Pharmaceutically acceptable silicon rubber and therapeutical set and the use thereof for surgical embolization

A silicon rubber embolization agent used in general as well as cerebral vascular surgery having a component A which is composed of: a linear, low viscosity polysiloxane selected from the group consisting of dialkyl, alkylaryl, alkenylalkyl, and diarylpolysiloxanes having reactive functional groups selected from the group consisting of hydroxyl, acyloxyl, alkoxyl and amino; a low viscosity cyclic dialkylpolysiloxane having the formula [R.sub.2 SiO].sub.4, wherein R is alkyl; a pharmaceutically acceptable iodo-containing organosilicium; or a non-metallic, organic X-ray contrast material, and a component B which is a therapeutically acceptable cross-linking catalyst.

BACKGROUND OF THE INVENTION 
The present invention relates to a new silicon rubber mixture, its use for 
embolization as well as a therapeutic set containing the said mixture. The 
new mixture and the therapeutic equipment can be used for the first time 
in the cerebrovascular surgery and general surgery, respectively, for 
surgical embolization by the aid of a catheter. 
Due to their localization or size certain parts of the human arterial 
system cannot be reached either via direct surgical exposure or 
endovascular approach, i.e. by means of the generally used rigid 
"Seldinger type" catheters (secondary and tertiary arteries). This problem 
has been solved by the use of balloon catheters of a diameter less than 1 
mm. These flexible catheters are provided with an inflatable natural 
rubber balloon head, which can utilize the so-called "parachute-effect" of 
the blood stream. These balloon-catheters have particular importance for 
the cerebral endovascular surgery. 
The cerebral arteries are surrounded by a stiff bony wall on the cranial 
base and have "syphons". Thus, the intracranial arteries become available 
only by using such catheters. The microcatheter filled with X-ray contrast 
medium, measurable by means of fluoroscopic screen, gives the possibility 
to follow exactly 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. However, the above method is of 
diagnostic importance only, because the catheter when sent to its 
destination is left for blocking, it will also block the functionally 
important main vessels due to secondary thrombosis. This complication can 
be eliminated if the balloon were left in the vessels isolated, by 
detaching and withdrawing the catheter. The isolation and the so-called 
"superselective" embolization is ensured by the physical possibility that 
the inflated balloon head which is fixed to the inner wall of the vessel 
to be blocked is stronger than the flexible connection between the balloon 
and the ending of the catheter. However, the detachment of the balloon 
head, filled with fluid, is dangerous on the one hand, as the balloon can 
leave its place; on the other hand it can be unsuccessful when 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, safe occlusion of the desired area. 
The object of the present invention is to provide a novel and useful 
therapeutic equipment by 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 
problems at imparting the catheter. 
The above balloon catheter method has been theoretically worked out 
recently by F. Sorbinenko [J. of Neurosurgery 41, 125-145 (1974)]. No 
material has been found, however, which allowed that the catheter could be 
detached effectively. Moreover, in the absence of the contrast material 
the position of the catheter could not be followed. 
P. Schaps in Zentralblatt fur Neurochirurgie 38, 105-10 (1977) describes 
the use of silicon together with a microcatheter and a balloon. However, 
the viscosity of the material used was so high that only ice-cooling 
technique could be applied. Moreover, this material contained no X-ray 
contrast material. 
G. Debrun, P. Lacour, J. Caron et al. [J. of Neurosurgery 49, 635-49 (1978) 
] describe similar methods. They report, however, difficulties with the 
impartation. In operations, detachment could be performed by using a 
coaxial catheter and thus, 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 elastomer (Silastic 382), methyl 
silicon oil and tantalum powder in the microcatheter technique. The 
disadvantage of said mixture was the much higher viscosity than was good 
for an easy injection, and on the other hand the use of tantalum powder, 
as X-ray contrast material obstructed the catheter by forming plugs. 
Moreover, the tantalum powder is toxic. 
In summary, there was no material available which corresponded to all the 
requirements as discussed above. These requirements are as follows: 
1. The low viscosity is very important: the material should be pressed 
through a catheter of 0.1 mm. inner diameter and 150 mm. length. This 
requirement is very hard to provide, considering that the fluid injected 
should harden within a short period. 
2. Due to the limited time for operations, the material should harden 
within a short time (i.e. 10 to 20 min.) so that sufficient time to inject 
the mixture (min. 3 to 4 min.) should also be provided. 
3. The material should evenly fill in the catheter with sufficient 
plasticity so that no bubble is allowed to occur. 
4. After hardening, however, the material should be rigid to a certain 
extent, i.e. it should break at the detachment point. 
5. It is very important for the precise dosing and control that the 
material should also give X-ray shadow. This characteristic provides that 
the position of the catheter and balloon, respectively, can be followed. 
6. Sterility, no toxic effect. 
SUMMARY OF THE INVENTION 
The silicon rubber mixture of the present invention consists of two-three 
components, respectively, one of which gives X-ray contrast. The 
therapeutic set according to the invention comprises a silicon rubber 
mixture, the catalyst for the polymerization of the mixture, as well as a 
microcatheter provided in a given case with an inflatable balloon catheter 
used for cerebral and other vessels and glandular ducts. 
A further subject of the invention is the use of the new silicon rubber 
mixture and therapeutic set, respectively, in different fields of therapy, 
for the first time in cerebrovascular operations, vascular surgery, etc. 
The silicon rubber mixture provided by the invention, forming component A 
of the therapeutic set fulfills all the above requirements. 
DETAILED DESCRIPTION OF THE INVENTION 
The silicon rubber mixture of the present invention consists of an 
appropriate mixture of two different fluid polysiloxanes and a non-toxic, 
physiologically acceptable contrast material. 
Thus, the silicon rubber mixture according to the invention consists of the 
following components: 
(a) a linear polysiloxane of low viscosity, preferably e.g. the so-called 
reactive silicon oil, i.e. a dialkyl-, alkylaryl-, alkenylalkyl- or 
diarylpolysiloxane which may contain reactive functional terminal groups, 
i.e. hydroxy, acyloxy, alkoxy or amino. Preferred polysiloxane is the 
dimethyl-polysiloxane-.alpha., .omega.-diol, the so-called "LMS". Physical 
data of the said compound are as follows: n=80-85, M=6-7000, 
d.sub.4.sup.25.degree. C.=0.976 g./cm.sup.3, n.sub.D.sup.25.degree. 
C.=1.4043, .sup.25.degree. 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 D.sub.4 ([R.sub.2 SiO].sub.4). or D.sub.5 ([R.sub.2 
SiO].sub.5). For purposes of the invention the D.sub.4 is highly 
preferred. Its sturcute is [(CH.sub.3).sub.2 SiO].sub.4, the 
octamethyl-cyclotetrasiloxane, the physical data of which are as follows: 
M=296, b.p.=175.degree. C./0.1 MPa, d.sup.20.degree. C.=0.9558 
g./cm.sup.3, n.sub.D.sup.20.degree. C.=1.3968, .sub.20.degree. C.=2 mPas 
(cP). 
The viscosity of the mixture of the linear and cyclic polysiloxanes should 
be between 10 and 100 mPs, at .sub.25.degree. C. 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 which serves also to lower the viscosity. 
(d) The fluid contrast material to be added to the mixture may be a 
physiologically acceptable silicium organic compound, which contains the 
iodine atom(s) giving the X-ray shadow built into a molecule. According to 
the invention, preferred contrast material is the 
bis-iodomethyl-tetramethyl-disiloxane. The iodine atom gives also the 
possibility of isotope labeling the material, when using e.g. I-131. The 
physical data of the said compound are as follows: M=414, b.p.=134.degree. 
C./1333,22 Pa, d.sub.4.sup.20 =1.172 g./cm.sup.3, n.sub.D.sup.20 =1.5263. 
Mixtures of a viscosity of higher than 100 mPas may also be applied and 
non-metallic iodine-containing organic X-ray contrast materials in 
extracted, solid or fine form may also be used. Such materials are used in 
the angiological diagnostics and are commercial products, i.e. Amipaque, 
Uromiro, etc. These materials are to be added to the above components in 
ground homogenized form. However, use of such materials is difficult and 
requires more attention and the particle size should be chosen in 
accordance with the field of application so that the particles do not 
obstruct the microcatheter and in the case of free embolization the 
particles do not get into the capillar vascular system. 
The silicon rubber system according to the invention, i.e. the component of 
the therapeutical set contains the linear polysiloxane mentioned above 
under paragraph (a) and should contain at least one of the materials under 
paragraphs (b) and (d). 
The therapeutic set contains beside the component A mentioned above, the 
component B which can be any of the catalysts used for medical purposes in 
polymerizing cold-vulcanizing gums characterized by providing a fluidity 
of 8 to 10 min and a hardening time of 20 to 25 min. 
It has been found that under the prescribed heat sterilizing conditions 
(120.degree. C. for 30 mins) both components contain the original chemical 
characteristics and the ability to polymerize. Furthermore, the materials 
are acceptable in bacteriological aspects. 
A further element of the therapeutic set is the microcatheter. Depending on 
the field of use, it may contain one or more lumina. The therapeutic set 
of the present invention may also contain, beside components A and B and 
the microcatheter, a balloon head made generally of natural silicone 
latex. This head has the importance for the first time in endovascular 
embolization wherein the silicon gum component is vulcanized in the ballon 
by the effect of the catalyst, thus forming a plug for blocking the said 
vessel. During free embolization, however, the use of balloon is not 
essential unless the wanted vascular area is not available otherwise. 
The therapeutic set can be used as follows: 
The microcatheter, provided in a given case with the balloon at its end, is 
led up to the target vessels or other duct-section. Then components A and 
B are ground and mixed to provide a homogenous mixture and the necessary 
amount is injected into the catheter through a calibrated tuberculin 
syringe. The injection is controlled by an X-ray fluoroscopic screen. 
After the rest of the material has hardened, the catheter is detached from 
the balloon head by a light, shifting and pulling. Subsequently the 
catheter is removed from the artery together with the silicon rubber 
vulcanized in the catheter. 
Another object of the invention is the use of the said silicones and the 
mixture thereof for pharmaceutical purposes. The new material has been 
provided for the endovascular operation technique for the first time. The 
material and equipment may be used, however, in any case wherein no direct 
surgical intervention is possible or external operative approach of the 
concerned vessels is not advised. 
The most important fields of the endovascular superelective embolization by 
means of balloon catheter are indicated among other as follows: 
1. Blocking arteriovenous fistulas, 
2. Embolization of arteriovenous angiomas, 
3. Embolization of feeding arteries of highly vascularized tumors in order 
to promote the direct surgical removal of such neoplasms. 
4. Endovascular occlusion of arterial saccular aneurisms. 
5. Blocking outlet duct systems of different exocrin glands. 
As mentioned, the embolization can be carried out by building the balloon 
into the vessel or other duct section to be blocked. The embolization may 
be performed, however, in the form of the so-called "free embolization" 
wherein the mixture of the components A and B according to the invention 
are injected directly into the pathological vascular area to be blocked, 
respectively, and the material is vulcanized in the vessel itself. It has 
been found that the materials and mixture of the invention are non-toxic 
either in themselves or during vulcanization. Thus, a further aspect of 
the present invention is the use of the materials and the mixture, 
respectively, described above, in the free-embolization technique. 
Based on animal tests, the above materials were used in about 30 successful 
human operations within a period of one and a half years in cases which 
could not be operated directly. It was proved that the hardened silicon 
remained in the natural rubber balloon resulting in a definitive occlusion 
of the target spot. Following the X-ray shadow, the position of the 
balloon can be seen by a simple X-ray control even years after the 
operation. In the case of free embolization the position of a polymerized 
silicon rubber can also be controlled. It has also been found that the 
materials of the present invention, such as other silicones widely used in 
the surgery (i.e. ventricule-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 this characteristic which makes possible the free embolization 
method described above.

The following are examples for the silicon rubber mixture of the present 
invention. 
EXAMPLE 1 
Component, A 10 g of dimethyl-polysiloxane-.alpha.,.omega.-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 .mu.m. 
The mixture is homogenized, and, before use, sterilized in vials. Compound 
B, 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 polymerization time of 15 mins. The catheter can be 
imparted after 15 to 25 mins. 
EXAMPLE 2 
Another possible component A is as follows: 10 g. of 
dimethyl-polysiloxane-.alpha.,.omega.-diol, viscosity 100 mPas, 2 g. of 
X-ray contrast material as in Example 1, 2 g. of methyl-silicon oil of 
dimethyl-polysiloxane basis, viscosity of 19 mPas. The catalyst component 
B and the amount thereof is the same as in Example 1. 
EXAMPLE 3 
Component A 
2.5 g. of dimethyl-polysiloxane-.alpha.,.omega.-diol, viscosity 100 mPas, 
2.5 g. of D.sub.4 (cyclic polysiloxane), viscosity 4-5 mPas, 0.75 g. of 
bis-iodomethyl-tetramethyl-disiloxane (fluid iodo-containing X-ray 
contrast material). The misture is homogenized, and then filled into vials 
and sterilized. As component B, T-5 or T-11 catalysts (Wacker dental 
catalyst product) may be used in an amount of 1 ccm. 
CLINICAL TESTS 
1. 35 year old man, miner. After craniocerebral trauma, he developed an 
extreme large fistula between the right internal carotid artery and 
cavernous sinus, resulting in typical eye-symptoms, bruit, headache, 
lesion of the right II., III., IV- and both VI. cranial nerves. Via 
percutan endovascular catherization the fistula had been closed with 2 
detached, siliconized balloons. Excellent clinical result, the patient is 
symptom-free even two years after the operation. 
2. 25 year old man, electrotechnician. Severe subarachnoidal bleeding, 
resulted in transient unconsciousness and hemiplegia on the left. The 
angiographies proved a congenital arteriovenous malformation of the right 
cerebral hemisphere. There was no possibility of direct surgical 
operation, because of the size of the angiom. Two main feeding arteries of 
the vascular malformation have been occluded with superselective 
balloonembolization. Significant clinical improvement: the patient can 
walk alone, is free of mental disturbance, continues his original 
profession, has married, and had no more hemorrhages since the operation. 
3. 53 year old woman, teacher. Giant saccular aneurysms on the cavernous 
portion of the left internal carotid artery, resulted in an earlier 
subarachnoidal hemorrhage and actual lesion of the left III. cranial 
nerve. For a safe occlusion, both the parent vessel and aneurysmal neck 
has to be embolized with a large balloon filled with silicone. The 
transient postoperative hemiparesis and aphasia as well as the oculomotor 
paresis have improved, the patient is practically free of symptoms after a 
period of a year and a half. 
4. 24 year old man. After frequent nasal hemorrhages and definitive 
obstruction of the nose, a large-size haemangiom of the face had been 
proved histologically. Because of the size and location, the direct 
surgical operation was unsuccessful. After the embolization of the feeding 
maxillar arterial branches we succeeded in subtotal surgical removal of 
this benign tumor. 
Although this method has been applied up until the present only when a 
direct surgical approach was impossible or too dangerous, there is a real 
possibility to extend the indication for routine cases of the mentioned 
diseases too, with better results and less hazard.