Making therapeutic foam
Abstract
Improved therapeutic sclerosing microfoams and methods and devices for making them are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

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Expired 26 May 2020, 6.3 years ago.
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35 claims: 3 independent, 32 dependent
- 1Zastrzeżenia patentowe 1. Sposób wytwarzania mikropianki do leczenia obliteracyjnego żylaków naczyń krwionośnych, znamienny tym, że przepuszcza się mieszaninę fizjologicznie dopuszczalnego gazu dyspergującego we krwi zawierającego w większej części ditlenek i/lub tlen oraz wodnego roztworu ciekłego środka do obliteracji żylaków, zawierającego roztwór polidokanolu lub tetradecylosiarczanu sodu (STS) w nośniku wodnym, roztwory hipertoniczne glukozy lub glukozy i solanki, glicerolu chromowego, oleinianu PL 201 186 B1 etanoloaminy, roztwory soli sodowej morhuato lub jodu, poprzez jeden lub więcej kanałów o co najmniej jednym wymiarze przekroju poprzecznego od 0,1 do 30 um, przy czym gaz i roztwór miesza się w komorze łączącej przed wprowadzeniem mieszaniny do tego jednego lub więcej kanałów, regulując stosunek gazu do cieczy w mieszaninie poprzez pobieranie odpowiednich przepływów gazu i cieczy, do uzyskania, po przepływie przez kanały, mikropianki o gęstości pomiędzy 0,07 g/ml do 0,19 g/ml i o okresie półtrwania co najmniej 2 minuty.
- 2Sposób według zastrz. 1, znamienny tym, że reguluje się stosunek gaz/ciecz w mieszaninie do wytworzenia mikropianki o gęstości od 0,09 g/ml do 0,16 g/ml.
- 3Sposób według zastrz. 1 albo 2, znamienny tym, że wytwarza się pęcherzyki gazu o średnicy co najmniej 25 um, z których co najmniej 50% ilościowo ma średnicę i nie większą niż 200 um i co najmniej 95% ma średnicę nie większą niż 280 um.
- 4Sposób według zastrz. 1 albo 2, znamienny tym, że wytwarza się pęcherzyki gazu o średnicy co najmniej 25 um, z których co najmniej 50% ilościowych ma średnicę i nie większą niż 150 um i co najmniej 95% ma średnicę nie większą niż 250 um.
- 5Sposób według zastrz. 1 albo 2, znamienny tym, że stosuje się mieszaninę gazu i ciekłego środka używanego do obliteracji żylaków w postaci aerozolu, dyspersji pęcherzyków w cieczy lub makropianki.
- 6Sposób według zastrz. 1 albo 2, znamienny tym, że stosuje się mieszaninę, w której stosunek gazu do cieczy w mieszaninie wynosi 1 gram ciekłego środka używanego do obliteracji żylaków do 6,25 do 14,3 objętości gazu, w standardowych warunkach temperatury i ciśnienia.
- 7Sposób według zastrz. 1, znamienny tym, że jako wodny nośnik stosuje się roztwór solanki.
- 8Sposób według zastrz. 1 albo 2, znamienny tym, że wytwarzając mikropiankę gaz i ciekłą mieszaninę przepuszcza się przez kanały mające średnicę wynosząca od 5 um do 25 um.
- 9Sposób według zastrz. 8, znamienny tym, że gaz i ciekłą mieszaninę przepuszcza się przez kanały, które są otworami w sicie lub przesiewaczu, umieszczonymi prostopadle do kierunku strumienia mieszaniny gaz/ciecz, mającymi średnicę od 10 um do 20 um.
- 10Sposób według zastrz. 8, znamienny tym, że gaz i ciekłą mieszaninę przepuszcza się przez kanały mające formę licznych otworów w jednym lub więcej elementach, poprzez które przepływa mieszanina.
- 11Sposób według zastrz. 10, znamienny tym, że gaz i ciekłą mieszaninę przepuszcza się przez jeden lub więcej elementów, których otwory tworzą 2% do 65% otwartej powierzchni.
- 12Sposób według zastrz. 10, znamienny tym, że gaz i ciekłą mieszaninę przepuszcza się przez rozmieszczone kolejno elementy składające się z porowatego materiału, przy czym mieszaninę przepuszcza się przez kanały każdego z elementów.
- 13Sposób według zastrz. 12, znamienny tym, że elementy z porowatego materiału rozmieszcza się wzdłuż kierunku strumienia mieszaniny w szeregu i w oddaleniu od siebie.
- 14Sposób według zastrz. 1 albo 2, znamienny tym, że mieszaninę gazu i cieczy przepuszcza się przez dany kanał lub kanały wielokrotnie.
- 15Sposób według zastrz. 1 albo 2, znamienny tym, że przepuszczany gaz spręża się do nadciśnienia 1 do 90 kPa.
- 16Sposób według zastrz. 15, znamienny tym, że przepuszczany gaz spręża się do nadciśnienia 10 do 30 kPa.
- 17Urządzenie do wytwarzania mikropianki do leczenia obliteracyjnego żylaków naczyń krwionośnych, znamienne tym, że zawiera pojemnik (1, 24), w którym znajduje się komora ciśnieniowa (4, 19) zawierająca wodny roztwór ciekłego środka (3, 18) do obliteracji żylaków, zwłaszcza roztworu polidokanolu lub tetradecylosiarczanu sodu (STS) w nośniku wodnym, polidokanolu, soli metalu alkalicznego tetradecylosiarczanu na przykład soli sodowej, roztworów hipertonicznych glukozy lub glukozy i solanki, glicerolu chromowego, oleinianu etanoloaminy, soli sodowej morhuato lub roztworów jodu, tor przepływu z co najmniej jednym otworem wylotowym (13) do przepływu cieczy z komory ciśnieniowej (4, 19) na zewnątrz i mechanizm uruchamiający do otwierania lub zamykania toru przepływu z komory ciśnieniowej (4, 19) na zewnątrz, przy czym mechanizm uruchamiający jest dostosowany do wymuszania przepływu płynu z komory ciśnieniowej (4, 19) poprzez tor przepływu i poprzez co najmniej jeden otwór wylotowy (13) przy pojemniku (1, 24) znajdującym się pod ciśnieniem i otwartym torze przepływu, a pojemnik (1, 24) zawiera co najmniej jedno źródło fizjologicznie dopuszczalnego, dyspergującego we krwi, gazu pod ciśnieniem, zawierającego w większej części ditlenek i/lub tlen, i ma otwory przepływu gazu (11a, 11 b) otwierane za pomocą mechanizmu uruchamiającego do PL 201 186 B1 wytwarzania mieszaniny gazu i cieczy poprzez ich kontakt, zaś tor przepływu prowadzący na zewnątrz pojemnika (1, 24) zawiera co najmniej jeden element, w których znajduje się co najmniej jeden kanał o wymiarze przekroju poprzecznego od 0,1 L m do 30 L m, do przepuszczania mieszaniny gazu i cieczy na zewnątrz pojemnika (1, 24) z uzyskaniem mikropianki o gęstości od 0,07 do 0,19 g/ml i okresie półtrwania co najmniej 2 minuty.
- 18Urządzenie według zastrz. 17, znamienne tym, że przed elementami z kanałami w pojemniku (1, 24) jest usytuowany dolny łącznik (9) do kontaktowania cieczy i gazu i regulowania stosunku łączenia gazu i cieczy przepuszczanych poprzez kanały dla uzyskania mikropianki o wymaganej gęstości.
- 19Urządzenie według zastrz. 17 albo 18, znamienne tym, że w torze przepływu w pojemniku (1) jest umieszczony element regulujący stosunek gazu i cieczy w mieszaninie do uzyskania mikropianki o gęstości wynoszącej od 0,09 do 0,16 g/ml.
- 20Urządzenie według zastrz. 18, znamienne tym, że pojemnik (1 zawiera komorę ciśnieniową (4) napełnioną gazem dyspergującym we krwi i ciekłym środkiem (3) do obliteracji żylaków, a tor przepływu stanowi rurka (12) zanurzona otworem wlotowym w ciekłym roztworze (3) w komorze (4).
- 21Urządzenie według zastrz. 20, znamienne tym, że rurka (12) ma otwór wylotowy osadzony w dolnym łączniku (10) do łączenia gazu i cieczy, przy czym źródło gazu jest połączone z torem przepływu cieczy w co najmniej jednym otworze przepływu gazu (11a, 11b).
- 22Urządzenie według zastrz. 17 albo 18, znamienne tym, że w torze przepływu jest umieszczony zawór dozujący (5) do otwierania lub zamykania toru przepływu, połączony z mechanizmem uruchamiającym (6), który ma element przyciskowy lub odchylający do otwierania toru przepływu na zewnątrz i wymuszania ciśnieniem gazu przepływu cieczy w górę rurki (12) i mieszania się w dolnym łączniku (9) z gazem z wytworzeniem aerozolu, dyspersji pęcherzyków w cieczy lub makropianki.
- 23Urządzenie według zastrz. 17 albo 18, znamienne tym, że w komorze ciśnieniowej (4), w torze przepływu cieczy przed zaworem dozującym (5) jest zamontowany co najmniej jeden element zawierający co najmniej jeden kanał o średnicy przekroju poprzecznego 0,1 Lm do 30 Lm, do wytwarzania mikropianki przy przejściu mieszaniny gazu i cieczy przez ten co najmniej jeden kanał.
- 24Urządzenie według zastrz. 17 albo 18, znamienne tym, że w torze przepływu cieczy za dolnym łącznikiem (9) jest zamontowany co najmniej jeden element zawierający co najmniej jeden kanał o średnicy przekroju poprzecznego 0,1 Lm do 30 Lm, do wytwarzania mikropianki przy przejściu mieszaniny gazu i cieczy przez ten co najmniej jeden kanał.
- 25Urządzenie według zastrz. 24, znamienne tym, że co najmniej jeden element z kanałami jest umieszczony w kołpaku zamontowanym na zaworze dozującym (5), za dolnym łącznikiem (10) do mieszania gazu i cieczy, przy czym głowica zawiera otwór wylotowy (13).
- 26Urządzenie według zastrz. 23, znamienne tym, że co najmniej jeden element z kanałami jest umieszczony w górnym łączniku (10) osadzonym pomiędzy dolnym łącznikiem (9) gazu i cieczy i zaworem dozującym (5).
- 27Urządzenie według zastrz. 17 albo 18, znamienne tym, że dolny łącznik (9) gazu i cieczy zawiera otwory przepływu gazu (11a, 11b) usytuowane powyżej powierzchni ciekłego roztworu (3).
- 28Urządzenie według zastrz. 17 albo 18, znamienne tym, że komora ciśnieniowa jest dostosowana do wytwarzania nadciśnienia 1 kPa do 900 kPa.
- 29Urządzenie według zastrz. 17 albo 18, znamienne tym, że w pojemniku (1) jest umieszczony drugi elastyczny szczelny pojemnik (22) na wodny roztwór ciekłego środka do obliteracji żylaków, przy czym drugi pojemnik (22) jest uszczelniony wokół rurki (12).
- 30Urządzenie według zastrz. 29, znamienne tym, że w pojemniku (1) jest umieszczona rurka (12) mająca jednodrogowy zawór doprowadzający (21) usytuowany pomiędzy dolnym łącznikiem (10) gazu i cieczy i wlotem rurki (12) w drugim elastycznym szczelnym pojemniku (22), który przy zamkniętym torze przepływu na zewnątrz jest także zamknięty, a komora drugiego elastycznego szczelnego pojemnika (22) z ciekłym roztworem (3) jest oddzielona od komory ciśnieniowej (4) z fizjologicznie dopuszczalnym gazem dyspergującym we krwi, zaś przy otwartym torze przepływu na zewnątrz, jednodrogowy zawór (21) jest otwarty dla uwalniania ciekłego roztworu (3) w górę rurki (12) do dolnego łącznika (10) gazu i cieczy dla wytworzenia aerozolu, dyspersji pęcherzyków w cieczy lub makropianki, przetwarzanych w mikropiankę przy przechodzeniu przez kanały.
- 31Urządzenie według zastrz. 17 albo 18, znamienne tym, że do otworu wylotowego (13) pojemnika (24) jest dołączony szczelnie przewód wlotowy (35) połączony z wielodrogowym zaworem (36) kierującym przepływem mikropianki, przy czym zawór wielodrogowy (36) ma wyloty połączone PL 201 186 B1 z dwoma przewodami wylotowymi (38) i jest przestawny do kierowania przepływu pianki do jednego z tych dwóch przewodów lub zamykania przewodu wlotowego (35), a jeden z przewodów wylotowych jest połączony z otworem strzykawki (34).
- 32Urządzenie według zastrz. 31, znamienne tym, że pojemnik (24) do wytwarzania mikropianki jest podtrzymywany i zabezpieczony przez co najmniej jeden element wspornikowy (27a, 27b).
- 33Urządzenie według zastrz. 31, znamienne tym, że pojemnik (24) jest umieszczony w sąsiedztwie wielodrogowego zaworu (22) na podporze (26), a wlot wielodrogowego zaworu (22) jest dostosowany do przyłączenia przewodu wylotowego (35) z pojemnika (24) do wytwarzania mikropianki.
- 34Urządzenie według zastrz. 33, znamienne tym, że z pojemnikiem (24) współpracuje element uruchamiający (29) do otwierania toru przepływu w pojemniku (24) do wytwarzania mikropianki do przewodu wlotowego (35).
- 35Zastosowanie urządzenia określonego w zastrzeżeniu 17 do wytwarzania leku do obliteracji żylaków.
Independent claims35
203 paragraphs in 8 sections, as filed
<td>REPUBLIC POLAND</td><td>(12) PATENT DESCRIPTION (19) PL (21) Application number: 351877</td><td>(11) 201 186 (13) B1</td>
<td></td><td>(22) Date of notification: 26/05/2000</td><td>(51) Int.Cl. A61K 9/12 (2006.01)</td>
<td></td><td>(86) Date and number of the international application: 2000-05-26, PCT / GB00 / 02045</td><td>A61P 9/14 (2006.01)</td>
<td>patent Office</td><td>(87) Date and publication number of the international application:</td><td></td>
<td>Polish Republic</td><td>12/07/2000, WO00 / 72821 PCT Gazette No. 49/00</td><td></td>
Method and device for the production of microfoam for the treatment of obliteration of varicose veins and the use of the device
<td></td><td>(73) The right holder of the patent: BTG INTERNATIONAL LIMITED, London, GB</td>
<td>(30) Priority: 1999-05-26, GB, 9912356.4</td><td>(72) Inventor (s):</td>
<td>(43) Application was announced: 30.06.2003 BUP 13/03</td><td>Tariq Osman, Alexandra Park, GB Sheila Bronwen Flynn, Aston, GB David Dakin Iorwerth Wright, High Wycombe, GB Anthony David Harman, Royston, GB</td>
<td>(45) The grant of the patent was announced: March 31, 2009 WUP 03/09</td><td>Timothy David Boorman, Kirby-le-Stoken, GB (74) Representative: Słomińska-Dziubek Anna, POLSERVICE, Kancelaria Rzeczników Patentowych Sp. z o. o</td>
(57) The method of producing microfoam for the treatment of sclerosing varicose veins consists in passing a mixture of physiologically acceptable blood dispersing gas containing mostly dioxide and / or oxygen and an aqueous solution of a liquid sclerosant containing a solution of polidocanol or tetradecyl sulfate. sodium (STS) in an aqueous carrier, hypertonic solutions of glucose or glucose and saline, chromium glycerol, ethanolamine oleate, solutions of morhuato sodium or iodine through one or more channels with at least one cross-sectional dimension from 0.1 to 30 μιτι, the gas and the solution mixed in the connecting chamber before introducing the mixture into the one or more channels, controlling the gas ratio to the liquid in the mixture by taking appropriate flows of gas and liquid, to be obtained after flowing through the channels, microfoam with a density between 0.07 g / ml and 0.19 g / ml and a half-life of at least 2 minutes. The device for carrying out the method comprises a container (1) in which there is a pressure chamber (4) containing an aqueous solution of a liquid sclerosant (3), a flow path with at least one outlet opening (13) for the flow of liquid from the pressure chamber (4). ) to the outside and an actuating mechanism to open or close the flow path from the pressure chamber (4) to the outside. The actuating mechanism is adapted to force fluid from the pressure chamber (4) to flow through the flow path and through the at least one outlet port (13), the container (1) containing at least one source of physiologically acceptable blood dispersant pressurized gas and has gas flow openings (11a, 11b) opened by an actuating mechanism to produce a gas-liquid mixture by contacting them. The flow path comprises at least one element with at least one channel with a cross-sectional dimension from 0.1 μτ to 30 μτ for passing a mixture of gas and liquid to the outside of the container (1) to obtain a microfoam with a density of 0.07 up to 0.19 g / ml and a half-life of at least 2 minutes. The device is used to produce a medicine for sclerosing varicose veins.
PL 201 186 B1
Description of the invention
The present invention relates to a method and device for the production of microfoam for the treatment of sclerosing varicose veins and the use of the device. The invention is particularly suitable for use in the treatment of various blood vessel disease states, particularly varicose veins and other disorders including vein malformation.
Varicose obliteration is based on the injection of liquid substances that obliterate varicose veins into the vein, which cause, among other things, a local inflammatory reaction, favoring the elimination of these abnormal veins. When a substance for sclerosing varicose veins is injected in liquid form, it mixes with the blood in the vein and is diluted in an unknown proportion. The effects are uncertain due to overdosing or underdosing, and are limited to short stretches of varicose veins. When the size of the treated varicose veins is reduced, the dilution is less and the results are more predictable.
Until recently, obliteration was the technique of choice for small and medium-sized varicose veins, and those with diameters equal to or greater than 7 mm were treated by surgery. Obliteration and surgery complemented each other, but obliteration treatment was still considered inadequate in cases of large varicose veins. In the cases of these large varicose veins, when the sclerosing substance was injected, its concentration in the vein, its homogeneous distribution in the blood, and the length of time it remained in contact with the inner walls of the treated vessel were not known.
In 1946, Orbach injected a few cubic centimeters of air into small varicose veins and confirmed the displacement of the blood inside the vessel that was occupied by the injected air. The varicose sclerosis solution introduced immediately afterwards was more effective if injected into the blood. However, in thick varicose veins, when air is injected, the described phenomenon of blood displacement by the injected air does not occur and the air forms an A-bubble inside the vein, making the method ineffective in these vessels.
The same author presented a few years later the concept of injecting a shaking foam with sodium tetradecyl sulfate, which is an anionic sclerosing detergent with good foaming ability. The process was of little use because of the large size of the bubbles formed and was dangerous because of the side effects caused by atmospheric nitrogen, which is only slightly soluble in blood. Both methods had a limited practical scope, being used only in cases of small varicose veins.
The use of injectable microfoam suitable for therapeutic use is now developed and described in European Patent No. 0656203 and United States Patent No. 5,676,962 (incorporated herein by reference). These patents describe a microfoam made from a varicose sclerosant which, when injected into a vein, displaces blood and brings the sclerosing agent into contact with the vascular endothelium at a known concentration and for a controllable period of time, causing obliteration of the entire affected segment.
The advantages of using this foam are that it makes it possible to determine the concentration of the sclerosing agent in the blood vessel, since the microfoam displaces the blood and is not diluted by it to the same extent as a normal liquid would be. In addition, it makes it possible to ensure a homogeneous distribution of the sclerosant product in the vein and to control the amount of time it is in contact with the inner walls of the vein. Neither of these factors is known precisely or can be controlled when using conventional liquid sclerosing agents.
The preparation of such a microfoam can be carried out using a solution of any sclerosant, especially polidocanol, an alkali metal salt of tetradecyl sulfate for example sodium salt, hypertonic glucose or glucose and saline solutions, chromic glycerol, ethanolamine oleate, sodium morhuato or iodine solutions.
However, this known method requires the preparation of the microfoam by a physician, pharmacist or assistant immediately prior to administration to the patient. Such a procedure allows for a variety of agents depending on the preparer with respect to gas content, bubble size and axis duration, all of which require attention with respect to the condition of the subject being treated. It also requires a high degree of concentration and knowledge, which may not be easy to reproduce under difficult conditions, i.e. when there is only a short time to prepare the foam.
PL 201 186 B1
The method detailed in the aforementioned patents requires rapid tamping with a brush in order to produce a foam with the correct properties. Other techniques described are not capable of producing such a homogeneous, permanent or injectable microfoam and particularly include gas bubbling operations, for example an inward sclerosing agent, such as by flow into a syringe filled with sclerosant. from the area around the side of the syringe plunger.
In addition, a problem with using air as a foam gas is that patients should not be unnecessarily injected with large volumes of nitrogen, especially when large vessels are turned off after filling with foam. There remains the possibility of a gas embolism with nitrogen.
The solubility of physiological gases in water-based fluids such as blood varies considerably. While nitrogen is almost twice as soluble in water as oxygen under standard conditions, carbon dioxide is more than fifty times more soluble in water-based fluids than nitrogen and more than twenty-five times more soluble than oxygen.
Table 1:
Gas solubility in water under standard conditions
<td>Gas</td><td>Molar fraction of solubility 10-5</td>
<td>Helium</td><td> 0,7</td>
<td>Nitrogen</td><td> 1,18</td>
<td>Oxygen</td><td> 2,3</td>
<td>Xenon</td><td> 7,9</td>
<td>Nitric oxide</td><td> 43,7</td>
<td>Carbon dioxide</td><td> 61,5</td>
It has been found that producing such a microfoam from gases introducing large amounts of gas readily dispersible in the blood, such as carbon dioxide, would be desirable in order to minimize the risk of creating a gas embolism. However, practitioners also recognize that this is a difficult task due to the high solubility of carbon dioxide in water.
It would also be desirable to produce a relatively stable microfoam with uniform properties, i.e., easily fabricated, by employing a relatively simple and reliable mechanism, rather than requiring the use of high-speed mixing or whipping, the duration of which can affect the properties of the foam.
It is particularly desirable that the microfoam so produced can be passed through a needle having a thickness suitable for injection into blood vessels without significantly converting back into its separate gaseous and liquid components and / or changing properties such as significantly increasing bubble size.
Such a needle may have a very small diameter, for example a 30 gauge needle has an inside diameter of 0.14 mm. It may be larger, such as an 18 to 22 gauge needle (inner diameter 0.838 to 0.394 mm), or a 19 to 21 gauge needle (inner diameter 0.686 mm).
The speed at which the foam is passed through the needle may be such that any foam is capable of breaking, but it is desirable to produce a foam that does not break under normal injection conditions, i.e. at rates compatible with the controlled injection of the foam into the vein. For example, it should withstand injection at a rate of 0.1 to 0.5 ml / second, more preferably 0.3 to 1 ml / second through a 19 to 21 gauge needle.
Furthermore, it is desirable to construct a device that is sterile with regard to the foam produced, especially with regard to microorganisms and pyrogens.
It is particularly desirable to construct a sealed device that works to produce a foam with predetermined properties suitable for a given treatment procedure without technical intervention by the practitioner or his assistants.
One form of device that could potentially have these desired properties would be a dispenser of the foam-producing type. However, for the preparation of microfoam to be injected into humans or animals, it is undesirable to use conventional gaseous propellants normally used in dispensing containers , such as isopropane. Means,
That the gas from which the foam is to be produced must itself be pressurized in order to enable the production of the foam.
It has been found that water-soluble gases such as carbon dioxide do not produce a stable foam in the preparation process merely by passing through a standard pressure metering valve, such as would be expected when converting a detergent solution such as one of polidocanol or sodium tetradecyl sulfate to foam. . It has been found that when such a gas is applied under pressure as a propellant for a sclerosing agent solution through a conventional dispensing valve, the foam produced, although initially having at least some degree of microfoam structure, is not sufficiently durable for use in the treatment of blood vessels as described in European in U.S. Patent No. 0656203 and U.S. Patent No. 5,676,962. Moreover, such foam cannot be passed through a syringe needle without appreciable recovery in the liquid and gas phases. It will be appreciated by those skilled in the art that the microfoam technique takes advantage of the ability of the gas to deliver a solution of the sclerosing agent to the wall of the vessel being treated, rather than allowing it to be diluted in the blood as a liquid phase.
The prior art among dispensing devices capable of producing foam is shown in U.S. Patent 3,471,064, which describes an apparatus in which air is introduced into a foaming liquid through a series of small openings in a dip tube of the apparatus. Such a device is not sterile because its contents are in fact open to the atmosphere. The properties of the foam produced in this way may change depending on the amount of air introduced. Another device is described in U.S. Patent No. 3,428,222 and uses a wick-based foaming element in a deformable container that re-draws air to produce foam.
U.S. Patent No. 3,970,219 describes sealed dispensing devices that can use pharmacologically inert gases to froth and eject liquid compositions, it describes devices to produce foam by passing a propellant through a material having 0.01 to 3 mm pores from the lower chamber to storing propellant gas in the upper foam storage chamber. The foaming liquid is either in the upper chamber or is absorbed onto the porous material by shaking the container, or is sucked from the lower chamber. This patent indicates that the foam liquid in the upper chamber drains into the lower chamber so that the thinner walled bubbles are ejected, and that the propellant gas should be "less soluble, such as nitrogen, a hydrofluorocarbon or a hydrocarbon when foaming. water-based lotions.
Similar bubble dispensing devices are used in equipment for use in "environmentally friendly dispensing devices which operate with low pressure air, ie using a hand pump." One device of this type is known, suitable for simple water-based preparations, as well as another device of this type, which is applicable to cosmetic preparations for the care of hair or skin. Such a device is also available as an additional option to the hand pump, as a foaming nozzle. This device is marketed as suitable for use in "making your own cleansing foam or shaving foam".
However, it has been found that using the hand pump-type devices available alone, which are by no means sterile, it is not possible to produce a good microfoam with high carbon dioxide contents, due to degassing, even by incorporating significant amounts of glycerol, which further stabilizes the microfoam. . In addition, when a significant back pressure is applied to the outlet of such a device, such as when attached to the outlet of a syringe to be filled with injection foam, the device becomes jammed. The use of a slow ejection rate in this device can cause wetting in the nozzle which leads to the formation of large bubbles due to air half-trap. In any case, the foam thus produced, with oxygen or carbon dioxide, tends to dry considerably, necessitating a high concentration of sclerosant and a tendency to break as it passes through the needle.
It is not preferable to unnecessarily use a high concentration of sclerosant in the solution as this could lead to overdosing in the event of failure of the prep and delivering a denser microfoam, i.e. containing more liquid than intended.
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There is therefore a need to provide a method and apparatus that is capable of producing a homogeneous injectable microfoam containing a relatively low concentration of sclerosing agent and a significant amount of blood dispersant gas, in a sterile manner, without volatile liquid propellants or the need for an operator to be directly involved in the control of its parameters.
For the purpose of this application, the terms have the following definitions:
Physiologically acceptable blood dispersant gas is a gas that is capable of being substantially completely dissolved or absorbed in blood.
A liquid sclerosing agent is a liquid that is capable of sclerosing blood vessels when injected into the lumen of the vessel.
Sclerosing or sclerosing treatment of varicose veins refers to the treatment of blood vessels by turning them off.
Aerosol is the dispersion of a liquid in a gas.
Most of the gas is more than 50% by volume.
Less gas is less than 50 vol.%.
Less amount of one liquid in another liquid means less than 50% of the total volume.
Atmospheric pressure and bar indicate 1000 mbar.
The half life of the microfoam is the time taken for half of the liquid in the microfoam to revert to the non-foamed liquid phase.
According to the invention, a method of producing microfoam for the treatment of sclerosing varices of blood vessels is characterized in that a mixture of physiologically acceptable blood dispersing gas containing a major part of dioxide and / or oxygen and an aqueous solution of a liquid sclerosant containing a solution of polidocanol or tetradecyl sulfate is passed. sodium (STS) in an aqueous carrier, hypertonic solutions of glucose or glucose and saline, chromium glycerol, ethanolamine oleate, solutions of morhuato sodium or iodine, through one or more channels with at least one cross-sectional dimension from 0.1 to 30 μm, the gas and the solution mixed in the connecting chamber before introducing the mixture into the one or more channels, by regulating the gas-to-liquid ratio in the mixture by taking appropriate gas and liquid flows, to be obtained after flowing through the channels, microfoam with a density between 0.07 g / ml and 0.19 g / ml and a half-life of at least 2 minutes.
Preferably the gas / liquid ratio of the mixture is controlled to produce a microfoam with a density of 0.09 g / ml to 0.16 g / ml.
Gas bubbles with a diameter of at least 25 μm are generated, of which at least 50% by volume have a diameter of not more than 200 μm and at least 95% have a diameter of not more than 280 μm, and preferably gas bubbles with a diameter of at least 25 μm are generated. of which at least 50% by volume have a diameter of not more than 150 μm and at least 95% of which have a diameter of not more than 250 μm.
A mixture of gas and liquid sclerosant in the form of an aerosol, dispersion of bubbles in liquid or macrofoam is used.
A mixture is used in which the ratio of gas to liquid in the mixture is 1 gram of a liquid sclerosant to from 6.25 to 14.3 volumes of gas under standard temperature and pressure conditions.
A brine solution is used as the aqueous carrier.
When generating the microfoam, the gas and liquid mixture are passed through channels having a diameter ranging from 5 nm to 25 µm.
The gas and liquid mixture are passed through channels, which are openings in the sieve or sifter, placed perpendicular to the direction of the gas / liquid mixture stream, having a diameter of 10 nm to 20 nm.
The gas and the liquid mixture are passed through channels having the form of multiple openings in one or more elements through which the mixture flows.
The gas and liquid mixture are passed through one or more elements whose openings make up 2% to 65% of the open area.
The gas and the liquid mixture are passed through the successively arranged elements of porous material, the mixture being passed through the channels of each element.
The porous material elements are disposed along the direction of the stream of the mixture in series and spaced apart.
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The mixture of gas and liquid is passed through the given channel or channels multiple times.
The gas passed through is compressed to a gauge pressure of 1 to 90 kPa gauge, and preferably to a gauge pressure of 10 to 30 kPa gauge.
According to the invention, a device for producing microfoam for the treatment of sclerosing varicose veins, is characterized in that it comprises a container in which there is a pressure chamber containing an aqueous solution of a liquid sclerosant, in particular a solution of polidocanol or sodium tetradecyl sulfate (STS) in an aqueous carrier, polidocanol , an alkali metal salt of tetradecyl sulfate, e.g. sodium salt, hypertonic glucose or glucose and saline solutions, chromium glycerol, ethanolamine oleate, sodium morhuato or iodine solutions, a flow path with at least one outlet to flow liquid from the pressure chamber to the outside, and an actuator to open or close the flow path from the pressure chamber to the outside; the actuating mechanism adapted to force fluid from the pressure chamber through the flow path and through the at least one exit port at the pressurized container with an open flow path, the container containing at least one source of physiologically acceptable blood dispersant gas under pressure. pressure, containing for the most part dioxide and / or oxygen, and has gas flow openings that are opened by an actuating mechanism for producing a gas-liquid mixture by contacting them, and the flow path leading outside the container comprises at least one element having at least one channel with a cross-sectional dimension of 0.1 μm or more to 30 μm, for passing the gas-liquid mixture out of the container to obtain a microfoam with a density of 0.07 to 0.19 g / ml and a half-life of at least 2 minutes.
A bottom connector may be positioned in front of the channel elements in the container to contact the liquid and gas and to adjust the mixing ratio of the gas and liquid passed through the channels to obtain a microfoam with the required density.
The flow path of the container is preferably arranged to regulate the gas-liquid ratio of the mixture to obtain the microfoam with a density of 0.09 to 0.16 g / ml.
The container contains a pressure chamber filled with blood dispersing gas and a liquid sclerosing agent, and the flow path is a tube immersed in the inlet opening in the liquid solution in the chamber.
The tube has an outlet embedded in a gas-liquid connection housing, the gas source being connected to the liquid flow path at the at least one gas flow opening.
Placed in the flow path is a metering valve to open or close the flow path connected to an actuator that has a push or deflection element to open the flow path outward and forcing the liquid to flow up the tube by gas pressure and mix with the gas in the lower connector to form aerosol, dispersion of bubbles in liquid or macrofoam.
In the pressure chamber, at least one element including at least one channel with a cross-sectional diameter of 0.1 Pm to 30 Pm is mounted in the liquid flow path upstream of the metering valve for producing microfoam as the gas-liquid mixture passes through the at least one channel.
Downstream of the lower fitting, at least one element is mounted in the liquid flow path, including at least one channel with a cross-sectional diameter of 0.1 µm to 30 µm, for producing microfoam as the gas-liquid mixture passes through the at least one channel.
At least one channel element is disposed in a hood mounted on the metering valve, downstream of the lower gas-liquid mixing connection, the head having an outlet opening.
At least one channeled element is disposed in the upper fitting seated between the lower gas and liquid fitting and the metering valve.
The lower gas-liquid connector includes gas flow openings located above the surface of the liquid solution.
Preferably, the pressure chamber is adapted to generate a pressure of 1 kPa to 900 kPa gauge.
The container may contain a second flexible sealed container for an aqueous solution of a liquid sclerosant, the second container being sealed around the tube.
Preferably also, the container houses a tube having a one-way delivery valve between the downstream gas-liquid connection and the tube inlet of a second flexible sealed container which is also closed when the outward flow path is closed.
The chamber of the second flexible sealed container with the liquid solution is separated from the pressure chamber with the physiologically acceptable blood-dispersing gas, and with the outward flow path open, the one-way valve is open to discharge the liquid solution up the tube to the lower gas connector. and a liquid to generate an aerosol, dispersion of bubbles in a liquid, or a macrofoam converted to microfoam as they pass through the channels.
An inlet conduit may be sealed to the outlet port in communication with a multipath valve directing the flow of the microfoam, the multipath valve having outlets connected to the two outlet conduits and adjustable to direct the foam flow into one of the two conduits or to close the inlet conduit, and one of the conduits has outlets connected to the two outlet conduits. the outlet is connected to the syringe opening.
In a preferred embodiment, the microfoam container is supported and secured by at least one support element. The container may be placed adjacent a multi-way valve on the support, and the inlet of the multi-way valve is adapted to connect an outlet conduit from the microfoam container. Associated with the container is an actuator to open a flow path in the microfoam container to the inlet conduit.
The use of the device defined above is the preparation of a medicament for sclerosing varicose veins.
The method and devices for producing sclerosant microfoam meet at least some of the aforementioned requirements by providing a new, durable, injectable sclerosant microfoam.
The subject of the invention is illustrated in the drawing in which Fig. 1 shows a cross-sectional view of a foam production device in one embodiment, Fig. 2 - a cross-sectional view of a foam production device in a second embodiment of the invention, Fig. 3 - a cross-sectional view of a syringe-type foam maker in a third embodiment with a set of sieves positioned across its dispensing chamber, Fig. 4 - cross-sectional view of the syringe-type foam maker in the fourth embodiment with a porous membrane mounted on the inner plunger rod; ml formed from oxygen / air / polidocanol, Fig. 6 - diagram showing the distribution of gas bubble diameters in microfoam with densities of 0.09 g / ml and 0.16 g / ml according to the invention, Fig. 7 - graph showing the effect of passing a preferred foam according to the fourth aspect of the invention through a 21 gauge needle compared to a control fresh microfoam and similarly aged; Figure 8 - bar graph and graph showing the effect of passing a 2 vol% dry microfoam solution having a density of 0.045 g / ml in polidocanol, such as using a prior art bubbler (Swedspray valve, insert and Ecosol head) through a 21 gauge needle, Fig. 9 - graph showing the effect of passing a 1% by volume solution of dry microfoam with a density of 0.045 g / ml in polidocanol, such as using a prior art bubbler (Swedspray valve, insert and Ecosol head) through a 21 gauge needle, Fig. 10 - elevation view of the device for producing foam in the form of a filling syringe according to the fourth embodiment of the invention; fig. 11 is a top view of the device of fig. 10.
The method of the invention is used to produce a microfoam for the removal of blood vessels and vascular malformations, containing a physiologically acceptable gas that readily disperses in the blood and an aqueous solution of a liquid sclerosant. The microfoam has a density of 0.07 to 0.19 g / cm<sup>3</sup> and it can be passed through a 21 gauge needle without more than 10% recycle to the gas and liquid, based on the amount of liquid recycle to the non-foamed liquid phase. The microfoam, when passing through said needle, does not return to the non-foamed liquid by more than 5% based on the liquid content, preferably not more than 2%.
The microfoam produced by the process of the invention is capable of passing through a needle with at least 50% by volume of gas bubbles with a diameter of at least 25 µm, not greater than 200 µm. It is conveniently measured under ambient conditions, preferably under standard conditions.
At least 50% of the quantitative gas bubbles in the microfoam have a diameter of not more than 150 µm, and at least 95% of the bubbles are not more than 280 µm in diameter. Preferably, at least 50% by volume of the gas bubbles with a diameter of 25 nm or greater have a diameter of not more than 120 L and more preferably at least 95% of the gas bubbles with a diameter of at most 250.
PL 201 186 B1
Preferably, the microfoam has a half-life as measured by filtration through a funnel with a foot diameter of 2 cm and a travel distance of 10 cm of at least 2 minutes, more preferably 2.5 minutes and most preferably 3 minutes. This can be checked at ambient temperature or STP. Most conveniently, the funnel is pre-equilibrated in a 25 ° C water bath prior to drying and applying the foam. Placing the syringe filled with microfoam upside down without plunger, above the funnel inserted into the graduated vessel allows convenient measurement of this parameter.
Preferably the density of the microfoam is from 0.09 to 0.16 g / ml, more preferably 0.11 g / ml to 0.14 g / ml.
In a preferred embodiment, the density of the microfoam, which is a measure of the liquid / gas ratio, is from 0.13 to 0.14 g / cm.<sup>3</sup>and has a half-life of at least 2.5 minutes, during which time the bubble size does not exceed that shown above.
The gas contained in the microfoam may contain less than 40% nitrogen by volume. Preferably the gas consists of at least 50% oxygen or carbon dioxide, more preferably 75% or more oxygen or carbon dioxide, and most preferably at least 99% oxygen or carbon dioxide, for example practically 100% oxygen or carbon dioxide. Preferably the oxygen or carbon dioxide is pharmaceutical grade.
As a sclerosing agent for varicose veins, an aqueous solution of polidocanol or sodium tetradecyl sulfate is used.
When the sclerosing agent is an aqueous solution of polidocanol, the concentration of the polidocanol is from 0.5 to 4% by volume in the liquid, preferably 1 to 3% by volume of the polidocanol, and most preferably 2% by volume in the liquid.
The sclerosant used for varicose veins may be prepared in water, but more preferably in a saline solution, particularly in 10 to 70 mM phosphate buffered saline, e.g. 50 mM phosphate buffered saline, and preferably at pH 6.0 to pH 8.0 for example around pH 7.0. Preferably the aqueous solution contains a small amount of alcohol, preferably 96% ethanol, for example between 2 and 6% by volume, more preferably about 4% by volume 96% ethanol.
The addition of glycerol to the aforementioned sclerosant increases the half-life of the resulting foam. However, there is a tendency with glycerol to block the mesh of the screen when using the screen described above, hence it should be used with care if the manufacturing device is to be reusable or when the valve bag concept is used.
A microfoam is produced according to the method of the invention which consists in passing a mixture of a physiologically acceptable blood dispersant gas and an aqueous liquid sclerosant through one or more channels having at least one cross-sectional dimension from 0.1 to 30 Lim. At the same time, the gas to liquid ratio is controlled until a microfoam is obtained having a density between 0.07 g / ml to 0.19 g / ml and a half-life of at least 2 minutes.
The gas / liquid ratio in the mixture is adjusted to obtain a microfoam with a density from 0.09 g / ml to 0.16 g / ml, more preferably from 0.11 g / ml to 0.14 g / ml and wherein 50% by volume or more of gas bubbles of at least 25 µm in diameter have a diameter of less than 200 µm.
A microfoam is obtained that has a half life of at least 2.5 minutes, more preferably of at least 3 minutes. The half-life may be as high as 1 or 2 hours or more, but is preferably less than 60 minutes, more preferably less than 15 minutes and most preferably less than 10 minutes.
Half-life is conveniently measured by filling the vessel with a known volume and weight of foam and draining the liquid into the graduated vessel. The amount collected per time unit makes it possible to calculate the half-life, i.e. the conversion of the microfoam back to its liquid and gaseous components. This is preferably carried out at standard temperature and pressure, but clinic or laboratory ambient conditions will suffice in practice.
The method of producing microfoam according to the invention provides a microfoam in which at least 50% by volume of its bubbles having a diameter of at least 25 m have a diameter of not more than 150 L m, and preferably at least 95% by volume of these gas bubbles have a diameter of not more than 280 L m. Even more preferably at least 50% by number of these gas bubbles have a diameter of not more than 130 Lm and even more preferably at least 95% by number of these gas bubbles have a diameter of not more than 250 Lm.
In preferred embodiments, the mixture of gas and liquid sclerosant is in the form of an aerosol, a dispersion of bubbles in a liquid, or a macrofoam. By macrofoam is meant a foam whose measured gas bubbles have the largest dimensions in millimeters, for example at least 1 mm, and larger than those which can be produced by the gentle process.
The two phases are mixed by shaking. Preferably, the gas and liquid are supplied in the form of an aerosol when the pressurized gas source and the mixing device for the two components are at the site of application. It may be advantageous to first produce the macrofoam in case the liquid and gas are only brought into contact at the point of use.
The ratio of gas to liquid in the mixture used is important from the point of view of regulating the structure of the produced microfoam so that its durability is optimal with regard to the method and conditions in which it is carried out. For optimal microfoam, preferably 1 gram of a liquid sclerosant is mixed with from 6.25 to 14.3 volumes (STP), more preferably 7 to 12 volumes (STP) of gas.
In the process of the invention, a physiologically acceptable blood dispersant gas containing a major part of carbon dioxide and / or oxygen is used. It may conveniently contain a minor portion of nitrogen or other physiologically acceptable gas. While the amount of nitrogen that may be present is that of air, the present invention makes it possible to use carbon dioxide and / or oxygen in the absence of nitrogen.
In one preferred embodiment, the gas used is a mixture of carbon dioxide and other physiological gases, particularly containing 3% or more carbon dioxide, more preferably 10 to 90% carbon dioxide, most preferably 30 to 50% carbon dioxide. The other component of this gas is preferably oxygen, with only a lower nitrogen content being preferred. Most preferably, the other component is oxygen.
In preferred embodiments of the process, a gas containing 50% by volume or more oxygen and the remainder of carbon dioxide, or carbon dioxide, nitrogen and traces of gases, may be used in amounts present in the atmospheric air. A gas containing 60 to 90 vol.% Oxygen and 40 to 10 vol.% Carbon dioxide, preferably 70 to 80 vol.% Oxygen and 30 to 20 vol.% Carbon dioxide, may also be used. In another example, a gas containing at least 99% oxygen is used.
A stream of sclerosant liquid and gas is passed under pressure through one or more channels with a diameter of 0.1 μm to 30 μm as described to produce a stable sclerosant microfoam based on blood dispersant gas for injection, previously thought to be possible only by supplying large amounts of energy, using high-speed brushes and mixers.
Preferably, the sclerosing agent for varicose veins is a solution of polidocanol or sodium tetradecyl sulfate in an aqueous vehicle, for example water, especially saline. More preferably the solution comprises 0.5 to 5% by volume of polidocanol, preferably in sterile water or physiologically acceptable saline, for example 0.5 to 1.5% by volume of saline. The concentration of sclerosant in the solution will be advantageously increased for certain abnormalities such as Klippel-Trenaunay syndrome.
Polidocanol is a mixture of monolauryl ethers of macromolecules of formula C12C25 (OCH2CH2) nOH, with an average n value of 9. It can be concluded that it is also possible to use a mixture with other alkyl chains, oxyalkyl chains of repeating units and / or with average n values for example 7 to 11, but for n = 9 it is the easiest to acquire.
The most preferred concentration of the sclerosant in the water-based liquid is 1-3% by volume in a solution, preferably polidocanol in water or saline, more preferably about 2% by volume. The water or saline also, at least in some cases, preferably contains 2-4% by volume of physiologically acceptable alcohol, for example ethanol. Preferably, the brine is buffered. A preferred buffered saline is phosphate buffered saline. The pH of the buffer is preferably adjusted to a physiological value, for example from pH 6.0 to pH 8.0, more preferably a pH of about 7.0. The sclerosant may also contain additional ingredients such as stabilizing agents, for example foam stabilizing agents, for example such as glycerol. In addition, the ingredients may include alcohols such as ethanol.
The aerosol, dispersion or macrofoam is preferably prepared by mixing gas and liquid from suitable jets under pressure. The mixing is conveniently carried out in a gas-liquid coupling device such as found in aerosol canisters. The connecting element may however be very simple, in the form of a single chamber or channel with millimeter dimensions, i.e. 0.5 to 20 mm in diameter, preferably 1 to 15 mm in diameter, to which separate inlets for gas and liquid lead. Conveniently the interconnection member has a structure that is commonly used in aerosol canisters but that is selected to obtain the correct gas to liquid ratio.
To allow the formation of a foam with a specific density. Appropriate inserts are selected to obtain the ratio specified in the above method.
However, mixing of gas and liquid can also be achieved inside a dip tube leading from the inside of the sclerosant solution located at the bottom of the pressurized container, the openings in the dip tube allowing gas to be introduced into the liquid stream coming from the bottom of the tube. In this case, the holes may have a diameter similar to the holes in the inserts. Such holes can conveniently be produced using laser drilling in a dip tube.
In order to produce a stable microfoam, the aerosol or the macrofoam produced is passed through at least one channel which has a diameter of 5 nm to 25 μm, more preferably 10 μm to 20 μm, which are straight channels, such as for holes in a sieve or screen. for example of metal or plastics, placed perpendicular to the flow of the gas / liquid mixture. The channel is suitably circular or elliptical in cross section, but this is not necessary. A number of such screens or screens may be used along the direction of the stream.
Most preferably the channels are in the form of a plurality of openings in at least one member positioned across the stream. Preferably the elements have a diameter of 2 to 30 mm, more preferably 6 to 15 mm, of the face to the jet, with 5 to 65% open area, for example 2% to 20% open area for woven screens and 20% to 70% open area surface for microporous membranes. The openings in a porous material such as a perforated body preferably include several hundred such channels, more preferably tens of thousands or one hundred thousand such channels, for example 10,000 to 500,000, exposed to a flowing gas-liquid mixture. Such material may be a perforated sheet or membrane, a screen, sifter or sinter. Even more preferably, a plurality of rows of porous material are sequentially aligned such that gas and liquid flow through the channels of each row. This leads to the production of a more homogeneous foam.
When several elements are used in series, they are preferably placed 1 to 5 mm apart, more preferably 2 to 4 mm apart, for example 3 to 3.5 mm apart.
In certain embodiments of the present invention it has been found that channels may be provided in the form of gaps between the fibers in a sheet of fibers disposed across the gas / liquid stream path, and the described dimension is not necessarily the largest diameter but the gap width through which the gas / liquid aerosol or macrofoam is formed. must swim across.
Alternatively, the gas-liquid mixture may be repeatedly passed through the same series of channels, for example obtained on one or more porous bodies, e.g. 2 to 2,000, more preferably 4 to 200 times, or as many times as necessary to conveniently obtain the microfoam and the required density shown above. It can be concluded that the more times the microfoam passes through the sieve, the more homogeneous it becomes.
The gas pressure used to pass through the channels will depend on the type of mechanism used to make the foam. When the gas is in a pressurized chamber such as an aerosol canister and in contact with the liquid, suitable pressures are typically in the range of 0.01 to 9 bar gauge pressure. When using screens, e.g. 1 to 8 screens in series having openings 10-20 nm in diameter, a gauge pressure of 0.1 to 5 atmospheres will be appropriate. Using 3-5 sieves with 20 nm apertures, it was found that 1.5-1.7 bar overpressure was sufficient to produce a good foam. For a 0.1 nm pore size membrane, a pressure of 5 bar gauge or more is preferred.
In one preferred embodiment of the invention, the mixture is passed through membrane-shaped channels, for example a polymer such as polytetrafluoroethylene, the membrane being formed of randomly connected fibers and having a rated effective pore size which may be many times smaller than its apparent size. pores. A particularly suitable solution for such a membrane is a double-oriented PTFE layer from Tetratec ™ USA, under the trade name Tetratex R ™, with standard porosity ratings from 0.1 to 10 nm. The preferred channel-forming pore size for the present method and device is 3 to 7 nm. This material may be laminated with a porous support material to provide reinforcement, which is advantageous since one pass through the membrane may be sufficient to produce a foam meeting the above stated durability requirements. However, it will be apparent to those skilled in the art that the use of more than one such membrane in series will result in an even more uniform foam under the given conditions.
It is assumed that the combination of delivering a stream of solution and a pressurized gas through a demand valve and then a stream through passages, e.g.
Or sinter, provides sufficient energy to produce a stable liquid sclerosing liquid microfoam based on water and a soluble gas, e.g. carbon dioxide and / or oxygen, previously thought to be possible only by supplying large amounts of energy using high speed brushes and mixers as described in the art.
In a preferred embodiment of the process according to the invention, a microfoam is produced having at least 50% by volume of gas bubbles with a diameter of at least 25 µm but not greater than 120 µm. Preferably at least 95% of its gas bubbles having a diameter of at least 25 µm are less than 250 µm in diameter. The diameter of such bubbles can be determined by the method set forth in Example 6 below.
The method according to the invention is carried out by means of a container in which a pressure chamber is located. For sterile feeding purposes it is at least partially filled with a sterile pyrogen-free solution of sclerosing agent in a physiologically acceptable aqueous solvent, but may otherwise be filled with such agent at the site of application. The container has a flow path for the solution from the pressure chamber through the outlet to the outside of the casing, and a mechanism that closes or opens the flow path from the chamber to the outside so that when the container is pressurized, fluid is forced along the flow path and through one or more more outlets. The gas from a source of compressed physiologically acceptable gas, that is, readily dispersible in blood, is brought into contact with the solution upon actuation of the mechanism.
The gas and solution are forced to flow along the flow path out of the enclosure through one or more, preferably a plurality, of the above-defined channels through which the solution and gas must flow to exit and thereby contact each other to form the microfoam.
Preferably the gas and liquid are passed through a gas-liquid interface, typically a link between the liquid path and at least one adjacent gas path, converting to an aerosol, bubble dispersion, or macrofoam prior to passage through the channels, but as explained, the mixture may be first transformed into a macrofoam, for example by shaking by hand or mechanically with the device.
The device according to the invention for producing microfoam suitable for use in the treatment of sclerosis of blood vessels, especially of veins, shown in Fig. 1 comprises a container 1 in which there is a pressure chamber 4 containing a solution 3 of sclerosing agent in a physiologically acceptable solvent. A solution flow path 3 is formed in the container with at least one outlet 13 through which solution 3 can flow from the pressure chamber 4 to the outside of the device by the use of a mechanism that closes or opens the flow path from the pressure chamber 4 to the outside, so that when the container 1 is pressurized, the flow path is open, the fluid flow is forced into the at least one outlet 13.
Container 1 has a source of physiologically acceptable gas, i.e. blood dispersant, under pressure, or an inlet for the supply of said gas. The gas is brought into contact with the solution by activating the mechanism for producing a gas-solution mixture.
At least one element is positioned in the flow path, which has at least one channel with a cross-sectional dimension, preferably a diameter, from 0.1 µm to 30 µm, through which the mixture of solution and gas is passed to be displaced outside the device. to produce a microfoam with a density of 0.07 to 0.19 g / ml and a half-life of at least a minute.
The device produces a foam in which at least 50% by volume of its gas bubbles with a diameter of at least 25 µm have a diameter of not more than 150 µm, more preferably at least 95% by volume of these gas bubbles of not more than 280 µm in diameter. more preferably at least 50% by number of said gas bubbles have a diameter of not more than 130 L m and even more preferably at least 95% by number of said gas bubbles have a diameter of not more than 250 L m.
The pressure chamber 4, e.g. the inside of the sealed container 1, is filled with blood dispersing gas and a liquid sclerosant and the flow path is a tube 12 submerged in the inlet opening below the level of the solution 3 in the pressure chamber 3 when the device is upright. Preferably the dip tube 12 has an outlet in the connector 10 for combining gas and liquid, the gas which is in the pressure chamber 4 above the liquid accessing the flow path to the outlet 13 of the device. The flow path is opened or closed
By valve 5, which is pressed or deflected to open a flow path to the outside of the device, whereby liquid flows up submerged tube 12 under the influence of gas pressure and mixes in connector 10 with this gas to form an aerosol, bubble dispersion in liquid or macrofoam.
In the flow path inside the pressure chamber 4, upstream of the valve 5 or downstream of the valve 5, is arranged an element having at least one channel for passing a gas-liquid mixture, i.e. dispersion of bubbles in liquid, aerosol or macrofoam, in order to foam them into a foam. This element can conveniently be placed in the head on the container 1 between the valve housing 5 and the outlet. Conveniently pressing the head activates the valve 5. Alternatively, the element is located inside the container 1 above the gas-liquid connection 10.
In an alternative embodiment of this device, the gas-liquid connection 10 may include holes in the dip tube 12 above the level of the solution 12 within the pressure chamber 4.
The gas pressure used will depend on the materials used and them, but is suitably 1 to 90 kPa, more preferably 10-30 kPa and even more preferably 15-17 kPa.
As shown in Fig. 2, the device in a preferred embodiment comprises a container 1 in which a second flexible sealed container 22, e.g. a bag, is housed with a supply valve 21 for gas and liquid forming a second internal chamber within the pressure chamber 4. The bag is sealed around tube 12 and filled with liquid. The supply valve 21 on the tube 12 is a one-way valve positioned between its tip inserted into the sclerosing agent liquid 3 and a gas-liquid connection 10, which remains closed when the outward flow path is closed to separate the liquid solution. 3 from physiologically acceptable blood dispersant gas around it in the pressure chamber 4. Upon opening the flow path outward, the supply valve 21 also opens and releases liquid up the tube 12 to the gas-liquid connector 10, where an aerosol is generated, which is then passed through the channels for conversion to microfoam. A suitable one-way valve 21 is a duckbill valve. Suitable types of valve track are aluminum foil / plastic laminate.
Conveniently, a one-way valve 21 is provided on top of tube 12 between it and gas-liquid connector 12. This allows the second container 22 to be filled before the one-way delivery valve 21 is used, and then the contents to be sterilized in the container 1 or other container.
Such a preferred device has several advantages. When the gas is oxygen, it is kept separate from the liquid before use and thus reduces the possibility of oxygen radicals reacting with the organic components in the liquid, for example A during sterilization processes such as irradiation. When the gas is carbon dioxide, the storage can lead to the dissolution of large volumes of gas in the liquid which, when released into the atmosphere or depressurized, could degass and start destroying the microfoam too quickly. Such separation also protects against the deposition of solidified components of the sclerosing agent in a dimension that is dangerous for the device openings, especially an unused can during storage or transport should be placed in a position other than vertical.
Preferably, the gas-liquid connector 10 is in the form of a member with a defined size orifice, such as the Ecosol device manufactured by Precision Valve Peterborough UK. In such a member, when the channels of a predetermined size are outside the pressure chamber, i.e. installed on the valve stem 5, the ratio of the area of the gas openings to the liquid openings should be 3 to 5, preferably around 4. When the channels are inside the chamber pressure 4, it is preferably larger.
In a further embodiment, shown in Figs. 3 and 4, the device for the production of microfoam for the treatment of sclerosis of varicose veins, particularly of veins, comprises a body 13 in which there is a pressure chamber 19 at least partially filled or fillable with a solution. A sclerosing agent for varicose veins in a physiologically acceptable solvent and / or a physiologically acceptable blood dispersant gas. A flow path through which the contents of pressure chamber 19 can pass out of the body 13 includes one or more outlets 14. The device includes a mechanism by which gas can be compressed in pressure chamber 19 so that its contents flow outward along the flow path and through one or more outlets 14. At least one element is positioned in the flow path to form at least one channel with a cross-sectional size, preferably a diameter, of 0.1 µm to 30 µm, through which the contents from the pressure chamber can be passed so that, when passed through the channels, the solution and the gas form a microfoam with a density of 0.07 to 0.19 g / ml and a half-life of at least 2 minutes.
PL 201 186 B1
The channeling elements in the passage or chamber may be stationary or may be moved by a manual device from outside the inner chamber.
The device shown in Figs. 3 and 4 is in the form of a syringe containing a syringe barrel and an operably cooperating piston 16 delimiting the pressure chamber 19. The piston 16 is the pressure-generating element in the chamber. The chamber contains a gas and a liquid to be used, and the chamber includes predetermined sized channels positioned at the tip of the needle-mounting body 13, for example at the needle-mounting hole.
In use, such a device is partially filled with the required varicose sclerosant liquid solution 18 and then filled with a physiologically acceptable gas, or vice versa, by pulling the syringe plunger 16 after connecting the mounting hole sequentially with the sources of these substances. Alternatively, they may be premixed in the form of a macrofoam or even a microfoam which has such disintegrating properties. When the gas and liquid are charged as separate phases, the contents of the syringe can be mixed to form a foam. The plunger 16 is then pushed towards the body of the syringe whereby the foam passes through the channels and transforms into microfoam having the durability required for use in the method. When the gas and liquid are charged together in the form of a foam, action of the piston 16 will create a microfoam.
The device preferably comprises two chambers connected to each other by a channel, for example by a needle connection port to the syringe body, through one or more channels 0.1 Pm-30 Pm in diameter. Thus, movement of the piston in one or both of the chambers leads to gas and liquid being passed through the predetermined sized channels the desired number of times to produce the desired foam.
Alternatively, an element forming a plurality of channels with the said dimensions, for example screens 20 or a porous membrane 22, is placed inside pressure chamber 19 so that it can be slid in any direction causing the contents of pressure chamber 19 to flow through its channels. Conveniently, this element, for example a porous membrane 22, can be installed on a support, such as a rod 21, coaxial to the plunger rod of a syringe. The porous channel forming element may be any of the elements described above, but is conveniently a screen 20 or porous membrane 22 mounted over a larger portion of the surface perpendicular to a line along the axis of the body 18 of the syringe pressure chamber 19 such that movement of the rod 21 in any direction along the length causes the element to move. and passing the chamber contents, gas and liquid, together through the channels. It can be seen that when such a device is filled with gas and liquid in the correct proportions, it can also be shaken to obtain a loose macrofoam in the first step.
Preferably, the body 13 defines a pressure chamber 19 in which there is a pressurized solution and gas, and the flow path is a conduit leading from the pressure chamber 19 inside the body 13 to a valve that closes the opening in the body wall.
The multi-channel forming elements for use in the apparatus of the present invention may be screens, sifters or agglomerates. Thus, several screens or perforated screens or agglomerates may be provided, in certain preferred embodiments, and in the assembly such elements are aligned with their larger surfaces perpendicular to the solution / gas exit path.
All critical dimensions of any device according to the invention are made of a material that does not change dimension when in contact with an aqueous substance. Thus, elements with functions such as an air-to-liquid interface and an element containing channels measuring 0.1 µm - 30 µm preferably should not absorb aqueous substances. They may be Nylon 66 when they are not likely to be exposed to the solution for longer than a few minutes. Where such exposure is likely, these parts are more preferably made of polyolefins such as polypropylene or polyethylene.
Preferably, the container or syringe is sized to produce up to 500 ml of microfoam from gas and solution, more preferably from 1 ml to 200 ml and most preferably from 10 to 60 ml of microfoam. In particular, the amount of pressurized gas in such containers should be sufficient to generate a sufficient amount of foam for the treatment, i.e. filling, of the at least one varicose human saphenous vein. Thus, preferred containers according to the invention may be smaller than those currently used for the supply of household effervescent type foams. Most preferably, the container is discarded after use or cannot be reused after opening to avoid sterility problems.
PL 201 186 B1
An assembly may be provided that maintains the gas pressure in the container while the foam is dispensed. However, when a significant gas pressure is obtained above the solution, this is not necessary.
In order to ensure that the microfoam delivered from the devices of the invention conforms to the description, i.e. has the desired density, bubble size and half-life described above, a reservoir is used to receive microfoam exiting from the microfoam preparation device as shown in Figure 10 and Figure 11. This device allows the first portion of microfoam to be discarded and the second portion to be collected in a delivery reservoir, such as a syringe 34, under sterile conditions.
According to the invention, the outlet 31 of the cap 30 of the microfoam generating device container 24 is connected to the inlet of an inlet conduit 35 adapted to be connected to a multipath valve 36, preferably a three-way valve, which can be arranged to directly pass the microfoam down the inlet conduit 35 to one or two adjacent outlet conduits 37. , 38 or close the inlet pipe. At least one of the two outlet lines 37, 38 is adapted to be connected to a syringe 34. Preferably, the device container 1 is supported by at least one support member 27a, 27b in an upright position to maintain safety, e.g. immersed tube.
The container 24 is positioned adjacent to the multi-way valve 22 on the support 26, and the inlet of the multi-way valve 22 is adapted to connect the outlet conduit 35 from the container 24 for producing microfoam. Associated with the container 24 is an actuator 29 to open a flow path in the microfoam container 24 to the inlet conduit 35.
Examples
Example 1
A standard aerosol canister fitted with a one-way pressure relief valve was half filled with a 3% v / v solution of polidocanol in sterile water and pressurized to 3 atmospheres using a 50:50 mixture of carbon dioxide and oxygen. Mounted on the valve stem is an actuator and a delivery head that has four plastic screens, just under 0.5 mm thick, with perforations 20 L m in diameter. These are general type screens found in the cap of the Swedspray-Eurospray ApRisC (RTM) foam actuator. The valve was fed through an Ecosol insert of the gas-to-liquid interface from a tube immersed in the surrounding chamber. The dimensions of the gas inlet (x2) to the liner are 0.15mm x 0.25mm while the single liquid inlet is 0.61mm, according to the Ecosol liner size selection. Upon actuation of the head, the metering valve releases the pre-mixed solution and gas into the screens, thereby producing a microfoam suitable for the treatment of sclerosis and dimensionally stable for at least 2 minutes, preferably 5 minutes, using glycerol in a polidocanol formulation.
Example 2
The device for producing a foam, shown in Fig. 1, is used for the implementation of the method. The device according to the invention comprises a container 1 in which a pressure chamber 4 is located, and a flow path in which is formed in the form of a tube 12 through which the gas-liquid mixture must flow. which increases the hygiene of the appliance.
Container 1 is a standard solution with a volume of 500 ml with an aluminum wall, the inner surface of which is coated with an epoxy resin resistant to polidocanol and oxygen (e.g. Hoba 7940-Holden UK). The bottom 2 of the container 1 has a dome facing inwards. The inner chamber 4 of the container 1, pre-purged with 100% oxygen for 1 minute, containing the liquid solution 3, which is 15 ml of 2% v / v polidocanol / 20 mmol of phosphate buffered saline solution, was then filled with oxygen at a pressure of 270 kPa (170 kPa gauge).
This is achieved by creating a positive pressure of 170 kPa of oxygen in a vessel filled with polidocanol.
The bottom dome 2 forms a circumferential surface around the bottom of the inner chamber 4 in which a level of polidocanol solution is maintained sufficient for the open end of the tube 12 at the bottom 2 to be immersed in this solution when the top of the dome is no longer covered with the solution. In this way, by providing an indicator on the outside of the container 1 showing the position of the dip tube 12, the container 1 can, if desired, be oriented to withdraw the last part of the solution. In practice, vertical orientation is sufficient.
The standard 2.54 cm diameter dispensing valve 5 (Precision Valves Peterborough) is clamped onto the top of the container 1 after the sterile portion has been filled with the solution and is activated by pressing the actuator cap 6 to release the contents by
Outlet port 13 adapted to engage with a syringe connector or multi-lumen connector (not shown). The connecting member 7 is disposed at the bottom of the dispensing valve 5 and by means of which four Nylon 66 screens are secured, preferably by an interference fit, by rings 8 of soft polyethylene (HDPE), all housed in an open-ended polypropylene housing. . These screens are 8 mm in diameter and contain 15% of the open area formed by 20 µm pores, the screens being spaced 3.5 mm apart, defined by HDPE rings.
The lower connector 9, located on the underside of the connecting member 7 for holding the sieves, has a housing 10 in which the tube 12 is mounted and has gas flow openings 11a, 11b through which gas flows from the pressure chamber 4 into the liquid stream lifting the tube 12 upon actuation of the actuating mechanism 6. This is conveniently achieved using an Ecosol insert device (previously described). The cross-sectional area of the gas flow openings 11a, 11b is selected such that the overall ratio of this area to the cross-sectional area of the tube 12 is controlled to ensure the required gas / liquid ratio is obtained. These are e.g. 0.25 mm x 0.33 mm in diameter for each gas flow opening 11a, 11b to 1.03 mm for the tube opening 12.
Example 3
The method of producing the foam according to the invention may be carried out with another embodiment of the device for producing foam as shown in Fig. 2. The container 1 of the apparatus of the present invention shown in Fig. 1 has been modified by using a foil second container 22, in the form of a bag in which it is contained. closed liquid solution 3, for example polidocanol solution, for sclerosing varicose veins. The bag 22 consists of an aluminum foil / plastic laminate sealed for gas permeation into the tube 12. At the top of the tube 12 there is a one-way supply valve 21 which serves to prevent the polidocanol from coming into contact with the contents of the tube 12 and the chamber 4 until the dosing valve 5 will not run. Upon such operation, the supply valve 21 opens and a liquid solution 3, preferably a polidocanol solution, rises in the submerged tube 12, thereby mixing with the air / oxygen gas mixture entering through the gas flow openings 11a, 11b. In this way, the connector 10 can be safely sterilized using radiation ionization, which may otherwise contribute to the interaction between the radicals in the gas and the organic component of the polidocanol solution. This structure of the device may also improve its performance in terms of initiating foam delivery. The second container 22 preferably contains only the liquid solution 3, with no headspace of gas above.
Example 4
The device of this example is identical to that indicated in Example 3 except that the polidocanol in the liquid was replaced with sodium tetradecyl sulfate at 1% by volume and all other ingredients were the same.
Example 5
An embodiment of the method has been carried out with the foam-making device of Fig. 3, which is in the form of a syringe specifically designed to produce microfoam according to the invention using the method of the invention. The body 13 of the syringe has a connecting outlet 14 and retaining flanges 15 and forms a pressure chamber 19 with the plunger 16. The pressure chamber 19 is pre-filled, or in use, with a liquid sclerosing solution 18, in this case polidocanol (as above). The piston 16 has a face 17 sealingly against the body 13, inert to the polidocanol solution and preventing the solution from permeating around the edges of the piston 16 when it is pressed to compress the contents of the pressure chamber 19.
A series of three spaced apart screens 20 of the type and configuration indicated in Example 2 are disposed between the sealed face 17 of the piston 16 and the connecting outlet 14 of the body 13. In this example, the screens 20 are arranged to leave a space between them and the connecting outlet 14. for the clinician to observe the foam generated as the gas / liquid mixture passes through the screens 20.
Operation of such a syringe device is preferably achieved by pushing the plunger 16 so as to reduce the volume of the chamber 19 filled with the sclerosing liquid 18 with a sterile sealing of the connecting outlet 14, for example with a foil sealing cap attached to its outer surface. The cap detaches, the connecting outlet 14 connects to a source of the required blood dispersant gas, and the piston 16 is pulled back to inject the required amount of gas and yield 16.
The ratio of gas to liquid is suitable for obtaining a macrofoam with a gas to liquid ratio of 7: 1 to 12: 1 after mixing, for example by shaking a syringe. To create the foam, the plunger 16 is pushed with equal pressure to force 1 ml / second of the foam and converting the macrofoam to microfoam.
It will be appreciated that the microfoam may be directly administered to the patient, but it is more convenient to transfer it directly to a chamber, for example a second syringe, to more easily define the large volume of foam that is required to remove a large saphenous vein. Thus, it is desirable to pass the microfoam between the two chambers through screens to render it even more uniform.
Example 6
Figure 4 shows a further embodiment of the inventive foam-making device, in the form of a syringe, designed to produce the inventive microfoam by the method of the invention. The syringe body 13 has an outlet 14 and retaining flanges 15 and a plunger 16 defining a pressure chamber 19. Pressure chamber 19 is pre-filled, or in use, with a liquid sclerosing solution 18, in this case polidocanol (as above). The piston 16 has a face 17 sealingly against the body 13, inert to the polidocanol solution and preventing the penetration of liquid solution around the edges of the piston 16 when it is pressed to compress the contents of the pressure chamber 19.
A rod 21 runs centrally and longitudinally through the piston axis, on which a Tetratex porous membrane 22 with an effective pore size of about 5 nm is mounted in a double clamping ring. The rod 21 has a handle 23 located outside the pressure chamber 19 of the syringe, which allows the diaphragm to move independently of the piston 16 to force the contents of the pressure chamber 19 through its pores.
Operation of such a syringe is preferably achieved by pushing the plunger 16 so as to reduce the volume of the pressure chamber 19 filled with the liquid sclerosing solution 18 with a sterile sealed connecting outlet 14, for example a foil sealing cap attached to its outer surface. The cap is disconnected, the connecting outlet 14 connected to a source of the required blood dispersant gas, and the plunger 16 is pulled back to inject the required amount of gas and obtain a gas to liquid ratio suitable for obtaining a macrofoam with a gas ratio after agitation, for example by shaking a syringe. for liquids 7: 1 to 12: 1. To produce a foam, the handle 23 on the rod 21 is moved so that the membrane passes repeatedly through the pressure chamber 19, for example 2 to 10 times, causing the gas and liquid to mix and form the foam. To dispense the foam directly to the patient, or into another syringe or container, the rod 21 is pulled back so that the attachment of the diaphragm 22 rests against the sealed face 17 of the piston 16 and the piston 16 is pushed with an equal pressure, for example 1 ml / second. Of course, when the foam is conveyed directly to the patient, a suitable needle is attached to the connector outlet 14.
Example 7
The inventive microfoam was produced in the apparatus described in Example 1 having the limiting dimensions of the gas channel and mixing as shown in Example 2, but differed in that the screen was placed in a dispensing cap, downstream with the valve, while gas / liquid mixing occurred in the liner. Precision Valves Ecosol devices countercurrent to the valve. 15 ml of an aqueous solution containing per 100 ml - polidocanol (Kreussler-Germany) (2 ml), 96% ethanol (4 ml) and 55 mmol of phosphate buffer (pH 7.0) (94 ml) are introduced into the chamber (500 ml). using air gas under a pressure of 150 kPa (100% oxygen). The properties of the microfoam produced by the actuation of the valve are shown in Figures 5 and 6.
Fig. 5 shows the bubble size distribution immediately after microfoam production. The foam density was 0.138 g / ml.
Fig. 6 shows the size of the bubble produced with a varying gas-to-liquid ratio obtained by changing the size of the gas / liquid contact surface by changing the area of the gas flow opening 11a, 11b, producing a foam with a density of 0.09 g / ml (closed diamonds) and a density of 0.16 g / ml (open diamonds).
Fig. 7 shows the effect of passage through the needle 21G on the bubble size distribution of the preferred microfoam (0.13 g / ml). The open squares show the fresh foam, the diamonds the control foam aged to adjust the injection time, and the closed triangles show the effect after passing through the needle.
PL 201 186 B1
Fig. 8 shows the effect of passing microfoam made with a Swedspray device (density 0.045 g / ml) through the needle. The closed diamonds represent the aged foam, while the open circles - after passing through the needle.
It was found that when 5% glycerol is added to the formulation, the half-life increases to approximately 4 minutes.
Bubble dimensions were calculated by drawing foam into a Syringe device through its connecting outlet, optionally attaching a 21G needle, and injecting foam between two glass plates separated by 23.25 micron diameter beads (e.g. available as microspheres from Park Labs USA). The Maxtascan / Global Lab Image technique was used to analyze the bubble size. The diameters of the uncompressed bubbles (Dr) were calculated from the diameters of the bubbles between the plates (Df) using the equation Dr = y3 Df<sup>2</sup>x / 2, where x is the distance between the plates. These measurements were made at ambient temperature and pressure.
It can be concluded that there may be bubbles much smaller than 25 µm in diameter, but cannot be counted. The indicated vesicle percentages are therefore valid for vesicles having dimensions in the range of 25 µm and above.
Example 8
As shown in an elevation view of Fig. 10 and a top view of Fig. 11, the device of Example 1, 2 or 3, for filling a syringe with microfoam made according to the invention, preferably has an attached base 26 having a structural recess 25 in which it is provided. placed bottom of the container 24. The container 24 is placed in a 1 cm deep recess 25 in the plastic base 26, the recess 25 having a diameter approximately 1 mm larger than the container 24 so as to obtain a sliding fit. The container 24 is also supported by two resiliently attached retaining arms 27a, 27b attached to a vertical support bar 28 that are deformable to match the diameter of the container.
Just above the top of the cap of the container used, an actuating arm 29 is mounted on the support rod 28, interlocking between the first actuated position (solid line) and the closing position (dotted line). In the actuated position, actuator arm 28 presses the cap of actuator 30 container 24 and thus opens container valve 24 and causes the microfoam to be released.
Also on the base 26 there is a recess 32 sized for sliding the syringe 34 with its plunger. There is also a restriction member 33 positioned so that the plunger is limited in its longitudinal movement during inflation to prevent the syringe from overfilling.
A flexible, transparent plastic conduit 35, inert to the sclerosant foam, is connected to the outlet 31 of the container 24 used and is attached to a three-way valve 36 attached to the base 26. The three-way valve 36 is actuated by turning the tap 37 to one of three positions: valve closed - no passage for microfoam; valve open to drain 38 whereby any microfoam that is not usable by visual inspection of the contents of conduit 35 is drained; and a valve open to the syringe 34 so that a predetermined amount of microfoam passes through the syringe outlet and fills it until the syringe plunger 34 reaches the stop member 33.
Example 9
According to Example 6, 20 ml of microfoam is introduced into a 20 ml syringe using the device of Example 7 and the syringe is disconnected from the device. A 19 gauge needle is attached either directly to the syringe inlet connector or via a catheter. Microfoam is administered into the varicose vein while monitoring the initial and final positions using a handheld ultrasound scanner such that the position of fresh foam is confined to the subject's vein. After 1 to 5 minutes, the vein narrows and then becomes fibrotic.
Contents8
10 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6 Sheet 7 Sheet 8 Sheet 9 Sheet 10
124 members in 36 offices
Priority claims2
| Document | Office | Kind | Date |
|---|---|---|---|
| 9912356 | United Kingdom | A | |
| 0002045 | United Kingdom | W |
Members124
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|---|---|---|---|
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| GB9913542D0 | United Kingdom | D0 | |
| CA2373939A1 | Canada | A1 | |
| CA2661728A1 | Canada | A1 | |
| WO0072821A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU4939700A | Australia | A | |
| CA2376229A1 | Canada | A1 | |
| WO0077146A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU4939500A | Australia | A | |
| PE20010281A1 | Peru | A1 | |
| NO20015742D0 | Norway | D0 | |
| NO20015742L | Norway | L | |
| NO20111034A1 | Norway | A1 | |
| EP1180015A1 | European Patent Office (EPO) | A1 | |
| CZ20014007A3 | Czechia | A3 | |
| EP1185606A1 | European Patent Office (EPO) | A1 | |
| BRPI0010891A | Brazil | A | |
| MA25413A1 | Morocco | A1 | |
| BR0011480A | Brazil | A | |
| TW482671B | Taiwan Province of China | B | |
| KR20020040667A | Republic of Korea | A | |
| TR2001003584T2 | Türkiye | T2 | |
| TR200103584T2 | Türkiye | T2 | |
| HK1041437A | Hong Kong, China | A | |
| HK1041437A1 | Hong Kong, China | A1 | |
| MXPA01012091A | Mexico | A | |
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| IL146394D0 | Israel | D0 | |
| MXPA01012732A | Mexico | A | |
| HU0201550A2 | Hungary | A2 | |
| HUP0201550A2 | Hungary | A2 | |
| EA200200022A1 | Eurasian Patent Organization (EAPO) | A1 | |
| BG106248A | Bulgaria | A | |
| CN1367819A | China | A | |
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| AU772515B2 | Australia | B2 | |
| NZ515647A | New Zealand | A | |
| US2004101480A1 | United States of America | A1 | |
| YU84201A | Yugoslavia, later Serbia and Montenegro (until 2006) | A | |
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| US6942165B1 | United States of America | B1 | |
| AU2005205772A1 | Australia | A1 | |
| RU2261700C2 | Russian Federation | C2 | |
| US2005266033A1 | United States of America | A1 | |
| EP1180015B1 | European Patent Office (EPO) | B1 | |
| AT313317T | Austria | T | |
| ATE313317T1 | Austria | T1 | |
| DE60024988D1 | Germany | D1 | |
| US2006049269A1 | United States of America | A1 | |
| EP1637127A2 | European Patent Office (EPO) | A2 | |
| US7025290B2 | United States of America | B2 | |
| DK1180015T3 | Denmark | T3 | |
| HK1041437B | Hong Kong, China | B | |
| EP1180015B8 | European Patent Office (EPO) | B8 | |
| ES2254177T3 | Spain | T3 | |
| SA00210274B1 | Saudi Arabia | B1 | |
| SA1174B1 | Saudi Arabia | B1 | |
| DE60024988T2 | Germany | T2 | |
| MY125539A | Malaysia | A | |
| PL192102B1 | Poland | B1 | |
| EP1185606B1 | European Patent Office (EPO) | B1 | |
| AT338807T | Austria | T | |
| ATE338807T1 | Austria | T1 | |
| DE60030560D1 | Germany | D1 | |
| DE60030560T2 | Germany | T2 | |
| IL146394A | Israel | A | |
| ES2269146T3 | Spain | T3 | |
| KR100720782B1 | Republic of Korea | B1 | |
| EP1637127A3 | European Patent Office (EPO) | A3 | |
| HU0201550A3 | Hungary | A3 | |
| HUP0201550A3 | Hungary | A3 | |
| US7357336B2 | United States of America | B2 | |
| US2008145401A1 | United States of America | A1 | |
| US2009041827A1 | United States of America | A1 | |
| PL201186B1This record | Poland | B1 | |
| AU2005205772B2 | Australia | B2 | |
| CA2373939C | Canada | C | |
| US2009256006A1 | United States of America | A1 | |
| US7604185B2 | United States of America | B2 | |
| BR0011480B1 | Brazil | B1 | |
| BRPI0011480B1 | Brazil | B1 | |
| CA2661728C | Canada | C | |
| BG65977B1 | Bulgaria | B1 | |
| EP2269578A2 | European Patent Office (EPO) | A2 | |
| BRPI0010891B1 | Brazil | B1 | |
| JP4846907B2 | Japan | B2 | |
| US8091801B2 | United States of America | B2 | |
| JP2012006930A | Japan | A | |
| CZ302999B6 | Czechia | B6 |
Numbers
- Publication
- 201186
- Application
- 35187700
Titles2
- English
- Making therapeutic foam
- Polish
- Sposób i urządzenie do wytwarzania mikropianki do leczenia obliteracyjnego żylaków naczyń krwionośnych i zastosowanie urządzenia
Classification
- CPC, 14
- A61K9/122
- A61K9/12
- A61K9/0019
- B05B7/0037
- B05B11/02
- B65D83/60
- B65D83/62
- A61K31/08
- A61P9/00
- A61P9/14
- B65D83/58
- B65D83/162
- A61M5/31
- B65D83/16
- IPC, 9
- A61J3 00
- A61K9 12
- A61K47 04
- A61K47 20
- A61K47 34
- A61M5 31
- A61P9 14
- B65D83 14
- B65D83 16