CA1182124A - Pharmaceutically acceptable silicon rubber and therapeutical set and the use thereof for surgical embolization - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention provides a new silicon rubber mixture which includes a linear polysiloxane of low viscosity, an X-ray contrast agent, and, optionally, a cyclic dialkyl-polysiloxane of low viscosity. The silicon rubber mixture can be used for surgical embolization with the aid of a catheter and can be detached from the catheter and the catheter withdrawn so that the silicon rubber can be used to embolize certain vessels without other ducts being permanently blocked by the catheter.

Description

The present inventlon rela-tes to new silicon rubber mix-tures, to the use of the mixtures for therapy and to therapeutic sets containing the said mixture. The new silicon rubber mixture and the therapeutic set can be used in the firs-t line in cerebro-vascular surgery and general surgery, respectively, for surgical embolization by means of a catheter.
The silicon rubber mixture of the present invention con-sists of two or three components, respectively, one oE which gives X-ray contrast. The therapeutic set according to the invention com-prises the above silicon rubber mixture, a catalyst for the polymer-ization of the mixture, and a microcatheter which may be provided in a given case with an inflatable balloon and other vessels and glandular ducts.
The invention also relates to the use of the new silicon rubber mixture and the therapeutic set in different fields of therapy, in the first line for cerebrovascular operations~ vascular surgery, etc.
Due to their location or size cer-tain parts of the human arterial system cannot be reached either via direct surgical expo-sure or endovascular approach i.e. by means of the generally usedrigid "Seldinger type" catheters (secondary and -tertiary arteries).
This problem has been solved by the use oE balloon catheters oE a diameter less than 1 mm. These flexible catheters are provided with an inflatable natural rubber balloon head, they can utilize the so-called "parachute-effect" of the blood stream. These balloon-catheters have the importance Eor the cerebral endovascular surgery in the first line.
I'he cerebral arteries are surrounded by a stiff bony wall ~- s on the cranial base and have "syphons". Thus, the intracranial arteries are available only by using such catheters. A micro-catheter filled with X-ray contrast medium, by means of fluoro-scopic screen, permits the possibility of following exac-tly the position of the balloon-head. When using -two or special balloon catheters at the same time, the catheter can also be directed into the secondary arteries. The above method is, however, of diagnostic importance only, because if the catheter at its destination is left for blocking, it will also block the functionally impor-tant main vessels due to secondary thrombosis. This complication can be eliminated if the balloon were left in the vessels isolated, by detachment and withdrawing the catheter. Isolation and so-called "superselective" embolization is ensured by the physical possibility that the inflated balloon head is Eixed to the inner wall of the vessel to be blocked more strongly that the flexible connection between the balloon and the ending of the catheter. The detachment of the balloon head, filled with fluid, is, however, dangerous on one hand as the balloon can leave its place, and on the other hand it can be unsuccessful because the fluid flows out of the balloon.
Filling a quickly hardening fluid in the catheter ensures the stable fixing of the balloon in the vessel and a permanent, saEe occlusion of the desired area.
An object of the present invention is to provide a novel and useful therapeutic set by the aid of which the above detachment and thus the embolization of certain vessels and permanent blocking of further ducts, respectively, can be performed easily and with great certainty without any problem at imparting the catheter.
The above balloon catheter method has been theoretically

- 2 -worked out recent]y by F. Sorbinenko [J. of Neurosurgery 41, 125-145 (1974)]. No material has been found, however, by the ald of which the catheter could be detached effec-tively; moreover, in the absence of the contrast ma-terial the position of the catheter could not be followed.
P. Schaps in Zentralblatt f~r Neurochirurgie 38, 105-10 (1977) describes the use of silicon -together with microca-theter and balloon, the viscosity of the material used was, however, so high that only ice-cooling technique could be applied, moreover, neither this material contained X-ray contrast material.
G~ Debrun, P. Lacour, J. Caron et al. [J. of Neurosurgery 49, 635-49 (1978)3 describe similar methods. They report, however, about difficulties in the impartation. In operation, detachment could be performed by using coaxial catheter, so the technique could not be used with safety for the intracranial vascular free operations.
S. K. Hilal, P. Sane, W. J. Michelson and A. Kossein, Neuroradiology 16, 430-33 (1978) describe the use of silicon elasto-mer (Silastic 382*), methyl silicon oil and tantalum powder in the microcatheter technique. Disadvantages of the said mixture were that the vicosity was much too high to permit easy injecting, and the use of tantalum powder, as X-ray contrast material obstructed the catheter by forming plugs. Moreover, tantalum powder is toxic.
Summarizing, there has been no material available which satisfies all the requirements as discussed above. These require-ments are as follows:
1. Low viscosity is very important: the material has *Trade Mark ~*. - 3 -

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to be pressed through a catheter of 0.1 mm inner diameter and 150 mm length. This requirement is very hard to satisfy, considering that the fluid injected is to harden within a short period.
2. Due to the limited time Eor operation, the material should harden within a short time (i.e. 10 -to 20 min.) so that sufficient time to inject the mixture (minimum 3 to 4 min.) should also be provided~
3. The material should evenly fill in the catheter with sufficient plasticity -that bubble formation does not occur.

4. After hardening, however, the material should be rigid to a certain extent, i.e. it should break at the detachment.

5. It is very important for the precise dosing and con-trol that the material should also give X-ray shadow. This charac-teristic provides that the position of the ca-theter and balloon, respectively, can be followed.

6. Sterility, no toxic effect.
The present invention provides a silicon rubber mixture suitable for use in surgical embolization procedures which comprises a linear polysiloxane oil of low viscosity, of formula I

X - - li O ~ O ~ X
l n R

wherein X is hydroxy, alkoxy, acyloxy or amino, R and Rl are inde-pendently alkyl, aryl, aralkyl, alkylaryl or alkenyl and n is an integer, and a pharmaceutically acceptable X-ray contrast medium which is an iodo-containing organo-silicon compound or a non-metallic organic X-ray compound, the mixture having a viscosity not - 4 _ greater than 1.00 mPas.
The silicon rubber mixture of the present invention may consist of an appropriate mixture oE two different fluid polysil-oxanes and a non-toxic, physiologically acceptable contrast material.
Thus, a preferred silicon rubber mixture according to the invention consists of the following components:

,.~, .
~ 5 -a) a linear polysiloxane oE low viscosity, preferably e.g~ the so-called reac-tive silicon oil, i.e. a clialkyl-, alkylaryl-~ alkenylalkyl- or diarylpoly-siloxane which may contain reactive functional terminal groups, i.e. hydroxy, acyloxy, alkoxy or amillo. Preferred polysiloxanes are the compounds of the general formula I

Rl ~ IR ¦ Rll X--- si--~ - si----o--si----x R Rl n R

wherein X is e.g. hydroxy, alkoxy, acyloxy or amino, and R and Rl independently represent alkyl, aryl, aralkyl or alkenyl groups and n is an optional integer.
Preferred polysiloxane is the dimethyl-polysiloxane~ -diol~ the so-called "LMS". Physical data of the said compound are as follows:

n = 80-85, M = 6-7000, d4 5 C = 0.976 g./cm ., 25 C 1 4043 n25 C = 80-100 m.Pa.s. (cP).

b) A cyclic dialkyl-polysiloxane, which has a very low viscosity. Such a cyclic dialkyl-polysiloxane derivative may be e.g. a dialkyl-polysiloxane, e.g.
the so-called D4 ([R2SiO]4) or D5 ([R2SiO]5). For the purposes of the invention the D4 is highly preferred. Its structure is !(CH3)2SiO]4, the octamethyl-cyclo-tetrasiloxane, the physical data of which are as follows:

M = 296, b.p. = 175C/0 1 MPa d20 C o 9558 / 3 20 C = 1 3968 n20 C = 2 mPas (cP).

The viscosity of the mixture of the linear and cyclic polysiloxanes should be between n25oc = 10 and 100 mPas, depending on the desired field of use.
c) The mixture contains in a given case methyl-silicon oil of a viscosity of 5 to 20 mPas wh~ch serves also the lowering of the viscosity.

d) The fluid contrast material to be added to the mixture may be a physio-logically acceptable silicium organic compound, which contains the iodine atom~s) giving the X-ray shadow built into the molecule. According to the invention, preferred contrast material is the bis-iodometllyl-tetramethyl-di-siloxane of the formula II

CH3 C~13 I - CH2 ~ 0 - Si - CH2 - I

The iodine ato~ gives also the possibility of isotope labeling the material, when using e.g. I-131. The physical da~a of the said compound are as follows:

M = 414, b.p. = 134 C/1333,22 Pa, D~20 = 1,172 g./cm3., nD20 = 1.5263. If mixtures of a viscosity of higher than 100 mPas may also be applied, non-metallic, iodine-containing organic X-ray contrast materials in extracted, solid, fine form may also be used. Such materials are used in the angiological diagnostics and are commercial products, i.e. Amipaque, ~b_~ Uromiro, etc. These materials are to be added to the components as above in a groundly homogenized form. Use of such materials, is, however difEicult and requires more attention as the particle size should also bc chosen in accordance with the field of application so that the particles should not obstruct the microcatheter and in case of free embolization they are not allow-ed to get into the capillary vascular system.
The silicon rubber system according to the invention, i.e.
component of the therapeutical set contai~ the linear poly~iloxane under point a) a~
above by all mean~ while it ~hould contain at least one of the material~ under b) and d)~
rhe therapeutical ~et co~tain~ be~ide the S component A mentionod above the component B which can be any of the cataly~t~ u~ed ~or medical purposes in polymerizing cold-vulcanizing gum~ characterized by pro~iding a fluidity of 8 to 10 min~ and a hardening time of ~0 to 25 min~.
It ha~ been ~ound that under the prescribed heat sterilizing conditions (120C for 30 mîn~ both component~ maintain the original chemical characteri~tics and abilitie3 in the polymerization and the materials are acceptable in bacteriological a~pects.
A ~urther element of the therapeutical ~et i~ the microcatheter. Depending on the field of use 9 it may contain one or more lumina. The therapeutical ~et o~ the pre~ent invention be~ides the component~ A and B and the microcatheter may also contain a balloon head made generally of natural late~
o~ silicone~ Thi~ head has the importanee in the firot line at endovascular ombolization wherein the ailicon gum component is vulcanized in the balloon on the effect of the catalyst thu~ forming a plug for blocking the said vessel. During free embolization~ however the u~e of balloon is not es~enti~l unles~ the wanted vascular area i2~ not available otherwi~e.

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The therapeutical ~et can be u~ed a~ follows:
~ he microcatheter~ provided in ~iven caYe with the balloon at it~ end i~ led up to tbe target ves~el~ or obh~r duct~~ection. ~hen compone~ta A a~d B are groundly mixed to provide a homogenous mixture and the nece~ary amount is inaected into the catheter through a calibrated tuberculin syringe9 ~he injection is controlled by ~-ray fluoro~copic ~oreen~ A~ter the rest o~ the material had hardened, the catheter i~
detached ~rom the balloon head by a light, ~hi~ting pulling, ~bsequentl~ the catheter i~ removed f`rom the artery together with the silicon rubber vulcanized in the catheter.
Another ob~ect of the invention i~ tha u~e 1~ o~ the said sili~one~ and the mi~ture thereoY for pharmaceutical purpo~es. ~he new material had bee~
provided for the endovascular operation technique in the fi.r~t li~e~ 'rhe ma-terial and equipment may be u~ed, however, in a~y ca~e wherein no direct ~urgical inter-vention i~ po~sible or external operative approach oYthe conoerned ve~sels i~ not advlaed.
~ he mo~t important Yields of the endova~cular ~uper~elective embolization by mea~s oY balloon catheter are indicated among other a~ Yollows:
25 1. Blocking arteriovenosus ~istulas, 2. Em.')olization of arteriovanous angiomas, 3t Embolization o~ ~eeding arteries of high-ly va~cularîzed tumor~ i~ order to promote the direct su~ical removal of ~uch neoplasm~.
40 Endova~cular oaclu~io~ of arterial ~accular aneurism~ .
5. Blocking oulet duct ~y~tern~ of different e~ocrin gland~
A~ mentioned, the emboliæation can be carried out by building the balloon into the ve~sel or other duct ~ection to be blockedO The embo~i~ation may be performed, howe~er~ in the form of the ~o-called "~ree embolizationl' wherein the mixture o~ the compo~ent~
and ~ according to the invention are injected directly into the pathological vascular axea to be blocked, re~pectively, and the material i~ vulcanized in the ves~el it~el~. It ha~ been found that the materials and mixt~re of the invention are non-to~ic either in themselve~ or during vulcanizationO ~h~ a further a~pect of the present invention i~ the u3e of the ~aterials and the mixture, respectively, described above~ in the above free-embolization technique~
~ ased on animal tests, the above materials were u~ed i~ abo~t 30 ~ucce~ul huma~ operations within a period o~ o~e and a half years in ca~es which could not be operated directly. It was proved that the polymeriæed silicon remained in the natural r~bber balloon re~ulted în de~initive occlu~ion of the target spot. ~ollowing the X~ray ~hadow, the .~

position of balloon can be seen by a simple X-ray control even years after the operation. In case of free embollzation the position of polymerized silicon rubber can also be controlled. It has also be found that the materials of the present invention~ like other silicones widely used in the surgery (i.e.
ventriculo-atrial shunts, articular and other plastics, dental materials, etc.) are entirely compatible and non-toxic. No infection or abnormal histological reaction could be detected. Essentially it is the characteristic which makes possible the free embolization method described above.
In the following we give some possible examples for the silicon rubber mixture of the present invention.
Example 1 10 g. of dimethyl-polysiloxane-~,~-diol, viscosity 50 to 2000 mPas 1 g. of powdered, dried X-ray contrast material (UROMIRO*), passed through a sieve of a size of 0.65 ~m.
The mixture is homogenized, and, before use, sterilized in vials. The catalyst, 1.5 ccm of T-5 (Wacker* dental catalyst product) is also sterilized in vial.
Mixing of the two components provides a "batch-time" of 8 mins and a polymeriza-tion time of 15 mins. The catheter can be imparted after 15 to 25 mins.

*Trade Mark - 1~

Ano-ther po39ible component A i~ ag follows:
10 gO o~ dimethyl-poly~ilogane~ diol, viaco~it,y 100 rnPa~
2 g. of X~ray con-trast material a0 in E~ample 1, 2 g. o~ meth~ ilicon oil o~ dlmethyl-poly~ilo~ane basi~ c09ity 19 mPa~.
~he component ~ and the amount thereo~ i~ the ~ame as in Egample lo 10 ~
Compone~t A:
2.5 g. of dimethyl-poly3ilo~ane-~3 ~ -diol, vi~3cosity 100 mPa~3, 2.5 g. of' D4 (cyclic poly~iloxane), vi~cosity 4-5 mPa~, 0.75 g. of bi~-iodomethyl-tetramethyl-disiloxane (~luid iodo-containing ~-ray contrast material) ~he mixture i~ homogeniæed, and then ~illed into vials and ~terilized. A.~ component R ~-5 or T-ll cataly~ts (Wacker product~) may be u~ed in an amount of 1 ccm~
Clinic 1. 35 year old man, miner. Af`ter craniocerebral trauma developed an extreme large ~istula between the right inter~al carotid artery and cavernou~ sin~, re~ulted in typical eye-symptoms, bruitg headache, le3ion o~
the right II., III., IV- and both YI. cranial nerve~
Via percutan endovascular catheteri~ation the ~i~tula had been clo~ed with 2 detached, 3iliconized balloon~.

~1 E~callent clinical re~ult, the patient is symptom-free eve~ two years after the operation, 2. 25 year old man, electrotechnician. More severe ~u~arachnoidal bleeding9 re~ulted in tra~ient un-consciouness and hemiplegia on the left~ ~he angio-grapbie~ pro~ed a congenital art~riovenous malforma-tion o~ -the total right cerebral hemisphere~ There wa~ no po~ibility o~ direct 9urgical operation~
because of the size o~ the angiomO Two mai~ feeding arterie~ of the va~cular malformation has been occluded with aupexselective balloon~embolization. Significa~t clinical improvements the patien-t can walk alone~
free of mental disturbance, continues his original profe~sion, got married, no more haemorrhage~ ~ince the operation~
3. 53 years old womanS teacherO Gian-t ~accular aneurysms on the ca~ernous por-tion of the left internal carotid artery, resulted in an earlier subarachnoidal haemorrhage and actually the le~ion of the ]eft III.
cranial nerv. In order to the sa~e ocolu~ion both the parent vessel and aneurysmal neck hacl to be embolized with a large balloon, filled vvith ~ilicone.
~he transient po~toperative hemiparesis and aphasia as well a~ the oculomotor paresis have improved, the patient is practically free of symptoms atter a period of a year and a halfa 4. 24 old man. After frequent nasal haemorrhages and .

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de~initive obstruction o~ the no~e a large-~lze haemangio~ of the face had been proved histologically.
Becau~e o~ ~he ~iæe and locali~ation tlle direct ~urgical operatio~ ~a~ un~ucce~ful~ A:fter the ~mboli~ation of' the feeding maxillar arterial branches we suoce~ded in subtotal ~ur~ical removal o~ this benignant tumor.
Although thi~ method has bee~ applied till pre~ent, when a direc^t ~urgical app.roach was impo~ible or more dangexous, there is a real possi~ility to exte~d the i~dication ~or the routine ca~e~ o~ the mentioned diseQ~es too, with better result~ and lower hazard.

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A silicon rubber mixture suitable for use in surgical embolization procedures which comprises a linear polysiloxane oil of low viscosity, of formula I

I

wherein X is hydroxy, alkoxy, acyloxy or amino, R and R1 are inde-pendently alkyl, aryl, aralkyl, alkylaryl or alkenyl and n is an integer, and a pharmaceutically acceptable X-ray contrast medium which is an iodo-containing organo-silicon compound or a non-metallic organic X-ray compound, the mixture having a viscosity not greater than 100 mPas.

2. A mixture according to claim 1 which also contains a cyclic dialkylpolysiloxane of low viscosity.

3. A mixture according to claim 1 wherein the linear poly-siloxane is a dimethyl-polysiloxane-.alpha.,.omega.-diol.

4. A mixture according to claim 2 wherein the cyclic dialkyl-polysiloxane is methyl-cyclo-tetrasiloxane.

5. A mixture according to claim 1, 2 or 3 which contains bis-iodomethyl-tetramethyl-disiloxane as X-ray contrast material.

6. A mixture according to claim 1, 2 or 3 which has a viscosity of 10 to 100 mPas.

7. A therapeutic set which is composed of a silicon rubber mixture as claimed in claim 1 as component A, in association with a therapeutically acceptable cross-linking catalyst as component B and a microcatheter.

8. A therapeutic set as claimed in claim 7 wherein there is a balloon at the end of the catheter.