GB2306469A - Sterilizing cyanoacrylate preparations - Google Patents
Sterilizing cyanoacrylate preparations Download PDFInfo
- Publication number
- GB2306469A GB2306469A GB9522435A GB9522435A GB2306469A GB 2306469 A GB2306469 A GB 2306469A GB 9522435 A GB9522435 A GB 9522435A GB 9522435 A GB9522435 A GB 9522435A GB 2306469 A GB2306469 A GB 2306469A
- Authority
- GB
- United Kingdom
- Prior art keywords
- preparation
- cyanoacrylate
- temperature
- package
- days
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
Abstract
Cyanoacrylate preparations for medical and surgical adhesive applications are sterilised by heating in a suitable container at a temperature of at least 160{C. The preferred container is a squeezable aluminium tube and the preferred temperature is above 170{C. Cyanoacrylate adhesive compositions sterilised by heat have improved shelf life compared to those sterilised by ionising radiation.
Description
ADHESIVE COMPOSITION
The present invention relates to cyanoacrylate preparations and, more particularly, to the sterilisation of cyanoacrylate preparations for use in medical or surgical procedures and to sterilised cyanoacrylate packages.
It is known to use 2-cyanoacrylate esters for bonding tissue in medical or surgical procedures performed upon the human or animal body. 2-cyanoacrylate esters polymerise rapidly, and often instantaneously, upon contact with tissue or fluid. The cyanoacrylate polymer is thereafter degraded, metabolised and removed from the body.
In order to be used for medical, including surgical, purposes, 2-cyanoacrylate ester preparations must be sterilised.
It is known to sterilise 2-cyanoacrylate preparations by the use of heat or of radiation. Both techniques tend to cause polymerisation of the cyanoacrylate monomer, or at least tend to reduce the shelf life. There therefore remains a demand in the market place for sterilised 2cyanoacrylate adhesive compositions which have a good shelf life.
It is believed that sterile 2-cyanoacrylate preparations now on the market have, in the main, been sterilised by the use of ionising radiation. Whilst ionising radiation has, therefore, apparently been perceived as the preferred method of sterilisation, there is a substantial capital cost associated with this procedure and it necessitates the careful use of dosimetry procedures. The biological effects of radiation can also create their own problems.
Cyanoacrylate monomer must be packaged in an inert and adequately water-resistant container, since atmospheric moisture causes polymerisation. Aluminium containers, and more particularly tubes, are sometimes used for cyanoacrylate sold for industrial or commercial purposes.
Polyolefin has been the material of choice for commercial medical-grade cyanoacrylate.
Polyolefin containers however are permeable to atmospheric moisture the ingress of which into the container detrimentally affects the properties and sbelf life of the stored cyanoacrylate. As already stated, both heat and ionising radiation tend to cause or promote polymerisation of 2-cyanoacrylate monomer, at least to the extend of reducing shelf life and, accordingly, sterile cyanoacrylate requires a container which will not promote or cause polymerisation during the sterilisation process. Aluminium has not found favour as a container for sterile cyanoacrylate.
The present invention provides a novel method of sterilising a 2-cyanoacrylate ester preparation. The method contradicts known teaching as to the stability of cyanoacrylate and yet enables production of a product of outstanding stability. The invention also provides a novel sterile 2-cyanoacrylate ester preparation and a novel package containing sterile cyanoacrylate.
The Method
In one aspect the invention provides a method of sterilising a 2-cyanoacrylate ester preparations, comprising heating the preparation to a temperature of at least 160 C. The prior art teaches that cyanoacrylate polymerises at a temperature of 160qC (US Patent No.
3360124). The sterilisation method is preferably formed at a temperature of at least 170t and more preferably at a temperature of about 180 C, or more.
The British Pharmacopoeia recommends heating at a minimum of 160t for not less than 2 hours, a minimum of 1700C for not less than 1 hour and a minimum of 180"C for not less than 30 minutes for effective sterilisation. In accordance with the present invention, the 2cyanoacrylate ester preparations are preferably heated for a period of time in accordance with the recommendations of the British Pharmacopoeia. It is most preferred that the cyanoacrylate preparation is maintained at a temperature of about 180 C for at least 30 minutes, and more preferably for about 45 minutes.Such processes have, against all expectations, been found capable of resulting in a product which not only equals the stability of prior art sterile cyanoacrylate preparations but exceeds the stability of such preparations by a considerable margin.
Thus it has surprisingly been found that when the method of the invention is performed upon 2-cyanoacrylate ester preparations contained in an aluminium container, it is possible for the sterilised cyanoacrylate to retain its fluidity for a period in excess of 220 days at SPEC.
This compares with fluidity retention periods at 55 C of 4 days and 6 days for two sterile cyanoacrylate products on the market. The method of the invention is therefore preferably performed upon a sealed aluminium container, although alternative thermally stable containers may be used. A particularly preferred container is an aluminium tube, cg. a tightly crimped aluminium tube.
The method of the invention is not restricted as to the method of heating but dry heat sterilisation is preferred. In an exemplary procedure, closed containers of cyanoacrylate preparation are placed in a dry heat steriliser preheated to iSOC. The steriliser temperature is allowed to return to 180 C and the containers are held in the steriliser for a period of at least 30 minutes and more normally of up to 45 minutes.
The Preparation
The method of the invention may be applied in principle to any 2-cyanoacrylate ester. The cyanoacrylate is preferably an aliphatic 2-cyanoacrylate ester and preferably an alkyl, cycloalkyl, alkenyl or alkoxyalkyl 2-cyanoacrylate ester. The alkyl group may have from 1 to 16 carbon atoms and is more preferably a Cry, alkyl ester and most preferably a C rCJalkyl ester. Suitable esters include the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, Omethoxyethyl and 2-ethoxyethyl esters of cyanoacrylic acid.
The cyanoacrylate preparation will contain any additives necessary to impart the desired properties to the preparation as viscosity, colour, X-ray opacity, etc. Commercial medical cyanoacrylate preparations contain one or more additives to prevent premature polymerisation. Usually, cyanoacrylate monomers are stabilised with anionic and free-radical polymerisation inhibitors. Anionic polymerisation inhibitors known in the art include soluble acidic gasses (for example sulfur dioxide), and phosphoric, carboxylic and organic sulphonic acids. Free-radical polymerisation inhibitors include hydroquinone, t-butyl catechol, hydroxyanisole, butylated hydroxyanisole and butylated hydroxytoluene.
The Package
The heat-sterilised cyanoacrylate preparations of the invention may be packaged in a container made of any suitable materiaL In this respect, the container must be heat-resistant up to the sterilisation temperature, present an adequate barrier to atmospheric moisture and be cyanoacrylate-compatible. Materials meeting these requirements include metal and glass.
A particularly preferred material is aluminium, especially aluminium formed into a squeezable tube. Preferred aluminium tubes comprise a nozzle which is hermetically sealed by a pierceable membrane of aluminium and are filled at their end remote from the nozzle prior to closure of the open end by tight crimping. In the result, therefore, preferred embodiments of the invention reside in a substantially hermetically sealed aluminium container, e.g. an aluminium tube, containing a sterile 2-cyanoacrylate ester preparation.
The present invention enables provision of 2-cyanoacrylate ester preparations which retain their fluidity at 550C for a prolonged period when in a sealed aluminium container. Preferred preparations are capable of retaining their fluidity at 55"C for a period of at least 50 days when in a sealed aluminium container, and more preferably for a period of at least 100 days.
Particularly preferred preparations are capable of retaining their fluidity at 55 'C for a period of at least 200 days, e.g. 220 days or more. As measured in this way, the invention enables provision of sterile adhesive having a stability in excess of 36 times that of two products currently on the market.
The invention is further illustrated in the following example
Example
A preparation was made of n-butyl 2-cyanoacrylate (NBCA) stabilised with 100 ppm SO 2and 1000 ppm butylated hydroxyanisole. The preparation was placed into aluminium tubes and sterilised by ionising radiation (y and electron beam radiation) and by heating. The stabilities of the resultant products were compared with each other and with the stabilities of two commercially available medical grade cyanoacrylates. The ability of the preparations to polymerise promptly upon application to tissue was checked by ascertaining polymerisation time on bovine plasma.
1. Sterilisation procedures:
NBCA was filled into aluminium tubes, which were hermetically closed by tight crimping.
a. Dry heat sterilisation: The tubes are placed in a preheated, validated dry heat steriliser. The tubes are kept for 45 minutes once the temperature levels at 1800C. (The theoretical sterilisation time at this temperature is 9 minutes. The recommended sterilisation cycle in British Pharmacopoeia (p.A197, Vol n, Ed. 1993) is 30 minutes at 180"C.) b. Ionising radiation: The tubes were placed in validated ionisation chambers where they received the prescribed dose of 25 kGy (British Pharmacopoeia, p.A198, Vol II, Ed.
1993) of y ore- beam exposure.
2. Polymerisation time on bovine plasma:
Freshly reconstituted bovine plasma in a suitable container is placed and equilibrated in a water bath at 37"C. Using a 27 Gauge needle a drop of NBCA is dropped on the plasma surface from a distance of2 cm. The time interval from the moment the drop hits the surface to the moment it polymerises (looses transparency) is measured with a stopwatch.
3. Stability at 55"C: Aluminium tubes containing NBCA prior to and following sterilisation are placed at a constant temperature of 55"C and monitored daily for fluidity of the cyanoacrylate by shaking. The number of days with retained fluidity is recorded. This is a widely practiced accelerated stability test for cyanoacrylate adhesives relating to their shelf-life.
The results are shown in Tables 1 and 2 below.
Table 1
Properties of NBCA following different sterilisation treatments
No Sterilisation Sterilisation Polymerisation Colour Viscosity Stability method details time on bovine increase at 55"C plasma after (days) sterili sation 1 none - 1 instant APHA - > 220 100 2 Y 25 kGy instant Gardner yes 12 5 3 e beam 25 kGy instant APHA yes 36 300 4 dry heat 45 min at instant APHA no > 220 180"C 200 Table 2
Comparison of properties of NBCA medical adhesives
NBCA Sterilisation Polymerisation Appearance Stability at method time on bovine 55'C (days) plasma Competitor unknown instant intentionally 4 No 1 coloured blue Competitor -radiation 2 seconds clear, 6 No 2 APHA 100 Product # 4 dry heat instant clear, > 220 of Ta ble 1 APHA 200
Claims (20)
- CLAIMS: 1. A method of sterilising a 2-cyanoacrylate ester preparation, comprising heating the preparation to a temperature of at least 160 C.
- 2. A method of claim 1, wherein the preparation is heated to a temperature of at least 170 C.
- 3. A method of claim 2, wherein the preparation is heated to a temperature of about 180eC.
- 4. A method of claim 3, wherein the preparation is maintained at a temperature of about 180"C for at least 30 minutes
- 5. A method of claim 4, wherein the preparation is maintained at a temperature of about 180"C for about 45 minutes.
- 6. A method of any of claims 1 to 5, wherein the preparation is contained in an aluminium container during performance of said heating.
- 7. A method of any of claims 1 to 6 wherein the preparation is an alkyl, cycloalkyl, alkenyl or alkoxyalkyl 2-cyanoacrylate preparation.
- 8. A method of claim 7, wherein the preparation is a C rC4alkyl 2-cyanoacrylate preparation.
- 9. A method of claim 8, wherein the preparation is n-butyl 2-cyanoacrylate preparation.
- 10. A method of any of claims 1 to 9, wherein the 2-cyanoacrylate ester preparation contains sulphur dioxide and butylated hydroxyanisole as stabilisers.
- 11. A package comprising a sealed aluminium container containing a sterile 2-cyanoacrylate ester preparation.
- 12. A package of claim 11, wherein the 2^cyanoacrylate preparation retains its fluidity at 55 C for a period of at least 50 days.
- 13. A package of claim 12, wherein the 2-cyanoacrylate ester preparation retains its fluidity at 55"C for a period of at least 200 days.
- 14. A package of any of claims 11 to 13, wherein the 2-cyanoacrylate ester preparation is defined in any of claims 7 to 10.
- 15. A package comprising a sealed container containing sterile 2-cyanoacrylate ester preparation, the preparation being capable of retaining its fluidity at 55 C for a period of at least 50 days when in a sealed aluminium container (cog. an aluminium tube).
- 16. A package of claim 15, wherein the preparation is thus capable of retaining its fluidity at 55"C for a period of at least 200 days.
- 17. A package of claim 15 or claim 16, wherein the preparation is as further defined in any of claims 7 to 10.
- 18. A sterile 2-cyanoacrylate ester preparation for use in medicine or surgery, the preparation being contained in a sealed aluminium container and optionally as defined in any of claims 12 to 14.
- 19. A sterile 2-cyanoacrylate ester preparation for use in medicine or surgery, the preparation being in a sealed container and being capable of retaining its fluidity at 55C for a period of at least 50 days when in a sealed aluminium container, and optionally being as defined in claim 16 or claim 17.
- 20. A method of bonding human or animal tissue, comprising applying to the tissue a preparation as defined in claim 18 or claim 19.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9522435A GB2306469B (en) | 1995-11-02 | 1995-11-02 | Sterilising cyanoacrylate preparations |
US08/740,405 US5874044A (en) | 1995-11-02 | 1996-10-29 | Heat sterilization of cyanoacrylate |
US08/914,190 US6136326A (en) | 1995-11-02 | 1998-01-30 | Heat sterilization of cyanoacrylate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9522435A GB2306469B (en) | 1995-11-02 | 1995-11-02 | Sterilising cyanoacrylate preparations |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9522435D0 GB9522435D0 (en) | 1996-01-03 |
GB2306469A true GB2306469A (en) | 1997-05-07 |
GB2306469B GB2306469B (en) | 1998-05-13 |
Family
ID=10783273
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9522435A Expired - Lifetime GB2306469B (en) | 1995-11-02 | 1995-11-02 | Sterilising cyanoacrylate preparations |
Country Status (2)
Country | Link |
---|---|
US (2) | US5874044A (en) |
GB (1) | GB2306469B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1230313A1 (en) * | 1999-10-29 | 2002-08-14 | Closure Medical Corporation | Cyanoacrylate solutions containing preservatives |
US6512023B1 (en) | 1998-06-18 | 2003-01-28 | Closure Medical Corporation | Stabilized monomer adhesive compositions |
US6579916B1 (en) | 2000-11-21 | 2003-06-17 | Medlogic Global Corporation | Methods for sterilizing cyanoacrylate compositions |
US7138441B1 (en) | 1999-05-29 | 2006-11-21 | United States Surgical Corporation | Bioabsorbable blends and surgical articles therefrom |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6143805A (en) * | 1998-02-18 | 2000-11-07 | Closure Medical Corporation | Electron beam sterilization of liquid adhesive compositions |
BR9913366A (en) | 1998-09-01 | 2002-02-13 | Closure Medical Corp | Kit, enclosure and container for storing and applying an adhesive material, process for applying an adhesive material to a surface to be treated, container assembly for storing and applying an adhesive material, and, process for forming an adhesive-containing package assembly sterilized |
JP4249395B2 (en) * | 1998-09-18 | 2009-04-02 | メドロジック グローバル リミテッド | Method for sterilizing a cyanoacrylate composition |
GB9820457D0 (en) | 1998-09-18 | 1998-11-11 | Medlogic Global Corp | Methods for sterilizing cyanoacrylate compositions |
US6412639B1 (en) * | 2000-04-28 | 2002-07-02 | Closure Medical Corporation | Medical procedure kit having medical adhesive |
WO2002054934A2 (en) * | 2000-11-21 | 2002-07-18 | Medlogic Global Limited | Method for sterilizing cyanoacrylate compositions |
US8110144B2 (en) * | 2004-09-17 | 2012-02-07 | Chemence Medical, Inc. | Process for sterilization of and cyanoacrylate adhesives compositions and devices |
US7862800B1 (en) | 2005-01-14 | 2011-01-04 | Henkel Ag & Co. Kgaa | Radiopaque cyanoacrylate compositions |
US8480718B2 (en) * | 2006-12-21 | 2013-07-09 | Warsaw Orthopedic, Inc. | Curable orthopedic implant devices configured to be hardened after placement in vivo |
US20080311323A1 (en) * | 2007-06-12 | 2008-12-18 | Chemence, Inc. | Cyanoacrylate Adhesive Compositions and Devices and Process for Sterilization Thereof |
US8729121B2 (en) * | 2007-06-25 | 2014-05-20 | Adhezion Biomedical, Llc | Curing accelerator and method of making |
WO2010008822A2 (en) | 2008-06-23 | 2010-01-21 | Adhezion Biomedical, Llc | Cyanoacrylate tissue adhesives with desirable permeability and tensile strength |
WO2009033135A1 (en) * | 2007-09-06 | 2009-03-12 | Suremilk, Llc. | Universal drinking adapter for beverage bottles to allow for liquid consumption and devices and kits for determining small molecules, metal ions, endotoxins, and bacteria found in milk, and methods of use thereof |
EP2742875B1 (en) | 2007-11-14 | 2016-02-24 | Adhezion Biomedical, LLC | Cyanoacrylate tissue adhesives |
US8293838B2 (en) * | 2008-06-20 | 2012-10-23 | Adhezion Biomedical, Llc | Stable and sterile tissue adhesive composition with a controlled high viscosity |
US8198344B2 (en) | 2008-06-20 | 2012-06-12 | Adhezion Biomedical, Llc | Method of preparing adhesive compositions for medical use: single additive as both the thickening agent and the accelerator |
US8609128B2 (en) * | 2008-10-31 | 2013-12-17 | Adhezion Biomedical, Llc | Cyanoacrylate-based liquid microbial sealant drape |
US9254133B2 (en) | 2008-10-31 | 2016-02-09 | Adhezion Biomedical, Llc | Sterilized liquid compositions of cyanoacrylate monomer mixtures |
US8652510B2 (en) | 2008-10-31 | 2014-02-18 | Adhezion Biomedical, Llc | Sterilized liquid compositions of cyanoacrylate monomer mixtures |
US8628710B2 (en) * | 2009-12-10 | 2014-01-14 | Kimberly-Clark Worldwide, Inc. | Plasticizer for thermoplastic polymer materials |
US8518315B2 (en) * | 2008-12-19 | 2013-08-27 | Kimberly-Clark Worldwide, Inc. | Plasticizer for thermoplastic materials |
US20100160484A1 (en) * | 2008-12-19 | 2010-06-24 | Macdonald John G | Xanthene-based plasticizer of resins and polymers |
JP5717100B2 (en) | 2009-02-20 | 2015-05-13 | コヴィディエン リミテッド パートナーシップ | Device for vein closure for the treatment of venous insufficiency |
US10143455B2 (en) | 2011-07-20 | 2018-12-04 | Covidien LLP | Enhanced ultrasound visualization of intravascular devices |
AU2011229797B2 (en) | 2010-03-23 | 2017-02-16 | Hyperbranch Medical Technology, Inc. | Disposable syringe applicators for multi-component formulations, and methods of use thereof |
US9309019B2 (en) | 2010-05-21 | 2016-04-12 | Adhezion Biomedical, Llc | Low dose gamma sterilization of liquid adhesives |
US8927603B2 (en) | 2010-06-07 | 2015-01-06 | Adhezion Biomedical, Llc | X-ray sterilization of liquid adhesive compositions |
US8550737B2 (en) | 2010-09-20 | 2013-10-08 | Adhezion Biomedical, Llc | Applicators for dispensing adhesive or sealant material |
US8808620B1 (en) | 2012-02-22 | 2014-08-19 | Sapheon, Inc. | Sterilization process design for a medical adhesive |
US9421297B2 (en) | 2014-04-02 | 2016-08-23 | Adhezion Biomedical, Llc | Sterilized compositions of cyanoacrylate monomers and naphthoquinone 2,3-oxides |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1159548A (en) * | 1965-12-09 | 1969-07-30 | Eastman Kodak Co | Surgical Adhesives |
Family Cites Families (7)
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US2926188A (en) * | 1957-05-06 | 1960-02-23 | Rohm & Haas | Process for preparing alpha-cyanoacrylates |
US3360124A (en) * | 1966-05-18 | 1967-12-26 | Ethicon Inc | Sterile alkyl ester of 2-cyanoacrylate |
US3527841A (en) * | 1968-04-10 | 1970-09-08 | Eastman Kodak Co | Alpha-cyanoacrylate adhesive compositions |
US4724177A (en) * | 1986-06-26 | 1988-02-09 | Russo Libby J | Brushing cyanoacrylates: packaging and method |
DE4229734A1 (en) * | 1992-09-05 | 1994-03-10 | Henkel Kgaa | Packaging for flowable products |
TW359683B (en) * | 1993-12-23 | 1999-06-01 | Loctite Ireland Ltd | Sterilized cyanoacrylate adhesive composition, and a method of making such composition |
US5436363A (en) * | 1994-10-03 | 1995-07-25 | Industrial Technology Research Institute | Method for making alkyl-α-cyanoacrylate from depolymerization of poly(alkyl-α-cyanoacrylate) |
-
1995
- 1995-11-02 GB GB9522435A patent/GB2306469B/en not_active Expired - Lifetime
-
1996
- 1996-10-29 US US08/740,405 patent/US5874044A/en not_active Expired - Lifetime
-
1998
- 1998-01-30 US US08/914,190 patent/US6136326A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1159548A (en) * | 1965-12-09 | 1969-07-30 | Eastman Kodak Co | Surgical Adhesives |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6512023B1 (en) | 1998-06-18 | 2003-01-28 | Closure Medical Corporation | Stabilized monomer adhesive compositions |
US7138441B1 (en) | 1999-05-29 | 2006-11-21 | United States Surgical Corporation | Bioabsorbable blends and surgical articles therefrom |
EP1230313A1 (en) * | 1999-10-29 | 2002-08-14 | Closure Medical Corporation | Cyanoacrylate solutions containing preservatives |
US6579916B1 (en) | 2000-11-21 | 2003-06-17 | Medlogic Global Corporation | Methods for sterilizing cyanoacrylate compositions |
Also Published As
Publication number | Publication date |
---|---|
US5874044A (en) | 1999-02-23 |
GB2306469B (en) | 1998-05-13 |
GB9522435D0 (en) | 1996-01-03 |
US6136326A (en) | 2000-10-24 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PE20 | Patent expired after termination of 20 years |
Expiry date: 20151101 |