Note: Descriptions are shown in the official language in which they were submitted.
JAB 1119 2180703
-1
FAST-DISSOLVING GALANTHAM~ HYDROBROMIDE TABLET
5 The present invention is concerned with a fast-dissolving tablet for oral ~llmini~tration
comprising as an active ingredient a ther~pellti~lly effective arnount of g~l~nth~mine
hydrobromide (1:1) and a ph~rm~cellticc.lly acceptable carrier, characterized in that
said carrier comprises a spray-dried mixture of lactose monohydrate and micro-
crystalline cellulose (75: 25) as a diluent, and a disintegrant; and with a direct
10 compression process of preparing such fast-dissolving tablets.
Galanthamine, a tertiary alkaloid, has been isolated form the bulbs of the (~;~uc~ n
snowdrops Galantanus woronowi (Proskurnina, N. F. and Yakoleva, A. P. 1952,
Alkaloids of Galanthus woronowi. ~. 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 Galan~hus nivalis (Boit, 1954). G~l~nth:~mine 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 anaestheticpractice in Eastern bloc countries (cf. review by Paskow, 1986) and also
experimentally in the West (cf. Bretagne and Valetta, 1965: Wislicki, 1967;
Consanitis, 1971).
G~l~nth~mine has been marketed by the company Waldheim (Sanochemia Gruppe) as
NivalinTM in Germany and Austria since the 1970s for indications such as facial
neuralgia.
30 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 Disease (AD)
and related dementias has been described in EP-0,236,684 (US-4,663,318). This
patent application 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,
~180703
the use of ~ nth~mine in the treatment of nicotine dependence using ~1mini~tration
via a tr~3n~1erm~l transport system (TTS) or patch is disclosed in WO-94/16708.
A number of applications by E. Snorrason disclose the use of g~l~nth~mine~
5 analogues thereof and pharmaceutically acceptable salts thereof for the preparation of
medicaments for treating mania (US-5,336,675), chronic fatigue syndrome (CFS)
(EP-0,515,302; US-5,312,817), and the negative effects of benzodia~pine treatment
(EP-0,515,301). In these applications and patents, e.g. in US-5,312,817, a number
of specific tablet formulations of g~l~nth~mine hydrobromide are given. In particular,
10 these formulations are as follows:
Composition of 1 tablet (60 mg) cont~ining 1 mg g~l~nth~mine hydrobromide
Galanthamine hydrobromide 0.001 g
Calcium phosphate 0.032 g
Lactose ~.~~S g
Wheat Starch 0.0056 g
Microcryst~lline Cellulose 0.015 g
Talc ~ 0007 g
Magnesium Stearate 0.0007 g
Composition of 1 tablet (80 mg) cont~ining 5 mg g~l~nth~mine hydrobromide; film-coat composition unknown [Nivalin~M, Waldheim, Ltd, Vienna, Austria] (F 3)
G~l~nth~min~ 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) con~ai~ lg 10 mg galanthamine hydrobromide
Galanthamine hydrobromide 0.010 g
35 Lactose 0.040 g
Wheat Starch 0.0234 g
Microcrystalline Cellulose 0.0374 g
218070~
-3-
Talc 0.0036 g
l\/l~gnesillm Stearate 0.0012 g
Gelatin 0.0044 g
5 These tablet formulations can be prepared using wet gr~n~ tion processes.
The dissolution (USP 23, <711> Dissolution, pp 1791-1793, Apparatus 2 (paddle,
50 rpm) of the commercially available NivalinlM 5 mg film-coated tablet is as follows:
Calculated concen ration (% w/w' of the active dose
(Tmimne) H20pH 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
6.23 21.38 5.25 12.80 41.95
51.75 86.33 43.88 37.70 91.05
80.88 97.63 79.78 66.18 98.88
93.28 98.60 87.88 82.70 102.08
100.75 99.20 90.70 90.93 101.63
10 In order to obtain government al~pr~val 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
15 time to a particular degree. In the present case, g~l~nth~mine 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)) are provided.
Compliance with this dissolution specification is only met by using a particular diluent
containing a disintigrant, and a second disintegrant.
2û
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
25 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, Apparatus2 (paddle, 50 rpm)).
218070~
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 Fl 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 Fl 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[M. 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 pelrollll,
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 Fl 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 core:
(a) from 2 to 10% g~l~nth~mine hydrobromide (1:1);
(b) from 83 to 93% spray-dried mixture of lactose monohydrate and microcrystalline
cellulose (75:25);
(c) from 0.1 to 0.4% glidant;
(d) from 3 to 8% insoluble crosslinked polymeric disintegrant; and
(e) from 0.2 to 1% lubricant.
~180703
--5
In particular, the tablets comprise:
(a) about 2 to 10% g~l~nth~mine hydrobromide (1:1);
(b) about 83 to 93% spray-dried mixture of lactose monohydrate and microcrystalline
celllllc se (75:25);
(c) about 0.2% colloidal anhydrous silica;
(d) about 5% crospolyvidone; and
(e) about 0.5% m~gnesium stearate.
The fast-dissolving g;~l~nth~mine hydrobromide (1:1) tablets according to the present
invention may in addition include other optional excipients such as, for example,
flavors, sweeteners and colors.
Tablets of galanthamine hydrobromide (1: 1) are conveniendy film-coated following
art-known coating procedures. Film-coated tablets are easier to swallow than
uncoated tablet cores, are usually easier to distinguish from other tablets - in particular
when the film-coat contains a dye or a pigment -, and may furthermore have an
improved stability (shelf-life). In the instant case, a mixture comprising a film-
forming polymer and a plasticizer, in particular hydroxypropyl methylcellulose and a
polyethyleneglycol, e.g. macrogol 6000, may be employed for film-coating tablet
cores as described hereinbefore. Of particular importance in the case of fast-
dissolving tablets, is the requirement that the film-coat should not adversely affect the
disintegration and dissolution of the active ingredient from the tablet. Therefore, the
weight of the film-coat conveniently is in the range of 3 to 5% of the uncoated tablet
core. As illustrated in the experimental part both the uncoated tablet cores and the
film-coated tablets according to the present invention (FS) both comply with thedissolution requirement of Q = 80 % after 30' (USP).
The tablets according to the present invention are suitable as unit dose forms for oral
~(lmini~tration to patients in need of g~l~nth~mine therapy. The tablets conveniently
comprise from 2 to 20 mg g~l~nth:~mine (2.563 to 25.63 mg galanthamine
hydrobromide (1:1)), in particular from 4 to lS mg galanthamine (5.026 to 19.2225
mg galanthamine hydrobromide (1:1)). They are best administered two times daily
(b.i.d), approximately every 12 hours, as this dosage regimen gives therapeutic
plasma levels of the active ingredient throughout the day.
The present invention is also concerned with a process of preparing fast-dissolving
galanthamine hydrobromide (1:1) tablets, comprising the steps of:
~180703
(i) dry blending the active ingredient, the disintegrant and the optional glidant with the
diluent;
(ii) optionally mixing the lubric~nt with the mixture obtained in step (i);
(iii) colllplt;ssing the mixture obtained in step (i) or in step (ii) in the dry state into a
5 tablet; and
(iv) optionally film-coating the tablet obtained in step (iii).
The dry blending can conveniently be pelr~ ed in a planetary mixer; the direct
compression in a tablet press; and the film-coating in a coating pan.
- 2180~0~
--7--
Experimental part
Example 1: Direct compression tablet formulation (F1)
Ingredients:
galanthamine hydrobromide 5 mg
lactose (anhydrous) 70 mg
powdered cellulose 19 mg
talc 4 mg
sodium lauryl sulphate1 mg
colloidal anhydrous silica O.S mg
magnesium stearate 0.5 mg
total weight 100 mg
Preparation:
15 The ingredients were intim~tely mixed in a planetary mixer and compressed in a
tabletting machine, thus preparing tablets of 100 mg each.
Example 2: Direct compression film-coated tablet formulation (F2)
Ingredients:
galanthamine hydrobromide 5.13 mg (4 mg g~l~nth~mine)
lactosemonohydrate SS.11 mg
microcrystalline cellulose 15.2 mg
talc 3.2 mg
sodium lauryl sulphate 0.8 mg
colloidal anhydrous silica 0.16 mg
magnesium stearate 0.4 mg
core weight 80 mg
hypromellose2910 SmPas 1.8mg
talc 0.8 mg
titanium dioxide (E 171) 0.1 mg
Macrogol 6000 0.3 mg
purified water* 17 mg
film-coated weight: 3 mg
total weight: 83 mg
*This component is not present in the final product.
~180703
-8-
Preparation:
The ingredients were intim~tely mixed in a planetary mixer and compressed in a
tabletting m~rhine, thus preparing tablets of 80 mg each. The tablet cores were then
film-coated in a coating pan.
Example 3: Direct compression film-coated tablet formulation (F5)
Ingredients:
g~l~nth:~mine hydrobromide 5.126 mg (4 mg g~l~nth~min~
spray-dried mixture of lactose monohydrate 221.194 mg
and microcrystalline cellulose (75:25)
crospolyvidone 12 mg
colloidal anhydrous silica 0.48 mg
magnesium stearate 1.2 mg
core total weigth 240 mg
hypromellose 2910 5 mPa.s 5.4 mg
talc 2.4 mg
titanium dioxide (E 171~ 0.3 mg
Macrogol 6000 0.9 mg
purified water* 51 mg
film-coat weight 9 mg
total weight 249 mg
*This component is not present in the final product.
Preparation:
The ingredients were intim~tely mixed in a planetary mixer and compressed in a
tabletting machine, thus preparing tablets of 240 mg each. The tablet cores were then
film-coated in a coating pan.
Example 4: Direct compression film-coated tablet formulation (F6)
Ingredients:
galanthamine hydrobromide 23.069 mg (18 mg galanthamine)
spray-dried mixture of lactose monohydrate 203.251 mg
and microcrystalline cellulose (75:25)
crospolyvidone 12 mg
~18070~
g
colloidal anhydrous silica 0.48 mg
magnesium stearate 1.2 mg
core total weighI 240 mg
hypromellose 2910 5 mPa.s 5.4 mg
talc 2.4 mg
titanium dioxide (E 171) 0.3 mg
Macrogol 6000 0.9 mg
purifiedwater* 51 mg
film-coat weight 9 mg
total weight 249 mg
*This component is not present in the final product.
15 Preparation:
The ingredients were intim~tely mixed in a planetary mixer and compressed in a
tabletting machine, thus ~l~aling tablets of 240 mg each. The tablet cores were then
film-coated in a coating pan.
20 Example 5
Comparative in-vitro dissolutions studies were performed on tablet formulations Fl,
F2, F5 (uncoated), F5 (film-coated), F6 (uncoated) and F6 (film-coated). The
medium was 500 ml of purified water at 37~C in Apparatus 2 (USP 23, <711>
Dissolution, pp. 1791-1793) (paddle,50 rpm).
25 The following results were obtained:
Fl
Calculated concentration (% w/w) of the active dose
Time(min) sample 1 sample2 sample3 sample4 sample5 sample6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
77.85 59.10 72.40 74.48 76.23 61.35 70.23
87.33 78.88 86.73 83.40 89.08 76.33 83.62
90.98 84.15 88.40 87.43 91.78 82.20 87.49
92.78 87.28 90.30 89.83 93.30 85.83 89.88
93.58 88.95 91.00 92.35 96.35 89.83 92.01
~80703
-10-
Calculated concen¢a ion (% w/w) of ~e active dose
Time(min) sample 1 sample2 sample3 sample4 sample5 sample6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
34.48 24.42 33.92 37.35 33.67 33.33 32.86
85.23 75.32 79.39 85.23 84.26 73.93 80.56
90.55 84.99 87.31 90.30 90.64 83.11 87.82
92.84 88.89 90.45 92.47 93.49 88.38 91.09
94.40 90.69 92.28 93.91 94.62 89.74 92.60
FS uncoated
Calculated concentraion (% w/w) of ~e acive dose
Time (min) sample 1 sample2 sample 3 sample4 sample 5 sample 6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
95.59 96.71 95.10 96.63 95.81 96.85 96.11
96.15 97.22 97.37 97.29 97.27 97.39 97.11
97.46 97.27 97.49 97.56 97.66 97.68 97.52
98.10 97.51 97.68 97.73 98.12 98.27 97.90
98.17 97.59 97.61 98.12 98.00 98.29 97.96
FSfilm-coated
Calculated concen~ation (% w/w) of ~e achve dose
Time(min) sample 1 sample2 sample 3 sample4 sample 5 sample6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
86.27 81.08 89.37 87.81 92.95 86.93 87.40
92.76 93.29 92.90 93.34 97.46 93.27 93.84
97.27 96.24 95.07 95.20 98.05 94.61 96.07
98.12 97.51 96.27 96.63 98.20 95.68 97.07
98.05 97.66 96.49 96.66 98.22 96.61 97.28
218~703
F6 uncoated
Calculated concentration (% w/w) of the active dose
Time (min) sample 1 sample 2 sample 3 sample 4 sample S sample 6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
S 94.02 94.33 93.18 93.59 95.13 93.29 93.92
lS 97.17 97.08 97.84 97.34 97.82 97.47 97.45
97.49 97.64 98.53 98.03 98.68 97.62 98.00
98.12 98.34 98.92 98.36 99.46 98.21 98.57
98.53 98.38 99.61 100.09 lOO.SS 98.40 99.26
F6film-coated
Calculated concentration (% w/w) of the active dose
Time(min) sample 1 sample2 sample 3 sample4 sampleS sample6 average
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
S 94.61 77.70 95.63 90.S1 83.90 78.94 86.88
lS 98.14 96.93 99.81 97.32 96.25 95.86 97.39
98.81 99.05 100.61 99.S1 99.29 97.97 99.21
99.74 99.61 100.70 99.59 100.13 99.90 99.9S
100.24 100.76 100.74 100.13 100.52 100.57 lOO.S0
Neither of Fl and F2 comply at stage 1 with the dissolution specification Q = 80% at 30
minutes; both FS (uncoated), FS (film-coated), F6 (uncoated) and F6 (film-coated)
comply at stage 1 with the dissolution specification Q = 80% at 30 minutes.
