U.S. patent application number 10/375399 was filed with the patent office on 2004-08-26 for fluid-jet pens configured for making modulated release bioactive agents.
Invention is credited to Ayres, James W., Dunfield, John Stephen.
Application Number | 20040166124 10/375399 |
Document ID | / |
Family ID | 32771456 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040166124 |
Kind Code |
A1 |
Dunfield, John Stephen ; et
al. |
August 26, 2004 |
Fluid-jet pens configured for making modulated release bioactive
agents
Abstract
The present invention is drawn to methods of preparing a
bioactive agent-containing emulsion for delivery to a biological
system. This method can comprise the step of jetting a bioactive
agent and a first fluid medium from a fluid-jet pen into a second
fluid medium to form a bioactive agent-containing emulsion, wherein
the second fluid comprises a continuous phase of the emulsion.
Alternatively, a method of preparing a bioactive agent-containing
liposome can comprise jetting a lipid-containing composition and a
bioactive agent from a fluid-jet pen into a medium to form a
bioactive agent-containing liposome carried by the medium.
Inventors: |
Dunfield, John Stephen;
(Corvallis, OR) ; Ayres, James W.; (Corvallis,
OR) |
Correspondence
Address: |
HEWLETT-PACKARD DEVELOPMENT COMPANY
Intellectual Property Administration
P.O. Box 272400
Fort Collins
CO
80527-2400
US
|
Family ID: |
32771456 |
Appl. No.: |
10/375399 |
Filed: |
February 25, 2003 |
Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 9/113 20130101;
A61K 9/1277 20130101; A61K 9/1075 20130101; A61K 9/10 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 009/00 |
Claims
What is claimed is:
1. A method of preparing a bioactive agent-containing emulsion for
delivery to a biological system, comprising jetting: (a) a
bioactive agent, and (b) a first fluid medium, from a fluid-jet pen
into a second fluid medium to form a bioactive agent-containing
emulsion, wherein the second fluid comprises a continuous phase of
the emulsion.
2. A method as in claim 1, wherein the first fluid medium includes
a surfactant.
3. A method as in claim 1, wherein the first fluid medium is polar,
and the second fluid medium is nonpolar.
4. A method as in claim 1, wherein the first fluid medium is
nonpolar, and the second fluid medium is polar.
5. A method as in claim 1, wherein the first fluid is substantially
hydrophobic, the second fluid is substantially hydrophilic, and the
bioactive agent comprises a hydrophobic moiety.
6. A method as in claim 1, wherein the first fluid is substantially
hydrophilic, the second fluid is substantially hydrophobic, and the
bioactive agent comprises a hydrophilic moiety.
7. A method as in claim 1, wherein the emulsion is a
microemulsion.
8. A method as in claim 7, wherein the microemulsion comprises a
surfactant present at from 0.1% to 10% by weight.
9. A method as in claim 8, wherein the microemulsion comprises a
surfactant present at from 0.1% to 1% by weight.
10. A method as in claim 1, wherein the fluid-jet pen is a thermal
fluid-jet pen.
11. A method as in claim 1, wherein the fluid-jet pen is a piezo
fluid-jet pen.
12. A method as in claim 1, further comprising the step of
positioning a jetting orifice of the fluid-jet pen within the
second fluid during the jetting step.
13. A method as in claim 1, wherein the bioactive agent and the
first fluid medium are in the form of a mixture prior to
jetting.
14. A method as in claim 1, wherein the bioactive agent and the
first fluid medium are admixed during the jetting step.
15. A method as in claim 1, wherein the fluid-jet pen exerts shear
force on the bioactive agent and the first fluid medium during
jetting.
16. A method as in claim 1, wherein the bioactive agent-containing
emulsion is a microemulsion, and wherein the second fluid has a
dropsize from 1 to 20 .mu.m in diameter.
17. A method as in claim 16, wherein the microemulsion is prepared
without added surfactant.
18. A method as in claim 1, wherein the emulsion is prepared at a
physiological temperature.
19. A method as in claim 1, wherein the emulsion formed is a
bioactive agent-containing water-in-oil-in-water emulsion.
20. A method as in claim 1, wherein the bioactive agent-containing
emulsion is prepared on-site for delivery to a biological
system.
21. A method as in claim 1, further comprising the step of
delivering the bioactive agent-containing emulsion to a biological
system.
22. A method as in claim 1, wherein the second fluid is within a
second fluid-jet pen, said second fluid-jet pen being configured
for firing the emulsion to a carrier medium.
23. A method as in claim 22, wherein the carrier medium is liquid
substrate.
24. A method as in claim 22, wherein the carrier medium is a solid
substrate.
25. A method as in claim 22, wherein the carrier medium is a tissue
or cellular site.
26. A method of preparing a bioactive agent-containing liposome,
comprising jetting: (a) a lipid-containing composition, and (b) a
bioactive agent, from a fluid-jet pen into a carrier medium to form
a bioactive agent-containing liposome carried by the carrier
medium.
27. A method as in claim 26, wherein the bioactive agent is
substantially hydrophilic or amphiphilic.
28. A method as in claim 26, wherein the bioactive agent is
substantially hydrophobic.
29. A method as in claim 26, wherein the fluid-jet pen is a thermal
fluid-jet pen.
30. A method as in claim 26, wherein the fluid-jet pen is a piezo
fluid-jet pen.
31. A method as in claim 26, wherein the lipid-containing
composition is a phospholipid.
32. A method as in claim 26, wherein the carrier medium is liquid
substrate.
33. A method as in claim 26, wherein the carrier medium is a solid
substrate.
34. A method as in claim 26, wherein the carrier medium is a tissue
or cellular site.
35. A method as in claim 26, wherein the bioactive agent-containing
liposome is formed in the fluid-jet pen prior to jetting.
36. A method as in claim 26, wherein the bioactive agent-containing
liposome is formed during jetting.
37. A method as in claim 26, further comprising the step of
delivering the bioactive agent-containing liposome to a biological
system.
38. A method as in claim 26, wherein the bioactive agent-containing
liposome is prepared on-site for delivery to a biological
system.
39. A bioactive agent release system, comprising a fluid-jet pen
containing: (a) a bioactive agent; and (b) a release agent, wherein
the fluid-jet pen is configured for jetting the bioactive agent and
the release agent, resulting in an association between the
bioactive agent and the release agent.
40. A system as in claim 39, wherein the association is an
emulsion.
41. A system as in claim 39, wherein the association is a
microemulsion.
42. A system as in claim 39, wherein the association is a
liposome.
43. A system as in claim 39, wherein the association is produced in
the fluid-jet pen prior to jetting.
44. A system as in claim 39, wherein the association is produced
prior to loading into the fluid-jet pen.
45. A system as in claim 39, wherein the association is produced
during jetting.
46. A system as in claim 39, wherein the bioactive agent and the
release agent are in two separate phases within the fluid-jet
pen.
47. A system as in claim 39, wherein the bioactive agent and the
release agent are mixed within the fluid-jet pen.
48. A system as in claim 39, wherein the fluid-jet pen containing a
bioactive agent; and a release agent are packaged in a sterile
environment, thereby providing a sterile association upon
jetting.
49. A composition prepared in accordance with the method of claim
1.
50. A composition prepared in accordance with the method of claim
26.
Description
FIELD OF THE INVENTION
[0001] The present invention is drawn to fluid-jet pens configured
for making liposome- and emulsion-containing bioactive agents. The
present invention is also drawn to methods for producing bioactive
agent-containing emulsions.
BACKGROUND OF THE INVENTION
[0002] There have been many approaches used to meet the problems of
regulating the delivery of bioactive agents, such as drugs, to
biological systems including humans, to achieve a proper dose
and/or a desired effect. In the prior art, successful bioactive
agent delivery vehicles have been designed that are capable of
maintaining the bioactive agent in its dissolved state over an
extended storage period, and the bioactive agent delivery vehicle
itself has been designed to remain stable over a predetermined
storage period. Commonly employed delivery vehicles for bioactive
agent delivery include lipid emulsions and microemulsions, as well
as liposome and liposphere compositions.
[0003] Emulsion particle or droplet sizes can range from about 200
nm to 1,000 nm. In the prior art, particle size of the lipid
emulsions has precluded the use of filters to sterilize such
compositions, and thus, heat sterilization has been used. A
drawback of the use of heat sterilization is that it can be
detrimental to various bioactive agents. Additionally, from a
manufacturing standpoint, emulsions have not been preferred for use
due to the requirement of the use of the high shear equipment that
is presently known, and because emulsions suffer from physical
stability problems such as creaming and cracking.
[0004] Microemulsions have also been used as bioactive agent
delivery compositions. Microemulsions are generally defined as
those systems containing a lipophilic and a hydrophilic component
wherein the average particle size of the dispersed phase is below
about 200 nm. Microemulsions are further characterized as being
clear or translucent preparations. The clarity and particle size
characteristics distinguish microemulsions from emulsions. The
smaller particle size range of microemulsions enables them to be
retained in the blood system for a longer period of time than
emulsions. Microemulsions are typically more physically stable than
emulsions and seldom suffer from creaming or cracking problems, but
phase separation problems may occur during storage under certain
conditions.
[0005] Liposomes are microscopic vesicles having single or multiple
lipid bilayers that can entrap hydrophilic compounds within their
aqueous cores. Polar (including hydrophilic) and nonpolar
(including hydrophobic) compounds may partition into lipid
bilayers. Liposomes have been formed in sizes as small as tens of
Angstroms to as large as a few microns, and can be carriers for
bioactive agents. Typically, liposomes have been prepared by
sonication, detergent dialysis, ethanol injection, French press
extrusion, ether infusion, and reverse phase evaporation. These
methods often leave residuals such as detergents or organics with
the final liposome. Many liposome products are not stable for long
periods of time.
[0006] Present liposome products can be difficult to sterilize.
Sterility is currently accomplished by independently sterilizing
component parts (including the lipid, buffer, bioactive agent, and
water) such as by the use of an autoclave or by filtration, and
then mixing in a sterile environment. This sterilization process
can be difficult, time consuming, and expensive since the product
must be demonstratively sterile after several processing steps and
these methods are not convenient in a retail pharmacy, a doctors
office, or in a patients home. Further, sterilizing a formed
liposome is usually not feasible as autoclave sterilization can
denature the liposome, and filtration can alter the features of
multilayered liposomes.
[0007] Ink-jet pens have primarily been used in the prior art to
form precise patterns of dots in the form of ink-containing images.
An ink-jet pen acts by ejecting fluid from a drop-generating device
known as a "printhead" onto a printing medium. The typical ink-jet
printhead has an array of precisely formed nozzles located on a
nozzle plate and attached to an ink-jet printhead substrate. The
substrate incorporates an array of firing chambers that receive
liquid ink (colorants dissolved or dispersed in a solvent) through
fluid communication with one or more ink reservoirs. Each chamber
can have a thin-film resistor, known as a "firing resistor,"
located opposite the nozzle so ink can collect between the firing
resistor and the nozzle. The printhead is held and protected by
outer packaging referred to as a print cartridge, i.e., ink-jet
pen. Upon energizing of a particular resistor element, a droplet of
ink is expelled through the nozzle toward the print medium, whether
paper, transparent film or the like. The firing of ink droplets is
typically under the control of a microprocessor, the signals of
which are conveyed by electrical traces to the resistor elements,
thereby forming alphanumeric and other characters on the print
medium. In the prior art, various emulsion techniques have been
implemented in ink-jet ink applications, e.g., both oil-in-water
(O/W) and water-in-oil (W/O).
SUMMARY OF THE INVENTION
[0008] The present invention relates to a method of preparing a
bioactive agent-containing emulsion for delivery to a biological
system can comprise jetting a bioactive agent and a first fluid
medium together from a fluid-jet pen into a second fluid medium to
form a bioactive agent-containing emulsion. In this embodiment, the
first fluid typically becomes part of a discontinuous phase, and
the second fluid comprises a continuous phase of the emulsion.
[0009] In an alternative embodiment, a method of preparing a
bioactive agent-containing liposome can comprise jetting a
lipid-containing composition and a bioactive agent, together from a
fluid-jet pen into a medium to form a bioactive agent-containing
liposome carried by the medium
[0010] In a system related to the methods herein, a bioactive agent
release system can comprise a fluid-jet pen containing a bioactive
agent and a release agent, wherein the fluid-jet pen is configured
for jetting the bioactive agent and the release agent, resulting in
an association between the bioactive agent and the release
agent.
[0011] Additional features and advantages of the invention will be
apparent from the detailed description which follows, taken in
conjunction with the accompanying drawings, which together
illustrate, by way of example, features of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] In the accompanying drawings:
[0013] FIG. 1 is a block diagram of a method of preparing emulsions
in accordance with an embodiment of the present invention; and
[0014] FIG. 2 is a block diagram of a method of preparing liposomes
in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
[0015] Before the present invention is disclosed and described, it
is to be understood that this invention is not limited to the
particular process steps and materials disclosed herein because
such process steps and materials may vary somewhat. It is also to
be understood that the terminology used herein is used for the
purpose of describing particular embodiments only. The terms are
not intended to be limiting because the scope of the present
invention is intended to be limited only by the appended claims and
equivalents thereof.
[0016] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
[0017] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used for convenience and
brevity, and thus, should be interpreted in a flexible manner to
include not only the numerical values explicitly recited as the
limits of the range, but also to include all the individual
numerical values or sub-ranges encompassed within that range as if
each numerical value and sub-range is explicitly recited. To
illustrate, a concentration range of "about 0.1% to about 5% by
weight" should be interpreted to include not only the explicitly
recited concentration of about 0.1% to about 5% by weight, but also
to include individual concentrations and the sub-ranges within the
indicated range. Thus, included in this numerical range are
individual concentrations such as 2% by weight, 3% by weight, and
4% by weight, and sub-ranges such as from 1% to 3% by weight, from
2% to 4% by weight, from 3% to 5% by weight, etc. This same
principle applies to ranges reciting only one numerical value. For
example, a range recited as "less than about 5% by weight" should
be interpreted to include all values and sub-ranges between 0% and
5% by weight. Furthermore, such an interpretation should apply
regardless of the breadth of the range or the characteristics being
described.
[0018] "Emulsion" generally shall include mixtures of nonpolar
materials and polar materials, and can include the presence of an
emulsifier and/or a surfactant. Emulsifier and surfactant are terms
that may be used interchangeably herein. The term "nonpolar" as
applied to materials is well-known in the literature and includes,
but is not limited to, materials typically referred to as
lipophilic, oils, and materials with a low HLB
(hydrophilic-lipophilic balance) value. The term "polar" is also
well-known in the literature and includes, but is not limited to,
materials typically referred to as hydrophilic, water, and
materials with a high HLB (hydrophilic-lipophilic balance) value.
Polar and nonpolar includes solids, e.g., drugs with a low water
solubility are nonpolar, as well as liquids. Traditionally,
emulsions have been defined as compositions that can be subject to
separation, creaming, and/or cracking, and define dispersions
having particle sizes from about 200 nm to 1000 nm in size.
Conversely, microemulsions are compositions that can appear clear,
even though they often include similar components as are present in
traditionally defined emulsions. However, microemulsions typically
include droplets that are smaller in size, i.e., from 5 nm to 200
nm. For purposes of the present invention, when emulsions are
referred to, what is meant includes a more general definition
including all compositions comprising dispersions of
nonpolar-in-polar emulsions, including but not limited to
oil-in-water, or polar-in-nonpolar emulsions, including but not
limited to water-in-oil. Thus, the term emulsion shall include
mixtures of nonpolar materials and polar materials no matter what
size of droplets are present, i.e., from the lower end droplet size
range of microemulsions to the higher end droplet size range of
traditional emulsions. As a result, in accordance with the present
invention, the term "microemulsion" defines a range of droplet
sizes that is within the lower droplet size range defined by the
general term "emulsion." It is also recognized that in some
references microemulsions are considered two phase systems with a
discontinuous phase and a continuous phase, e.g., polar in nonpolar
microdroplets, and other references consider that microemulsions
are not true emulsions but are one-phase systems with solubilized
nonpolar materials in polar materials, or vice-versa. For purposes
of this invention, microemulsions include both, and both are
included when traditional nomenclature such as continuous and
discontinuous phases is used herein.
[0019] The term "microemulsion" includes nonpolar-in-polar, e.g.,
oil-in-water (O/W), and polar-in-nonpolar, e.g., water-in-oil
(W/O), compositions wherein the dispersion droplet is from >0 nm
to 200 nm in size. In one embodiment, an amphiphilic compound, such
as a surfactant and/or emulsifier, can be present. In another
embodiment, when dealing with emulsions at a microfluidic level,
i.e., droplet sizes from 1 to 20 .mu.m in diameter, an amphiphilic
compound is not necessarily required, but can optionally be
present.
[0020] The term "liposome" includes microscopic, and often,
spherical vesicles that contain a hydrophilic polar inner core and
one or more outer layers comprising lipids, such as phospholipids.
The inner core can comprise a bioactive agent, such as a drug. The
bioactive agent may alternatively be more closely associated with
the lipids than the polar center of the vesicle. A characteristic
of liposomes is that they enable water-soluble and water insoluble
materials to be used together in a formulation without the
requirement of use of surfactants or emulsifiers other than the
lipids which form a bilayer, e.g., phospholipids. However, a
variety of ingredients can be utilized in production or
modification of liposomes as are known in the literature including,
but not limited to, neutral or positive charged or negatively
charged phospholipids and surfactants. Non-limiting examples of
materials used for the preparation of liposomes includes, for
example, phosphatidyl choline, phosphatidic acid,
phosphatidylglycerol, phosphatidylserine,
disteroylphophatidylcholi- ne, dipalmitoylphosphatidylcholine,
cholesterol, triolein, stearylamine,
1,2,-bis(hexadecylcycloxy)-3-trimethyaminopropane,
N-((1-2,3-dioleyoxy)propyl)-N,N,N-triethyammonium,
1,2-dioleyoxy-3-(trimetylammonium
propane),3-beta-(N,N-dimethylaminoethan- e)carbamylcholesterol,
surfactants, emulsifiers, and polyethylene glycols.
[0021] "Fluid-jet pen" includes pen architecture that is
substantially similar or the same as that found in the ink-jet
arts. Thermal-ink-jet pens or piezo-ink-jet pens provide such
examples. The reason the term "fluid-jet pen" is used rather than
"ink-jet pen" is because the pens used in accordance with the
present invention are optimized for emulsion/microemulsion or
liposome jetting and/or production. Modification, if desired, may
include design to induce turbulence, multiple fluidic coupling
channels which may have mixing chambers, break-up baffles, stirring
members, turbulence inducing design, and other mixing structures
generally not present in ink-jet pens. No ink per se is typically
jetted, though ink may be included as a marker in a formulation
along with bioactive material.
[0022] "Bioactive agent" includes organic and inorganic drugs, as
well as other agents such as proteins and peptides, that are
biologically active when introduced to a biological system.
Bioactive agent includes at least therapeutics and diagnostics
which means any therapeutic or diagnostic agent now known or
hereinafter discovered that can be jetted as described herein.
Examples of therapeutics, without limitation, are listed in U.S.
Pat. No. 4,649,043, which is incorporated herein by reference.
Additional examples are listed in the American Druggist, p. 21-24
(February, 1995), which is also incorporated herein by reference.
The term "diagnostic" means, without limitation, a material useful
for testing for the presence or absence of a material or disease,
and/or a material that enhances tissue imaging.
[0023] "Biological system" includes a cell, cells, cellular
cultures, tissues, organisms, and also includes more advanced
systems, such as animals, including humans.
[0024] "Lipid-containing composition" or "lipid" can include, but
is not limited to, substances known as fats and oils. Fats are
triglycerides that are solids at room temperature and oils are all
triglycerides that are liquid at room temperature. Lipids are
substantially insoluble in water. Examples of lipids that can be
used in accordance with the present invention include phospholipids
and sterols.
[0025] The term "substantially" when used with another term shall
include from mostly to completely. Thus, a fluid said to be
substantially hydrophobic is hydrophobic to the extent that it
generally repels water. However, such a fluid may contain
compositional components that are not hydrophobic, though likely
such compositions will be present in smaller amounts than the
composition providing the hydrophobic characteristic.
[0026] The term "association" when referring to a biological agent
and a release agent includes physical and chemical attractions or
entrapments between the components. This association can be in the
context of liposome or an emulsion formation, including
microemulsions.
[0027] The term "release agent" includes any substance that can be
jetted with a bioactive agent that results in an association
between the bioactive agent and the release agent. Liposome-forming
compositions as well as emulsion-forming compositions are included
as release agents.
[0028] In accordance with embodiments of the present invention, a
method of preparing a bioactive agent-containing emulsion for
delivery to a biological system can comprise jetting a bioactive
agent and a first fluid medium, together from a fluid-jet pen into
a second fluid medium to form a bioactive agent-containing
emulsion, wherein the second fluid comprises a continuous phase of
the emulsion. In many embodiments, a surfactant can be present in
the first fluid medium, or the second fluid medium, or both.
[0029] Both polar-in-nonpolar such as water-in-oil (W/O), and
nonpolar-in-polar, such as oil-in-water (O/W) emulsions, can be
used. In the drug delivery arena, oil-in-water embodiments are more
common. However, water-in-oil embodiments can also be used in areas
of drug delivery, e.g., oral administration or injections, but are
more common in cosmetic applications and the like.
[0030] In nonpolar-in-polar embodiments, the first fluid can be
substantially hydrophobic, the second fluid can be substantially
hydrophilic, and the bioactive agent can comprise a hydrophobic or
amphiphilic moiety. In further detail, thermal or piezo fluid-jet
architecture can be designed to produce microemulsions underwater,
especially in oil-in-water (O/W) embodiments, which are preferred
in drug-delivery. In one embodiment, a mixture of
drug/surfactant/oil can flow within a reservoir of a fluid-jet pen,
and then be ejected from a firing chamber of the pen from the
surface or with the orifice immersed in water or another polar
environment, in a "drop-on-demand" fashion if desired. Thus,
controlled microdroplets can then become surrounded by a continuous
external polar, e.g., aqueous phase. Self-alignment of the
surfactant can occur at the droplet/continuous interface. In the
ink-jet ink arts, a thermal ink-jet pen cannot typically be placed
underwater because of pen "drool" or leakage. However, such leakage
can be minimized or removed when the pen contains a nonpolar oil
material and a drug. Further, for embodiments of this invention,
pen architecture and back pressure, if desired, can be modified to
minimize drooling of the liquid phase being dispensed by the pen
whether the immersion liquid is polar or nonpolar. With this
process, very concentrated microemulsions can be produced by
continued ejection of a drug and oil, for example, into a fixed
volume of an aqueous phase, with rapid stirring and circulation if
desired of the continuous phase. This provides an industrial
advantage because, in the prior art, production of a concentrated
product without (or with minimal) filtration and clean-up has been
difficult to obtain.
[0031] In polar-in-nonpolar embodiments, the first fluid can be
substantially hydrophilic, the second fluid can be substantially
hydrophobic, and the bioactive agent can comprise a hydrophilic
moiety. Thus, the bioactive agent can be hydrophilic or
amphiphilic. This type of emulsion can be used in cosmetic
applications, for example, as well as in some drug
preparations.
[0032] In some embodiments, the bioactive agent can be relatively
insoluble in a first phase, and can be prepared as a suspension of
microparticulate size, often with a surfactant. This composition
can be jetted into the continuous phase to produce an emulsion
wherein the discontinuous phase contains microparticulate solids as
well as the first liquid phase.
[0033] As previously defined, the-general term "emulsion" includes
both microemulsions and traditionally defined emulsions. However,
in one more detailed embodiment, the emulsion can be a
microemulsion. One advantage of the present invention is the use of
a fluid-jet pen as a homogenizer. Because of the way a fluid-jet
pen ejects fluid, microemulsions can be prepared that utilize less
surfactant than has been required in the prior art. Many
microemulsions utilize about 20% surfactant or more to generate
microemulsions. However, by utilizing fluid-jet pen architecture to
generate the microemulsions, less surfactant can be required. For
example, surfactant can, in general, be present at from 0% to 90%
by weight, from 0% to 20% by weight, or even from 0% to 10% by
weight, depending on the polarity and characteristics of the
liquids/materials and surfactants involved. To obtain
microemulsions without the presence of surfactant, i.e., 0% by
weight, microemulsions can be generated at a microfluidic level.
Further, heat controls within an ink-jet system, especially at the
point of drop formation as well as for the entire pen, allows
additional control over droplet size and allows introduction of
thermal energy. This, in turn, can influence molecular
self-alignment and reduce the amount of surfactant needed to
produce desired droplet dispersion.
[0034] In many applications now available, microemulsions produced
are typically designed to be "shelf-stable" for six months or
longer. Conversely, with the present invention, a microemulsion can
now be produced "on demand" and used within a short time period if
desired, thus minimizing the requirement for long shelf life
(though microemulsions having a long shelf life can be produced).
Thus, microemulsions can be prepared using surfactant amounts that
have typically been used to form emulsions having from 200 to 1000
nm droplet size. The use of less surfactant (or even no surfactant
on a microfluidic level) can reduce the introduction of side
effects associated with surfactant, including diarrhea, reduction
of vitamin absorption, localized cell damage such as when applied
to nasal tissue, and other known side effects.
[0035] The components present in a fluid-jet pen prior to jetting
can be stored in a reservoir in many forms. For example, the
bioactive agent and first fluid medium can be mixed together, such
as in a dispersed state. Alternatively or additionally, further
mixing of the bioactive agent and the first fluid medium can occur
during jetting. As fluid-jet pen architecture generally includes a
firing chamber and very small capillary tubes, the firing chamber
can cause turbulence in the capillary tubes, effectuating
emulsification. In this embodiment, shear forces provided by the
capillary tubes and/or orifice plate can act as a homogenizer, and
assist in forming emulsions, or even microemulsions.
[0036] In another aspect of the present invention, emulsions can be
prepared at a predetermined temperature. In one embodiment, the
microemulsion can be prepared at a physiological temperature and
immediate delivery to a biological system can be implemented.
[0037] The present invention can also be used to generate multiple
emulsions. This embodiment can include water-in-oil-in-water
emulsions, which are particularly useful with drugs that are
difficult to solubilize. For example, an oil can be floated on top
of water (layered in the pen), or provided in separate flow
channels, and the fluid-jet pen architecture can be configured to
feed both of the layers or channels so that when firing occurs, a
drop of water inside oil is fired to form a discontinuous phase
into a continuous phase of water. In this embodiment, the second
fluid medium is the continuous phase of water, and the
discontinuous phase is the oil-containing water vesicle formed. The
bioactive agent can be associated with the oil-containing water
vesicle, and can be in either the oil or the water of the vesicle.
A more general embodiment can include the formation of a
polar-in-nonpolar-in-polar multiple emulsion. In an alternate
embodiment, a similar pen architecture may be used to fire a drop
of a first fluid in a layer or channel through a second fluid in a
layer or channel such that the product droplets are an emulsion of
the first fluid in the second fluid. If the droplets were to be
collected and combined, then the first fluid would typically be the
discontinuous phase and the second fluid would typically be the
continuous phase of the emulsion. But, in this case, the emulsion
produced may be delivered directly to a biological system without
intermediate collection. This allows formation of the emulsion and
delivery of the bioactive agent in the emulsion directly to a
patient or tissue at the time of emulsion formation. Typically, a
bioactive agent can be included in the discontinuous phase but in
some embodiments the bioactive agent can be included in the
continuous phase wherein the discontinuous phase contains
ingredients that modify or influence the behavior of the bioactive
agent. The discontinuous phase may be polar or nonpolar as
appropriate, and the continuous phase may be polar or nonpolar as
appropriate.
[0038] One advantage of the present invention is that bioactive
agent-containing emulsions can be prepared on-site for delivery to
a biological system. By "on-site," what is meant is that the
emulsions can be prepared in a close proximity to a patient or
other biological system, just prior to delivery. Examples include:
at a doctor's office, at a pharmacy, at a hospital, at a lab where
delivery is to occur, e.g., such as to a cellular or tissue
culture, etc. Further, several advantages can be realized when
delivering the emulsions of the present invention to a biological
system, particularly when the biological system is a human patient.
For example, droplets of low solubility drugs can be made to be
very small, e.g., microemulsions, and therefore, can exhibit
increased bioavailability and may demonstrate decreased toxicity.
With certain microemulsions, lymphatic absorption can also be
effectuated. Further, prolonged emulsion stability is not required
since the emulsion can be used soon after preparation or even
delivered directly to the patient tissue which, in turn, allows
reduction of the amount of surfactant required, if desired, as
discussed previously.
[0039] In accordance with embodiments of the present invention, the
second fluid can also be configured to be within a second fluid-jet
pen. Thus, the fluid-jet pen can fire the first fluid into the
second fluid, and the resulting emulsion can be fired immediately
(or later in time) from the second fluid-jet pen into or onto a
carrier medium. The second fluid-jet pen or multiple fluid-jet pens
can be combined with the first fluid jet pen within a single
structure housing the architecture. The carrier medium can be a
liquid substrate, such as oil or water, or can be a substrate, such
as a particulate or larger substrate, e.g., an implant. Still
further, the carrier medium can be a tissue or cellular site.
[0040] Turning to another embodiment of the present invention, a
method of preparing a bioactive agent-containing liposome can
comprise jetting a liposome forming composition and a bioactive
agent, together from a fluid-jet pen into a medium to form a
bioactive agent-containing liposome carried by the medium. As is
known in the art, liposomes do not form spontaneously, and thus,
energy is introduced with a lipid, such as a phospholipid, to
effectuate formation. The vesicle developing formulation, e.g.,
phospholipid, containing a bioactive agent can be fired into an
appropriate carrier medium for delivery. By "carrier medium," what
is meant is any liquid or solid that acts as a substrate to accept
or collect jetted liposomes. One such carrier medium includes an
aqueous medium, wherein the drug-containing liposome is jetted into
an isotonic solution. If desired, the firing can be directed into a
plate or baffles, or sequential firing from one chamber into
another and recycling is possible (similar to multiple
homogenization passes) prior to final jetting from the pen.
Alternatively, the carrier medium can be a solid substrate such as
an implant, or can be the ultimate tissue or cellular site that the
liposomes are configured to treat or contact. In other words, the
medium does not have to be an intermediate application medium, but
can be a biological system itself. For example, jetting liposomes
containing drugs directly onto/into tissues such as nasal,
ophthalmic, or oral mucosal tissues, or other tissues during
surgery, can occur. With respect to the bioactive agent, in one
embodiment, it can be hydrophilic or amphiphilic. Further, the
fluid-jet pen can be a piezo fluid-jet pen or a thermal fluid-jet
pen.
[0041] Liposomes can be formed for jetting from a fluid-jet pen in
a few different ways. For example, a bioactive agent-containing
liposome is formed in the fluid-jet pen prior to jetting, such as
by treating the fluid-jet pen containing the bioactive agent and
the lipid-containing composition with sonication. Thus, after
sonication, the fluid-jet pen will contain the bioactive
agent-containing liposomes, which can be jetted from the fluid jet
pen on demand (similarly, emulsions can be formed in the pen prior
to jetting, such as through sonication). Alternatively, a bioactive
agent-containing liposome can be formed by the jetting process
itself, utilizing forces exerted on compositions during the jetting
process. In either embodiment, the step of delivering the bioactive
agent-containing liposome to a biological system can be carried out
as part of the jetting process, just after jetting, or at a later
time, being limited by the length of time such a bioactive
agent-containing liposome is considered to be able to provide a
therapeutic affect.
[0042] In one embodiment, liposomes can be prepared on-site for
delivery to a patient or other biological system, minutes or
seconds prior to delivery (or as part of the delivery itself). This
provides a great advantage in the art of liposome storage and
delivery, because storage time can be minimized or eliminated, as
liposomes are not typically stable over long periods of time,
particularly without the presence of stabilizers, e.g.,
polyethylene glycol. Liposomes made by sonication agglomerate in
just 10 days and even supercritical fluid produced liposomes may
agglomerate in 35 days. At least 6 months stability is required by
the FDA, usually 2 years is necessary, and 5 years is preferred.
"On-site" or "on-demand" formulations that can be provided by the
present invention fill a need in the art, particularly since many
liposomes are unstable or have a short shelf life. Both single and
multiple shell liposomes are known to break down over time, and
drug can pass through the shell by diffusion. In fact, it has been
difficult to make liposomes that last more than from 24 hours to 6
months, depending on the formulation. In accordance with the
present invention, liposomes can be injected into saline, or some
other compatible carrier liquid, and delivered without a drying
step, or ejected onto a solid support for use, or can be jetted
onto mucosal surfaces (mouth, nose, vagina, wounds, veins, etc.
Alternatively, one can jet a liposome onto a patch or onto the
skin, and then the liposomes can be covered with a polymer patch,
or even overprinted using another fluid-jet pen formulation. Still
further, through fluid-jet technology, liposomes can even be driven
into the mucosal cells using forces and/or thermal control provided
by the fluid-jet pen. It will now readily be recognized that all
these applications and more are now available for liposomes,
emulsions, and microemulsions.
[0043] Turning to another embodiment, a bioactive agent release
system can comprise a fluid-jet pen containing a bioactive agent
and a release agent, wherein the fluid-jet pen is configured for
jetting the bioactive agent and the release agent, resulting in an
association between the bioactive agent and the release agent. This
system can produce associations in the form of emulsions, including
microemulsions, and liposomes. The association can be produced in
the fluid-jet pen prior to jetting, such as by sonication or other
known processes in the pen or prior to filling the pen such as may
be desirable, e.g., for off-axis material feed systems, and the
fluid-jet pen is used primarily for delivery purposes.
Alternatively, a fluid-jet pen filled with the bioactive agent and
the release agent can be sonicated or otherwise mixed or processed
prior to firing if desired to pre-form some liposomes or emulsions,
depending on the formulation. Alternatively, the association can be
produced during jetting itself. Still further, the association can
be produced by a combination of premixing or preforming within the
fluid-jet pen, and during jetting.
[0044] Within the fluid-jet pen, the bioactive agent and the
release agent can either be in two separate phases within the
fluid-jet pen, such as in layers or such as in a more dispersed
mixture or in separate chambers. Under either scenario, the
fluid-jet pen containing the bioactive agent and the release agent
can be packaged in a sterile or clean environment, thereby
providing a sterile association upon jetting from the pen. This is
significant in that liposomes and some emulsions cannot be
autoclaved for sterilization after production, as such
sterilization processes can destroy the bioactive agent, the
liposome shell(s), and/or emulsion properties. Thus, fluid-jet pens
can be filled with a bioactive agent and releasing agent, i.e.,
vesicle-forming or microemulsion agent and may contain excipients
that influence release, and packaged in a sterile manner, thereby
removing the need to sterilize upon jetting from the fluid-jet pen
at the time of production and delivery to a biological system.
Hospitals, pharmacies, or the like, could benefit from such a
process. This "point of use" or "on-site" feature of microemulsion
and liposome formation using fluid-jet pens also opens applications
for "at home" production of compositions for delivery, for example
to the nose or mouth, as well as topically. Still further, these
formulations can be delivered onto a solid substrate such as inside
a capsule or onto a paper or other substrate for ingestion. Other
advantages of using a fluid-jet pen as described herein are
on-demand drop delivery at readily controlled frequencies and
control of location of drop placement. Production range is from as
little as one drop which can be jetted from a single orifice device
to large numbers of drops jetted from multiple orifices of
ganged-together devices are possible.
[0045] Reference will now be made to the exemplary embodiments
illustrated in the drawings, and specific language will be used
herein to describe the same. It will nevertheless be understood
that no limitation of the scope of the invention is thereby
intended. Alterations and further modifications of the inventive
features illustrated herein, and additional applications of the
principles of the inventions as illustrated herein, which would
occur to one skilled in the relevant art and having possession of
this disclosure, are to be considered within the scope of the
invention.
[0046] Turning now to the Figures, exemplary embodiments that can
be used to implement the methods of the present invention are
provided.
[0047] In FIG. 1, a system 8 of preparing emulsions, including
microemulsions, is shown as a flow chart. Flow lines representing
movement of ingredients to or from containers or chambers are not
numbered but are clearly apparent to one skilled in the art. In
this embodiment, a nonpolar formulation 16 can be prepared by
combining one or more nonpolar ingredient(s) 10, such as oils, with
an optional first excipient 12 and a bioactive material 14. A final
nonpolar mixture 28 can then be prepared by combining the nonpolar
formulation 16 with one or more other ingredients such as a buffer
18, other excipients 20, surfactants 22, other or additional
nonpolar bioactive material 24, and/or solvent 26. Note that the
arrangement of the blocks in FIG. 1 represents only one possible
sequence of combining materials, and does not require any
particular combination or sequence of mixing, but is meant to
include many possible combinations and permutations thereof.
Further, not all components shown are critical and the number of
ingredients is not limited to the number of boxes, as would be
known by one skilled in the art after considering the present
disclosure.
[0048] With the present embodiment, sterilization can occur for the
materials before loading into the reservoir chamber or after
loading into the reservoir chamber of the pen apparatus. In one
embodiment, the final nonpolar mixture 28 can now be contained in
the fluid-jet pen reservoir for jetting into a sterile polar
mixture 44 to form an emulsion 32 in which the nonpolar mixture is
the discontinuous phase and the sterile polar mixture 44 is the
continuous phase, as will be described. A variety of materials may
be included in forming the polar mixture 44, including polar
solvent 36, polar bioactive material 38, buffer 40, and excipient
42. The temperature of polar mixture 44 or the dispensing or
jetting of this mixture through an orifice, as is appropriate, can
be controlled or regulated by thermal control means 46.
[0049] The final nonpolar mixture 28 and the polar mixture 44 can
be combined by using thermal control means 34, 46, respectively, as
noted above. This can be accomplished by jetting nonpolar mixture
28 under the surface of a rapidly mixing sterile polar mixture 44,
thereby forming emulsion 32. The resulting emulsion 32 can be
collected or incorporated to form a resulting usable composition 50
which can be in a variety of forms, as desired (via thermal control
34 or some other mechanism). Examples of resulting compositions 50
include fine sprays (nebulize), capsules, surfaces of implantable
devices, substrate materials, within a carrier fluid such as part
of an IV, or to a tissue cell. Thermal control 48 can also be
appropriately placed to enable utilization and/or dispensing of the
resulting composition. Thermal control can be carried out in a
number of ways, including by using thermal fluid-jetting processes,
or by more traditional thermal control methods. As shown, thermal
control can optionally be carried at one or more of many steps,
such as at steps enumerated at 30, 34, 46, and 48 for example.
Other thermal control steps can also be used, as would be know to
those skilled in the art.
[0050] With respect to one of the embodiments described, a single
fluid-jet pen apparatus can be configured such that the final
nonpolar mixture 28 can be mixed with the polar mixture 44 within a
single fluid-jet pen, and the resulting emulsion 32 produced
therein can be dispensed directly, without incorporation into a
composition 50, as desired including as an aerosol, or as a
positive material on the surface of a desired substrate material.
In this embodiment (and in others), the dispensing of the final
nonpolar mixture to be mixed with a polar mixture may be carried
out in such a way that a variety of mixing techniques such as
sonication, turbulent flow, and others known in the art, may be
employed. Thus, the interior design of a fluid-jet pen may be
configured such as to introduce mixing by turbulent flow
processes.
[0051] In still another embodiment, it is anticipated that the
final nonpolar mixture 28 can be delivered into a firing area of a
fluid-jet pen, along with the final polar measure in such a way
that one mixture "floats "on top of the other mixture. In this
embodiment, within the firing chamber, one mixture (28 or 44) can
be jetted through the other mixture (44 or 28, respectively), such
that an emulsion 32 is produced wherein the first jetted mixture
becomes the discontinuous phase and the mixture through which
jetting occurs becomes the continuous phase. If jetting an emulsion
directly onto a substrate, such as into a fluid substrate or onto a
solid substrate, then the emulsion can be prepared prior to
jetting. Appropriate architecture for such an embodiment can
include a fluid-jet pen that jets a first fluid into the firing
chamber of a second fluid-jet pen containing a second fluid. The
second fluid-jet pen can be configured to jet the emulsion. Such an
embodiment can be characterized by a first fluid-jet pen within a
fluid-jet pen, i.e., first pen jets into second pen forming
emulsion followed by second pen jetting emulsion. Such an array and
utilization can readily be determined by one skilled in the art of
fluid-jet pen technology.
[0052] Though not shown in FIG. 1, in another embodiment, multiple
channels within a fluid-jet pen structure can be designed such that
a first liquid is jetted into a second liquid that is jetted
through a third liquid using channel and orifice structures
appropriate to produce an emulsion of the first liquid in the
second liquid in the third liquid. If the first and third liquids
are polar (typically aqueous) and the second liquid is nonpolar
(typically oil), then a polar-in-nonpolar-in-po- lar, (typically
water-in-oil-in-water) emulsion is produced.
[0053] Turning now to FIG. 2, an exemplary embodiment of a system
60 for using a fluid-jet pen to dispense liposomes on site to a
target location is provided. Specifically, a lipid formulation 62
can comprise a single lipid or a combination of lipids in a
mixture. The lipid(s) of the formulation can be phospholipids
involved in formation of any bilayer or multilayer structure of a
liposome. The lipid formulation 62 can be combined with other
nonpolar materials to form a nonpolar lipid mixture 74. As shown,
the other nonpolar materials can include, but are not limited to,
buffer 64, excipient 66, surfactant 68, nonpolar bioactive material
70, and typically includes a solvent 72. In one embodiment, the
nonpolar lipid mixture 74 can be loaded into an enclosing medium
that acts as a reservoir chamber for a fluid-jet pen. The enclosing
medium reservoir chamber can be, typically, in an enclosing medium
tray or other holding device wherein the tray or other holding
device is under the control of a transport mechanism and transport
controller. Any conventional technique for aligning parts may be
utilized to facilitate loading of the nonpolar lipid mixture 74
into the reservoir chamber. The interior of the reservoir chamber
may be a simple walled structure but preferably contains an
interior structure that produces a relatively enlarged surface area
compared to a simple walled structure. For example, honeycomb
structure, separated multi-aligned structure, spiral or circular
structure, or another type of structure can be used to increase the
amount of contact surface area (sometimes called theoretical
plates) within the chamber. A variety of such structures are
well-known in the engineering arts.
[0054] In the illustrated embodiment, the solvent 72 can be
evaporated from the nonpolar lipid mixture 74 to produce a residual
film of nonpolar lipid materials 76 on the interior surfaces of a
reservoir chamber. Such a chamber can then be flushed with nitrogen
if desired and is typically sealed in those cases where a sterile
product is desired. All materials can be sterilized prior to
filling of the reservoir, either separately or in combination, and
the entire process may take place in a sterile environment.
Alternatively, the materials may be sterilized after the solvent is
evaporated either before or after the pan is sealed. The simplest
process that does not result in unacceptable degradation of
materials or adverse disruption of the lipid film on the interior
surfaces of the reservoir chamber is typically selected. In some
cases, the solvent 72 utilized in the process may impart sterility.
In any event, a nonpolar lipid material 76 is obtained that can be
utilized for further processing I the formation of liposomes.
[0055] When production of liposomes is desired, a polar bioactive
mixture 88 can be added to a reservoir chamber 78 with the residual
film of nonpolar lipid materials 76.
[0056] The polar bioactive mixture 88 can be prepared using a polar
solvent 80 (typically water), polar bioactive material 82, buffer
84, and excipients 86. Thermal control 90 can also be provided such
that the polar solvent comes in contact with the lipid film 76 in
the reservoir chamber at a temperature that allows liposome
formation, typically within plus or minus 15 degrees centigrade of
the glass transition temperature of the liposomal forming lipids,
and more typically within 10 degrees of the glass transition
temperature of the liposome forming lipids. The polar bioactive
mixture 88 can be sterile and can be introduced through a
sterilizing filter containing port in the reservoir chamber or
elsewhere in the inlet line. Contents of the chamber can be mixed
to provide contact between the incoming polar bioactive mixture 88
and the incoming lipid film 76 using one of a variety of mixing
methods, as indicated by control boxes, including mixing 90,
sonication 92, agitation 94. Also, temperature regulation or
thermal jetting or mixing can be enabled by means of thermal
control 98. The generated liposomes within the reservoir chamber
can be distributed by means of dispenser 100 onto one of many
substrates 104 (including fluid and solid substrates), such as to a
cellular culture, tissue or a cell, to carrier fluid 104, e.g., IV,
for pulmonary delivery, to capsules, to the surface of implantable
devices, or to a substrate material, for example. Again, a thermal
means 102 can be utilized to regulate dispensing of the liposomes
from dispenser 100 or facilitate the delivery of the liposomes to
the substrate 104.
[0057] In accordance with the present invention, in one embodiment,
the liposomes can be dispensed into a carrier fluid that is stored
for later use during which storage time does not affect the
liposomes in such a way to provide undesirable properties.
[0058] In the embodiment described in FIG. 2 above, there are
modular components that can be brought together to produce
liposomes using, for example, a polar fluid introduced into the pen
at a time when liposome production is desired. In another
embodiment, a single fluid-jet pen architecture can contain
chambers and/or flow channels with jetting and mixing and
dispensing controls such that all the liposome formation materials
are stored within a single fluid-jet pen albeit in separated
chambers such that on activation the polar solvent material stored
within the pen is combined with the lipid materials stored within
the pen to produce liposomes. The pen architecture can provide
jetting of liposomes formed within the pen through one or more
orifices into mixing chambers within the pen in a circulating
fashion to modify the liposome structure or size prior to movement
to another chamber and then jetting liposome formulations out of
the fluid-jet pen.
[0059] While the invention has been described with reference to
certain preferred embodiments, those skilled in the art will
appreciate that various modifications, changes, omissions, and
substitutions can be made without departing from the spirit of the
invention. It is therefore intended that the invention be limited
only by the scope of the appended claims.
* * * * *