CA1040500A - Surgical tubular device having a slippery surface - Google Patents
Surgical tubular device having a slippery surfaceInfo
- Publication number
- CA1040500A CA1040500A CA222,559A CA222559A CA1040500A CA 1040500 A CA1040500 A CA 1040500A CA 222559 A CA222559 A CA 222559A CA 1040500 A CA1040500 A CA 1040500A
- Authority
- CA
- Canada
- Prior art keywords
- tube
- water
- copolymer
- tubular device
- hydrophilic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1036—Making parts for balloon catheter systems, e.g. shafts or distal ends
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/04—Macromolecular materials
- A61L29/041—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0009—Making of catheters or other medical or surgical tubes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
Abstract
ABSTRACT OF THE DISCLOSURE
Surgical tubular device intended for being temporarily introduced into the cavities of a living body, such as a cathe-ter, an intubation or sounding tube, a cystoscope or similar.
That device consist entirely or partially intended for being temporarily introduced into the cavities of a living body, consisting entirely or partially in a hydrophilic copolymer of acrylonitrile with hydrophilic comonomers selected from the group consisting of acrylamide, acrylic acid, methacrylamide, methacrylic acid, ethylene sulphonic cid and their salts, said copolymer being swelled with an aqueous liquid, the surface of the part which is introduced into the body containing neutra-lized anionic groups making it highly slippery in contact with water, and the part expected to be exposed to the atmosphere during the application to the body being protected against drying by a layer of an elastic polymer or copolymer impermea-ble for water and water vapors.
Surgical tubular device intended for being temporarily introduced into the cavities of a living body, such as a cathe-ter, an intubation or sounding tube, a cystoscope or similar.
That device consist entirely or partially intended for being temporarily introduced into the cavities of a living body, consisting entirely or partially in a hydrophilic copolymer of acrylonitrile with hydrophilic comonomers selected from the group consisting of acrylamide, acrylic acid, methacrylamide, methacrylic acid, ethylene sulphonic cid and their salts, said copolymer being swelled with an aqueous liquid, the surface of the part which is introduced into the body containing neutra-lized anionic groups making it highly slippery in contact with water, and the part expected to be exposed to the atmosphere during the application to the body being protected against drying by a layer of an elastic polymer or copolymer impermea-ble for water and water vapors.
Description
5~0 The present invention relates to surgical tubular devices intended for being temporarily introduced into the cavi-ties of a living bod~, such as catheters, tracheal or gas~ric intubation or sounding tubes, tubes for removal of tracheal or pulmollary secretions, cyctoscopes and similar, consisting enti.re~
ly or partially of hydrophilic copolymexs o~ acrylonitrile con-taining either acrylamide or acrylic acid and, if desired, a small amount of other co-monomers.
The above mentioned copolymers swell in water or aqueous solutions. When they are swollen, they are pliable, elastic and strong. Their properties can be changed by changing the degree ; -of hydrolysis, when the copolymer was prepared by partial hydro-lysis of polyacrylonitrile, or by changlng the content of hydro-philic units, when the oopolymer was obtained by copolymerization of a monomer mixture. ~t lower degrees of hydrolysi~, or with lower content of hydrophilic units, the copolymers can be oriented by stretching. ~hey have in an oriented state a comparatively high ela~ticity. At a higher content of hidro~hilic units, they are rubbery. ~hey cont~in up to about 85~o water at the swelling equilibrium.
~he outer layer or surface layer, cf the part of the su.rgical device which is introduced into the cavities of the living body, suoh as into the larynx, the tracheal the urethra etc., contains neutralized anions as side-substituents, such as carboxylic, sulphonic, sulphuric or phosphoric groups attached to the copolymer main chain by covalent bonds. ~he part of the device which is exposed to the atmospnere during the application to the patient is permanently protected against drying by a layer of a polymer or copolymer impermeable for water and wate:r vapors.
~he water-swelled copol~ner hydrogel according to the invention can also serve to sustain the release of appro-'"' ' "
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.
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priate drugs which can be absorbed therein prior or during the storage.
Up to now~ the surgical tubular devices of the abo~e me~tioned kind are manufactured from rubber or from highly plasticized polyvinylchlQride, or from other similar hydro-phobic polymers imperm~able for water and aqueous ~olutes.
Prom a physiological standpoint, such polymers are very different from the living ~issues~ ~heir surface has a compa-ratively high coefficient of friction with respect to the mucous membranesO ~hus, the surgical devices used hitherto often hurt the t1ssues. ~o a~oid this, they must be lubricated before use, conseque~'ly increasing infection hazard.
Moreover, hydrophobic catheters, intubation sounds and similar cannot absorb drugs which would then gradually diffuse into the surrounding mucous membrane.
It has been therefore suggested to provide these h~drophobic tubular devices ~ith a thin layer of sparingly cross-linked glycol methacrylate polymer having a water intake of usually about 40 % by weight, and thus being capable to absorb water-soluble drugs. ~he mai~ drawback of such coati~gs is that a~ intermediate layer must be formed first, on which the hydrogel i5 laid by cross-linking polymerization of a mono-mqr mixture. ~he intermediate layer must have a swelling capa-city lower than the outer hydrogel layer and simultaneously a good adhesion to ru~ber or plasticizea PYC, otherwise the hydrogel layer would easily separate. ~he tenacity and elasti-city of tha cross-linked ethyle~eglycol methacrylate polymers is comparatively low and their layer must ~ot be too thick.
~hereby the possibility to i~corporate a sufficient amo~t of drugs is rather limited.
.. ',~'.'.,..... ~11 .
It has been already suggested to manufacture tube~
entirely from swelled copolymers of acrylonitrile wlth acryla-mide, said tubes being provided with highly slippery surface layer. However, simple tubes of this kind cannot be directly used as intubation or sounding tubes or catheters, ~hey rather form a starting a material for the surgical tubular device ac-cording to the present invention.
It has been found that a faulness functioning of such devices can only be obtained if the part which is exposed to the a-tmosphere during the application to a patient is protected against drying as well as against slipping into the cavities of the living body. A hydrophobic layer prevents the protected part from bein~ shrunk and brittle by drying, As a result, the hydrogel t-ube remains elas-tic and pliable in lt~ whole length and be ea~ily joint with necessary supplementary parts such as funnels, syringes, metering pumps and outlets of containers, by slipping its end on a fitting. As hydrophobic protecting layer, a natural or synthetic rubber can be applied, by using a self vulcanizing latex and dipping therein the respective part of the tubular de~ice. Alternatively, an insulating slee~ing from silicone or other rubber can be slipped onto the hydrogen tube. The putting on is easy iE the sleeving is first ~welled in a volatile liquid such as benæene or toluene. After evapora-ting the swelling liquid, the sleeve shrinks to its previous inside diameter and adheres by its high elasticity firmily to the hydrogel tube~
The part of the tubular device intended to be introduced into a cavity of a living body i~ made ~lippery by a suitable chemical treatment, forming anionic side groups covalently bonded with the copolymer. ~s anionic groups~ carboxylic, sulphonic, sulphuric and pho~phoric acid groups neutrali~ed '' ' "' ' ' ' -- ~04~50~) with physiologically innocuous cations suoh as sodium, potas-~um or lithium cations are particularly suitable. ~hat treat ment only affects a thi~ surface layer which is thereby made extremely slippery, the main part of the cross-section of the tube remaining unchanged.
Suitable chemical agents are, e.g., aqueous solutions of alkali metal hydroxides, causing a saponification of the -nitrile and amids groups to carboxyls~ or mixtures o~ concen-trated sulphuric acid with glycerol or other soluble polyol, or rapors of chlorosulphonic acid or sulphur trioxideO Groups o~ phosphoric acid can be also introduced9 using known methods.
~ he shape of the surgical device according to this in~ention does not substantially dif~er ~rom that o~` the known dev~ces made from rubber or plastici~ed PVC. ~he extremi-ty o~ that device i~ ~ree o~ sharp edges and preferably rounded, with either axial or side opening. Any complicated ~orm can even be made using special extrusion dies and inflatable pockets ~rom highly elastic hydrogels based on copolymers of acrylonitrile with acrylamide or acrylic acid. In~latable pockets ~rom part o~ thin hydrogel tubes are slid on the tubular device and cçmented thereto but partially.
~ he copolymers from which the hydrophilic part of the device i~ made should not contain more than 80 molar percent of acrylonitrile units and preferably 40 to 65 molar percent, otherwise the desired character of elastic hydrogel~ could not be achieved. Then~nimUm co~te~t of acrylo~itrile units i9 determined by requirements concerning the physical parameters such as the toughness, the elasticity, the mod~lus, the swelling capacity etc. Said parameters depend on the density o~ the non-covalent network ~ormed by the polyacrylonitrile within the water-swelled amorphous hydrophil~c chains consisting o~ acryl-amide or acrylic acid units. Consequently, i~ a random copo-. .
_ ~ _ , ` ~34~5~
ly~er is used, the molar portion of acrylonitrile units shouldbe higher -than in case of a block copolymer the undivided long polyacrylonitrile segments of which have better opportunity to form crystalline domains than the same number of acrylonitrile units dispersed randomly along the chains. Although block copo-lymers of this kind are shape-retaining, even if the molar por-tion o~ acrylonitrile un~ts is very low, and have a swelling capacity in water exceeding 95 % by weight, it is advisable to keep the content of acrylonitrile units higher than about 20 (molar) and she swelling capacity in water lower than about 80 % (weight), in order to maintain the strength and pliability wlthin reasonable limits. ~-~ est results are obtained if the copol~mer used is a multi-block copolymer containing in each macromolecule several ~equences o~ acrylonitrile units alternating with sequences of acrylamide units. Such mul-ti-block copolymers can be obtained by homogeneous acid hydrolysis of polyacrylonitrile plasticized or dissolved in acidic solvents of polyacrylonitrile having a negligible chain transfer constant. ~he gels or solutions are first exposed at temperatures at which first acrylamide units are formed on the polyacrylonitrile chains, e.g. in the case of concentrated nitric acid at temperatures above 20C. ~hen the temperature is decreased so that no further isolated acrylamide groups are formed, the hydrolysis spreading from the acrylamide units already formed by "zipper mechanism"~ Strong mineral acids can be used as ~olvents and sim~ltaneously hydrolytic agents, e.g. concentrated nitric or phosphoric acid, or slightly diluted sulphuric acid. Sulphuric acid is a very strong hydro-lytic agent but nitric acid is a better solvent. ~hu~, it is advantageous to use concentrated nitric acid as solvent and to add a small amount o~ sulphuric acid to -the . ~ . ~ . . . . .
~4~S~) solution~ Polyacrylonitrile in the form of a fine powder can be dispersed in nitric acid at temperatures below 20C at which the rate of swelling is low, and then the temperature can be slowly increased while stirring so that the dispersion is gradually transformed into a viscous homogeneous solution. If an acrylonitrile homopolymer is used, the ~olution is briefly heated up to about 30 - 40C to initiate the zipper hydrolysis, and then leLt standing at 0 - 20C until the desired degree of hydrolysis is reached. ~he lower the temperature is, the longer the sequences or "blocXs" in the copolymer are~ HoweYer, the nece~sary time increases, whe~ the temperature decreases.
~ est results are obtained if the steps o~ the hydro-lysis are distinctly separated, Similarly, i~ acrylonitrile is polymerized directly in an acidlc solvent such as in nitric acid or in an aqueous solution containing zinc chloride or lithium bromide, the step of partial hydrolysis should be distinctly separated form the step of polymerization. This oan be achieved, -e.g.~ by polymerizing acrylonitrile in concentrated nitric acid at low temperatures, using a suitable redox initiator. A~ter the polymerization is finished, the rate of hydrolysis is increased either by adding sulphuric acid, or by increasing the temperature, and then decreasing it again, as mentioned above.
I~ the polymerization is carried out in concentrated aqueous solutions co~taining zinc chloride, lithium bromide or other salts capable of dissolving polyacrylonitrile, the rate o~ -hydrolysis may be increased best by dissolving hydrogen halide in the polymer solution, or respectively in the solvent and the pla~ticized gelO ~his method ca~ be perfor~ed advantageously in such a way that a viscous solution of polyacrylo~itrile in ~0 one o~ the above mentioned salt solution~ is extruded into a coag~lating bath in which the tube i9 only partially coagulated.
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~he tube is then left standing for several hours until the salts are distrlbuted by diffusion, so as to obtain a rubbery gel containing from about 20 to about 40 ~ of polyacrylbnitrile.
~he gel can be then partially hydrolyzed either by increasing the tempera-ture to about 70 to about 120C, or better by treat-ment with gaseous hydrogen halide at -20 to about 30C until the desired degree of hydrolysis is achieved. ~he salts are .
then washed out and the hydrogen halide neutralized; in the case of a zinc chloride containing solvent, a diluted aqueous solution of a substance yielding anions forming insoluble ~inc compounds is preferably used. Such anions ~re carbonates7 bicarbonates, chromates, phosphates, hydroxides and others contained in ~olution. ;:
Although acrylamide is preferred as hydrophilic compo-nent, e~pecially if formed by a cont.rolled partial acid hydro-lysis as mentioned above, it is also possible to u~e other hydrophilic components such as acrylic acid9 methacrylamide, methacrylic acid, sodium ethylene sulphonate, sodium styrene sulphonate7 maleine anhydride, itaconic acid or other mono-: `
olel~nic acids capable to copolymerize with acrylonitrile.
N-alkyl- or N-hydroxyalkyl amides of acrylic and me-thacrylic acid can be also used. Hydrophilic co-monomers can be incorporated in ~uch an amount that the partial hydrolysis can. be dispensed with, Best resul-ts are obtained if the amount of co-monomer units in the starting copolymer prior to the partial hydrolysis is lower than about 10 mol. percent, and preferably lower than ~-about 2 %. Beside the hydrophilic co monomers mentioned in the preceding paragraph, also hydrophobic co-monomers can be employed such as lower al~yl esters of acrylic and methacrylic acids, vinyl pyridine 9 vinyl carbazole, styrene, alpha-methyl , . , . .. . . . ~ . .
5~0 styrene, alpha-ohlor styrene, or vinyl pyrrolidone.
It is also possible to polymerize acrylonitrile under crosslinking conditions in said acidic solvents having negli-gible chain transfer constant, either by adding a s~all amount of a suitable crosslinking agent such as Zthylene glycol dimethacrylate or N,~-methylene bis-methacrylamide, or by carrying out the polymerization at such a high monomer concen-tration that the chain transler onto the mo~omer causes cross-linking. In these cases, the polymerization must be carried out in a mold, because the crosslinked gels cannot be shaped.
A lyogel elastic tube is obtained, consisting of polyacxyloni-trile plasticized with eOg. nitric acid or aqueous ~inc chloridesolution. Partial k~drolysis is then carried out in the above described manner.
Simple sounding tubes used e.g. ~or taking samples of gastric juice or for the removal of secretions can be made from tubes having their end tips rounded by working in dxy or half-dry state, or by pressing at incxeased temperatures in presence of a polyacrylonitrile solventO ~he part to be exposed to atmosphere is coated with a suf~iciently elastic polymer such as rubber to prevent drying. ~he other part is made slippery by treating with ~trong al~ali lyes or other chemical agents oapable of formi~g anionic side groups on the copolymer chain.
side opening can be made with or without closing the original axial opening of the tube. ~he closing of the end to be inserted into the cavity of the living body can be carried out ~n various ways, e.g. by cementing a shaped stopper from the same or similar h~drogel into the ope~ing, or b~ shaping the end of the not yet fully coag~lated tube just leaving the sxtrusion die.
For cementing a shaped stopper into the end of the tube, any polyacrylonitrile solven-t can be used such as , ~4~5~0 dimethyl formamid~ or dimethyl sulpho~ide. ~he cementing is preferably carried out with both stopper and tube swelled with water, glycerol or similar, because dry hydrophilic pol~-mers - ~erogels - tend to spontaneously cracking i~ cont~ct w~th solvents.
According to another embodiment of the manufacturing process, usual surgical tubular devices ~rom rubber or plasticized PVC are coated with a layer of the aforesaid hydro-philic acrylonitrile copolymers either by dipping them into a ~opolymer solution and coagulating the latter, for example in cold water, or by spraying or painting said copolymer solu-tions, with also a subsequent coagulation, or, better, by slip-ping a thi~ tube from said hydrophilic swelled copo:Lymer onto said tubular device. ~he slipping of the thin tube on the device is made easier by previously swelling said thin hydrogel tube in a mixture of a polyacrylonitrile solvent with water9 or by increasing temporarily the lnside diameter o~ the thiD
tube by radial orientation, In the ~irst case, the solvent of polyacrylonitrile is washed out and the outer tube shrinks, '!' '~'' adhering ~ir~y to the tubular device. In the other case, the same effect i~ attained by immersing into hot water in which the radial orientation relaxes to the original inside diametexO
~he rounded end can be covered unifo~ly with the hydrophilic copolymer by molding the overlapplng thin hydrogel tube in presence of a solvent of polyacrylonitrile and removi~g the solvent by washi~g i~ water. It also possible to prepare the ~hin hydrogel tube with ths end closed at the extrusio~ die.
~he thin outer tube c~n cover the part to be inserted, the part to be exposed to atmosphere being left bare.
More comple~ surgical tubular devices provided with one or two c4axial channels for flushing out the urinary s~
bladder with drug solutions, or provided with an inflatable pocket holding the tubular device in desired position, can be manufactured using suitable ex~rusion die~ with more th~n one inlet for coagulating liquid so that coaxial channels are formed. Instead of such tubular channels coaxial grooves on the tube surface can be created using suitable extrusion dies ~uch as shown in ~ig. 1b and 1c o~ the accompagnying drawing.
~he tube with groo~es is covered by a thin hydrogel tube of the same or similsr, highly elastic hydrogel. If the end of the tubular device is ~ormed by dipping into a hydrogel solution and coagulation, a~y part o~ the groove or grooves which has to remain free can be protected from filling with hydrogel by a suitable water-soluble polymer such as carboxymethyl cellulose which is finslly washed out. ~nother way to preser~e the groove i~ to iDsert a wire or similar which is pulled out after the fiDished treatment.
~ he upper hyarogel tube can be cemented to thé main tube except the part forming an inflatable pocket which communi-cates with one end of the cha~nel, the other eDd of the channel being joint with a suitable filling devioe provided with a check valve. ~he part forming the pocket can be previously coated with sodium salt of carboxymethyl cellulose or with another ~rater-soluble polymer which is washed out after the remaining parts have been cemented togetherO
~ he inflatable pocket forming an integral part of the outer thin hydrogel tube possesses the advantage that the whole surface is entirely smooth. Physiologic saline with which ~he pocket is filled may contain drugs such as bacteriostatics7 ~actericides and anaesthetics which dif~use gradually through the inflated hydrogel membrane. ~he main tube can have a recess underneath the inflatable pocket, if desired.
_ 10 --5~Q
The outer thin tube can be closed at one end before being slipped onto the main catheter tube~ forming a slender ~ack 80 that the whole catheter including its tip is uniformly and smoothly covered with hydrogelO The l~ecessary side-opening - can be made before or after slipping the thi~ tube onto the main tube.
To avoid any dead space near the opening, the end of ~he closed catheter can be filled with a stopper ceme~ted thereto ~
or with a polymer solution coagulated afterwar~s. ;
I~ the main tube of the tubular aevice is made from rubber or similar hydrophobic material, it is only suf~icient to cover with a thir hydrogel tube the part to be introduced into the body, Another possibility is to make the whole part to be introduced into the living body of hydrogel, the part to be exposed to the atmosphere being made from rubber or similar~
~he two parts are joint by cementing together their ends adapted thereto.
~ he outer hydrogel thin tube can be cemented to the main tube on the ends only so that the whole space between them can ~e filled with physiologic saline containing, lf desired, suitable drugs. Thereby the outer tube is pressed against the mucous membrane of e.g. the urethra, sealing it completely.
The end protruding lnto the bladder is simultaneously inflated to prevent the catheter from slipping out.
~ he hydrophilic copolymer of acrylonitrile can be subsequently cross-liDked,if desired. The catheter is then treated with a suitable cross-linking agent such as an aqueous aoid formaldehyde solution, or a suitable diepoxide reacting with hydroxylic and amidic side groups, or with a di-isocyanate.
~0 ~he cros~-linking with formaldehyde can be also carried out in an appropriate stage of waæhing when the gel contains still . ' . ' -5~nitric or sulphuric acidO When using gaseous hydrogen halide to increase the rate of hydrolysis, gaseous formaldehyde can be admixed thereto. ~he cross-linking can be carried out either be~ore imparting anionic groups to the surface layer, or there-a~ter.
If the catheter or similar is sterilized with ethylene oxide, some hydrophilic groups -0~ H2CX2o7nH may be formed on the surface, decreasing also the coef~icient of friction of the swelled hydrogel.
~he hydrogels absorb easily various drugs, pexmitting sterilization and sustained release of drugs for a long time.
An important step in manufacturing surgical tub~1ar devices isthe shaping of the end tip which is introduced into the body. The end must be quite smooth, suitably rounded and inseparably joint with the tube. ~here are several ways how to form the ending. First of all, it i~ possible -to mold the extruded tube just at the extrusion die when the tube is not yet fully coagulated, c:~osing simultaneously the water inlet through the axial mandrel. Thereby the inside diameter is reduced to zero and a stick or a monofil is temporarily formed instead of a tube. In order to maintain the diameter constant, ~he feed of the polymer solution can be simultaneously increased.
A~ter a short time interval the ~eed of water i9 renewed and the ~eed of the polymer solution reduced to the original value -compare ~ig. 4 and 5. ~he thick monofilament sections are then cut in the middle, and so are the tube sections between them.
The ends are rounded by grinding, preferably under a not enti-rely dry condition. ~he ends can be also frozen before grinding.
Another way is to mold the ends using heat and pressure in 3 presence of a solvent of polyacrylonitrile.
_ 12 -It is also possible to mold the extruded tube using a suitable tool instead of interrupting the inlet of the coaOGula~
ting liquid through the axial mandrelO Such tool may be a sort of pliers, or a ring-like inflatable air tube constricting the extruded tube along a short path - see ~ig. 6. ~he process can be automatized.
Another way to close the end of the tube consists in dipping the end into a viscous hydrogel solution and sucking the latter into the tube to the desired level. ~he tube is prefe-rably inclined 90 as to obtain a bevelled bottom. ~he hydrogel solution is rapidly coaO~ulated in water and the solvent washed out. Using a hydrogel stopper has been already men-tioned.
The end of the tubular device can be worked mechani- ;
cally. Finally the surface i9 made slippery under wet condition by imparting anionic groups thereto.
In the accompagnying drawing, Fig. 1 illustrates diagrammatically three different cross-sections of the hydrogel -main tube, together with cross-sections o~ the corresponding cxtrusion dies.
Fig. 2 is an axial sectlon of the catheter according to Example 4. Fig. 3 illustrates a glass mold as described in Example 5, employed for polymerization-casting under cross-linking conditions.
Fig. 4 is an axial section through the extruded tube at the point where the feeding of the coagulating bath through the axial inlet of the die was temporarily interrupted and the feed of the po~ymer solution simultaneously increased to keep the outer diameter unchanged.
Fig. 5 is an axial section of an extruded tube at the point where the feed of the coaO~ulating liquid through the axial mandrel was entirely interrupted, the feed of the polymer solution being simultaneously throttled, as described in :. . .
~4~S~
~xample 11.
Fig. 6 shows diagrammaticallyg in an axial section, a tool for molding the just extruded, only superficially coag~lated tube. The result is similar to that shown in ~ig. 5 (compare ~xample 12).
Several methods for manufacturing surgical tub~lar devices of the invention are described in the following non-limitative ~xamples. All parts and percentages are given by weight, if not stated otherwise.
Example 1.
Polyacrylonitrile with an average degree of polyme-rization of 4500, prepared by precipitation polymerization in an aqueous medium using an ammonium persulphate - potassium pyrosulphite redox initiator, was dried under reduced pressure at 40C and ground to fine powder. ~he powder was dispersed in the ratio 1:12.5 (by weight) in 70~ colorless nitric acid cooled to -42C, with 0,1 ~o of urea pre~iously added. The dispersion was stirred without cooli~g until its temperature increased to 18C. ~he highly viscous polyacrylonitrile solution was then left standing at 18C for 120 hours, actinic light being excluded. The solutio~ was briefly degassed and extruded through a circular no~zle 1 (see ~ig. 1a), provided with a~
axial inlet 2 for water, into a 2 m long horizontal coagulation bath, fresh water being introduced at the distant end and diluted nitric acid being removed by an overflow near the extrusion die. ~he coagulated tube was drawn off at a rate of 6 m per hour. The axial inlet was fed with water under a p~es-eure of 15 cm water column. ~he washed tube had 4 mm inside diameter and 1 mm wall thickness. It contained 55 ~0 of water at swelling equilibrium.
. .
~ r ~4~ 0 ~ rom the sr~me hydrogel solution, a thick "monofil"
was extruded without feeding water through the axial inlet.
The thoroughly washed "monofil" had 4 mm diameter, equal to the inside diameter of the tube. '~he tube was then cut to 40 cm long pieces, and the "monofil" to 1.5 cm long piece~ which were then partially dried to about a 20% water content. One end was rounded on a grinder, the other cut in a 45 angle. ~hestopper thus obtained was partially ~welled again in water so that it could be easily inserted into the end of the tube. ~oth the stopper and the tube end were then wetted with dimethyl sulpho-xide. ~he stopper was slid into the tube and the ~hole left ~or ~ hours aside. Then a circular 4 mm hole was bored through the tube just above the stopper. 'rhe enA of the tube was rounded smooth and the catheter washed in luke-warm wa-ter until all dimethyl sulphoxide was removed. '~he other end of the oatheter was stoppered and dipped into a self-vulcanizing rubber latex in a length which is supposed to be exposed to the atmosphere when the catheter is applied to a patient. ~he dipping was repeated until a sufficiently thick rubber layer was obtained. ~he remaining part of the catheter was immersed overnight in a mixture of 75 p. of glycerol with 25 p. of water, wiped off and immersed for one minute into a 85a warm concen-trated sulphuric acid. '~he catheter was then brie M y rinsed in water, immersed for 5 minutes in a surplus of a diluted sodium bicarbonate solution and washed in water again. After having been sterilized with eth~lene oxide the catheter was packed in a sterile polypropylene foil packing containing 20 ~1 of sterile physiologic saline and sealed gas-tightly. ~he physiologic saline may contain, optionally, a suitable anaesthe-tic such as the hydrochloride of diethylaminoethyl p-amino-~e~zoate, and a bacteriCide. ~he catheter was of the "one use" type, but i-t co~ld be also reused, if needed~ and , '~ ' ' . . r~
5~
sterili~ed again at temperatures up to 100C 9 using chemical sterilizing agents.
~xample 2.
160 p. of acrylonitrile were dissolved in 837 p. o~
colorless 65~o nitric acid; 1.2 p. of urea, dissolved in 2 p~ of water, were added. After complete dissolution of the colloidal urea nitrate, the solution was initiated with 1 p. of a 10~
ammonium persulphate a~ueous solution and sucked into a 1000 ml iipette, provided with a gxound joint and tightly stoppered.
~ho pipette was left standing ~or 72 hours at 22C in the darkness and then for 240 hours in a refrigerator at 10C. The highly viscous solution was then extruded at room temperature -through an extrusion die provided with an axial inlet ~or water The polymer solution was extruded by means of carbon dioxide from a pressure bottle at 5 atm. gauge. ~he extruded tube was dra~m off through an aqueous coagulation bath like in ~xample 1, ~he drawing off velocity and the feed of water through the axial inlet were adjusted so as to obtain a coagu-lated and washed tube having a 3.2 mm inside diameter and 0.85 mm wall thickness. Its material - a multi-block copolymer of acrylonitrilewith acrylamide - contained 58 % o~ water at swelling equilibrium and displayed el~stomeric characteristics.
One end of the tube was filled with the same polymer solution by s~cking it into the inclined tube. The tube end was then rapidly coagulated in water, neutralized in a diluted sodium bicarbonate solution and washed in water. ~he coagulated solutio~ formed a stopper, fi~ly ~ound with the tube. ~he end was then rounded by grinding under half-dry condition, and a 3.2 mm opening was bored through the tube at the point where the stopper was nearest to the tube end. After new swelllng in water and wiping the surface with filtering paper, the other end of the tube was stoppered and the catheter was immersed ~ _ 16 -1~4~5Q~
in a mixture of 75 p. of glycerol and 25 p. of water for 9 hours in its whole length. Then the surface was wiped off and the catheter i~mersed in a length of 20 cm with its rounded end down, into 96% sulphuric dcid at 23C. The treatment lasted ~0 minutes. The acid was then rinsed off and the catheter neutra-lized i~ a surplus of a 1~o aqueous sodium bicarbonate solution.
The part not treated with the acid was immersed again in 75 glycerol for 12 hours, the surface wiped off and dipped repeatedLy in a 10% polyvinyl acetate solution in acetone.
~he uppermost layer was obtained by dipping in a self-vulca-nizing ~ubber latex and drying at 85C. The catheter was sterilized and gas-tightly sealed in a polyethylene foil package containing 20 ml of physiological saline containing, if desired, drugs aocording to a physician's prescription. In application to a patient, the part introduoed into urethra was very smooth and ~lippery, while the remaining part exposed to the atmosphere ; -was permanently elastic and non slippery so that it could be easily fixed with an adhesive tape. Its properties remained unchanged during a several weeks lasting application.
Example 3.
~ sing the method aescribed in Example 2, a hydrogel tu~e was prepared having 4mm inside diameter and 0.3 mm wall thickness. The tube was swelled in a 65 % dimethyl sulphoxide, the rest being water, at 60C, and slipped onto a 5 mm thick catheter from plasticized PVC. The hydrogel tube overlapped the end of the catheter by about 15 mm and reached 25 cm from the end. ~he overlapping end, containing still dimethyl sulpho--, ~ide, was then heat-softened and pressed into a hot matrix bored ~hrough polytetrafluoroethylene. Dimethyl sulphoxide was then washed out in luke-warm water whereby the hydrogel tube shrank and adhered firmly to the PVC catheter. The surface was then treated for 45 seco~ds with a 30% sodium lye and thoroughly . .
_ 17 -..
.. : : , . ... . . . . . . ... . .
4~5~
washed, then sterilized and packaged as described in -the fore-going Examples.
Example 4.
A hydrogel tube was prepared in the way disclosed in Example 2, using, however, an extrusion die adjusted to form coag~lated tube having the wall thicker at one side and pro-vided with an axial groove 3 (see Fig. 1b). ~he catheter as a w~ole is diagrammatically illustrated in ~ig. 2. Its end 4 was dipped into a hydrogel solution and shaped according to ~xample 2 in such a way that the groove 3 was filled with the gel up to 10 mm above the stopper. ~urther 30 mm of the tube sur,ace were coated with an aqueous solution of sodium salt of carboxymethyl cellulose. A thi~ hydrogel tube 5 swelled in dimethyl sulphoxide diluted with 30 5~ of water was slipped onto the main tube and left for 4 hours aside. The overlapping end was molded as described in Example 3 and the whole washed thoroughly in water. ~he outer tube 5 adhered fir~ly to the mai~ tube 6. A thin rubber tubi~g 7 was inserted lnto the upper e~d of the axial groove 3 and fixed thereto. After annexing a rubber c~eck valve to the rubber -tubing 7 and washing the car-bo~yymethyl cellulose salt out from the part form~ng the pocket, the pocket 8 co~ld be inflated with physiological saline.
The treatment with a 100C hot mixture of 4 p. of aoncentrated su1phuric acid with 1 p. of glycerol for 15 seconds, neutra-lizi~g and washing made the catheter sur~ace slippery in a desired length ~he remaining part 9 o~ the catheter ~as covered with a sleeve from silicone rubber, swelled previously ~n ~oluene. After evaporating toluene, the sleeve adhered firmly to the catheter, protect~ng in agai~st dr~ing After ha~ing bored or cut the opening 10 the catheter was sterilized and packaged according to ~xample 1.
.~ :
_ 18 - ~ ,; :
S~
~xampls 5.
A catheter was made according to ~xample 2 except that the part to be exposed to the air was manufactured entirely from plasticized PVC and inserted with its tapering end i~to the hydrogel main tube, the outer hydrogel t~in tube described in Example 4 being slid onto the main tube in a length overlapping the joint of the two parts of the catheter.
Example 6.
Surgica~ tubular de~ice of the invention can be also manufactured by polymerization casting under crosslinking con~
ditions. A mold illustrated diagrammatically in ~ig. 3 was used, consisting in two about 40cm long ~lass tubes 11 and 12, the outer one ha~ing a 6 mm inslde diameter, the inner one a 4 mm outer diameter. ~he tubes ~ere assembled coaxially by means of two stoppers 13 and 14 provided with holes for filling and deaera-tion. ~he polyethylene stopper 14 formed s~m~lta-neously a filling funnel. ~he inserted end 15 Qf the tube 12 was sealed round and the end 16 of the tube 11 was closed with `'' a silicone rubber stopper 17 hollowed out to mold the rounded end of the casting. ~he mold was pre-cooled to -30C and '~uickly filledup with an equally cooled mixture of 72 p. of a 70 % aqueous zinc chloride solution and 27 p. of anhydrous acrylonitrile. The cool mi~ture was initiated immedia-tely before filling into the mold by adding 0.5 p. o~ a 5% aqueous pot,assium pyrosulphite and 0.5 p. o~ a aqueous ammonium per-,~ulphate solutions and stirring thoroughly, while cooling from out5ide with an ethanol bath to which solid carbon dioxide ,-was gradually added so as to keep the bath temperature at about -25 to about -35C, ~he lilled mold was then put into a freezer at -~0C. The zinc chloride solution contained a sufficient amount of ferric chloride so that the polymerization .
-- 19 _ ., .
s~o proceeded rather rapidly even at low temperatures. After 6 hours in the refrigerator the mold was taken out and left standing at room temperature for further 2 hours. Then the inner glass tube 12 was pulled out, stoppers 14 and 17 removed and the strong rubbery tube from plastici~ed polyacrylonitrile was pulled out using a double hook from a ~hick steel wire, catching the stopper 13 polymerized in t~e rubbery gel. ~he removal of the rubbery polymer casting was comparatively easy due to its high elasticity and strength. The end with the stopper 13 was cut off, a hole was bored at the closed end and the molding was then hanged on the lid of a tall glass beaker ha~ing 200 cf concen-trated hydrochloric acid poured on its bottom. A
slow stream of hydxogen chloride, d$1uted with 90% of nitrogen, was led slowly through the molding from a capillar~ tube. After 36 hours at 18~ the partial hydrolysis was flnished. '~he molding was immersed into a 0.5 % sodium bicarbonate aqueous solution, hanging from the lid of another tall beaker. The precipitated white voluminous sediment was perindicall~ sucked of~ from the bottom and replaced with the same ~olume of fresh bicarbonate solution. l~hen no further precipitate was formed, the molding was washed first in diluted nitric acid and then in water to neutral reaction. The molding was transparent, pliable and elastic in swelled condition. I-t~ outer diameter was 5 mm. ~he open end was stoppered and a thin rubber sleeve with 4.5 outside diameter was sWelled in ben~ene so as to be easily slid on the catheter in a length of about 10 cm. After evaporating benzene the rubber sleeve shrank and adhered firmly to the catheterO ~he remaining part ~ith the rounded end was dried to a 20% water content and immersed for 10 seconds into a 50C warm fuming sulphuric acid, rinsed with water and neutralized with a diluted sodium bicarbonate solution. After -- ~0 --washing to neutrality, the cathe-ter ~as swelled again with water and sterilized and packaged as described in the foregoing ~am-ples.
Example 7.
8 p. of anhydrous acrylonitrile and 8 p. of crystalline acrylamide were dissolved in 84 p. of a mixture, consisting of 3 volume p. o~ 70% aqueous ~inc chloride solution and 2p. o~ satu-rated aqueous calcium chloride solution. ~he mixture was ini-tiated wlth 0.15 ~ of potassium pyrosulphite and the same amount -o~ ammonium persulphate, related to the sum of the two monomers.The solution was then stirred under carbon dioxide for 6 hours.
Thereafter a half portion of the same redox initiator was added and the stirririg was continued at ambient temperature for 4 further hours. ~he viscous solut1on thus obtained was deaera-ted, using a water jet pump and extruded using an extrusion die as described in ~xample 1. Wash waters were precipitated with sodium bicarbonate and the precipitate utilized for the recovery 3~ Zi~C chloride. The tube was cut to pieces of an apprDpriate length, and a stopper fromthe same hydrogel was cemented into one end of each tube, using a iO% solution of the same hydrogel i~ dimethyl sulphoxide. ~he catheter was put aside for 3 hours, dimethyl sulphoxide washed out in water, the catheter dried to a content of 20% water and the end rounded. An opening was bored just above the stopper. The catheter was swelled in water to equilibrium and two thiras o~ its length was immersed ~or 40 seconds in an 80~ warm mixture o~ 4 p. concentrated ~lphuric acid with 1 p. of anhydrous ethylene glycol. ~he acid was then rinsed off with a stream of tap water and the catheter ~eutralized in a surplus of a diluted sodium bicarbonate solution. ~he remaining one thixd OL its length wa~ then co~ered with a thin rubber sleeve as described in ~ample 6.
..
~ 4~ S ~ 0 Prior to the partial coating with the rubber sleeve, the catheter was immersed for 30 minutes into an 80C warm aqueous solution of 0.5 % of formaldehyde and 0~5 % of concentrated hydrochloric acid and then washed thoroughly in water. ~he catheter was wiped with filtering paper and left for 30 minutes in the air at ambient temperature. Then it was immersed for 30 seconds into a 80C warm mixture of sulphuric acid and glycerol 1:4~ rinsed, néutralized~ washed, sterilized and packaged as described in Example 1, ~ample,8.
~he process described in Example~ ~ was repeated except that the outer thin tube was only cemented to the main tube at the two ends in a length of about 15 mm, ~hus, the space between the hydrogel tubes could be filled with physiologic ~aline containing drugs, if desired, ~he outer thin tube was thereby slightly pressed against the urethra closing the latter tightly. ~he end protruding into the bladder was sim~ltaneously inflated.
Example ~.
The hydrogel tube was formed by extxusion according to Example 1, interrupti~g, however, the water inlet into the axial mandrel periodically in about 90 cm intervals and increasing simultaneously the rate of extrusion so that a hydrogel stick with full cross section was formed bet~Jeen two closed endings as shot~ in Fig, 4 in an axial section. The tubes as well as the sticks be~Jeen them were cut in the middle so that the ends could be rounded and bored in half-dry condition. ~-~
~he dead space in the end could be removed either by inserting a bevelled stopper and cementing it to the interior of the tube end, or by introducing a suitable amount of a highly vi9cous hydrogel solution through the side opening and coagula-ting and washing it in water.
, . . .
s~
In the same way, thin tubes, closed at one end, can be made, to be slipped onto the main tube or onto a ready made cathetex.
Example 10.
A mold like that illustrated in ~ig. 3 was made of poly$etra nuoroethylene in such a way that the outer assembled tube consists in two exactly fit-ting longitudinal halves clamped tightly together.- ~he end of the inner_~ube was bevelled so as to exclude dead space at the opening. ~he mold was filled with a homogeneous mixture of 30 p. of acrylonitrile, 69 p. of 65%
~itric acid, 0.2 p. of urea, 0.6 p. of potassium persulphate~
1 p, of acetyl~cetone and OJOO2 P. of ferric nitrate, precooled to 0C. The filled mold was kept at -1C for 24 hours~ then left standing at room temperature for 6 hour3, heated for one hour to 30C and then left standing for 300 hours at 14C, ~he mold was then dismantled, the molding having the inner tube still in washed in water to neutral reaction and the inner tube pulled out. A 3.5 mm hole was cut at the end using a circular knife, the catheter left for 30 minutes in the air to get the surface almost dry, and then it was exposed to di-luted vapors of chlorosulphonic acid ~or two minutes. Neutra-l~zing, washing, and sterilizing followed. ~he part supposed to protrude in the air during the application to a patient was covered with a thin rubber sleeve as described in Example 6.
Example 11.
12 p. o~ acrylonitrile were dissolved in 88 p. of a mixture of 70~o aqueous zinc chloride solution and saturated calcium chloride solution (volume ratio 3 2)o ~he mixture was cooled to -10C, whereafter 0.015 p. of potassium pyro-sulphite and 0.02 p. of ammonium persulphate were stirred in.
~he polymerl~ing mixture ~as cooled while stirring under inert ~ L~4~5~(~gas so that the temperature did not exceed 20C. Zinc chloride solution contained a sufficient amount of catalytically active impurities, particularly iron and titani~m compounds, so that it was not necessary to add ferric or cupric salts as usual.
~he very viscous solution thus obtained was heated to ~0C
and deaerated. It was then e~truded as described in ~xample 1 into a coagulation bath containing 45 ~0 of zinc and calcium chlorides in the same ratio aa used in the polymerization step.
~he concentratio~ of the salts was kept constant by adding water countercurrently and removing the bath gradually near the extrusion die. The coagulated tube was drawn off with such a velocity that a tube with desired inside and outside diameter was obtained, and the path length in the bath was chosen so as to obtain a rubbery salt plasticized polyacrylonitrile con-taining about 30~ of the polymer. ~he rubber-like transparent tube was wiped off between two rollers coated with foamed rub-ber and cut to about 40 cm long pieces. ~he tubes were flushed with dry air to remove the remaining bath from their interior and hanged with their ends into the holes of a perforated plate, leaving the passage through the tubes free. ~he perforated plate formed a horizontal partition of a 20 litres PV~ container filled with nitrogen containing 5 % of hydrogen chloride and 0.2% of formaldehyde. ~he gas circulated by means of a by-pass and a small circulating pump through the gel tubes and round them. ~he partial hydrolysis lasted 24 hours at 19C
~he tubes were washed ten times in a diluted aaueous sodium bicarbonate solution and finally in distilled water. A further treatment followed, according to ~xample 1.
Similar rubbery tubes plasticized with zinc chloride solution can be obtained by only par-tially coagulating the ~ - 24 -, ~., .
.. , , ~.. ,' .
: ~ , 4~5`~0 polyacrylonitrile solution in plain water so that a coagulated skin covers a core containing a uncoagulated viscous solution. ..
After several hours at room temperature the concentration of zinc chloride becomes uniform throughout the whole cross section due to dif~usion. ~hus all what is needed is to increase the polymer concentration to about 25 - 35 % and to leave the tube until the zinc chloride concentration is equalized. ~he tempe-rature and the time of the partial hydrolysis with hydrogen chloride, as well asthe co.nce.ntration of the latter, are adjusted 10 so as to obtain an uniformly hydrolyzed polymer.
Instead of using a gel stopper, it is possible also to stop periodically the water inlet into the axial mandrel of the extrusion die and to thro~t.le simultaneously the feed o~ the polymer solution so that the tube gets periodioally closed as shown in Fig. 5. ..
Example 12.
150 p. of anhydrous acrylonitrile were dissolved in 846 p. of 65~ colorless nitric acid, and 1.2 p. of urea, dissolved in 2 p. of water, was stirred therein. ~he solution was cooled do~m to -5C and the polymerization started by addi-tion of 1 p. o~ a 10~o aqueous solution of ammonium persulphate and 1 p. o~ acetyl acetone and 0.001 p. of ferric nitrate. ~he solution was kept at 0C for 24 hours, left standing overnight at room temperature and heated while stirring slowly to 30C :~
for 2 hours. ~hereafter the highly viscous solution was left standing for 300 hours at 10C. ~he highly viscous so.lution was then extruded as described in ~xample 2, and only the not yet fully coagulated tube near the extrusion die was led through a device illustrated in Fig. 69 consisting of a hollow ring 18, the inner wall o~ which was formed by a rubber tube 19 inflated periodically.by leading compressed air into the hollow ring - 25 - ;
r<l ~ o~sl~
18. The device moved, when inflated1 along a short path relatively to the tube, returning when deflated into the starting position. The effect was similar to that shown in Fig, 5. ~he washed tube was cut to individual ca-the-ters which were then made slippery by introducing an:ionic neutralized groups into the surface layer ~nd provided with a rubber sleeve as described in the foregoing ~xamples.
.
;
,
ly or partially of hydrophilic copolymexs o~ acrylonitrile con-taining either acrylamide or acrylic acid and, if desired, a small amount of other co-monomers.
The above mentioned copolymers swell in water or aqueous solutions. When they are swollen, they are pliable, elastic and strong. Their properties can be changed by changing the degree ; -of hydrolysis, when the copolymer was prepared by partial hydro-lysis of polyacrylonitrile, or by changlng the content of hydro-philic units, when the oopolymer was obtained by copolymerization of a monomer mixture. ~t lower degrees of hydrolysi~, or with lower content of hydrophilic units, the copolymers can be oriented by stretching. ~hey have in an oriented state a comparatively high ela~ticity. At a higher content of hidro~hilic units, they are rubbery. ~hey cont~in up to about 85~o water at the swelling equilibrium.
~he outer layer or surface layer, cf the part of the su.rgical device which is introduced into the cavities of the living body, suoh as into the larynx, the tracheal the urethra etc., contains neutralized anions as side-substituents, such as carboxylic, sulphonic, sulphuric or phosphoric groups attached to the copolymer main chain by covalent bonds. ~he part of the device which is exposed to the atmospnere during the application to the patient is permanently protected against drying by a layer of a polymer or copolymer impermeable for water and wate:r vapors.
~he water-swelled copol~ner hydrogel according to the invention can also serve to sustain the release of appro-'"' ' "
': , .
.
~ SQ O
priate drugs which can be absorbed therein prior or during the storage.
Up to now~ the surgical tubular devices of the abo~e me~tioned kind are manufactured from rubber or from highly plasticized polyvinylchlQride, or from other similar hydro-phobic polymers imperm~able for water and aqueous ~olutes.
Prom a physiological standpoint, such polymers are very different from the living ~issues~ ~heir surface has a compa-ratively high coefficient of friction with respect to the mucous membranesO ~hus, the surgical devices used hitherto often hurt the t1ssues. ~o a~oid this, they must be lubricated before use, conseque~'ly increasing infection hazard.
Moreover, hydrophobic catheters, intubation sounds and similar cannot absorb drugs which would then gradually diffuse into the surrounding mucous membrane.
It has been therefore suggested to provide these h~drophobic tubular devices ~ith a thin layer of sparingly cross-linked glycol methacrylate polymer having a water intake of usually about 40 % by weight, and thus being capable to absorb water-soluble drugs. ~he mai~ drawback of such coati~gs is that a~ intermediate layer must be formed first, on which the hydrogel i5 laid by cross-linking polymerization of a mono-mqr mixture. ~he intermediate layer must have a swelling capa-city lower than the outer hydrogel layer and simultaneously a good adhesion to ru~ber or plasticizea PYC, otherwise the hydrogel layer would easily separate. ~he tenacity and elasti-city of tha cross-linked ethyle~eglycol methacrylate polymers is comparatively low and their layer must ~ot be too thick.
~hereby the possibility to i~corporate a sufficient amo~t of drugs is rather limited.
.. ',~'.'.,..... ~11 .
It has been already suggested to manufacture tube~
entirely from swelled copolymers of acrylonitrile wlth acryla-mide, said tubes being provided with highly slippery surface layer. However, simple tubes of this kind cannot be directly used as intubation or sounding tubes or catheters, ~hey rather form a starting a material for the surgical tubular device ac-cording to the present invention.
It has been found that a faulness functioning of such devices can only be obtained if the part which is exposed to the a-tmosphere during the application to a patient is protected against drying as well as against slipping into the cavities of the living body. A hydrophobic layer prevents the protected part from bein~ shrunk and brittle by drying, As a result, the hydrogel t-ube remains elas-tic and pliable in lt~ whole length and be ea~ily joint with necessary supplementary parts such as funnels, syringes, metering pumps and outlets of containers, by slipping its end on a fitting. As hydrophobic protecting layer, a natural or synthetic rubber can be applied, by using a self vulcanizing latex and dipping therein the respective part of the tubular de~ice. Alternatively, an insulating slee~ing from silicone or other rubber can be slipped onto the hydrogen tube. The putting on is easy iE the sleeving is first ~welled in a volatile liquid such as benæene or toluene. After evapora-ting the swelling liquid, the sleeve shrinks to its previous inside diameter and adheres by its high elasticity firmily to the hydrogel tube~
The part of the tubular device intended to be introduced into a cavity of a living body i~ made ~lippery by a suitable chemical treatment, forming anionic side groups covalently bonded with the copolymer. ~s anionic groups~ carboxylic, sulphonic, sulphuric and pho~phoric acid groups neutrali~ed '' ' "' ' ' ' -- ~04~50~) with physiologically innocuous cations suoh as sodium, potas-~um or lithium cations are particularly suitable. ~hat treat ment only affects a thi~ surface layer which is thereby made extremely slippery, the main part of the cross-section of the tube remaining unchanged.
Suitable chemical agents are, e.g., aqueous solutions of alkali metal hydroxides, causing a saponification of the -nitrile and amids groups to carboxyls~ or mixtures o~ concen-trated sulphuric acid with glycerol or other soluble polyol, or rapors of chlorosulphonic acid or sulphur trioxideO Groups o~ phosphoric acid can be also introduced9 using known methods.
~ he shape of the surgical device according to this in~ention does not substantially dif~er ~rom that o~` the known dev~ces made from rubber or plastici~ed PVC. ~he extremi-ty o~ that device i~ ~ree o~ sharp edges and preferably rounded, with either axial or side opening. Any complicated ~orm can even be made using special extrusion dies and inflatable pockets ~rom highly elastic hydrogels based on copolymers of acrylonitrile with acrylamide or acrylic acid. In~latable pockets ~rom part o~ thin hydrogel tubes are slid on the tubular device and cçmented thereto but partially.
~ he copolymers from which the hydrophilic part of the device i~ made should not contain more than 80 molar percent of acrylonitrile units and preferably 40 to 65 molar percent, otherwise the desired character of elastic hydrogel~ could not be achieved. Then~nimUm co~te~t of acrylo~itrile units i9 determined by requirements concerning the physical parameters such as the toughness, the elasticity, the mod~lus, the swelling capacity etc. Said parameters depend on the density o~ the non-covalent network ~ormed by the polyacrylonitrile within the water-swelled amorphous hydrophil~c chains consisting o~ acryl-amide or acrylic acid units. Consequently, i~ a random copo-. .
_ ~ _ , ` ~34~5~
ly~er is used, the molar portion of acrylonitrile units shouldbe higher -than in case of a block copolymer the undivided long polyacrylonitrile segments of which have better opportunity to form crystalline domains than the same number of acrylonitrile units dispersed randomly along the chains. Although block copo-lymers of this kind are shape-retaining, even if the molar por-tion o~ acrylonitrile un~ts is very low, and have a swelling capacity in water exceeding 95 % by weight, it is advisable to keep the content of acrylonitrile units higher than about 20 (molar) and she swelling capacity in water lower than about 80 % (weight), in order to maintain the strength and pliability wlthin reasonable limits. ~-~ est results are obtained if the copol~mer used is a multi-block copolymer containing in each macromolecule several ~equences o~ acrylonitrile units alternating with sequences of acrylamide units. Such mul-ti-block copolymers can be obtained by homogeneous acid hydrolysis of polyacrylonitrile plasticized or dissolved in acidic solvents of polyacrylonitrile having a negligible chain transfer constant. ~he gels or solutions are first exposed at temperatures at which first acrylamide units are formed on the polyacrylonitrile chains, e.g. in the case of concentrated nitric acid at temperatures above 20C. ~hen the temperature is decreased so that no further isolated acrylamide groups are formed, the hydrolysis spreading from the acrylamide units already formed by "zipper mechanism"~ Strong mineral acids can be used as ~olvents and sim~ltaneously hydrolytic agents, e.g. concentrated nitric or phosphoric acid, or slightly diluted sulphuric acid. Sulphuric acid is a very strong hydro-lytic agent but nitric acid is a better solvent. ~hu~, it is advantageous to use concentrated nitric acid as solvent and to add a small amount o~ sulphuric acid to -the . ~ . ~ . . . . .
~4~S~) solution~ Polyacrylonitrile in the form of a fine powder can be dispersed in nitric acid at temperatures below 20C at which the rate of swelling is low, and then the temperature can be slowly increased while stirring so that the dispersion is gradually transformed into a viscous homogeneous solution. If an acrylonitrile homopolymer is used, the ~olution is briefly heated up to about 30 - 40C to initiate the zipper hydrolysis, and then leLt standing at 0 - 20C until the desired degree of hydrolysis is reached. ~he lower the temperature is, the longer the sequences or "blocXs" in the copolymer are~ HoweYer, the nece~sary time increases, whe~ the temperature decreases.
~ est results are obtained if the steps o~ the hydro-lysis are distinctly separated, Similarly, i~ acrylonitrile is polymerized directly in an acidlc solvent such as in nitric acid or in an aqueous solution containing zinc chloride or lithium bromide, the step of partial hydrolysis should be distinctly separated form the step of polymerization. This oan be achieved, -e.g.~ by polymerizing acrylonitrile in concentrated nitric acid at low temperatures, using a suitable redox initiator. A~ter the polymerization is finished, the rate of hydrolysis is increased either by adding sulphuric acid, or by increasing the temperature, and then decreasing it again, as mentioned above.
I~ the polymerization is carried out in concentrated aqueous solutions co~taining zinc chloride, lithium bromide or other salts capable of dissolving polyacrylonitrile, the rate o~ -hydrolysis may be increased best by dissolving hydrogen halide in the polymer solution, or respectively in the solvent and the pla~ticized gelO ~his method ca~ be perfor~ed advantageously in such a way that a viscous solution of polyacrylo~itrile in ~0 one o~ the above mentioned salt solution~ is extruded into a coag~lating bath in which the tube i9 only partially coagulated.
SQO
~he tube is then left standing for several hours until the salts are distrlbuted by diffusion, so as to obtain a rubbery gel containing from about 20 to about 40 ~ of polyacrylbnitrile.
~he gel can be then partially hydrolyzed either by increasing the tempera-ture to about 70 to about 120C, or better by treat-ment with gaseous hydrogen halide at -20 to about 30C until the desired degree of hydrolysis is achieved. ~he salts are .
then washed out and the hydrogen halide neutralized; in the case of a zinc chloride containing solvent, a diluted aqueous solution of a substance yielding anions forming insoluble ~inc compounds is preferably used. Such anions ~re carbonates7 bicarbonates, chromates, phosphates, hydroxides and others contained in ~olution. ;:
Although acrylamide is preferred as hydrophilic compo-nent, e~pecially if formed by a cont.rolled partial acid hydro-lysis as mentioned above, it is also possible to u~e other hydrophilic components such as acrylic acid9 methacrylamide, methacrylic acid, sodium ethylene sulphonate, sodium styrene sulphonate7 maleine anhydride, itaconic acid or other mono-: `
olel~nic acids capable to copolymerize with acrylonitrile.
N-alkyl- or N-hydroxyalkyl amides of acrylic and me-thacrylic acid can be also used. Hydrophilic co-monomers can be incorporated in ~uch an amount that the partial hydrolysis can. be dispensed with, Best resul-ts are obtained if the amount of co-monomer units in the starting copolymer prior to the partial hydrolysis is lower than about 10 mol. percent, and preferably lower than ~-about 2 %. Beside the hydrophilic co monomers mentioned in the preceding paragraph, also hydrophobic co-monomers can be employed such as lower al~yl esters of acrylic and methacrylic acids, vinyl pyridine 9 vinyl carbazole, styrene, alpha-methyl , . , . .. . . . ~ . .
5~0 styrene, alpha-ohlor styrene, or vinyl pyrrolidone.
It is also possible to polymerize acrylonitrile under crosslinking conditions in said acidic solvents having negli-gible chain transfer constant, either by adding a s~all amount of a suitable crosslinking agent such as Zthylene glycol dimethacrylate or N,~-methylene bis-methacrylamide, or by carrying out the polymerization at such a high monomer concen-tration that the chain transler onto the mo~omer causes cross-linking. In these cases, the polymerization must be carried out in a mold, because the crosslinked gels cannot be shaped.
A lyogel elastic tube is obtained, consisting of polyacxyloni-trile plasticized with eOg. nitric acid or aqueous ~inc chloridesolution. Partial k~drolysis is then carried out in the above described manner.
Simple sounding tubes used e.g. ~or taking samples of gastric juice or for the removal of secretions can be made from tubes having their end tips rounded by working in dxy or half-dry state, or by pressing at incxeased temperatures in presence of a polyacrylonitrile solventO ~he part to be exposed to atmosphere is coated with a suf~iciently elastic polymer such as rubber to prevent drying. ~he other part is made slippery by treating with ~trong al~ali lyes or other chemical agents oapable of formi~g anionic side groups on the copolymer chain.
side opening can be made with or without closing the original axial opening of the tube. ~he closing of the end to be inserted into the cavity of the living body can be carried out ~n various ways, e.g. by cementing a shaped stopper from the same or similar h~drogel into the ope~ing, or b~ shaping the end of the not yet fully coag~lated tube just leaving the sxtrusion die.
For cementing a shaped stopper into the end of the tube, any polyacrylonitrile solven-t can be used such as , ~4~5~0 dimethyl formamid~ or dimethyl sulpho~ide. ~he cementing is preferably carried out with both stopper and tube swelled with water, glycerol or similar, because dry hydrophilic pol~-mers - ~erogels - tend to spontaneously cracking i~ cont~ct w~th solvents.
According to another embodiment of the manufacturing process, usual surgical tubular devices ~rom rubber or plasticized PVC are coated with a layer of the aforesaid hydro-philic acrylonitrile copolymers either by dipping them into a ~opolymer solution and coagulating the latter, for example in cold water, or by spraying or painting said copolymer solu-tions, with also a subsequent coagulation, or, better, by slip-ping a thi~ tube from said hydrophilic swelled copo:Lymer onto said tubular device. ~he slipping of the thin tube on the device is made easier by previously swelling said thin hydrogel tube in a mixture of a polyacrylonitrile solvent with water9 or by increasing temporarily the lnside diameter o~ the thiD
tube by radial orientation, In the ~irst case, the solvent of polyacrylonitrile is washed out and the outer tube shrinks, '!' '~'' adhering ~ir~y to the tubular device. In the other case, the same effect i~ attained by immersing into hot water in which the radial orientation relaxes to the original inside diametexO
~he rounded end can be covered unifo~ly with the hydrophilic copolymer by molding the overlapplng thin hydrogel tube in presence of a solvent of polyacrylonitrile and removi~g the solvent by washi~g i~ water. It also possible to prepare the ~hin hydrogel tube with ths end closed at the extrusio~ die.
~he thin outer tube c~n cover the part to be inserted, the part to be exposed to atmosphere being left bare.
More comple~ surgical tubular devices provided with one or two c4axial channels for flushing out the urinary s~
bladder with drug solutions, or provided with an inflatable pocket holding the tubular device in desired position, can be manufactured using suitable ex~rusion die~ with more th~n one inlet for coagulating liquid so that coaxial channels are formed. Instead of such tubular channels coaxial grooves on the tube surface can be created using suitable extrusion dies ~uch as shown in ~ig. 1b and 1c o~ the accompagnying drawing.
~he tube with groo~es is covered by a thin hydrogel tube of the same or similsr, highly elastic hydrogel. If the end of the tubular device is ~ormed by dipping into a hydrogel solution and coagulation, a~y part o~ the groove or grooves which has to remain free can be protected from filling with hydrogel by a suitable water-soluble polymer such as carboxymethyl cellulose which is finslly washed out. ~nother way to preser~e the groove i~ to iDsert a wire or similar which is pulled out after the fiDished treatment.
~ he upper hyarogel tube can be cemented to thé main tube except the part forming an inflatable pocket which communi-cates with one end of the cha~nel, the other eDd of the channel being joint with a suitable filling devioe provided with a check valve. ~he part forming the pocket can be previously coated with sodium salt of carboxymethyl cellulose or with another ~rater-soluble polymer which is washed out after the remaining parts have been cemented togetherO
~ he inflatable pocket forming an integral part of the outer thin hydrogel tube possesses the advantage that the whole surface is entirely smooth. Physiologic saline with which ~he pocket is filled may contain drugs such as bacteriostatics7 ~actericides and anaesthetics which dif~use gradually through the inflated hydrogel membrane. ~he main tube can have a recess underneath the inflatable pocket, if desired.
_ 10 --5~Q
The outer thin tube can be closed at one end before being slipped onto the main catheter tube~ forming a slender ~ack 80 that the whole catheter including its tip is uniformly and smoothly covered with hydrogelO The l~ecessary side-opening - can be made before or after slipping the thi~ tube onto the main tube.
To avoid any dead space near the opening, the end of ~he closed catheter can be filled with a stopper ceme~ted thereto ~
or with a polymer solution coagulated afterwar~s. ;
I~ the main tube of the tubular aevice is made from rubber or similar hydrophobic material, it is only suf~icient to cover with a thir hydrogel tube the part to be introduced into the body, Another possibility is to make the whole part to be introduced into the living body of hydrogel, the part to be exposed to the atmosphere being made from rubber or similar~
~he two parts are joint by cementing together their ends adapted thereto.
~ he outer hydrogel thin tube can be cemented to the main tube on the ends only so that the whole space between them can ~e filled with physiologic saline containing, lf desired, suitable drugs. Thereby the outer tube is pressed against the mucous membrane of e.g. the urethra, sealing it completely.
The end protruding lnto the bladder is simultaneously inflated to prevent the catheter from slipping out.
~ he hydrophilic copolymer of acrylonitrile can be subsequently cross-liDked,if desired. The catheter is then treated with a suitable cross-linking agent such as an aqueous aoid formaldehyde solution, or a suitable diepoxide reacting with hydroxylic and amidic side groups, or with a di-isocyanate.
~0 ~he cros~-linking with formaldehyde can be also carried out in an appropriate stage of waæhing when the gel contains still . ' . ' -5~nitric or sulphuric acidO When using gaseous hydrogen halide to increase the rate of hydrolysis, gaseous formaldehyde can be admixed thereto. ~he cross-linking can be carried out either be~ore imparting anionic groups to the surface layer, or there-a~ter.
If the catheter or similar is sterilized with ethylene oxide, some hydrophilic groups -0~ H2CX2o7nH may be formed on the surface, decreasing also the coef~icient of friction of the swelled hydrogel.
~he hydrogels absorb easily various drugs, pexmitting sterilization and sustained release of drugs for a long time.
An important step in manufacturing surgical tub~1ar devices isthe shaping of the end tip which is introduced into the body. The end must be quite smooth, suitably rounded and inseparably joint with the tube. ~here are several ways how to form the ending. First of all, it i~ possible -to mold the extruded tube just at the extrusion die when the tube is not yet fully coagulated, c:~osing simultaneously the water inlet through the axial mandrel. Thereby the inside diameter is reduced to zero and a stick or a monofil is temporarily formed instead of a tube. In order to maintain the diameter constant, ~he feed of the polymer solution can be simultaneously increased.
A~ter a short time interval the ~eed of water i9 renewed and the ~eed of the polymer solution reduced to the original value -compare ~ig. 4 and 5. ~he thick monofilament sections are then cut in the middle, and so are the tube sections between them.
The ends are rounded by grinding, preferably under a not enti-rely dry condition. ~he ends can be also frozen before grinding.
Another way is to mold the ends using heat and pressure in 3 presence of a solvent of polyacrylonitrile.
_ 12 -It is also possible to mold the extruded tube using a suitable tool instead of interrupting the inlet of the coaOGula~
ting liquid through the axial mandrelO Such tool may be a sort of pliers, or a ring-like inflatable air tube constricting the extruded tube along a short path - see ~ig. 6. ~he process can be automatized.
Another way to close the end of the tube consists in dipping the end into a viscous hydrogel solution and sucking the latter into the tube to the desired level. ~he tube is prefe-rably inclined 90 as to obtain a bevelled bottom. ~he hydrogel solution is rapidly coaO~ulated in water and the solvent washed out. Using a hydrogel stopper has been already men-tioned.
The end of the tubular device can be worked mechani- ;
cally. Finally the surface i9 made slippery under wet condition by imparting anionic groups thereto.
In the accompagnying drawing, Fig. 1 illustrates diagrammatically three different cross-sections of the hydrogel -main tube, together with cross-sections o~ the corresponding cxtrusion dies.
Fig. 2 is an axial sectlon of the catheter according to Example 4. Fig. 3 illustrates a glass mold as described in Example 5, employed for polymerization-casting under cross-linking conditions.
Fig. 4 is an axial section through the extruded tube at the point where the feeding of the coagulating bath through the axial inlet of the die was temporarily interrupted and the feed of the po~ymer solution simultaneously increased to keep the outer diameter unchanged.
Fig. 5 is an axial section of an extruded tube at the point where the feed of the coaO~ulating liquid through the axial mandrel was entirely interrupted, the feed of the polymer solution being simultaneously throttled, as described in :. . .
~4~S~
~xample 11.
Fig. 6 shows diagrammaticallyg in an axial section, a tool for molding the just extruded, only superficially coag~lated tube. The result is similar to that shown in ~ig. 5 (compare ~xample 12).
Several methods for manufacturing surgical tub~lar devices of the invention are described in the following non-limitative ~xamples. All parts and percentages are given by weight, if not stated otherwise.
Example 1.
Polyacrylonitrile with an average degree of polyme-rization of 4500, prepared by precipitation polymerization in an aqueous medium using an ammonium persulphate - potassium pyrosulphite redox initiator, was dried under reduced pressure at 40C and ground to fine powder. ~he powder was dispersed in the ratio 1:12.5 (by weight) in 70~ colorless nitric acid cooled to -42C, with 0,1 ~o of urea pre~iously added. The dispersion was stirred without cooli~g until its temperature increased to 18C. ~he highly viscous polyacrylonitrile solution was then left standing at 18C for 120 hours, actinic light being excluded. The solutio~ was briefly degassed and extruded through a circular no~zle 1 (see ~ig. 1a), provided with a~
axial inlet 2 for water, into a 2 m long horizontal coagulation bath, fresh water being introduced at the distant end and diluted nitric acid being removed by an overflow near the extrusion die. ~he coagulated tube was drawn off at a rate of 6 m per hour. The axial inlet was fed with water under a p~es-eure of 15 cm water column. ~he washed tube had 4 mm inside diameter and 1 mm wall thickness. It contained 55 ~0 of water at swelling equilibrium.
. .
~ r ~4~ 0 ~ rom the sr~me hydrogel solution, a thick "monofil"
was extruded without feeding water through the axial inlet.
The thoroughly washed "monofil" had 4 mm diameter, equal to the inside diameter of the tube. '~he tube was then cut to 40 cm long pieces, and the "monofil" to 1.5 cm long piece~ which were then partially dried to about a 20% water content. One end was rounded on a grinder, the other cut in a 45 angle. ~hestopper thus obtained was partially ~welled again in water so that it could be easily inserted into the end of the tube. ~oth the stopper and the tube end were then wetted with dimethyl sulpho-xide. ~he stopper was slid into the tube and the ~hole left ~or ~ hours aside. Then a circular 4 mm hole was bored through the tube just above the stopper. 'rhe enA of the tube was rounded smooth and the catheter washed in luke-warm wa-ter until all dimethyl sulphoxide was removed. '~he other end of the oatheter was stoppered and dipped into a self-vulcanizing rubber latex in a length which is supposed to be exposed to the atmosphere when the catheter is applied to a patient. ~he dipping was repeated until a sufficiently thick rubber layer was obtained. ~he remaining part of the catheter was immersed overnight in a mixture of 75 p. of glycerol with 25 p. of water, wiped off and immersed for one minute into a 85a warm concen-trated sulphuric acid. '~he catheter was then brie M y rinsed in water, immersed for 5 minutes in a surplus of a diluted sodium bicarbonate solution and washed in water again. After having been sterilized with eth~lene oxide the catheter was packed in a sterile polypropylene foil packing containing 20 ~1 of sterile physiologic saline and sealed gas-tightly. ~he physiologic saline may contain, optionally, a suitable anaesthe-tic such as the hydrochloride of diethylaminoethyl p-amino-~e~zoate, and a bacteriCide. ~he catheter was of the "one use" type, but i-t co~ld be also reused, if needed~ and , '~ ' ' . . r~
5~
sterili~ed again at temperatures up to 100C 9 using chemical sterilizing agents.
~xample 2.
160 p. of acrylonitrile were dissolved in 837 p. o~
colorless 65~o nitric acid; 1.2 p. of urea, dissolved in 2 p~ of water, were added. After complete dissolution of the colloidal urea nitrate, the solution was initiated with 1 p. of a 10~
ammonium persulphate a~ueous solution and sucked into a 1000 ml iipette, provided with a gxound joint and tightly stoppered.
~ho pipette was left standing ~or 72 hours at 22C in the darkness and then for 240 hours in a refrigerator at 10C. The highly viscous solution was then extruded at room temperature -through an extrusion die provided with an axial inlet ~or water The polymer solution was extruded by means of carbon dioxide from a pressure bottle at 5 atm. gauge. ~he extruded tube was dra~m off through an aqueous coagulation bath like in ~xample 1, ~he drawing off velocity and the feed of water through the axial inlet were adjusted so as to obtain a coagu-lated and washed tube having a 3.2 mm inside diameter and 0.85 mm wall thickness. Its material - a multi-block copolymer of acrylonitrilewith acrylamide - contained 58 % o~ water at swelling equilibrium and displayed el~stomeric characteristics.
One end of the tube was filled with the same polymer solution by s~cking it into the inclined tube. The tube end was then rapidly coagulated in water, neutralized in a diluted sodium bicarbonate solution and washed in water. ~he coagulated solutio~ formed a stopper, fi~ly ~ound with the tube. ~he end was then rounded by grinding under half-dry condition, and a 3.2 mm opening was bored through the tube at the point where the stopper was nearest to the tube end. After new swelllng in water and wiping the surface with filtering paper, the other end of the tube was stoppered and the catheter was immersed ~ _ 16 -1~4~5Q~
in a mixture of 75 p. of glycerol and 25 p. of water for 9 hours in its whole length. Then the surface was wiped off and the catheter i~mersed in a length of 20 cm with its rounded end down, into 96% sulphuric dcid at 23C. The treatment lasted ~0 minutes. The acid was then rinsed off and the catheter neutra-lized i~ a surplus of a 1~o aqueous sodium bicarbonate solution.
The part not treated with the acid was immersed again in 75 glycerol for 12 hours, the surface wiped off and dipped repeatedLy in a 10% polyvinyl acetate solution in acetone.
~he uppermost layer was obtained by dipping in a self-vulca-nizing ~ubber latex and drying at 85C. The catheter was sterilized and gas-tightly sealed in a polyethylene foil package containing 20 ml of physiological saline containing, if desired, drugs aocording to a physician's prescription. In application to a patient, the part introduoed into urethra was very smooth and ~lippery, while the remaining part exposed to the atmosphere ; -was permanently elastic and non slippery so that it could be easily fixed with an adhesive tape. Its properties remained unchanged during a several weeks lasting application.
Example 3.
~ sing the method aescribed in Example 2, a hydrogel tu~e was prepared having 4mm inside diameter and 0.3 mm wall thickness. The tube was swelled in a 65 % dimethyl sulphoxide, the rest being water, at 60C, and slipped onto a 5 mm thick catheter from plasticized PVC. The hydrogel tube overlapped the end of the catheter by about 15 mm and reached 25 cm from the end. ~he overlapping end, containing still dimethyl sulpho--, ~ide, was then heat-softened and pressed into a hot matrix bored ~hrough polytetrafluoroethylene. Dimethyl sulphoxide was then washed out in luke-warm water whereby the hydrogel tube shrank and adhered firmly to the PVC catheter. The surface was then treated for 45 seco~ds with a 30% sodium lye and thoroughly . .
_ 17 -..
.. : : , . ... . . . . . . ... . .
4~5~
washed, then sterilized and packaged as described in -the fore-going Examples.
Example 4.
A hydrogel tube was prepared in the way disclosed in Example 2, using, however, an extrusion die adjusted to form coag~lated tube having the wall thicker at one side and pro-vided with an axial groove 3 (see Fig. 1b). ~he catheter as a w~ole is diagrammatically illustrated in ~ig. 2. Its end 4 was dipped into a hydrogel solution and shaped according to ~xample 2 in such a way that the groove 3 was filled with the gel up to 10 mm above the stopper. ~urther 30 mm of the tube sur,ace were coated with an aqueous solution of sodium salt of carboxymethyl cellulose. A thi~ hydrogel tube 5 swelled in dimethyl sulphoxide diluted with 30 5~ of water was slipped onto the main tube and left for 4 hours aside. The overlapping end was molded as described in Example 3 and the whole washed thoroughly in water. ~he outer tube 5 adhered fir~ly to the mai~ tube 6. A thin rubber tubi~g 7 was inserted lnto the upper e~d of the axial groove 3 and fixed thereto. After annexing a rubber c~eck valve to the rubber -tubing 7 and washing the car-bo~yymethyl cellulose salt out from the part form~ng the pocket, the pocket 8 co~ld be inflated with physiological saline.
The treatment with a 100C hot mixture of 4 p. of aoncentrated su1phuric acid with 1 p. of glycerol for 15 seconds, neutra-lizi~g and washing made the catheter sur~ace slippery in a desired length ~he remaining part 9 o~ the catheter ~as covered with a sleeve from silicone rubber, swelled previously ~n ~oluene. After evaporating toluene, the sleeve adhered firmly to the catheter, protect~ng in agai~st dr~ing After ha~ing bored or cut the opening 10 the catheter was sterilized and packaged according to ~xample 1.
.~ :
_ 18 - ~ ,; :
S~
~xampls 5.
A catheter was made according to ~xample 2 except that the part to be exposed to the air was manufactured entirely from plasticized PVC and inserted with its tapering end i~to the hydrogel main tube, the outer hydrogel t~in tube described in Example 4 being slid onto the main tube in a length overlapping the joint of the two parts of the catheter.
Example 6.
Surgica~ tubular de~ice of the invention can be also manufactured by polymerization casting under crosslinking con~
ditions. A mold illustrated diagrammatically in ~ig. 3 was used, consisting in two about 40cm long ~lass tubes 11 and 12, the outer one ha~ing a 6 mm inslde diameter, the inner one a 4 mm outer diameter. ~he tubes ~ere assembled coaxially by means of two stoppers 13 and 14 provided with holes for filling and deaera-tion. ~he polyethylene stopper 14 formed s~m~lta-neously a filling funnel. ~he inserted end 15 Qf the tube 12 was sealed round and the end 16 of the tube 11 was closed with `'' a silicone rubber stopper 17 hollowed out to mold the rounded end of the casting. ~he mold was pre-cooled to -30C and '~uickly filledup with an equally cooled mixture of 72 p. of a 70 % aqueous zinc chloride solution and 27 p. of anhydrous acrylonitrile. The cool mi~ture was initiated immedia-tely before filling into the mold by adding 0.5 p. o~ a 5% aqueous pot,assium pyrosulphite and 0.5 p. o~ a aqueous ammonium per-,~ulphate solutions and stirring thoroughly, while cooling from out5ide with an ethanol bath to which solid carbon dioxide ,-was gradually added so as to keep the bath temperature at about -25 to about -35C, ~he lilled mold was then put into a freezer at -~0C. The zinc chloride solution contained a sufficient amount of ferric chloride so that the polymerization .
-- 19 _ ., .
s~o proceeded rather rapidly even at low temperatures. After 6 hours in the refrigerator the mold was taken out and left standing at room temperature for further 2 hours. Then the inner glass tube 12 was pulled out, stoppers 14 and 17 removed and the strong rubbery tube from plastici~ed polyacrylonitrile was pulled out using a double hook from a ~hick steel wire, catching the stopper 13 polymerized in t~e rubbery gel. ~he removal of the rubbery polymer casting was comparatively easy due to its high elasticity and strength. The end with the stopper 13 was cut off, a hole was bored at the closed end and the molding was then hanged on the lid of a tall glass beaker ha~ing 200 cf concen-trated hydrochloric acid poured on its bottom. A
slow stream of hydxogen chloride, d$1uted with 90% of nitrogen, was led slowly through the molding from a capillar~ tube. After 36 hours at 18~ the partial hydrolysis was flnished. '~he molding was immersed into a 0.5 % sodium bicarbonate aqueous solution, hanging from the lid of another tall beaker. The precipitated white voluminous sediment was perindicall~ sucked of~ from the bottom and replaced with the same ~olume of fresh bicarbonate solution. l~hen no further precipitate was formed, the molding was washed first in diluted nitric acid and then in water to neutral reaction. The molding was transparent, pliable and elastic in swelled condition. I-t~ outer diameter was 5 mm. ~he open end was stoppered and a thin rubber sleeve with 4.5 outside diameter was sWelled in ben~ene so as to be easily slid on the catheter in a length of about 10 cm. After evaporating benzene the rubber sleeve shrank and adhered firmly to the catheterO ~he remaining part ~ith the rounded end was dried to a 20% water content and immersed for 10 seconds into a 50C warm fuming sulphuric acid, rinsed with water and neutralized with a diluted sodium bicarbonate solution. After -- ~0 --washing to neutrality, the cathe-ter ~as swelled again with water and sterilized and packaged as described in the foregoing ~am-ples.
Example 7.
8 p. of anhydrous acrylonitrile and 8 p. of crystalline acrylamide were dissolved in 84 p. of a mixture, consisting of 3 volume p. o~ 70% aqueous ~inc chloride solution and 2p. o~ satu-rated aqueous calcium chloride solution. ~he mixture was ini-tiated wlth 0.15 ~ of potassium pyrosulphite and the same amount -o~ ammonium persulphate, related to the sum of the two monomers.The solution was then stirred under carbon dioxide for 6 hours.
Thereafter a half portion of the same redox initiator was added and the stirririg was continued at ambient temperature for 4 further hours. ~he viscous solut1on thus obtained was deaera-ted, using a water jet pump and extruded using an extrusion die as described in ~xample 1. Wash waters were precipitated with sodium bicarbonate and the precipitate utilized for the recovery 3~ Zi~C chloride. The tube was cut to pieces of an apprDpriate length, and a stopper fromthe same hydrogel was cemented into one end of each tube, using a iO% solution of the same hydrogel i~ dimethyl sulphoxide. ~he catheter was put aside for 3 hours, dimethyl sulphoxide washed out in water, the catheter dried to a content of 20% water and the end rounded. An opening was bored just above the stopper. The catheter was swelled in water to equilibrium and two thiras o~ its length was immersed ~or 40 seconds in an 80~ warm mixture o~ 4 p. concentrated ~lphuric acid with 1 p. of anhydrous ethylene glycol. ~he acid was then rinsed off with a stream of tap water and the catheter ~eutralized in a surplus of a diluted sodium bicarbonate solution. ~he remaining one thixd OL its length wa~ then co~ered with a thin rubber sleeve as described in ~ample 6.
..
~ 4~ S ~ 0 Prior to the partial coating with the rubber sleeve, the catheter was immersed for 30 minutes into an 80C warm aqueous solution of 0.5 % of formaldehyde and 0~5 % of concentrated hydrochloric acid and then washed thoroughly in water. ~he catheter was wiped with filtering paper and left for 30 minutes in the air at ambient temperature. Then it was immersed for 30 seconds into a 80C warm mixture of sulphuric acid and glycerol 1:4~ rinsed, néutralized~ washed, sterilized and packaged as described in Example 1, ~ample,8.
~he process described in Example~ ~ was repeated except that the outer thin tube was only cemented to the main tube at the two ends in a length of about 15 mm, ~hus, the space between the hydrogel tubes could be filled with physiologic ~aline containing drugs, if desired, ~he outer thin tube was thereby slightly pressed against the urethra closing the latter tightly. ~he end protruding into the bladder was sim~ltaneously inflated.
Example ~.
The hydrogel tube was formed by extxusion according to Example 1, interrupti~g, however, the water inlet into the axial mandrel periodically in about 90 cm intervals and increasing simultaneously the rate of extrusion so that a hydrogel stick with full cross section was formed bet~Jeen two closed endings as shot~ in Fig, 4 in an axial section. The tubes as well as the sticks be~Jeen them were cut in the middle so that the ends could be rounded and bored in half-dry condition. ~-~
~he dead space in the end could be removed either by inserting a bevelled stopper and cementing it to the interior of the tube end, or by introducing a suitable amount of a highly vi9cous hydrogel solution through the side opening and coagula-ting and washing it in water.
, . . .
s~
In the same way, thin tubes, closed at one end, can be made, to be slipped onto the main tube or onto a ready made cathetex.
Example 10.
A mold like that illustrated in ~ig. 3 was made of poly$etra nuoroethylene in such a way that the outer assembled tube consists in two exactly fit-ting longitudinal halves clamped tightly together.- ~he end of the inner_~ube was bevelled so as to exclude dead space at the opening. ~he mold was filled with a homogeneous mixture of 30 p. of acrylonitrile, 69 p. of 65%
~itric acid, 0.2 p. of urea, 0.6 p. of potassium persulphate~
1 p, of acetyl~cetone and OJOO2 P. of ferric nitrate, precooled to 0C. The filled mold was kept at -1C for 24 hours~ then left standing at room temperature for 6 hour3, heated for one hour to 30C and then left standing for 300 hours at 14C, ~he mold was then dismantled, the molding having the inner tube still in washed in water to neutral reaction and the inner tube pulled out. A 3.5 mm hole was cut at the end using a circular knife, the catheter left for 30 minutes in the air to get the surface almost dry, and then it was exposed to di-luted vapors of chlorosulphonic acid ~or two minutes. Neutra-l~zing, washing, and sterilizing followed. ~he part supposed to protrude in the air during the application to a patient was covered with a thin rubber sleeve as described in Example 6.
Example 11.
12 p. o~ acrylonitrile were dissolved in 88 p. of a mixture of 70~o aqueous zinc chloride solution and saturated calcium chloride solution (volume ratio 3 2)o ~he mixture was cooled to -10C, whereafter 0.015 p. of potassium pyro-sulphite and 0.02 p. of ammonium persulphate were stirred in.
~he polymerl~ing mixture ~as cooled while stirring under inert ~ L~4~5~(~gas so that the temperature did not exceed 20C. Zinc chloride solution contained a sufficient amount of catalytically active impurities, particularly iron and titani~m compounds, so that it was not necessary to add ferric or cupric salts as usual.
~he very viscous solution thus obtained was heated to ~0C
and deaerated. It was then e~truded as described in ~xample 1 into a coagulation bath containing 45 ~0 of zinc and calcium chlorides in the same ratio aa used in the polymerization step.
~he concentratio~ of the salts was kept constant by adding water countercurrently and removing the bath gradually near the extrusion die. The coagulated tube was drawn off with such a velocity that a tube with desired inside and outside diameter was obtained, and the path length in the bath was chosen so as to obtain a rubbery salt plasticized polyacrylonitrile con-taining about 30~ of the polymer. ~he rubber-like transparent tube was wiped off between two rollers coated with foamed rub-ber and cut to about 40 cm long pieces. ~he tubes were flushed with dry air to remove the remaining bath from their interior and hanged with their ends into the holes of a perforated plate, leaving the passage through the tubes free. ~he perforated plate formed a horizontal partition of a 20 litres PV~ container filled with nitrogen containing 5 % of hydrogen chloride and 0.2% of formaldehyde. ~he gas circulated by means of a by-pass and a small circulating pump through the gel tubes and round them. ~he partial hydrolysis lasted 24 hours at 19C
~he tubes were washed ten times in a diluted aaueous sodium bicarbonate solution and finally in distilled water. A further treatment followed, according to ~xample 1.
Similar rubbery tubes plasticized with zinc chloride solution can be obtained by only par-tially coagulating the ~ - 24 -, ~., .
.. , , ~.. ,' .
: ~ , 4~5`~0 polyacrylonitrile solution in plain water so that a coagulated skin covers a core containing a uncoagulated viscous solution. ..
After several hours at room temperature the concentration of zinc chloride becomes uniform throughout the whole cross section due to dif~usion. ~hus all what is needed is to increase the polymer concentration to about 25 - 35 % and to leave the tube until the zinc chloride concentration is equalized. ~he tempe-rature and the time of the partial hydrolysis with hydrogen chloride, as well asthe co.nce.ntration of the latter, are adjusted 10 so as to obtain an uniformly hydrolyzed polymer.
Instead of using a gel stopper, it is possible also to stop periodically the water inlet into the axial mandrel of the extrusion die and to thro~t.le simultaneously the feed o~ the polymer solution so that the tube gets periodioally closed as shown in Fig. 5. ..
Example 12.
150 p. of anhydrous acrylonitrile were dissolved in 846 p. of 65~ colorless nitric acid, and 1.2 p. of urea, dissolved in 2 p. of water, was stirred therein. ~he solution was cooled do~m to -5C and the polymerization started by addi-tion of 1 p. o~ a 10~o aqueous solution of ammonium persulphate and 1 p. o~ acetyl acetone and 0.001 p. of ferric nitrate. ~he solution was kept at 0C for 24 hours, left standing overnight at room temperature and heated while stirring slowly to 30C :~
for 2 hours. ~hereafter the highly viscous solution was left standing for 300 hours at 10C. ~he highly viscous so.lution was then extruded as described in ~xample 2, and only the not yet fully coagulated tube near the extrusion die was led through a device illustrated in Fig. 69 consisting of a hollow ring 18, the inner wall o~ which was formed by a rubber tube 19 inflated periodically.by leading compressed air into the hollow ring - 25 - ;
r<l ~ o~sl~
18. The device moved, when inflated1 along a short path relatively to the tube, returning when deflated into the starting position. The effect was similar to that shown in Fig, 5. ~he washed tube was cut to individual ca-the-ters which were then made slippery by introducing an:ionic neutralized groups into the surface layer ~nd provided with a rubber sleeve as described in the foregoing ~xamples.
.
;
,
Claims (9)
1. Surgical tubular device intended for being tempo-rarily introduced into the cavities of a living body, consisting entirely or partially in a hydrophilic copolymer of acrylonitrile with hydrophilic comonomers selected from the group consisting of acrylamide, acrylic acid, methacrylamide, methacrylic acid, ethylene sulphonic acid and their salts, said copolymer being swelled with an aqueous liquid, the surface of the part which is introduced into the body containing neutralized anionic groups making it highly slippery in contact with water, and the part expected to be exposed to the atmosphere during the application to the body being protected against drying by a layer of an elastic polymer or copolymer impermeable for water and water vapors.
2. Surgical tubular device according to claim 1, wherein the hydrophilic copolymer is a multi-block copolymer containing in each macromolecule several sequence of acrylo-nitrile units separated by sequences of acrylamide or acrylic acid units.
3. Surgical tubular device according to claim 1, wherein the said anionic groups are selected from the group consisting of carboxylic, sulphonic, sulphuric and phosphoric acid side substituents.
4. Surgical tubular device according to claim 1, wherein the outer layer is formed by an uninterrupted thin tube of the said hydrophilic copolymer, covering an elastic inner tube.
5. Surgical tubular device according to claim 4, wherein the thin outer tube is partially cemented to the inner tube, the loose part forming an inflatable pocket connected by a passage or channel with the end exposed to the atmosphere during the application.
6. Surgical tubular device according to claim 5, wherein said passage or channel is formed by a longitudinal groove in the surface of the inner tube, covered by the said thin outer tube.
7. A method of manufacturing surgical tubular devices intended for being temporarily introduced into the cavities of a living body, consisting entirely or partially in a hydrophilic copolymer of acrylonitrile with hydrophilic comonomers selected from the group consisting of acrylamide, acrylic acid, methacrylamide, methacrylic acid, ethylene sulphonic acid and their salts, said copolymer being swelled with an aqueous liquid, the surface of the part which is intro-duced into the body containing neutralized anionic groups making it highly slippery in contact with water, and the part expected to be exposed to the atmosphere during the application to the body being protected against drying by a layer of an elastic polymer or copolymer impermeable for water and water vapors, wherein the endings to be introduced into the body are formed by shaping tubes extruded into a coagulating bath near the extrusion die where the coagulation is not yet finished.
8. Method according to claim 7, wherein the shaping is performed by interrupting periodically the inlet of water through an axial mandrel in the extrusion die.
9. Method according to claim 7, wherein the shaping is performed by constricting the not yet coagulated tube and simultaneously interrupting the inlet of water through the axial mandrel in the extrusion die.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS1981A CS173836B1 (en) | 1974-03-19 | 1974-03-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1040500A true CA1040500A (en) | 1978-10-17 |
Family
ID=5355567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA222,559A Expired CA1040500A (en) | 1974-03-19 | 1975-03-19 | Surgical tubular device having a slippery surface |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4026296A (en) |
| JP (1) | JPS50132787A (en) |
| AR (1) | AR202163A1 (en) |
| BR (1) | BR7501541A (en) |
| CA (1) | CA1040500A (en) |
| CS (1) | CS173836B1 (en) |
| DE (1) | DE2511198A1 (en) |
| DK (1) | DK108975A (en) |
| FR (1) | FR2264565B1 (en) |
| GB (1) | GB1464818A (en) |
| IT (1) | IT1034335B (en) |
| NL (1) | NL7503219A (en) |
| SE (1) | SE7502584L (en) |
| ZA (1) | ZA751385B (en) |
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| DE2915271A1 (en) * | 1979-04-14 | 1980-10-16 | Storz Karl | Resectoscope for treatment of urethral and bladder lesions - contains endoscope coaxially sheathed by outer shaft sleeve, with annular space in between for anti-friction agent |
| US4557724A (en) * | 1981-02-17 | 1985-12-10 | University Of Utah Research Foundation | Apparatus and methods for minimizing cellular adhesion on peritoneal injection catheters |
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| HUE051305T2 (en) * | 2003-08-08 | 2021-03-01 | Hollister Inc | A hydrophilic catheter in a package |
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| US8864730B2 (en) | 2005-04-12 | 2014-10-21 | Rochester Medical Corporation | Silicone rubber male external catheter with absorbent and adhesive |
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| US11896505B2 (en) * | 2005-10-31 | 2024-02-13 | Scott M. Epstein | Methods for making and using a structural hydrogel polymer device |
| ES2426272T3 (en) * | 2006-06-08 | 2013-10-22 | Hollister Incorporated | Catheter product container |
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| ES2604253T3 (en) * | 2007-11-19 | 2017-03-06 | Hollister Incorporated | Steam hydrated catheter assembly and manufacturing method |
| GB0816365D0 (en) * | 2008-09-08 | 2008-10-15 | Univ Belfast | Polymeric material |
| US20110029050A1 (en) * | 2008-11-18 | 2011-02-03 | John Elefteriades | Intra-ventricular brain cooling catheter |
| EP3064230B1 (en) | 2009-07-10 | 2019-04-10 | Boston Scientific Scimed, Inc. | Use of nanocrystals for a drug delivery balloon |
| EP2453938B1 (en) * | 2009-07-17 | 2015-08-19 | Boston Scientific Scimed, Inc. | Nucleation of drug delivery balloons to provide improved crystal size and density |
| JP2013500125A (en) | 2009-07-29 | 2013-01-07 | シー・アール・バード・インコーポレーテッド | Improved drainage device and / or catheter with retractable sleeve and method of using the same |
| WO2011019359A1 (en) | 2009-08-13 | 2011-02-17 | C. R. Bard, Inc. | Catheter having internal hydrating fluid storage and/or catheter package using the same and method of making and/or using the same |
| US10912917B2 (en) | 2009-12-23 | 2021-02-09 | C. R. Bard, Inc. | Catheter assembly/package utilizing a hydrating/hydrogel sleeve and method of making and using the same |
| US20110160645A1 (en) * | 2009-12-31 | 2011-06-30 | Boston Scientific Scimed, Inc. | Cryo Activated Drug Delivery and Cutting Balloons |
| EP2542291A4 (en) | 2010-03-04 | 2013-08-07 | Bard Inc C R | Catheter assembly/package utilizing a hydrating/hydrogel sleeve and a foil outer layer and method of making and using the same |
| US20110319902A1 (en) | 2010-06-26 | 2011-12-29 | Scott Epstein | Catheter delivery system |
| US10751206B2 (en) | 2010-06-26 | 2020-08-25 | Scott M. Epstein | Catheter or stent delivery system |
| EP2611476B1 (en) | 2010-09-02 | 2016-08-10 | Boston Scientific Scimed, Inc. | Coating process for drug delivery balloons using heat-induced rewrap memory |
| US9707375B2 (en) | 2011-03-14 | 2017-07-18 | Rochester Medical Corporation, a subsidiary of C. R. Bard, Inc. | Catheter grip and method |
| US8669360B2 (en) | 2011-08-05 | 2014-03-11 | Boston Scientific Scimed, Inc. | Methods of converting amorphous drug substance into crystalline form |
| WO2013028208A1 (en) | 2011-08-25 | 2013-02-28 | Boston Scientific Scimed, Inc. | Medical device with crystalline drug coating |
| US9872969B2 (en) | 2012-11-20 | 2018-01-23 | Rochester Medical Corporation, a subsidiary of C.R. Bard, Inc. | Catheter in bag without additional packaging |
| US10092728B2 (en) | 2012-11-20 | 2018-10-09 | Rochester Medical Corporation, a subsidiary of C.R. Bard, Inc. | Sheath for securing urinary catheter |
| US8998882B2 (en) | 2013-03-13 | 2015-04-07 | C. R. Bard, Inc. | Enhanced pre-wetted intermittent catheter with lubricious coating |
| WO2016033234A1 (en) | 2014-08-26 | 2016-03-03 | C.R. Bard, Inc | Urinary catheter |
| US10758704B2 (en) | 2015-06-26 | 2020-09-01 | Coloplast A/S | Urinary catheter assembly |
| US10471183B2 (en) | 2015-12-22 | 2019-11-12 | Access Vascular, Inc. | High strength biomedical materials |
| CN109789290B (en) | 2016-09-27 | 2021-08-03 | 科洛普拉斯特公司 | Hydration catheter with cannula |
| US11577008B2 (en) | 2017-06-21 | 2023-02-14 | Access Vascular, Inc. | High strength porous materials incorporating water soluble polymers |
| US11865269B2 (en) | 2017-09-11 | 2024-01-09 | Hollister Incorporated | Hydrophilic medical device with removable moisture control/barrier layer |
| CA3070865A1 (en) | 2017-09-19 | 2019-03-28 | C.R. Bard, Inc. | Urinary catheter bridging device, systems and methods thereof |
| EP3793626B1 (en) | 2018-05-17 | 2022-12-07 | Hollister Incorporated | Methods of making sleeved hydrophilic catheter assemblies |
| DK180417B1 (en) | 2018-07-20 | 2021-04-22 | Coloplast As | INTERMITTING URINCATHER FITTING |
| CN109490500B (en) * | 2018-11-28 | 2024-01-26 | 安徽理工大学 | Hard sediment water sample layered sampling and real-time monitoring device |
| WO2020125908A1 (en) | 2018-12-20 | 2020-06-25 | Coloplast A/S | Urine collecting bag |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1220114A (en) * | 1967-05-12 | 1971-01-20 | Ceskoslovenska Akademie Ved | Method of joining polyglycolmethacrylates together with other materials |
| US3566874A (en) * | 1968-08-13 | 1971-03-02 | Nat Patent Dev Corp | Catheter |
| CS158458B1 (en) * | 1972-05-02 | 1974-11-25 |
-
1974
- 1974-03-19 CS CS1981A patent/CS173836B1/cs unknown
-
1975
- 1975-03-03 US US05/554,625 patent/US4026296A/en not_active Expired - Lifetime
- 1975-03-06 ZA ZA00751385A patent/ZA751385B/en unknown
- 1975-03-07 SE SE7502584A patent/SE7502584L/xx unknown
- 1975-03-13 GB GB1043375A patent/GB1464818A/en not_active Expired
- 1975-03-13 AR AR257951A patent/AR202163A1/en active
- 1975-03-14 DE DE19752511198 patent/DE2511198A1/en not_active Withdrawn
- 1975-03-17 IT IT21337/75A patent/IT1034335B/en active
- 1975-03-17 BR BR1541/75A patent/BR7501541A/en unknown
- 1975-03-18 DK DK108975A patent/DK108975A/da not_active Application Discontinuation
- 1975-03-18 NL NL7503219A patent/NL7503219A/en unknown
- 1975-03-18 FR FR7508346A patent/FR2264565B1/fr not_active Expired
- 1975-03-19 JP JP50032487A patent/JPS50132787A/ja active Pending
- 1975-03-19 CA CA222,559A patent/CA1040500A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT1034335B (en) | 1979-09-10 |
| GB1464818A (en) | 1977-02-16 |
| CS173836B1 (en) | 1977-03-31 |
| BR7501541A (en) | 1975-12-23 |
| FR2264565A1 (en) | 1975-10-17 |
| AU7920075A (en) | 1976-09-23 |
| US4026296A (en) | 1977-05-31 |
| DK108975A (en) | 1975-09-20 |
| AR202163A1 (en) | 1975-05-15 |
| NL7503219A (en) | 1975-09-23 |
| ZA751385B (en) | 1976-02-25 |
| JPS50132787A (en) | 1975-10-21 |
| SE7502584L (en) | 1975-09-22 |
| FR2264565B1 (en) | 1979-03-09 |
| DE2511198A1 (en) | 1975-09-25 |
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