DE2903894A1 - BLOOD DIALYSIS METHOD AND DEVICE FOR CARRYING OUT THE METHOD USING STABILIZED LIQUID MEMBRANE CAPSULES - Google Patents

Description

-τ-

Our No. 22 298 Pr / Ec / br

Exxon Research and Engineering Company Plorham Park, N.J., V.St.A.

Device for blood dialysis using stabilized Plüssig membrane capsules

The invention relates to liquid membrane capsule systems that Coalescence-resistant were made with the help of an irreversible coating, for example made of sodium carboxymethyl cellulose and aluminum sulphate and which has been added to an emulsion-suspension system, as a result, irreversibly coated beads are formed, which are both the emulsion of an inner and an outer Phase and the suspension phase included. As a result of this irreversible coating, the liquid memberan systems retain their original size distribution for a long period of time without stirring. aside from that the liquid membrane capsule systems are resistant to tearing, caused by bile, surfactants with high HLB (13 or more), stress pancreatin, or solids can be caused. Such irreversibly coated liquid membrane capsule systems are of advantage in those medical fields where it is desired, highly stable liquid membrane systems to. have in which the detox chemicals as the inner phase of the liquid membrane are encapsulated.

909831 / 088B

These liquid membrane capsule systems are particularly suitable for treatment outside the body. Such irreversibly coated liquid membrane capsule systems are also useful in detoxification and water purification systems, wherein strong, long lasting encapsulated materials are desirable for toxin or waste concentration are wherein the treatment is not as gentle as that performed in laboratory conditions , i.e. these irreversibly coated liquid membrane capsule systems are useful for general industrial applications.

Use of stabilized liquid membrane capsules (LMC) outside the body

One of the most attractive uses of this stabilized LMC is in treating patients with the LMC in an external device that contains these LMCs. One outside of the body itself The device located is of course outside the body, but with the patient via a body fluid tied together. For chronic uremia, the most common treatment outside the body is hemodialysis. Here blood is removed from the patient and passed through the hemodialyser before it is delivered to the patient is returned. In the device, the blood passes through a solid dialysis membrane on one side and on the other Side of this membrane is a large volume of dialysis fluid (i.e. about 200 l) for thinning the Used toxins from the blood. The required volume the dialysis fluid can be reduced as much as possible (i.e. to about 11) by continuously removing the Toxins with the stabilized LMC that are in a circulatory system

909831/0885

β -

leading to dialysis fluid is suspended. The volume of the dialysis fluid can be reduced by about 99%.

A newer type of treatment outside the body is hemofiltration. Here the blood is ultrafiltered _s the ultrafiltrate discarded and sterile saline is infused back into the patient. Here, the need for large volumes of sterile saline could be eliminated by treating the ultrafiltrate with LMC to remove the toxins and re-infusing the treated ultrafiltrate. Of course, the LMC dated. Ultrafiltrate can be removed, for example by gravity and / or filtration, before it is re-infused into the patient.

One type of out-of-body treatment still under investigation is hemoperfusion. Here it becomes blood removed from the patient is treated directly with sorbents prior to re-infusion. The present LMCs could can be used to remove the toxins from the blood by suspending the LMC directly in the blood. Of course they would have to be removed before re-infusion.

Another type of dialysis in extensive clinical uses is peritoneal dialysis. In this method, sterile fluid is introduced into the abdominal cavity where they are separated from the blood by the natural peritoneal membrane and is used to dilute the toxins. This fluid is later withdrawn from the abdominal cavity and discarded and replaced with more sterile liquid. The volume of sterile liquid could be largely be reduced by an outside of the body yourself

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located device for the treatment of the. Abdominal cavity drained fluid with suspended LMC before reinfusing the purified fluid. Preferably, the LMC is removed from the liquid prior to re-infusion. However, if LMCs that are completely broken down by the body were used, this complete removal would not be necessary. The stabilized liquid membrane capsules (LMC) of the present invention represent a very significant improvement over the various apparatuses used for hemodialysis. Hemodialysis machines are improved and significantly reduced in size through the use of the LMC. The volume of the dialysis fluid used can be reduced by up to more than 99%. Because instead of using a large volume of dialysis fluid to dilute the ingested toxins, the LMC captures the toxin or the toxin converted to ammonia and carries it away in a small volume. This is achieved by using devices for suspending LMC, in which the internal phase is citric acid, in the dialysis fluid which, with the aid of urease, has converted the urea into ammonia. The LMC removes the ammonia. The combination of dialysis fluid and LMC is fed into a contact zone where they meet activated carbon and phosphate ion exchange materials to remove other toxins. The dialysis fluid and suspended LMC can then be separated by conventional means such as filtration, settling, etc., with the purified small volume of dialysis fluid being returned to contact the blood while the LMC is used to treat another volume of dialysis fluid. This separation is a purely optional measure. To be precise, the apparatus can be both discontinuous and

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operated continuously.

In peritoneal dialysis, the saline solution is purified using LMC, wherein the internal phase is citric acid, using means for suspending the LMC in the contaminated saline solution withdrawn from the abdominal cavity. This combination is contacted in a contact zone with immobilized urease, which converts urea to ammonia, which in turn is removed by the LMC _; Activated carbon and phosphate ion exchange material to remove toxins and suspended matter * The saline solution and LMC are then separated from each other in a separator. The purified saline is returned to the abdominal cavity and the LMC is used to purify another portion of the saline. _:

In a similar way, during hemofiltration, the LMC, which in turn contains 2itronic acid, is removed from the ultra-filtrate, which contains toxins suspended and this combination led, for example, to a contact device, in which it is immobilized Urease, activated carbon and phosphate ion exchange material are contacted in the same way As with peritoneal dialysis, the ultrafiltrate is cleaned of ammonia and other toxins by the LMC separated and reintroduced into the blood, which makes the use of saline solution unnecessary and thus in The body is reintroduced its own purified plasma, which contains the essential components necessary for are favorable to the patient.

Figure 1 is a highly simplified scheme of the present invention showing the outer layer of the irreversible Coating and the continuous emulsion phase inside of the coating layer, i.e. the microdroplets,

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which consist of an inner phase suspended in the continuous outer phase.

The irreversibly coated coalescence-resistant liquid membrane capsule system according to the invention is mainly used Use in medical applications, for example in the treatment of chronic uremia as a valuable one Help for dialysis. In such applications, the irreversibly coated liquid membrane capsule system contains a internal aqueous phase containing a reactive substance such as a toxin trap or an enzyme such as urease. The outer phase contains a layer of oil that is a reinforcing agent and / or a surfactant has been added. These inner / outer phase droplets (emulsion) become in turn suspended in a suspension phase, typically a saline-like medically acceptable solution. Each of these inner / outer droplet suspension phase materials are, in turn, encapsulated by the irreversible coating system of the invention, whereby large portions of the Liquid membrane capsule system become coalescence-resistant.

In the manufacture of the device, the microdroplets shown in the figure are by any in the "Eefchnik customary measures, i.e. dropwise addition of the inner phase material to the oil phase with appropriate Stir. The encapsulation phase can be a hydrocarbon oil phase, which when the application of the encapsulated System is a medical one, is non-toxic. The same goes for the reinforcing agents and / or surfactants that can be used according to the invention. The inner phase contains the reactive substrate and can be selected from those substances that are either associated with the penetrated toxin form a complex, making it impermeable

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towards the return over the outer phase boundary or react with the toxin, which makes it "not is made toxic. -. The suspension phase is in such a way that it dilutes the liquid membrane system, whereby it is suitable for injection or ingestion as the case may be is made. The choice of the suspension system is left to the practitioner who makes the efforts listed below undertakes what also applies to the concentration of the emulsion in the suspension phase, since this Parameters depend on the intended use! In such situations where the liquid membrane capsule system is to be used for medical purposes, the suspension phase must of course not be toxic and will preferably consist of a sala-like solution.

Liquid membrane compositions which contain an aqueous inner phase surrounded by a non-aqueous outer hydrophobic oil phase and which are suspended in an aqueous suspension medium are made coalescence-resistant by incorporating an irreversible coating material into the phase of the suspension medium. The liquid membrane compositions generally contain an aqueous internal phase. The aqueous internal phase can contain any material which can be suspended or dissolved in an aqueous medium. In general, the aqueous phase solution can contain from 0 to 60% solutes or from 0 to the saturation point of the solute. Preferably the aqueous internal phase is a dilute solution, ie with less than 10 % solute. The composition of the material in the aqueous phase is left to the practitioner. As such, the aqueous internal phase can be pure water if so desired, or it can be. contain acidic or basic material or it may contain a drug or an enzyme or a toxin trap if the

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entire Plussig membrane used for medical purposes shall be.

When the material in the aqueous internal phase is an acid, the concentration can be between 0 and the saturation point. Such materials that are acidic or contain basic or aqueous inner phase, are normally used in water purification processes. This aqueous inner phase is in turn encapsulated by an outer phase, which contains a hydrophobic non-aqueous oil phase. The composition of the oil phase is, in turn, up to the practitioner leave, the final composition of the intended use of the liquid membrane composition. When the liquid membrane composition is used for to be used for medical purposes, "" '* of course the outer oil phase components will not be toxic.

The oil is such that it is compatible with the fluids present in the environment of the application, for example in the GI tract _; is not miscible. The oil must also be immiscible with the final suspension phase, as described in detail below. Normally, the polynuclear aromatic oils are known to be harmful to the body and are therefore outside the scope of application when the materials are to be used for medicinal purposes or to be administered to the human body by ingestion or injection.

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subsequently changed

Some examples of oils that can be used in forming the compositions of the invention for use in the body include hydrocarbon oils that have been refined to remove toxic components and have molecular weights up to 1,000, such as paraffins, isoparaffins, naphthenes and not -Multinuclear aromatics. Particularly desirable are the mineral oils which have been highly refined for human ingestion use. A mixture of 1 to 60 % "

Moftootein

and mineral oil can also be used.

Oils or treated oils from Tier-5, F; ohen can also be used or herbal sources if used cannot be converted in the application environment. For example, vegetable oils and animal fats, which have been strongly hydrogenated so that they contain at least 10 wt .- # more hydrogen than at normal saturation, be used. Furthermore, silicone fluids can make up the repeating unit

OH,

-Si-O-

included. The fluorinated hydrocarbon oils can also be used. Each of these oils should have a viscosity of about 1 to 1,000 cSt at the temperature at which they are used. A preferred viscosity range is from about 1 to 130 cSt at about 37.8 ⁰ C (100 ° P). In particularly preferred cases, the oils have a viscosity of 9 to 17 cSt. Mineral oils are the most preferred constituent of the oil phase. For general use, the oil of the external phase comprises a material which is immiscible with the aqueous internal phase. and not with the

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aqueous phase or the components of the aqueous phase or reacts with the suspension phase. This outer oil phase optionally contains a surface-active agent in solution. In general, the surface-active agents have an HLB (hydrophilic-lipophilic balance) value in the range from H to 5 »5. The most preferred HLB value is 4.2 to 4.4. In general, the amount of surfactant used is from 0 to 5% by weight . Ideally, the amount of surface-active agent used is 0 if the material used for the coating consists of carboxymethyl cellulose. In addition, the external oil phase must contain a reinforcing agent. The amount of reinforcing agent that is generally used is 0, 5 to 40 wt .- ^, preferably 2 to 10 wt .- #. Ideally, the same material is used as both a surfactant and a reinforcing agent.

Surface-active agents used according to the invention are known, for example, from U.S. Patent 3,779,907. An in-depth treatise on surfactants " is published under the title "Surface Active Agents and Detergents" by Schartz, Perry and Berch in Interscience Publishers, Inc. New York, New York, and another paper is in "Surface Chemistry" by Osipow, Reinhold Publishing Company, New York, New York, 1962, chapter The only requirement according to the present invention must be met is that the surfactant must be oil soluble, i.e. an HLB of Must have <8.

Vex-different polyamine derivatives, which are both surface-active Agents that also act as reinforcing agents are useful in the present invention. The pre-

909831/0880

Added polyamine derivatives are those with the general formula:

R ₃

5 7

r \

C-C-N

I!

wherein .R ₃₅ R ₁₄₅ . Rr _; , C ™ Rg, FCj 'Rg * Bg "mcl y jeviölls hydrogen atoms, C.- to C ₀ ~ Alky gruppens Cg to C ₂₀ aryl groups - to C mean _2Q alkaryl groups or substituted derivatives of the foregoing _groups;?! and χ represents an integer from 1 to 100. Preferably, R ^ »Rg » R ₇ , Rg and R "denote hydrogen atoms and χ represents a number from 3 to 20. y can furthermore contain nitrogen groups containing hydrogen atoms, nitrogen groups containing hydrogen and oxygen atoms, and alkyl radicals with up to 10 carbon atoms, the nitrogen- and / or contain oxygen atoms. The above-mentioned substituted derivatives are preferably derivatives containing oxygen, nitrogen, sulfur, phosphorus and halogen atoms.

Other polyamine derivatives useful in the present invention are the polyisobutylene succinic anhydride derivatives of the following formulas:

909831 / 088Ö

BAD ORiGiNAL

H ¹ - C-

H — ΟΙ H

and

S,

R ¹ -C

■ I

Η— C

• Η

- C-OH

- c- ce

a:

ο.

wherein R 'is a hydrocarbon radical of 10 to 60 Means carbon atoms.

The most preferred polyamine derivatives have the general formula:

TY ι

HC 4— C-CH2 CH ₃ \

- c

H_ C - C

H 0

(a)

H
- I.
- C — Ν "

When the liquid membrane capsules (LMCs) in medical Application forms, especially for injection or ingestion, are to be used, the surfactants, if used, must not be harmful be for the human body. Not ^ Jionic Surfactants are the preferred surfactants for the practice of this embodiment of US Pat Invention. A surface-active agent is nonionic if, when added to the aqueous phase, it is the suspending Phase or the inner aqueous phase is not split into ions.

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Examples of oil-soluble surfactants which have the desired properties are i.a. Sorbitan monooleate and other types of sorbitan fatty acid esters, e.g. sorbitan, sorbitan monolaurate, sorbitan monopalmitate, sorbitan stearate, sorbitan tristearate, Sorbitan trioleate, polyoxyethylene sorbitan, Fatty acid esters and mono- and diglycerides. Preferred surfactants include those described above Polyamine derivatives.

This emulsion, consisting of an inner aqueous phase and an outer oil phase, is in turn suspended in a suspension phase which is an aqueous material = the composition of this suspended aqueous material can again be left to the discretion of the practitioner. In general, the aqueous suspending phase must, when the liquid membrane capsules are intended for a medical application, ^non-: be non-toxic and is represented in this case is generally a medically acceptable saline. For other forms of application, this aqueous suspending phase can contain any useful constituent. The quantitative ratio of the suspending phase to the emulsion, shown as Vs / Ve (volume of the suspending phase to the volume of the emulsion), is in the range from 1: 1 to 5: 1, the preferred ratio being 2: 1 to 3: 1.

This total suspension containing an emulsion is made by adding substances of the type such as sodium carboxymethyl cellulose, which optionally include a trivalent metal salt or a salt of a divalent one as a constituent Heavy metal of the aluminum sulphate type was added, made resistant to coalescence.

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The blends of the present invention are resistant to coalescence, i.e.. the overdone Liquid membrane capsules do not coalesce when one leaving them in a container that is not subjected to agitation or agitation; this means that the coated liquid membrane capsules do not disintegrate to a significant extent into a divided drop size, whereby such disintegration would be characterized by an increase in the overall size of each LMC drop. Coalescence can be divided into three different areas ·. There is the strong coalescence where two separate phases are observed at the time of inspection. One phase is the emulsion from the aqueous interior and the non-aqueous outer phase, which at the time of inspection is completely separate from the suspending Phase is.

The next lower level of coalescence is the minimum coalescence. At the time of the inspection, the liquid membranes can be identified as separate phases; ie the constituent which constitutes an emulsion of an inner aqueous and an outer non-aqueous phase is observed to be still in suspension. However, a change in the size distribution is observed at the time of inspection. A widening of the size range by a factor of 3 is found. If, for example, at time O, ie immediately after the end of the movement, the liquid membrane capsules have a size range from X to 3X with an average size of 1.3X, while at the time of inspection, an arbitrary time after t = 0, the size range of X ranges to 1OX and the average size reads at 1.7X to 2, IX, which is an increase of 30 to 60 % of the average size. X is defined as the smallest liquid membrane particle and is typically 5 to 50 µm.

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Ira general reveals formulations that have minimal coalescence at the time of inspection exhibit negligible coalescence some time prior to inspection.

Negligible coalescence is the last category, and liquid membrane capsules with negligible coalescence exist as separate materials at the time of inspection; This means that the emulsion remained in suspension with a minimal change in the average particle size and the particle size distribution:! fit. Ee is observed no widening of the Größenbereicbes. For example, if at time O the size distribution ranges _{from X to JX with an average value of 1 S 3X>} while at the time of inspection, an arbitrary time after time O, the size range is from X to 3X, with the average size at 1.7X a negligible coalescence is assumed. A negligible coalescence is defined in such a way that no change occurs in the size range of the liquid membrane capsules and only a change of less than 30 % is found in the average size.

Non-irreversibly coated, known liquid membrane capsules produce a strong coalescence in one minute up to an hour. Some formulations of irreversibly coated membrane liquid capsules yield a minimum Coalescence over a period of 2 hours to 2 years. Other formulations from irreversibly coated Liquid membrane capsules only produce negligible coalescence after storage for 1 year or more.

909831/0888 ORIGINAL BATHROOM

The irreversibly coated membrane liquid capsules of the present invention can also be made by the following Attempts are marked.

Emulsions suspended in a suspension phase were coated with a preselected coating material. These irreversibly coated liquid membrane capsules were then exposed to a suspending phase containing a surfactant with a high HLB value (HLB value greater than 8, e.g. bile or Renex 69O) and / or solids (0.03 to 0.07 % Pancreatin, silica gel), with gentle stirring (stirrer with propeller mechanism at up to 60 rpm). Under these experimental conditions, strong coalescence resulted in an increase in the average size of the liquid membrane capsules of up to 5-fold. Size of the original liquid membrane capsules ranged in 5 to 15 minutes. Visual observation indicated that after this period of time the material contained some non-spherically shaped liquid membrane capsules. Uncoated, known liquid-Memb _s j? Is endemic, have been subjected to the test, coalesced to form separate emulsion and suspension phases within one minute after the termination of emotion. Under the experimental conditions, a minimal coalescence is described by the following change in the size distribution, which occurs gradually over the course of 2 hours. Here, as in the experiments described above, a broadening of the size range by a factor of 3 is observed, but this time after the liquid membrane capsules have been continuously used for 2 hours

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exposed to a high HLB surfactant and / or solids as described above. For example, at time t = 0, if the size range was from X to 3X, with the average size being 1.3X, then the size range after 2 hours was X to 10X, with the average size being 1.7X to 2.1X (ie, an increase in size of 30 to 60 #), with X being the smallest size of a liquid Merabran capsule. In order to be classified as liquid membrane capsules with minimal coalescence, the liquid membrane capsules coalise with the formation of separate emulsion and suspension phases within one day after the end of the agitation. If a liquid membrane capsule is to have negligible coalescence under the process conditions, the size range of the liquid membrane capsules must be maintained as above and the average diameter of the liquid membrane capsules must only increase by less than 30 % , but this time within 2 hours. In order for a liquid membrane capsule to have minimal coalescence, the liquid membrane capsules may only be put into a liquid membrane capsule after a period of more than 1 day without stirring during visual inspection. Separate emulsion and suspension phases. When the irreversibly coated membrane liquid capsules of the present invention are subjected to the above experimental conditions, they fall into the latter two categories. The irreversibly coated liquid membrane capsules of the present invention are generally produced by converting the component consisting of the aqueous inner phase into the component consisting of the outer light-aqueous oil phase

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encapsulated by shearing the two materials at a shear rate of e.g. 500 to 8000

-1 '

reciprocal seconds (see) mixed together.

This emulsion is in turn suspended in a suspending phase by adding the emulsion to the suspending phase and applying a shear rate of 50 to 8000 seconds. ¹ for a period of 0.5 to 150 seconds per 100 g of material in total (suspending phase plus emulsion). When using higher shear rates (ie> 1000 sec.), The microdroplet size of the emulsion must be <1 μm to prevent excessive leakage during the coating process. A quantity of irreversible coating materials, for example sodium carboxymethylellulose with a molecular weight of 80,000 to 800,000, was added to the suspending phase before the liquid membrane capsules were manufactured. Preferably, the sodium carboxymethyl cellulose is of the lower viscosity types having a molecular weight of 80,000 to 200,000. Instead of sodium carboxymethyl cellulose, albumin or hydroxypropyl cellulose or xanthum gum (a polysaccharide) can also be used as one of the irreversible coating materials. As further alternatives for these materials, long-chain polymers with surface effectiveness; ie those polymers which are commercially available as emulsion stabilizers and which have the ability to form gels or to crosslink their chains under the influence of trivalent cations or divalent heavy metal cations can be used. After the formation of these liquid membrane capsules, which comprise a combination of an emulsion in water, the last water phase containing the irreversible coating material, which here for reasons of expediency as sodium

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Carboxymethylcellulose is called> another material is added, which is a trivalent Represents metal salt or a divalent heavy metal salt.

_{Al 2} ^ ₂ aluminum acetate or aluminum hydroxide can be used as examples of such salts. Furthermore, any salt containing a trivalent cation or any divalent heavy metal cation, for example copper (I) ", copper (II) - _s silver- * iron (IX) - _} uranium, chromium, tin (II) -, »Lead or zirconium salts 5, can be used. This trivalent cation or divalent heavy metal cation is explained here for reasons of expediency using the example of aluminum sulfate The weight ratio is preferably 50 to 999: 1, preferably 70 to 200: 1. The typical pH value of the cellulose material in water is about 5.5 NaOH, can be set higher, for example up to about 8.0. The type of addition of the aluminum raw material is important. If aluminum sulfate is added as a solid, it is added to the suspending phase before the e emulsion is suspended in the suspending phase, ie before the liquid membrane capsules are formed. If the aluminum sulfate is added in the form of an aqueous solution, it is also added before the formation of the liquid membrane capsules, namely dropwise to the irreversible coating material contained in the suspending phase. In this case the suspending phase (containing

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the cellulose material and Al) have a pH of 3.0 to 5.5> regardless of whether the pH of the suspending Phase (containing only the cellulose material) adjusted to a value of up to 8 before the addition of the Al was or not. When the Al is added in this way, best results are obtained when the Emulsion phase and the suspending phase shear

no Λ

speeds of 4000 to 5000 seconds for a duration of 0.8 to 1.3 seconds per 100 g are subjected.

According to another embodiment, a solution containing the aluminum sulfate is mixed with citric acid or another acid _9, for example any alkali metal salt of citric acid or maleic acid or a short-chain carboxylic acid or metal salt acids, the. pH of the solution containing the acid and Al was adjusted to 2 to 7 and the solution was added after the liquid membrane capsules were formed. The pH of this material containing cations, which is added after the liquid membrane capsules have been formed, is preferably adjusted to 5-7 by adding sodium hydroxide. When the aluminum sulfate is added from a citric acid solution, the molar ratio of citrate as citric acid to aluminum is typically 0: 1 to 1: 1, preferably 0.6: 1 to 1: 1. When this embodiment is used, the shear rate for the formation of the LMC is preferably 70 to 700 sec. " ¹ for a period of 1 to 150 sec / 100 g of material (suspending phase plus emulsion). The citric acid aluminum sulfate is in the Added a lapse of 1 to 5 minutes after the LMCs are formed while stirring the LMCs at a shear rate of 5 to 40 % of that used to form the LMCs.

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29Q389A

In summary, it should be stated that this is irreversible coated LMC mixture an emulsion of an aqueous inner and a non-aqueous outer phase, suspended represents in an aqueous suspending phase, the aqueous suspending phase being a Addition of an irreversible coating material (ICC) in a concentration of 0.5 to 100 g ICC per liter suspending phase, preferably from 1 to 50 g of ICC per liter of suspending phase. For this is optionally a 2 ~ or 5-valent heavy metal salt in a weight ratio of ICC to salt of 50 to 999: 1 given. The typical pH value of the suspension phase containing the ICC is about 5.5. If that A material consisting of a salt of a trivalent or divalent heavy metal cation is added from a solution is, the salt is preferably dissolved in an acidic solution, the pH of which is between about 2 and 7> preferably between about 5 and 7. In such an embodiment, the molar ratio of acid is to the salt of the trivalent or divalent heavy metal =? cation at 0: 1 to 1: 1, preferably 0.6: 1 to 1: 1.

In the following table examples are irreversible coated LMC, the method of its manufacture and the resistance obtained when left standing without movement was observed.

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TABLE I.

Example emulsion game oil phase

96% Markol 87 ⁺ k% polyamine A

Composition inner phase

Citric Acid $ 60.9 *

5 g / l NaOl ή g / l NaHCO,

96% Markol 87 ⁺ * \% polyamine A

Citric Acid $ 69.9 suspending phase

properties

Concentration, Arfc of the long chain polymer

/ Sodium carboxy-. ' methyl cellulose 20 g / l

[Lower type
Viscosity)

10 g / l

20 g / l 5.0 g / l

10 g / l

96% Markol 87 ⁺ k% polyamine A

59.2 percent -.% Tartaric acid

95 % Markol H polyamine A 1% sorbitan monooleate 10 g / l sodium carboxymethyl cellulose

(Low viscosity type

8 g / l egg albumin

10 96% Markol k% polyamine A

⁺ White oil with a viscosity of 17 cSt at 37.8 ° C

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TABLE I (port setting)

290389 *

Suspending phase properties

example

pH of the
suspending phase

Components of the suspending phase (in addition to the long-chain polymer)

Ratio of suspending phase to emulsion

1 b , 5 20 g / l NaHCO ₃ 2: 1 2 2: 1 3 2: 1 H 2: 1 5 1: 1 6th 7.7 2: 1

7.7

7.7

20 g NaHCO ₃ / l

1.5 g Al 18 H

5g NaCl 4g NaHCO

1.5 g A1 ₂ (SO ₄ ) ₃ * 18 H ₂ O per liter 2: 1

2: 1

2: 1

2: 1

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- 3g? -

TABLE I (continued)

For example, shear conditions, shear, shear duration per shrinkage mass, material, l / sec. Sec ./. (100 g) trivalent cation (Al) properties

Type of addition

Weight ratio of long chain Polymers' to cation

378

133

76

v /

"" as citric acid ^ Al solution LMC formation at a shear rate of 27 / sec. " / with continued! " ISch © ration after [Addition of the jsi ~ luronic acids Al solution at speed vo; 27 / sec. for 7300 sec / 100 g only for

72/1

72/1

32/1

I78 / I

36OO

1.3 Al added in a volume of water equal to the volume of the suspending phase after LMC formation at a seer speed of 3600 / sec. for 3 sec / 100 g

19th

36OO

10 j pulyer before LMC formation in suspending Phase brought

76

378

133

vl / Al in suspending Long-chain polymer phase present prior to LMC formation

76/1

ir

61/1

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TABLE I (port setting)

trivalent cation (Al) properties

resistance

Molar ratio of chelating agent (Citrate) to Al

pH value stability of the citrate / (degree of Al solution coalescence)

Inspection time

1 2 1 /1 7th
I. minimal
minimal 3 months
21 months 3 I. minimal
strong 3 months
21 months 4th 2 minimal
strong 10 mins
1 day ι f 2 negligible 1 year

5 negligible
strong 1 day
2 weeks 6th minimal 8 months 7th minimal 1-4 days 8th strong 10 min. 9 minimal 1-4 days 10 strong 1/2 hour

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Example 11

Emulsion: 96% IP17J 4 % polyaminesA) 100g 59.2 $ tartaric acid 75g

manufactured in a colloid mill, 900 g material for the duration

circulated for 10 minutes, 85 % open (shear rate 4,000 sec. " ¹ )

Suspending phase: 1.5 g Al ₂ (SO ^) ₃ * 18H ₂ O J

10 g sodium carboxymethyl- ^ water cellulose (Matheson _s Coleman & Bell) J.

400 ml of the suspending phase and 200 ml of the Emulsinn were circulated in a colloid mill (JW Greer; Gifford Wood Model W 200) at full power and 85 % open setting to form the liquid membrane suspension. 270 ml of the suspension were combined with 225 ml of an albumin solution, 8 g of albumin, 20 g of NaHCO, / 1 H ₃ O and 10 mM bile and 0.5 % pancreatin were added. In »comparison with the irreversibly coated liquid membrane capsules, when the reversibly coated (with methyl cellulose) liquid membrane capsules were brought into contact with. Extreme coalescence was observed in bile and pancreatin within 5 minutes. The remaining suspension stood in the container without agitation for a period of 5 1/2 months at room temperature.

100 ml of the 5 1/2 month old suspension (33 ml liquid membrane capsules) and 500 ml of an albumin solution were combined in a beaker and at a speed

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of 500 ml per minute for a period of 48 hours over one layer (diameter 5 cm, length 15 cm) pumped by glass beads. The beads were used to make other sorbent systems used in a dialysate system could be used to simulate. The suspension apparently retained its original appearance during the pumping process. There was no significant change after 2 1/2 hours of pumping occurred in the size of the liquid membrane capsules.

Over a period of 19 hours, the pH of the suspending phase changed very little (from 8.16 to 7.06), which indicated that under these severe and long-lasting conditions only a very little leakage of the inner phase occurred.

Example 12

Emulsion: same as in Example 11 suspending phase: 20 g of sodium carboxymethyl

cellulose per liter of water

the
By stirring 30 ml / suspending phase and 15 nl of the emulsion for 1 minute in a glass vessel with a diameter of 5.5 cm with the aid of a propeller stirrer (diameter 4 cm, 3 blades inclined at 45 °) at 1,800 rpm A suspension was formed at a shear rate of 400 seconds. A 45.7 cm length of 0.D. steel tube in the jar served as the baffle. The distance between the tip of the propeller and the impact surface was 3 mm. The propeller speed was reduced to 132 rpm,

909831/0388

and 3 ml of a solution containing 0.608 g of citric acid and 3.2 g of Al ₂ (SO ^) · 18H ₂ O per 100 ml of water was added. Before the addition, the pH of the citric acid aluminum solution was adjusted to 7.0 with NaOH.

90 ml of the suspension were added to 270 ml of a solution containing 20 g / l NaHCO 3 and 20 mg / 100 ml NH. FIG. 2 shows the removal of ammonia with the Plussig membrane capsules coated in the above manner. The rate constant of 0.31 per minute at a pH of 7.8 is a good comparison at 0.40 / min. for a system with reversible coated Plussig membrane capsules.

For: Exxon Research and Engineering Company Florham Rark, // N. J., V. St. A,

Dr.H.J.Wolff Attorney at Law

909831 / D8 $ 8

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Claims (1)

Claims Blood dialysis device in which urea and other toxins are removed from the blood by passage of the Urea and other toxins through a membrane into a urease-containing dialysis fluid or through the peritoneal membrane into a sterile saline solution in the abdominal cavity or by passage of urea and blood plasma containing other toxins through a membrane j characterized by means for contacting of the stream containing the urea and other toxins with an improved stabilized coalescence resistant Liquid membrane capsule (LMC), containing an aqueous inner phase, which of a non-aqueous outer oil phase is surrounded and thereby forms an emulsion which is suspended in an aqueous suspension phase is, which is an aqueous component and also an irreversible coating component from a long-chain Has polymer that has surface activity and the ability to gel or chain the chain, wherein the aqueous inner phase of the LMC is citric acid, which removes ammonia from the dialysis fluid, Devices for guiding the dialysis fluid and the suspended LMC over activated carbon and phosphite ion exchange materials into a contact zone that removes the other toxins from the dialysis fluid and ^ 09831/0888 BATH ORIGINAL Remove the LMC and facilities for returning the dialysis fluid and LMC to the membrane, or facilities for guiding the peritoneal saline solution or the plasma contacted with the LMC into a Contact zone containing immobilized urease, activated carbon and phosphate ion exchange material ■ containing urea to ammonia, which is removed by the LMC and removes other toxins from the saline or plasma, means for separating the plasma or saline from the LMC, means for returning the plasma to the blood or the saline to the abdominal cavity ^and devices to recycle the recovered LMC and contact it with another volume of peritoneal saline or plasma for treatment. The hemodialysis device of claim 1 wherein blood is passed by the patient over one side of the dialysis membrane, which diffuses toxins from the blood, whereby the Toxins are absorbed through the dialysis fluid on the other side of the membrane and being purified Blood is returned to the patient, characterized by a suspended in the dialysis fluid stabilized coalescence-resistant5 liquid membrane capsule system (LMC) containing an aqueous inner phase which is separated from a non-aqueous outer oil phase is surrounded and thereby forms an emulsion which is suspended in an aqueous suspension phase, one aqueous component and also an irreversible coating component made from a long-chain polymer 809831/0888 which has surface activity and the ability to gel or chain the chain wherein the aqueous internal phase of the LMC is citric acid which removes ammonia from the dialysis fluid. Means for passing the dialysis fluid and the suspended LMC over activated carbon and phosphate ion exchange materials, which remove the converted ammonia and solids from the suspended LMC to the dialysis membrane, the LMC reducing the volume of the dialysis fluid used by about 99%. Apparatus according to claim Λ for cleaning the saline solution used in peritoneal dialysis, characterized by devices for contacting the toxin-laden saline solution withdrawn from the body with an improved stabilized coalescence-resistant liquid membrane capsule (LMC) containing an aqueous inner phase which is not of a non aqueous outer oil phase is surrounded and thereby forms an emulsion which is suspended in an aqueous suspension phase which has an aqueous component and also an irreversible coating component made of a long-chain polymer that has surface activity and the ability to gel or to crosslink the chain, wherein the aqueous internal phase of the LMC is citric acid, means for circulating the saline solution containing the LMC over a bed of immobilized urease, activated carbon and phosphate ion exchange material into a contact zone wherein the urea is converted to ammonia, the is removed by the LMC and the saline of other toxins 909831/08 88 and means for separating the saline solution from the LMC and recycling the purified Saline to the abdominal cavity while the recovered LMC with a different volume of peritoneal Saline solution is contacted for treatment. . Apparatus for hemofiltration according to claim Λ , wherein blood from the patient is passed over one side of an ultrafiltration membrane, wherein the side of the membrane which is opposite the side contacted with blood is kept under lower pressure than the contact side, whereby an ultrafiltrate through the Membrane is performed, which consists essentially of a plasma depleted in high molecular weight proteins, but contains a substantial concentration of toxins, characterized by means for suspending an improved stabilized coalescence-resistant.Plussig-Membrankapsi (LMC) in the ultrafiltrate, where, at the capsule a aqueous inner phase which contains from a non-aqueous outer Is surrounded by the oil phase and thus forms an emulsion, which is suspended in an aqueous suspension phase, which is an aqueous component and also an irreversible one Coating component made from a long chain polymer, which has surface activity and ability possesses to gel or to crosslink the chain in which the aqueous inner phase of the LMC is citric acid, Equipment for guiding the ultrafiltrate and the suspended LMC over immobilized urease, activated carbon and phosphate ion exchange material in a contact zone, wherein the urea is converted to ammonia which is removed by the LMC and the ultrafiltrate cleansed of other toxins, facilities for 909831/0888 2303894 Separating the purified ultrafiltrate and the discarded from the contact zone LMC and facilities for Returning the purified ultrafiltrate to the blood, the LMC being circulated and with another Volume of ultrafiltrate is contacted. 5. Apparatus according to claim 1, characterized in that that as an irreversible coating component of the LMC sodium carboxymethyl cellulose, hydroxypropyl cellulose, Xanthan gum or albumin can be used. 6. Apparatus according to claim 5, characterized in that that the stabilized liquid membrane capsule also in the aqueous suspension phase, in addition to the aqueous component and the irreversible coating component, contains a salt which has a trivalent cation or has a divalent heavy metal cation. 7. The device according to claim 6, characterized in that the salt used in the stabilized liquid membrane capsules Al "(SO ₄ ) ₃ · 18H .-, O, aluminum acetate, aluminum hydroxide, trivalent or divalent heavy metal cation salt of copper, silver, iron, uranium , Chromium, tin, lead or zirconium, wherein the ratio of irreversible coating component to salt on a weight basis is 50: 999. 909831/0888 8. Apparatus according to claim 7, characterized in that the irreversible coating component is sodium carboxymethylcellulose _{and the salt Al 2} (SO ₄ J _{3 -ISH 2} O) in the stabilized liquid membrane capsules. 909831/0888