U.S. patent application number 10/931480 was filed with the patent office on 2006-03-02 for plasma polymerization for encapsulating particles.
This patent application is currently assigned to Board of Regents, The University of Texas System. Invention is credited to Ceren Susut, Richard B. Timmons.
Application Number | 20060045822 10/931480 |
Document ID | / |
Family ID | 35943438 |
Filed Date | 2006-03-02 |
United States Patent
Application |
20060045822 |
Kind Code |
A1 |
Timmons; Richard B. ; et
al. |
March 2, 2006 |
Plasma polymerization for encapsulating particles
Abstract
The present invention includes systems, methods and compositions
for the encapsulation of particles. In one form, the system
comprises one or more particles, a rotatable reaction chamber in a
plasma enhanced chemical reactor to accept one or more particles,
and at least one carbonaceous compound to be used in the rotatable
reaction chamber, wherein the carbonaceous compound is polymerized
onto a surface of one or more particles forming a polymer film
encapsulating one or more particles. Using systems, methods, and
compositions of the present invention, any particle encapsulated
with a degradable or nondegradable polymer film may be introduced
and/or released into an environment. The polymer film as well as
introduction of encapsulated particles and release therefrom into
an environment are controlled by the present invention.
Inventors: |
Timmons; Richard B.;
(Arlington, TX) ; Susut; Ceren; (Washington,
DC) |
Correspondence
Address: |
GARDERE WYNNE SEWELL LLP;INTELLECTUAL PROPERTY SECTION
3000 THANKSGIVING TOWER
1601 ELM ST
DALLAS
TX
75201-4761
US
|
Assignee: |
Board of Regents, The University of
Texas System
Austin
TX
|
Family ID: |
35943438 |
Appl. No.: |
10/931480 |
Filed: |
September 1, 2004 |
Current U.S.
Class: |
422/130 |
Current CPC
Class: |
B01J 2219/0886 20130101;
B05D 1/62 20130101; B01J 19/088 20130101; B01J 2219/0841 20130101;
C08F 2/00 20130101; B01J 2219/0809 20130101; B01J 2219/0832
20130101 |
Class at
Publication: |
422/130 |
International
Class: |
B01J 19/00 20060101
B01J019/00 |
Claims
1. A system for encapsulating one or more particles comprising: one
or more particles; a rotatable reaction chamber in a plasma
enhanced chemical reactor to accept one or more particles; and at
least one carbonaceous compound to be used in the rotatable
reaction chamber, wherein the carbonaceous compound is polymerized
onto a surface of one or more particles forming a polymer film
encapsulating one or more particles.
2. The system of claim 1, wherein one or more particles are
selected from the group consisting of pharmaceutical composition,
food, semiconductor material, amino acid, protein, carbonaceous
compound, nucleic acid, vitamins, mineral, elemental molecule,
fatty acid, lipid, photolabile compound and combinations
thereof.
3. The system of claim 1, wherein the carbonaceous compound is a
carbon-containing monomer capable of polymerizing into a degradable
or nondegradable polymer.
4. The system of claim 1, wherein polymer film formation is
controlled by one or more reaction conditions selected from the
group consisting of power input, peak power, coating time, duty
cycle, flow rate of the carbonaceous compound, reactor pressure,
quantity of particles, and combinations thereof.
5. The system of claim 4, wherein power input is selected from the
group consisting of pulsed radio frequency and continuous wave
radio frequency.
6. The system of claim 5, wherein applying pulsed radio frequency
power promotes polymer film growth during plasma off time.
7. The system of claim 6, wherein increasing the plasma off time
increases the density of monomeric functional groups retained in
the polymer film.
8. The system of claim 4, wherein reducing the duty cycle increases
one of the group consisting of retention of functional groups in
the polymer film, polymer film growth during plasma off periods,
hydrophilicity of a polar polymer film, hydrophobicity of a
nonpolar polymer film, and combinations thereof.
9. The system of claim 4, wherein reducing peak power increases one
of the group consisting of wettability of the polymer film,
linearity in the structure of the polymer film, and combinations
thereof.
10. The system of claim 4, wherein increasing coating time
increases polymer film thickness.
11. The system of claim 4, wherein reducing the duty cycle reduces
cross-linkages in the polymer film.
12. A method for encapsulating one or more particles comprising the
step of: polymerizing at least one carbonaceous compound onto a
surface of one or more particles to form a polymer film
encapsulating one or more particles, wherein the carbonaceous
compound is polymerized in a rotatable reaction chamber of a plasma
reactor using radio frequency power.
13. The method of claim 12, wherein one or more particles are
selected from the group consisting of pharmaceutical composition,
food, semiconductor material, amino acid, protein, carbonaceous
compound, nucleic acid, vitamins, mineral, elemental molecule,
fatty acid, lipid, photolabile compound and combinations
thereof.
14. The method of claim 12, wherein the carbonaceous compound is a
carbon-containing monomer capable of polymerizing into a degradable
or nondegradable polymer.
15. The method of claim 12, wherein polymer film formation is
controlled by one or more reaction conditions selected from the
group consisting of power input, peak power, coating time, duty
cycle, flow rate of the carbonaceous compound, reactor pressure,
quantity of particles, and combinations thereof.
16. The method of claim 15, wherein power input is selected from
the group consisting of pulsed radio frequency and continuous wave
radio frequency.
17. The method of claim 16, wherein applying pulsed radio frequency
power promotes polymer film growth during plasma off time.
18. The method of claim 17, wherein increasing the plasma off time
increases the density of monomeric functional groups retained in
the polymer film.
19. The method of claim 15, wherein reducing the duty cycle
increases one of the group consisting of retention of functional
groups in the polymer film, polymer film growth during plasma off
periods, hydrophilicity of a polar polymer film, hydrophobicity of
a nonpolar polymer film, and combinations thereof.
20. The method of claim 15, wherein reducing peak power increases
one of the group selected from wettability of the polymer film,
linearity in the structure of the polymer film, and combinations
thereof.
21. The method of claim 15, wherein increasing coating time
increases polymer film thickness.
22. The method of claim 15, wherein reducing the duty cycle reduces
cross-linkages in the polymer film.
23. A system for encapsulating one or more pharmaceutical
compositions comprising: one or more pharmaceutical compositions; a
rotatable reaction chamber in a plasma enhanced chemical reactor to
accept one or more pharmaceutical compositions; and at least one
carbonaceous compound to be used in the rotatable reaction chamber,
wherein the carbonaceous compound is polymerized onto a surface of
one or more pharmaceutical compositions forming a polymer film
encapsulating one or more pharmaceutical compositions.
24. The system of claim 23, wherein the one or more pharmaceutical
compositions are selected from the group consisting of acetyl
salicylic acid or 4-isobutyl-.alpha.-methylphenylacetic acid, and
combinations thereof.
25. The system of claim 23, wherein the carbonaceous compound is a
carbon-containing monomer capable of polymerizing into a degradable
or nondegradable polymer.
26. The system of claim 23, wherein polymer film formation is
controlled by one or more reaction conditions selected from the
group consisting of power input, peak power, coating time, duty
cycle, flow rate of the carbonaceous compound, reactor pressure,
quantity of particles, and combinations thereof.
27. The system of claim 26, wherein power input is selected from
the group consisting of pulsed radio frequency and continuous wave
radio frequency
28. The system of claim 27, herein applying pulsed radio frequency
power promotes polymer film growth during plasma off time.
29. The system of claim 28, wherein increasing the plasma off time
increases the density of monomeric functional groups retained in
the polymer film.
30. The system of claim 26, wherein reducing the duty cycle
increases one of the group consisting of retention of functional
groups in the polymer film, polymer film growth during plasma off
periods, hydrophilicity of a polar polymer film, hydrophobicity of
a nonpolar polymer film, and combinations thereof.
31. The system of claim 26, wherein reducing peak power increases
one of the group consisting of wettability of the polymer film,
linearity in the structure of the polymer film, and combinations
thereof.
32. The system of claim 26, wherein increasing coating time
increases polymer film thickness.
33. The system of claim 26, wherein reducing the duty cycle reduces
cross-linkages in the polymer film.
34. A method for encapsulating one or more pharmaceutical
compositions comprising the step of: polymerizing at least one
carbonaceous compound onto a surface of one or more pharmaceutical
compositions to form a polymer film encapsulating one or more
pharmaceutical compositions, wherein the carbonaceous compound is
polymerized in a rotatable reaction chamber of a plasma reactor
using radio frequency power.
35. The method of claim 34, wherein one or more pharmaceutical
compositions consisting of from the group consisting of acetyl
salicylic acid or 4-isobutyl-.alpha.-methylphenylacetic acid, and
combinations thereof.
36. The method of claim 34, wherein the carbonaceous compound is a
carbon-containing monomer capable of polymerizing into a degradable
or nondegradable polymer.
37. The method of claim 34, polymer film formation is controlled by
one or more reaction conditions selected from the group consisting
of power input, peak power, coating time, duty cycle, flow rate of
the carbonaceous compound, reactor pressure, quantity of particles,
and combinations thereof.
38. The method of claim 37, wherein power input is selected from
the group consisting of pulsed radio frequency and continuous wave
radio frequency.
39. The method of claim 38, wherein applying pulsed radio frequency
power promotes polymer film growth during plasma off time.
40. The method of claim 39, wherein increasing the plasma off time
increases the density of monomeric functional groups retained in
the polymer film.
41. The method of claim 37, wherein reducing the duty cycle
increases one of the group consisting of retention of functional
groups in the polymer film, polymer film growth during plasma off
periods, hydrophilicity of a polar polymer film, hydrophobicity of
a nonpolar polymer film, and combinations thereof.
42. The method of claim 37, wherein reducing peak power increases
one of the group consisting of wettability of the polymer film,
linearity in the structure of the polymer film, and combinations
thereof.
42. The method of claim 37, wherein increasing coating time
increases polymer film thickness.
43. The method of claim 37, wherein reducing the duty cycle reduces
cross-linkages in the polymer film.
44. A composition prepared by the system of claim 1.
45. A composition prepared by the method of claim 12.
46. A composition prepared by the system of claim 23.
47. A composition prepared by the method of claim 34.
48. A system for controlling release of one or more particles into
an environment, the system comprising: one or more particles; a
rotatable reaction chamber in a plasma enhanced chemical reactor to
accept one or more particles; and at least one carbonaceous
compound to be used in the rotatable reaction chamber, wherein the
carbonaceous compound is polymerized onto a surface of one or more
particles forming a polymer film encapsulating one or more
particles, and wherein one or more reaction conditions in the
rotatable reaction chamber control polymer film formation and
release of one or more particles into the environment.
49. The system of claim 48, wherein one or more reaction conditions
are selected from the group consisting of power input, peak power,
coating time, duty cycle, flow rate of the carbonaceous compound,
reactor pressure, quantity of particles, and combinations
thereof.
50. The system of claim 48, wherein increasing power input reduces
rate of release of particles into the environment.
51. The system of claim 48, wherein increasing coating times
reduces rate of release of particles into the environment.
52. The system of claim 48, wherein increasing power peak reduces
rate of release of particles into the environment.
53. The system of claim 48, wherein increasing duty cycle reduces
rate of release of particles into the environment.
54. A composition prepared by the system of claim 48.
55. A method for controlling release of one or more particles into
an environment, the method comprising the steps of: polymerizing a
carbonaceous compound onto a surface of one or more particles to
form a polymer film encapsulating one or more particles; and
releasing encapsulated particles into one or more environments,
wherein the carbonaceous compound is polymerized in a rotatable
reaction chamber of a plasma reactor and one or more reaction
conditions in the rotatable reaction chamber control polymer film
formation, and wherein reaction conditions used in the rotatable
reaction chamber control release of encapsulated particles into one
or more environments.
56. The system of claim 55, wherein one or more reaction conditions
are selected from the group consisting of power input, peak power,
coating time, duty cycle, flow rate of the carbonaceous compound,
reactor pressure, quantity of particles, and combinations
thereof.
57. The system of claim 56, wherein increasing power input reduces
rate of release of particles into the environment.
58. The system of claim 56, wherein increasing coating times
reduces rate of release of particles into the environment.
59. The system of claim 56, wherein increasing power peak reduces
rate of release of particles into the environment.
60. The system of claim 56, wherein increasing duty cycle reduces
rate of release of particles into the environment.
61. A composition prepared by the method of claim 55.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to the encapsulation of
particles, and more specifically to particle encapsulation using a
plasma polymerization process.
[0002] Particle encapsulation, in which a particle is surrounded or
coated by at least one layer of a surface, has many beneficial
uses. Unfortunately, current methods of encapsulation generally
require a number of technical steps and result in encapsulated
products with poor stability. In addition, most methods result in
low product yields, due, in part, to the limited tolerance of the
starting materials to industrial operating conditions and the
numerous technical difficulties associated with the encapsulation
process, with product recovery and inadequate recycling from the
reaction systems.
[0003] Particle encapsulation, for example, offers a method in
which a particle may be introduced to an environment in a more
controlled manner. The control is generally imposed by varying
different aspects of the coating, such as its composition. Such
control generally falls into one of two categories: temporal
control and distribution control. Temporal control introduces the
particle to the environment over an extended time period or at a
pre-specified time. Here, the aim is to match the rate of particle
introduction to the rate of particle elimination from the
environment. Thus, the particle concentration appears to be
regulated and often for a much longer time. This technique is
particularly beneficial when introducing a particle into a biologic
system for therapeutic purposes, because the overall therapeutic
index is improved.
[0004] Distribution control, on the other hand, provides for the
introduction of a particle at at least one specific environmental
location. Such control may be desired when the particle is not
required or presents/encounters problems when introduced to the
entire environment. In biologic systems, distribution control may
reduce or eliminate the occurrence of undesirable side effects.
[0005] Current approaches to particle encapsulation include
layer-by-layer assembly of polyelectrolytes, emulsion-solvent
evaporation processes, formation of hydrogel films, and the
preparation of systems based on thiolated polymers, sol-gel
carriers, and granulation techniques. While current approaches do
provide satisfactory results for introducing particles to an
environment; these approaches are complex, involve a number of
technical steps, generate large amounts of waste products, and are
often inadequate in truly controlling the introduction of the
particle into the environment.
[0006] Clearly, then, there remains a need to provide for more
efficient compositions, systems and methods for introducing
particles to an environment in which the particle introduction may
be better controlled temporally and/or site-specifically.
SUMMARY OF THE INVENTION
[0007] The present invention solves the current problem associated
with inefficient systems and methods of introducing particles to an
environment. The present invention provides for a novel plasma
polymerization approach for controlling the introduction and
release of a particle to an environment.
[0008] Generally, and in one form, the present invention provides
for the encapsulation of one or more particles using plasma
enhanced chemical vapor depositions (PECVD). The PECVD coats
particles with at least one layer of a coating material. PECVD is
capable of controlling coating of the particle. In addition, the
coating material controls particle introduction into an
environment. The coating material and, hence, control of particle
introduction into an environment, is dependent on the encapsulation
process as well as the composition of the coating of the present
invention. In one embodiment, the coating material is a polymeric
film comprising at least one carbonaceous compound. The
carbonaceous compound is a degradable or nondegradable
carbon-containing compound capable of being polymerized on a
surface of a particle and, as such, encapsulating the particle.
[0009] The present invention also provides for a system for
encapsulating one or more particles comprising one or more
particles, a rotatable reaction chamber in a plasma enhanced
chemical reactor to accept one or more particles, and at least one
carbonaceous compound to be used in the rotatable reaction chamber,
wherein the carbonaceous compound is polymerized onto a surface of
one or more particles forming a polymer film encapsulating one or
more particles. The particle may be a pharmaceutical composition
(e.g., drug), food, semiconductor material, amino acid, protein,
carbonaceous compound, nucleic acid, vitamins, mineral, elemental
molecule, fatty acid, lipid, photolabile compound, as examples. The
carbonaceous compound is a carbon-containing monomer capable of
polymerizing into a degradable or nondegradable polymer.
[0010] Reaction conditions that promote polymerization and/or
encapsulation generally include power input, peak power, coating
time, duty cycle, flow rate of the carbonaceous compound, reactor
pressure, and quantity of particles. By altering one or more of the
reaction conditions, polymerization is controlled. By controlling
polymerization, one can ultimately control the release and rate of
release of the encapsulated constituents into an environment.
Aspects of the coating or polymer film that may be controlled
include film growth, thickness, number, density and quality of one
or more monomeric functional groups, hydrophilicity or
hydrophobicity, wettability, linearity, cross-linking, and various
combinations thereof.
[0011] In another form, the present invention is a method for
encapsulating one or more particles comprising the step of
polymerizing a carbonaceous compound onto a surface of one or more
particles to form a polymer film encapsulating one or more
particles, wherein the carbonaceous compound is polymerized in a
rotatable reaction chamber of a plasma reactor using radio
frequency power.
[0012] In still another form, the present invention provides for
methods and systems for controlling release of one or more
particles into an environment, the system comprising one or more
particles, a rotatable reaction chamber in a plasma enhanced
chemical reactor to accept one or more particles, and at least one
carbonaceous compound to be used in the rotatable reaction chamber,
wherein the carbonaceous compound is polymerized onto a surface of
one or more particles forming a polymer film encapsulating one or
more particles, and wherein reaction conditions used in the
rotatable reaction chamber control polymer film formation and
release of one or more particles into the environment. Particles
are released from the encapsulating polymer film by a number of
processes that include dissolution of the particle, degradation of
the polymer film, and/or passage of the particle through the
polymer film.
[0013] In yet another form the present invention provides for
compositions prepared by systems and methods of the present
invention. Compositions include organic and inorganic compositions,
such as pharmaceutical compositions, as examples.
[0014] Those skilled in the art will further appreciate the
above-noted features and advantages of the invention together with
other important aspects thereof upon reading the detailed
description that follows in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] For more complete understanding of the features and
advantages of the present invention, reference is now made to the
detailed description of the invention along with the accompanying
figures, wherein:
[0016] FIG. 1 depicts a schematic diagram of a plasma reactor in
accordance with one aspect of the present invention;
[0017] FIG. 2 depict FT-IR absorption spectra obtained for pulsed
plasma polymerization of allyl alcohol at 1/5 ms/ms and peak powers
of 100 W and 25 W;
[0018] FIG. 3 depict FT-IR absorption spectra obtained for pulsed
plasma polymerization of allyl alcohol at 1/5 ms/ms and 25 W for
coating times of 60 and 30 minutes;
[0019] FIG. 4 depict FT-IR absorption spectra obtained for CW
plasma polymerization of allyl alcohol at powers of 10 W and 25
W;
[0020] FIG. 5 depict release rates of acetylsalicylic acid coated
with of polyallylalcohol as a function of power input;
[0021] FIG. 6 depict release rates of acetylsalicylic acid coated
with polyallylalcohol as a function of coating time;
[0022] FIG. 7 depict release rates of acetylsalicylic acid coated
with polyallylalcohol as a function of plasma duty cycle employed
during coating;
[0023] FIG. 8 depict release rates of ibuprofen coated with
polyallylalcohol as a function of power input, all other plasma
variables held constant;
[0024] FIG. 9 depict release rates of ibuprofen coated with
polyallylalcohol as a function of coating times, all other plasma
variables held constant;
[0025] FIG. 10 depict release rates of ibuprofen coated with
polyallylalcohol as a function duty cycles, all other plasma
variables held constant;
[0026] FIG. 11 depict continuous wave plasma polymerization of
allyl alcohol with different power input values;
[0027] FIG. 12 depict FT-IR absorption spectra obtained for plasma
polymerization of perfluorohexane at 1/3 ms/ms and peak powers of
30 W and 50 W;
[0028] FIG. 13 depict FT-IR absorption spectra obtained for plasma
polymerization of perfluorohexane at 50 W and duty cycles of 1/3
ms/ms and 1/5 ms/ms;
[0029] FIG. 14 depict release rates of acetylsalicylic acid coated
with polyperfluorohexane as functions of duty cycles;
[0030] FIG. 15 depict release rates of acetylsalicylic acid coated
with polyperfluorohexane as a function of coating time and amount
of crystals coated in each run;
[0031] FIG. 16 depict release rates of ibuprofen coated with
polyperfluorohexane as functions of power input and amount of
crystals coated;
[0032] FIG. 17 depict release rates of ibuprofen coated with
polyperfluorohexane as a function of coating times;
[0033] FIG. 18 depict release rates of ibuprofen release coated
with polyperfluorohexane a function of duty cycles;
[0034] FIG. 19 depict release rates of acetylsalicylic acid coated
with polymethylmethacrylate as a function of power input;
[0035] FIG. 20 depict release rates of acetylsalicylic acid coated
with polymethylmethacrylate as a function of coating time;
[0036] FIG. 21 depict release rates of acetylsalicylic acid coated
with polymethylmethacrylate a function of duty cycles;
[0037] FIG. 22 depict release rates of ibuprofen coated with
polymethylmethacrylate as a function of power input;
[0038] FIG. 23 depict release rates of ibuprofen coated with
polymethylmethacrylate as a function of amount of crystals coated
in each run;
[0039] FIG. 24 depict release rates of ibuprofen coated with
polymethylmethacrylate a function of duty cycles;
[0040] FIG. 25 depicts a TLC result after running with
acetylsalicylic acid samples in accordance with one aspect of the
present invention;
[0041] FIG. 26 depicts a TLC result after running with ibuprofen
samples in accordance with one aspect of the present invention;
[0042] FIG. 27 depicts zero-order release kinetics of
acetylsalicylic acid coated with polyallyl alcohol as a function of
peak power;
[0043] FIG. 28 depicts zero-order release kinetics of
acetylsalicylic acid coated with polyallyl alcohol as a function of
coating time;
[0044] FIG. 29 depicts zero-order release kinetics of
acetylsalicylic acid coated with polyallyl alcohol as a function of
plasma duty cycle;
[0045] FIG. 30 depicts first-order release kinetics of
acetylsalicylic acid coated with polyallyl alcohol as a function of
peak power;
[0046] FIG. 31 depicts first-order release kinetics of
acetylsalicylic acid coated with polyallyl alcohol as a function of
coating time;
[0047] FIG. 32 depicts first-order release kinetics of
acetylsalicylic acid coated with polyallylalcohol as a function of
plasma duty cycle; and
[0048] FIG. 33 depicts light scattering of acetylsalicylic acid in
accordance with one aspect of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0049] Although making and using various embodiments of the present
invention are discussed in detail below, it should be appreciated
that the present invention provides many inventive concepts that
may be embodied in a wide variety of contexts. The specific aspects
and embodiments discussed herein are merely illustrative of ways to
make and use the invention, and do not limit the scope of the
invention.
[0050] In the description which follows like parts may be marked
throughout the specification and drawing with the same reference
numerals, respectively. The drawing figures are not necessarily to
scale and certain features may be shown exaggerated in scale or in
somewhat generalized or schematic form in the interest of clarity
and conciseness.
[0051] Discovering new and improved techniques for particle
encapsulation has become one of today's fastest growing areas of
research. While many of these techniques have biologic, chemical,
and pharmaceutical applications, other applicable fields include
electronics, the food industry, optics, data management,
agriculture, and material sciences, as examples. In general, the
primary purpose of encapsulation is to be able to control and/or
delay particle release into the environment. In the pharmaceutical
and medical device industry, another purpose for particle
encapsulation is to improve particle effectiveness when introduced
into a biologic system and to reduce any negative consequences
associated with introduction of the particle. In addition, the
encapsulated constituents (e.g., particle) should reduce costs
associated with its introduction, e.g., reduce dosing, reduce
administration of concomitant agents or particles, and reduce the
necessity for specialized personnel and/or equipment. The present
invention is capable of accomplishing these and other tasks as is
further described below.
Coating Material
[0052] Coating materials of the present invention are used to
prepare coatings that encapsulate particles of the present
invention. Coating materials are monomers or carbonaceous compounds
(molecules containing at least one carbon) that, upon
polymerization (e.g., by deposition), yield polymers or polymer
films that are degradable or nondegradable. In many instances,
monomers are carbonaceous compounds capable of forming at least one
polymer or polymer film degradable by chemical and/or physical
processes. Degradation of the polymer or polymer film is then
dependant, in part, on the encapsulation process, as described
herein. Monomers are also carbonaceous compounds capable of forming
at least one polymer or polymer film that is not degradable. As
such, the encapsulating polymer or polymer film is capable of
releasing the particle via one or more processes, such as
dissolution of all or a portion of the particle, chemical
degradation of the encapsulating polymer, physical degradation of
the encapsulating polymer, and/or passage of the all or a portion
of the particle through the polymer (e.g., through pores, spaces,
or openings in the polymer or polymer film). Release of a particle
encapsulated by such a degradable or nondegradable polymer is also
dependent, in part, oh the encapsulation process, as described
herein.
[0053] Degradable polymers include natural polymers (e.g.,
polysaccharides) as well as synthetic polymers, which are easy to
manipulate (e.g., polyesters, polyanhydrides, polyamides,
phosphorous-containing polymers). Examples of degradable coatings
or polymer films prepared by the present invention are listed in
TABLE 1. The coating materials that form such coatings or polymers
are the monomeric subunits. Examples of these monomeric subunits
include ethylene, vinyl alcohol, acrylic acid, carbophil, ethylene
glycol, glycolic acid, saccharide, lactic acid, esters, ortho
esters, phosphazenes, anhydrides, amides, as examples.
TABLE-US-00001 TABLE 1 Coating materials of the present invention.
Backbone Structure Coating Material Comments C--C Polyethylene
Zero-order temporal control achieved by (PE) diffusion from
matrices. Vinyl-based Poly(vinyl alcohol) Bioadhesive hydrogels.
C--C (PVA) Surface stabilizer in microsphere formulation.
Poly(acrylic acid) Bioadhesive polymer. Hydrogels of PAA (PAA)
reversibly swell as a function of pH. Polycarbophil Hydrogels.
Mucoadhesive properties allow temporal and distribution control.
C--O Polyethylene glycol Used as diffusion-limited tablet
formulation, (PEG) cross-linked hydrogels and polymer conjugates.
C--O, C.dbd.O Poly(glycolic acid) Biosynthetic poly(esters) used in
the formulation (PGA) of matrices containing human growth hormone.
Poly(lactic acid) (PLA) Poly(ortho esters) Degradable polymers.
Number of applications of 3,9-diethylidene-
2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU)- based poly(ortho
esters). Poly(anhydrides) Heterogeneous surface erosion.
Polyanhydride matrices used in microencapsulation of insulin,
enzymes and growth factors. Phosphorous-based Poly(phosphazenes)
Amino acid side chains generate flexible P.dbd.N, P--O materials
that degrade to amino acid, phosphate and ammonia poly[bis(glycine
ethyl ester)phosphazene].
[0054] A degradable polymer generally releases its encapsulated
particle into an environment through a process that includes
degradation of the encapulating polymer. A degradable polymer, as
with a nondegradable polymer, may also have pores, spaces, or
openings through which all or portions of the particle may
pass.
[0055] Degradation of a degradable polymer generally occurs via
bond cleavage and/or erosion. For biologic systems, degradation
often occurs via enzymatic cleavage or hydrolysis, in which the
polymer backbone is cut using a chemical process. With erosion, a
physical process occurs, generally involving surface erosion or
bulk erosion.
[0056] One feature of the present invention is that degradation of
a polymer or polymer film may be controlled. Similarly, the present
invention is capable of controlling other characteristics of a
polymer or polymer film that affect particle release. Hence, the
present invention is capable of controlling the release of a
particle into an environment. Such control occurs because the
present invention is capable of altering one or more conditions of
the polymer or polymer film. Coating conditions include altering
the surface area of a coating, adjusting the cross-linking of the
coating material, altering the wetness, hydrophilicity or
hydrophobicity of the coating, changing the density of side groups
or functional groups in the coating or coating material, and/or
altering the overall thickness of the coating. These coating
conditions may be altered for an encapsulation process involving
degradable and/or nondegradable polymers. In some instances,
encapsulation may include more than one polymer.
[0057] In one aspect of the present invention, coating materials
such as allyl alcohol, perfluorohexane (C.sub.6F.sub.14) and
methylmethacrylate are provided. Coatings or polymer films obtained
by plasma polymerization of allyl alcohol and methyl methacrylate
are hydrophilic. Coatings or polymer films obtained by plasma
polymerization of perfluorohexane are hydrophobic. Chemical
stuctures of (a) allyl alcohol, (b) perfluorohexane, and (c) methyl
methacrylate are shown below. H.sub.2C.dbd.CH--CH.sub.2--OH (a)
F.sub.3C--(CF.sub.2).sub.4--CF.sub.3 (b) ##STR1##
[0058] With the present invention, the carbonaceous compound may be
pretreated before use. For allyl alcohol--an oxygen containing
organic monomer that is very soluble at pHs ranging from 1 to
10--as well as perfluorohexane (C.sub.6F.sub.14)--a perfluorocarbon
compound that is sparingly soluble at pHs ranging from 1 to 10--the
compounds were degassed by freeze-thaw cycles before use. A similar
procedure was also performed for methyl methacrylate. Each
carbonaceous compound is also handled in the proper manner based on
its chemical composition, as is well known in the art. For
examples, allyl alcohol and perfluorohexane were protected from
light and stored at room temperature, while methyl methacrylate was
protected from light and stored in the refrigerator at 4 degrees
Centigrade.
[0059] Perfluorocarbon compounds, such as perfluorohexane, yield
plasma polymerized fluorinated films that exhibit good adhesion to
many organic and inorganic substrates, have low intermolecular
forces, low friction coefficient, and are biocompatible. The
present inventors have previously shown that a pulsed plasma
polymerization process may be used with perfluorocarbon compounds
to create polymers and polymers films. (See U.S. Pat. No.
5,876,753; U.S. Pat. No. 6,306,506; U.S. Pat. No. 6,214,423; all of
which are herein incorporated by reference) Polymers of
hexafluoropropylene oxide (C.sub.3F.sub.6O),
perfluoro-2-butyltetrahydrofuran (PF2BTHF, C.sub.8F.sub.16O) and
perfluoropropylene (C.sub.3F.sub.6) create excellent coatings or
films that are capable of attaching to substrate surfaces.
Particles
[0060] Particles of the present invention are organic or inorganic
molecules that may be surrounded or coated by at least one layer of
a coating material. Generally, preferred particles are those that
remain functional after coating. Functional particles may undergo
some structural alteration(s) during coating; however, their
general function remains. Particles may include pharmaceutical
compositions (e.g., drugs), food, semiconductor materials,
proteins, carbonaceous compounds, nucleic acids, vitamins,
minerals, elemental molecules, fatty acids, lipids, photolabile
compounds, as examples.
[0061] In various embodiments, a pharmaceutical composition, for
example aspirin and/or ibuprofen, may be used as the particle.
Aspirin, chemically referred to as acetyl salicylic acid, is an
antipyretic, anti-inflammatory analgesic with a carboxylic acid
backbone group rendering the molecule soluble in various solvents.
Acetyl salicylic acid, shown below as structure (d), may be
detected by UV-visible spectroscopy and is available in crystal
form. While uniformly sized particles may be used with the present
invention, it is not necessary. In some instances, particles of
different sizes may be preferred. For crystals such as aspirin,
uniformity may be obtained by grinding and sieving the crystals
followed by drying under vacuum (e.g., 100 degrees Centigrade
overnight). ##STR2##
[0062] Ibuprofen, chemically referred to as
4-isobutyl-.alpha.-methylphenylacetic acid, is an acidic,
non-steroidal, anti-inflammatory composition with limited
solubility in low pH (<7) solutions and high solubility at
higher pH (>7) solutions. Ibuprofen has a carboxylic acid
backbone group as shown in structure (e) and may be detected by
UV-visible spectroscopy. For ibuprofen, crystals were sieved and
used without drying. ##STR3## Plasma Enhanced Chemical Vapor
Depositions (PECVD)
[0063] PECVD provides for a solventless, pin-hole free, single-step
encapsulation process in which the encapsulating or coating
material may be modified depending on the process, itself. For
example, the process is able to control encapsulation, and hence,
particle introduction into an environment, by adjusting the side
groups, thickness, wetness, surface area and/or composition of the
coating material.
[0064] With the present invention, both pulsed and the more
conventional continuous-wave (CW) plasma approaches may be used.
For example, the present inventors have shown that using a pulsed
plasma approach provides excellent film chemistry control during
polymer formation and control of film thickness (Susut C and
Timmons R B, Plasma enhanced chemical vapor depositions to
encapsulate crystals in thin polymeric films: a new approach to
controlling drug release rates, International Journal of
Pharmaceutics, 2004, in press; herein incorporated by reference).
Pulsed applications may limit undesirable plasma-induced chemical
changes to particles. In addition, under pulsed reaction
conditions, significant film formation occurs during plasma off
periods (and undesirable high energy reactions between ion-radical
and particle are minimized).
Sample Reaction Conditions Using a Pulsed Radio Frequency Plasma
Reactor
[0065] A 360.degree. rotatable plasma reactor was employed to help
achieve uniform and complete coating of particles. A cylindrical
Pyrex glass reactor of 5 centimeter internal diameter and 45
centimeter in length was used as the plasma chamber. Radio
frequency (RF) power to the reactor was provided through two
concentric metal rings separated by a distance of 20 centimeter.
The volatile reaction products and unreacted monomer were collected
in a liquid nitrogen cold trap located downstream of the reactor. A
butterfly valve controller with pressure transducer (MKS Baratron
Model 252A) was used both to monitor and control pressure in the
reactor. The flow rate of the monomer was controlled and monitored
by a flowmeter placed upstream of the reactor. Ferrofluidic valves,
inserted at both ends of the reactor tube, permitted complete
rotation of the reactor chamber under vacuum conditions. The
rotation rate was controlled with a variable speed motor (Dayton
Model 4Z827D) connected by pulley to the reactor.
[0066] A schematic of a plasma reactor of the present invention,
with its associated electronics, is shown in FIG. 1. In this
embodiment, the reactor includes a radio frequency amplifier (ENI
model A300), a pulse generator (Tektronix model 2101), a function
generator (Wavetek model 166), a frequency counter (Hewlett-Packard
model 5315A) and a capacitor/inductor matching network used to tune
the circuit to minimize reflected power. Applied and reflected
power were measured in volts with an oscilloscope (BK Precision
model 2120B) which was also used to monitor the matching network.
The matching network was employed to minimize the reflected energy
during the course of each run. The entire reactor was located
inside a Faraday cage to prevent radiation of the RF energy to the
external environment. While a radio frequency of 13.56 MHz was
used, other frequencies may also be used as seen fit or as
required.
[0067] Carbonaceous compounds of the present invention were
deposited onto particles using a reactor, similar to one described
above. Those skilled in the art will appreciate that the features
described may also be modified as needed. For most reactions, the
rotation rate was kept steady (e.g., 4 rev/minute for
acetylsalicylic acid crystal particles or 3 rev/minute for
ibuprofen crystal particles). The lower rotation rate for ibuprofen
minimized the adsorption of the smaller particles on the walls of
the reactor chamber by electrostatic forces. The quantity of
particles placed in the reaction chamber, in each run, was, in some
cases, used as a variable and this effect was evaluated.
[0068] Self-aggregation and/or electrostatic forces were reduced by
several methods, including increasing the monomer flow rate,
decreasing the rotation rate of the reactor chamber and/or limiting
the peak power to 100 Watts or less. Applying vibration to the
reactor walls as well as applying a surface treatment to minimize
adhesions may also be employed. In addition, it is also possible to
recover coated particles that have adhered to the reactor wall. In
general, the percent recovery (ratio of the amount of recovered
particles that are coated vs. total amount of particles introduced
into the reactor) may typically range from 50% to 99%. One skilled
in the art will appreciate that other typical ranges may apply.
Reactor Preparation
[0069] Before each coating, the reactor chamber was pre-cleaned
(e.g., with soap and water and acetone). It was then vacuumed to a
background pressure (e.g., approximately 10 mTorr). Next, the
reactor was treated with an oxygen plasma discharge (e.g., 100
Watts at 100 mTorr pressure, operated at a duty cycle of 1/3 ms/ms
or 1/5 ms/ms). Pre-cleaning removes polymer residues from the
chamber due to previous coatings. After the oxygen plasma
discharge, particles would be placed into the reactor. The two ends
of the chamber were stoppered (e.g., with glass wool) to keep the
particles in the chamber during coating. The reactor chamber was
then evacuated to the background pressure.
Plasma Polymerization
[0070] In general, and for example coatings provided herein, the
reaction chamber was rotated constantly. Using the pulsed plasma
approach, significant polymer film formation occurred during plasma
off periods, a time when undesirable high energy reactions between
ion-radical and particles are minimized. A process of continuous
wave plasma polymerization may also be employed to encapsulate
particles.
[0071] The average power employed under pulsed plasma conditions
was calculated according to the formula shown below (1), where
.tau..sub.on and .tau..sub.off are the plasma on and off times and
P.sub.peak is the peak power. By using pulsed plasma
polymerization, the average power employed during film formation
was often much lower than the power employed under continuous wave
reaction conditions, because of the relatively longer plasma off
times compared to plasma on times. P average = .tau. on .tau. on +
.tau. off .times. P peak ( 1 ) ##EQU1##
[0072] Deposition (polymerization) of the coating or polymer film
of the present invention was controlled by altering a number of
variables associated with the plasma reactor. Variables included
duty cycle, power input, peak power, flow rate of the monomer,
pressure of the reactor, coating time period and quantity of
particles introduced into the reaction chamber at a time.
[0073] With the present invention, suitable plasma on/off times
(duty cycles) were generally in the millisecond range. As used
herein, duty cycles are reported as on/off times per cycle and
provided in units of ms/ms. Suitable peak powers ranged from about
25 W to about 100 Watts. Suitable coating periods were typically
between about 20 minutes and 1 hour. In some cases,
self-aggregation of particles may help determine the coating time
period. The amount of particles coated at a time typically ranged
from about 0.5 grams to about 4.0 grams. Flow rates were about 1.5
cm.sup.3 (STP)/minute to about 2.00 cm.sup.3 (STP)/minute. The
pressure of the reactor typically varied from about 150 mTorr to
about 350 mTorr. Those skilled in the art will appreciate that,
while typical ranges and values are provided, there is no reason
that other values may not be applied, as needed.
Characterization of Plasma Polymers
[0074] To help characterize the coating or polymer film deposited
by the present invention, replicate runs of certain carbonaceous
compounds were provided in which the carbonaceous compound was
deposited on one or more solid substrates, such as silicon wafers
and KBr surfaces. The FT-IR spectra were collected with a Bruker
Vector 22 spectrophotometer using 4 cm.sup.-1 resolution. Spectra
were recorded in absorption mode on polymer films deposited on KBr
discs. The thickness of the films deposited on silicon wafers were
measured using a Tencor Alpha Step 200 profilometer. A syringe
needle was employed to scribe a scratch on the films. Thickness
calculations were based on the difference between the height of the
film and original height of the substrate.
Particle Introduction and Release into an Environment
[0075] The environmental conditions for introduction of one or more
particles into an environment may also be manipulated to alter
particle release. For example, in one aspect of the present
invention, the environment for acetyl salicylic acid was 0.1 M HCl
solution (to simulate gastric fluid). For ibuprofen, the
environment was a pH 7.0 phosphate buffered solution (to simulate
intestinal fluid).
[0076] The quantity of particles introduced into an environment was
assessed using a UV-visible spectrophotometer (Jasco). The maximum
absorption wavelength for acetylsalicylic acid was determined to be
276 nm. Absorbance versus time measurements were taken periodically
using 1-cm quartz cuvettes. Stock solutions were prepared with 10
mg of particles in 100 ml of solution. Each solution was stirred
constantly in a 100 ml volumetric flask. At the end of each period,
an aliquot was transferred into a cuvette; the liquid was returned
to the volumetric flask as soon as the absorbance data were taken.
The maximum absorption wavelength for ibuprofen was determined to
be 264 nm. With the exception of pH change, the same procedures as
employed for acetyl salicylic acid were followed for ibuprofen. For
kinetic analysis, model fittings were performed using Microsoft
Excel.
Thin-Layer Chromatography (TLC)
[0077] Silica gel, polyester-backed TLC plates of thickness 250
.mu.m were used to analyze the separation and/or breakdown of
compounds after polymerization and after particle release into an
environment. Before use, TLC plates were dried in an oven for about
1 hour at 110 degrees Centigrade to remove adsorbed atmospheric
moisture.
[0078] For calculations, the distinction between different
components in a mixture was determined by a physical constant
called retention factor (R.sub.F) which is based on the
preferential interaction between the compound and the TLC plate. It
is known that each compound generally has a different retention
factor. If a compound is converted, separated, or structurally
altered during plasma polymerization, it will generally have a
different RF value. Thus, free particles and encapsulated particles
were prepared by dissolving 10 mg of each in 1 ml of
dichloromethane.
[0079] All TLC solutions were freshly made and aliquots of 5 .mu.l
were applied as spots approximately 1 cm apart onto 5.times.17 cm
silica gel TLC plates. A chloroform-acetone (4+1) solvent system
was used. Plates were air-dried and analyzed by iodine vapor.
Retention factors were calculated for each encapsulated particle
and compared to the value obtained for unencapsulated (i.e., free)
particle. These values were compared to those known in the
literature.
Plasma Polymerization of Allyl Alcohol
[0080] Allyl alcohol was used as a representative carbonaceous
compound for coating particles of the present invention. It was
determined that as the RF duty cycle was reduced, the retention of
the monomer's oxygen content increased, leading to an increase in
the hydrophilicity of the coating or polymer film (also referred to
herein as film). An increase in the plasma off time also caused an
increase in the --OH group incorporation in the coating thus
increasing surface density of polar groups. In addition,
significant polymer film growth occurred during the plasma off
times. Deposition per pulse cycle was shown to increase at constant
on time and power, as the off time increased.
FT-IR Analysis of Plasma Polymerized Allyl Alcohol Films
[0081] Plasma polymerized allyl alcohol films were examined as a
function of power, coating time and pulsed or continuous wave
modes. Some results are illustrated in FIGS. 2-4. FIG. 2 shows the
increase in the retention of the monomer's oxygen content as peak
power was adjusted from 100 W to 25 W, where relative intensities
of the O--H group (.about.3400 cm.sup.-1) and C--H group
(.about.2900 cm.sup.-1) are clearly visible. Here, decreasing peak
power increased the wettability of the coating or polymer film. In
addition, increasing peak power created additional C.dbd.O groups
(.about.1700 cm.sup.-1); the extent of C.dbd.O formation, relative
to OH incorporation in the polymer film, decreased with decreasing
peak power.
[0082] FIG. 3 shows that the intensities of stretching vibrations
of all the groups decreases as coating time decreased. No
additional peaks were observed. The same general observations were
made for the spectra obtained for CW plasma polymerization of allyl
alcohol at powers 10 and 25 W.
[0083] Regarding FT-IR analysis of the films with changing RF duty
cycles, there was a progressive increase in the retention of the
monomer's oxygen content with decreasing RF duty cycles. In
addition there was a continual shift in the O--H stretching
frequency to lower wave numbers with increased O--H incorporation
as a result of H-bonding. The trends mentioned above applied for
duty cycles from 1/2 ms/ms and 1/5 ms/ms; similar trends occurred
for RF duty cycles less than 1/5 ms/ms. In addition, there was a
slight increase in the retention of the monomer's oxygen content
with duty cycles from 1/2 to 1/5 ms/ms.
Plasma Polymerized Allyl Alcohol Films Encapsulating
Acetylsalicylic Acid Crystals
[0084] Some of the reaction and coating conditions for coating
particles of acetylsalicylic acid with one or more carbonaceous
compounds of allyl alcohol are illustrated in TABLE 2. Polished Si
substrates were also coated and profilometer measurements were
made. Pressure in the reactor was about 160 mTorr with a constant
rotation rate of about 4 rev/min. The approximate quantity of
particles introduced into the reaction chamber for each run (e.g.,
AA1, AA2, etc) was about 4 grams. Actual particle sizes ranged from
about 1 to about 100 microns; mean size was approximately 30
microns, as observed by light scattering measurements.
TABLE-US-00002 TABLE 2 Examples when coating particles of
acetylsalicylic acid with allyl alcohol. Monomer RF Duty Film
Flowrate Peak Cycle Coating Thick- Energy Coat- (cm.sup.3(STP)/
Power On/off Time ness Efficiency ing min) (Watts) (ms/ms) (min)
(kA.degree.) (mA.degree./J) AA1 1.5 100 1/5 30 4.9 160 AA2 1.5 25
1/5 30 4.0 530 AA3 1.5 25 1/5 60 7.4 500 AA4 1.5 25 1/3 60 4.0 180
AA5 1.5 50 1/5 30 5.9 390
[0085] TABLE 2 shows the variations in film thickness. For pulsed
plasma polymerization of allyl alcohol, the energy efficiency of
film formation (mA.degree./J) increased with decreasing power input
(samples AA1, AA5 and AA2). Ablation reactions may be significant
at higher power inputs. Changing the coating time (other variables
held constant) effected film thickness. For example, when coating
time was doubled, the film thickness increased by a factor of 2.
Decreasing the duty cycle increased the energy efficiency of film
formation and indicated that there was significant film growth
during plasma off periods.
[0086] FIGS. 5-7 show the effects of power, coating time and RF
duty cycle on the rate of release of particles into an environment
(illustrated as percent particle release versus immersion time).
Uncoated crystals are identified as free crystals or bare crystals.
Plasma coatings deposited on the particles (e.g., acetylsalicylic
acid crystals) effected the rate of release of particles. In FIG.
5, the quantity of particles introduced into an environment
(release rates) are shown as a function of the peak power employed
during coating. Changing the power input had a large effect on the
release rate. For example, doubling the power input during coating
led to a 2-fold increase in the time required for complete release
of the particle. Complete release (introduction of particles into
the environment) was 80 minutes for AA2 (at 25 W), 220 minutes for
AA5 (at 50 W) and 400 minutes for AA1 (at 100 W).
[0087] FIG. 5 also shows that polymer film composition is affected
by power input. Polymer cross-linking increased when peak power was
increased. Increased cross-linking provided a less porous barrier
and reduced the release rate. The increased cross-linking of the
polymer film at higher peak powers is consistent with FT-IR and XPS
analysis and consistent with other information known in the art.
When the release rates were evaluated (release for first 20 minutes
as the rate of rise or slope), it was observed that there was an
initial release rate of 2.58 for AA2 (25 W), 0.886 for AA5 (50 W)
and 0.616 for AA1 (100 W) (see k values in FIG. 5). Adjusting the
power from 100 W to 50 W increased the initial release rate by a
factor of 1.4; decreasing the power by the same ratio to 25 W
increased the release rate 3 fold.
[0088] The duration of the plasma coating time had an effect on
particle release rate. FIG. 6 shows that doubling the coating time
increased the time required for complete release of the particle by
a factor of 2 (from 80 minutes for AA2 to 160 min for AA3). The
slope from AA2 to AA3 decreases by 0.7 (from 2.58 to 1.8).
[0089] FIG. 7 shows the effect of duty cycle on release rates. Two
different plasma duty cycles were used: 1/3 ms/ms and 1/5 ms/ms.
Coating runs were 60 minutes. Polymer film deposited with a lower
duty cycle (1/5 ms/ms) were almost twice as thick as those of the
higher, 1/3 ms/ms duty cycle (7.45 kA.degree. versus 4.00
kA.degree.). Despite a greater polymer thickness, the release rate
of particles coated with a duty cycle of 1/5 ms/ms was about 1.4
times faster than particles coated with a duty cycle of 1/3 ms/ms.
Higher duty cycles typically introduce more cross-linking
accounting for the slower release rate.
[0090] As described above, the present invention is used to control
the characteristics of a coating or polymer film deposited on a
particle using a pulsed or continuous wave radio frequency. The
control factors include coating time, peak power input and pulsed
plasma duty cycle. The present invention also controls polymer film
thickness and polymer film cross-linking, as well as the rate of
release of the particle from the polymer film.
Plasma Polymerized Allyl Alcohol Films Encapsulating Ibuprofen
Crystals
[0091] Some of the reaction and coating conditions for coating
particles of ibuprofen with allyl alcohol are illustrated in TABLE
3. IA1, IA2, IA3, and IA4 were performed under pulsed conditions
and IA5 and IA6 were performed under continuous wave conditions.
The pressure in the reactor was about 260 mTorr with a constant
rotation of about 3 rev/min. Approximately 0.8 grams of crystals
were used each time; crystals were typically smaller than 35 .mu.m.
TABLE-US-00003 TABLE 3 Examples of conditions when coating
particles of ibuprofen with allyl alcohol. Monomer RF Duty Film
Flowrate Peak Cycle Coating Thick- Energy Coat- (cm.sup.3(STP)/
Power On/off Time ness Efficiency ing min) (Watts) (ms/ms) (min)
(kA.degree.) (mA.degree./J) IA1 2.0 50 1/3 40 N/A N/A IA2 2.0 50
1/5 40 N/A N/A IA3 2.0 50 1/3 20 N/A N/A IA4 2.0 30 1/3 40 N/A N/A
IA5 2.0 10 CW 10 4.2 690 IA6 2.0 25 CW 10 5.2 350
[0092] TABLE 3 shows that increasing the power under
continuous-wave conditions effects the energy efficiency of film
formation; increased power decreased the energy efficiency of
polymer film formation. Note that for each run, total CW power
input was comparable to the power used in the pulsed experiments,
because the average power under pulsed plasma conditions
corresponded to 1/6.sup.th or 1/4.sup.th of the peak power
reported.
[0093] The release rates of encapsulated ibuprofen were examined as
a function of peak power, coating time and plasma duty cycle. Both
CW and pulsed conditions were evaluated and some of the results
shown in FIGS. 8-11.
[0094] In general, the rate of release of ibuprofen was faster than
the rate of release of acetyl salicylic acid. This faster rate is
largely a reflection of the higher solubility of ibuprofen. FIG. 8
shows that with a pulsed plasma deposition time of 40 minutes,
there was a decrease in the ibuprofen release rate by a factor of
3.6, when peak power increased from 30 W to 50 W.
[0095] Increasing the coating time increased the time required to
complete particle release (see FIG. 9). IA3 took 36 minutes for
complete particle release, whereas IA1 took 90 minutes; coating
time was doubled from IA3 to IA1. In addition, power input results
closely correlate with results for coating time.
[0096] FIG. 10 shows the effect of duty cycle on release rates. As
with acetyl salicylic acid particles, release rates were sensitive
to changes in duty cycle. A higher duty cycle resulted in a lower
particle release rate. For example, changing the duty cycle from
1/5 ms/ms to 1/3 ms/ms, increased the time to complete particle
release from 47 minutes to 90 minutes with a slope in the first 6
minutes of 6.33 to 3.17, respectively (see also FIG. 8).
[0097] When depositing the polymer film using CW conditions with
different peak powers (10 W and 25 W, TABLE 3), the release rate
was also affected as shown in FIG. 11. While lower power inputs
were used with CW depositions (10 W and 25 W for CW vs. 30 W and 50
W for pulsed), the average power input, computed as duty
cycle.times.peak power, were generally the same for each. In
addition, CW depositions produced similar film thicknesses as those
produced with pulsed plasma depositions.
Plasma Polymerization of Perfluorohexane
[0098] Plasma polymerization characteristics of perfluorocarbons
have been provided by the present inventors (see U.S. Pat. Nos.
5,876,753; 6,306,506; 6,214,423; 6,329,024; 6,482,531). CF.sub.x
radicals, especially CF.sub.2 radicals and F atoms in gas phase are
important for polymer film formation. CF.sub.2 radicals are
generally thought to be responsible for the formation of the linear
portion of deposited fluorocarbon polymer films, whereas quaternary
C--CF.sub.n type radicals are involved in cross-linking. The same
holds true for perfluorohexane. Films produced by plasma
polymerization of perfluorocarbons vary from a highly cross-linked
structure at high plasma duty cycle to a more linear CF.sub.2
dominated structure at low plasma duty cycle. Decreasing the duty
cycle reduces the cross-linkages. Similarly, as the peak power is
decreased, a more linear polymer structure is observed; CF.sub.2
content increases at low peak power.
[0099] Coatings produced using perfluorocarbons are generally
highly hydrophobic. A rough and fibrous-like morphology appears to
be responsible for this, because high power inputs accompanied by
relatively long plasma off times resulted in fibrous-like
ultrahydrophobic surfaces on the polymers films. With the present
invention, plasma polymerization of a hydrophobic polymer film,
such as perfluorohexane, can also be manipulated to control the
introduction and release of a particle into an environment.
FT-IR Analysis of Plasma Polymerized Perfluorohexane Films
[0100] Plasma polymerized perfluorohexane films were examined as a
function of peak power and plasma duty cycle. (See FIGS. 12 and 13)
FT-IR analysis of perfluorohexane films showed a single broad band
at .about.1200 cm.sup.-1 indicating the presence of a wide range of
CF stretching frequencies leading to a heterogeneous, highly
crosslinked fluorocarbon film. Film compositions were similar with
the application of different duty cycles. Polymer films of
perfluorohexane are typically hydrophobic.
Plasma Polymerized Perfluorohexane Films Encapsulating
Acetylsalicylic Acid Crystals
[0101] Some of the reaction and coating conditions for coating
particles of acetylsalicylic acid with perfluorohexane are
illustrated in TABLE 4. TABLE-US-00004 TABLE 4 Examples when
coating acetylsalicylic acid with perfluorohexane. Amount of
Crystals Coated Peak Power RF Duty Cycle Coating Coating In Each
Run (gr) (Watts) On/off (ms/ms) Time (min) AP1 4 100 1/5 60 AP2 4
100 1/3 60 AP3(1) 4 100 1/5 30 AP3(2) 3 100 1/5 60 AP3(3) 2 100 1/5
90 AP3(4) 1 100 1/5 120
[0102] For TABLE 4, the flow rate of the monomer was about 1.5
cm.sup.3 (STP)/min and pressure in the reactor was about 130 mTorr
with a constant rotation rate of about 4 rev/min. For AP3, rather
than a single run, about 4 grams were introduced into the chamber
and one gram of sample was removed every 30 minutes, signified as
AP3(1), AP3(2), AP3(3), AP3(4), for a total of two hours.
[0103] Referring to TABLE 4, the duration of plasma coating times
were observed to have an effect on particle release rates (see AP1
and AP2). For AP3 runs, the effect of coating time on quantity of
particles was evaluated. The results are indicated as percent
release versus immersion time in the simulated gastric solution
(FIGS. 14 and 15). FIG. 14 shows that duty cycle had an effect on
initial release rate (measured as slope taken in the first 20
minutes of release) and for complete particle release. With a
change in duty cycle of 1/5 ms/ms (AP1) to 1/3 ms/ms (AP2), there
was a 41% increase in the time required for complete particle
release; the initial rate of release decreased by a factor of 0.83.
The thickness of the film deposited at 1/3 ms/ms was, however,
higher than that produced at 1/5 ms/ms.
[0104] FIG. 15 shows that increasing the coating time decreased the
rate of release. For example, the initial rate of release for
AP3(1), AP3(2), AP3(3) and AP3(4) are 1.55, 0.81, 0.39 and 0.25
corresponding to coating times of 30, 60, 90 and 120 minutes,
respectively. As such, the present invention is able to control the
coating of a polymer film that is hydrophobic as well as
hydrophilic.
Plasma Polymerized Perfluorohexane Films Encapsulating Ibuprofen
Crystals
[0105] Some of the reaction and coating conditions for coating
particles of ibuprofen with perfluorohexane are illustrated in
TABLE 5 TABLE-US-00005 TABLE 5 Examples of conditions used when
coating ibuprofen with perfluorohexane. Amount of RF Duty Coat-
Film Crystals Peak Cycle ing Thick- Energy Coat- Coated In Power
On/off Time ness Efficiency ing Each Run (gr.) (Watts) (ms/ms)
(min) (kA.degree.) (mA.degree./J) IP1 1 50 1/3 40 2.5 84 IP2 1 50
1/5 40 1.6 83 IP3 1 50 1/3 20 1.3 86 IP4 1 30 1/3 40 2.4 130 IP5
0.5 100 1/3 40 N/A N/A
[0106] For TABLE 5, the flow rate of the monomer was about 2.0
cm.sup.3 (STP)/min and the pressure in the reactor was about 300
mTorr with a constant rotation rate of about 3 rev/min. Polished
silicon wafer substrates were also coated and profilometer
measurements were made.
[0107] With pulsed plasma polymerization of perfluorohexane,
increasing the peak power decreased the energy efficiency of film
formation, similar to allyl alcohol film formation. Changing the
coating time (other variables held constant) greatly effected film
thickness. For example, doubling the coating time, doubled film
thickness.
[0108] FIGS. 16-18 illustrate the effects of power, coating time,
RF duty cycle and amount of coated crystals on rate of release (as
percent release vs. immersion time in simulated intestinal fluid).
While release rates are generally faster for ibuprofen-coated
crystals as compared with acetyl salicyclic acid-coated crystals,
the rate is, in a large part, thought to be due to the greater
solubility of ibuprofen and the smaller size of its crystals.
Overall, increasing the peak power or coating time delayed the
release of perfluorohexane-coated particles; increasing the plasma
duty cycle also delayed release.
Plasma Polymerization of Methyl Methacrylate
[0109] Films formed by the polymerization of methyl methacrylate
have polyester groups that are biocompatible. Such polymer films
are typically very stable in phosphate buffered solutions (pH=7.4)
and resist hydrolysis. Through X-ray photoelectron spectroscopy
(XPS) analysis, it was observed that oxygen content in such films
increased as the peak power decreased. As peak power increased, the
deposition rate was observed to decrease. In addition, polymer film
growth occurred during the off periods with pulsed plasma
deposition. Comparison of coatings produced under pulsed plasma and
CW conditions, showed that more ester groups were incorporated with
pulsed polymerization and ester groups retention was enhanced as
the average power was reduced.
Polymerized Methyl Methacrylate Films Encapsulating Acetylsalicylic
Acid Crystals
[0110] Some of the reaction and coating conditions for coating
particles of acetylsalicylic acid with methyl methacrylate are
illustrated in TABLE 6. For TABLE 6, the flow rate of the monomer
was about 2.0 cm.sup.3 (STP)/min and the pressure in the reactor
was about 230 mTorr with a constant rotation rate of about 3
rev/min. Polished silicon wafer substrates were also coated and
profilometer measurements were made. TABLE-US-00006 TABLE 6
Examples when coating acetylsalicylic acid with methyl
methacrylate. Amount of RF Duty Coat- Film Crystals Peak Cycle ing
Thick- Energy Coat- Coated In Power On/off Time ness Efficiency ing
Each Run (gr.) (Watts) (ms/ms) (min) (kA.degree.) (mA.degree./J)
AM1 4 50 1/3 30 5.5 240 AM2 4 50 1/5 60 N/A N/A AM3 4 50 1/3 60 N/A
N/A AM4 4 100 1/3 30 6.1 130
[0111] As with the other carbonaceous compounds, TABLE 6 shows that
increasing the peak power from 50 W to 100 W increased the film
thickness but decreased the overall energy efficiency of a polymer
film of methyl methacrylate. In TABLE 6, N/A represents those
samples where the tackiness of methyl methacrylate did not allow
for the measurement of film thickness or energy efficiency.
[0112] FIGS. 19-21 show the effects of power input, coating time
and RF duty cycle on the rate of release of particles into an
environment (illustrated as percent particle release versus
immersion time in simulated gastric fluid).
[0113] As with polymer films of polyallyl alcohol and
polyperfluorohexane, FIGS. 19 and 20 show that with films of
polymethyl methacrylate, increasing the power input (FIG. 19) and
coating times (FIG. 20) reduced the rate of release of particles
into the environment. For example, increasing the peak power input
from 50 to 100 W decreased the release rate by a factor of 5.5.
Doubling the coating time decreased the release rate by a factor of
2.4.
[0114] FIG. 21 shows that changing the plasma duty cycle from 1/5
ms/ms to 1/3 ms/ms during plasma polymerization decreased the
initial release rate by a factor of 1.5. While these changes were
larger than those for polymer films of polyallylalcohol, all
results remained consistent. The larger changes are generally due
to the fact that films deposited with methyl methacrylate compounds
were generally thicker than coatings deposited by the other
carbonaceous compounds.
Plasma Polymerized Methyl Methacrylate Films Encapsulating
Ibuprofen Crystals
[0115] Some of the reaction and coating conditions for coating
particles of ibuprofen with methyl methacrylate are illustrated in
TABLE 7. TABLE-US-00007 TABLE 7 Examples of conditions when coating
ibuprofen with methyl methacrylate. Amount of Crystals Coated Peak
Power RF Duty Cycle Coating Coating In Each Run (gr.) (Watts)
On/off (ms/ms) Time (min) IM1 0.5 100 1/3 20 IM2 0.5 50 1/3 20 IM3
1 50 1/3 20 IM4 1 50 1/5 20
[0116] For TABLE 7, the flow rate of the monomer was about 2.0
cm.sup.3 (STP)/min and the pressure in the reactor was about 300
mTorr with a constant rotation rate of about 4 rev/min. The amount
of crystals used with IM1 and IM2 was about 0.5 gram and about 1
gram used for IM3 and IM4. Polished silicon wafer substrates were
also coated and profilometer measurements were made.
[0117] FIGS. 22-24 show the effects of power input, quantity of
particles coated and RF duty cycle on the rate of release of
particles into an environment (illustrated as percent particle
release versus immersion time in simulated intestinal fluid).
[0118] Referring now to FIG. 22, doubling the power input (IM2 to
IM1) led to an 138% increase in the time required for complete
release of particles into the environment. When looking at the
initial release rate, doubling the peak power decreased the initial
release rate by a factor of 3.6.
[0119] FIG. 23 shows that the above release behavior was
independent of the quantity of coated particles. For example,
doubling the quantity of coated particles from 0.5 grams to 1.0
grams had little effect on particle release rates; complete
particle release was similar for IM2 and IM3.
[0120] FIG. 24 shows that the release behavior for ibuprofen
particles coated with methyl methacrylate was consistent with the
release behavior of similar particles coated with other
carbonaceous compounds (e.g., allyl alcohol and perfluorohexane).
As with other carbonaceous compounds, increasing the duty cycle
decreased release rate of ibuprofen particles coated with
polymethyl methacrylate.
TLC Analysis
[0121] Using thin-layer chromatography, it was observed that
particles of the present invention were not degraded or converted
to other compounds of different molecular weight or R.sub.f value
as a result of plasma deposition; no additional spots other than
those corresponding to the particle were observed on any of the TLC
plates. FIGS. 25 and 26 are representative of the many analyses
that were performed with various particles with and without a
number of different coatings. All analyses revealed the same
results.
[0122] For FIGS. 25 and 26, a calculation of the retention factor
for particles of acetylsalicylic acid (FIG. 25, lanes 1 to 4) or
ibuprofen (FIG. 26, lanes 1-4) were made. The average retention
factor for acetylsalicylic acid particles (FIG. 25, lanes 1 to 4)
was calculated to be 0.14, while the retention factor of ibuprofen
particles (FIG. 26, lanes 1 to 4) was calculated to be 0.39. In
both FIGS. 25 and 26, lane 1 contained the uncoated (free) particle
that did not undergo plasma deposition, while lanes 2-4 contained
plasma deposited particles of acetylsalicylic acid (FIG. 25) or
ibuprofen (FIG. 26). These data are consistent with what is known
in the art; with a chloroform-acetone (4+1) solution as the solvent
and using silica as the adsorbent, the retention factor for
acetylsalicylic acid is generally about 0.18 and the retention
factor for ibuprofen is generally about 0.46. Four reference
compounds were used: methohexitone, quinalbarbitone, clonazepam and
paracetamol.
[0123] The above examples illustrate that plasma deposition
(polymerization) of at least one carbonaceous compound on the
surface of a particle results in the encapsulation of that particle
with a polymer film. The carbonaceous compound may be hydrophilic
and/or hydrophobic, capable of forming a hydrophilic or hydrophobic
polymer film, respectively. As described herein, plasma deposition
is used to control aspects of the coating or polymer film (e.g.,
surface area, cross-linking, wettability, extent of hydrophilicity
or hydrophobicity, number and/or density of side groups, overall
thickness) via reaction conditions such as power input, peak power,
coating time, pulsed plasma duty cycle, as examples. The control of
polymerization directly effects and, thus, controls the
introduction of the encapsulated particle into the environment.
This introduction is typically a function of the rate of release,
including the initial rate of release of the particle and the total
time for complete particle release, as examples.
[0124] With the present invention, plasma deposition is capable of
controlling particle introduction into an environment. The control
depends, in part, on one or more plasma deposition variable(s)
(e.g., reaction conditions) that may be altered. Some of the
variables and their effects on the rate of particle release are
illustrated in TABLE 8. TABLE-US-00008 TABLE 8 Examples of plasma
deposition variables and their effects. Variable Rate of Release
Power increase Decreased Coating time increase Decreased Duty cycle
increase Decreased
[0125] With the present invention, a polymeric film functions
similar to a permeation barrier between a particle and an
environment. When an encapsulated particle is introduced to an
environment, typically there is dissolution of all or part of the
particle into the environment. As such, altering reaction
conditions such as power input, coating time, and/or duty cycle
during plasma deposition of the present invention, will alter
particle dissolution. For example, as illustrated, increases in
coating or polymer film thickness reduced the rate of release of a
particle encapsulated by a polymer film. Increasing the power input
or plasma duty cycle during coating reduced the porosity of the
polymer film, increased the extent of cross-linking of the polymer
film, and reduced the rate of release of the particle encapsulated
by the polymer film.
Kinetic Analysis of Particle Release Rates
[0126] Kinetic analyses of release rates were performed using
either zero-order or first-order kinetics. For zero-order kinetics,
there is typically an initial diffusion of water into the
encapsulated particle followed by a saturated solution in which
both liquid and undissolved solid remain in equilibrium. This
process obeys equation (2), where M.sub.r is the amount of particle
released at time t; M.sub.0 is the total amount of particle before
dissolution; k.sub.0 is the zero-order release constant and t is
time. M r M 0 = k 0 .times. t ( 2 ) ##EQU2##
[0127] Zero-order kinetic data for acetylsalicylic acid crystal
particles coated with polyallyl alcohol are shown in FIGS. 27-29,
which included data for the release of 60% of the total particles.
The R value for FIGS. 27-29, was, on average, 0.97 and ranged from
0.977 to 0.946
[0128] For first-order kinetics, there is typically an initial,
rapid influx of a solution into the encapsulated particle. The
particle is then solubilized followed by a slower diffusion phase
as the particle diffuses out of the encapsulated coating and the
solution inside the coating becomes less concentrated with time.
The equation used for first-order kinetics is shown as equation
(3), where M.sub.t is the amount of particle remaining at time t;
M.sub.0 is the total amount of particle before dissolution; k.sub.1
is the first-order release constant; and t is time. M r M 0 = k h
.times. t 1 .times. / .times. 2 ( 3 ) ##EQU3##
[0129] First-order kinetic data for acetylsalicylic acid crystal
particles coated with polyallyl alcohol are shown in FIGS. 30-32,
which included data for the release of 60% of the total particles.
The R values for FIGS. 27-29, were 0.9992, 0.9957, 0.9975 and
0.9788.
[0130] The above figures indicate that particle release rates are
more in accord with first-order rather than zero-order kinetics.
The first-order rate constants were 0.12 to 0.0054 min.sup.-1,
representing a factor in excess of 20 for the variation of release
rates.
[0131] The data also show that there is room for further control of
release rates, for example, by using longer coating time periods,
possibly in combination with other reaction conditions, such as
higher power inputs. While all potential possibilities for altering
reaction conditions are not presented, the possibilities are
obvious to one of ordinary skill in the art.
[0132] Kinetic analyses were similarly performed for particles of
acetylsalicylic acid crystals coated with a polymer film of
polymethyl methacrylate or polyperfluorohexane. With these
coatings, particle release also appeared to involve first-order
rather than zero-order kinetics. TABLE 9 summarized some of the
analyses. TABLE-US-00009 TABLE 9 Kinetic analyses for
acetylsalicylic acid coated with polyperfluorohexane (AP) or
polymethylmethacrylate (AM). Zero-order kinetics First-order
kinetics Run k (min.sup.-1) R.sup.2 k (min.sup.-1) R.sup.2 AP3(1)
0.009 0.3994 0.012 0.7134 AP3(2) 0.004 0.8137 0.006 0.9402 AP3(3)
0.003 0.9784 0.004 0.9949 AP3(4) 0.001 0.962 0.002 0.9896 AP1 0.002
0.9636 0.003 0.9905 AP2 0.002 0.9719 0.002 0.9895 AM1 0.017 0.9787
0.024 0.9973 AM2 0.010 0.9613 0.014 0.998 AM3 0.007 0.9779 0.009
0.997 AM4 0.003 0.9903 0.004 0.9951
[0133] Light scattering measurements for particles of
acetylsalicylic acid molecules are shown in FIG. 33. The results
are based on conditions that included sieving particles through a
35 .mu.m mesh. FIG. 33, shows that the particles varied in size,
ranging, on average, from 10 and 20 .mu.m. More or less uniform
particles may also be used with the present invention.
[0134] The present invention shows that deposition of a polymer
film or coating using plasma polymerization is a new and improved
way to introduce and control the release of a particle into an
environment. Using systems, methods, and compositions of the
present invention, one can prepare any encapsulated particle coated
with any degradable and/or nondegradable polymer and alter particle
release rates to control particle introduction into an environment.
The control of particle introduction into the environment may be a
temporal and/or site-specific control. For example, polymer film
deposition may be controlled by altering reaction conditions, such
as power input, peak power, coating time, duty cycle, flow rate of
the carbonaceous compound, reactor pressure, and/or quantity of
particles during preparation of the coated particles. These
conditions control aspects of the coating or polymer film,
including polymer film growth, polymer film thickness, the density
of polar groups in the polymer film, the number of functional
groups in the polymer film, the hydrophilicity or hydrophobicity of
the polymer film, wettability of the polymer film, linearity of the
polymer film, and extent of cross-linkages in the polymer. In this
way, a polymer film of the present invention may be finely tuned in
order to obtain any required combination of temporal and/or
site-specific release of particles into an environment.
[0135] The present invention also provides for compositions
prepared by systems and methods described herein. Such
compositions, systems, and/or methods may include one or more
carbonaceous compounds as well as one or more different types of
particles. Indeed, such variations may be specifically manufactured
to optimally control release of one or more particles into an
environment. Optimally control may include combining particles with
similar or different coatings, wherein the differences include the
coating composition, thickness, number and/or type of functional
group, hydrophobicity, hydrophilicity, wettability, linearity,
cross-linking, and combinations thereof. With the present
invention, one or more different compositions may also be combined
to yield a desired particle release property.
[0136] While specific alternatives to steps of the invention have
been described herein, additional alternatives not specifically
disclosed but known in the art are intended to fall within the
scope of the invention. Thus, it is understood that other
applications of the present invention will be apparent to those
skilled in the art upon reading the described embodiment and after
consideration of the appended claims and drawing.
* * * * *