WO1981000701A1

WO1981000701A1 - Female sterilization

Info

Publication number: WO1981000701A1
Application number: PCT/US1980/001171
Authority: WO
Inventors: R Krall
Original assignee: Population Res Inc
Priority date: 1979-09-12
Filing date: 1980-09-11
Publication date: 1981-03-19
Also published as: EP0036871A1; AU6338680A; NO811509L; BR8008824A; DK194381A; EP0036871A4; JPS56501599A

Abstract

Methyl cyanoacrylate in combination with an organic carboxylic acid, sulfur dioxide, and a component selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, butylated hydroxyanisole and mixtures thereof. A sealed ampule for the storage of a methyl cyanoacrylate composition (10) as seen in figure 2 comprises: a container body (12) and a slidable sealing piston (20) both made with polytetrafluorethylene, and a diaphragm stopper (16) sealing the end of the chamber opposite the piston (20).

Description

FEMALE STERILIZATION

1. 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 sterilization results. Methyl cyanoacrylate (MCA) is a well known chemical product that has found application in the field of permanent sterilization of human females. Sterilization is accomplished by the introduction of small quantities of MCA into the fallopian tubes. Its contact there with body moisture 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 polymerization inhibitor to MCA to reduce the tendency to autocatalyze 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. Unfortunately, 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 inhibited MCA having a "shelf-life" on the order of three to four months. Even then, the sterilization ra suits are less than is desirable.

In general, the use of these various, separate inhibitors, as practiced in the prior art, has tended to decrease 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 uninhibited MCA, without providing a satisfactory "shelf-life" of the MCA. For example, when phosphoric acid inhibitor is 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 "shelf-life" of the MCA improved to as long as six months to over a year, but successful sterilization results are provided which are comparable to those obtained when uninhibited MCA is used, i.e., in close to 100% of the test cases.

Another separate problem which has detrimentally affec ted the "shelf-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.

Brief Summary of the Invention

Broadly, the invention provides a new inhibited MCA composition including amounts of an acid, sulfur dioxide and either hydroquinone, hydroquinone monomethyl ether or butylated hydroxyanisole (BHA). The constituents are preferably used in a very pure form eg., 99.9% pure or better where possible. An improved ampule container arrangement is orovided for MCA. 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-cyanoacryl 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, phosphoric acid and phosphoric anhydride may be readily separated by distilling the MCA away from the inhibitors under reduced 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 described in detail herein. Generally, it is prepared by pyrolyzing the poly Calkyl)-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 -COOH group) acid is added ranging in amount from about 12,500 ppm to about 60.,000 ppm, about 15,000 ppm + about 100 being 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 tissue, 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 (SO₂) is also added to the MCA ranging in amounts from about 500 ppm to about 1500 ppm, about 750 ppm + ahout 250 Being preferred. Satisfactory, moisture free, high, purity SO₂ is commercially available from many suppliers. It is dried by the supplier by passing it through a drying tower and is available. 99.9% pure.

Hydroquinone, hydroquinone monomethyl ether or butylated hydroxyanisole (BHA) 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 commercially 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 substantial range specified, as desired. That is, when one or more of the additives are increased in amount it is not necessary to decrease the relative amounts of other additives. Any combination of relative amounts within the specified ranges will provide the improvements of the invention as described 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 - 750 ppm + 250 ppm - 99.9% purity Hydroquinone - 100 ppm + 10 ppm - 99.9% purity Balance MCA - 99.9% purity 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, preferably of polytetrafluorethylene (PTFE) 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 Wilington, 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 composition 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 piston is then moved to force the material thru the needle out of the container. Piston stopper 20 carries an "O" 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 "O" 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 "O" 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 facilitate 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 + 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 incorporated herein by reference. As additional protection for the stability of the MCA composition in the ampule, a nitrogen bubble 32, containing less than 0.5 ppm oxygen is included in the ampule.

Nitrogen of this guaranteed purity level is commercially 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 detrimentally affects MCA. Having described the .Invention, the exclusive property rights to which applicant is entitled are defined in the following claims:

Claims

II . CLAIMS

1. An MCA composition exhibiting both improved shelf-life and improved effectiveness for female sterilization; the composition consisting essentially of MCA, an organic carboxylic acid ranging in amount from about 12,500 ppm to about 60,000 ppm, sulfur dioxide ranging in amount from about 500 ppm to about 1500 ppm and a component selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, hutylated hydroxyanisole and mixtures thereof, the component ranging in. amount from about 50 ppm to about 250 ppm.

2. The composition of Claim 1 wherein, the amount of acid is ahout 15,000 ppm.

3. The composition of Claim 1 wherein the amount of sulfur dioxide is about 750 ppm.

4. The composition of Claim 1 wherein the amount of the selected component is about 100 ppm.

5. The composition of Claim 1 wherein the acid is glacial acetic acid.

6. The composition of Claim 5 wherein the amount of acid is about 15,000 ppm.

7. The composition of Claim 1 wherein the acid is propionic acid.

8. The composition of Claim 1 wherein the acid is butyric acid.

9. The composition of Claim 1 wherein the acid is benzoic acid.

10. The composition of Claim 1 wherein the selected component is hydroquinone.

11. The composition of Claim 10 wherein the amount of hydroquinone is ahout 100 ppm.

12. The composition of Claim 1 wherein the acid is glacial acetic acid and the selected component is hydroquinone.

13. The composition of Claim 12 wherein the acid amount is about 15,000 ppm, the sulfur dioxide amount is about 750 ppm, and the. hydroquinone amount is ahout 100 ppm.

14. The composition of Claim 1 wherein the selected component is hydroquinone monomethyl ether.

15. The composition of Claim 14 wherein the amount of hydroquinone monomethyl ether is about 100 ppm.

16. The composition of Claim 1 wherein the acid is glacial acetic acid and the selected component is hydroquinone monomethyl ether.

17. The composition of Claim 16 wherein the acid amount is about 15,000 ppm, the sulfur dioxide amount is ahout 750 ppm and the hydroquinone monomethyl ether amount is about 100 ppm.

18. The composition of Claim 12 wherein the acid amount is about 15,000 ppm.

19. The composition of Claim 12 wherein the hydroquinone amount is ahout 100 ppm.

20. The composition of Claim 16 wherein the acid amount is about 15,000 ppm.

21. The composition of Claim 16 wherein the hydroquinone monomethyl ether amount is about 100 ppm.

22. An ampule for storing MCA and similar compositions comprising: a container body composed of polytetrafluorethylene defining a cylindrical chamber for holding the composition to be stored; a slidahle sealing piston member composed of a block polymer of polytetrafluorethylene and polyethylene posi tioned at one end of the chamber, the piston having a peripheral ring seat; an "O" ring fitted in the peripheral seat and in compressive relationship with, the inner wall of the chamber, and a diaphragm stopper sealing the other end of the chamber.

23. An ampule defining a storage chamber for a MCA sterilization composition, the chamber including a quantity of deoxygenated nitrogen.

24. The ampule of Claim 23 wherein the oxygen level of the nitrogen is less than about 0.5 ppm.

25. The ampule of Claim 22 wherein the "O" ring and the diaphragm are coated with polytetrafluorethylene.