I. DESCRIPTION

Background of Prior Art

This ^* invention is directed to an improved methyl cyanoacrylate composition for use in female sterilization. The improved composition provides improved inhibition and long-term storage i.e., longer "shelf-life" of monomeric methyl cyanoacrylate. It also provides enhanced sterili¬ zation results. Methyl cyanoacrylate CMCA). is a well known chemical product that has found application in the. field of permanent sterilization of human females. Sterilization is accom¬ plished by the introduction of small quantities of MCA in¬ to the fallopian tubes. Its contact there with body ois- ture polymerizes the MCA and blocks the fallopian tubes. With the passage of time, fibrous. tissue growth replaces the MCA and permanent sterilization results. This use and procedure is described in the U.S. Patent Nos. 3,822,702 and 3,948,259. The property" of polymerization which makes MCA useful in female sterilization also makes it difficult to store i.e., it has a short "shelf-life". MCA polymerizes under a variety of conditions including exposure to even trace '. amounts of moisture, oxygen, heat, high energy radiation, and exposure to active organic sites. Consequently, it is difficult to store MCA for any period of time due to its tendency to autocatalyze itself into a solid cured polymer during storage.

It is known that one can add quantities of polymeri- zation inhibitor to MCA to reduce the tendency to autocata¬ lyze itself during storage. For example, acetic acid, sulfur dioxide, phosphoric acid and hydroquinone have all been used individually as separate inhibitors for MCA and can provide a "shelf-life" up to five or six years. Un- fortunately, to obtain long "shelf-life" requires the use of such large amounts of inhibitor that the sterilization action of the MCA is drastically and detrimentally affected.

Thus, in the prior art, each, of the foregoing inhibitors has been -used individually in relatively low amounts to provide inJiil-ited MCA having a "shelf-lif " on the order of three to four months ^* . Even then, the sterilization ra- suits are le_ss than is desirable.

In general, the use of these various, separate inhibi¬ tors, as practiced in the prior art, has tended to decreas the. number of successful sterilizations i.e., those in which there is complete closure of the fallopian tubes and permanent sterilization, as compared to the use of unin¬ hibited MCA, ^* _* _ithout providing a satisfactory "shelf-life" of the MCA. For example, when phosphoric acid inhibitor i used, "closures" resulted at best in only about 58% of the test results and the maximum "shelf-life" was about four months.. On the other hand, with, the improved composition of this invention, not only is the "shel -life" of the MCA improved to as long as six months to over a year, but suc¬ cessful sterilization results are provided which are com¬ parable to thosrε obtained when uninhibited MCA is used, i.e., in close to 100% of the test cases.

Another separate problem which has detrimentally affe ted the "shel -life" of MCA has been found to exist in the ampule containers used therefor. In accordance with this invention, improved ampules of gas impermeable materials are provided and a nitrogen bubble is included therein which is substantially oxygen free.

3rief Summary of the Invention

Broadly, the invention provides a ne -inhibited MCA composition including amounts of an acid, sulfur dioxide and either hydroquinone, hydroquinone monomethyl ether or butylated hydroxyanisole (BHAl . The constituents are pre¬ ferably used in a very pure form eg., 99.9% pure or better where possible. An improved ampule container arrangement is orovided for MCA.

OMPI

Brief Description of the Drawings

Figure 1 is a perspective view of an embodiment of an ampule according- to the invention;

Figure 2 is a cross-sectional view of the ampule shown in Figure 1 taken along line 2-2 of Figure 1, and

Figure 3 is a perspective view of the piston stopper utilized in the. ampule shown in Figures 1 and 2.

Detailed Description of Invention

The MCA referred to herein, methyl-2-cyanoacr l_-te, may Be. any of the commercial forms thereof in which the supplier's inhibitors have been substantially removed i.e., to a purity level of at least about 99.9%. "Eastman 910" is an example of the moat readily available commercial form. It may be obtained from Eastman Chemical Products, Inc. , Box 431, Kingsport, Tennessee 37662.

Commercially added inhibitors eg., hydroquinone, phos¬ phoric acid and phosphoric anhydride may be readily separa¬ ted by distilling the MCA away from the inhibitors under re¬ duced pressure to remove the MCA as the distillate. This should he repeatedly carried out to obtain a high purity MCA eg., one on the order of 99.9% or higher.

Preferably, the MCA will be prepared especially for use in the invention without inhibitors so as to provide high purity material. The preparation of MCA is known to those familiar with the chemical arts and need not be des¬ cribed in detail herein. Generally, it is prepared by pyrolyzing the polyCalkyl).-2—cyanoacrylates. produced when formaldehyde is condensed with the corresponding alkyl cyanoacetates. Detailed information is available in U.S. Patent 2,763,677 entitled "Process For Making Monomeric Alfa-cyanoacrylates" , issued in 1956.

To the substantially inhibitor-free and preferably high, purity MCA, an organic carboxylic (.containing -C00H group) acid is added ranging in amount from about 12,500 p _m to about 60.,000 ppm, about 15,000 ppm + about 100 be¬ ing preferred. The term "ppm" is used herein throughout

on a mole/mole basis.

Glacial acetic acid is the preferred acid although other organic carboxylic acids, not harmful to body tissu such as ^* propionic acid, butyric acid or benzoic acid and many other organic carboxylic acids may be used. However-, preferably such acids will be of high purity eg., 99.9% or better.

Sulfur dioxide (SO-) is also added to the MCA ranging in amounts from about 500 ppm to about 1500 ppm, about 750 ppm + a out 250 Being preferred. Satisfactory, mois¬ ture free, high, purity S0 ₂ is commercially available from many suppliers. It is dried by th supplier by passing it through a drying tower and is available. 99.9% pure.

Hydroquinone, hydroquinone monomethyl ether or buty¬ lated hydroxyanisole CBHA) are also added to the MCA eithe individually or as- a mixture of any two or three thereof. This component of the new composition provided herein may range in amount from about 50 ppm to ahout 250 ppm, about 100. ppm - about 10. being preferred. Hydroquinone is. the preferred component. These components are all commerciall available in recrystallized form at purity levels of 99.9% or higher.

The relative amounts of the additives specified above for the MCA composition may be varied within the substan¬ tial range specified, as desired. That is, when one or mo of the additives are increased in amount it is not necessa to decrease the relative amounts of other additives. Any combination of relative amounts within the specified range will provide the improvements of the invention as describe herein. Any departure from these ranges will drastically and detrimentally affect the results obtained i.e., "shelf life" and sterilization effectiveness.

EXAMPLE

Acetic Acid - 15,000 ppm + 100 ppm - 99.9% purity Sulfur dioxide - 75Q ppm + 250 ppm - 99.9% purity Hydroquinone - 100 ppm + 10 ppm - 99.9% purity Balance MCA - 99.9% purity

O-v

Closure was observed in hetter than 90% of the test cases utilizing the above example composition.

Referring to Figures 1 - 3, the containers in which MCA sterilization compositions 10 are stored take the form of a sealed ampule comprising a cylindrical tube 12, pre¬ ferably of polytetrafluorethylene CPTFE) sealed at one end 14 by a stopper or diaphragm 16 of rubber or the like which has been spray coated with PTFE 17. At the other end 18 is a closure member, preferably in the form Of a movable piston 20 molded from Tefzel 280 from Dupont de Nemours Co. of ilington, Delaware. This material is a block polymer of polytetrafluorethylene and polyethylene. For sealing the other end of the ampule and for moving toward the diaphragm stopper 16 to force the MCA composi- ^' tion 10 from the ampule chamber 22 which is formed between the two ends thereof. This is accomplished by inserting the needle of a hypodermic syringe through the diaphragm stopper. The pis.ton is then moved to force the material thru the needle out of the container. Piston stopper 20 carries an "0" ring 24 fitted in a seat 26 on the piston. Piston 20 may take a variety of shapes, one of which is shown in the drawing for providing effective sealing in cooperation with the inner diameter of the cylinder 12. Preferably, the materials of the "0" ring will be a high modulus rubber such as butyl, natural, buma, neoprene rubber and the like. Similar materials will be used for diaphragm member 16. The "0" ring and inner diameter of cylinder 12 will be relatively sized so as to provide a compression seal therebetween. To render the "O" ring impervious to the entrance of oxygen into the ampule or the loss of sulfur dioxide therefrom, it will be spray coated with polytetrafluorethylene as is the diaphragm 16. Several sprayed coats of polytetrafluorethylene, preferably four are used. Four sprayed coats will ordinarily provide _a coating of about 1 mil thickness, which is satisfactory. Container end 14 includes a neck portion 28 to facili¬ tate the press fitting of a metal cap 30 thereto for the

purpose of holding diaphragm 16 in place and sealed to cylinder 12 as shown.

The various ^* plastic parts of the container are molded to tolerances ^* of about -f 1 mil of the desired size and are press fit together.

A specific design configuration shown for the ampule is more completely described in co—pending application Serial No. 63,964 filed August 6, 1979 which is incorpor¬ ated herein by reference. As additional protection for the stability of the MCA composition in the ampule, a nitrogen bubble 32, contain¬ ing less ^* than 0.5 ppm oxygen is included in the ampule.

Nitrogen of this guaranteed purity level is commer¬ cially available from many- suppliers . The container is assembled and filled in a 0.5 ppm oxygen-free nitrogen environment. Consequently, the nitrogen bubble is readily formed in the container. The presence of this bubble protects the MCA from exposure to oxygen which detrimen¬ tally affects MCA. Having described the .Invention, the exclusive propert rights to which applicant is entitled are defined in the following claims: