AU2001100198B4 - Pharmaceutical composition containing citalopram - Google Patents
Pharmaceutical composition containing citalopram Download PDFInfo
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- AU2001100198B4 AU2001100198B4 AU2001100198A AU2001100198A AU2001100198B4 AU 2001100198 B4 AU2001100198 B4 AU 2001100198B4 AU 2001100198 A AU2001100198 A AU 2001100198A AU 2001100198 A AU2001100198 A AU 2001100198A AU 2001100198 B4 AU2001100198 B4 AU 2001100198B4
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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Description
P/00/011 28/5/91 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990
ORIGINAL
INNOVATION SPECIFICATION Application Number: Lodged: Invention Title: PHARMACEUTICAL COMPOSITION CONTAINING CITALOPRAM The following statement is a full description of this invention, including the best method of performing it known to us Pharmaceutical composition containg Citalopram The present invention relates to a novel pharmaceutical composition containing citalopram, 1-[ 3 -(dimethylamino)propyl]- -(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Background of the Invention.
Citalopram is a well-known antidepressant drug that has the following structure:
NC
O CH3 CH3 It is a selective, centrally active serotonin (5-bydroxyryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram. The citalopram prepared was isolated in crystalline form as the oxalate, the hydrobromide and the hydrochloride salt, respectively. Furthermore, the citalopram base was obtained as an oil 175 C/0.03 mmHg). The publication also outlines the manufacture of tablets containing salts of citalopram. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
Manufacture of crystalline citalopram base is disclosed in co-pending DK 2000 00402. This patent publication describes the preparation of crystalline citalopram base and the use of crystalline citalopram base as an intermediate in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. The publication also outlines the manufacture of tablets containing citalopram base.
Citalopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopramn hydrobrornide, lactose and other excipients.
It is well recognised that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
Further, active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
The problem of small particle size and poor flowability, is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active is ingredient either alone or in combination with a filler and/or other conventional tablet ingredients.
One such granulation method is the "wet" 'granulation process. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water or another wetting agent an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
An alternative to the "wet" granulation methoa is the "melt" granulation, which is also known as the "thermal plastic" granulation process, where a low melting solid is used as the granulation agent. Initially, the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and formn granules. The binder solidifies upon cooling forming a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
330
AU
The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 pm that, as many other particulate products with a small particle size, has very poor flow properties. Thus, in order to achieve appropriate dosing of the citalopram during tabletting, it was considered necessary to make a granulate of citalopram with larger particle size and improved flow properties.
The citalopram tablet that is marketed is a tablet made from granulated citalopram hydrobromide with various excipients.
In view of the fact that direct compression is much simpler and cheaper than the processes involving granulation there is a desire for a process for direct compression of citaloprain hydrobromide.
is The obstacles that hitherto have hindered direct compression of citalopram tablets have now been circumvented after extensive laboratory research.
It has been found that larger particles, i.e. particles of a size comparable to the size of the filler, may be prepared by a new and inventive crystallisation process and that these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such large particles.
It has also been found, that tablets with surprisingly small variation in the content of citalopram may be prepared by direct comression of citalopram hydrobromide having a significantly smaller particle size than the filler. Accurate dosing in capsules may also be achieved despite the small particle size of citalopram.
Objects of the Invention It is the object of the present invention to provide a novel pharmaceutical unit dosage form containing citalopram with a suitable large particle size, wherein said unit dosage form may be prepared by direct compression.
A second object of the invention is to provide a capsule containing citalopram.
330 AU A third object of the invention is to provide large crystals of a pharmaceutically acceptable salt of citalopram suitable for use in direct compression.
A fourth object of the invention is to provide a method for manufacture of large crystals of a pharmaceutically acceptable salt of citalopram.
SUMMARY OF THE INVENTION The invention then, inter alia, comprises the following alone or in combination: A solid unit dosage form comprising citalopram as an active ingredient, wherein the dosage form is prepared by direct compression of a mixture of crystals of citalopram with a median particle size of at least 40 gm and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule.
Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage form with a median particle size of at least 40 gim.
A method for the manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 gm and suitable for use in a solid unit dosage form wherein a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled down to a second temperature then seeded by addition of crystals of said citalopram salt followed by a holding time at said second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by conventional solid/liquid separation techniques.
The direct compression of citalopram, a filler and other pharmaceutically acceptable excipients into tablets has the great advantage, that the granulation and a drying step is avoided. Further, as the granulation step is avoided, it is no longer necessary to add a binding agent.
As used herein, "direct compression" means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients, without the active ingredient having been subjected to an intermediate granulation process in order to embed it in a larger particle and improve its fluidity properties.
As used herein, "binder" means an agent, which is used in wet or melt granulation processes and acts as a binder in the granulated product.
As used herein, "particle size distribution" means the distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment. Median particle size", correspondingly, means the median of said particle size distribution.
As used herein, "refluxing temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
Thus in one embodiment of the invention, the present invention relates to a tablet prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a capsule prepared by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in a hard gelatine capsule.
In another embodiment, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size of at least tm, preferably in the range of 40-200 ptm, even more preferred 45-150 gm and most preferred 50-100 im.
Flow, segregation and demixing properties and, hence, the suitability of the citalopram crystals for direct compression depend, besides the median particle size, on the particle side distribution.
Preferably, the solid unit dosage forms according to the invention do not contain a binder The solid unit dosage form according to the invention may contain 2-60 w/w active ingredient calculated as citalopram base, preferably 10-40 w/w active ingredient calculated as citalopram base, and more preferred 15-25 w/w active ingredient calculated as citalopram base, Suitably, the solid unit dosage form of the invention contains 20 w/w active ingredient calculated as citalopram base.
In particular, the present invention relates to a solid unit dosage form wherein the active ingredient is citalopram hydrobromide, or citalopram hydrochloridc.
Preferably the active ingredient contained in the solid unit dosage form of the invention is citalopram hydrobromide.
The solid unit dosage form according to the invention may contain a filler selected from lactose, or other sugars e.g. sorbitol, mnnitol, dextrose and sucrose, calcium phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulphate and/or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention does not contain lactose.
Suitably the filler is a microcrystalline cellulose such as ProSolv manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation.
Besides the active ingredient and filler, the solid pharmaceutical unit dosage forms may include various other conventional excipients such as disintegrants, and optionally minor amounts of lubricants, colorants, and sweeteners.
330 AU Lubricants used according to the invention may suitably be one or more of the following metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
Suitably the lubricant is magnesium stearate oj zalcium stearate Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified comrnstarch, pregelatizined starch and natural starch.
The solid, pharmaceutical unit dosage form of the invention may be prepared by conventional methods using a tablet press with forced feed capability.
The filled, hard gelatine capsule of the invention may be prepared by conventional methods using a capsule filler suitable for powder filling.
In one embodiment of the present invention the crystals of a pharmaceutically acceptable salt of citalopram have a median particle size in the range of 40 200 im, preferably 45 150 jAm and even more preferred 50- 120 mn.
In a preferred embodiment of the present invention the crystals are of citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide.
In yet another embodiment of the present invention crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 im and suitable for use in a solid unit dosage form are crystallised from a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system, Said solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, wherein the methanol:water weight ratio preferably is in the range of 5:1 to 50:1; even more preferred 10:1 to 30:1 and most preferred 15:1 to 25:1. Said pharmaceutically acceptable salt of citalopramn is preferably dissolved in the solvent system at a temperature in the range between °C and the refluxing temperature of the solvent system, preferably between 60 °C and 330 AU the refluxing temperature and more preferred between 64 'C and the refluxing temperature. The amounts of pharmaceutically acceptable salt of citalopram and solvent used are preferably corresponding to a solvent:solute weight ratio in the range of 0.5:1 to 5:1, more preferred 0.7:1 to 2:1 and most preferred 0.9:1 to 1.5:1- The solution of a pharmaceutically acceptable salt of citalopram is cooled down to a temperature, the seeding temperature, in the range of 20-40 preferably 25-35 'C, whereupon it is seeded with citalopram crystals and kept at said seeding temperature for a holding time for crystal growth in the range of 30 minutes to 7 days, preferably I hour to 4 days and more preferred 12 to 36 hours. After said holding time, the I0 crystallisation batch is gradually cooled down in a controlled way from the seeding temperature to the temperature at which the crystals will be isolated from the mother liquor wherein said gradual cooling down is done over a time span in the range of minutes to 6 hours, preferably 15 minutes to 4 hours and more preferred 30 minutes to 2 hours. The crystals of said pharmaceutically acceptable salt of citalopram are preferably isolated from the mother liquor at a temperature in the range of 0-20 'C, more preferred 5-15 0 C, using conventional separation techniques, e.g. filtration.
The small crystals of a pharmaceutically accr.table salt of citalopram used in one embodiment of the invention may be produced according to methods described in US 4,136,193 The crystals of citalopram base used in one embodiment of the invention may be produced according to methods described in NL patent No. 1016435.
In the following, the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be construed as limiting.
330 AU Example 1 Crystallisation of citalopram hydrobromid. into large crystals Citalopramn hydrobromide (200 g) is dissolved in a mixture of methanol (200 g) and water (20 g) at 69 The solution is cooled down to 30 seeded with citalopram hydrobromide crystals and kept at 30 °C for 24 hours, whereupon it is cooled down to °C within 1 hour. The crystals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the resulting crystals is listed in table 1.
Example 2 Crystallisation of citalopram hydrobromide into large crystals Citalopram hydrobromide (12.0 kg) is dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux. The solution is cooled down to 30 seeded with citalopram hydrobromide crystals (27 g) and kept at 30 °C for 16 hours, whereupon it is tooled down to 10 °C within 1 hour. The crystals are isolated by filtration, washed with cold (10 methanol (3.5 kg) and dried. The particle size distribution for the resulting crystals is listed in table 1.
Example 3 Crystallisation of citalopram hydrobromide into small crystals Citalopram hydrobromide (200 kg) is dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56 The solution is cooled down to 15 seeded with citalopram hydrobromide crystals (50 hexane (1600 L) is gradually added within minutes, whereupon the suspension is left standing with moderate stirring and cooling for 8 hours. The crystals are isolated by filtration, washed first with a cold mixture of acetone (50 L) and hexane then with cold (10 OC) hexane (220 L) and dried. The particle size distribution for the resulting crystals is listed in table 1.
330 AU Example 4 Crystallisation of citalopram as the free base.
Citalopram hydrobromide (101 g) is suspended in water (500 mL) and toluene (500 nL). NaOH (60 mL, 5 N is added and the mixture (pH>10) is stirred for 15 min before the phases are separated. The organic phase is washed with water (2 x100 mL) and filtered through a pad of filter help. The volatiles are removed in vacuo and the title compound is obtained as an oil. n-Heptane (400 mL) is added and the mixture is heated to 70 On cooling, crystals forms. The white crystals of citalopram base are filtered off and dried at ambient temperature over night in vacuo, Table 1: Particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv Quantile Example 1 Example 2 Example 3 ProSolv (Jm) (mtm) (nm) (m) 465.43 549.42 96,96 279.94 342.89 352.23 72.27 231.66 96.87 52.70 14.04 114.17 16.54 11.97 1.19 32.10 8.23 6.67 0.82 20.56 Example Tablet prepared by direct compression of small citalopram hydrobromide crystals.
Tablet ingredients: Citalopram, HBr ProSolv SMCC90 Magnesium stearate 5800 a 23055 g 145 g (20 w/w) (79 5 w/w) (0.5 w/w) 330 AU
II
Citalopram hydrobromide crystals from examiple 3 and ProSolv SMCC90 were blended at 7 rpm for 10 min in a 100 litre Bohle PTM 200 mixer. Magnesium stearate was added and blending continued for 3 min.
25 kg of the resulting mixture was tabletted (125.000 tablets/hour) on a 30 station Fette P 1200/IC tablet press fitted with oblong, embossed, scored 5,5 x 8 mm punches. Tablet core weight was set to 125 mg. The nominal yield was 200.000 tablets. The tablet press was run until the mixture level was just above the forced feeder, i.e. the tabletting was continued as long as possible in order to identify possible segregation tendencies in the last quantities of mixture.
Tablet properties: Diametrical crushing strength: 70 N Disintegration time: 30 seconds Friability: NA Weight variation: 0.84% relative standard deviation (measured on 20 tablets) Punch adhesion: None observed Citalopram content in the composition during compression.
Tablets were sampled throughout the compression in order to measure segregation tendency. Since there is a significant size difference between the active ingredient, citalopram hydrobromide, and the inert filler, ProSolv SMCCP0, as seen in table 1, it would be expected that the unequally sized components would segregate, i.e. de-mix, during transfer from blending vessel to tablet press hopper or sitting in the tablet press hopper during tabletting.
Sampling was performed 50 times at regular intervals during tabletting, corresponding to sampling at every 4000 tablets produced. Two tablets were withdrawn for each sample.
330 AU 12 The tablets were assayed by a validated metd using UV-absorption in an aqueous solution, thus analysing in total 100 tablets. The relative standard deviation in citalopram content was 1.6% The variability in tablet strength is surprisingly low in view of the small particle size ofcitalopram hydrobromide as compared to the inert filler.
One possible explanation for this surprising and beneficial result may be that the tendency to segregation between small citalopram crystals and larger filler particles is uniquely balanced by the poor flow properties of the small crystals.
Example 6 Tablet prepared by direct compression of large citalopram hydrobromide crystals.
Tablet ingredients: Citalopram, HBr (20 w/w) ProSolv SMCC90 (79.5 w/w) Magnesium stearate (0.5 w/w) Citalopram hydrobromide crystals from example 2 and ProSolv SMCC90 were blended. Magnesium stearate was added and blending continued.
Tablets (125 mg nominel weight) were produced.
The tablets had satisfactory technical properties.
330 AU 4 JI -t 1 13 Example 6 Tablet prepared by direct compression of citalopram crystals.
Tablet ingredients: Citalopram base (16 w/w) ProSolv SMCC90 (83.3 w/w) Magnesium stearate (0,7 w/w) Citalopram base crystals from example 4 were sieved through sieve aperture of 0.3 mm and mixed with ProSolv SMCC90 for 3 minutes in a Turbula mixer. Magnesium stearate was added and blending continued for 30 seconds.
Tablets were produced on a single punch tablet ing machine Korsch EKO.
Tablet properties: Tablet strength, mg: Nominel tablet weight, mg: 125 Tablet diameter, mm: 7 Tablet shape: Film coating, special doomed Diametrical crushing strength: 61.6 N Disintegration time, min: I Friability: 0.1 Mean tablet weight: 125.4 Weight variation: 0.22 relative standard deviation The tablets produced had satisfactory technical properties.
330 AU
Claims (4)
1. A solid unit dosage form comprising citalopram as an active ingredient, wherein the dosage form is prepared by direct compression of a mixture of crystals of citalopram with a median particle size of at least 40 tm and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule.
2. The solid unit dosage form according to claim 1 wherein the active ingredient is crystals of citalopram hydrobromide.
3. The solid unit dosage form according to claim 1 or 2 wherein the median particle size of the crystals is in the range of 40 to 200 jtm.
4. Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage form according to any one of claims 1 to 3 wherein the median particle size of the crystals is at least 40 jim. Method of manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 [tm and suitable for use in a solid unit dosage form according to any one of claims 1 to 3, wherein a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled down to a second temperature, then seeded by addition of crystals of said citalopram salt, followed by a holding time at said second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by conventional solid/liquid separation techniques. DATED this 28th day of May 2002 H. LUNDBECK A/S WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA KJS:JPF:VRH UIP1005AU00
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200001202 | 2000-08-10 | ||
| DKPA200001202 | 2000-08-10 | ||
| DKPA200001614 | 2000-10-27 | ||
| DKPA200001614 | 2000-10-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2001100198A4 AU2001100198A4 (en) | 2001-08-16 |
| AU2001100198B4 true AU2001100198B4 (en) | 2002-06-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001100198A Expired AU2001100198B4 (en) | 2000-08-10 | 2001-07-26 | Pharmaceutical composition containing citalopram |
| AU2001279591A Abandoned AU2001279591A1 (en) | 2000-08-10 | 2001-07-30 | Pharmaceutical composition containing citalopram |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| AU2001279591A Abandoned AU2001279591A1 (en) | 2000-08-10 | 2001-07-30 | Pharmaceutical composition containing citalopram |
Country Status (34)
| Country | Link |
|---|---|
| EP (1) | EP1318805A2 (en) |
| JP (1) | JP2003531153A (en) |
| KR (1) | KR20030024833A (en) |
| CN (1) | CN1446089A (en) |
| AR (1) | AR030095A1 (en) |
| AT (1) | AT5744U1 (en) |
| AU (2) | AU2001100198B4 (en) |
| BE (1) | BE1013559A6 (en) |
| BG (1) | BG107578A (en) |
| BR (1) | BR0113250A (en) |
| CA (1) | CA2353693C (en) |
| CH (2) | CH694241A5 (en) |
| CZ (1) | CZ2003397A3 (en) |
| DE (2) | DE20113195U1 (en) |
| EA (1) | EA200300247A1 (en) |
| ES (1) | ES2172481B2 (en) |
| FI (1) | FI5176U1 (en) |
| FR (1) | FR2812811B1 (en) |
| GB (1) | GB2368014B (en) |
| GR (1) | GR1004193B (en) |
| HR (1) | HRP20030054A2 (en) |
| HU (1) | HUP0103071A3 (en) |
| IE (1) | IES20010693A2 (en) |
| IL (1) | IL154050A0 (en) |
| IS (1) | IS6021A (en) |
| IT (1) | ITMI20011637A1 (en) |
| MX (1) | MXPA03000837A (en) |
| NL (1) | NL1018741C1 (en) |
| NO (1) | NO20013891L (en) |
| NZ (1) | NZ523785A (en) |
| PL (1) | PL359824A1 (en) |
| SK (1) | SK2842003A3 (en) |
| WO (1) | WO2001080619A2 (en) |
| YU (1) | YU9003A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IES20010693A2 (en) * | 2000-08-10 | 2002-07-10 | Lundbeck & Co As H | Pharmaceutical composition containing citalopram |
| AU2001100195B4 (en) * | 2001-01-05 | 2001-12-20 | H Lundbeck As | Pharmaceutical composition containing citalopram. |
| GB0206708D0 (en) * | 2002-03-21 | 2002-05-01 | Cipla Ltd | Pharmaceutical salts |
| US6812355B2 (en) | 2002-10-22 | 2004-11-02 | Sekhsaria Chemicals Limited | Process for the manufacture of citalopram hydrobromide from 5-bromophthalide |
| EA013116B1 (en) * | 2002-12-23 | 2010-02-26 | Х. Лундбекк А/С | Escitalopram hydrobromide, use thereof and pharmaceutical composition thereof |
| WO2004103361A2 (en) * | 2003-05-20 | 2004-12-02 | Ranbaxy Laboratories Limited | A pharmaceutical dosage form of citalopram |
| HU227491B1 (en) * | 2003-11-25 | 2011-07-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Tablet containing citalopram hydrogen bromide |
| WO2006038217A1 (en) * | 2004-10-05 | 2006-04-13 | Strides Acrolab Limited | An improved drug delivery system of citalopram hydrobromide and process for producing the same |
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| US1358915A (en) * | 1919-04-14 | 1920-11-16 | Amici Domenico | Aeroplane |
| GB1358915A (en) * | 1971-09-13 | 1974-07-03 | Merck & Co Inc | Directly compressed tablet and composition therefor |
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| GB8814057D0 (en) * | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
| US5296507A (en) * | 1990-09-06 | 1994-03-22 | H.Lundbeck A/S | Treatment of cerbrovascular disorders |
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| IES20010693A2 (en) * | 2000-08-10 | 2002-07-10 | Lundbeck & Co As H | Pharmaceutical composition containing citalopram |
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