AU695723B2 - New oral pharmaceutical formulation containing magnesium salt of omeprazole - Google Patents

Description

WO 96/01622 PCT/SE95/00816 1 NEW ORAL PHARMACEUTICAL FORMULATION CONTAINING MAGNESIUM SALT OF OMEPRAZOLE Field of the invention.

The present invention is related to a new pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole, to a method for the manufacture of such a formulation, and to the use of such a formulation in medicine.

Background of the invention.

The compound known under the generic name omeprazole, 5-methoxy-2(((4methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-lH-enzimidazole, is described i.a. in EP-A 0 005 129.

Omeprazole is useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, said substances may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. Omeprazole may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Further, omeprazole may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.

WO 96/01622 PCT/SE95/00816 2 Omeprazole is susceptible to degradation/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than three is shorter than ten minutes. Omeprazole may be stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light.

From what is said about the stability properties of omeprazole, it is obvious that an oral dosage form of omeprazole must be protected from contact with the acid gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of omeprazole can occur.

A pharmaceutical oral dosage form of omeprazole may well be protected from contact with acidic gastric juice by an enteric coating. In US-A 4,786,505 an enteric coated omeprazole preparation is described. Said omeprazole preparation contains an alkaline core comprising omeprazole, a subcoating and an enteric coating.

The hard gelatine capsules containing an enteric coated pellet formulation of omeprazole marketed by the Applicant today, are not suitable for press-through blister packages. Thus, there has been a demand for development of new enteric coated preparations of omeprazole with good chemical stability as well as improved mechanical stability making it possible to produce well functioning and patient-friendly packages.

Certain salts of omeprazole including alkaline salts of omeprazole are described in EP-A 0 124 495. In said patent specification the requirements and importance regarding storage stability of omeprazole for incorporation in pharmaceutical preparations are emphasized.

WO 96/01622 PCT/SE95/00816 3 There is however, a demand for the development of new enteric preparations of omeprazole with enhanced stability and for environmental aspects there is also a strong desire for the use of water based processes in production of pharmaceutical products.

The isolation and purification in full manufacturing scale of the magnesium omeprazole salts described in EP-A 0 124 495 presents one major problem in that the magnesium omeprazole salt particles are very fragile making pharmaceutical manufacturing processes utilising this product less attractive in full scale production. Manufacturing of magnesium omeprazole without a separate crystallisation step gives a product which is less suitable as a pharmaceutical substance.

In order to use the magnesium salt of omeprazole, in this specification denoted magnesium omeprazole, in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that said magnesium omeprazole possesses a combination of properties which makes such full scale manufacturing feasible.

The combination of physical properties of the novel magnesium omeprazole product described in W095/01977 with respect to the degree of crystallinity, particle diameter, density, hygroscopicity, low water content and low content of other solvents is favorable and permits the manufacture of magnesium omeprazole in a form which is advantageous for the manufacture of the new pharmaceutical formulations.

The novel form of magnesium omeprazole can be formulated into differ%,t dosage forms for oral and rectal administration. Examples of such formulations are tablets, granules, pellets, capsules, suppositories and suspensions.

I l~s LIIIPPr II W 6/01622 PC./SE95/00816 s o o o e u o One object of the present invention is to provide a pharmaceutical formulation of magnesium omeprazole.

Another object of the present invention is to provide a process for full scale production of pharmaceutical formulations of omeprazole, especially an enteric coated dosage form of omeprazo]e, which is resistant to dissolution in acid media and which dissolves rapidly in neutral to alkaline media and which has a good stability even against discoloration.

Yet another object of the invention is to provide an environmental friendly completely water-based process for the manufacture of pharmaceutical formulations of omeprazole.

A further object of the present invention is to provide a dosage form comprising omeprazole which is suitable for press-through blister packages and which also has an improved patient acceptance.

Description of the invention 15 In accordance with the invention, there is provided an oral enteric S coated formulation containing a core material comprising an active substance coated with one or more enteric coating layers characterized in that the core material as active substance contains a magnesium salt of carprazole having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction and an the core material enteric coating layer(s), and the enteric coating is such that its thickness does not deleteriously influence the S release of oreprazole into aqueous solutions at pH values predcminantly present in the small intestine.

25 In general, the basis of the new dosage form is the following: core material in the form of pellets, granules, beads or tablets containing the novel form of a magnesium salt of cmeprazole, with one or more enteric coating layers on said core material, is provided by the invention, it having been found that a nagnesium cmeprazole having a degree of crystallinity which is higher than 70%, and with the enteric coating having the indicated prcperty, is advantageous in S the manufacture of pharmaceutical formulations of cneprazole S according to the present invention- 0 T 0 /(PrV WO 9G/01622 PCI'/SE95/0081G Th-e process of forming the enteric coated dosage fo-rm is, preferably water-based. Also thae enteric coating proczess step can be carried out using a water-based process which is desirable both f or the working exnvirrmnt inside the pharmaceutical plant andi for global environmental reasonsetailed description of the invention The invention provides a new pharmaceutical forrrulation; a prccess for the mnumfacture of the pharmaceutical formulation; the use of the fornulation in mredicine; and a press-through blister package.

Maginesium gmeprazole A magnesiumf cneprazole advantageous for the in-arnacturing of the clained formu~lation is described in the specification of Australian Patent No. 679766, corresponding to WO 95/01977, hereby incorporated in a whole by reference. Said rragnesixn cmeprazole has a degree of crystallinity of not less than 70., preferably higher than 7S-. as determined by X-ray pader diffraction.

Pharmaceutical formulations containing the magnesium omeprazole are manufactured as described herein below.

Core material 20 The novel magnesium salt of omeprazole, herein referred to as magnesium omeprazole, is mixed wi6th phar-maceutical constituents to obtain preferred handling and processing properties and a suitable concentraton of the active substance in the final n-ixture. Pharmaceutical constituents such as Fillers, binders, lubricants, disintegrading agents, surfactants and other pharmaceutically acceptable additives, can be used. The core my also contain an alkaline pharmaceutically acceptable RAu /0 WO 96/01622 PCT/SE95/00816 6 substance (or substances). The op'inally added alkaline substance(s) is not essential for the invention. However. it may further improve the chemical stability of the formulations. Such pharmaceutically acceptable substances can be chosen among, but are not restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as A1 2 0 3 .6MgO.CO 2 .12H 2 0,(Mg 6 Al 2 (OH)16CO 3 .4H 2 0), MgO.A1 2 0 3 2SiO 2 .nH20 or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.

The powder mixture is then formulated into pellets, granules, beads or tablets by pharmaceutical procedures. The pellets, granules, beads or tablets are used as core material for further processing.

Enteric coating layer The enteric coating layer is applied in one or more layers onto the formulated core material by coating procedures in suitable equipments such as pan coating, coating granulator or fluidized bed apparatus using solutions of polymers in water, or by using latex suspensions of said polymers or optionally using polymer solutions in suitable organic solvents. As enteric coating polymers can be used one or more of the following, for example solutions or dispersions of acrylates (methacrylic acid/methacrylic acid methylester copolymer), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymer(s).

Preferably water-based polymer dispersions such as for example compounds known L ~d, WO 96/01622 PCr/S95/00816 7 under the trade names Aquateric® (FMC Corporation) Eudragit@ (Rbhm Pharma), Aqoat T M (Shin-Etsu Chemical), OpadryT" (Colorcon) or similar compounds are used to obtain enteric coatings. The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer for example cetanol, triacetdn, citric acid esters such as, those known under the trade name Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, polyethylene glycol (PEG) or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-50 of the enteric coating polymer(s). Additives such as talc, colorants and pigments may also be included into the enteric coating layer or sprayed onto the enteric coated material as an overcoat The products identified by the trade names set out immediately above are all included arrmng the chemical names nentioned for enteric coating tmaterial on page 6 above. For instance, Aquateric 4 is based on cellulose acetate phthalate; Eudragit is based on polyrmeric netbacrylates; Aqoat 4 is based on hydraxypropyl methylcellulose acetate succinate; and Cpadry M is based on polyvinyl acetate phthalate.

The thickness of the enteric coating may vary widely without influencing the release rate of omcprazolc. To protect the acid susceptible cmeprazole compound 20 and to obtain an acceptable acid resistance, the enteric coating constitutes at least an amount of 1.0 by weight of the core weight, preferably at least 3.0 and more preferably more than 8.0 The upper amount of the applied enteric coating is normally only limited by processing conditions. This possibility to increase the thickness of the enteric coating without deleterious intluence on the release rate of 25 omeprazole is especially desirable in large scale processes. The enteric coating layer(s) may be applied on the pre-processed formulation without exactly controlling the thickness of the applied coating layer(s).

Thus, the formulation according to the invention consists of core material containing magnesium omeprazole. The core material is coated with enteric coating(s) rendering the dosage form insoluble in acid media, but disintegrating/dissolving in neutral to alkaline media such as, for instance the liquids present in the proximal part of the small intestine, the site where dissolution ,V is wanted.

l~e a WO 96/01622 PCT/SE95/00816 8 Final dosage form The final dosage form is either an enteric coated tablet or capsule or in the case of enteric coated pellets, beads or granules, these pellets, beads or granules are dispensed in hard gelatin capsules or sachets. The final dosage form may further be coated with an additional layer containing pigment(s) and/or colourant(s), It is essential for the long term stability during storage that the water content of the final dosage form containing magnesium omeprazole (enteric coated tablets, capsules, granules, beads or pellets) is kept low.

Process A process for the manufacture of a dosage form according to the present invention represents a further aspect of the invention. After the forming of the core material, said material is coated with enteric coating layer(s). The coating(s) are carried out as described above. Further another aspect of the invention is that the pharmaceutical processes can be completely water-based.

The preparation according to the invention is especially advantageous in reducing gastric acid secretion. It is administered one to several times a day. The typical daily dose of the active substance varies and will depend on various factors such as the individual requirements of the patients, the mode of administration and the disease. In general the daily dose will be in the range of 1-400 mg of omeprazole.

The invention is illustrated in detail by the following examples. Examples 1-2 disclose compositions of different enteric coated tablets containing magnesium omeprazole. Said examples also show the result of a gastric acid resistance test in vitro. Example 3 discloses an enteric coated pellet formulation. Said example also shows the result of a gastric acid resistance test in vitro.

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WO 96/01622 PCT/SE95/00816 9

EXAMPLES

Example 1 Tablet formulation containing magnesium omeprazole being produced as described in W095/01977.

Amount omeprazole Ingredient (mg/tabl) Tablet core Magnesium omeprazole 11.2 Mannitol 68.7 Microcrystalline cellulose 25.0 Sodium starch glycolate Hydroxypropyl methylcellulose Talc Sodium stearyl fumarate Water purified 50.0 Enteric coating layer Methacrylic acid copolymer 9.1 Polyethylene glycol Titanium dioxide 0.82 Colour iron oxide, red-brown 0.04 Colour iron oxide, yellow 0.02 Water purified 45.0 Polish Paraffin powder 0.05 qs~- sb-T- lll WO 96/01622 PCT/SE95/00816 Tablets with the composition described above have been manufactured in a laboratory scale of about 20 000 tablets.

Description of manufacturing Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulcs; and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally mixed with and-adherent and lubricant substances. The milled granulate is compressed to tablets with a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.

Water used in the manufacture of the tablets is removed during subsequent processing.

Investigation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymes, pH 1.2. After six hours the tablets were removed, washed and analysed for omeprazole content using HPLC. The amount of omeprazole is taken as acid resistance.

Tablet Acid resistance Strength (mg) 101 (98 103) Example 2 Tablet formulation containing magnesium omeprazole being produced as described in W095/01977.

Amount omeprazole Ingredient (mg/tabl.) I IIV---Pllg WO 96/01622 PCT/SE95/00816 11 Table core Magnesium omeprazole 45.0 Mannitol 34.9 Microcrystalline cellulose 25.0 Sodium starch glycolate Hydroxypropyl methylcellulose Talc Sodium stearyl fumarate Water purified 50.0 Enteric coating layer Metacrylic acid copolymer 9.1 Polyethylene glycol Titanium dioxide 0.51 Colour iron oxide red-brown 0.43 Water purified 45.0 Polish Paraffin 0.05 Description of manufacturing Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. The milled granulate is compressed to tablets with a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.

Water used in the manufacture of the tablets is removed during subsequent processing.

i -y ~__II WO 96/01622 ?CT/SE95/00816 12 Investidation of acid-resistance Six individual tablets were exposed to artificial gastric fluid without enzymes, pH 1.2. After six hours the tablets were removed, washed and analysed for omeprazole content using HPLC. The amount of omeprazole is taken as acid resistance.

Tablet Acid resistance Strength (mg) 40 95 (92-101) Example 3 Enteric coated pellet formulation containing magnesium omeprazole being produced as described in W095/01977.

Pellet Core Magnesium omeprazole 1.5 kg Non-pareil pellets 1.5 kg Hydroxypropyl methylcellulose 0.23 kg Water purified 4.0 kg Enteric-coating layer Uncoated pellets 500 g Methacrylic acid copolymer 300 g Triethyl citrate 90 g Mono- and diglycerides (NF) 15 g Polysorbate 80 1.5 g Water purified 1290 g WO 96/01622 PCT/SE95/00816 13 Description of manufacturing.

Suspension layering was performed in a fluid bed apparatus. Magnesium omeprazole was sprayed onto inert non-pareil cores from a water suspension containing the dissolved binder. The prepared pellets were enteric-coated in a fluid bed apparatus.

Investigation of acid resistance.

Pellets were added to gastric fluid USP (without enzyme), 37 0 C (paddle) 100 r/min. After 2 hours the actual amount of omeprazole remaining intact in the formulation was determined.

Acid resistance (n=6) Pellets omeprazole mg 94 (93 st

Claims (19)

1. An oral enteric coated formulation containing a core material comprising an active substance coated with one or mrre enteric coating layers characterized in that the core material as active substance contains a magnesium salt of aeprazole having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction and on the core material enteric coating layer(s), and the enteric coating is such that its thickness does not deleteriously influence the release of cnrprazole into aqueous solutions at pH values predcninant. present in the small intestine.

2. A formulation according to claim 1, wherein the formulation is a tablet formulation.

3. A formulation according to claim 1, wherein the formulation is a pellet formulation. i'5

4. A formulation according to claim 1, wherein the enteric coating comprises an enteric coating material, optionally containing one or more pharmaccutically I acceptable plasticizers, dispersants, colorants and pigments.

A formulation according to claim 4, wherein the enteric coating comprises water-based polymer solutions or dispersions of acrylates, hydroxypropyl 20 methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and/or cellulose acetate phthalate.

6. A formulation according to claim 1, wherein the enteric coating constitutes from 1.0 by weight of the weight of the core material.

7. A formulation according to claim 6, wherein the enteric coating constitutes at -fRA least 3.0 by weight of the weight of the core material. I I WO 96/01622 PCT/SE95/00816

8. A formulation according to claim 6, wherein the enteric coating constitutes at least 8.0% by weight of the weight of the core material.

9. A formulation according to claim 1, wherein an additional coating layer is applied as an overcoat on the enteric coated formulatian, which overcoat optionally ccoprises one or more pharmaceutically acceptable plasticizers, dispersants, colorants and pigments.

A process for the manufacture of a formulation according to any one of claims 1 to 9 in which core mat(. rial containing the magnesium cmeprazole is coated with one or more enteric coating layer the anteric coating being such that its thickness does not deleteriously influence the release rate of cmeprazole into aqueous solutions at p{ values predcminantly present in the small intestine.

11. A process according to claim 10 in which the enteric coated formulation is further coated with an overcoat.

12. A formulation when obtained by the process of claim 10 or 11.

13. An oral enteric coated formulation according to any one of claims 1 to 9 and 12, specifically formulated for use in a given field of therapy.

14. An oral enteric coated formulation according to any cne of claims 1 to 9 and 32, formulated for use in inhibiting gastric acid secretion in mammals and nan. *o

15. An oral enteric coated formulation according to any one of claims 1 to 9 and 12, formulated for use in the treatment of gastric acid related diseases in mannals and man.

16. Use of an oral enteric coated foraulation according to any one of claims 1 to 9 and 12, in the manufacture of a medicament, said S p medicanent being suitable specifically for inhibiting gastric acid 6 u) I secretion in mnamals and man. /TO WO 96/01622 PCT/SE95/00816 16

17. Use of an oral enteric coated fornulation according to any one of claims 1 to 9 and 12, in the manufacture of a medicament, said medicanment being suitable specifically for treatment of gastric acid related diseases in rramnals and man.

18. A press-through blister package cxxprising a forrlation according to any one of claims 1 to 9 and 12.

19. A rmethod for inhibiting gastric acid secretion in mawrals and man by administering to a host in need thereof, a therapeutically effective dose of an enteric coated fornualation according to any one of claims 1 to 9 and 12. A metod for the treatment of gastric acid related diseases in mamals and man by adinistering to a bst in need thereof, a therapeutically effective dose of an enteric coated fornulaticn according to any one of claims 1 to 9 and 12. DATED this 10th day of July 1998 ASIRA ARTITEBOLAGG, By its Patent Attorneys, E. F. WELLINGIN CD., By: S (Bruce Wellingta) A S A/KA/4471 r as INTERNATIONAL SEARCH REPORT International application No. PCT/SE 95/00816 A. CLASSIFICATION OF SUBJECT MATTER IPC6: A61K 9/24 A61K 9/52, A61K 31/44 According to Internationa Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC6: A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched SE,DK,FI,NO classes as above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) WPI, WPIL, CLAIMS, EMBASE, MEDLINE, CA C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P,X WO 9501783 Al (ASTRA AKTIEBOLAG), 19 January 1995 1-16,19 (19.01.95) P,A WO 9501977 Al (ASTRA AKTIEBOLAG), 19 January 1995 1-16,19 (19.01.95) A EP 0342522 Al (EISAI CO., LTD.), 23 November 1989 1-16,19 (23.11.89) A EP 0247983 A2 (AKTIEBOLAGET HASSLE), 1-16,19 2 December 1987 (02.12.87) D Further documents are listed in the continuation of Box C. j See patent family annex. Special categories of cited documents: later document published after the international filing date or priority e l date and not in conflict with the application but cited to understand document d.fiing the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance E eriter document but published on or after the international filing date document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive L' document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance: the claimed invention cannot be "0 document referring to an oral disclosure, use, exhibition or other considered to involve an inventiv step when the document is means combined with one or more other such documents, such combination meansbeing obviou to a person iled in the art document published prior to the international filing date but later than being obvious to a person skilled in the art the pnonty date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 06 -11- 1995 October 1995 Name and mailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Anneli Jnsson Facsimile No. +46 8 666 02 86 Telephone No. +46 8 782 25 00 Form PCT/ISA/210 (second sheet) (July 1992) INTERNATI ONAL SEARCH REPORT International application No. PCT/SE 95/00816 Box I Observations where certain claims were found unsearchable (Continuation of Item 1 of first sheet) This international search report has not been established in respectofcertain claims under A-ticle 17(2)(a) for the following reasons: 1. Claims Nos.: 17-18 because they relate to subject matter not required to be searched by this Authority, namely: See PCT Rule 39.1(iv): Methods for treatment of the human or animal body by surgery or therapy, as well as diagnostic methods. 2. Claims Nos.: because they relate to parts ofthe international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. O Claims Nos.: Sbecause they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention Is lacking (Continuation of Item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searched without effortjustifying an additional fee, this Authority did not invite payment of any additional fee. 3. F1 As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. j No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest The additional search fees were accompanied by the applicant's protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISAI210 (continuation of first sheet (July 1992) Form PCTASA12Z10 (continuaion of first sheet (July 1992) i INTERNATIONAL SEARCH REPORT International application No. Information on patent family membersPC/E9081 Patent document Publication Patent family Publication cited in search report dateI member(s) date WO-Al- 9501783 19/01/95 NONE WO-Al- 9501977 19/01/95 NONE EP-Al- 0342522 23/11/89 SE-T3- 0342522 DE-U- 6890056 30/01/92 ES-T- 2051919 01/07/94 FI-B,C- 93422 30/12/94 JP-A- 1290628 22/11/89 US-A- 5035899 30/07/91 EP-A2- 0247983 02/12/87 SE-T3- 0247983 AU-B,B- 601974 27/09/90 AU-A- 7191287 05/11/87 CA-A- 1292693 03/12/91 DE-A- 3783394 18/02/93 OK-B- 169988 24/04/95 EP-A,A,A 0496437 29/07/92 EP-A,A- 0567201 27/10/93 ES-T- 2006457 01/01/94 GB-A- 2189698 04/11/87 IlK-A- 135294 09/12/94 IE-B- 61416 02/11/94 JP-C- 1863556 08/08/94 JP-A- 5294831 09/11/93 JP-A- 62258320 lq'71/87 NO-B,C- 174239 V"I-1 SG-A- 154294 1 r SU-A- 1820837 3. 3 US-A- 4786505 22/11/88 Form PCT/isAJim (patent family annex) (July 1992)