Mixing device

A mixer for the mixing of components, comprising a continuous inner surface that is non-retaining to the components, wherein a first portion of the inner surface opposably contacts a second portion of the inner surface during mixing, and a means for supplying a component to the mixer; a kit including the mixer, and methods of using the mixer to prepare compositions.

BACKGROUND OF THE INVENTION 
The field of the invention is containers for shipping, storing, and 
activating biologically active powders. One such powder is bioceramic 
precursor powder which is mixed with a liquid to form a paste which is 
inserted where needed to make synthetic bone. 
SUMMARY OF THE INVENTION 
The invention features a mixing area or portion having a continuous inner 
surface that is non-retaining to the components to be mixed, wherein a 
first portion of the inner surface opposably contacts a second portion of 
the inner surface during mixing. For example, the mixing area or portion 
can be a flexible mixing pouch which has a continuous inner surface that 
is non-retaining to the components, wherein a portion of the inner surface 
opposably contacts another portion during the mixing of two or more 
components. The disclosed mixer devices include the mixing area or portion 
(e.g., the device can include a mixing pouch wherein a portion of the 
pouch has a continuous inner surface that is nonretaining) and a means for 
supplying one or more additional components to the mixing pouch for mixing 
with a first component. In use, the mixing pouch generally includes a 
pre-measured amount of the first component. For example, the first 
component can be contained within the pouch and be a medically useful 
substance or mixture, and a second component can be a liquid. The first 
component can include a powder, such as a bioceramic precursor powder. 
In one embodiment, the means for supplying the second component to the 
pouch includes a neck attached to the pouch. The neck can be removably or 
permanently attached to the pouch. The supplying means can further include 
additional features such as a cap, plug, or cover for the neck; a needle 
port or needle penetrable material on the pouch or on the neck; a needle 
or tube attached to the pouch, the neck, or a valve opening; a manual 
valve or a check valve attached to the pouch or the neck; a protecting 
member and a handling means, including a holder or cartridge; a permeable 
membrane; a frangible membrane attached to the inner surface of the neck 
or the pouch; or a combination thereof. A valve can be a one-way valve or 
a multiple-way valve. One embodiment includes a retaining structure 
attached to the inner surface of the neck. Thus, after the frangible 
membrane is broken, the retaining structure separates pieces of the broken 
frangible membrane from the components to be mixed. The mixer can be 
adapted to be used with a mechanical mixing device, or to be manually 
mixed. 
After mixing, the mixed contents of the pouch is removed. In one 
embodiment, the pouch can be opened with a cutting instrument, such as a 
knife or scissors. Alternatively, the mixer device can be adapted to 
include a means for evacuating or expelling the mixed components, such as 
a bioceramic paste, from the mixing pouch. Such expelling means include a 
valve attached to the neck through which mixed components can be ejected. 
The valve through which mixed components are ejected can also be a means 
for supplying a second component. The same or different valve openings can 
be used to introduce and expel material. The expelling means can include a 
needle or a tube attached to the pouch, the neck, or a valve. Mixed 
components can thereby be ejected through the needle or tube. 
A preferred embodiment includes a single neck attached to the mixing pouch. 
The neck is configured for introducing a second component into the mixing 
pouch and for expelling mixed components from the pouch. The mixing pouch 
is preferably formed of an elastic material and can be sterilized. 
The invention also features a method for preparing a medically useful 
composition, such as a bioceramic paste, using the disclosed mixer. The 
method includes a) providing a disclosed mixer wherein the first and 
second components are in sterile form; b) introducing the second 
component, e.g., a liquid, through the supplying means; c) mixing the 
combined components in the mixing pouch; and d) removing the components 
from the pouch. The disclosed mixer can be, for example, a mixer including 
a first component which is medically useful and a second component which 
is a liquid. 
Another embodiment of the invention is a kit that includes: a) a disclosed 
mixer wherein the first component is in sterile form; and b) a syringe 
containing the second component in sterile form. The first and second 
components are preferably premeasured. A third or a third and fourth 
component may be included. 
The invention facilitates the complete mixing of a powder and a liquid. The 
single piece construction of the device means that there are no seams or 
comers in the pouch where unmixed material might otherwise be trapped. 
Another advantage of the mixer of the invention is that it is inexpensive 
to produce, which is especially advantageous in light of the fact that it 
is intended to be disposable. 
Other features and advantages of the invention will be apparent from the 
following description of the preferred embodiments thereof, and from the 
claims.

DETAILED DESCRIPTION 
The invention relates to a mixing device having a mixing area or mixing 
portion with a continuous inner surface that is non-retaining with respect 
to the components to be mixed. The mixing portion also has opposable sides 
that intermittently or temporarily contact each other during manual or 
mechanical mixing. A mixing area is the portion of the mixing device which 
comes into contact with the combined materials to be mixed. In one 
preferred embodiment, the mixing device comprises a pouch, wherein the 
pouch includes a mixing area having a continuous inner surface that is 
non-retaining with respect to the components to be mixed. 
In the mixing process, two functions must occur: the movement of the pouch 
material in opposition to itself should be easily performed, in most cases 
by hand, and there must be no structures or features within or on the 
inner surface of the pouch which would tend to trap one or more of the 
components to be mixed or otherwise deleteriously affect the mixing 
process and result in incomplete mixing. Since the pouch is flexible, 
these same considerations apply to the outer topography of the pouch, as 
they can affect the shape of the pouch inner surface during the mixing 
process. Pouch designs meeting the above criteria are said to have a 
mixing area with a non-retaining inner surface. The features of the inner 
pouch surface should not significantly hinder the evacuation of the mixed 
components or reaction products therefrom. 
The requirements regarding the surface topography and geometry to produce a 
non-retaining surface can vary, depending on the type of components to be 
mixed. For example, in the case of dry powders, preferred pouches will be 
smooth and free of entrapping edges, pits, corners, or seams. In other 
embodiments, one or more of these potentially entrapping features may be 
present, provided their dimensions are significantly smaller than the 
grain or particulate size of the powder. Thus mixing of powders with a 
minimum particle size of 100 .mu.m diameter would not be adversely 
affected by the presence of 1 .mu.m diameter pits or 1 .mu.m high edges. 
In the case of the mixing of low viscosity liquids or gases, edges may be 
tolerated provided they are not so severe as to hinder pouch movement 
during mixing or hinder the evacuation process. 
Structure 
FIG. 1 illustrates a preferred embodiment of a mixer 10. Bioceramic 
precursor powder 11 is held inside a pouch 12 which is formed of one piece 
of flexible elastic material, which might be, for example, polyurethane, 
silicone, Krayton, polyethylene, rubber latex, or another elastomer. Neck 
14, with mouth 15, is formed of the same piece of material as pouch 12. 
Pouch 12 and neck 14 are formed so as to have no seams which might hinder 
the uniform mixing of powder 11. A protective insert 16 made, for example, 
of polypropylene tubing, may be used to reinforce neck 14. A stopper 18, 
preferably made of rubber, closes the mouth 15. The dimensions of mixer 10 
are: height of pouch 11: 4.5 cm; height of neck 14: 4.5 cm; width of 
pouch: 0.3 cm; volume of pouch, not including neck: 15 ml. Alternative 
measurements are: height of pouch: 3.4 cm; height of neck: 3.4 cm; width 
of pouch: 1.3 cm; volume of pouch: 5 ml. 
Manufacture 
There are several ways to manufacture mixer 10 using known container 
manufacturing techniques. For example, the mixer can be injection molded, 
dipping molded, rotational molded, or blow molded. All of these methods 
are conventional and well-known and need not be described herein. 
The pouch 12 should be made of a flexible material. The pouch has opposable 
sides which contact each other when the pouch is manually or mechanically 
compressed during mixing. In some instances, the pouch should be flexible 
enough to be compressed by hand. In other embodiments, where mixing is 
carried out by a mechanical or other non-manual approach, a more rigid 
(although still somewhat flexible) material may be employed. In some 
embodiments, the entire inner surface of the device is non-retaining. 
The neck 14 may be manufactured to be continuous with pouch 12, or may be 
affixed separately. The neck may be of any useful length and does not 
generally participate in the mixing function, but rather provides a means 
for the storage of additional components, means for introducing components 
to be mixed, means for expelling the mixed components, and space to add 
additional features such as caps, labels, handles, injection ports, vents, 
attachments and the like. 
Any form of attachment between the neck and the pouch may be used as long 
as it does not tend to trap components to be mixed or adversely interfere 
with the entry or evacuation of components into or out of the mixing area 
of pouch 12. The requirements for materials used in manufacturing the 
neck, or the means of attaching the neck to the pouch will be dictated by 
the intended functionality of the neck. The neck may be manufactured 
continuously with the pouch as a single entity, or may be attached to the 
pouch by any suitable means such as but not limited to a connector 
attached to the pouch by glue, compression fitting, friction fitting, or 
threads. The connector may be a distinct piece or continuous with either 
the pouch or the neck. 
Additional features attached to the neck or the pouch include protective 
inserts, caps, ports, check valves, manual valves, vents, plugs, needles, 
cartridges, handles, labels, and holders. Manufacture and attachment of 
such additional features will be guided by considerations known in the 
art. The sealed mixer may be sterilized if required. 
In the general construction of the mixer, multiple bulbs may be joined at 
the neck to allow discrete mixing steps. Mixtures in different bulbs can 
then later be combined. The mixer can be used to mix not just bone paste, 
but a variety of materials. The mixer is not limited to holding a powder, 
but can be used to mix liquids, pastes, powders, or combinations. The 
mixer may also include venting means for gases produced by chemical 
reactions of mixed components. 
Use 
The disclosed mixer allows for the storage, shipping, combining and mixing 
of components without the need for opening the package prior to mixing. 
Thus the invention is particularly well suited for the shipment of sterile 
powders for sterile reconstitution with liquids or sterile mixing with 
other powders without the risk of contamination. In one embodiment, a 
mixer of the invention is used as a package for shipping, storing, and 
mixing a bioceramic precursor powder for use as a surgical synthetic bone 
replacement material which is stored in powder form and mixed with a 
liquid immediately before use to form a paste. Many bioceramic precursor 
powders are known, e.g., those disclosed in U.S. Pat. No. 5,178,845, 
hereby incorporated by reference. 
The mixer is shipped from a manufacturer to a medical center in the form of 
a kit which includes a sterile pre-filled syringe and needle containing 
sterile water or buffer. The mixer is sealed and sterile, and contains the 
bioceramic precursor powder. The kit also optionally includes a spatula 
and/or syringe for the application of the paste by the user, and an 
optional portable mechanical mixer. The mixer and powder are stored in a 
medical facility until needed. When there is a surgical procedure where 
synthetic bone is needed, liquid is injected into the pouch through the 
neck above the end of the protective member present on the stopper and the 
powder-liquid mixture is mixed by hand while still inside the pouch. When 
the components are mixed sufficiently to form a paste, the neck is cut, 
and the paste is squeezed out of the pouch into a syringe or a petri dish, 
depending on the surgical requirements. The mixer is discarded after 
extrusion of the paste. 
Referring to FIG. 1, in mixer 10, the neck includes a reservoir 19 
containing a component 20 to be mixed with a second component 11 within 
the pouch. The frangible seal 21 between the storage compartment and the 
pouch insures separation of the components during shipping and storage. 
Component 20 is introduced into the pouch by breaking the frangible seal 
21, and transferring component 20 into the pouch, where mixing is carried 
out (see also FIGS. 7A-7D). Similarly, component 42 is introduced by 
breaking frangible membrane 41 (FIGS. 7B and 7D). Frangible membranes 21 
and 42 can be broken simultaneously or in series to accommodate a variety 
of mixing sequences. 
Referring now to FIGS. 2, 3, 4, and 5, a preferred stopper for insertion 
into the neck of the mixer is shown, including head 22, lip 24, and 
injection site 26 and handling means 28. Water is added to the mixer by 
insertion of a needle into the upper neck region; the protective member 
protects the user from accidentally inserting the needle entirely through 
the device and causing injury to himself. 
In preferred embodiments, the pouch has a capacity of about 1 to 20 ml, and 
allows convenient manual mixing of components contained therein. In 
smaller sizes (less than 10 ml) mixing is accomplished by manually 
kneading, pinching, or squeezing the flexible pouch, for example, with the 
thumb and forefinger of one hand. In larger sizes, the fingers of both 
hands may be employed simultaneously, or other methods such as use of a 
fist or palm of the hand may also be effective. Larger embodiments are 
mixed by mechanical means, for example, including a holder and one or more 
plungers. In one embodiment, reproducible and highly controlled mixing of 
the components within the mixer is obtained through the use of a 
mechanical mixer adapted to accept the flexible pouch and to mix the 
components therein. 
Any number of components may be introduced into the pouch provided their 
total volume does not exceed the volume of the pouch itself. Likewise, any 
introducer means appropriate for supplying the material to be mixed to the 
pouch may be employed. While it is possible for introducer means to exist 
on the pouch itself (e.g., a syringe needle penetrable pouch material, or 
the use of a gas or liquid permeable or semi-permeable pouch), in most 
cases this will be avoided because the presence of the introducer means 
can deleteriously affect the non-retaining character of the pouch inner 
surface. The means for introducing additional components to the pouch will 
most often be present in the neck or specific attachments thereto. 
Suitable introducer means include but are not limited to mechanical 
valves, check valves, ports, permeable or semi-permeable membranes, needle 
septa, needles, frangible membranes, semi-permeable membranes, and the 
like. 
The neck generally performs two functions, supplying the second component, 
e.g., a liquid, to the pouch and ejecting the mixed components from the 
pouch. The neck may include several compartments which can be breached to 
introduce their contents into the pouch. The neck can also be reinforced 
with a protective insert, and/or fitted with a handle to facilitate 
holding the mixer. 
In the preferred embodiment, a liquid second component is supplied to the 
pouch with a syringe through a rubber stopper. Where a substance is 
introduced via a syringe needle through the upper portion of the neck, a 
specialized stopper is used. The stopper limits the possibility of an 
accidental needle stick to the user by preventing unintended passage of 
the needle entirely through the neck. The specialized stopper, shown in 
FIG. 5, features a protecting member, generally flat, which extends into 
the neck. The needle is introduced into the neck at a point above the 
lower extent of the protecting member. In embodiments wherein a syringe is 
used for the introduction of a component, the mixed contents can be 
expelled back into the same syringe or expelled into a different syringe. 
In another embodiment, a component is introduced into the pouch, or mixed 
components are removed from the pouch, via a peacock or manual valve 
(one-way or multiple-way valve) attached to the neck of the mixing device. 
Multiple valves include two-way valves, three-way valves, four-way valves, 
five-way valves, and so on. One or more components can be simultaneously 
or sequentially introduced into the mixing pouch through a multiple valve 
when opened in one direction without material flowing back out. The mixed 
contents of the mixing pouch can also be removed or extruded through the 
valve when opened in the opposite direction. The multiple valve also has a 
closed position that provides a closed, optionally sterile system during 
mixing. Examples of check valves include the 500 Series check valves 
available from Smart Products, San Jose, Calif., although there are other 
suitable valves that are small, corrosion resistant, chemically inert to 
the components to be mixed, and have a cracking pressure between about 0.5 
and 10.0 psi. The cracking pressure may vary depending on the inner 
diameter of the valve openings, a needle or tube, and the viscosity or 
particle size of the mixed components. 
As an alternative to a manual valve, an embodiment can include a check 
valve that relies on the crack pressure concept. A check valve may be a 
one-way check valve or a multiple-way check valve (e.g., two-way, 
three-way, or four-way check valve). The cracking pressures of a check 
valve is the pressure at which the valve allows material to flow. For 
example, for a liquid to push into the device, the required pressure may 
be about 3 psi. Pressure greater than or equal to the crack pressure is 
necessary to initiate and sustain flow through a valve into the mixing 
during the passage of the component or mixture. A valve may be made of a 
hard plastic material, or another material such as hard rubber, a metal, 
or a metal alloy. In some cases, the valve is used in combination with a 
selectively permeable membrane that allows differential flow of 
components, e.g., allow liquids to pass through but retain powders or 
particles. 
Yet another embodiment features a needle or tube 32 or 34 attached to pouch 
12 or neck 14 of the mixing device to allow the contents of the mixing 
pouch to be expelled from the pouch through the needle, e.g., by manually 
or mechanically squeezing the pouch (FIGS. 6A-6D). The needle or a tube, 
with a removable seal or screwable or snap-off cap 36, may be glued to the 
pouch, for example, at an angle to the neck or opposing the neck (FIG. 
6B). The needle or tube may be straight, angled, or curved (FIG. 6C), and 
may be attached at an angle (FIG. 6D) or perpendicular to the tangent of 
the pouch (FIG. 8B). The shape of the needle or tube, and the angle at 
which it is attached relative to the pouch or neck, is chosen for 
convenience in mixing and expelling the mixed contents. FIG. 6B includes a 
cap or plug 36 on the end of needle 32 and a needle penetrable material 38 
on the neck. FIG. 6C includes a valve 39 attached to the neck and a curved 
needle 32. FIG. 6D includes a needle 32 at an angle to the neck and a 
needle port 34. Suitable needles include those having a gauge of 16 or 
greater, such as 18 or 24 or higher. 
In another embodiment, the mixing device includes a membrane, preferably a 
frangible membrane. A frangible membrane 21, 23, or 41 (FIGS. 1 and 7A-7D) 
is a thin, generally plastic, material that is impermeable and inert to 
the contents of the mixing pouch, and yet easily broken by physical force 
or pressure. The membrane 21 provides one or more barriers to separate two 
or more pre-measured components prior to mixing, e.g., during packaging, 
shipping, and storage (FIGS. 7B and 7D). A membrane can be within the neck 
of the pouch (FIGS. 7A-7C), or within the pouch itself (FIG. 7D). After 
the membrane is broken, multiple components (e.g., components 20 and 42 in 
FIGS. 7B and 7D) come into contact with each other and/or an additional 
component added by a supplying means. An embodiment may contain one or 
more frangible membranes (FIGS. 7A-7D). The membrane does not shred or 
disintegrate into pieces which could mix with the contents of the pouch. 
Alternatively, there is a retaining structure 45, such as a filter, mesh, 
or screen that catches pieces of the membrane, thereby preventing the 
pieces from mixing with the components in the pouch (FIG. 7C). In addition 
to plastics such as polyethylene, polyvinyl chloride, polycarbonate, and 
polyethylene glycol, the membrane may comprise materials such as non-woven 
papers, ceramics, or glass. 
Following completion of the mixing process the mixed components (or 
reaction products or combination thereof) may be stored within the pouch. 
The mixed components can be ejected in a variety of ways. The mixed 
contents can be removed providing an opening, for example, by removing a 
cap or a plug or by cutting the neck or the pouch. The contents are 
removed with an implement such as a syringe, a pipette or a spatula. 
Alternatively, the neck may be fitted with a valve or needle through which 
the mixture is squeezed out. The flexible nature of the pouch facilitates 
extrusion of the components, since a pouch may be squeezed or rolled like 
a toothpaste tube. Manual squeezing includes squeezing or rolling the 
mixed contents out of the pouch. Mechanical squeezing also includes the 
optional use of a cartridge 50 or a holding or handling device 51, either 
of which may be fitted with a plunger or pestle 52 to provide added 
control or leverage during mixing or evacuation of the pouch after mixing 
(FIGS. 8A and 8B). In some embodiments, a needle is attached to the 
cartridge or holding device, or to the neck of the pouch. The plunger is 
pushed, thereby expelling the contents of the pouch through a valve or a 
needle. In the preferred embodiment, a neck is cut with scissors, and the 
surgeon squeezes the mixture out of the pouch. 
OTHER EMBODIMENTS 
From the above description, one skilled in the art can easily ascertain the 
essential characteristics of the present invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various conditions. Thus, 
other embodiments are within the claims.