CA1116088A - Injectable embolization and occlusion solution - Google Patents
Injectable embolization and occlusion solutionInfo
- Publication number
- CA1116088A CA1116088A CA320,450A CA320450A CA1116088A CA 1116088 A CA1116088 A CA 1116088A CA 320450 A CA320450 A CA 320450A CA 1116088 A CA1116088 A CA 1116088A
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- solution
- prolamine
- zein
- ethanol
- occlusion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0452—Solutions, e.g. for injection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Proteomics, Peptides & Aminoacids (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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- Materials For Medical Uses (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The disclosure describes an injectable embolization and occlusion solution which contains a prolamine in a physio-logically compatible solvent. This solution serves for the selected closure of organs, their duct systems, or blood vessels, and is introduced to the required site in a simple way with the aid of cannulas, catheters, endoscopes, or suitable applicators under X-ray control, and is precipitated there in the aqueous medium, in order to stop the flow of secretions from, or the flow of blood to, the appertaining organs or parts of an organ, staunch acute internal bleeding, completely obliterate patholog-ically modified sections of vessels, or temporarily or defini-tively block these or fill them with a biological material.
The disclosure describes an injectable embolization and occlusion solution which contains a prolamine in a physio-logically compatible solvent. This solution serves for the selected closure of organs, their duct systems, or blood vessels, and is introduced to the required site in a simple way with the aid of cannulas, catheters, endoscopes, or suitable applicators under X-ray control, and is precipitated there in the aqueous medium, in order to stop the flow of secretions from, or the flow of blood to, the appertaining organs or parts of an organ, staunch acute internal bleeding, completely obliterate patholog-ically modified sections of vessels, or temporarily or defini-tively block these or fill them with a biological material.
Description
~ 3 Our ref. : ~ 546 Case : GEE-445;~File 237 734 ETHICON, INC.
Somerville, Bridgewater Townshipj N.J., USA.
"Injectable e~bolization and occlusion solution"
The present invention relates to an inJectable embolization and occlusion solution, which serves for the selected closure of organs, their duct systems, or blood vessels, and is introduced to the required site in a simple way with the aid of cannul&s, catheters, endoscopes, or suitable applicators under X-ray control, and i8 precipitated there ln the aqueous medium, in order to stop the flow of secretions from, or the flow of blood to, the appertaining organs or parts of' an organ, staunch acute internal bleeding, completely obliterate pathologicall~y modified sections of vessels, or temporarily or definitively block these or fill them ~ith a biological material. I~4 a radioactive substance or an artificial iso-tope such as 133I with a suitable half-life and/or a cytostatic agent are added to the solution according to the invention, then the therapeutic effect obtained by cutting off the blood suppl~ in the embolization of blood vessels supplying a tu~our is reinf'orced by the ~ixed radioacti~e substances and cytostatic agents, distributed in the entire arterial tree. The addition of an artificial isotope with a shorter hal4-life can serve the purpose of not only radiation therapy but also of diagnosis.
.
Occlusion of the pancreatic ducts for the separate elimination of the secretory function of the pancreas has so far been possible only by a transduodenal suture o~ the orifice of the ductus pancreatlcus with a purse-string ligature, with subsequent plastic shaping of the papilla, or else by a complete pancreaticoduodenectom~, ~ith the relevant associated interventions. Attempts have also been made to effect the transduodenal occlusion of the terminal section of the ductus pancreaticus by the in~ection of a plastic. The operations for the treatment of chronic and acute pancreatitis place a very great strain on the patients and cannot be done at an ad~anced age. The ligation of the ductus pancreaticus has . .
~: : :~: : ,,: . :
. ' ` ' ,, , ~
~ . . .
': ::~ : ` '' '::: :' ' ' led to acute pancre~titis in most cases; the occlu3ion with a plastic has not yet been fully success~ul without the occurrence of side sffects.
Another disadvantage of both methods is that pancreatic fistulae can be for~ed after the removal of biopsy samples for differential diagnosis (chronic pancreatitis - pancreatic carcinoma).
Arterial catheter embolizatio~ has so far been carried out in the case of renal carcinoma (pre-operatively and palliatively), gastrointestinal bleeding, renal bleeding (arteriovenous ~istulae), pelvic fracture, bone tumours, varicose bleeding, vaginal bleeding (in the case of portio carcinoma), and intracerebral arteriorenous fistulae.
The ideal embolizing material is not yet available. A wide variety of substances have been used, such as autologous thrombi, plastics, synthetic substances (e.g. polystyrene, polyurethanes, ~olyvinyl alcohol, or silicone resins), autologous muscle fibres, fat, fibrin foam, gelatin foam, aIkyl cyanoacrylates and isopropyl palmitate (cf. M. The}en et al., Fortschr. Rontgenstr., vol. 124, 3 (1976), pp. 232-235). In practice, these substances have been found unsatis~actory in their technical application. The introduction of solids with -the aid of a catheter is difficult. The absence of X-ray contrast media makes monitoring problem-atic. In the case of alkyl cyanoacrylate monomers it is dif~icult to control spontaneous polymerization.
The aim of the present invention is to provide an in~ectable embolization and occlusion solution, which is applied at the right viscosity and then made to solidify at the required site in the vessel. This is done on the basis of the surprising discovery that, when a solution containing a substantial amount of a prolamine is used, reliable closure of organs, their duct systems, or blood vessels is obtained without the occurrence of side effects. Another aim of the present invention is to provide a process for the closure of organs, their duct systems, or blood vessels in animals and man with the aid of an in~ectable embolization and occlusion solution, which process ensures a reliable closure without the occurrence of side effects.
The present invention thus relates to th~ subJect described in the Claims.
: - , : :: , , : :
. ~ :
. ~
.
' ~ 5 ., The embolization and occlusion ~olution is prepared ln practice as ~ollow5 The physiologic~lly compatible solvent ~- preferably a mixture of uater and an alcohol with 2-5 carbon atoms -- is made ready for use. I~
a contrast medium, a cytostatic agent7 an an-timicrobial substance, or a specific pancreas inhibitor is to be used, it i5 added to the solvent in the required amount. The prolamine is dissol~ed in the solvent with care-ful stirring. The p~ of the solution is ad~usted to about 6.5-6.8 and pre~
ferably to about 6.65, uith a physiologically com~atible acid or base.
The density of the solution at 25~C is about 1.05-l.l and preferably 1.08 g/ml. The viscosity of the solution at 25C i5 about 350-oO0 and preferably ~00-500 centipoise. The viscosity is checked after 12-14 h.
If the viscosity of the solution is to be raised, a physiologically compatible oil is added at this point, with careful stirring. The solution is then ready for use and can be poured e.g. into am~oules or small bottles.
Directly before the filling operation a conventional sterilizing agent such as propylene oxide may be added to the solu-tion.
In experiments in which the solution according to the invention was injected into the ductus pancreaticus no pancreatic fistula has yet occurred in any of the cases.
In the case of an infected duct system closure of the duct is not possible because of the risk of acute pancreatitis. ~Ihen a pancreatic cyst is present there is a danger that it uill be enlarged and will rupture.
~one of the disadvantages mentioned here occurred when the solution according to the invention was used in animal experlments. The pancreas treated in this way never developed acute pancreatitis. The pancreatic tissue re-formed without any change in the structure and function of the islet cells. In contrast to the case of complete pancreatoduodenectomy, where the island organ is removed, only in ver~ rare cases has the long-term treatment of diabetes that develops been successful.
Pancreatitis uas produced b~ artificial infection in animal experiments on dogs. It was found, surprisingly, that the symptoms rapidly disappeared after the occlusion of the infected pancreas by the introduction of the solution according to the invention. The first clinical trials on human ~, , : ', ,;, ' .. ,:
....
.
., ... ~ ~ .: ~ .
. ,., ~ . . ::
subJects indicate that the therapy of pancreatitis in man ~s al~o possible.
Prolamines form the main protein components of cereal grains and flour.
Unlike all other proteins, the~ can be extracted from flour ~rith 80%
alcohol, but they are insoluble in absolute alcohol and water. The most important prol~mines are zein, gliadin, and hordein. Zein is pre~erred in the prese~t invention.
The prolamine, preferably zein, can be used in an amount of 3-60 and preferably 5-45 wt-%.
It has been found, surprisingly, that the solution accordine to the present invention, which contains a prolamine, is particularl~ suitable~ because prolamines are physiologically harmless substances that can be applied in the liquid form with an ad~ustable viscosity and then solidify at the required site in the vessel.
UnliXe all other proteins, prolamines are soluble in dilute alcohols and other solvents, but they are insoluble in water. Example~ of solvents for prolamines are C2-C5 alcohols (methanol dissolves them only to a small extent and denatures them), ethylenediamine, l-acetylpiperidine, ethylene glycol, propylene glycol, glycerol, N-methylacetamide, form~ide, hydra-zine, dimethylformamide, and dimethyl sulphoxide. When choosing the solvent for the occlusion solution according to the invention, the optimal suitability of the solvent as regards its physical properties and precipi-tation mechanism must be weighed against its possible toxicity. The preferred solvent is a mixture of ethanol and water, and the amount of water can vary between 4 and 50~, according to how quic~ly the prolamine is to precipitate out.
In ethanol, prolamines form viscous and slightly thixotropic solutions.
~t a constant prolamine content, the viscosity of the solutions increases with increasing ethanol concentration (see Table 1).
At a constant ethanol concentration the viscosit~ increases with increasing concentration ~f the prolamine (Table 2).
; ~ , : ,, , , ' ,;., , - :,. . ;: .
~ 7 ,, Table 1. Viscosity o~ a 35~ ~T/V zein solution in 50-95% v/v ethanol Ethanol /~J V/Y Cp' (25C~
31~0 - . ........ . ,.. _... .
Table 2. Viscosity of 5-40% w/~ zein solutions in 60~ ~/v o~ ethanol . cp (25C) 1$
Prolamines are decomposed into amino acids by hydrolytic cleavage.
The analysis of a zein hydrolysate shows that zein contains substantial quantities of glutamic acid ~23%~, leucine ~1~%~, proline ~9%), and L,alanine (9%~, but no lysine or tryptophan. Being proteins, prolamines are expected to be absorbed by the body in ~ivo~ and this has in fact been confirmed in animal experiments on rats and ra~its. Small rods made of zein, with a length of 1-2 cm, were implanted intramuscularly, ~nd both .
, .,, : . . . . , , . , ; ................ , ,.~ , . , , , , ~.. ; . . . .
- : , . :: : :, ' :, ' , .: ' : ' ' . : . . :: . : : : , ~ 8 . .
the adsorption and the tissue reactions were compared with those - observed after the implantation of catgut. ~e results showed that the prolamine zein is absorbed in about the same per:iod of time, 4-6 weeks, as catgut, and this process is accompanied by leucocyte infiltration, which seems to be slightly more extensive in the case of zein. It has been ~ound, however, that this i5 not due primarily to zein but to impurities present in commercial prol~mines. In particular, it is necessary to remove the colouring matter of zein, i.e. 3,3'-carotenediol, by boiling in petroleum ether.
Prolamines differ in their behaviour to some extent according to the species and the variety of the cereal and the conditions under which the plants grow and ripen. This circumstance must be taken into account when making up a preparation. The decisive factor is not a ~xed concentration but a certain ~iscosity of the prolamine in the solve~t used.
The molecular weight of prolamines is 25,000-407000. The viscosity of a prolamine solution is undoubtedly connected with the molecular weight, but so is ~lso the time of a~sorption. By cross-linking with tanning substances such as chromic acids, formaldehyde and glutaric dialdehyde, the time of absorption can be increased as desired; this also changes the solubility of the prolamines and the properties of the gels made from them. Treat-ment with ionizing radiation (2.5 Mrad) does not provoke recognizable undesirable changes in prolamines. Even the viscosity of prolamine solutions remains unchanged. Irradiation with gamma rays is the pre~erred way to sterilize such solutions. However, the additïon of liquid propylene oxide (0.5 - 1.0~ w/v) to prolamine solutions in a mi.xture of ethanol and water~lso ensures a satisfactory sterility without changing the consistency and the compatibility.
In catheter embolization with prolamine solutions the aim is to adJust the viscosity of the solution to the highest possible value, so as to pre-vent the escape of the prolamine solution through the capillaries and into the ~enous system. Furthermore~ the water content of the mixture of water and solYent must be as high as possible, so that the prolamine is precipitated as quickl~ as possible when it comes into contact with the aqueous medi~m of blood. The solutio~s ~ust be thin enough to be applicable through catheters ~2-4 Charr.~. Cohesion and adhesion must be so controlled :
that no dra~m "thread" is fo~med when the catheter i~ being withdrawn after the emboliæa-tion, and the embolus does not; adhere to the catheter.
This can be ensured by the addition of a physio].ogically compatible oil.
An example of such oils is groundnut oil, which considerably increases the viscosity of the solution of prolamines in ethanol-water mixtures if the amount of prolamine is kept constant with res~ect to the amount of solvent (see Table 3), and even substantially more if the prolamine content is kept constant with respect to the total amount of the preparation.
Vegetable oils are particularly suitable because they are physiologically harmless and are metabolized in the body. Examples o~ oils that can be used are groundnut oil, olive oil, poppyseed oil, and almond oil. The amount of oil in an occluding solution according to the invention can be between 5 and 45~ w/w. The oil is added to the ~rolamine solution after the prolPmine has been completely dissolved. The use of an emulsi~ier is not necessary, because prolamines have a certain emulsifying action.
Table 3. ~iscosity of 35% w/v zein solutions in 60~ v/v ethanol after the addition of various amounts of groundnut oil Amou~t of groundnut .p ~2~ `
oil added (~" w/w) _ . , _ _ _ _ . _____ _ The increase in viscosity depends on the viscosity of the oil added, which in turn depends on the melting point. For exam~le, the addition of the same amount of poppyseed oil and groundnut oil to a certain solution of a prolamine in aqueous ethanol leads to different viscosities. Such additions of oil do not only affect the viscosity, but also reduce the adhesion and the internal elasticity of the prolamine solution~ This can , . . .
be demonstrated on the change in the dripping rate ~num~er of drops per minute) and the weight of the droplets when pouring zein solutions con-.. . .
~; ' ' .'~ ' ' ' ~ :
.:
,. , ~, , :. : :
; ~ ' ~ ,'' ' '':
. ~ . . : . .
.. , , :.
taining dif~erent amounts o~ oil (see l'able 4).
Table 4 Dripping rate and droplet weight of zein solutions ~ith different poppyseed oîl contents _ _ _ _ _ . _ _ .
¦ PPpyseed oil, Drops/min Droplet ~ei~ht, ¦%, w/w mg ;25 20 18 16 i8 145 _ 12 16 The breaking-of~ at the catheter after the occlusion of th0 vessel can thus be optimized by an appropriate choice o~ the nature and the propor-tions o~ the components.
The addition o~ an oil also has another significance. Prolamines in solution precipitate out in an aqueous medium in the form o~ relatively solid blocks. ~en the solutions contain emulsified oils, however, oil globules are trapped in the precipitated prola~ine block, imparting to it a porous structure. This makes it easier for the body's connective tissues to proliferate over them during the absorption process. There is a quicker organization of the embolus, which ensures a definitive closure of the vessel and excludes any re-canalization.
~ompounds that are soluble in water and in the solvent of the prolamine and are customarily employed in angiography can be used as X-ray contrast media, examples being sodium amidotrizoate (sodium N,N-diacetyl-3,5-diamino-2,4,6-triiodobenzoate), 5-acetamino-2,4,6-triiodoisophthalic acid methyl amide-3, sodium acetrizoate (sodium 3-acetamino-2,~,6~triiodobenzoate~ and sodi~m
Somerville, Bridgewater Townshipj N.J., USA.
"Injectable e~bolization and occlusion solution"
The present invention relates to an inJectable embolization and occlusion solution, which serves for the selected closure of organs, their duct systems, or blood vessels, and is introduced to the required site in a simple way with the aid of cannul&s, catheters, endoscopes, or suitable applicators under X-ray control, and i8 precipitated there ln the aqueous medium, in order to stop the flow of secretions from, or the flow of blood to, the appertaining organs or parts of' an organ, staunch acute internal bleeding, completely obliterate pathologicall~y modified sections of vessels, or temporarily or definitively block these or fill them ~ith a biological material. I~4 a radioactive substance or an artificial iso-tope such as 133I with a suitable half-life and/or a cytostatic agent are added to the solution according to the invention, then the therapeutic effect obtained by cutting off the blood suppl~ in the embolization of blood vessels supplying a tu~our is reinf'orced by the ~ixed radioacti~e substances and cytostatic agents, distributed in the entire arterial tree. The addition of an artificial isotope with a shorter hal4-life can serve the purpose of not only radiation therapy but also of diagnosis.
.
Occlusion of the pancreatic ducts for the separate elimination of the secretory function of the pancreas has so far been possible only by a transduodenal suture o~ the orifice of the ductus pancreatlcus with a purse-string ligature, with subsequent plastic shaping of the papilla, or else by a complete pancreaticoduodenectom~, ~ith the relevant associated interventions. Attempts have also been made to effect the transduodenal occlusion of the terminal section of the ductus pancreaticus by the in~ection of a plastic. The operations for the treatment of chronic and acute pancreatitis place a very great strain on the patients and cannot be done at an ad~anced age. The ligation of the ductus pancreaticus has . .
~: : :~: : ,,: . :
. ' ` ' ,, , ~
~ . . .
': ::~ : ` '' '::: :' ' ' led to acute pancre~titis in most cases; the occlu3ion with a plastic has not yet been fully success~ul without the occurrence of side sffects.
Another disadvantage of both methods is that pancreatic fistulae can be for~ed after the removal of biopsy samples for differential diagnosis (chronic pancreatitis - pancreatic carcinoma).
Arterial catheter embolizatio~ has so far been carried out in the case of renal carcinoma (pre-operatively and palliatively), gastrointestinal bleeding, renal bleeding (arteriovenous ~istulae), pelvic fracture, bone tumours, varicose bleeding, vaginal bleeding (in the case of portio carcinoma), and intracerebral arteriorenous fistulae.
The ideal embolizing material is not yet available. A wide variety of substances have been used, such as autologous thrombi, plastics, synthetic substances (e.g. polystyrene, polyurethanes, ~olyvinyl alcohol, or silicone resins), autologous muscle fibres, fat, fibrin foam, gelatin foam, aIkyl cyanoacrylates and isopropyl palmitate (cf. M. The}en et al., Fortschr. Rontgenstr., vol. 124, 3 (1976), pp. 232-235). In practice, these substances have been found unsatis~actory in their technical application. The introduction of solids with -the aid of a catheter is difficult. The absence of X-ray contrast media makes monitoring problem-atic. In the case of alkyl cyanoacrylate monomers it is dif~icult to control spontaneous polymerization.
The aim of the present invention is to provide an in~ectable embolization and occlusion solution, which is applied at the right viscosity and then made to solidify at the required site in the vessel. This is done on the basis of the surprising discovery that, when a solution containing a substantial amount of a prolamine is used, reliable closure of organs, their duct systems, or blood vessels is obtained without the occurrence of side effects. Another aim of the present invention is to provide a process for the closure of organs, their duct systems, or blood vessels in animals and man with the aid of an in~ectable embolization and occlusion solution, which process ensures a reliable closure without the occurrence of side effects.
The present invention thus relates to th~ subJect described in the Claims.
: - , : :: , , : :
. ~ :
. ~
.
' ~ 5 ., The embolization and occlusion ~olution is prepared ln practice as ~ollow5 The physiologic~lly compatible solvent ~- preferably a mixture of uater and an alcohol with 2-5 carbon atoms -- is made ready for use. I~
a contrast medium, a cytostatic agent7 an an-timicrobial substance, or a specific pancreas inhibitor is to be used, it i5 added to the solvent in the required amount. The prolamine is dissol~ed in the solvent with care-ful stirring. The p~ of the solution is ad~usted to about 6.5-6.8 and pre~
ferably to about 6.65, uith a physiologically com~atible acid or base.
The density of the solution at 25~C is about 1.05-l.l and preferably 1.08 g/ml. The viscosity of the solution at 25C i5 about 350-oO0 and preferably ~00-500 centipoise. The viscosity is checked after 12-14 h.
If the viscosity of the solution is to be raised, a physiologically compatible oil is added at this point, with careful stirring. The solution is then ready for use and can be poured e.g. into am~oules or small bottles.
Directly before the filling operation a conventional sterilizing agent such as propylene oxide may be added to the solu-tion.
In experiments in which the solution according to the invention was injected into the ductus pancreaticus no pancreatic fistula has yet occurred in any of the cases.
In the case of an infected duct system closure of the duct is not possible because of the risk of acute pancreatitis. ~Ihen a pancreatic cyst is present there is a danger that it uill be enlarged and will rupture.
~one of the disadvantages mentioned here occurred when the solution according to the invention was used in animal experlments. The pancreas treated in this way never developed acute pancreatitis. The pancreatic tissue re-formed without any change in the structure and function of the islet cells. In contrast to the case of complete pancreatoduodenectomy, where the island organ is removed, only in ver~ rare cases has the long-term treatment of diabetes that develops been successful.
Pancreatitis uas produced b~ artificial infection in animal experiments on dogs. It was found, surprisingly, that the symptoms rapidly disappeared after the occlusion of the infected pancreas by the introduction of the solution according to the invention. The first clinical trials on human ~, , : ', ,;, ' .. ,:
....
.
., ... ~ ~ .: ~ .
. ,., ~ . . ::
subJects indicate that the therapy of pancreatitis in man ~s al~o possible.
Prolamines form the main protein components of cereal grains and flour.
Unlike all other proteins, the~ can be extracted from flour ~rith 80%
alcohol, but they are insoluble in absolute alcohol and water. The most important prol~mines are zein, gliadin, and hordein. Zein is pre~erred in the prese~t invention.
The prolamine, preferably zein, can be used in an amount of 3-60 and preferably 5-45 wt-%.
It has been found, surprisingly, that the solution accordine to the present invention, which contains a prolamine, is particularl~ suitable~ because prolamines are physiologically harmless substances that can be applied in the liquid form with an ad~ustable viscosity and then solidify at the required site in the vessel.
UnliXe all other proteins, prolamines are soluble in dilute alcohols and other solvents, but they are insoluble in water. Example~ of solvents for prolamines are C2-C5 alcohols (methanol dissolves them only to a small extent and denatures them), ethylenediamine, l-acetylpiperidine, ethylene glycol, propylene glycol, glycerol, N-methylacetamide, form~ide, hydra-zine, dimethylformamide, and dimethyl sulphoxide. When choosing the solvent for the occlusion solution according to the invention, the optimal suitability of the solvent as regards its physical properties and precipi-tation mechanism must be weighed against its possible toxicity. The preferred solvent is a mixture of ethanol and water, and the amount of water can vary between 4 and 50~, according to how quic~ly the prolamine is to precipitate out.
In ethanol, prolamines form viscous and slightly thixotropic solutions.
~t a constant prolamine content, the viscosity of the solutions increases with increasing ethanol concentration (see Table 1).
At a constant ethanol concentration the viscosit~ increases with increasing concentration ~f the prolamine (Table 2).
; ~ , : ,, , , ' ,;., , - :,. . ;: .
~ 7 ,, Table 1. Viscosity o~ a 35~ ~T/V zein solution in 50-95% v/v ethanol Ethanol /~J V/Y Cp' (25C~
31~0 - . ........ . ,.. _... .
Table 2. Viscosity of 5-40% w/~ zein solutions in 60~ ~/v o~ ethanol . cp (25C) 1$
Prolamines are decomposed into amino acids by hydrolytic cleavage.
The analysis of a zein hydrolysate shows that zein contains substantial quantities of glutamic acid ~23%~, leucine ~1~%~, proline ~9%), and L,alanine (9%~, but no lysine or tryptophan. Being proteins, prolamines are expected to be absorbed by the body in ~ivo~ and this has in fact been confirmed in animal experiments on rats and ra~its. Small rods made of zein, with a length of 1-2 cm, were implanted intramuscularly, ~nd both .
, .,, : . . . . , , . , ; ................ , ,.~ , . , , , , ~.. ; . . . .
- : , . :: : :, ' :, ' , .: ' : ' ' . : . . :: . : : : , ~ 8 . .
the adsorption and the tissue reactions were compared with those - observed after the implantation of catgut. ~e results showed that the prolamine zein is absorbed in about the same per:iod of time, 4-6 weeks, as catgut, and this process is accompanied by leucocyte infiltration, which seems to be slightly more extensive in the case of zein. It has been ~ound, however, that this i5 not due primarily to zein but to impurities present in commercial prol~mines. In particular, it is necessary to remove the colouring matter of zein, i.e. 3,3'-carotenediol, by boiling in petroleum ether.
Prolamines differ in their behaviour to some extent according to the species and the variety of the cereal and the conditions under which the plants grow and ripen. This circumstance must be taken into account when making up a preparation. The decisive factor is not a ~xed concentration but a certain ~iscosity of the prolamine in the solve~t used.
The molecular weight of prolamines is 25,000-407000. The viscosity of a prolamine solution is undoubtedly connected with the molecular weight, but so is ~lso the time of a~sorption. By cross-linking with tanning substances such as chromic acids, formaldehyde and glutaric dialdehyde, the time of absorption can be increased as desired; this also changes the solubility of the prolamines and the properties of the gels made from them. Treat-ment with ionizing radiation (2.5 Mrad) does not provoke recognizable undesirable changes in prolamines. Even the viscosity of prolamine solutions remains unchanged. Irradiation with gamma rays is the pre~erred way to sterilize such solutions. However, the additïon of liquid propylene oxide (0.5 - 1.0~ w/v) to prolamine solutions in a mi.xture of ethanol and water~lso ensures a satisfactory sterility without changing the consistency and the compatibility.
In catheter embolization with prolamine solutions the aim is to adJust the viscosity of the solution to the highest possible value, so as to pre-vent the escape of the prolamine solution through the capillaries and into the ~enous system. Furthermore~ the water content of the mixture of water and solYent must be as high as possible, so that the prolamine is precipitated as quickl~ as possible when it comes into contact with the aqueous medi~m of blood. The solutio~s ~ust be thin enough to be applicable through catheters ~2-4 Charr.~. Cohesion and adhesion must be so controlled :
that no dra~m "thread" is fo~med when the catheter i~ being withdrawn after the emboliæa-tion, and the embolus does not; adhere to the catheter.
This can be ensured by the addition of a physio].ogically compatible oil.
An example of such oils is groundnut oil, which considerably increases the viscosity of the solution of prolamines in ethanol-water mixtures if the amount of prolamine is kept constant with res~ect to the amount of solvent (see Table 3), and even substantially more if the prolamine content is kept constant with respect to the total amount of the preparation.
Vegetable oils are particularly suitable because they are physiologically harmless and are metabolized in the body. Examples o~ oils that can be used are groundnut oil, olive oil, poppyseed oil, and almond oil. The amount of oil in an occluding solution according to the invention can be between 5 and 45~ w/w. The oil is added to the ~rolamine solution after the prolPmine has been completely dissolved. The use of an emulsi~ier is not necessary, because prolamines have a certain emulsifying action.
Table 3. ~iscosity of 35% w/v zein solutions in 60~ v/v ethanol after the addition of various amounts of groundnut oil Amou~t of groundnut .p ~2~ `
oil added (~" w/w) _ . , _ _ _ _ . _____ _ The increase in viscosity depends on the viscosity of the oil added, which in turn depends on the melting point. For exam~le, the addition of the same amount of poppyseed oil and groundnut oil to a certain solution of a prolamine in aqueous ethanol leads to different viscosities. Such additions of oil do not only affect the viscosity, but also reduce the adhesion and the internal elasticity of the prolamine solution~ This can , . . .
be demonstrated on the change in the dripping rate ~num~er of drops per minute) and the weight of the droplets when pouring zein solutions con-.. . .
~; ' ' .'~ ' ' ' ~ :
.:
,. , ~, , :. : :
; ~ ' ~ ,'' ' '':
. ~ . . : . .
.. , , :.
taining dif~erent amounts o~ oil (see l'able 4).
Table 4 Dripping rate and droplet weight of zein solutions ~ith different poppyseed oîl contents _ _ _ _ _ . _ _ .
¦ PPpyseed oil, Drops/min Droplet ~ei~ht, ¦%, w/w mg ;25 20 18 16 i8 145 _ 12 16 The breaking-of~ at the catheter after the occlusion of th0 vessel can thus be optimized by an appropriate choice o~ the nature and the propor-tions o~ the components.
The addition o~ an oil also has another significance. Prolamines in solution precipitate out in an aqueous medium in the form o~ relatively solid blocks. ~en the solutions contain emulsified oils, however, oil globules are trapped in the precipitated prola~ine block, imparting to it a porous structure. This makes it easier for the body's connective tissues to proliferate over them during the absorption process. There is a quicker organization of the embolus, which ensures a definitive closure of the vessel and excludes any re-canalization.
~ompounds that are soluble in water and in the solvent of the prolamine and are customarily employed in angiography can be used as X-ray contrast media, examples being sodium amidotrizoate (sodium N,N-diacetyl-3,5-diamino-2,4,6-triiodobenzoate), 5-acetamino-2,4,6-triiodoisophthalic acid methyl amide-3, sodium acetrizoate (sodium 3-acetamino-2,~,6~triiodobenzoate~ and sodi~m
2-iodohippurate. These do not change the basic characteristics and especially the viscosity -- of prola~ine solutions (see Table 5~
The contrast medium enclosed in the precipitated prolamine block makes an X-rat~ control of the occlusion possible not only during the application but also at later times, in order to check its efficiency and the chanees that have QC curred.
.
:.... , . . .~. ~ . . : . . . - . . .
.: . . , . , ~
:: :. - . :. ., .;. . ,., : . . .
, .. . . - . - : . "
~able 5. Viscosity o~ a 35% w/v zein solution in a 60~ ~/v ethanol after the addition of various amount3 of an X~ray contrast medium (sodium amidotrizoate) _ _ Contrast medium ~sodium amidotrizoate), cp (25C3 % ~/v ... '.
_ , ~0 810 _ _ .
When lone-term X-ray control is planned or desirable and the site favours the escape of the soluble contrast medium by dif~usion, as for examrle, in the case of a partial palliative renal embolization, one can use water-insoluble contrast media such as barium sulphate or the contrast media mentioned above but in the acid form instead of the form o~ sodium salts. To prevent the sedimentation of the particles in the solution, an accurate control o~ the particle size is therefore necessary. The particles should be smaller than ~0 ~m(sieve No. I~oo, USP XIX).
Embolization of the supplying blood vessel leading to a tumour-containing organ or part of an organ ensures isolation from the blood circulation, and the prolamine is then distributed in the entire arterial system, including the capillaries~ By the addition of cytostatic agents to the occluding solution according to the in~ention, it is possible to localize a high dose of the cytostatic agent in the region of the tu~our without e.Yposing the RES (reticulo-enaothelial system) to the cytostatic agent, which is by definition destructive. One can use as c~tostatic agents either alkylating substances, such as Melphalan, Dichloren and Triaziquone, or antimetabolites, such as folic acid antagonists, purine anta~onists, and pyri~idine antagonists.
The antimicrobial substance can be almost an~ known drug of this kind, 2nd preferably an antibiotic or a sulphonamide, but also a quaternary ~ 12 ammonium compo~d. The concentration sho~d be a multiple of the ~C
(minimum inhibitory concentrationl o~ the substance for the microorganisms expected in the case of the indication in question (e.g. 1000-10,000 ~g/ml o~ streptomycin or 500~-50,000 yg/ml of penicillin G1.
To optimize the therapeutic effect aimed at by occluding t'ne ductus pancreaticus in severe pancre~titis, one can add to the solution pancreas inhibitors such as BAEE (benzoyl~1-arginine ethyl ester), TAME (p-toluene~
sulphon~l-l-arginine methyl ester), inter--globulin, or serum ~l-anti-tr~psin.
The following examples serve to elucidate the present invention.
Exam~le 1.
Injectable embolizing solutions were prepared from the following components:
A) Ethanol, 60% v/v250 ml Sodium amidotrizoate 60 g Zein 70 g Poppyseed oil 50 g Propylene oxide 4 g B) Ethanol, 70%, v/v250 ml Sodium amidotrizoate 65 g Zein 60 g Groundnut oil 60 g Propylene oxide 4 g C) Ethanol, 60% ~/Y250 ml Amidotrizoic acid70 g Zein 60 g Groun &ut oil 60 g Propylene oxide 4 g The preparation o~ solutions A, B, and C started with measuring out the ethanol in the re!quired concentration, after which sodium amidotrizo~te .. . .
.:
- ,. . .
.
' ' ' ' ' ~ .. ~. : ' `~ ,.:
.. .
or the corresponding free acid was disso].ved in it. Instead of the qodium salt, equimola~ ~uantities of the acid and NaOH can also be used.
The density and the pH were checked. Zein was added, with careful stir-ring, and after complete dissolution (12-14 h~, the viscosity was checked. The oil was then added and emulsified by stirring. ~he stirring must be done carefully: too intense a stirring leads to the incorporation o~ air and uncontroI~dchanges in viscosity. Propylene oxide (PO) was added directly before the solution was poured înto ampoules or bottle~
~ith a beaded edge. One must make sure here that the temperature of the solution is sufficiently low, in order to prevent evaporation of the propylene oxide and thus uncontrolled variations in its concentration, which could possibly endanger the sterility of thé finished solution.
ExamPle ?
Catheter embolization of the arteria renalis in the pig _____________________.._____________ _ _________________ The catheter embolization of the arteria renalis was carried out i~ the pig with 3.5 ml of a preparation according to the invention (35% w/v of zein in 60% v/v o~ ethanol and 7% w/w of groundnut oil); 34 days later the following findings were obtained:
The histological picture showed a considerable destruction of the renal tissue, affecting the arteries, the ~edulla, and the renal cortex.
In the arter.ial lumens there were variously lar~e remains of the embolus substance in the course of absorption, the rest being already extensively absorbed.
The absorption occurred through leucocytic agglomerates penetrating the lumen of the vessel in large numbers. The arterial walls ~ere destroyed by leucocyte infiltration and granulation tissue, and their architecture had been completely obliterated. The broad infiltrate and granulation tissue also encroached on the adJacent veins, so that these were similarly destroyed and often unrecognizable. The renal medulla was almost completely covered by granulation tissue and fibrous organization, with massi~e proliferation of fibroblasts and collagen fibre formation. The system of efferent collecting tubules was extensively obliterated or made atrophic by the fibrous organization? which partly affected the renal cortex as well.
In other respects the renal cortex showed bands of infarct necrosis, already , `
:
: ' ' . : . .
~ 14 described macroscopically. Thie destroyed renal tubules already showed ~
calcification in some cases.
The section of the arteria renalis exa~ined separately showed, in the region of the border-shiaped wall thickening, similar changes in the blood vessel, with circumscribed necrosis and granulation tissue, inclusion of leucocytes, and proliferation of cormective tissue (histological stains:
haematoxylin-eosin, PAS reaction, elastica - ~an Gieson's stain).
Clinical trials have shown that a pre-operative emboli~ation of the arteria renalis does not lead to any cc)mplications. A controlled closure of the renal artery occurred, ~hich was confirmed on the subse~uent operative extirpation of the organ. The operation was greatly facilitated by this pre-operative embolization. Loss of blood and a possible escape of tumour cells through the vena renalis were prevented. ~he embolization and its monitoring on the X-ray screen presen-t no technical difficulties.
Similar results were obtained with the emboliæing solutions according to Example 1.
.
:
, .
The contrast medium enclosed in the precipitated prolamine block makes an X-rat~ control of the occlusion possible not only during the application but also at later times, in order to check its efficiency and the chanees that have QC curred.
.
:.... , . . .~. ~ . . : . . . - . . .
.: . . , . , ~
:: :. - . :. ., .;. . ,., : . . .
, .. . . - . - : . "
~able 5. Viscosity o~ a 35% w/v zein solution in a 60~ ~/v ethanol after the addition of various amount3 of an X~ray contrast medium (sodium amidotrizoate) _ _ Contrast medium ~sodium amidotrizoate), cp (25C3 % ~/v ... '.
_ , ~0 810 _ _ .
When lone-term X-ray control is planned or desirable and the site favours the escape of the soluble contrast medium by dif~usion, as for examrle, in the case of a partial palliative renal embolization, one can use water-insoluble contrast media such as barium sulphate or the contrast media mentioned above but in the acid form instead of the form o~ sodium salts. To prevent the sedimentation of the particles in the solution, an accurate control o~ the particle size is therefore necessary. The particles should be smaller than ~0 ~m(sieve No. I~oo, USP XIX).
Embolization of the supplying blood vessel leading to a tumour-containing organ or part of an organ ensures isolation from the blood circulation, and the prolamine is then distributed in the entire arterial system, including the capillaries~ By the addition of cytostatic agents to the occluding solution according to the in~ention, it is possible to localize a high dose of the cytostatic agent in the region of the tu~our without e.Yposing the RES (reticulo-enaothelial system) to the cytostatic agent, which is by definition destructive. One can use as c~tostatic agents either alkylating substances, such as Melphalan, Dichloren and Triaziquone, or antimetabolites, such as folic acid antagonists, purine anta~onists, and pyri~idine antagonists.
The antimicrobial substance can be almost an~ known drug of this kind, 2nd preferably an antibiotic or a sulphonamide, but also a quaternary ~ 12 ammonium compo~d. The concentration sho~d be a multiple of the ~C
(minimum inhibitory concentrationl o~ the substance for the microorganisms expected in the case of the indication in question (e.g. 1000-10,000 ~g/ml o~ streptomycin or 500~-50,000 yg/ml of penicillin G1.
To optimize the therapeutic effect aimed at by occluding t'ne ductus pancreaticus in severe pancre~titis, one can add to the solution pancreas inhibitors such as BAEE (benzoyl~1-arginine ethyl ester), TAME (p-toluene~
sulphon~l-l-arginine methyl ester), inter--globulin, or serum ~l-anti-tr~psin.
The following examples serve to elucidate the present invention.
Exam~le 1.
Injectable embolizing solutions were prepared from the following components:
A) Ethanol, 60% v/v250 ml Sodium amidotrizoate 60 g Zein 70 g Poppyseed oil 50 g Propylene oxide 4 g B) Ethanol, 70%, v/v250 ml Sodium amidotrizoate 65 g Zein 60 g Groundnut oil 60 g Propylene oxide 4 g C) Ethanol, 60% ~/Y250 ml Amidotrizoic acid70 g Zein 60 g Groun &ut oil 60 g Propylene oxide 4 g The preparation o~ solutions A, B, and C started with measuring out the ethanol in the re!quired concentration, after which sodium amidotrizo~te .. . .
.:
- ,. . .
.
' ' ' ' ' ~ .. ~. : ' `~ ,.:
.. .
or the corresponding free acid was disso].ved in it. Instead of the qodium salt, equimola~ ~uantities of the acid and NaOH can also be used.
The density and the pH were checked. Zein was added, with careful stir-ring, and after complete dissolution (12-14 h~, the viscosity was checked. The oil was then added and emulsified by stirring. ~he stirring must be done carefully: too intense a stirring leads to the incorporation o~ air and uncontroI~dchanges in viscosity. Propylene oxide (PO) was added directly before the solution was poured înto ampoules or bottle~
~ith a beaded edge. One must make sure here that the temperature of the solution is sufficiently low, in order to prevent evaporation of the propylene oxide and thus uncontrolled variations in its concentration, which could possibly endanger the sterility of thé finished solution.
ExamPle ?
Catheter embolization of the arteria renalis in the pig _____________________.._____________ _ _________________ The catheter embolization of the arteria renalis was carried out i~ the pig with 3.5 ml of a preparation according to the invention (35% w/v of zein in 60% v/v o~ ethanol and 7% w/w of groundnut oil); 34 days later the following findings were obtained:
The histological picture showed a considerable destruction of the renal tissue, affecting the arteries, the ~edulla, and the renal cortex.
In the arter.ial lumens there were variously lar~e remains of the embolus substance in the course of absorption, the rest being already extensively absorbed.
The absorption occurred through leucocytic agglomerates penetrating the lumen of the vessel in large numbers. The arterial walls ~ere destroyed by leucocyte infiltration and granulation tissue, and their architecture had been completely obliterated. The broad infiltrate and granulation tissue also encroached on the adJacent veins, so that these were similarly destroyed and often unrecognizable. The renal medulla was almost completely covered by granulation tissue and fibrous organization, with massi~e proliferation of fibroblasts and collagen fibre formation. The system of efferent collecting tubules was extensively obliterated or made atrophic by the fibrous organization? which partly affected the renal cortex as well.
In other respects the renal cortex showed bands of infarct necrosis, already , `
:
: ' ' . : . .
~ 14 described macroscopically. Thie destroyed renal tubules already showed ~
calcification in some cases.
The section of the arteria renalis exa~ined separately showed, in the region of the border-shiaped wall thickening, similar changes in the blood vessel, with circumscribed necrosis and granulation tissue, inclusion of leucocytes, and proliferation of cormective tissue (histological stains:
haematoxylin-eosin, PAS reaction, elastica - ~an Gieson's stain).
Clinical trials have shown that a pre-operative emboli~ation of the arteria renalis does not lead to any cc)mplications. A controlled closure of the renal artery occurred, ~hich was confirmed on the subse~uent operative extirpation of the organ. The operation was greatly facilitated by this pre-operative embolization. Loss of blood and a possible escape of tumour cells through the vena renalis were prevented. ~he embolization and its monitoring on the X-ray screen presen-t no technical difficulties.
Similar results were obtained with the emboliæing solutions according to Example 1.
.
:
, .
Claims (10)
1. Injectable embolization and occlusion solution, charac-terized in that it contains a prolamine in a physiologically compatible solvent.
2. Solution as claimed in claim 1, characterized in that the prolamine is zein, and the solvent is a mixture of a C2-C5 alcohol and water.
3. Solution as claimed in claim 2, characterized in that the alcohol consists of ethanol.
4. Solution as claimed in claim 3, characterized in that the concentration of the ethanol is between 50 and 96% v/v and the concentration of the zein is between 5 and 45% w/v.
5. Solution as claimed in claims 1-3, characterized in that 5-45% w/w of a physiologically compatible oil is emulsified in the solution.
6. Solution as claimed in claims 1-3, characterized in that the solution contains an X-ray contrast medium.
7. Solution as claimed in claims 1-3, characterized in that the solution contains a radioactive substance.
8. Solution as claimed in claims 1-3, characterized in that the solution contains at least one cytostatic agent.
9. Solution as claimed in claims 1-3, characterized in that the solution contains at least one antimicrobial substance.
10. Solution as claimed in claims 1-3, characterized in that the solution contains at least one specific pancreas inhibitor.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2803869A DE2803869C2 (en) | 1978-01-30 | 1978-01-30 | Injectable embolization and occlusion solution |
DEP2803869.9 | 1978-01-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1116088A true CA1116088A (en) | 1982-01-12 |
Family
ID=6030689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA320,450A Expired CA1116088A (en) | 1978-01-30 | 1979-01-29 | Injectable embolization and occlusion solution |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS54123281A (en) |
AT (1) | AT363599B (en) |
AU (1) | AU525929B2 (en) |
CA (1) | CA1116088A (en) |
DE (1) | DE2803869C2 (en) |
FR (1) | FR2415464A1 (en) |
GB (1) | GB2014043B (en) |
NL (1) | NL191433C (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0115549B1 (en) * | 1983-02-03 | 1987-11-25 | Ethicon, Inc. | Paste for hemostasis and for temporary relief of defects in the traumatism of bones |
EP0128578A1 (en) * | 1983-06-14 | 1984-12-19 | Byk Gulden Lomberg Chemische Fabrik GmbH | Ethanolic suspensions of contrast agents |
CA1225585A (en) * | 1983-06-30 | 1987-08-18 | Maria T. Litvinova | Composition for embolization of blood vessels |
US4680171A (en) * | 1985-03-15 | 1987-07-14 | William Shell | Visualization of a bloodstream circulation with biodegradable microspheres |
DE19608278A1 (en) * | 1996-02-23 | 1997-08-28 | Schering Ag | Pharmaceutical compositions containing perfluoroalkyl-containing metal complexes, and their use in tumor therapy and interventional radiology |
US6180113B1 (en) | 1996-02-23 | 2001-01-30 | Schering Ag | Pharmaceutical agents that contain perfluoroalkyl-containing metal complexes |
KR970069028A (en) * | 1996-04-01 | 1997-11-07 | 김은영 | Manufacturing method of chemical color exclusive emulsion |
US6333020B1 (en) * | 1999-05-13 | 2001-12-25 | Micro Therapeutics, Inc. | Methods for treating AVM's using radio active compositions |
DE10261694A1 (en) * | 2002-12-30 | 2004-07-15 | Brassel, Friedhelm, Prof. Dr.med. | Liquid embolism |
CH712511B1 (en) * | 2006-09-18 | 2017-11-30 | Forim-X Ag C/O Prof Dr Med Richard Dirnhofer | X-ray contrast media for postmortem, experimental and diagnostic angiography. |
PT2063916E (en) | 2006-09-18 | 2015-02-25 | Forim X Ag | X-ray contrast agent for post-mortem experimental and diagnostic angiography |
CN107935870A (en) * | 2017-11-09 | 2018-04-20 | 华中药业股份有限公司 | A kind of synthetic method of 2 methylamino, 5 chlorobenzophenone |
CN113813392A (en) * | 2021-10-23 | 2021-12-21 | 哈尔滨工业大学 | Preparation method of blood cell-like drug carrier |
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GB311382A (en) * | 1928-05-10 | 1930-08-07 | H A Metz Lab Inc | Improvements in or relating to the manufacture of spinal anaesthetic solutions |
CA958642A (en) * | 1969-06-11 | 1974-12-03 | Milos Sovak | Contrast media for radiography |
-
1978
- 1978-01-30 DE DE2803869A patent/DE2803869C2/en not_active Expired
-
1979
- 1979-01-17 AU AU43430/79A patent/AU525929B2/en not_active Ceased
- 1979-01-26 JP JP730879A patent/JPS54123281A/en active Granted
- 1979-01-26 NL NL7900649A patent/NL191433C/en not_active IP Right Cessation
- 1979-01-29 FR FR7902217A patent/FR2415464A1/en active Granted
- 1979-01-29 CA CA320,450A patent/CA1116088A/en not_active Expired
- 1979-01-29 AT AT0065679A patent/AT363599B/en not_active IP Right Cessation
- 1979-01-29 GB GB7903005A patent/GB2014043B/en not_active Expired
Also Published As
Publication number | Publication date |
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FR2415464B1 (en) | 1983-07-01 |
DE2803869C2 (en) | 1983-12-29 |
GB2014043B (en) | 1982-08-11 |
AU4343079A (en) | 1979-08-09 |
AU525929B2 (en) | 1982-12-09 |
NL191433C (en) | 1995-07-04 |
JPH0129774B2 (en) | 1989-06-14 |
DE2803869A1 (en) | 1979-08-02 |
GB2014043A (en) | 1979-08-22 |
JPS54123281A (en) | 1979-09-25 |
AT363599B (en) | 1981-08-10 |
ATA65679A (en) | 1981-01-15 |
NL7900649A (en) | 1979-08-01 |
FR2415464A1 (en) | 1979-08-24 |
NL191433B (en) | 1995-03-01 |
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