WO1997033632A2 - Alginate containing antimicrobial composition - Google Patents
Alginate containing antimicrobial composition Download PDFInfo
- Publication number
- WO1997033632A2 WO1997033632A2 PCT/GB1997/000715 GB9700715W WO9733632A2 WO 1997033632 A2 WO1997033632 A2 WO 1997033632A2 GB 9700715 W GB9700715 W GB 9700715W WO 9733632 A2 WO9733632 A2 WO 9733632A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alginate
- composition
- glass
- carrier material
- finely divided
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0095—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
Definitions
- the present invention relates to an anti-raicrobial composition for use in medical or veterinary applications.
- compositions A wide variety of gels, creams, ointments, lotions etc are available for application to a body surface.
- the exact content of such compositions generally depends upon the purpose of application which may be, for example, to clean a body surface, to promote healing of any wound or injury, to prevent an exposed area of the body from drying out, to prevent infection etc.
- the composition may include an active ingredient which is administered to the patient by application of the composition.
- One example of a commercially available gel is INTRASITETM produced by Smith & Nephew Ltd.
- This hydrogel contains hydrated carboxymethylcellulose as its main ingredient, and is applied to wounds in gel form as a primary treatment in order to clean the exposed surface by aiding removal of cell debris, dirt etc.
- the gel In addition to acting as a sloughing agent, the gel also keeps the wound from drying out, thereby promoting healing.
- Another example of a gel suitable for use on a wound dressing is described in EP-A-0586260 of Courtaulds Fibres Ltd.
- the gel disclosed is an alginate gel having an alginate content of 2 to 11 percent by weight.
- Surgical dressings based on gel forming alginates have a significant contribution to make in wound management and are generally presented as preformed components of gels and pastes and as fibres of calciura or mixed calcium/sodium salts.
- alginate-ba ⁇ ed surgical dressings the starting raw material is usually the sodium salt which is supplied by the alginate producer as a dry powder. Attempts to utilise alginate as topical powders for direct application to wounds have not proved successful. This is because the irregularly dispersed powder does not wet easily and clumping occurs leading to clusters of dry particles which can be sites of local irritation. There is incomplete gelling as a result and the desired sealing of the wound with a smooth hydrogel coating is not achieved.
- alginate being used herein to refer to alginates, the derivatives and salts thereof
- carrier material a different finely divided carrier material
- Suitable carrier materials include proteins (eg casein), salts (eg sodium, zinc, calcium, magnesium and potassium salts) and water-soluble glass. Desirably the carrier material is water-soluble or water miscible.
- the alginate/carrier combination acts in synergy to promote healing and cell growth.
- tissue response was clearly better for the mixed powders than that seen with either material on its own.
- tissue response was clearly better for the mixed powders than that seen with either material on its own.
- tissue response was clearly better for the mixed powders than that seen with either material on its own.
- the present invention provides an admixture of alginate or a derivative or salt thereof together with a carrier material.
- a carrier material Generally both main components are finely divided, i.e. are in powder, particulate or granular form.
- the finely divided alginate and carrier material components may each have a diameter size of 150 ⁇ m or less.
- the mode particle size for either component is lOOum or less. More preferably the mode particle size for either component is 60 ⁇ m or less, for example 30-60 ⁇ m.
- Suitable mixtures include those having a ratio of from 20:80 to 80:20 (% by weight) of alginate:carrier.
- Preferred mixtures include those having an alginate:carrier ratio in the range of 20:80 to 50:50, preferably 20:80 to 30:70, for example 25:75.
- Water-soluble glasses are a preferred form of carrier material. The use of glasses which can dissolve in water and body fluid and which are applied internally of the body are well-known. These glasses are formed from phosphorus pentoxide and may be modified to dissolve over a period of minutes, months or even years, as required.
- UK Patent Specification number 2,030,559 describes the use of selenium-impregnated water-soluble glass for providing controlled release of the selenium as a trace element into cattle and sheep, the glass being applied as a subcutaneous insert.
- UK Patent Specification number 2,037,735 also describes a subcutaneous implant of water-soluble glass, and in this case the glass is impregnated with copper; minor quantities of trace elements such as boron, arsenic, iodine, manganese, chromium, silver, gold and gallium may also be included.
- Water-soluble glass has also been proposed for use in prosthetics, for example in UK Patent Specification number 2,099,702, and for use in anticorrosive paints, as described in UK Patent Specification number 2,062,612. Further the literature provides for the use of such glasses in the controlled release of ferrous and ferric ions into the human or animal body by ingestion or implantation of the glass (UK Patent Specification number 2,081,703), and for the use of glasses in the controlled release of ions such as lithium, sodium, potassium, caesium, rubidium, polyphosphate, calcium and aluminium to patients by inclusion of the glass in a drip feed line (UK Patent Specification number 2,057,420).
- WO-A-89/01793 relates to apparatus for antimicrobial use in passage of fluid to or from a living body, the apparatus comprising a conduit for insertion into the body, a reservoir for fluid and a connector member for connecting said conduit to said reservoir external of the body, wherein said connector member includes a water-soluble glass impregnated with elemental silver or a compound of silver, said water-soluble glass defining at least a part of a passageway for fluid to flow between the reservoir and the conduit.
- the water-soluble glass is a silver containing water-soluble glass.
- the silver content will be introduced into the glass composition in the form of silver orthophosphate.
- Suitable glasses include, for example, the ARGLAESTM glass of Giltech Limited.
- said glass is adapted by the use of glass modifiers to give a sustained release of silver ions over a set period.
- the water-soluble glass comprises an alkali metal oxide M 2 0, an alkaline earth oxide MO, phosphorus pentoxide P 2 0 5 and silver oxide (Ag 2 0) or silver orthophosphate (Ag 3 P0 ⁇ ,) .
- said glass contains not more than 40 mole % M 2 0 or MO, not less than 10 mole % M 2 0 or MO, and not more than 50 mole % nor less than 38 mole % phosphorus pentoxide, with the inclusion of 0.05 to 5.0 mole % silver oxide or orthophosphate.
- Said alkali metal oxide may be sodium oxide (Na 2 0), potassium (K 2 0) or a mixture thereof; and said alkaline earth oxide may be calcium oxide (CaO), magnesium oxide (MgO), zinc oxide (ZnO) or a mixture thereof.
- the glass may also contain less than 5 mole % silicon dioxide (Si0 2 ), boric oxide (B 2 0 3 ), sulphate ion (SO*, 2" ), a halide ion, copper oxide (CuO) or a mixture thereof.
- the soluble glasses used in this invention comprise phosphorus pentoxide (P 2 0 5 ) as the principal glass-former, together with any one or more glass-modifying non-toxic materials such as sodium oxide (Na 2 0), potassium oxide (K 2 0), magnesium oxide (MgO), zinc oxide (ZnO) and calcium oxide (CaO).
- the rate at which the silver-release glass dissolves in fluids is determined by the glass composition..
- the dissolution rates in water at 38°C ranging from substantially zero to 25mg/cm 2 /hour or more can be designed.
- the most desirable dissolution rate R of the glass is between 0.01 and 2.0mg/cm/hour.
- the water-soluble glass is preferably a phosphate glass, and the silver may advantageously be introduced during manufacture as silver orthophosphate (Ag 3 P0 4 ) .
- the content of silver and other constituents in the glass can vary in accordance with conditions of use and desired rates of release, the content of silver generally being up to 5 mole %.
- the optimum rate of release of silver ions into an aqueous environment may be selected by circumstances and particularly by the specific function of the released silver.
- the invention provides a means of delivering silver ions to an aqueous medium at a rate which will maintain a concentration of silver ions in said aqueous medium of not less than 0.01 parts per million and not greater than 10 parts per million.
- the required rate of release may be such that all of the silver added to the system is released in a short period of hours or days and in other applications it may be that the total silver be released slowly at a substantially uniform rate over a period extending to months or even years .
- the glass may be formed by a number of methods. It may simply be cast by conventional or centrifugal procedures, or it may be prepared via one or more stages of rod, fibre or tube drawing. Other preparation techniques include foamed glass. Following glass formation it will be comminuted into finely divided form.
- alginate component derivatives and salts of alginates are acceptable for use in the present invention.
- Sodium and calcium salts of alginate or a combination of these two salts is preferred.
- Sodium alginate is especially preferred.
- the composition of the present invention is an admixture of sodium alginate powder and water soluble glass (eg ARGLAESTM of Giltech Limited) in a ratio of alginate:glass of 25:75 by weight.
- water soluble glass eg ARGLAESTM of Giltech Limited
- the water soluble glass releases calcium ions as it dissolves.
- the calcium ions displace some of the sodium ions in the sodium alginate thus forming calcium alginate.
- the presence of calcium alginate stabilises the alginate gel.
- composition may be pre-mixed, or alternatively the alginate may be kept separately from the carrier material and the ingredients admixed together immediately prior to use. This enables a particular blend to be formulated to suit the wound or condition in question.
- the composition of th ⁇ present invention may contain an active ingredient.
- active ingredient is used herein to refer to any agent which affects the metabolism or any metabolic or cellular process of the patient (including growth factors and living cells), promotes healing, combats infection, hypergranulation or inflammation. Antibiotics and other anti-bacterial agents, steroids, painkillers etc are all suitable.
- the active ingredient may be in delay-release or controlled-release form.
- composition of the present invention may be used to clean a body surface, to promote healing of a wound or injury, to prevent an exposed area of the body from drying out or to prevent infection.
- the present invention provides a method of treating the human or non-human (preferably mammalian) animal body, said method comprising applying a finely divided admixture of an alginate (a derivative or salt thereof) and a carrier material, such as a (preferably silver-containing) water-soluble glass, to a body surface, for example to a wound.
- a carrier material such as a (preferably silver-containing) water-soluble glass
- Fig i illustrates a mass of in l mmatory cells at the site of implantation of a composition of just silver ion releasing glass, 7 days after implantation.
- Fig 2 illustrates a mass of inflammatory cells and the damage to the muscle bed at the site of implantation of alginate, 2 days after implantation.
- Fig 3 is a higher magnification of the same tissue block as in. Fig 2.
- Fig 4 illustrates a mass of inflammatory cells sitting on and infiltrating the muscle bed at the site of implantation of a composition of just alginate, 7 days after implantation.
- Fig 5 is a higher magnification of the same tissue block as in Fig 4.
- Fig 6 illustrates a number of inflammatory cells and the broken up muscle bed at the site of implantation of a composition of alginate and a water soluble glass carrier, 2 days after implantation.
- Fig 7 illustrates a number of inflammatory cells and a normal muscle bed at the site of implantation of a composition of alginate and a water soluble glass carrier, 7 days after implantation.
- CRG/silver powder [D301893 Ag 3 mole%] .. CRG/Ag Alginate powder [lot No 544831] Alginate CRG/silver powder and Alginate powder [50:50] mix Alginate/CRG/Ag
- the silver containing controlled release glass (herein referred to as "CRG/silver”) had the following composition Na C 27.5 mole % CaO 22 mole % Ag 2 0 3.5 mole % P 2 0 5 47 mole %
- the silver content of the glass was added in the form of silver orthophosphate, but is expressed as "silver oxide" according to convention. 100% of the glass particles had a diameter of less than 53 ⁇ m.
- the alginate used was a pure sodium alginate salt, commercially available as ManucolTM LKX of Kelco International Limited, United Kingdom.
- the volume mode particle size of the sodium alginate is 41.46 ⁇ m and 99.4% of the particles had a diameter of less than 49.99 ⁇ m.
- tissue was examined for any obvious signs of inflammation, and a block of tissue/muscle containing the implant site was removed.
- the block was immediately frozen, sectioned on a cryostat microtome to produce sections 7 ⁇ m thin and stained using haematoxylin and eosin. The sections were examined by light microscopy.
- Fig 3 shows a higher magnification of the response from the same tissue block as Fig 2.
- Inflammatory cells can be seen invading the muscle fibres. Most of the pink stained material visible was alginate, clearly well dispersed. Muscle fibres (also stained pink) could be seen in the top right corner. Alginate could be seen, stained pink.
- the alginate/silver mix seemed to attract less cells to the site at 2 days. At 7 days the response was fairly similar to that seen with the samples examined alone and no exudate was formed. However, after 14 days the healing response seemed much accelerated with this sample. Clean, normal muscle tissue was observed, with little evidence of inflammatory infiltration.
- the powders tried were casein, sodium chloride, zinc oxide, sodium borate, magnesium sulphate, magnesium chloride, calcium tetraborate and potassium iodide.
- Each powder was admixed individually with sodium alginate (ManucolTM LKX) in a ratio of 3:1. The admixture was then applied to a damp simulated wound, covered with a dressing and left for 48 hours.
- sodium alginate ManucolTM LKX
- Admixtures with zinc oxide and calcium tetraborate did not appear to wet out at all.
- the admixture with sodium borate did wet out adequately, but formed a rubbery coating on the simulated wound which did not stick to the dressing.
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- Chemical & Material Sciences (AREA)
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- Materials Engineering (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9532381A JP2000506920A (en) | 1996-03-13 | 1997-03-13 | Antibacterial ingredients including alginate |
EP97908343A EP0888139A2 (en) | 1996-03-13 | 1997-03-13 | Alginate containing antimicrobial composition |
AU20329/97A AU2032997A (en) | 1996-03-13 | 1997-03-13 | Alginate containing antimicrobial composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9605247.7 | 1996-03-13 | ||
GBGB9605247.7A GB9605247D0 (en) | 1996-03-13 | 1996-03-13 | Composition |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09142776 A-371-Of-International | 1998-09-11 | ||
US10/425,411 Continuation US20040081706A1 (en) | 1996-03-13 | 2003-04-29 | Alginate containing antimicrobial composition |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997033632A2 true WO1997033632A2 (en) | 1997-09-18 |
WO1997033632A3 WO1997033632A3 (en) | 1997-10-23 |
Family
ID=10790293
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1997/000715 WO1997033632A2 (en) | 1996-03-13 | 1997-03-13 | Alginate containing antimicrobial composition |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0888139A2 (en) |
JP (1) | JP2000506920A (en) |
AU (1) | AU2032997A (en) |
CA (1) | CA2247986A1 (en) |
GB (1) | GB9605247D0 (en) |
WO (1) | WO1997033632A2 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998044965A1 (en) * | 1997-04-05 | 1998-10-15 | Giltech Limited | Implantation composition comprising glass particles |
WO2000043047A2 (en) * | 1999-01-19 | 2000-07-27 | Stericon, L.L.C. | Hypertonic aqueous solutions of polybasic acid salts |
WO2000047245A1 (en) * | 1999-02-11 | 2000-08-17 | Giltech Limited | Biodegradable composite material for tissue repair |
EP1252901A1 (en) * | 2001-04-25 | 2002-10-30 | Les Laboratoires Brothier | Powdered wound dressing and method for producing the same |
US7329417B2 (en) | 2001-02-08 | 2008-02-12 | Coloplast A/S | Medical dressing comprising an antimicrobial silver compound |
GB2490516A (en) * | 2011-05-03 | 2012-11-07 | Systagenix Wound Man Ip Co Bv | Polysaccharide mould for wound treatment |
US10842496B2 (en) | 2018-12-17 | 2020-11-24 | Ethicon Llc | Implantable sphincter assistance device with tuned magnetic features |
US11051931B2 (en) | 2018-10-31 | 2021-07-06 | Cilag Gmbh International | Active sphincter implant to re-route flow through gastrointestinal tract |
US11071619B2 (en) | 2018-12-17 | 2021-07-27 | Cilag Gmbh International | Coupling assembly for implantable sphincter assistance device |
US11298136B2 (en) | 2018-12-19 | 2022-04-12 | Cilag Gmbh International | Implantable sphincter assistance device with deformable elements |
US11324512B2 (en) | 2018-10-26 | 2022-05-10 | Torax Medical, Inc. | Magnetic sphincter augmentation device for urinary incontinence |
US11376146B2 (en) | 2018-12-17 | 2022-07-05 | Cilag Gmbh International | Tissue interface features for implantable sphincter assistance device |
US11399928B2 (en) | 2018-12-19 | 2022-08-02 | Cilag Gmbh International | Linking elements for implantable sphincter assistance device |
US11478347B2 (en) | 2018-12-17 | 2022-10-25 | Cilag Gmbh International | Sphincter sizing instrument |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1787627A1 (en) | 2005-11-17 | 2007-05-23 | 3M Innovative Properties Company | Anti-microbial dental impression material |
CA2706637C (en) * | 2007-11-27 | 2016-11-29 | Algipharma Ipr As | Use of alginate oligomers in combating biofilms |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7408580A (en) * | 1974-06-26 | 1975-12-30 | Philips Nv | Powder prepns for burn treatment - contg silver sulfadiazine and a swellable carrier |
WO1990008470A1 (en) * | 1989-01-27 | 1990-08-09 | Giltech Limited | A medicinal substance for topical application |
EP0512855A2 (en) * | 1991-05-09 | 1992-11-11 | E.R. Squibb & Sons, Inc. | Absorbent wound filler |
US5356614A (en) * | 1989-09-11 | 1994-10-18 | Mixro-Collagen Pharmaceutics, Ltd. | Process of preparing microparticulate collagen collagen-based products produced thereby and method of applying same |
WO1996017595A1 (en) * | 1994-12-06 | 1996-06-13 | Giltech Limited | Foamable formulation and foam |
-
1996
- 1996-03-13 GB GBGB9605247.7A patent/GB9605247D0/en active Pending
-
1997
- 1997-03-13 CA CA 2247986 patent/CA2247986A1/en not_active Abandoned
- 1997-03-13 JP JP9532381A patent/JP2000506920A/en not_active Ceased
- 1997-03-13 WO PCT/GB1997/000715 patent/WO1997033632A2/en not_active Application Discontinuation
- 1997-03-13 AU AU20329/97A patent/AU2032997A/en not_active Abandoned
- 1997-03-13 EP EP97908343A patent/EP0888139A2/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7408580A (en) * | 1974-06-26 | 1975-12-30 | Philips Nv | Powder prepns for burn treatment - contg silver sulfadiazine and a swellable carrier |
WO1990008470A1 (en) * | 1989-01-27 | 1990-08-09 | Giltech Limited | A medicinal substance for topical application |
US5356614A (en) * | 1989-09-11 | 1994-10-18 | Mixro-Collagen Pharmaceutics, Ltd. | Process of preparing microparticulate collagen collagen-based products produced thereby and method of applying same |
EP0512855A2 (en) * | 1991-05-09 | 1992-11-11 | E.R. Squibb & Sons, Inc. | Absorbent wound filler |
WO1996017595A1 (en) * | 1994-12-06 | 1996-06-13 | Giltech Limited | Foamable formulation and foam |
Non-Patent Citations (1)
Title |
---|
AMERICAN PHARM. ASSOC./ PHARM. SOCIETY OF GREAT BRITAIN: "Handbook of pharmaceutical Excipients" 1986 , AMERICAN PHARM. ASSOCIATION , WASHINGTON XP002039040 153140 see page 257 - page 258 * |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998044965A1 (en) * | 1997-04-05 | 1998-10-15 | Giltech Limited | Implantation composition comprising glass particles |
US6447805B1 (en) | 1997-04-05 | 2002-09-10 | Giltech Limited | Implantation composition comprising glass particles |
WO2000043047A2 (en) * | 1999-01-19 | 2000-07-27 | Stericon, L.L.C. | Hypertonic aqueous solutions of polybasic acid salts |
WO2000043047A3 (en) * | 1999-01-19 | 2000-11-30 | Stericon L L C | Hypertonic aqueous solutions of polybasic acid salts |
WO2000047245A1 (en) * | 1999-02-11 | 2000-08-17 | Giltech Limited | Biodegradable composite material for tissue repair |
US7531005B1 (en) | 1999-02-11 | 2009-05-12 | Tyco Healthcare Group Lp | Biodegradable composite material for tissue repair |
US7329417B2 (en) | 2001-02-08 | 2008-02-12 | Coloplast A/S | Medical dressing comprising an antimicrobial silver compound |
EP1252901A1 (en) * | 2001-04-25 | 2002-10-30 | Les Laboratoires Brothier | Powdered wound dressing and method for producing the same |
GB2490516A (en) * | 2011-05-03 | 2012-11-07 | Systagenix Wound Man Ip Co Bv | Polysaccharide mould for wound treatment |
WO2012150429A1 (en) | 2011-05-03 | 2012-11-08 | Systagenix Wound Management Ip Co. B.V. | Wound treatment |
US9849182B2 (en) | 2011-05-03 | 2017-12-26 | Kci Usa, Inc. | Wound treatment |
US11324512B2 (en) | 2018-10-26 | 2022-05-10 | Torax Medical, Inc. | Magnetic sphincter augmentation device for urinary incontinence |
US11051931B2 (en) | 2018-10-31 | 2021-07-06 | Cilag Gmbh International | Active sphincter implant to re-route flow through gastrointestinal tract |
US10842496B2 (en) | 2018-12-17 | 2020-11-24 | Ethicon Llc | Implantable sphincter assistance device with tuned magnetic features |
US11071619B2 (en) | 2018-12-17 | 2021-07-27 | Cilag Gmbh International | Coupling assembly for implantable sphincter assistance device |
US11376146B2 (en) | 2018-12-17 | 2022-07-05 | Cilag Gmbh International | Tissue interface features for implantable sphincter assistance device |
US11478347B2 (en) | 2018-12-17 | 2022-10-25 | Cilag Gmbh International | Sphincter sizing instrument |
US11298136B2 (en) | 2018-12-19 | 2022-04-12 | Cilag Gmbh International | Implantable sphincter assistance device with deformable elements |
US11399928B2 (en) | 2018-12-19 | 2022-08-02 | Cilag Gmbh International | Linking elements for implantable sphincter assistance device |
Also Published As
Publication number | Publication date |
---|---|
CA2247986A1 (en) | 1997-09-18 |
WO1997033632A3 (en) | 1997-10-23 |
GB9605247D0 (en) | 1996-05-15 |
AU2032997A (en) | 1997-10-01 |
JP2000506920A (en) | 2000-06-06 |
EP0888139A2 (en) | 1999-01-07 |
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