US3384544A - Injectable solutions or suspensions of antigens in optically clear colloidal solutions - Google Patents

Injectable solutions or suspensions of antigens in optically clear colloidal solutions Download PDF

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Publication number
US3384544A
US3384544A US642727A US64272767A US3384544A US 3384544 A US3384544 A US 3384544A US 642727 A US642727 A US 642727A US 64272767 A US64272767 A US 64272767A US 3384544 A US3384544 A US 3384544A
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Prior art keywords
tween
solution
solutions
toxoid
water
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US642727A
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Clive A Walton
Clarence L J Coles
Ernst L Neustadter
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Glaxo Laboratories Ltd
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Glaxo Laboratories Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • injectable compositions for veterinary or human medicine in which an antigen is dissolved or suspended in a particular type of vehicle.
  • This vehicle comprises a physiologically acceptable lipophilic dispersion medium, water and at least one physiologically acceptable nonionic surface active substance. It exists in the form of an optically clear colloidal solution in which the aggregates of water and surface active substance are of a size Within the range of 50-800 A. and the ratio of water to surface active substance is within the range of 1:1 to 1:10.
  • the water content of the composition is within the range of 0.522.5% by weight.
  • This invention concerns a novel type of injectable composition of use in medicine and incorporating one or more high-molecular weight physiologically active substances.
  • the present invention is particularly concerned with the problem of formulating high molecular weight, hydrophilic, oil-insoluble physiologically active substances such as bacterial toxoids and other antigens in an oily medium without losing the desired physiological activity and without encountering the above-described difficulties associated with the use of emulsions.
  • optically clear solutions of non-ionic amphiphilic surface active material and Water in a physiologically acceptable lipophilic dispersion medium have the remarkable property of holding in solution a wide variety of high molecular weight hydrophilic substances such as antigens, polysaccharides, nucleic acids, etc., and of releasing such physiologically active substances on injection.
  • Such media are also particularly advantageous as delayed release vehicles for insoluble antigens such as living or dead micro-organisms.
  • compositions consisting of or containing water in solution in a physiologically acceptable lipophilic dispersion medium, which is liquid at body temperature, by means of one or more non-ionic, amphiphilic, physiologically acceptable surface active substances, said water having dissolved or suspended therein one or more physiologically-active micro-organisms and/or physiologically active high molecular weight hydrophilic oil-insoluble materials.
  • solution is used herein to indicate a system in which the water is held by the surface-active material in a continuous lipophilic dispersion medium and that the resulting systems are virtually optically clear when viewed by transmitted light, as distinct from emulsions or suspensions which are cloudy or opaque, unless additional components such as thickening agents are added which themselves lend opacity to the solutions.
  • Optically clear solutions of the kind utilised in the present invention include all colloidal solutions wherein the aggregates of water and surface-active materials are of a diameter below about 800 A. and thus no longer cause appreciable opacity to visible light.
  • the size range of the aggregates is thus approximately 50-800 A.; above about A. within this range the solutions are sometimes termed microemulsions. This is in contradistinction to normal or macroemulsions wherein the droplet size is of the order of 2,000 A.
  • the conditions required for formation of solutions are such that the resulting aggregates are thermodynamically stable, in contrast to macroemulsions which are necessarily thermodynamically unstable, even though the equilibrium conditions of phase separation may be greatly delayed (L. I. Osipow, J. Soc. Cosmetic Chem. 1963 14, 277-288; L. M. Prince, J. Colloid and Interface Science, 23, -173).
  • the physiologically active material may itself be solubilised in the above sense to give a clear solution or may remain in suspension; micro-organisms of course will always he in suspension. Even suspensions of the above kind may sometimes be virtually optically clear in transmitted light if the refractive index of the organisms is close to that of the mediuml
  • the new compositions being in general optically clear solutions, are not only more elegant in appearance than emulsions or suspensions but have manufacturing advantages. They are far easier to sterilise because filtration methods may be employed and the preparations are, in general, more stable to transport vibration and temperature fluctuation on storage. They may be readily produced by simply mixing the components without energetic homogenisation which could in somecases be detrimental to the physiologically active substances. These factors are of considerable economic value.
  • the solutions can be prepared to have viscosity levels permitting easy handling and injection.
  • compositions according to this invention may be held in the compositions according to this invention and substantially non-viscous compositions, suitable for injection through a narrow bore needle, may be prepared quite simply, without the need for expensive equipment for particle size reduction and control in the case of suspensions, or homogenising machinery in the case of emulsions, which processes are diflicult to control.
  • thicker compositions may be obtained if required, by varying the nature of the wetting agent and lipophilic dispersion medium.
  • compositions according to the invention may thus include one or more physiologically active high molecular weight susbtances.
  • These substances will preferably be non-dialysable, their molecular weight being preferably above 1,000, and they include, for example, antigenic substances, e.g., bacterial toxoids, etc., proteins, polysaccharides, nucleic acids, etc.
  • antigenic substances e.g., bacterial toxoids, etc.
  • proteins e.g., proteins, polysaccharides, nucleic acids, etc.
  • the microorganisms which may be present can be, for example, living or dead bacteria or viruses.
  • veterinary field for example, in the veterinary field,
  • hydrophilic oil-insoluble substances that can be dissolved in the compositions according to this invention will depend in each case on the components that are present, especially the surface-active components.
  • amphiphilic surface liquidisers include physiologically acceptable fatty acid aldehydes, ketones and, in particular, amphiphilic alcohols, for example mono, dior polyhydric alcohols having 3-10 carbon atoms, e.g., n-decanol, 2-ethyl-hexane-l,3-di0l, 4-methyl-cyclohexanol, etc.
  • the weight ratio of added surface liquidiser to total amphiphilic material advantageously employed to obtain transparent stable solutions is strongly dependent on the temperature range over which clarity is required. The amount is also dependent on the nature of the oil and other amphiphilic surface-active agents employed. In our preferred mixtures We have found the percentage by weight of surface liquidiser based on the total amphiphilic material for clarity at body temperature advantageously to be 40%, preferably from 025%. It may be noted that the minimum quantity of amphiphilic surface-active material required to produce a clear solution may often be lower when a surface liquidiser is present.
  • the new vehicle used in the compositions according to the invention is optically clear and is capable of holding considerable quantities of hydrophilic substances in a clear solution in oil.
  • Such solutions may readily be prepared in a thin non-viscous form suitable for injection in contrast to the conventional waterin-oil emulsions which are usually too thick to be easily injected.
  • thicker solutions may be obtained.
  • the lipophilic dispersion medium may, for example, be an oil which is liquid at body temperature.
  • the lipophilic component is preferably liquid at 35 (3., more preferably at room temperature and below, to facilitate handling of injectable preparations.
  • Triton X 100 Polyoxyethylene (10) octyl pheno fatty acid esters or mixtures thereof such as tridecyl myristate, n-octyl oleate or vegetable oils such as coconut oil.
  • the surface active material When the lipophilic material is an ester or a straight or branched chain aliphatic hydrocarbon, such as paraffin oil or squalane, the surface active material preferably possesses an H.L.B. (hydrophile-lipophile balance) value in the range 7 to 12, advantageously between 8 and 11, the optimal value being between 8.5 and 10. It should be noted that where a mixture of surface active agents is used, it is the H.L.B. value of the mixture which should fall within the above range.
  • H.L.B. hydrophile-lipophile balance
  • the preferred surface active agents fall in the follow ing four classes:
  • Fatty acid esters of sugar alcohol anhydrides for example of sorbitan or mannitan.
  • Fatty acid moieties in such substances include oleate, stearate, laurate residues etc.
  • Soroitan mono-oleate and mannitan mono-oleate are especially useful and mannitan mono-oleate is obtainable in a. specially purified grade widely used in injectable preparations.
  • Commercial products of this class include Arlacel A (mannitan mono-oleate), Arlacel 8O (sorbitan mono-oleate) and Arlacel 2O (sorbitan mono-laurate).
  • Polyoxyethylene sorbitan mono-oleate and monolaurate are particularly useful.
  • Commercial products of this class include Tween (polyoxyethylene (20) sorbitan mono-oleate), Tween 20 (polyoxyethylene (20) sorbitan mono-laurate), Tween 81 (polyoxyethylene (5) sorbitan mono-oleate), Tween 85 (polyoxyethylene (20) sorbitan trioleate), Tween 61 (polyoxyethylene (4) sorbitan mono-stearate) and Tween 65 (polyoxyethylene (20) sorbitan tristearate).
  • the numerical values given in parentheses in the nomenclature for the above products refers to the approximate number of oxyethylene units. The products are, in fact, always mixtures and this figure merely represents the average chain length.
  • the surface active material and the lipophilic material must be compatible with the biologically active component.
  • compositions according to the invention may, if
  • H.L.B. values of these surface can in some cases be modified by heating to relatively active combinations are all about 10. 30 high temperatures, for example above 40 C., whereby As indicated previously, the preferred HLB. values water separates out to give a turbid appearance. It is prestated above are those which apply when the lipophilic ferred, therefore, that the compositions remain clear on medium is a straight or branched chain hydrocarbon and, heating to at least body temperature. It should be borne especially, paraifin oil or squalane. Where other lipophilic in mind that some animals have a relatively high body media are selected, the optimal H.L.B. values will differ temperature, for example the body temperature of sheep although they can readily be ascertained by experiment. is normally around C.
  • the percentage of water in the compositions may vary
  • the new compositions according to the invention are widely and up to about 22.5% water can be incorporated intended for pharmaceutical and veterinary use.
  • the virin oils such as liquid parafiin while still maintaining a tually clear compositions according to the invention in adclear solution.
  • the association of a large 40 dition to the physical advantages described above have quantity of water with the physiologically active material also shown surprisingly marked adjuvant effects on the may not be necessary and as little as 0.5 water or even properties of the active material. Thus, for example, in less may be present.
  • the high molecular weight the case of Cl.
  • the height component is difficult to obtain in concentrated aqueous of the antibody response was increased in our experiments solution, as is often the case with bacterial toxoids and by a factor of ten and the duration of protection was also particularly where a mixture of several toxoids is reincrease-d.
  • the percentage of water should and indeed human vaccines, it is important that the durabe, for example 10 to 15% with Tween 81 as surfactant. tion of protection be as long as possible and if the num- Such percentages can be obtained by using relatively large her of injections necessary to give protection can be miniquantities of surface active agent.
  • centage of water be kept relatively low, for example in that the increased effectiveness of the active material is the range 0.5% to 7%, more preferably between 2.5% and due to delayed release from the lipophilic medium. 6.0%, so that the amount of surface active agent present
  • active agent is preferably in the range 1:1 to 1:10, advantageously 1:4 to 1:7, for example about 1:5.
  • compositions of the invention may be prepared in of a P y Of 4,500 -f m1 1.45 a number of ways.
  • Puremor extract llght Whlte P a n Oil
  • volthe surface active agent may be dissolved in the oil and for 100 the aqueous material to be added thereto, preferably slow- M thod of preparation ly. It is also possible to mix the aqueous components with the hydrophobic phase and to add surface active material to produce solubilisation.
  • the surface active agent may 70 (1) A solution of 10 grams of Arlacel 80 in sufiicient Puremor to produce 191 ml. was sterilised by passage through a Millipore membrane filter.
  • Tween 20 was sterilised by autoclaving at 10 p.s.i. hydrophobic 'P mixed Subsequently therewith one (3) Tween 20 (3.25 ml.) was aseptically measured into further methOdis especially useflllwhefe the Physiological 95.5 ml. of sterile Arlacel 80 solution, and the toxoid ly active material is available only in dilute solution, namesolution added. The mixture was stirred until homogeneous ly to prepare an emulsion of the aqueous and hydroand packed.
  • Clostridium welchii type D purified formol toxoid solution containing 4,000 Lf/ml. v./v Puremor extra light white parafiin oil, to
  • Method of preparation (1) 15.0 grams of Tween 81 was dissolved in sufficient Puremor to produce 148 ml. of solution. This solution was sterilised by passage through a sterile Millipore membrane filter.
  • Triton X-100 was sterilised by autoclaving at 10 p.s.i.
  • Triton X-100 was mixed aseptically with 50 ml. Triton X-l5 solution. The toxoid was added and the product made to 100 ml. with sterile Puremor.
  • Method of preparation A mixture of toxoids to the proportions shown were freeze dried, and reconstituted in water for injection to produce 5 ml. of antigen solution per ml. of vaccine.
  • EXAMPLE 8 Percent Tween 81 w./v 15.0 Brucella abortus strain 45/20, packed cells w./v 5.0 Thixin-R w./v 1.0 Puremor, to by volume 100 Method of preparation (1) The packed cells (which contain approximately 50% water) were dispersed thoroughly in sterile Tween 81.
  • Tween 80 and Tween 81 were autoclaved at 10 p.s.i. for 30 min. to sterilise.
  • EXAMPLE 10 Formula: Percent Infectious Bronchitis virus suspension v./v 20 Tween 81 1 w./v 20 Puremor to by volume 100 1 sterilised by filtration.
  • Vacuum approximately 28 inches of mercury, was applied to the system, and water at 27 C. circulated through the jacket. Water was condensed from the system, stirring continually, until the product was clear. The product was made to 5 ml. with Puremor.
  • the moisture content of the product was measured as 11.7 percent w./w.
  • Tetanus vaccine Percent Tween 80 W./v 2.0 Tween 81 w./v 18.0 Clostridium tetani purified formol toxoid solution at 150 Lf/ml. v./v 5.0 Puremor, to 100.0
  • Tween 81 and 4 g. of Tween 80 were dissolved in sufficient Puremor to produce 190 mls. of solution. This solution was sterilised by passage through a sterile Millipore membrane filter.
  • EXAMPLE 13 Pertussis vaccine: Percent Tween 81 w./v 20.0 Cell suspension containing 200x B. Pertussis organisms/ml. v./v 5.0 Puremor, to 100.0
  • EXAMPLE 14 Tween 60 (polyoxyethylene sorbitan monostearate) g 10 Arlacel 8O (sorbitan monoleate) g 10 2-ethy1-1,3-hexanediol g 4.8 Mixture of suitable solutions to contain, for each ml.
  • An injecta'ble composition comprising a parenterally effective quantity of at least one physiologically active antigenic substance dissolved in a liquid vehicle consisting essentially of an optically clear colloidal solution containing a physiologically acceptable lipophilic dispersion medium liquid at 35 C. selected from the group consisting of aliphatic hydrocarbons and long chain fatty acid esters, water and :at least one physiologically acceptable non-ionic amphiphilic surface active substance, the aggregates of Water and surface active substance having a size range between 50-800 A., the ratio of water to surface active substance being within the range of 1:1 to 1:10, and said composition containing from 0.5-22.5% by weight of water.
  • composition -as claimed in claim 1 which contains microorganisms in suspension as an antigenic substance.
  • composition as claimed in claim '1 in which said lipophilic dispersion medium is a hydrocarbon selected from the group consisting of aliphatic and cycloaliphatic hydrocarbons.
  • composition as claimed in claim 5 in which the hydrocarbon is a member selected from the group consisting of purified paraflin oil and squalane.
  • composition .as claimed in claim 10 in which said surface active substance is polyoxyethylene (5) sorbitan mono-oleate.
  • a composition as claimed in claim 15 in which said amphiphilic substance of shorter chain length is an alcohol selected from the group consisting of monohydric, dihydric and polyhydric alcohols, said alcohol having 3-110 carbon atoms.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
US642727A 1966-06-08 1967-06-01 Injectable solutions or suspensions of antigens in optically clear colloidal solutions Expired - Lifetime US3384544A (en)

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Application Number Priority Date Filing Date Title
GB25595/66A GB1171125A (en) 1966-06-08 1966-06-08 Improvements in or relating to Injectable Preparations

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BE (1) BE699678A (nl)
FR (1) FR7316M (nl)
GB (1) GB1171125A (nl)
IT (1) IT1035004B (nl)
NL (1) NL159283B (nl)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3678149A (en) * 1970-01-26 1972-07-18 Samuel J Prigal Method of enhancing the action of a medicament
US4053585A (en) * 1974-06-25 1977-10-11 National Research Development Corporation Immunological preparations
US4156719A (en) * 1977-02-28 1979-05-29 Yamanouchi Pharmaceutical Co., Ltd. Compositions for rectal use
US4530832A (en) * 1978-12-07 1985-07-23 Schering Corporation Method of vaccination for prevention of Bordetella bronchiseptica infection
EP0521562A1 (en) * 1991-06-26 1993-01-07 Yamanouchi Europe B.V. Vesicles in non-polar media
WO1999021533A2 (en) * 1997-10-24 1999-05-06 Neorx Corporation Delivery vehicles for bioactive agents and uses thereof
US20070014805A1 (en) * 2005-07-07 2007-01-18 Sanofi Pasteur Immuno-adjuvant emulsion

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2629871A (en) * 1970-03-17 1972-09-14 Merck & Co., Inc Solubilization of water and aqueous solutions in non-aqueous liquids
EP0059521B1 (en) * 1981-03-03 1985-01-02 Centraal Diergeneeskundig Instituut Water-in-oil emulsion for use in the potentation of the immune system of animals
FR2501526A1 (fr) * 1981-03-13 1982-09-17 Montagne Noire Produits Chimiq Nouveaux emulsionnants et leur application pour la production de vaccins
US4707470A (en) * 1985-05-17 1987-11-17 Smithkline Beckman Corporation Polyene antibiotic emulsion formulation
GB2222770B (en) * 1988-09-16 1992-07-29 Sandoz Ltd Pharmaceutical compositions containing cyclosporins
US6007840A (en) * 1988-09-16 1999-12-28 Novartis Ag Pharmaceutical compositions comprising cyclosporins
US5688761A (en) * 1991-04-19 1997-11-18 Lds Technologies, Inc. Convertible microemulsion formulations
DE69229779T2 (de) * 1991-04-19 1999-12-23 Lds Technologies Inc Konvertierbare mikroemulsionsverbindungen
US6262022B1 (en) 1992-06-25 2001-07-17 Novartis Ag Pharmaceutical compositions containing cyclosporin as the active agent
ATE147619T1 (de) 1992-05-13 1997-02-15 Sandoz Ag Opthalmische zusammensetzungen enthaltend ein cyclosporin
ES2168271T3 (es) 1992-09-25 2002-06-16 Novartis Ag Composiciones farmaceuticas que contienen ciclosporinas.
WO1994008610A1 (en) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Pharmaceutical emulsion compositions
DK17093D0 (da) * 1993-02-15 1993-02-15 Lyfjathroun H F Farmaceutisk praeparat til topisk administrering af antigener og/eller vacciner til pattedyr via slimhinder
ATE218359T1 (de) 1994-11-03 2002-06-15 Novartis Erfind Verwalt Gmbh Neue zubereitungsformen des cyclosporins zur oralen applikation mit einfacher zusammensetzung und hoher bioverfügbarkeit und verfahren zu deren herstellung
SI0750907T1 (en) * 1995-06-30 2002-08-31 American Cyanamid Company Stable macrolide and macrolide vaccine compositions
DE19549852B4 (de) 1995-11-29 2009-06-04 Novartis Ag Cyclosporin enthaltende Präparate
US6245349B1 (en) 1996-02-23 2001-06-12 éLAN CORPORATION PLC Drug delivery compositions suitable for intravenous injection
AU728221B2 (en) 1996-06-05 2001-01-04 Ashmont Holdings Limited Injectable compositions
TR199901686T2 (xx) 1997-01-30 1999-09-21 Norvartis Ag Esasen ya�s�z farmakolojik kompozisyonlar� i�eren sert jelatin kaps�ller.
US7732404B2 (en) 1999-12-30 2010-06-08 Dexcel Ltd Pro-nanodispersion for the delivery of cyclosporin

Citations (7)

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US2966443A (en) * 1959-06-22 1960-12-27 American Cyanamid Co Trivalent poliomyelitis live virus vaccine
US3096249A (en) * 1960-05-10 1963-07-02 Samuel J Prigal Emulsion composition
US3099601A (en) * 1959-10-02 1963-07-30 Anchor Serum Company Bacterin in aqueous polyethylene, mineral oil emulsion
US3149036A (en) * 1961-10-16 1964-09-15 Merck & Co Inc Adjuvant vaccine with aluminum monostearate, mannide monooleate, vegetable oil, and an aqueous phase immunolgical agent
USRE25721E (en) * 1965-01-26 Swine erysipelas vaccine
US3185625A (en) * 1961-11-08 1965-05-25 Brown Ethan Allan Injectionable substances
US3240670A (en) * 1960-08-12 1966-03-15 Beecham Group Ltd Injectable pharmaceutical emulsions containing liquid organopolysiloxanes

Patent Citations (7)

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USRE25721E (en) * 1965-01-26 Swine erysipelas vaccine
US2966443A (en) * 1959-06-22 1960-12-27 American Cyanamid Co Trivalent poliomyelitis live virus vaccine
US3099601A (en) * 1959-10-02 1963-07-30 Anchor Serum Company Bacterin in aqueous polyethylene, mineral oil emulsion
US3096249A (en) * 1960-05-10 1963-07-02 Samuel J Prigal Emulsion composition
US3240670A (en) * 1960-08-12 1966-03-15 Beecham Group Ltd Injectable pharmaceutical emulsions containing liquid organopolysiloxanes
US3149036A (en) * 1961-10-16 1964-09-15 Merck & Co Inc Adjuvant vaccine with aluminum monostearate, mannide monooleate, vegetable oil, and an aqueous phase immunolgical agent
US3185625A (en) * 1961-11-08 1965-05-25 Brown Ethan Allan Injectionable substances

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3678149A (en) * 1970-01-26 1972-07-18 Samuel J Prigal Method of enhancing the action of a medicament
US4053585A (en) * 1974-06-25 1977-10-11 National Research Development Corporation Immunological preparations
US4156719A (en) * 1977-02-28 1979-05-29 Yamanouchi Pharmaceutical Co., Ltd. Compositions for rectal use
US4530832A (en) * 1978-12-07 1985-07-23 Schering Corporation Method of vaccination for prevention of Bordetella bronchiseptica infection
EP0521562A1 (en) * 1991-06-26 1993-01-07 Yamanouchi Europe B.V. Vesicles in non-polar media
WO1993000069A1 (en) * 1991-06-26 1993-01-07 Brocades Pharma B.V. Vesicles in non-polar media
WO1999021533A2 (en) * 1997-10-24 1999-05-06 Neorx Corporation Delivery vehicles for bioactive agents and uses thereof
WO1999021533A3 (en) * 1997-10-24 1999-07-08 Neorx Corp Delivery vehicles for bioactive agents and uses thereof
US20070014805A1 (en) * 2005-07-07 2007-01-18 Sanofi Pasteur Immuno-adjuvant emulsion
US8703095B2 (en) * 2005-07-07 2014-04-22 Sanofi Pasteur S.A. Immuno-adjuvant emulsion

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BE699678A (nl) 1967-12-08
NL159283B (nl) 1979-02-15
FR7316M (nl) 1969-10-06
NL6707702A (nl) 1967-12-11
IT1035004B (it) 1979-10-20
GB1171125A (en) 1969-11-19
DE1617502A1 (de) 1972-02-10

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