This invention relates to a filter device and method for treating
parenteral fluids. More particularly, this invention relates to a filter device
and method for treating parenteral nutrient admixtures.
Individuals at risk of malnutrition or who are unable to obtain sufficient
nutrients by enteral means must be fed intravenously. The use of total parenteral
nutrition (TPN) - the administration of nutrients via a peripheral or central vein
- has grown rapidly over the past several years. Unfortunately, infection is a
potential major complication of TPN. This is of particular concern with malnourished
and debilitated patients with compromised immune systems.
Microbiologic contamination of TPN mixtures may occur during preparation
of the mixture, during administration, or via manipulation of the catheter. Accordingly,
a total nutrient admixture (TNA) which contains all daily nutritional requirements
in a single container is highly desirable because of the reduced likelihood of
contamination due to the reduced number of manipulations of the intravenous delivery
system. Reduced work loads of health care personnel are also a positive result
of the use of single container TNA systems vis-a-vis conventional TPN systems
requiring multiple nutrient containers. Typically, a TNA admixture contains three
primary components: lipids in the form of an emulsion, glucose, and amino acids.
Other components may include electrolytes, trace elements, and vitamins. The lipid
emulsion is typically stabilized by an emulsifying agent such as a phospholipid
which the filtering medium should not absorb.
While TNA systems offer the benefits noted above, one potential drawback
is that the TNA system provides a better growth media for potentially pathogenic
microorganisms. For example, the growth of fungal organisms, such as
Candida albicans, in parenteral nutrient formulations poses an infectious
threat because they are able to thrive in a variety of nutrient systems. Further,
while Candida albicans has been shown to proliferate in both conventional
TPN formulations and TNA admixtures, in at least one study growth was found to
be stimulated in TNA admixtures. Similarly, studies have shown that TNA systems
support bacterial growth significantly better than conventional TPN solutions.
In addition to the problems noted above, the lipid emulsion component
results in the TNA admixture being opaque, making proper inspection of the mixture
impossible. This may lead to a variety of problems including undetected fat particles
having a size ranging from a few to as large as about 20 micrometers in diameter,
creating the danger of fat embolus.
While problems with TNA systems have been recognized for some time,
the benefits of such systems have been found to outweigh the attendant difficulties,
and their use has grown at a rapid rate. At present, in the vicinity of 80% of
all TPN deliveries in Western Europe are in the form of TNA. The use of TNA systems
also continues to expand in both the United States and Japan. Accordingly, there
is an ongoing and growing need for means to alleviate difficulties with the use
of TNA systems.
Attempts to alleviate the problems associated with TNA systems have
focused on the use of membrane filters with pore ratings of 1.2 micrometers. While
such filters are presently being used, they suffer from limitations. Specifically,
such filters have limited flow capacity such that they exhibit excessive pressure
buildup and plugging with concomitant limited onstream filter life. Excessive
pressure build up is a serious problem with parenteral nutrient systems since the
liquid nutrient is typically administered using a pump designed only to operate
at relatively low pressures, e.g., less than 1.76 x 10&sup4; kg/m² (25 psi), typically
less than 1.05 x 10&sup4; kg/m² (15 psi), and, in many applications, at less than
0.70 x 10&sup4; kg/m² (10 psi). Because these pumps are not engineered to operate
at higher pressures, the parenteral fluid administration system typically includes
an occlusion alarm which shuts down the pump at a relatively low pressure. Accordingly,
excessive pressure build up and plugging of a filter device is a potentially serious
problem. Additionally, membrane filters with pore ratings of 1.2 micrometers provide
only limited ability to remove fine particulate and microbiological contaminants.
There is, therefore, a need for a filter device having an enhanced
capability for filtration of fine particulate matter and microorganisms and having
the capability of removing significant amounts of bacteria, the capacity to remove
pyrogenic matter, such as bacterial endotoxins, and which, in addition, has a
relatively high volumetric capacity, typically up to 3 liters of TNA at a flow
rate of up to about 300 milliliters per hour, coupled with low pressure drop and,
thus, good onstream life. Ideally, such a device would also have a relatively
small hold up volume of about 5 cubic centimeters or less.
In accordance with this invention, a filter device for treating parenteral
nutrient fluids, more particularly lipid-containing parenteral nutrient fluids,
is provided comprising a housing including an inlet and an outlet and defining
a fluid flow path between the inlet and the outlet and a liquid filtration element
comprising a synthetic, polymeric microporous structure having a pore rating of
less than 1.2 micrometers positioned inside the housing across the flow path.
In a preferred device, the microporous liquid filtration element
comprises first and second filter media in series. The first or upstream microporous
medium is preferably a matrix of microfibers followed by a second or downstream
microporous medium with a finer pore rating than the first medium and less than
1.2 micrometers, both media preferably being wettable by the parenteral nutrient
fluid. Additionally, a preferred device also comprises one or more non-wetting
or liquid-repellant microporous structures to provide for gas/liquid separation
via gas venting.
In accordance with the invention, parenteral nutrient fluid, more
particularly lipid-containing parenteral nutrient fluids such as TNA admixtures,
is treated by passing it through a liquid filtration element comprising a synthetic,
polymeric microporous structure having a pore rating of less than 1.2 micrometers.
Preferably, the element comprises first and second filter media in series with
the second or downstream filter medium having a pore rating of less than 1.2 micrometers
and being finer than that of the upstream medium.
In the accompanying drawings:
- Figure 1 is a top plan view of a filter device embodying the invention in which
there are two liquid-repellant structures, one on each side of a liquid filtration
- Figure 2 is a bottom plan view of the filter device of Figure 1;
- Figure 3 is a longitudinal sectional view taken along the line III-III of the
device of Figure 1; and
- Figure 4 is a cross-sectional view taken along the line IV-IV of the device
of Figure 1.
The present invention provides for a filter device for treating parenteral
nutrient fluid containing a lipid comprising: (1) a housing including an inlet
and an outlet and defining a fluid flow path between the inlet and the outlet;
and (2) a liquid filtration element positioned inside the housing across the flow
path comprising a synthetic polymeric microporous structure having a pore rating
of less than 1.2 micrometers and adapted to remove fine particulate and biological
contaminants from the parenteral nutrient fluid.
The present invention also provides for a filter device for treating
parenteral nutrient fluid containing a lipid comprising: (1) a housing including
a fluid inlet and a liquid outlet and defining a liquid flow path between the fluid
inlet and the liquid outlet, the housing further including a gas vent outlet and
defining a gas flow path between the inlet and the gas vent outlet; (2) a liquid
filtration element positioned inside the housing across the liquid flow path, the
liquid filtration element comprising a synthetic, polymeric, microporous structure
having a pore rating of less than 1.2 micrometers and adapted to remove fine particulate
and biological contaminants from the parenteral nutrient fluid with a pressure
drop of about 1.05 x 10&sup4; kg/m² (15 psi) or less while passing the parenteral
nutrient fluid at a flow rate of up to about 300 milliliters per minute; and (3)
a non-wetting, liquid-repellant, microporous structure positioned inside the housing
across the gas flow path adapted to vent gas from the parenteral nutrient fluid.
The present invention further provides for a method for treating
a parenteral nutrient fluid containing a lipid comprising passing the parenteral
fluid through a liquid filtration element comprising a synthetic polymeric microporous
structure having a pore rating of less than 1.2 micrometers.
A filter device for treating parenteral fluids embodying the invention
generally comprises a housing including an inlet and an outlet and defining a
fluid flow path between the inlet and the outlet and a liquid filtration element
comprising a synthetic, polymeric microporous structure positioned inside the
housing across the flow path. In a preferred embodiment of the filter device, the
liquid filtration medium is wettable by the parenteral fluid and is comprised
of first and second media, the filter device further comprising a microporous
non-wetting or liquid-repellant component to provide for gas/liquid separation.
The liquid filtration element preferably comprises two media in series.
The first or upstream medium is characterized by a pore rating of greater than
that of the second or downstream medium. Preferably, the first medium comprises
a synthetic polymeric microfibrous matrix. The first medium is preferably wettable
by the parenteral fluid. A preferred way of rendering the first medium wettable
is by covering the surfaces of the medium with a grafted superstrate polymer (that
is, a layer of polymer formed at and covering the surfaces of the medium) to render
the medium wettable by the liquid with which it comes in contact in carrying out
the method of this invention.
The second or downstream medium is characterized by a pore rating
of less than 1.2 micrometers. In a preferred embodiment, the second medium comprises
a microporous structure having a pore rating of less than about 1.0 micrometer,
more preferably in the range of from 0.5 to 0.8 micrometer. As with the first
medium, it is preferred that the second medium be wettable by the parenteral fluids
with which it comes in contact. A variety of synthetic, polymeric, microporous
structures may be used as the second or downstream medium provided they do not
adversely affect the parenteral fluid being filtered, e.g., by releasing harmful
components into the fluid, and they have the requisite physical properties to provide
the desired filtration characteristics. Preferred materials include skinless,
hydrophilic, microporous, polyamide membranes of the type described in U. S. Patent
4,340,479. Particularly preferred are skinless, hydrophilic, microporous nylon
66 membranes of this type available from Pall Corporation under the trademark
ULTIPOR®. Microporous polyvinylidene difluoride membranes of the type disclosed
in U. S. Patents 4,203,848 and 4,618,533 may also be used as may microporous media
with low non-specific protein adsorption, such as those described in U. S. Patents
4,886,836, 4,906,374, and 4,964,989. Charge-modified polyamide membranes with
a positive zeta potential in alkaline media, such as those described in U. S. Patent
4,702,840 and available from Pall Corporation under the trademark BIODYNE B®
may also be used. Polyamide membranes with controlled surface properties such
as those described in U. S. Patent 4,707,266, as well as other microporous, synthetic,
polymeric structures with the requisite pore rating including microfibrous matrices,
may also be used.
As noted above, it is preferred that the liquid filtration element
be wettable by the parenteral nutrient fluid. In those instances where the medium
is not wettable by the parenteral nutrient fluid, it may be rendered wettable
by any method which does not adversely affect the filtration process. In addition
to radiation grafting, suitable surface active agents, such as polyether polyhydroxy
block copolymers, may be employed.
The liquid filtration element of the present invention is preferably
in the form of a flat web or sheet, although other forms including pleated, cylindrical,
or other geometric shapes suitable for incorporation into a filter may be used.
When the liquid filtration element comprises first and second media, a composite
filter sheet may be formed and used as a flat, planar sheet. Alternatively, the
composite sheet may be formed into a pleated or accordion form and used in that
form. As another less preferable alternative, the first and second filter media
can be formed as separate sheets which can be used independently in a series arrangement.
The liquid filtration element has a pore rating of less than 1.2 micrometers,
preferably less than about 1.0 micrometer, more preferably from 0.5 to 0.8 micrometer.
Particularly preferred as a second or downstream medium are hydrophilic microporous
nylon 66 membranes with a pore rating of about 0.65 micrometers.
A microfibrous matrix, as the term is used herein, indicates a three-dimensional
network of interconnected fibers, whether melt-blown, staple, or continuous, which
together form a coherent structure suitable for use as a filter medium. Preferred
microfibrous matrices are made from melt-blown thermoplastic polymeric fibers,
such as polyolefins, particularly polypropylene, polyesters, particularly polybutylene
terephthalate, and polyamides, such as nylon 66, where the fiber diameter is typically
in the range of from 1 to 4 micrometers, typically having void volumes ranging
from 60 to 90% and thicknesses in the range of from 0.13 to 2.54 mm (0.005 to
While a liquid filtration element comprising two media is preferred,
the element may consist of a single medium. When a single medium is used, a microfibrous
matrix is preferred because of the enhanced dirt capacity of such a structure
a microporous membrane formed from a synthetic plastic material
having a continuous matrix structure and which has, relative to a microfibrous
matrix, relatively uniform pore sizes and limited dirt capacity, making it more
prone to pressure build up and clogging.
Pore ratings, as that term is used herein, may be determined using
the Latex Sphere Test. This test determines the removal rating of a filtration
medium by measuring the efficiency of the medium in removing uniform diameter
polystyrene microspheres in a liquid medium. Typically, a dilute suspension of
spheres (0.01 to 0.1 weight percent) is prepared in water containing 0.1 weight
percent Triton X-100, an octyl phenoxypolyethoxyethanol with about nine and one-half
ethylene oxide units per molecule, available from Rohm & Haas Company. The
size of the spheres can vary from 0.038 to 5 microns. They are commercially available
from Dow Chemical Company. A volume of about 10 cubic centimeters of the suspension
per 6.45 cm² (per square inch) (of the filtration medium) is passed through the
medium and the filtrate is collected in a test tube. The concentration of microspheres
in the filtrate can be measured by any number of means, for example, visually,
or by use of a nephelometry device (i.e., turbidity meter). The smallest diameter
microsphere which is retained at a 99.9% efficiency, i.e., 999 out of 1,000, determines
the pore rating.
The filter device of the subject invention preferably further comprises
a liquid-repellant or non-wetting component or structure acting in concert with
the liquid filtration element which, as noted above, is preferably wetted by the
parenteral nutrient liquid.
Any liquid-repellant or non-wetting porous material may be used which
is effective in repelling and, therefore, does not pass a liquid under the conditions
encountered in carrying out the method of this invention, thereby providing for
venting of gas which may be present in the parenteral nutrient fluid to be filtered.
Generally, the pore size of such a material should be less than about 15 micrometers.
To preclude bacteria from entering the device via the liquid-repelling structure
of the filter device (which in use must be open to the atmosphere to allow the
gas to be vented), the pore size should be less than about 0.3 micrometer, preferably
0.2 micrometer or less. Preferred materials are the liquid-repelling membranes
disclosed in U. S. Patent 4,954,256. These membranes have a critical wetting surface
tension (CWST) of less than about 28 dynes/centimeter, rendering them liquid-repelling
or non-wetting by liquids with surface tensions well below that of water's surface
tension of 72 dynes/centimeter. CWST is defined in U. S. Patent No. 4,954,256,
and in greater detail in U. S. Patent No. 4,925,572. Of these, particularly preferred
is a microporous, polymeric membrane having a pore rating of about 0.2 micrometer
comprising a nylon 66 membrane substrate to which has been bonded to the surface
a superstrate fluoropolymer formed from a monomer containing an ethylenically
unsaturated group and a fluoroalkyl group.
The housings for the porous medium can be fabricated from any suitably
impervious material, including any impervious thermoplastic material. For example,
the housing may preferably be fabricated by injection molding from a transparent
or translucent polymer, such as an acrylic, polystyrene, or polycarbonated resin.
Not only is such a housing easily and economically fabricated, but it also allows
observation of the passage of the fluid through the housing.
The filter device in accordance with this invention may be fashioned
in a variety of configurations including those described in U. S. Patent 3,803,810.
Preferably, the device will have a hold up volume of 20 cubic centimeters or less.
A preferred configuration, as depicted in Figures 1-4, can be constructed with
a hold up volume of less than 5 cubic centimeters. Indeed, a device as described
in Figures 1-4 was used in Example 1 below which had a hold up volume of only about
1.5 cubic centimeters.
Referring, then, to the drawings, a preferred general configuration
is shown in Figures 1-4 which depict, in schematic form, the components of a filter
device in accordance with the invention and which show the flow paths of the liquid
and of gas which is separated from the liquid and vented to the atmosphere.
In Figures 1 to 4, a filter device 10 embodying the invention generally
comprises a transparent housing 11 and a liquid filtration element 12 positioned
within the housing 11. In the liquid filtration element depicted in the drawings,
the liquid filtration element 12 comprises a first filter medium 13 and a second
filter medium 14 in flat, planar composite filter sheet form.
The housing may have a variety of configurations. Preferably, liquid
hold up volume is minimized. As depicted in the drawings, in a preferred device,
an inlet 15 communicates with a first chamber 16 which is in fluid communication
with the liquid filtration element 12 as well as with two non-wetting or liquid-repellant
microporous structures 17 and 18 which allow gas to be vented from the device.
The housing 11 includes an inlet 15 and an outlet 19 defining a fluid
flow path between the inlet 15 and the liquid outlet 19 with the liquid filtration
element 12 disposed across the liquid flow path. The inlet and outlet may be variously
configured. For example, the inlet 15 may be configured as a spike which can be
inserted into a container of parenteral fluid. Alternatively, as shown in the
drawings, both the inlet and the outlet can be configured as tube connectors. In
addition to the chamber 16 depicted in Figures 3 and 4, the housing 11 has interior
walls 20 and 21 which, in combination with the exterior walls for the housing
11, the liquid-repellant, microporous structures 17 and 18, and the liquid filtration
element 12, define three additional chambers 22, 23, and 24. Chambers 22 and 24
include gas vents or outlets 25 for venting to the atmosphere gas separated from
the incoming parenteral nutrient fluid.
The flow of parenteral nutrient liquid in the filter device 10 after
entry of the parenteral nutrient fluid via the inlet 15 is depicted in Figure
3 by arrows in the chambers 16 and 23. As depicted in Figure 3, the liquid component
of the parenteral fluid entering inlet 15 passes into the chamber 16, then through
the liquid filtration element 12 into chamber 23, and then flows out of the filter
device via the outlet 19.
The flow path of gas that may be present in the incoming parenteral
nutrient fluid is depicted in Figure 4 by arrows in chambers 16, 22, and 24. As
depicted, the gas enters the chamber 16 and passes freely through the non-wetting
or liquid-repellant structures 17 and 18 into the chambers 22 and 24 and then
out the gas outlets or vents 25.
The invention will be better understood by reference to the following
examples which are offered by way of illustration and not by way of limitation.
A microfibrous matrix comprised of approximately 1.6 micrometer diameter
polypropylene fibers having a basis weight of 4.5 milligrams per square centimeter
was prepared by melt blown fiber extrusion. A final web thickness of about 0.08
mm (0.003 inch) was achieved by hot calendering using commercially available calendering
equipment. The microfiber web was then surface modified in order to render it
hydrophilic. Gamma radiation (Cobalt 60) was used to graft co-polymerize hydroxypropyl
acrylate and methacrylic acid in a monomer ratio of 9:1 with the polypropylene
fiber surface and render the matrix wettable by a TNA parenteral admixture. A
liquid filtration element in the form of a flat sheet comprising two layers of
this grafted web and having a pore rating of 0.8 micrometer was assembled into
the device described (in Figure 1) which had a hold up volume of about 1.5 cubic
centimeters and an effective liquid filtration surface area of about 10.97 cm²
(1.7 square inches). The two non-wetting or liquid-repellant structures were polytetrafluoroethylene
membranes with a nominal pore rating of 0.1 micrometer, each of about 0.97 square
centimeters (0.15 square inch). This device was then subjected to a filtration
test using 2.7 liters of a typical central formula TNA admixture which contained
amino acid, dextrose, a lipid emulsion, a multi-vitamin solution, and electrolytes.
Flow was provided by means of a peristaltic pump at a rate of 300 milliliters
per hour, and the upstream applied pressure (effectively the pressure drop across
the liquid filtration element) was monitored by means of a gauge upstream of the
filter device. Throughout the duration of the test (2.7 liters total volume),
the pressure did not rise significantly and remained between 5.6 X 10³ kg/m²
and 6.3 X 10³ kg/m² (8 and 9 psi).
A microporous polyvinylidene fluoride (PVDF) membrane was solution
cast under conditions which produced a 0.65 micrometer pore rating in its dry,
unmodified state. A liquid filtration element in the form of a disc having a diameter
of 2.86 cm. (1.125 inches) was cut from this membrane and assembled into a reusable
plastic housing jig having an effective flow area of 4.97 cm² (0.77 square inch).
The membrane was prewetted in isopropyl alcohol prior to use since it was not wetted
spontaneously by the TNA solution. The membrane was then tested for the filtration
of TNA formulation of the same composition and in the same manner as in Example
1 except that flow was provided by means of a volumetric infusion pump (Model IMED
960 available from IMED Corporation) and the flow was adjusted to 150 milliliters
per hour. During this test, the pressure was observed to increase steadily. At
170 milliliters of total volume throughput, the upstream pressure exceeded 1.05
x 10&sup4; kg/m² (15 psi), the pump alarm sounded, and the pump shut down, ending
The filtration test of Example 2 was repeated except that a prefilter
consisting of a surface modified, polybutylene terephthalate polyester microfiber
matrix microporous medium was positioned as a prefilter in the housing upstream
of the downstream or second filter medium (PVDF membrane). The microfiber matrix
was modified using a mixture of hydroxyethyl methacrylate and methacrylic acid
in a monomer ratio of 0.35:1 using gamma radiation from a Cobalt 60 source. The
prefilter had a voids percent of about 72%, a CWST equal to 94 dynes per centimeter
rendering it readily wettable by the TNA formulation, an average fiber diameter
of 2.4 micrometers, and a pore rating of about 2 micrometers. After pre-wetting
of the PVDF membrane as in Example 2, a filtration test gas run using a portion
of the same TNA formulation used in Example 2. The same flow rate as in Example
2, 150 milliliters per hour, was also used. In contrast to Example 2, 620 milliliters
of TNA solution were filtered without exceeding a pressure of about 4.9 X 10³
kg/m² (7 psi). In particular, the pressure leveled off at about 4.2 X 10³
kg/m² (6 psi) after 170 milliliters of TNA had been filtered and remained relatively
constant for the entire remaining volume of filtered TNA admixture. The results
clearly demonstrates the beneficial effect of the prefilter section which resulted
in a significantly lower applied pressure and thus a larger volume filtered.
A nylon 66 membrane having a pore rating of 0.65 micrometer was tested
in the same manner as was used in Example 2 except that the TNA admixture did
not contain multi-vitamins and no prefilter section was utilized. The results showed
the pressure drop to rise consistently as the TNA formulation was filtered. After
270 milliliters volume of throughput, the pressure exceeded 1.05 x 10&sup4; kg/m²
(15 psi) and the pump stopped.
The same TNA admixture was used as in Example 4 to test the membrane
and prefilter combination described below and the same test method was also used.
The prefilter was the same as that used in Example 3 and the membrane was the same
as the nylon 66 membrane used in Example 4. The results showed that the pressure
drop leveled off at about 3.16 x 10³ kg/m² (4.5 psi) and did not rise significantly
(only about 0.70 X 10³ kg/m² (1 psi)) over the test period during which a
total volume of 1.5 liters was filtered. A comparison of Examples 4 and 5 reveals
the benefit of the prefilter in the latter example which greatly extends the volume
of the TNA admixture that can be filtered without excessive pressure build up.
Examples 4 and 5 demonstrate the benefits derived from the use of
A particularly preferred filter device in accordance with the subject
invention has the configuration depicted in Figures 1-4 and utilizes a hydrophilic
nylon membrane with a pore rating of about 0.65 micrometer in combination with
a prefilter as described in Example 3 above and two non-wetting or liquid-repellant
structures of a nylon 66 membrane having a CWST of less than 28 and a pore rating
of about 0.2 micrometer. Preparation of such a liquid-repellant membrane is described
in U. S. Patent 4,954,256.
While the invention has been described in some detail by way of illustration
and example, it should be understood that the invention is susceptible to various
modifications and alternative forms and is not restricted to the specific embodiments
set forth in the Examples. It should also be understood that these Examples are
not intended to limit the invention but, on the contrary, the intention is to
cover all modifications, equivalents, and alternatives falling within the spirit
and scope of the invention.