeia XXI (1985). The paddle speed was 100 rpm, 
the temperature was 37.degree. C. and the medium was 900 ml water. 
Results are given in Table 3. 
TABLE 3 
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Time (hr) wt. % Hydromorphone released 
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1 35 
2 50 
3 59 
4 66 
5 72 
6 76 
7 80 
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In vitro dissolution studies were conducted on tablets prepared as 
described in Example 1. The dissolution method was the USP Paddle Method 
described in US Pharmacopoeia XXI (1985). The paddle speed was 100 rpm, 
the temperature was 37.degree. C. and the media were USP Buffers (pH 1.6, 
6.5 and 7.2). 
Results are given in Table 4. 
TABLE 4 
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wt % Hydromorphone released 
Time (hr) pH 1.6 pH 6.5 pH 7.2 
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1 34.7 36.0 36.6 
2 48.1 51.2 51.0 
3 58.5 61.7 61.1 
4 66.5 70.0 69.8 
6 79.1 81.8 81.8 
8 88.2 90.6 90.7 
10 95.1 97.7 99.2 
12 100.0 100.0 100.0 
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Clinical Studies 
A. A single dose, randomised, comparative, pharmacokinetic study was 
conducted on 4 subjects employing, 
(i) A hydromorphone hydrochloride tablet prepared as described in Example 
1, (a 4 mg dose), and 
(ii) A normal release hydromorphone hydrochloride tablet (Dilaudid., Trade 
Mark; a 4 mg dose). 
Analysis of the plasma samples for hydromorphone was performed by a double 
antibody radioimmunoassay. Plasma was assayed by incubating first with 
.sup.125 Iodohydromorphone and antimorphine antiserum (raised in oats 
against a 6-hemisuccinyl morphine-BSA conjugate), and subsequently with a 
solid phase bound antiserum suspension (Sac Cel. anti sheep/goat, Trade 
Mark). Following the addition of water the samples were centrifuged and 
the supernatant was removed. The radioactivity in the remaining pellet was 
counted on a multi-gamma counter for 60 seconds. Results are given in 
Table 5. 
TABLE 5 
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Mean Plasma Conc. (ng/ml.sup.-1) 
Time (hr) Example 1 Dilaudid 
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0.50 0.9 9.4 
1.0 3.8 8.8 
1.50 4.4 8.6 
2.0 4.2 7.8 
2.5 4.5 7.9 
3.0 4.8 6.2 
4.0 4.3 3.5 
6.0 3.0 3.2 
8.0 1.4 1.6 
10.0 1.6 1.0 
12.0 1.0 0.5 
24.0 1.1 0.5 
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B. A single dose, randomised, comparative, pharmacokinetic study was 
conducted on 12 subjects employing. 
(i) A hydromorphone hydrochloride table prepared as described in Example 1 
(a 4 mg dose), and `(ii) A normal release hydromorphone hydrochloride 
tablet (Dilaudid; Trade mark; a 4 mg dose). 
Analysis of the plasma samples for hydromorphone was performed by the 
radioimmunoassay described in study A. Results are given in Table 6. 
TABLE 6 
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Mean Plasma Conc. (ng/ml) 
Time (hr) Example 1 Dilaudid 
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0.5 2.3 5.8 
1.0 3.7 7.0 
1.5 3.9 7.3 
2.0 4.4 6.4 
2.5 4.5 5.9 
3.0 4.3 5.3 
4.0 4.3 4.4 
6.0 3.7 3.1 
8.0 3.1 2.5 
10.0 2.5 2.3 
12.0 2.1 2.0 
24.0 1.4 1.1 
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C. A single dose, comparative, pharmacokinetic study was conducted on 24 
subjects employing, 
(i) A hydromorphone hydrochloride tablet prepared as described in Example 1 
(a 4 mg dose) and, 
(ii) A normal release hydromorphone hydrochloride tablet (Dilaudid, Trade 
Mark, a 4 mg dose). 
Analysis of the plasma samples for hydromorphone was performed and the 
results are given in table 7. 
TABLE 7 
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Mean Plasma Concn. (ng/ml) 
Time (hr) Example 1 Dilaudid 
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0 0.12 0.15 
0.5 0.57 2.68 
1.0 0.67 2.23 
1.5 0.74 1.78 
2.0 0.75 1.47 
2.5 0.72 1.11 
3.0 0.69 0.94 
3.5 0.65 0.82 
4.0 0.59 0.77 
5.0 0.71 0.53 
6.0 0.59 0.40 
8.0 0.40 0.29 
10.0 0.49 0.26 
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