US3459858A - Chewable tablets of antibacterial agents - Google Patents

Chewable tablets of antibacterial agents Download PDF

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Publication number
US3459858A
US3459858A US665297A US3459858DA US3459858A US 3459858 A US3459858 A US 3459858A US 665297 A US665297 A US 665297A US 3459858D A US3459858D A US 3459858DA US 3459858 A US3459858 A US 3459858A
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tablets
tetracycline
sodium
dicloxacillin
hetacillin
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US665297A
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Alphonse P Granatek
Michael P De Murio
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Bristol Myers Co
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Bristol Myers Co
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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • U.S. Cl. 424227 Claims ABSTRACT OF THE DISCLOSURE pleasant tasting, chewable tablets of certain antibacterial agents such as amplicillin are prepared by the use in the formulation of both mannitol and solid polyethylene glycol, e.g. about 300 mgm. mannitol and 1.0 to mgm. Carbowax 6000 per tablet.
  • This invention relates to therapeutic, antibacterial compositions suitable for oral administration. More particularly, this invention relates to certain chewable tablets containing ampicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin or dicloxacillin and also containing both mannitol and solid polyethylene glycol.
  • Chewable tablets containing mannitol are well-known, as illustrated by U.S. Patent 3,145,146 to Lieberman et al. and Erythrocin chewable tablets marketed by Abbott Laboratories. Tablets containing solid polyethylene glycol, but not also mannitol, have been disclosed, as by Cooper et al. in U.S. Patent 2,857,313 and by Gakenheimer in U.S. Patent 2,540,253.
  • a medicament such as the antibacterial agents of the present invention, that is, et-aminobenzylpenicillin (also called ampicillin), hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloxacillin. Therefore it is desirable to provide the medicament in the form of a chewable tablet.
  • the antibacterial agent cannot simply be combined with a conventional binder to form a pleasant tasting chewable tablet.
  • a chewable therapeutic tablet comprising from about 0.0625 to 0.250 gm. of an antibacterial agent selected from the group consisting of a-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloxacillin, from about 0.300 to 0.400 mg. of mannitol and from about 0.001 to 0.020 gm.
  • an antibacterial agent selected from the group consisting of a-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloxacillin
  • oxacillin cloxacillin and dicloxacillin include the free acid forms and the nontoxic, pharmaceutically acceptable cationic salts of those penicillins.
  • the preparation and properties thereof have been described, inter alia, in US. Patents 2,996,501, 3,239,507 and 3,317,389.
  • Ampicillin is the generic name for D-()-a-aminobenzylpenicillin.
  • ampicillin includes the free acid (i.e. amphoteric) form, the anionic salts with acids such as hydrochloric acid, the cationic salts with bases such as sodium hydroxide and the hydrates of that penicillin.
  • Their preparation and properties have been described, inter alia, in U.S. Patents 2,985,648, 3,140,282, 3,144,445 and 3,157,640 and in an application of our colleagues Herbert H. Silvestri and David A. Johnson filed Oct. 29, 1962 as U.S. Ser. No. 233,943 and issued Apr. 27, 1965 as U.S. Patent 3,180,862.
  • Hetacillin is the generic name for 6-(2,2-dimethyl-5- oxo-4-phenyl-l-imidazolidinyl)penicillanic acid which has the structure
  • the term hetacillin includes the free acid illustrated above and its nontoxic, pharmaceutically acceptable cationic salts of the acidic carboxylic acid group and its nontoxic, pharmaceutically acceptable acid addition anionic salts (i.e., salts of the basic nitrogen).
  • Their preparation and properties are described in Belgian Patent 642,851 and in an application of our colleagues David A. Johnson and Charles A. Panetta filed Jan. 6, 1965, as U.S. Ser. No. 423,677 and issued Aug. 3, 1965, as U.S. Patent 3,198,804.
  • tetracycline as used herein includes tetracycline in any of its forms such as the amphoteric compound, hydrates, acid addition salts, alkali metal salts, alkaline earth metal salts, other metal salts, salts with ammonia or amines, chelates, double salts and complexes.
  • the preferred forms of tetracycline are amphoteric tetracycline, tetracycline hydrochloride and the tetracycline sodium hexametaphosphate complex described in U.S. Patent No. 2,791,609.
  • salts which are effective include metal salts such as sodium, potassium, calcium, aluminum, magnesium, zirconium and the like and normal organic and inorganic acid addition salts such as the bromide, sulfate, nitrate, orthophosphate, acetate, tartrate, citrate and the like. Use may also be made in the present invention of other physiologically active tetracycline products such as rapidly hydrolyzed esters, chelates and complexes.
  • the chewable tablets of this invention may be formed according to the following technique.
  • the antibacterial agent and mannitai (and, if desired, glycine and sodium cyclamate) are mixed together in a blender.
  • sodium saccharin and flavor concentrates are blended separately, added to the main mixture and the composition is blended for minutes.
  • the mixture is micropulverized and one-third of the magnesium stearate and one-half of the solid polyethylene glycol, e.g. Carbowax 6000 are added to the pulverized mixture.
  • the mixture is blended minutes and compacted by slugging.
  • the compacted material is milled and screened to separate the to mesh granules.
  • the fines and granules larger than 20 mesh are collected and compacted by slugging, milled and again screened to remove the 20 to 40 mesh granules. This process is repeated until the total amount of fines is less than 15%. Additional magnesium stearate (one-third of the total amount) and the remaining solid polyethylene glycol should be added to the second slugging process to prevent binding. The remaining magnesium stearate is added to the granules and the mixture is blended for 15 minutes. It is then tabletted.
  • oxacillin cloxacillin, dicloxacillin or a form of tetracycline which has previously been coated as by spray-drying with a mixture of ethyl cellulose and spermaceti wax as illustrated by the following procedure I (which does not form part of the present invention) for preparing coated sodium dicloxacillin:
  • MANUFACTURING INSTRUCTIONS (1) Dissolve the spermaceti wax in approximately 8 liters of methylene chloride. The operation is carried out in a 20 liter glass container with the aid of a mixer (e.g. a Lightning mixer). No heat is required.
  • a mixer e.g. a Lightning mixer
  • step #1 To the clear solution obtained in step #1, add the ethyl cellulose in small portions while maintaining agitation. Stir until a clear and relatively viscous solution is obtained.
  • the inlet air gauge will read-115-120 C.
  • the outlet air gauge will read-55 C.
  • the tablets of this invention are especially useful for pediatric use i.e., for the administration of the specified antibacterial agents, e.g. a-aminobenzylpenicillin, to young children who are unable or refuse to swallow regular tablets.
  • the tablets of this invention offer all of the established therapeutic benefits of other oral preparations of the specified antibacterial agents, e.g. a-aminobenzylpenicillin.
  • they may be used for the control of infections due to the specified antibacterial agents, e.g. otaminobenzylpenicillin, sensitive organisms such as respiratory tract, genitourinary tract, and gastrointestinal tract infections.
  • the ot-aminobenzylpenicillin, hetacillin and tetracycline tablets of this invention are effective against gram-positive as well as many gram-negative organisms; and the oxacillin, dicloxacillin and cloxacillin tablets are particularly effective against gram-positive bacteria, including especially those resistant to benzylpenicillin.
  • the tablets are administered in the same dosages as other oral preparations of the specified antibacterial agents, e.g. ozaminobenzylpenicillin.
  • the tablets may be administered to provide daily about 50 mg. a-aminobenzylpenicillin or cloxacillin or oxacillin (or 25 mg. of the tetracycline or of hetacillin or 12.5 mg. of dicloxacillin) per kg. of body weight per day given in three or four divided doses; in particularly severe infections this dosage is doubled.
  • Example 1 Into a suitable blender there are placed tz-aminobenzylpenicillin trihydrate (160 parts by weight), mannitol (350 parts by weight), glycine parts by weight), and sodium cyclamate (75 parts by weight) and the mixture is blended for about 15 minutes. Sodium saccharin (7.5 parts by weight) and dry flavoring agents (1.80 parts by weight) are blended separately for 15 minutes and added to the foregoing mixture. The composition is then mixed for 10 minutes following which it is micropulverized in a mill.
  • Magnesium stearate (4 parts by weight) and Carbowax 6000, a polyethylene glycol having an average molecular weight of 6000 to 7500 (1 part by weight) are added to the pulverized composition and the mixture is blended for 15 minutes.
  • the blended mixture is then compacted by slugging and the compacted material is reduced to particulate form by passing it through a mill.
  • the mixture is then screened to remove the 20 to 40 mesh granules.
  • the fines and the granules larger than 20 mesh are compacted, milled and again screened to collect the 20 to 40 mesh granules. This process is repeated until the amount of fines is reduced to less than 15%.
  • magnesium stearate (4 parts by weight) and Carbowax 6000 (1 part by weight) are added to the granules, at least 85% of which are 20 to 40 mesh, and the mixture is blended 15 minutes and then formed into one-half inch flat, beveled tablets.
  • the hardness of the tablets as determined on a Strong-Cobb-Arner hardness tester, is between to kgs.
  • Each tablet contains the following amounts of ingredients:
  • the resultant tablets have a pleasant taste and are easily ingested by children.
  • Example 2 In a blender there are mixed for 15 minutes tetracycline hexametaphosphate, mannitol, sodium saccharin, dry flavor, sodium cyclamate and glycine. There is then added a mixture of flavors and dissolved in methylene chloride. This entire mixture is blended for another 15 minutes and is then micropulverized in a mill. The micropulverized mixture is placed in a blender and suflicient methylene chloride is added to form a uniform moist granulation. The wet granulation is passed through a granulating machine and dried overnight at room temperature. The dried granulation is pulverized in a mill and magnesium stearate is added. The mixture is blended for 15 minutes and compacted by slugging.
  • the compacted material is then passed through a mill to reduce the particle size.
  • the granular material is screened to separate the -40 mesh granules.
  • the fines and the granules larger than 20 mesh are compacted and again reduced in size and screened to collect the 20-40 mesh granules. This process is repeated until the fines are less than 15% of the total composition.
  • the 20-40 mesh granules and remaining fines are placed in a blender and magnesium stearate and Carbowax 6000 (a polyethylene glycol having an average molecular weight of 6000 to 7500) are added.
  • the mixture is blended for 15 minutes and put through a tabletting machine.
  • the resultant tablets have a hardness as determined on a Strong- Cobb-Arner hardness tester, of 8 to 10 kgs.
  • Each tablet contains the following amounts of ingredients:
  • the resultant tablets have a pleasant taste and are easily ingested by children.
  • Example 3 In the manner of Example 1, chewable hetacillin tablets are prepared containing in each tablet the following amounts of ingredients:
  • Example 4 In the manner of Example 1, four lots of chewable tablets are produced in which the a-aminobenzylpenicillin is replaced, on a per tablet basis, with mgm. sodium oxacillin, 125 mgm. sodium cloxacillin and 62.5 and 125 mgm. sodium dicloxacillin, respectively, which has been previously coated as described above.
  • the examples above illustrate the use of a single antibacterial agent in the tablets of the present invention but the invention is not limited thereto.
  • the glycine in the formulations given above can be replaced by a therapeutic dosage of a second antibacterial agent to provide, for example, an antibacterial composition comprising a mixture of about one to two parts by weight of hetacillin or ampicillin with one part by weight of dicloxacillin.
  • antibacterial agents such as antihistamines, sulfa drugs (e.g. sulfadiazine, sulfabenzamide, sulfacetamide, sulfanilamide, sulfapyridine, sulfathiazole, sulfapyrazine, sulfaguanidine, sulfathalidine, sulfasuxidine, sulfisoxazole, sulfamylon, phthalysulfacetamide, N'-3,4-dimethylbenzoylsulfanilamide, benzylsulfanilamide and N-2-(2- quinoxalyl)sulfanilamide), lipotropic agents (particularly methionine, choline, inositol and beta-sitosterol and mixtures thereof), stimulants of the central nervous system (e.g.
  • sulfa drugs e.g. sulfadiazine, sulfabenzamide, sul
  • analgesics e.g. aspirin, salicylamide, sodium gentisate', p-acetylaminophen01, phenacetin, codeine
  • laxatives e.g. phenolphthalein
  • sedatives e.g. barbiturates, bromides
  • salts of penicillin e.g. potassium penicillin G, procaine penicillin G, l-ephenamine penicillin G, dibenzylamine penicillin G, other salts disclosed by US. Patent 2,627,491; these combinations are particularly useful to enable variation of the pattern of blood levels obtained), phenoxymethylpenicillin and salts thereof, other antibiotic agents (e.g.
  • streptomycin dihydrostreptomycin, bacitracin, polymixin, tyrothricin, erythromycin, Aueromycin, Terramycin, oleandomycin, chlora-mphenicol, magnamycin, novobiocin, cycloserine; in some cases such combinations attack a wider range of organisms or show synergistic eificacy or provide decreased toxicity with equal eflicacy), vitamins (e.g. vitamins A, A B B B B and members of that family, folic acid and members of that family, vitamins C, D D and E), hormones (e.g. cortisone, hydrocortisone 9oz.
  • vitamins e.g. vitamins A, A B B B B and members of that family, folic acid and members of that family, vitamins C, D D and E
  • hormones e.g. cortisone, hydrocortisone 9oz.
  • fluorocortisone 9m fluorohydrocortisone, prednisone and prednisolone
  • anabolic agents e.g. 11, 17-dihYdI'OXY-9tX-fill01'0-17'0C-methy1 4 androsten 3- one; 17a-ethyl-19-nortestosterone
  • antifungal agents e.g. mycostatin
  • hetacillin free acid is taken as the standard with an activity of 1000 mcg./mgm. and when other salts are used, the weight taken is that which gives an equivalent amount of activity, i.e., 1096 mgms. of potassium hetacillin are equivalent in activity to 1000 mgms. of hetacillin free acid.
  • the relationship is stoichiometric.
  • arnpicillin in the standard with an activity of 1000 meg/mgm. is anhydrous ampicillin and thus ampicillin trihydrate has a potency of 865 mcg./mgm.
  • the standard is the free acid with an activity of 1000 mcg./mgm. and thus the sodium salt is 920 mcg./mgm.
  • a chewable therapeutic tablet comprising from about 0.0625 to 0.250 gm. of an antibacterial agent selected from the group consisting of a-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloxacillin, from about 0.300 to 0.400 gm. of mannitol and from about 0.001 to 0.020 gm. of solid polyethylene glycol.
  • an antibacterial agent selected from the group consisting of a-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloxacillin, from about 0.300 to 0.400 gm. of mannitol and from about 0.001 to 0.020 gm. of solid polyethylene glycol.
  • a chewable therapeutic tablet comprising from about 0.0625 to 0.250 gm. of an antibacterial agent selected from the group consisting of u-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloracillan, from about 0.300 to 0.400 gm. of mannitol and from about 0.001 to 0.020 of solid polyethylene glycol having an average molecular weight in the range of 6000 to 7500.
  • an antibacterial agent selected from the group consisting of u-aminobenzylpenicillin, hetacillin, a form of tetracycline, oxacillin, cloxacillin and dicloracillan, from about 0.300 to 0.400 gm. of mannitol and from about 0.001 to 0.020 of solid polyethylene glycol having an average molecular weight in the range of 6000 to 7500.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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US665297A 1964-05-20 1967-09-05 Chewable tablets of antibacterial agents Expired - Lifetime US3459858A (en)

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US36899164A 1964-05-20 1964-05-20
US66529767A 1967-09-05 1967-09-05

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3692896A (en) * 1968-06-14 1972-09-19 Isumura Juntendo Co Ltd Process for the preparation of water-soluble tablets
FR2200006A1 (de) * 1972-09-25 1974-04-19 Warner Lambert Co
WO1988009173A1 (en) * 1987-05-27 1988-12-01 Akzo N.V. DRY, RAPIDLY SOLUBLE, COMPOSITIONS OF beta-LACTAM ANTIBIOTICS
US20050019396A1 (en) * 2003-07-25 2005-01-27 Galen (Chemicals) Limited Doxycycline metal complex in a solid dosage form

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8909793D0 (en) * 1989-04-28 1989-06-14 Beecham Group Plc Pharmaceutical formulation
JP5256425B2 (ja) * 2005-04-08 2013-08-07 リングアル コンセグナ ピーティーワイ エルティーディー 口腔送達システム

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3145146A (en) * 1961-10-31 1964-08-18 Warner Lambert Pharmaceutical Modified mannitol for pharmaceutical tablets

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3145146A (en) * 1961-10-31 1964-08-18 Warner Lambert Pharmaceutical Modified mannitol for pharmaceutical tablets

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3692896A (en) * 1968-06-14 1972-09-19 Isumura Juntendo Co Ltd Process for the preparation of water-soluble tablets
FR2200006A1 (de) * 1972-09-25 1974-04-19 Warner Lambert Co
WO1988009173A1 (en) * 1987-05-27 1988-12-01 Akzo N.V. DRY, RAPIDLY SOLUBLE, COMPOSITIONS OF beta-LACTAM ANTIBIOTICS
EP0293975A1 (de) * 1987-05-27 1988-12-07 Akzo N.V. Trockene schnell lösliche Zusammensetzung von beta-Lactam-Antibiotika
JPH02500591A (ja) * 1987-05-27 1990-03-01 アクゾ・エヌ・ヴエー β‐ラクタム抗生物質の乾燥した急速溶解性の組成物
US20050019396A1 (en) * 2003-07-25 2005-01-27 Galen (Chemicals) Limited Doxycycline metal complex in a solid dosage form
US7485319B2 (en) * 2003-07-25 2009-02-03 Warner Chilcott Company, Inc. Doxycycline metal complex in a solid dosage form
US20110171299A1 (en) * 2003-07-25 2011-07-14 Warner Chilcott Company, Inc. Doxycycline metal complex in a solid dosage form
US8415331B2 (en) 2003-07-25 2013-04-09 Warner Chilcott Company, Llc Doxycycline metal complex in a solid dosage form

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SU380002A3 (de) 1973-04-20
AT282060B (de) 1970-06-10
GB1248189A (en) 1971-09-29
GB1113492A (en) 1968-05-15

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