CA2180703A1 - Fast-dissolving galanthamine hydrobromide tablet - Google Patents
Fast-dissolving galanthamine hydrobromide tabletInfo
- Publication number
- CA2180703A1 CA2180703A1 CA002180703A CA2180703A CA2180703A1 CA 2180703 A1 CA2180703 A1 CA 2180703A1 CA 002180703 A CA002180703 A CA 002180703A CA 2180703 A CA2180703 A CA 2180703A CA 2180703 A1 CA2180703 A1 CA 2180703A1
- Authority
- CA
- Canada
- Prior art keywords
- tablet
- film
- tablet according
- disintegrant
- glidant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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 micro-crystalline cellulose (75: 25) as a diluent, and a disintegrant; and with a direct compression process of preparing such fast-dissolving tablets.
Description
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~
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 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~
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 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 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.
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~
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 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~
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 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 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.
Claims (10)
1. 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.
2. A tablet according to claim 1 wherein the disintegrant is crospolyvidone or croscarmellose.
3. A tablet according to claim 1 or 2 wherein the carrier further comprises a glidant and a lubricant.
4. A tablet according to claim 3 wherein the glidant is colloidal anhydrous silica and wherein the lubricant is magnesium stearate.
5. A tablet according to any one of claims 1, 2, 3 and 4 comprising by weight based on the total weight:
(a) from 2 to 10% galanthamine 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.
(a) from 2 to 10% galanthamine 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.
6. A tablet according to claim 5 comprising (a) about 2 to 10% galanthamine hydrobromide (1:1);
(b) about 83 to 93% spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25);
(c) about 0.2% colloidal anhydrous silica;
(d) about 5% crospolyvidone; and (e) about 0.5% magnesium stearate.
(b) about 83 to 93% spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25);
(c) about 0.2% colloidal anhydrous silica;
(d) about 5% crospolyvidone; and (e) about 0.5% magnesium stearate.
7. A tablet according to any one of claims 1, 2, 3, 4, 5 or 6 which is film-coated.
8. A tablet according to claim 7 wherein the film-coat comprises a film-forming polymer and a plasticizer.
9. A tablet according to claim 8 wherein the film-coat weighs from about 3 to 5% of the uncoated tablet core.
10. A process of preparing a tablet according to any one of claims 1 to 9 comprising the steps of:
(i) dry blending the active ingredient, the disintegrant and the optional glidant with the diluent;
(ii) optionally mixing the lubricant with the mixture obtained in step (i);
(iii) compressing the mixture obtained in step (i) or in step (ii) in the dry state into a tablet; and (iv) optionally film-coating the tablet obtained in step (iii).
(i) dry blending the active ingredient, the disintegrant and the optional glidant with the diluent;
(ii) optionally mixing the lubricant with the mixture obtained in step (i);
(iii) compressing the mixture obtained in step (i) or in step (ii) in the dry state into a tablet; and (iv) optionally film-coating the tablet obtained in step (iii).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002180703A CA2180703A1 (en) | 1996-07-08 | 1996-07-08 | Fast-dissolving galanthamine hydrobromide tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002180703A CA2180703A1 (en) | 1996-07-08 | 1996-07-08 | Fast-dissolving galanthamine hydrobromide tablet |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2180703A1 true CA2180703A1 (en) | 1998-01-09 |
Family
ID=4158561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002180703A Abandoned CA2180703A1 (en) | 1996-07-08 | 1996-07-08 | Fast-dissolving galanthamine hydrobromide tablet |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2180703A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2018874A2 (en) | 1998-08-07 | 2009-01-28 | Targacept, Inc. | Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor |
| WO2011100373A1 (en) | 2010-02-09 | 2011-08-18 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
| WO2014144801A1 (en) | 2013-03-15 | 2014-09-18 | Agenebio Inc. | Methods and compositions for improving cognitive function |
| US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| US10159648B2 (en) | 2015-05-22 | 2018-12-25 | Agenebio, Inc. | Extended release pharmaceutical compositions of levetiracetam |
| US10806717B2 (en) | 2013-03-15 | 2020-10-20 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
-
1996
- 1996-07-08 CA CA002180703A patent/CA2180703A1/en not_active Abandoned
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2018874A2 (en) | 1998-08-07 | 2009-01-28 | Targacept, Inc. | Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor |
| WO2011100373A1 (en) | 2010-02-09 | 2011-08-18 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
| US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| US10624875B2 (en) | 2012-11-14 | 2020-04-21 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| WO2014144801A1 (en) | 2013-03-15 | 2014-09-18 | Agenebio Inc. | Methods and compositions for improving cognitive function |
| US10806717B2 (en) | 2013-03-15 | 2020-10-20 | The Johns Hopkins University | Methods and compositions for improving cognitive function |
| US11160785B2 (en) | 2013-03-15 | 2021-11-02 | Agenebio Inc. | Methods and compositions for improving cognitive function |
| US10159648B2 (en) | 2015-05-22 | 2018-12-25 | Agenebio, Inc. | Extended release pharmaceutical compositions of levetiracetam |
| US10925834B2 (en) | 2015-05-22 | 2021-02-23 | Agenebio, Inc. | Extended release pharmaceutical compositions of levetiracetam |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6099863A (en) | Fast-dissolving galanthamine hydrobromide tablet | |
| EP1275391B1 (en) | Pharmaceutical compositions containing irbesartan and a diuretic | |
| US20150246035A1 (en) | Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion | |
| US20030092724A1 (en) | Combination sustained release-immediate release oral dosage forms with an opioid analgesic and a non-opioid analgesic | |
| RU2000111506A (en) | PROLONGED TABLETS FOR THE TREATMENT OF PARKINSON'S DISEASE | |
| AU780011B2 (en) | Matrix tablet enabling the prolonged release of trimetazidine after administration by the oral route | |
| EP0749308B1 (en) | Film coated tablet of paracetamol and domperidone | |
| KR20150002550A (en) | Pharmaceutical capsule composite formulation comprising tadalafil and tamsulosin | |
| KR100846945B1 (en) | Swallow tablet comprising paracetamol | |
| CA2180703A1 (en) | Fast-dissolving galanthamine hydrobromide tablet | |
| HU226132B1 (en) | Fast-dissolving galanthamine hydrobromide tablet | |
| CN112263581A (en) | Double-layer tablet compound preparation for treating PE and ED and preparation method thereof | |
| US20040192706A1 (en) | Method and compositions for treating anxiety | |
| AU2012202717B2 (en) | Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion | |
| JPH09136843A (en) | Hypertensor | |
| MXPA96002103A (en) | Pharmaceutical compositions containing irbesar |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |