Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-06-01
2002-03-19
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C514S813000, C514S879000, C514S777000, C514S781000
Reexamination Certificate
active
06358527
ABSTRACT:
The present invention is concerned with a fast-dissolving tablet for oral administration comprising as an active ingredient a therapeutically effective amount of galanthamine hydrobromide (1:1) and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) as a diluent, and a disintegrant; and with a direct compression process of preparing such fast-dissolving tablets.
Galanthamine, a tertiary alkaloid, has been isolated from the bulbs of the Caucasian snowdrops
Galantanus woronowi
(Proskurnina, N. F. and Yakoleva, A. P. 1952, Alkaloids of
Galanthus woronowi
II. Isolation of a new alkaloid. (In Russian.) Zh. Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated from the common snowdrop
Galanthus nivalis
(Boit, 1954). The chemical name of galanthamine is [4aS-(4a&agr;, 6&bgr;, 8aR*)]-4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a, 3, 2-ef][2]benzazepin-6ol; both the base compound and its hydrobromide are laevorotatory. Galanthamine is a well-known acetylcholinesterase inhibitor which is active at nicotinic receptor sites but not on muscarinic receptor sites. It is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically effective dosages.
Galanthamine has been used extensively as a curare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow, 1986) and also experimentally in the West (cf. Bretagne and Valetta, 1965: Wislicki, 1967; Consanitis, 1971).
Galanthamine has been marketed by the Waldheim (Sanochemia Gruppe) as Nivalin™ in Germany and Austria since the 1970s for indications such as facial neuralgia.
The use of galanthamine or an analogue or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for treating Alzheimer's Dementia (AD) and related dementias has been described in EP-0,236,684 (U.S. Pat. No. 4,663,318). This patent only has a generic disclosure of possible dosage forms of galanthamine.
The use of galanthamine for treating alcoholism and the administration via a transdermal transport system (TTS) or patch is disclosed in EP-0,449,247. Similarly, the use of galanthamine in the treatment of nicotine dependence using administration via a transdermal transport system (TTS) or patch is disclosed in WO-94/16708.
A number of applications by E. Snorrason disclose the use of galanthamine, analogues thereof and pharmaceutically acceptable salts thereof for the preparation of medicaments for treating mania (U.S. Pat. No. 5,336,675), chronic fatigue syndrome (CFS) (EP-0,515,302; U.S. Pat. No. 5,312,817), and the negative effects of benzodiazepine treatment (EP-0,515,301). In these applications and patents, e.g. in U.S. Pat. No. 5,312,817, a number of specific tablet formulations of galanthamine hydrobromide are given. In particular, these formulations are as follows:
Composition of 1 tablet (60 mg) containing 1 mg galanthamine hydrobromide
Galanthamine hydrobromide
0.001
g
Calcium phosphate
0.032
g
Lactose
0.005
g
Wheat Starch
0.0056
g
Microcrystalline Cellulose
0.015
g
Talc
0.0007
g
Magnesium Stearate
0.0007
g
Composition of 1 tablet (80 mg) containing 5 mg galantharmine hydrobromide; film-coat composition unknown [Nivalin™, Waldheim, Ltd, Vienna, Austria] (F 3)
Galanthamine hydrobromide
0.005
g
Calcium phosphate
0.024
g
Lactose
0.004
g
Wheat Starch
0.004
g
Microcrystalline Cellulose
0.04
g
Talc
0.002
g
Magnesium Stearate
0.001
g
Composition of 1 tablet (120 mg) containing 10 mg galanthamine hydrobromide
Galanthamine hydrobromide
0.010
g
Lactose
0.040
g
Wheat Starch
0.0234
g
Microcrystalline Cellulose
0.0374
g
Talc
0.0036
g
Magnesium Stearate
0.0012
g
Gelatin
0.0044
g
These tablet formulations can be prepared using wet granulation processes.
The dissolution (USP 23,<711> Dissolution, pp 1791-1793, Apparatus 2 (paddle, 50 rpm; 500 ml water or aqueous buffer at 37° C.)) of the commercially available Nivalin™ 5 mg film-coated tablet (F3) is as follows:
Time
Calculated concentration (% w/w) of the active dose
(min)
H
2
O
pH 4.5 USP
pH 6.5 USP
pH 7.5 USP
0.1N HCl
0
0.00
0.00
0.00
0.00
0.00
5
6.23
21.38
5.25
12.80
41.95
15
51.75
86.33
43.88
37.70
91.05
30
80.88
97.63
79.78
66.18
98.88
45
93.28
98.60
87.88
82.70
102.08
60
100.75
99.20
90.70
90.93
101.63
In order to obtain government approval to market a drug, one must not only show that the active ingredient has the stated activity and is safe to use, but it is also necessary to show that the formulation of the active ingredient will give a reproducible result in various patients. For example, in the case of solid formulations shaped as tablets, it is a prerequisite that the tablets disintegrate and dissolve within a particular period of time to a particular degree. In the present case, novel galanthamine hydrobromide tablets having a dissolution of at least 80% after 30 minutes (Q=80% after 30′) (USP 23, <711> Dissolution, pp 1791-1793, Apparatus 2 (paddle, 50 rpm; 500 ml purified water at 37° C.)) are provided. Compliance with this dissolution specification is only met by using a particular diluent containing disintegrant, and a second disintegrant.
Thus the present invention relates to a tablet comprising as an active ingredient a therapeutically effective amount of galanthamine hydrobromide (1:1) and a pharmaceutically acceptable carrier, characterized in that said carrier comprises a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) as a diluent, and a disintegrant. Said tablets have a dissolution of at least 80% after 30 minutes (Q=80% after 30′) (USP 23, <711> Dissolution, pp 1791-1793, Apparatus 2 (paddle, 50 rpm)).
Initial experiments started out using either lactose anhydrous or lactose monohydrate as diluent, and either powdered cellulose or microcrystalline cellulose as disintegrant (see tablet formulations F1 and F2 in the Experimental Part). A particular problem which occurred during feeding the dry blend into the tablet press for direct compression, was segregation of the tablet excipients, thus causing the tablets to have a variable composition. In addition, the tablets formulations F1 and F2 did not comply at Stage 1 with the dissolution specification of Q=80% after 30′. In order to solve the percieved problems, the diluent was substituted for a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac™. In addition to having a reduced tendency to segregate during feeding into the tablet press, the dry blend comprising the above diluent was further found to have excellent rheological properties (flowability), as well as to be easily miscible with the active ingredient and other tablet excipients. The dissolution specification was not met, however, unless a disintegrant having a large coefficient of expansion was employed, more in particular, if an insoluble or poorly soluble cross-linked polymer such as, for example, crospolyvidone or croscarmellose was employed. The amount of said disintegrants in the fast-dissolving tablets according to the present invention conveniently ranges from about 3 to about 8% (w/w), preferably about 5% (w/w).
In order to make the blending and the direct compression processes easier to perform, the carrier further comprises a glidant and a lubricant. Preferably, the glidant is colloidal anhydrous silica and the lubricant is magnesium stearate. In the initial experiments (see F1 and F2), talc was used as a glidant and sodium lauryl sulphate as a wetting agent/lubricant. The former was found to affect the dissolution properties of the tablets adversely (retarding the dissolution of the active ingredient) and the latter was found to be entirely superfluous and easy to omit from the tablet formulation.
Fast-dissolving tablets according to the present invention comprise by weight based on the total weight of the tablet co
De Conde Valentin Florent Victor
Gilis Paul Marie Victor
Appollina Mary A.
Janssen Pharmaceutica N.V.
Spear James M.
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