AU732785B2 - Process for the preparation of an oral solid dosage form containing diclofenac - Google Patents
Process for the preparation of an oral solid dosage form containing diclofenac Download PDFInfo
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- AU732785B2 AU732785B2 AU11322/99A AU1132299A AU732785B2 AU 732785 B2 AU732785 B2 AU 732785B2 AU 11322/99 A AU11322/99 A AU 11322/99A AU 1132299 A AU1132299 A AU 1132299A AU 732785 B2 AU732785 B2 AU 732785B2
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- Prior art keywords
- diclofenac
- cyclodextrin
- inclusion compound
- dosage form
- salt
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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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
- A61K9/2095—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
Description
Our Ref: 715413 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT
S
S
S
S
S
Applicant(s): Address for Service: Novartis AG Schwarzwaldallee 215 CH-4058 Basel
SWITZERLAND
DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Invention Title: Process for the preparation of an oral solid dosage form containing diclofenac The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 4-19580/A Process for the preparation of an oral solid dosage form containing diclofenac The present invention relates to a novel advantageous process for the preparation of an oral solid dosage form containing diclofenac or a pharmaceutically acceptable salt thereof, to the inclusion compound of diclofenac or a pharmaceutically acceptable salt thereof with -cyclodextrin, useful as intermediate for said process, as well as to a process for the preparation of said inclusion compound.
A variety of therapeutic agents of different structure, especially non-steroidal antiflammatory drugs (NSAID), is available for the treatment of painful inflammatory diseases, e.g. rheumatism.
Numbered among this group of NSAIDs of first choice is the sodium salt of diclofenac, i which has long been introduced in numerous countries under the registered trademark Voltaren® (Ciba-Geigy) and which is available in different dosage forms such as dragdes, suppositories or injection solutions.
Quite generally, the oral administration of this therapeutic agent in solid dosage forms such as tablets or dragees affords advantages over other, for example parenteral, dosage forms. Diseases that have to be treated by administering injections are felt purely subjectively to be more serious than other diseases in the treatment of which the administration of tablets or dragdes is little noticed. The suitability of such dosage forms for self-medication by patients themselves is especially advantageous, whereas parenteral dosage forms, aside from a few exceptions, have to be administered by the physician or authorised auxiliary medical personnel.
With the exception of less directly compressable therapeutic agents such as acetylsalicylic acid, phenobarbitone, phenacetin, coffein, ascorbic acid, ammonium chloride or potassium chloride, tablets or dragees are prepared in multi-step processes in which granulates are formed as intermediates. Granulates can be produced by different methods, typically by moist granulation or compacting. The granulates are subsequently compressed to tablets -2that may be coated in a further step to film-coated tablets or sugar-coated drag6es. The technical literature takes the unequivocal view that the direct compression of therapeutic agents without granulate formation has advantages over the compression of granulates, which have to be prepared in a first step with an additional process step. So far it is not known of diclofenac or a salt thereof that this important therapeutic drug can be compressed direct to break-resistant tablets.
A further advantage of tablets and dragdes obtained by direct compression results from the increased concentration of the therapeutic agent, which can usually be raised to over 50 by weight. Usually, therefore, smaller amounts of excipients are required for direct compression than for the compression of granulates. Given a predetermined tablet size, therefore, it is possible to increase the concentration of therapeutic agent or, given a predetermined dose, to reduce the size of the tablet Hence it is the object of this invention to prepare solid oral dosage forms such as tablets or dragdes containing the therapeutic drug diclofenac, or a pharmaceutically acceptable salt thereof, by direct compression. This object is achieved by utilisation of the surprising discovery that the therapeutic drug diclofenac, or a salt thereof, with y--cyclodextrin forms a defined inclusion compound that can be compressed direct to tablets or drages.
Accordingly, the invention relates to a process for the preparation of a compressed dosage form for the therapeutic drug diclofenac or a pharmaceutically acceptable salt thereof, **which comprises preparing an inclusion compound consisting of diclofenac, or a pharmaceutically acceptable salt thereof, and y-cyclodextrin, and compressing said inclusion compound directly, with the addition of optional excipients conventionally employed in the preparation of solid dosage forms, and, if desired, further processing the compressed tablet core so obtained to another solid dosage form.
A further object of the invention is the inclusion compound as defined herein formed from diclofenac, or a pharmaceutically acceptable salt thereof, and y-cyclodextrin, which can be used as intermediate in the process for the preparation of a directly compressed dosage form. The characterisable inclusion compound formed from diclofenac sodium salt and y-cyclodextrin is especially preferred.
A further object of the invention is the process for the preparation of said inclusion compound.
The terms used throughout this specification are defined as follows within the scope of the description of the present invention: The term "compressed dosage form" embraces tablets or dragdes that disintegrate in the stomach or in the interconnecting part of the gastrointestinal tract (duodenum) and which are able to release the therapeutic drug diclofenac or a pharmaceutically acceptable salt thereof, with or without controlled release of the active drug.
Tablets or dragdes (without control of drug release) are single-dose, solid dosage forms for peroral administration that can be prepared by direct compression of the inclusion compound formed from diclofenac, or a pharmaceutically acceptable salt thereof, and y-cyclodextrin, with or without the addition of suitable excipients, by means of standard tabletting methods. Dragees are distinguished from tablets by providing them with an additional coating, typically a sugar, shellac, coloured or film coating.
Compressed dosage forms with controlled release of therapeutic drug are distinguished by accelerated or delayed, as well as quantitatively controlled, release of drug. Thus tablets with accelerated release of therapeutic drug are formed with disintegrants such as crosslinked polyvinyl pyrrolidone (Polyplasdone® XL or Kollidon® CL) or reactive excipients (effervescent mixtures) that effect rapid disintegration of the tablet in the S: presence of water, for example so-called effervescent tablets that contain an acid in solid form, typically citric acid, which acts in water on a base containing chemically combined carbon dioxide, for example sodium hydrogencarbonate or sodium carbonate, and releases carbon dioxide.
Compressed dosage forms with delayed release and, preferably, quantitatively controlled release, of the therapeutic drug are defined in the technical literature by different terms such as enteric-coated tablets, tablets with modified drug release, release systems or oral therapeutic systems. These definitions meet a therapeutically determined objective, typically the delayed release of a drug to effect a reduction of local overconcentrations because of the risk of irritation to gastric or intestinal mucosa (ulcer problems), reduction of the release of a loading dose administered in initial overconcentration, or prolonged release. A wide range of dosage forms are known whose properties are defined by terms such as sustained release, controlled release, prolonged release, repeat or repeated release or delayed release. The preferred dosage forms are controlled release or sustained release -4forms that not only delay release of the active drug over a period of time but also release it in a controlled amount. Such dosage forms are known as oral osmotic systems (OROS), coated tablets, matrix tablets, film-coated tablets, press-coated tablets, multilayer tablets and the like.
A pharmaceutically acceptable salt of diclofenac, o-(2,6-dichlorophenylamino)phenylacetic acid, q.v. Merck Index, Eleventh Edition No. 3071, is preferably the sodium or potassiuim salt, and also the salt with an amine, e.g. a mono-, di- or tri-C 1
-C
4 alkylamine, e.g. dietlamine or triethylamine, hydroXY-C 2
-C
4 alkylaniine, e.g. ethanolamine, :hydroxy-C 2
-C
4 aikyl-Cl-C 4 alkylamine, e.g. dimethylethanolamine, or a quaternary :anumonium salt, e.g. the tetramethylammonium salt or the choline salt of diclofenac.
The respective inclusion compound consisting of diclofenac, or a pharmaceutically acceptable salt thereof, and y-cyclodextrin is novel and is an object of the invention. The following characteristic data are given for the inclusion compound of diclofenac sodium salt with y-cyclodextrin, hereinafter referred to as y-cyclodextrin-diclofenac sodium: 1. Elemental analysis (based on the anhydrous sample): Element theory found y-cyclodextrin-diclofenac-Na: C .46.11% 45.73% H 5.68 6.36 N 0.87% 1.15% Cl 4.39 4.35 Na 1.42% 1.43% y-cyclodextrin-diclofenac-K: C 45.61% 45.75% H 5.58 5.53 N 0.86 0.82 Cl 4.35 4.41 K 2.40 2.36 Z. Thermoagravimetric analysis The samples are stored for 9 days at 52 relative humidity and room temperature. The measurement is made using the Perkin-Elmer TGS 2 thermnogravimetric system.
Substance diclofenac-Na diclofenac-K y-cyclodextrin Temperature up to 100 0
C
up to 200*C up to 280 0
C
up to 10 0
C
up to200 0
C
up to280 0
C
up to 100 0
C
up to 200 0
C
up to 280 0
C
up to 100 0
C
up to200 0
C
up to 280 0
C
up to 1000( up to200*C up to 280 0
C
Mass loss 20.7 20.8 22.2 <0.1 <0.1 0.2 15.7% 17.3% 19.3 12.3 13.7 65.3% 4.6% 6.5 10.5 y-cyclodextrin-diclofenac-Na y-cyclodextrin-diclofenac-K -6- 3. Differential scanning~ calorimetry (DSC): The samples are stored for 9 days at 52 relative humidity and room temperature. The measurement is made using a Perkin-Elmer thermoanalyser (Series 7).
Substance Peak [OCJ All [J/g] diclofenac-Na 56.6 114.2 79 :130.3 6 roo diclofenacK 297.9 y-cyclodextrin 100.3 8 130.1 16 y-cyclodextrin-diclofenac-Na 127.2 37 180.6 17 y-cyclodextrin-diclofenac-K 78.1 3 216.3 22 4. X-Ray Dowder analysis The measurement is made using a Guinier camera (FR 552, Enraf-Nonius) in gamma-ray geometry. The diagrams are recorded by copper-Kax 1 -radiation (X 1.54060 x1I00- 0 m) on X-ray film. A diagram of quartz recorded on the same film is used for calibrating the camera radius.
The following Table lists the lattice distances (d-values and the relative intensities of the most important reflexes with d-values 3.5. 10-10 in): d-yalues [1010m Intensities y-cyclodextrin-diclofenac-Na 15.40 average *14.60 strong *8.40 weak 7.70 average 7.30 weak 6.40 average 6.10 very weak *5.51 very strong 4.86 weak 4.60 very weak 4.39 very weak 4.06 average 3.65 weak -8d-values [10.10 m] Intensities 'y-cyclodextrin-diclofenac-K 15.10 strong 14.60 average 13.40 strong 8.40 weak 8.20 very weak 7.7.70 average .7.50 average 7.30 very strong 6,50 weak 5.95 very weak *5.71 very weak *5.51 very weak 5.23 average 4.96 average 4.79 very weak 4.74 very weak :4.61 very wa 4.45 weak 4.41 weak 4.37 average 4.26 average 4.20 weak 4.12 weak 4.04 average 3.91 very weak 3.84 very weak 3.78 very weak 3.73 weak 3.67 very weak 3.64 weak 3.50 very weak -9- IR Spectroscopy: The diclofenac sodium-y-cyclodextrin 1: 1 mixture is prepared by dry mixing the salt of diclofenac with y-cyclodextrin. The measurement is made with a FTIR spectrophotometer IFS 48 supplied by Bruker. The wave numbers are given in The shape of the bands is described in more detail by qualifying affixes: vst, very strong; st strong; av average; wk weak; b broad.
0 ~0 *0 0 0 00w*00 0 *0**00 0* *00 0* 0 0***00 0 000* *0 00 0
S
I.
0@*0*0 0 Diclofenac-Na 1576 vst 1556 vst 1508 vst 1391 vst 953 wk 868 av 839 av 716 av 685 av Diclofenac-K 1504 s 1468 st 1452 st 1304 st 1153 w 947 av 766 av 746 av 717 w y-Cyclodextrin 1639 av,b 1369 av 941 av 854 wk 708 av 1-Cyclodextrin 1414 av 1369 av 1157 st 941 av 758 av 708 av Dlclofenac-Na+ y-cyclodextrin 1: 1 mIxture 1636 wk 1578 av 1556 av 1508 av 1389 av,b 943 av 843 wk 714 av Diclofeniac-Ki- T-cyclodextrin 1:1I-mixture 1504 st, 1468 st 452 St 306 w 1146 w 951 W 768 av 746 av 717 w Didofenac-Nay-cyclodextrin inclusion cmpd.
1634 wk 1578 av 1560 wk 1504 av 1377 av,b 941 av 860 wk,b 706 av Diclofenac-Ky-cyclodextrin inclusion cpd.
1506 st 1472 av 1456 st 1315 av 1144 w 939 w 775 w 744 w 702 w 6. Circular dichroism: The spectra are recorded with a Jasko 710 dichrograph.
The molar ellipticity for y-cyclodextrin-diclofenac sodium 102 60 M-'cm- 1 and for y-cyclodextrin-diclofenac-potassium 84 60 (at 272 nm in 69 mM phosphate buffer solution, pH 7,4).
Excipients customarily used for the preparation of solid dosage forms are preferably excipients for tabletting, especially those that are suitable for direct compression, e.g.
powder binders such as starch, e.g. potato starch, wheat starch and corn starch, microcrystalline cellulose, e.g. products that are commercially available under the registered trademark Avicel®, Filtrak®, Heweten® or Pharmacel®, highly dispersed silica, e.g. Aerosil®, mannitol, lactose, and also polyethylene glycol, preferably having a molecular mass of 4 000 to 6 000, crosslinked polyvinyl pyrrolidone (Polyplasdone® XL or Kollidon® crosslinked carboxymethyl cellulose (Acdisol® CMC-XL), carboxymethyl cellulose [Nymcel® (Nyma)], carboxymethyl starch [Explotab® (Mendell) or Primojel® (Scholtens)], dicalcium phosphate, e.g. Emcompress®, or talcum.
The addition of minor amounts of glidants such as magnesium stearate is also useful.
Further excipients are siliconised talcum, aluminium stearate, stearic acid, palmitic acid, skimmed milk powder, stearyl, cetyl and myristyl alcohol, Lanette® 0, paraffin or hydrogenated fats. With respect to tabletting, attention is drawn to the comprehensive technical literatiure on the subject The compression to tablet cores can be carried out in a conventional tabletting machine, e.g. in an EK-0 Korsch eccentric tabletting machine, preferably at a compression greater than 10 kN. The tablet cores may vary in shape and be, for example, circular, oval, oblong, cylindrical and the like, and may also vary in size depending on the concentration of therapeutic drug. They may furthermore be transparent, colourless, coloured and also marked so as to impart to these products an individual appearance and to make them instantly recognisable. The use of dyes can serve to enhance the appearance as well as to identify the compositions. Dyes suitable for use in pharmacy typically include carotinoids, iron oxides or chlorophyll.
-11- The compressed tablet cores formed by direct tabletting can, if desired, be further processed in per se known manner to another solid dosage form, typically to dragdes that are provided with an additional coating, e.g. a sugar, shellac, coloured or film coating.
Attention is drawn to the numerous known methods employed in the art of tabletting, e.g.
spray coating in a fluidised bed, e.g. by the known methods using apparatus available from Aeromatic, Glatt, Wurster or Hiittlin, in a spray vat by the Accela Coata method, or to the submerged-coil coating method. The excipients commonly used in confectioning are employed in such methods.
A further object of this invention is the per se known process for the preparation of the inclusion compound of diclofenac, or a pharmaceutically acceptable salt thereof, in y-cyclodextrin, which comprises reacting diclofenac, or a pharmaceutically acceptable salt thereof, with y-cyclodextrin in the presence of water.
This process can be carried out using a number of process variants, typically by a) adding water to a mixture of diclofenac, or a pharmaceutically acceptable salt thereof, with y-cyclodextrin, and stirring the mixture at elevated temperature, preferably in the range from 50-60 0 C, and then, without or after cooling, precipitating or crystallising the resultant inclusion compound, or b) adding water to a mixture of diclofenac, or the salt thereof, and Y-cyclodextrin, and subsequently precipitating or crystallising the rsultant inclusion compound, or c) in any order, adding a minor amount of water first to diclofenac or to the salt thereof or y-cyclodextrin, kneading or agitating the moistened paste and adding thereto the second component of the inclusion compound, or d) preparing an aqueous suspension of diclofenac, or the salt thereof, and y-cyclodextrin, converting said suspension into a solution by adjusting the pH to the alkaline range, typically by adding a base such as a solution of ammonia or dilute aqueous sodium or potassium hydroxide solution, and thereafter neutralising this solution with an acid or a buffer solution, conveniently by adding dilute aqueous sulfuric acid or hydrochloric acid or acetic acid, and subsequently precipitating or crystallising the resultant inclusion compound, and then, after carrying out any one of process variants a) to purifying or isolating the resultant inclusion compound.
-12- The inclusion compound can be purified or isolated by washing the precipitated or crystallised product with a minor amount of an organic solvent, e.g. ethanol or acetone, in which in particular diclofenac or the salt thereof dissolves more readily than the inclusion compound.
y-Cyclodextrin is also known as cyclooctaamylose, q.v. Merck Index, Eleventh Edition, No. 2724. This excipient is a commercially available (Wacker Chemie) degradation product of starch and consists of 8 glucose units that are linked to one another in cyclic conformation through glycosidic bonds.
Specification: water content when filled: D.E. (dextrose equivalent): ignition residue: minimum cone. of y-cyclodextrin: cone. of t-cyclodextrin: cone. o p-cyclodextrin: cone. of linear oligosaccharides: turbidity of a 10 solution at 420 nm: (1 cm layer thickness): manufacturer: 6.6 0.05 <0.05 >99.5 <0.1% <0.1% <0.1 (max.) 0.16 Wacker Chemie (DE) Example 1 1.1 preparation of the inclusion compound: 12.31 g (38.7 mmol) of diclofenac sodium and 50.19 g (38.7 mmol) of y-cyclodextrin are dissolved in c. 150 ml of water at 75 0 C. Thesolution is filtered and slowly allowed to cool to room temperature, whereupon colourless needle-shaped crystals precipitate. After standing for 3 days in a refrigerator, the crystals are isolated by centrifugation at 10 0 C and 400 rpm. The crystalline residue is washed with a small amount of ice-water and dried to constant weight at 40 0 C in a drying oven under vacuum 200 mbar). Yield: 39.30 g (62.9 of theory) based on the anhydrous substance (water content: 7.31 after Karl-Fischer titration).
13- 1.2 Direct tabletting: y-cyclodextrin-diclofenac sodium 100 mg (69.9%) Avicel® PH 102 35 mg (24.5%) polyvinyl pyrrolidone PXL 6 mg 4.2%) Aerosil 200 1 mg 0.7%) magnesium stearate 1 mg 0.7 -Cyclodextrin-diclofenac-sodium is mixed with 0.5-1,0 magnesium stearate and pressed to talbets of 250 mg wight ata pressure of about 130 MN/m 2 in a Korsch DSKi 118 eccentric tabletting machine equipped with compacting pressure registration and a plain punch of 9 mm diameter. The tablets obtained have a height of 3.0 0,01 mm and a :i breaking resistance of 120 32 N measured in a Schleuniger 6 D fractographer (Schleuniger Prodrutronic AG, CH-4501 Solothurn).
Example 2 -cyclodextrin-diclofenac-sodium 250.0 mg (69.9 Avicel® PH 102 87.5 mg (24.5%) polyvinyl pyrrolidone PXL 15.0 mg 4.2%) Aerosil 200 2.5 mg 0.7%) magnesium stearate 2.5 mg 0.7 The inclusion compound and the excipients are mixed in a Turbula® T2C mixer for min.. The magnesium stearate is added to this mixture and mixing is continued for 3 min.. Then 358 mg of the formulation mixture are filled into each of the matrices and processed to tablets at about 80 MN/m 2 in a Korsch DSKi 118 eccentric tabletting machine with compacting pressure registration und a plain punch of 6 mm diameter. The tablets obtained have a height of 4.2 0.04 mm and a breaking resistance of 160 23 N measured in a Schleuniger 6 D fractographer.
-14- Example 3 y-cyclodextrin-diclofenac-sodium 250.0 mg (67.8 corn starch 49.6 mg (15.2%) Na-carboxymethyl starch 19.5 mg 6.0 Aerosil® 200 4.5. mg 1.4 magnesium stearate 2.1 mg 0.6%) The inclusion compound and the excipients are mixed in a Turbula® T2C mixer for 15 min.. The magnesium stearate is added to this mixture and mixing is continued for 3 min.. Then 326 mg of the formulation mixture are filled into each of the matrices and processed to tablets at about 180 MN/m 2 in a Korsch DSKi 118 eccentric tabletting machire with compacting pressure registration und a plain punch of 9 mm diameter. The tablets obtained have a height of 4.0 0.05 mm and a breaking resistance of 110 21 N measured in a Schleuniger 6 D fractographer.
Example 4 o diclofenac-Na 50,0 mg (15,4 -cyclodextrin 200,0 mg (61,4 corn starch 49,6 mg (15,2%) Na-carboxymethyl starch 19,5 mg Aerosil 200 4,5 mg 1,4%) magnesium stearate 2,1 mg 0,6%) Diclofenac-Na, y-cyclodextrin and Na-carboxymethyl starch 32,4 g corn starch und 2,2 g AEROSIL are admixed for 15 minutes in a mixer "Kitchen Aid" (Hobalt, Regensdorf CH) at speed level 1. 100 g water is added in portions, and the mixture obtained is mixed for further 15 minutes. The mixture is meshed through a screen and dried until a moisture content of about 10 (relative to the mass of the dry composition) is reached. The powder is admixed for 15 minutes in the TURBULA mixer with the remaining amounts of corn starch and AEROSIL. The magnesium stearate is then added and the mixture is further mixed for another 3 minutes. Then 326 mg of the formulation mixture are filled into each of the matrices and processed to tablets at about 150 MN/m 2 in a Korsch DSKi 118 eccentric tabletting machine with compacting pressure registration und a plain i punch of 9 mm diameter. The tablets obtained have a height of 4.02 0.02 mm and a breaking resistance of 195 22 N.
Example In a manner analogous to Example 1 tablets are manufactured characterized by a content of 261 mg y-cyclodextrin-diclofenac-potassium. The tablets obtained have a height of 3,4 0,1 mm and a breaking resistance of 180 26 N.
Example 6 In a manner analogous to Example 3 tablets are manufactured characterized by a content of 261 mg y-cyclodextrin-diclofenac-potassium. The tablets obtained have a height of 4.5 0,1 mm and a breaking resistance of 190 22 N.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will S be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
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Claims (10)
1. A process for the preparation of a compressed dosage form for diclofenac, or a pharmaceutically acceptable salt thereof, which comprises preparing the inclusion compound consisting of diclofenac or a pharmaceutically acceptable salt thereof and y-cyclodextrin, and compressing said inclusion compound directly, with the addition of optional excipients conventionally employed in the preparation of solid dosage forms, and, if desired, further processing the compressed tablet core so obtained to another solid dosage form.
2. A process according to claim 1 for the preparation of an inclusion compound consisting of diclofenac sodium and y-cyclodextrin.
3. A process according to either claim 1 or claim 2, wherein the inclusion compound consisting of diclofenac sodium and y-cyclodextrin is compressed directly to tablets.
4. A process according to claim 1, wherein the tablets are further processed to drag6es.
5. A process according to claim 1 comprising preparing the inclusion compound in the form of a crystal.
6. A compressed dosage form as obtained by a process according to any one of claims 1 to
7. A compressed dosage form according to claim 6 comprising diclofenac in the form of a sodium salt.
8. A compressed dosage form as disclosed in Examples 1 to 6 of the specification.
9. The inclusion compound formed from a pharmaceutically acceptable salt of diclofenac and y-cyclodextrin. The inclusion compound formed from diclofenac sodium and y-cyclodextrin.
17- 11. A process for the preparation of an inclusion compound formed from the diclofenac or a pharmaceutically acceptable salt thereof and y-cyclodextrin, which comprises a) adding water to a mixture of diclofenac, or a pharmaceutically acceptable salt thereof, with y-cyclodextrin, and stirring the mixture at elevated temperature, and, without or after cooling, precipitating or crystallizing the resultant inclusion compound, or b) adding water to a mixture of diclofenac, or the salt thereof, with y-cyclodextrin, and subsequently precipitating or crystallising the resultant inclusion compound, or c) in any order, adding a minor amount of water first to diclofenac or to the salt thereof or y-cyclodextrin, kneading or agitating the moistened paste and adding thereto the second component of the inclusion compound, or d) preparing an aqueous suspension of diclofenac, or the salt thereof, and y-cyclodextrin, converting said suspension into a solution by adjusting the pH to the alkaline range, and thereafter neutralising this solution with an acid or a buffer solution, and subsequently precipitating or crystallising the resultant inclusion compound, and then, after carrying out any one of process variants a) to purifying or isolating the resultant inclusion compound. 12. A process of claim 11, wherein the inclusion compound is formed from diclofenac sodium and y-cyclodextrin. DATED this 17th day of February 1999 NOVARTIS AG By its Patent Attorneys DAVIES COLLISON CAVE DAVIES COLLISON CAVE
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU11322/99A AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1711/93 | 1993-06-08 | ||
| AU69712/94A AU6971294A (en) | 1993-06-08 | 1994-05-24 | Process for the preparation of an oral solid dosage form containing diclofenac |
| AU11322/99A AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU69712/94A Division AU6971294A (en) | 1993-06-08 | 1994-05-24 | Process for the preparation of an oral solid dosage form containing diclofenac |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1132299A AU1132299A (en) | 1999-03-04 |
| AU732785B2 true AU732785B2 (en) | 2001-04-26 |
Family
ID=3753164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11322/99A Expired AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU732785B2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5959632A (en) * | 1982-09-28 | 1984-04-05 | Teikoku Chem Ind Corp Ltd | Sustained release composition |
| JPS5984821A (en) * | 1982-11-04 | 1984-05-16 | Teikoku Chem Ind Corp Ltd | Slowly solubilized composition |
| EP0449731A1 (en) * | 1990-03-28 | 1991-10-02 | Laboratoires Crinex | Anti-inflammatory and/or analgesic pharmaceutical composition for perlingual administration |
-
1999
- 1999-01-13 AU AU11322/99A patent/AU732785B2/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5959632A (en) * | 1982-09-28 | 1984-04-05 | Teikoku Chem Ind Corp Ltd | Sustained release composition |
| JPS5984821A (en) * | 1982-11-04 | 1984-05-16 | Teikoku Chem Ind Corp Ltd | Slowly solubilized composition |
| EP0449731A1 (en) * | 1990-03-28 | 1991-10-02 | Laboratoires Crinex | Anti-inflammatory and/or analgesic pharmaceutical composition for perlingual administration |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1132299A (en) | 1999-03-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |