U.S. patent application number 12/536465 was filed with the patent office on 2010-11-25 for identification features.
This patent application is currently assigned to NANOINK, INC.. Invention is credited to John Edward Bussan, Sylvain Cruchon-Dupeyrat, Linette Demers, Ray Eby, Joseph S. Fragala, Cedric Loiret-Bernal, Michael Nelson, Bjoern Rosner, Raymond Roger Shile, Hua Zhang.
Application Number | 20100297190 12/536465 |
Document ID | / |
Family ID | 43123926 |
Filed Date | 2010-11-25 |
United States Patent
Application |
20100297190 |
Kind Code |
A1 |
Loiret-Bernal; Cedric ; et
al. |
November 25, 2010 |
IDENTIFICATION FEATURES
Abstract
Methods for providing pharmaceutical compositions and objects
with identification regions and identification features which are
difficult to detect. Microlithography, nanolithography, and
stamping methods are used. The identification features can be
positive protrusions or negative indentations with respect to the
surface. The identification regions can comprise bar codes and
holograms. DPN printing or other lithographies such as electron
beam lithography, optical lithography, or nanoimprint lithography
can be used to prepare stamps, which are then used to prepare the
identification features. Redundant patterns can be formed. The
invention is useful for counterfeit prevention. An apparatus for
stamping the identification features is also described.
Inventors: |
Loiret-Bernal; Cedric;
(Evanston, IL) ; Demers; Linette; (Evanston,
IL) ; Rosner; Bjoern; (Chicago, IL) ; Nelson;
Michael; (Libertyville, IL) ; Eby; Ray; (Grays
Lake, IL) ; Fragala; Joseph S.; (San Jose, CA)
; Shile; Raymond Roger; (Los Gatos, CA) ; Zhang;
Hua; (Evanston, IL) ; Bussan; John Edward;
(Naperville, IL) ; Cruchon-Dupeyrat; Sylvain;
(Chicago, IL) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
NANOINK, INC.
|
Family ID: |
43123926 |
Appl. No.: |
12/536465 |
Filed: |
August 5, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11109877 |
Apr 20, 2005 |
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12536465 |
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60563443 |
Apr 20, 2004 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
B30B 15/34 20130101;
B30B 15/065 20130101; A61P 43/00 20180101; G06K 19/06028
20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61P 43/00 20060101 A61P043/00 |
Claims
1-25. (canceled)
26. A method of making a pharmaceutical composition having at least
one identification region and at least one identification feature
comprising: (i) providing a stamp which has a surface to form at
least one identification region having at least one identification
feature, wherein the identification feature has a lateral dimension
of about 100 microns or less; (ii) providing a pharmaceutical
composition having a surface; and (iii) contacting the stamp and
the pharmaceutical composition under conditions so that the
pharmaceutical composition comprises a surface having the at least
one identification region having at least one identification
feature, wherein the identification feature has a lateral dimension
of about 100 microns or less.
27. The method according to claim 26, wherein the feature does not
comprise added chemicals.
28. The method according to claim 26, wherein the contacting is
carried out at a temperature of about 25.degree. C. to about
400.degree. C.
29. The method according to claim 26, wherein the contacting is
carried out at a pressure of about 0.01 MPa to about 1,000 MPa.
30. The method according to claim 26, wherein the contacting is
carried out for a time of about 0.1 seconds to about 50
seconds.
31. The method according to claim 26, wherein the contacting is
carried out for a time of about 0.1 seconds to about 50 seconds, at
a pressure of about 0.01 MPa to about 1,000 MPa, and at a
temperature of about 25.degree. C. to about 400.degree. C.
32. The method according to claim 26, wherein the identification
feature has a lateral dimension of about 100 microns or less.
33. The method according to claim 26, wherein the identification
feature has a lateral dimension of about one micron or less.
34. The method according to claim 26, wherein the identification
feature has a height dimension of about one micron or less.
35. The method according to claim 26, wherein the identification
feature has a height dimension of about 250 nm or less.
36. The method according to claim 26, wherein the pharmaceutical
composition comprises a plurality of identification features which
are separated from each other by an average distance of about 100
microns or less.
37. The method according to claim 26, wherein the identification
region is about 10,000 square microns or less.
38. The method according to claim 26, wherein the identification
feature comprises an indentation into the surface.
39. The method according to claim 26, wherein the identification
feature comprises a protrusion out from the surface.
40. The method according to claim 26, wherein identification region
comprises a bar code.
41. The method according to claim 26, wherein identification region
comprises a hologram.
42-48. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application Ser. No. 60/563,443 filed Apr. 20, 2004 to
Loiret-Bernal et al. entitled "Identification Features", (attny
docket no. 083847-0239), which is hereby incorporated by reference
in its entirety including the specification, working examples,
figures, and claims.
FIELD OF INVENTION
[0002] The present invention relates generally to objects and
compositions having identification regions and identification
features which are difficult to detect, particularly with the naked
eye. In particular, pharmaceutical compositions are of interest
which have microscale and nanoscale identification regions and
features such as bar codes and holograms which comprise dots,
lines, or other geometric figures.
BACKGROUND OF THE INVENTION
[0003] Methods are known for providing objects and compositions
including food and pharmaceutical compositions with identification.
See, for example, U.S. Pat. Nos. 4,189,996; 4,548,825; 5,006,362;
5,118,369; 5,376,771; 5,457,895; and 5,529,767. U.S. Pat. No.
6,481,753 to Van Boom et al. describes use of thermochromic inks to
print variable confidential information for use in detection of
copying or scanning. U.S. Pat. No. 6,692,030 to Phillips describes
use of nanopatterns on a substrate for use in detecting copying. In
many cases, however, prior methods have not been experimentally
verified, or poorly demonstrated, and are generally inadequate for
addressing present needs for identification. In particular, present
identification needs have accelerated in view of heightened
security concerns because of terrorism. Moreover, the economics of
pharmaceutical development, especially, has resulted in expensive
pharmaceuticals which can have price variation from country to
country. This can encourage counterfeit and illegal trade
activities. Also, governmental concern for health in view of drug
counterfeiting is increasing.
[0004] Hence, a present need exists to provide objects and
compositions, particularly pharmaceutical compositions, with
microscale and nanoscale identification features which are
difficult to detect, particularly with the naked eye or simple low
resolution magnification methods such as a conventional magnifying
glass. Technology is needed which can provide high throughput and
is otherwise commercially attractive and in compliance with health
regulations. A need also exists to develop technology wherein an
identification feature can be put onto the object itself rather
than a mere package for the object. In particular, the technology
hurdles become great when feature sizes go from a micro scale
regime into a nanoscale regime such as below one micron, and in
particular, below 100 nm. In recent years, some advances in
lithography have been reported but these advances have not been
applied to the identification problems noted above.
[0005] In a preferred embodiment, the present invention also
generally relates to nanolithography and etching, and more
particularly, to systems capable of DIP PEN NANOLITHOGRAPHY.TM.
printing (DPN.TM. printing) and deposition, coupled with etching
and/or other methods for pattern transfer. DIP PEN
NANOLITHOGRAPHY.TM. and DPN.TM. are trademarks for NanoInk, Inc.,
Chicago, Ill.). These methods unexpectedly can be advantageous and
useful in the commercial context of counterfeit prevention.
SUMMARY OF THE INVENTION
[0006] Exemplary embodiments of the present invention are
summarized in this non-limiting summary section. In one embodiment,
the invention enables one to prevent counterfeiting and other fraud
with use of identification features which are not generally visible
to the naked eye.
[0007] In one embodiment, the invention provides a pharmaceutical
composition comprising: a pharmaceutical composition having a
surface, wherein the surface comprises at least one identification
region, the region having at least one identification feature, the
feature having a lateral dimension of about 100 microns or
less.
[0008] Also provided is a pharmaceutical composition comprising: a
pharmaceutical composition having a surface, wherein the surface
comprises at least one identification region, the region having a
plurality of identification line features, the lines having a line
width of about one micron or less and a line length of at least one
micron.
[0009] In another embodiment, the invention also provides an object
comprising an object having a surface, wherein the surface
comprises at least one identification region, the region having at
least one identification feature, the feature having a lateral
dimension of about 500 microns or less. In addition, the invention
also provides a composition comprising: a composition having a
surface, wherein the surface comprises at least one identification
region, the region having at least one identification feature, the
feature having a lateral dimension of about 500 microns or
less.
[0010] In another embodiment, the invention further provides a
method of making a pharmaceutical composition having at least one
identification region and at least one identification feature
comprising: (i) providing a stamp which has a surface to form at
least one identification region having at least one identification
feature, wherein the identification feature has a lateral dimension
of about 100 microns or less; (ii) providing a pharmaceutical
composition having a surface; and (iii) contacting the stamp and
the pharmaceutical composition under conditions so that the
pharmaceutical composition comprises a surface having the at least
one identification region having at least one identification
feature, wherein the identification feature has a lateral dimension
of about 100 microns or less.
[0011] Still further, the invention provides a method of making a
composition having at least one identification region and at least
one identification feature without etching after formation of
identification feature consisting essentially of: (i) providing a
stamp which has a surface to form at least one identification
region having at least one identification feature; (ii) providing a
composition having a surface; and (iii) contacting the stamp and
the composition under conditions so that the composition comprises
a surface having the at least one identification region having at
least one identification feature.
[0012] Also provided is an apparatus for forming identification
features for pharmaceutical compositions comprising:
[0013] a pressure ram;
[0014] optionally, a stamp attached to the pressure ram for
imprinting at least one identification feature on a pharmaceutical
composition;
[0015] a mount for holding at least one non-wafer pharmaceutical
composition;
[0016] wherein the pressure ram presses the stamp against the at
least one pharmaceutical composition held by the pharmaceutical
composition mount with a desired amount of force to form at least
one identification feature on the at least one pharmaceutical
composition.
[0017] Still other embodiments for the invention are described
throughout the specification. Basic and novel features and
advantages of the invention are many. For example, the
identification features cannot be easily copied. Moreover, the
identification features are difficult to read by copiers because
specialized tools, methods, and personnel can be needed to read the
identification features. High throughput is possible. Versatility
can be found in the wide variety of identification features which
can be formed including overt and covert embodiments. Chemicals,
labels, and inks are not necessarily added to a pharmaceutical in
the process of providing it with identification which is useful for
governmental compliance. Small line widths can be achieved such as,
for example, about 20 nm to about 50 nm, and small line separations
can be achieved such as, for example, less than 50 nm or even less
than 10 nm. Complex geometries can be formed including, for
example, disks with smooth border, arcs, hollow circles, crossed
lines without bleeding, sharp corners, and closely grouped sets of
narrow features. Additional advantages can be found in the
following description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows SEM scans of a silicon master stamp.
[0019] FIG. 2 shows AFM scan of a silicon master stamp with a
height line scan (after etching).
[0020] FIG. 3 shows optical micrographs and AFM scans of barcode
regions in a silicon master stamp including pattern redundancy with
multiple pens.
[0021] FIG. 4 shows a general fabrication process for patterning
and etching to generate a high resolution stamp.
[0022] FIG. 5 shows two stamp fabrication processes for high
resolution which use DPN printing and etching.
[0023] FIG. 6 shows AFM images of micropatterns on silicon stamp,
fabricated by microcontact printing and RIE.
[0024] FIG. 7 shows AFM image of a micro-imprinted tablet film
coating and height scans.
[0025] FIG. 8 shows optical images comparing the original
micron-scale stamp with the imprinted surface of the tablet film
coating.
[0026] FIG. 9 shows how the NSCRIPTOR instrument is used for
designing barcode patterns.
[0027] FIG. 10 shows a tablet after printing.
[0028] FIG. 11 shows an optical image and an AFM image of a stamped
pill surface.
[0029] FIG. 12 shows a front view of the apparatus used to test
temperature, time, and pressure of stamping process.
[0030] FIG. 13 shows a front view of an apparatus that may be used
to apply the identification features of the present invention.
[0031] FIG. 14 shows a perspective view of the apparatus shown in
FIG. 13.
[0032] FIG. 15 shows an enlarged view of the stamp holder, stamp,
and pharmaceutical form mount portions of the apparatus shown in
FIG. 14.
[0033] FIG. 16 shows schematic of the stamp and pharmaceutical
composition during application of identification features.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] Priority U.S. provisional patent application Ser. No.
60/563,443 filed Apr. 20, 2004 to Loiret-Bernal et al. entitled
"Identification Features", (attny docket no. 083847-0239), which is
hereby incorporated by reference in its entirety including the
specification, working examples, figures, and claims.
I. Pharmaceutical Composition
[0035] The problems of pharmaceutical and drug compositions which
can be subjected to counterfeiting are described in, for example,
the FDA report "Combating Counterfeit Drugs" February 2004 and
"FDA's Counterfeit Drug Task Force Interim Report" October 2003 and
other technical literature provided in this patent application. A
wide variety of pharmaceutical drugs and compositions, and there
function, are known in the art and are generally described in, for
example, (i) Physicians' Desk Reference, 49 Ed, 1995 including
brand name and generic drugs, and (ii) Goodman and Gilman's, The
Pharmacological Basis of Therapeutics, 2001. Pharmaceutical
compositions can be useful for both human and animal treatment.
[0036] One embodiment of the invention comprises a pharmaceutical
composition comprising: a pharmaceutical composition having a
surface, wherein the surface comprises at least one identification
region having at least one identification feature which has a
lateral dimension of about 500 microns or less, and preferably
about 100 microns or less.
[0037] The pharmaceutical composition is not particularly limited
and a wide variety of pharmaceutical compositions are known in the
art including pharmaceutical drugs in various shapes and sizes such
as pills, tablets, caplets, capsules, and the like. Pill embossing
and its variants can be the subject of the invention for
pharmaceutical compositions. For example, tablets and caplets can
be used after compressing or coating. Two-piece hard gelatin can be
used, before or after filling with powder, gel, or liquid. Pill
surface structures can include sugar shell, soft-shell, dipped or
enrobed, enteric, or aqueous coated tablets, waxed tablets, and dry
coatings.
[0038] The pharmaceutical compositions can contain active
ingredients and passive ingredients, and in different embodiments,
these can be distributed differently. The pharmaceutical
composition can have an exterior region or surface which can be
processed to include one or more identification regions by, for
example, imprinting or embossing, whether hot or cold embossing.
Hence, the pharmaceutical composition can be processible and
susceptible to, for example, heat and pressure effects which allow
for imprinting or embossing. The pharmaceutical composition
generally can comprise an active pharmaceutical ingredient (API)
but the invention is not particularly limited to how the API is
distributed throughout the pharmaceutical composition. For example,
the API could be in the interior or could be subjected to a coating
process. A composition could be provided with the identification
feature and then combined with the API. Hence, for example, the
surface of the pharmaceutical composition may have little if any of
the API but yet it is still part of the pharmaceutical composition.
The API can be a solid, liquid, or gel API as long as the ultimate
pharmaceutical composition can be processed to include the
identification features described herein.
[0039] The surface of the pharmaceutical composition can be an
exterior surface which represents an interface with air. In
addition, however, the surface of the pharmaceutical composition
could be an interior surface. For example, an interior surface can
be prepared by generating a desired surface having desired surface
features and then combining that surface with another composition
so that the desired features are no longer directly exposed to the
air but can be detected, even though they are now interior
surfaces. For example, an identification region can be generated
and then overcoated with a protective film, coating, or layer,
which include but are not limited to thin conformal films. The
surface of the pharmaceutical composition can be generally flat and
smooth, although at the scale of the identification features
described herein the surface can be generally rougher. Or the
surface can be non-flat or curved, including spherical, oval, or
bi-convex. An interior surface can be desirable to avoid scratching
or rubbing of the identification region. Alternatively, the
identification region may comprise one or more features, which
protect the information-bearing part from erasure or damage. For
example, a raised ring or frame surrounding the identification
features may avoid mechanical abrasion of the identification.
[0040] The surface of the pharmaceutical composition can comprise
non-identification regions and one or more identification regions.
An identification region can be an area which is different from the
non-identification regions and can have, for example, features for
identification (identification features) which are not present in
the non-identification regions. Examples of identification regions
include bar codes, including for example one-dimensional or
two-dimensional bar codes conforming to the standards of the
Uniform Code Council. Other examples include text, symbols,
holograms and other engineered patterns that can be clearly
interpreted.
[0041] In many cases, a full inspection of the identification
region will be needed to make the identification. In other words,
only inspecting some of the identification features may not give
sufficient information to provide adequate identification. For
example, if a bar code identification region comprises a series of
10 lines, reading only five of the lines may not give the
information needed. The identification region can be characterized
by an identification region area which has an enclosing perimeter
around the identification features so that all of the
identification features can be found within the enclosing
perimeter. This area can be for example, about 10,000 square
microns or less, or about 1,000 square microns or less, or about
400 square microns or less, or about 4 square microns or less, or
about one square micron or less. The identification region can be,
for example a square region with a lateral length and width of 100
microns.times.100 microns, respectively, or 20 microns.times.20
microns, or 2 microns.times.2 microns. Or the identification region
can be, for example, a generally rectangular region or circular
region. In many cases, two or more identification regions are
desired in case one or more of the identification regions become
unreadable by scratching, rubbing, or some other undesirable event.
For example, the surface can comprise more than 20, more than 30,
more than 40, or more than 50 identification regions. The
identification region can be sufficiently large to be seen by the
naked eye or an optical microscope, even when identification
features within the identification region can be sufficiently small
that they cannot be seen by the naked eye or even with an optical
microscope.
[0042] Identification generally can enable a recognition.
Identification can be also a verification or an authentication. It
can encompass both tracing and tracking as well as authentication,
including both bar codes and holograms for example. For example, a
pharmaceutical composition imprinted with both a micron-scale
optical grating and a nanometer-scale bar code can be both uniquely
authenticable by the end-user as genuine, visually, and uniquely
traceable as certifiable to an origin.
[0043] The identification features are not particularly limited by
any shape and can be, for example, dots, circles, lines,
rectilinear structures, curvilinear structures, or bar codes,
whether linear or radial. Other examples include geometric objects
such as, for example, triangles or rectangles. The identification
features can be space filling such as, for example, a disk or can
be non-space filling such as, for example, a donut or circle with a
hollowed out interior. The identification features can form
holographic patterns and can be, for example, periodic arrays of
lines or dots. The identification features can also form a
trademark, service mark, or some other indicia of good will to the
customer or branding mark. Dates, names, and other useful
commercial information can be provided. In general, the
identification features are not complex technological patterns such
as a complex circuit pattern. Rather, in general, the function of
the identification feature is for identification, not another
utility. Generally, it is desired to make the feature as simple as
possible while still retaining the function of being an
identification feature. For example, bar code technology can be
applied at this scale wherein, for example, the width, spacing, and
length of lines, and ratios thereof, can be varied to provide
information. Preferably, a plurality of identification features can
be used and in many cases, only one identification feature is
insufficient to provide the needed identification. Preferably, for
example, a plurality of linear structures is used in a bar code
format.
[0044] The identification features can be a positive structure with
respect to the surface or a negative structure with respect to the
surface. For example, a negative structure can be an indentation,
whereas a positive structure can be a protrusion. Hence, for
example, a line identification feature could be stamped into a
surface to generate an indentation of the line, or a region of a
surface could be stamped which resulted in a line protruding from
the surface after stamping. Whether positive or negative, the
identification feature should be durable and if a positive
identification is not sufficiently durable, it can be converted to
a negative identification feature.
[0045] In general, identification features are preferred which are
durable over time. Identification features can be, for example,
overcoated as needed to improve the durability. Durability can
depend on the softness and material glass transition temperature
effects of the surface. One skilled in the art can test the
durability and develop conditions and surface treatments which
improve durability. In general, the identification region and
identification feature can be durable for a period of at least one
year, for at least five years, and at least 10 years, so that the
identification can be carried out even after passage of time. For
example, a useful passage of time is the expiration date of a pill.
In general, materials to be stamped have a glass transition
temperature above about 25.degree. C. so that at usual room
temperature the material is sufficiently glassy to durably hold the
identification feature. For example, the composition's glass
transition temperature can be, for example, about 40.degree. C. or
more, or alternatively, about 60.degree. C. or more, or
alternatively, about 80.degree. C. or more.
[0046] The identification regions and features can be characterized
by dimensional measurements such as lateral dimensions or vertical
dimensions with respect to the surface. Conventional methods can be
used to measure these dimensions including methods described herein
and the working examples. Conventional data processing including
image processing, pattern recognition, curve fitting and optical
character recognition (OCR) can be carried out to provide
dimensions and average dimensions and generally to provide useful
data.
[0047] The identification regions can each have one or more
identification features which can be characterized by a lateral
dimension with respect to the surface. The lateral dimension can
be, for example, a width or a length such as, for example, a circle
diameter or a line width, or the relative or absolute position
compared to a known mark. The lateral dimension is different from a
vertical dimension such as height. For an identification feature
which is a line, the lateral dimension of length can be
sufficiently long that it can be viewed with the naked eye or an
optical microscope, whereas the lateral dimension which is width
can be sufficiently small that it cannot be seen with a naked eye
or optical microscope. The size of the lateral dimensions can be
sufficiently small so that the identification features are
invisible to the naked eye and difficult to detect by conventional,
simple methods. Rather, difficult, relatively expensive methods can
be used to detect small identification features including
microscopic and nanoscopic features. At least one of the lateral
dimensions can be made small. For example, the identification
feature can have a lateral dimension of, for example, about 500
microns or less, or about 400 microns or less, or about 300 microns
or less, or more particularly, about 250 microns or less, or more
particularly, about 100 microns or less, or more particularly,
about 10 microns or less. Or the identification feature can have a
lateral dimension of, for example, about one micron or less, or
more particularly, about 500 nm or less, or more particularly,
about 250 nm or less, or more particularly, about 100 nm or less.
There is no particular limit to how small the lateral dimension can
be as long as the identification feature can be detected. For
example, the lateral dimension can be at least about 1 nm, or more
particularly, at least about 10 nm, or more particularly, at least
about 100 nm, or more particularly at least about one micron.
Hence, exemplary ranges for the lateral dimension include about one
nm to about 500 microns, about 10 nm to about 100 nm, about 100 nm
to about one micron, and about one micron to about 500 microns.
[0048] For barcodes, the line length is not particularly limited
but can vary from nanoscopic to microscopic. For example, lines can
be about one micron to about 50 microns long, or about 5 microns to
about 25 microns long, and yet have a line width of only about 50
nm to about 150 nm wide.
[0049] The identification features can be in the form of a pattern
of repeating features such as dots or lines, wherein the features
are characterized by an average lateral dimension such as average
circle diameter or line width. The lateral size dimensions
described herein can be computed into average lateral
dimensions.
[0050] The identification features can have a vertical dimension
such as a height dimension or a depth dimension, and these terms
are used interchangeably and for both positive structures and
negative structures. The height dimension is not particularly
limited and can be, for example, about five microns or less, or
about one micron or less, or more particularly, about 500 nm or
less, or more particularly about 250 nm or less, or more
particularly about 150 nm or less. There is no particular lower
limit to the height dimension as long as the identification feature
can be detected. The height dimension can be, for example, about
one nm or more, or about 10 nm or more, or about 25 nm or more.
Exemplary ranges can be, for example, about one nm to about one
micron, or about 10 nm to about 500 nm, or about 25 nm to about 250
nm. Again, if a pattern of repeating identification features are
used, the vertical dimension can represent an average
dimension.
[0051] In addition to the lateral dimension and the height
dimension, the invention can be also characterized by a separation
dimension which represents the distance between the identification
features such as a separation distance or a pitch. In other words,
the one or more identification features can be separated from each
other by a particular distance, and this distance can be an average
distance for an array of identification features. For example, if
the identification features are a series of lines, a distance can
be measured between the centers of the lines, or if the
identification features are a series of dots, a distance can be
measured between the centers of the dots. The distance of
separation is not particularly limited but smaller separation
distances are preferred so that the identification is invisible to
the unaided eye. For example, the one or more identification
features can be separated from each other by an average distance of
about 500 microns or less, or more particularly, about 100 microns
or less, or more particularly, about 10 microns or less, or more
particularly, about one micron or less, or more particularly, about
500 nm or less.
[0052] The pharmaceutical composition can also be characterized by
the density of the identification features. For example, a
plurality of parallel lines can be generated wherein there is at
least one line per every two microns, or at least one line per
every one micron, or at least one line per every 0.5 microns. See
for example FIG. 1, wherein a height profile scan be used to
determine a density.
[0053] The information associated with the identification region
and features may be obtained by determining one or more of the
aforementioned characteristics and optionally a mathematical
function or algorithm.
[0054] The surface also can comprise one or more marks which can be
detected by an optical microscope or an unaided eye. The at least
one mark can be located outside of the identification region.
Examples include an X shaped mark. The marks, for example, can have
lateral dimensions such as line width at the micron scale such as
10 microns or more, at least 50 microns or more, at least 100
microns or more.
[0055] The pharmaceutical compositions can be packaged into unit
forms and used in commerce as collections of unit forms. Hence, for
example, a package of a drug can be provided to a doctor or patient
having, for example, 20 unit forms of the pharmaceutical
composition, or a bottle with a cap can be provided having a 100
unit forms. If desired, all of the pharmaceutical compositions in
unit form can be marked with at least one identification region
having at least one identification feature. If desired, only
selected unit forms can be marked for identification. Hence, for a
large collection of unit forms, a copier may have difficulty
knowing which unit form has been marked with the identification
region and features. All or only a fraction of pharmaceutical
compositions packaged in bulk form may include one or more of the
identification region and features.
[0056] FIG. 10 illustrates a working example showing a tablet
appearance after printing. In this working example, the tablet has
a small visible mark where the stamp pressed slightly into the
tablet coating. The surface of the impression is smooth and
reflective. In a preferred embodiment, stamping conditions are
selected so that the tablet appearance does not to the unaided eye
provide a signal that it has been stamped and has identification
regions or features. Even if the eye can detect that a stamp is
present, however, the particular identification region and feature
can be virtually impossible to copy.
[0057] FIG. 7 is taken from a working example described further
below. It shows AFM images of micropatterns on a pharmaceutical
film coating for a pharmaceutical drug. FIG. 8 is also taken from a
working example which further shows optical images.
[0058] FIG. 11 is a working example and shows identification
features which are nanopatterns imprinted onto a pharmaceutical
film coating.
[0059] The pharmaceutical compositions, their properties, and
endurance over time and use, can be further tasted by use of known
ASTM tests such as, for example, D4169; D5276; D642; D4169; D999;
D4729. These are important for examining the impact of
distribution. For example, these methods can be used to test for
compression and thermal properties. Drop testing, manual handling,
compression testing, repetitive shock, loose load vibration, random
vibration, vehicle vibration, and other testing can be
examined.
II. Methods of Making the Pharmaceutical Composition
[0060] Another embodiment of the invention is making pharmaceutical
compositions which have at least one identification region and at
least one identification feature. For example, the invention
provides a method of making a pharmaceutical composition having at
least one identification region and at least one identification
feature comprising: (i) providing a stamp which has a surface to
form at least one identification region having at least one
identification feature; (ii) providing a pharmaceutical composition
having a surface; and (iii) contacting the stamp and the
pharmaceutical composition under conditions so that the
pharmaceutical composition comprises a surface having the at least
one identification region having at least one identification
feature. The stamp can be removed from the pharmaceutical
composition under conditions so that the image of the stamp is
transferred to be an image on the pharmaceutical composition in
sufficiently high quality to be useful in commerce. The surface of
the stamp and the surface of the pharmaceutical composition of
course are related in that images on each are spatially in a
positive-negative relationship. In other words, a positive image on
a stamp provides a negative image on a stamped surface, and a
negative image on a stamp provides a positive image on a stamped
surface. In conducting the contacting step, the stamp and
pharmaceutical composition move relative to each other. One of the
two can be held stationary while the other one moves to initiate
contact. For example, the stamp can be held stationary or the
pharmaceutical composition can be held stationary.
[0061] Taken from a working example described further below, FIG. 8
illustrates, for example, the ability to compare the image of the
stamp with the image of the material stamped.
[0062] Conditions for stamping can be varied depending on the
pharmaceutical composition and the results desired. The proper
tradeoff between quality of stamping and production rate can be
achieved. For example, the time of stamping can be varied; the
pressure of stamping can be varied; the surface treatment of the
contacting surfaces can be varied; the instrument used for stamping
can be varied. The stamping time is not particularly limited but
can be, for example, about 0.001 seconds to about 50 seconds, about
0.01 seconds to about 50 seconds, about 0.1 seconds to about 50
seconds, or about 0.5 seconds to about 25 seconds, or about 1
second to about 10 seconds. The stamping temperature can be, for
example, about 25.degree. C. to about 400.degree. C., or about
50.degree. C. to about 300.degree. C., or about 100.degree. C. to
about 250.degree. C. Heat used to vary temperature can be supplied
through the stamp, through the pharmaceutical composition, or
through the surrounding medium such as air. Generally, temperature
is selected to avoid degrading any of the composition or
cosmetically interfering such as discoloring the composition.
Stamping force and pressure is not particularly limited but can be
adjusted together with the stamp time and temperature to give the
best balance of quality and production rate. Examples of stamping
pressure include, for example about 0.01 MPa to about 1,000 MPa,
and more particularly, about 0.1 MPa to about 100 MPa, and more
particularly, about one MPa to about 15 MPa.
[0063] Other known stamping and molding methods can be adapted and
used. For example, release coatings are known in the molding arts
and can be used including for example hydrophobic release coatings.
Hydrophobic materials can be used to form the stamp or surface coat
the stamp, including monolayers such as self-assembled monolayers
including reactive silane compounds.
Trichloro/trialkoxysilane-based self-assembled monolayer coatings
can be useful, for example.
[0064] Stamps can be used repeatedly such as, for example, at least
one hundred times, at least 1,000 times, or at least 10,000 times.
Anti-fouling methods can be carried out to prevent undesirable
material from building up on the stamp over time and with use. For
example, coatings can be put on the stamp to improve anti-fouling
and durability. Use of hard coatings including diamond like
coatings (DLC) can be utilized, for example.
[0065] An important advantage of the present invention is that (1)
it does not generally require the deposition of a film prior to
stamping; (2) upon formation of the image, addition post-processing
and etching is generally not needed, and (3) the method can be
applied to curved and other non-flat surfaces. For example, by
contrast, nanoimprint lithography (NIL) is a method which generally
involves the fabrication of microchips on a wafer including (a)
deposition of a thin, polymer film and (b) subsequent processing,
including etching, after the image is formed and transferred from a
stamp to a surface. See, for example, Chou et al. Applied Physics
Letters 67(21), 1995. More recent examples of imprint
nanolithography technical literature also includes U.S. Pat. Nos.
6,656,398; 6,696,220; and 6,719,915 (Step and Flash Imprint
Lithography). A basic and novel feature of the present invention is
that these additional processing steps, in particular additional
etching steps, can be eliminated. Hence, the invention can provide,
for example, a method of making a pharmaceutical composition having
at least one identification region and at least one identification
feature consisting essentially of: (i) providing a stamp which has
a surface to form at least one identification region having at
least one identification feature; (ii) providing a pharmaceutical
composition having a surface; and (iii) contacting the stamp and
the pharmaceutical composition under conditions so that the
pharmaceutical composition comprises a surface having the at least
one identification region having at least one identification
feature. Additional etching is not needed.
III. Other Objects and Compositions with Identification
Features
[0066] As described in Sections I and II, a particular preferred
example of the invention is a pharmaceutical composition, and
methods of making the pharmaceutical composition. In general, the
various embodiments of the invention can be applied to
pharmaceutical goods which are susceptible to counterfeiting,
including for example high priced pharmaceuticals, prescription
drugs, and blockbuster drugs with large sales volume, wherein price
differentials exist from country to country and the economic
incentive to counterfeit is high, as described above. The
description above for pharmaceutical compositions, and methods of
making, generally can be also adapted to apply to other
compositions and objects which can be subjected to counterfeiting
fraud such as the confectionary compositions and consumer goods
like CDs or DVDs.
[0067] Hence, the invention also relates to objects and
compositions which have a surface, wherein the surface comprises at
least one identification region having at least one identification
feature. The surface, identification region, and the identification
feature are described further above in Section I. An object broadly
can be a variety of items including items of commerce and is not
particularly limited by any shape or form. It can be man-made or
natural. Typically, an object can have a particular use or function
and can comprise one or many compositions. A composition also
broadly can be a variety of materials, chemical compounds,
elements, mixtures, blends, composites, metals, glasses, polymers,
ceramics, and the like and is not limited by a particular use or
function. The identification feature on the object or composition
can have relatively small lateral and vertical dimensions. The
feature can be a positive feature, protruding from the surface, or
a negative feature, extending into the surface.
[0068] One embodiment, for example, comprises an object comprising:
an object having a surface, wherein the surface comprises at least
one identification region having at least one identification
feature which has a lateral dimension of about 500 microns or
less.
[0069] Another embodiment is for a composition comprising: a
composition having a surface, wherein the surface comprises at
least one identification region having at least one identification
feature which has a lateral dimension of about 500 microns or
less.
[0070] Preferred examples of objects include currency, consumer
products, paper, money, documents, entertainment media, compact
disks, DVDs, nickel masters, flat wafers, disk drive heads,
semiconductor chips, integrated circuits and their components,
packaging containers and materials including packaging containers
and materials for pharmaceuticals, jewelry, precious raw materials,
personal and institutional identification devices, medical devices,
bottle tampering-evident seals, syringes, jewelry and collectibles.
In particular, syringes, pre-loaded syringes, vaccines and vaccine
vials, and injectable drug vials, including bottle seal, medical
devices including catheters and implantable devices, and packaging
labels can be used. In general, objects which are susceptible to
counterfeiting or copying are particularly of use.
[0071] Preferred examples of compositions include pharmaceutical,
medications, drugs, food, and confectionary.
[0072] In general, the composition can be a material which can be
imprinted. They can be, for example, thermoplastic materials which
can soften with heat and then become hard at lower temperatures.
Thermosetting or crosslinking compositions can be also used wherein
the material is in a soft form and then subjected to imprinting.
Curing or hardening steps can be then carried out to lock in the
imprinting.
[0073] The invention also relates to methods of making the objects
and the compositions by methods analogous to those described in
Section II.
[0074] If desired, a material can be provided with the at least one
identification region having at least one identification feature,
and then the material can be combined with an API.
IV. The Stamp
[0075] The pharmaceutical compositions, as well as other objects
and compositions, can be made with one or more stamps which provide
the surface with the identification feature. The invention provides
a stamp for use in making a pharmaceutical composition, or other
objects and compositions, the stamp comprising a surface having at
least one identification region, and the region having at least one
identification feature. In general, the stamps can be master stamps
and can be used repeatedly, or can be used to produce other
stamps.
[0076] Because the stamp can have a shape which is transferred to
the pharmaceutical composition, or other objects and compositions,
the dimensions described herein for the identification features and
identification regions can also be used to describe the stamp. For
example, a stamp which has an identification feature having a 100
nm height can result in a pharmaceutical composition, or other
composition or object, having an identification feature with 100 nm
height. The stamp's 100 nm positive protrusion can produce a 100 nm
negative inversion.
[0077] In particular, the identification regions and features on
the stamp can be characterized by dimensional measurements such as
lateral dimensions or vertical dimensions with respect to the
surface. Conventional methods can be used to measure these
dimensions including methods described herein and the working
examples. Conventional data processing including image processing,
pattern recognition, curve fitting and optical character
recognition (OCR) can be carried out to provide dimensions and
average dimensions and generally to provide useful data.
[0078] The identification regions of the stamp can each have one or
more identification features which can be characterized by a
lateral dimension with respect to the surface. The lateral
dimension can be, for example, a width or a length such as, for
example, a circle diameter or a line width, or the relative or
absolute position compared to a known mark. The lateral dimension
is different from a vertical dimension such as height. For an
identification feature which is a line, the lateral dimension of
length can be sufficiently long that it can be viewed with the
naked eye or an optical microscope, whereas the lateral dimension
which is width can be sufficiently small that it cannot be seen
with a naked eye or optical microscope. The size of the lateral
dimensions can be sufficiently small so that the identification
features are invisible to the naked eye and difficult to detect by
conventional, simple methods. Rather, difficult, relatively
expensive methods can be used to detect small identification
features including microscopic and nanoscopic features. At least
one of the lateral dimensions can be made small. For example, the
identification feature of the stamp can have a lateral dimension
of, for example, about 500 microns or less, or about 400 microns or
less, or about 300 microns or less, or more particularly, about 250
microns or less, or more particularly, about 100 microns or less,
or more particularly, about 10 microns or less. Or the
identification feature can have a lateral dimension of, for
example, about one micron or less, or more particularly, about 500
nm or less, or more particularly, about 250 nm or less, or more
particularly, about 100 nm or less. There is no particular limit to
how small the lateral dimension can be as long as the
identification feature can be detected. For example, the lateral
dimension can be at least about 1 nm, or more particularly, at
least about 10 nm, or more particularly, at least about 100 nm, or
more particularly at least about one micron. Hence, exemplary
ranges for the lateral dimension include about one nm to about 500
microns, about 10 nm to about 100 nm, about 100 nm to about one
micron, and about one micron to about 500 microns.
[0079] For barcodes on the stamp, the line length is not
particularly limited but can vary from nanoscopic to microscopic.
For example, lines can be about one micron to about 50 microns
long, or about 5 microns to about 25 microns long, and yet have a
line width of only about 50 nm to about 150 nm wide.
[0080] The identification features on the stamp can be in the form
of a pattern of repeating features such as dots or lines, wherein
the features are characterized by an average lateral dimension such
as average circle diameter or line width. The lateral size
dimensions described herein can be computed into average lateral
dimensions.
[0081] The identification features on the stamp can have a vertical
dimension such as a height dimension or a depth dimension, and
these terms are used interchangeably and for both positive
structures and negative structures. The height dimension is not
particularly limited and can be, for example, about one micron or
less, or more particularly, about 500 nm or less, or more
particularly about 250 nm or less, or more particularly about 150
nm or less. There is no particular lower limit to the height
dimension as long as the identification feature can be detected.
The height dimension can be, for example, about one nm or more, or
about 10 nm or more, or about 25 nm or more. Exemplary ranges can
be, for example, about one nm to about one micron, or about 10 nm
to about 500 nm, or about 25 nm to about 250 nm. Again, if a
pattern of repeating identification features are used, the vertical
dimension can represent an average dimension.
[0082] In addition to the lateral dimension and the height
dimension for identification features on the stamp, the invention
can be also characterized by a separation dimension which
represents the distance between the identification features such as
a separation distance or a pitch. In other words, the one or more
identification features can be separated from each other by a
particular distance, and this distance can be an average distance
for an array of identification features. For example, if the
identification features are a series of lines, a distance can be
measured between the centers of the lines, or if the identification
features are a series of dots, a distance can be measured between
the centers of the dots. The distance of separation is not
particularly limited but smaller separation distances are preferred
so that the identification is invisible to the unaided eye. For
example, the one or more identification features can be separated
from each other by an average distance of about 500 microns or
less, or more particularly, about 100 microns or less, or more
particularly, about 10 microns or less, or more particularly, about
one micron or less, or more particularly, about 500 nm or less.
[0083] The stamp can also be characterized by the density of the
identification features. For example, a plurality of parallel lines
can be generated wherein there is at least one line per every two
microns, or at least one line per every one micron, or at least one
line per every 0.5 microns. See for example FIG. 1, wherein a
height profile scan be used to determine a density.
[0084] The information associated with the identification region
and features may be obtained by determining one or more of the
aforementioned characteristics and optionally a mathematical
function or algorithm.
[0085] The surface of the stamp also can comprise one or more marks
which can be detected by an optical microscope or an unaided eye.
The at least one mark can be located outside of the identification
region. Examples include an X shaped mark. The marks, for example,
can have lateral dimensions such as line width at the micron scale
such as 10 microns or more, at least 50 microns or more, at least
100 microns or more.
[0086] The stamp can also comprise the identification regions
described above for the pharmaceutical composition. The
identification region can be characterized by an identification
region area which has an enclosing perimeter around the
identification features so that all of the identification features
can be found within the enclosing perimeter. This area can be for
example, about 10,000 square microns or less, or about 1,000 square
microns or less, or about 400 square microns or less, or about 4
square microns or less, or about one square micron or less. The
identification region can be, for example a square region with a
lateral length and width of 100 microns.times.100 microns,
respectively, or 20 microns.times.20 microns, or 2 microns.times.2
microns. Or the identification region can be, for example, a
generally rectangular region or circular region. In many cases, two
or more identification regions are desired in case one or more of
the identification regions become unreadable by scratching,
rubbing, or some other undesirable event. For example, the surface
of the stamp can comprise more than 20, more than 30, more than 40,
or more than 50 identification regions. The identification region
can be sufficiently large to be seen by the naked eye or an optical
microscope, even when identification features within the
identification region can be sufficiently small that they cannot be
seen by the naked eye or even with an optical microscope.
[0087] The material of the stamp is not particularly limited. In
general, the stamp can have a surface which is made of a harder or
stiffer material than the material of the surface to be stamped.
Materials that can provide high aspect ratio structures can be
used. For example, materials can be used which can be subjected to
etching processes which result in high aspect ratios such as, for
example, reactive ion etching. Stamp material can be, for example,
silicon, silicon oxide, quartz, and nickel, and other substrates
popular for semiconductor processing.
[0088] Stamps can be also treated to increase the durability of the
stamp. For example, stamp surfaces can be coated with diamond like
coatings (DLC), or nickel films to increase hardness and decrease
wear. Stamps fabricated from silicon substrates can be oxidized to
increase the hardness of the stamp surface.
[0089] A master stamp can be used to produce daughter stamps which
are substantially identical but inverted copies of the master.
[0090] In another embodiment, indirect nanolithography can be used
to selectively remove or modify areas in a resist film coating a
substrate. The patterned substrate can be subjected to etching to
generate negative relief features, such as trenches, in the
substrate. Stamps with negative relief features will result in
positive features when used for printing. Negative relief stamps
can be replicated to generate secondary stamps that have positive
features.
[0091] FIG. 2 is a working example described further below. It
provides an AFM scan of a stamp which has an identification region
and identification features which can be transferred to the object,
composition, and pharmaceutical composition. For example, it
comprises at least six identification features and in particular at
least nine identification features. The positive features rising
out of the surface have a generally triangular shape according to
the height profile analysis. The scan shows nine lines in
approximately parallel arrangement. The center of the line can be
used to measure a separation distance.
[0092] FIG. 6 is another working example further described below.
Here, a pattern of dots are used. The density of dots in the
cross-sectional height profile is better than one dot per 10
microns. FIG. 1 is a working example and shows SEM scans of several
stamps. FIG. 3 is a working example and shows a plurality of
identification regions on one stamp. Each identification region
comprises a series of identification features which are barcode
lines.
[0093] In the nanolithography regime, nanoimprint lithography is a
method which can be used in some cases to generate features having
lateral dimensions below 200 nm using a stamp on polymer-coated
semiconductor wafer. See, for example, U.S. Pat. Nos. 5,772,905 to
Chou ("Nanoimprint Lithography"); 6,309,580 to Chou; 6,482,742 to
Chou; and 6,518,189 to Chou. The method employs use of stamps
having protruding features and made of stiff materials. These
references can be used to practice the invention both with respect
to the final stamp and the methods of making and using the stamp.
Commercial products including stamping instruments and molds or
masks are available from Nanonex Corp. (Princeton, N.J.), Suss
Microtech AG (Munich, Germany); EV Group (Schareding, Austria);
Molecular Imprints Inc (Austin, Tex.); and Obducat (Malmo,
Sweden).
[0094] Generally, stamp materials which can be used in NIL can be
used in this invention. If silicon materials are used, they can be
oxidized to silicon dioxide to improve properties such as, for
example, durability.
V. Method of Making the Stamp
[0095] A variety of methods can be used to make the stamp. These
methods can be carried out with use of microlithography or
nanolithography and can provide excellent high resolution
identification features. For example, DPN printing, nanoimprint
lithography, microcontact printing, electron beam lithography, ion
beam lithography, laser-based lithography, optical lithography,
nanografting, and the like can be used.
[0096] For example, in one embodiment, the invention provides a
method for making a stamp comprising the steps of (i) writing a
pattern with a resist material by nanolithography or
microlithography on a substrate, (ii) etching the patterned
substrate, and optionally (iii) further treating the patterned and
etched substrate to form the stamp. For example treatment step
(iii) can comprise removing the resist, or any other layers which
are undesired in the final stamp.
[0097] In one embodiment, direct write nanolithography can be used
to pattern a monolayer resist on a substrate. The patterned
substrate can be subjected to etching including wet etching or dry
etching to remove areas unprotected by the resist. Finally, the
resist itself can be removed. The resist can be, for example, a
compound which covalently bonds or chemisorbs to the substrate. The
resist can be, for example, an alkanethiol on a gold substrate. The
substrate can be, for example, fused silica having an outer layer
of metal with an intermediate adhesion layer as needed. The direct
write nanolithographic method can be carried out with use of a
nanoscopic tip to transfer resist material to the substrate by
deposition.
[0098] In another embodiment, illustrated in FIG. 4, direct write
nanolithography can be used to pattern a resist on a substrate. The
resist can be a curable material such as, for example, a UV curable
or heat curable polymer. Etching can be carried out and the resist
removed.
[0099] FIGS. 5A and 5B further illustrate embodiments for stamp
fabrication. Two process pathways are illustrated which each begin
with a fused silica substrate and end with a fused silica stamp.
These processes can be used also to make stamps in silicon
substrates.
[0100] In the left pathway (FIG. 5A), a thermally oxidized silicon
or fused silica substrate is provided which comprises further a
gold surface layer and an interfacial adhesion layer of chromium.
DPN printing can be carried out to produce a pattern of an
alkanethiol on the gold surface. Wet etching can be carried out to
etch away the gold layer not protected by the resist. Dry etching
can be carried out to further remove chromium and silica. Finally,
the resist, gold, and chromium can be further removed to yield the
stamp.
[0101] In the right pathway (FIG. 5B), a fused silica substrate is
provided which further comprises a chromium surface layer. DPN
printing can be carried out to produce a pattern of a polymer
resist on the chromium. The polymer can be cured by heat or light.
After curing, dry etching by, for example, chlorine can be carried
out to remove chromium. Finally, the resist, chromium, and silica
can be removed to yield the stamp.
[0102] A stamp made by the methods disclosed above can be
replicated into secondary stamps, as many identical stamps may be
required for commercial production. Furthermore, the identification
features present on the master stamp may be replicated multiple
times on a secondary stamp, providing redundancy as discussed
above. The master stamp may be replicated e.g. by stamping, molding
into a soft material (or other methods known to the art), followed
by a hardening or coating step, for example polymeric curing,
vacuum physical vapor deposition, electroless plating,
electroplating or a combination thereof.
[0103] In another embodiment, the stamp is replicated on a thin
film or foil which is wrapped around a cylinder, then hardened or
coated by a hard material. Alternatively, a cylinder may be rolled
over the stamp, duplicating the stamp features on said cylinder.
See the related art in Chou et al. JVST B 16(6), 1998. The cylinder
is then used as a stamp by rolling it over the desired
pharmaceutical composition or object.
[0104] The processes are further described in the working
examples.
VI. Direct-Write Nanolithography and DPN Printing in Making the
Stamp
[0105] In a preferred method, direct-write nanolithography is used
in the process to prepare the stamp. A preferred method is the use
of deposition of inks or patterning compounds from a fine, sharp
needle like structure which can be, for example, a scanning probe
cantilever with or without a tip. The needle like structure can
have the patterning compound at the end and can be used to deposit
the ink or patterning compound to a substrate. A preferred method
of direct-write nanolithography is DPN printing. This method
provides for exceptionally high resolution and good patterning
capability.
[0106] For example, DPN printing technology and etching procedures
are described in pending patent application to Mirkin et al.
"Fabrication of Solid-State Nanostructures including sub-50 nm
Solid-State Nanostructures Based on Nanolithography and Chemical
Etching" filed Dec. 3, 2003 (Ser. No. 10/725,939), which is hereby
incorporated by reference in its entirety. This application also
describes a series of geometric patterns which can be used for the
identification features.
[0107] In addition, DPN.TM. printing and deposition methods are
extensively described in the following patent applications and
patent publications, which are hereby incorporated by reference in
their entirety and support the disclosure for the present
inventions, particularly with respect to the experimental
parameters for carrying out the deposition:
[0108] 1. U.S. Provisional application 60/115,133 filed Jan. 7,
1999 ("Dip Pen Nanolithography"). This describes applications of
deposited monolayers as etch resists.
[0109] 2. U.S. Provisional application 60/157,633 filed Oct. 4,
1999 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby").
[0110] 3. U.S. Regular patent application Ser. No. 09/477,997 filed
Jan. 5, 2000 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby"), now U.S. Pat. No.
6,635,311 to Mirkin et al. issued Oct. 21, 2003. A wide variety of
inks and substrates are described which show chemisorption between
the ink and the substrate and can be used as an etch resist.
[0111] 4. U.S. Provisional application 60/207,713 filed May 26,
2000 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby"). This application, for
example, describes wet chemical etching, working examples,
references, and figures, which are all incorporated by reference in
their entirety.
[0112] 5. U.S. Provisional application 60/207,711 filed May 26,
2000 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby").
[0113] 6. U.S. Regular application Ser. No. 09/866,533 filed May
24, 2001 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby"). This application, for
example, describes wet chemical etching, working examples (e.g.,
example 5), references, and figures, which are all incorporated by
reference in their entirety. Computer control of the
nanolithographic deposition is also described.
[0114] 7. U.S. patent publication number 2002/0063212 A1 published
May 30, 2002 ("Methods Utilizing Scanning Probe Microscope Tips and
Products Therefor or Produced Thereby").
[0115] 8. U.S. patent publication number 2002/0122873 A 1 published
Sep. 5, 2002 ("Nanolithography Methods and Products Produced
Therefor and Produced Thereby").
[0116] 9. PCT publication number WO 00/41213 A1 published Jul. 13,
2000 based on PCT application no. PCT/US00/00319 filed Jan. 7, 2000
("Methods Utilizing Scanning Probe Microscope Tips and Products
Therefor or Produced Thereby").
[0117] 10. PCT publication number WO 01/91855 A1 published Dec. 6,
2001 based on PCT application no. PCT/US01/17067 filed May 25, 2001
("Methods Utilizing Scanning Probe Microscope Tips and Products
Therefor or Produced Thereby").
[0118] 11. U.S. Provisional application 60/326,767 filed Oct. 2,
2001, ("Protein Arrays with Nanoscopic Features Generated by
Dip-Pen Nanolithography"), now published 2003/0068446 on Apr. 10,
2003 to Mirkin et al.
[0119] 12. U.S. Provisional application 60/337,598 filed Nov. 30,
2001, ("Patterning of Nucleic Acids by Dip-Pen Nanolithography")
and U.S. regular application Ser. No. 10/307,515 filed. Dec. 2,
2002 to Mirkin et al.
[0120] 13. U.S. Provisional application 60/341,614 filed Dec. 17,
2001, ("Patterning of Solid State Features by Dip-Pen
Nanolithography"), now published 2003/0162004 Aug. 28, 2003 to
Mirkin et al.
[0121] 14. U.S. Provisional application 60/367,514 filed Mar. 27,
2002, and publication no. 2003/0185967 on Oct. 2, 2003 to Eby et
al. This patent application describes computer control of
nanolithographic procedures.
[0122] 15. U.S. Provisional application 60/379,755 filed May 14,
2002, ("Nanolithographic Calibration Methods") and U.S. regular
application Ser. No. 10/375,060 filed. Feb. 28, 2003 to
Cruchon-Dupeyrat et al. This patent application describes computer
control of nanolithographic calibration procedures.
[0123] 16. U.S. patent application Ser. No. 10/689,547 filed Oct.
21, 2003 to Crocker et al. ("Nanometer-Scale Engineered Structures,
Methods, and Apparatus for Fabrication Thereof, and Application to
Mask Repair, Enhancement and Fabrication"). This describes for
example use of nanolithography to make photomasks and nanoimprint
lithography stamps.
[0124] 17. U.S. patent application Ser. No. 10/705,776 filed Nov.
12, 2003 to Cruchon-Dupeyrat ("Methods and Apparatus for Ink
Delivery to Nanolithographic Probe Systems"). This describes, for
example, use of reactive ion etching to make deep structures.
[0125] 18. U.S. Provisional application 60/544,260 filed Feb. 13,
2004 ("Direct-Write Nanolithography with Stamp Tip: Fabrication and
Applications"). This describes, for example, elastomer modification
of tips.
[0126] 19. U.S. Provisional application 60/547,091 filed Feb. 25,
2004 ("Methods for Patterning Conductive Material."). This
describes, for example, use of tipless cantilevers.
[0127] In general, state of the art DPN.TM. printing and
deposition-related products, including hardware, software, and
instrumentation are also available from NanoInk, Inc. (Chicago,
Ill.), and these can be used to carry out the present invention.
For example, commercially available products include NSCRIPTOR,
DPN-System-1, environmental chamber, probes, pens, inkwells,
substrates, substrate holders, and various accessories including
ink dispensing kits, ink dispersion syringes, replacement needles,
and probe clips. NSCRIPTOR features for example InkCAD system
control, closed loop scanning, and a series of computer programs to
facilitate automation. Calibration can be carried out with InkCal.
Probes can be single probes, passive multiple probe arrays, active
probes, or probes for AC mode.
[0128] Parallel methods of the DPN printing process in active mode
can be carried out as described in, for example, U.S. Pat. No.
6,642,129 to Liu et al. issued Nov. 4, 2003.
[0129] In addition, the following papers describes wet chemical
etching procedures used in conjunction with direct-write
nanolithography, and is hereby incorporated by reference in its
entirety including figures, references, and working examples: Zhang
et al., "Dip-Pen Nanolithography-Based Methodology for Preparing
Arrays of Nanostructures Functionalized with Oligonucleotides";
Adv. Mat., 2002, 14, No. 20, October 16, pages 1472-1474; Zhang et
al., "Biofunctionalized Nanoarrays of Inorganic Structures Prepared
by Dip-Pen Nanolithography"; Nanotechnology, 2003, 14, 1113-1117
(see further parts V and VI below).
[0130] FIG. 9 illustrates use of NanoInk's NSCRIPTOR DPNWriter in
designing and writing patterns. Using computer generated images,
which can be translated into physical patterns on surfaces, a wide
variety of useful identification features and regions can be
generated.
VII. Use of Lithography in Identification Processes
[0131] The invention provides the use of lithography, including
microlithography and nanolithography, in the identification of
objects and compositions which are subject to counterfeiting
including pharmaceutical compositions. The lithography can be
indirectly used to prepare stamps, and then the stamps can be used
to provide the identification features on the objects and
compositions. Alternatively, the lithography can be used to
directly write the identification features on the objects and
compositions. Direct-write methods of lithography are preferred
including the methods described above in Section VI and references
cited therein. Methods which comprise use of deposition of material
from a scanning probe microscopic tip can be used including AFM
methods. Methods involving cantilevers can be used including both
tip and tipless cantilevers.
VIII. The Stamping Instrument
[0132] In general, stamping instruments and components for stamping
such as stamps are commercially available. They range from
automatic production machines to manual research machines, and they
can be adapted as needed to accommodate the stamps described
herein. Other terms used in the art for stamping instruments
including stamping machines, imprinting machines, marking machines,
presses, and the like. Instruments are particularly of use when
they are adapted to process pharmaceutical compositions and be in
compliance with federal regulations for pharmaceuticals. The
instrument generally comprises mechanical and electrical components
which continuously and automatically deliver an object such as a
pill or a tablet for stamping to a stamping site. The instrument
also generally comprises mechanical and electrical components which
provide for stamping of the object at the stamping site. The
instrument further comprises mechanical and electrical components
which continuously and automatically transport the object away from
the stamping site after stamping. As known in the art, conveyor
systems can be used to transport the objects in a continuous,
high-speed, manufacturing operation. The instruments also can
comprise components which provide for printing, sorting,
inspecting, and feeding. The stamping methods generally can be
coupled with other methods used to process pharmaceutical
compositions.
[0133] Some examples from the technical literature are noted, and
the complete disclosures of these following patents are
incorporated herein by reference in their entirety for their
description of instrumentation for processing of compositions
including pharmaceutical compositions.
[0134] For example, U.S. Pat. Nos. 5,023,437 and 4,591,279 to
Speicher et al. are incorporated and describe marking the surface
of objects with bar codes, including a marking machine. U.S. Pat.
No. 4,574,694 is incorporated and also describes a stamping
machine.
[0135] U.S. Pat. No. 4,189,996 to Ackley et al. is incorporated and
describes an apparatus adapted to transport and imprint indicia
around the circumference of generally cylindrical objects such as
capsules. See also U.S. Pat. No. 3,272,118 to Ackley et al which is
incorporated. Additional patents assigned to Ackley include U.S.
Pat. Nos. 5,630,499; 5,878,658; 6,286,421; 6,314,876; 6,450,089;
and 6,481,347, which are incorporated.
[0136] U.S. Pat. No. 5,376,771 to Roy is incorporated and describes
a high speed process for digital laser marking of pharmaceutical
compositions including an instrument in FIG. 1.
[0137] Stamping instruments and components including tablet presses
including rotary tablet presses are available from a variety of
companies including, for example, Ackley Machine Corp. (Moorestown,
N.J.); R. W. Hartnett Co. (Philadelphia, Pa.); CapPlus Technologies
(CPT); and Fette Compacting America (Rockaway, NJ &
Schwarzenbek, Germany).
[0138] In addition, see, e.g., stamping instruments and components
from companies marketing NIL including Suss Microtech AG
(Garching/Munich Germany); EV Group (Schareding, Austria); Nanoex
Corp. (Princeton, N.J.); Molecular Imprints (Austin, Tex.); and
Obducat (Malmo, Sweden).
[0139] For an automated stamping instrument, the production rate
for stamping can be controlled to provide the best balance of
quality and speed. The production rate for stamping can be, for
example, at least 1,000 units per hour, or at least 10,000 units
per hour, or at least 100,000 units per hour, or at least 1,000,000
units per hour.
[0140] A stamping instrument was constructed and used to carry out
the working examples described below and is further illustrated in
FIGS. 13-16. This instrument can be adapted to provide continuous
operation under automated conditions with computer control.
[0141] The stamping instrument can comprise (i) a device which is
adapted to be coupled to a stamp; (ii) a mount which is adapted for
holding an object or composition, wherein the device and the mount
are operably connected to provide relative motion and stamping of
the object or composition by the stamp.
[0142] A stamp can be coupled to the device and uncoupled from the
device, and replaced as desired with a different stamp. Hence, a
stamp can comprise not only a surface having the image to be
stamped but also, if desired, coupling features which allow
coupling of the stamp to the device.
[0143] A support structure can be used to operably connect the
device and the mount and assist in providing the relative motion
and stamping. For example, the support structure can comprise a ram
bearing and a pressure ram. The support structure can include an
operably connected pressure ram which can move in relation to the
support structure through, for example, a ram bearing and provide
motion of the stamp relative to the mount. The support structure
can also comprise a heater, for controlling temperature of the
stamping, and a stamp holder. The mount can be connected to the
support structure through a press base. The mount can comprise
components which hold the object or composition to be stamped such
as, for example, one or more holding jaws. The support structure
can also comprise a damping element such as a spring which provides
for force and pressure measurement. As stamping is carried out, and
pressure is generated and released, the pressure of stamping can be
measured via the damping element. One or more measurement devices
to measure pressure, temperature, time, or other experimental
variables can be operably coupled to the instrument. Computers,
including hardware, software, and data storage can be operably
coupled to the instrument.
[0144] The composition can be a pharmaceutical composition.
[0145] More particularly, the stamping instrument can comprise (i)
a stamping force application device which is adapted to be coupled
to a stamp for stamping an object, a composition, or a
pharmaceutical composition, (ii) a mount for holding the object,
the composition, or the pharmaceutical composition to be stamped,
wherein the stamping force application device and the mount for
holding the object, the composition, or the pharmaceutical
composition are operably connected to provide measurement of
stamping conditions and relative motion for stamping. The force
application device, for example, can comprise a press support
structure, a pressure ram, and a ram bearing as described further
below. The mount for holding the object can be adapted to provide
for damping and measurement of force and pressure.
[0146] FIGS. 13-16 illustrate one embodiment of an apparatus for
applying by stamping at least one identification region having at
least one identification feature to pharmaceutical compositions
consistent in the present invention.
[0147] As shown in FIG. 13, the apparatus can have a pressure ram
10 housed in a ram bearing 11. A heater/stamp holder 12, which can
hold the stamp 13 and heat it if desired to a desired temperature,
can be connected at one end of the pressure ram 10 and can be
positioned over the pharmaceutical composition to be stamped, which
is shown as a pill (50). This pharmaceutical composition can be
held in place by a pharmaceutical composition mount 14, which is
shown as jaws, positioned under the heater/stamp holder 12.
[0148] The pharmaceutical composition mount 14, shown as jaws, can
be mounted on a press base 15. This press base 15 can be in turn
connected to an internal press base spring 16 and a load cell
17.
[0149] The apparatus shown in FIG. 13 can be operated by moving the
pressure ram 10 in a downward direction guided by the ram bearing
11, which can be part of a support structure 18 not shown directly
in FIG. 13 but shown in FIG. 14. The stamp 13 mounted on the
heater/stamp holder 12, which is mounted on the pressure ram 10, is
thereby pushed into the pharmaceutical composition, shown as a
pill, which is held by the pharmaceutical composition mount 14. The
force applied to the pharmaceutical composition held by the
pharmaceutical composition mount 14 compresses the internal press
base spring 16. The press base spring 16 dampens the force applied
to the pharmaceutical composition. The load cell 17 measures the
amount of force applied to the pharmaceutical composition. Thus,
the load cell 17 can be used to apply a desired and consistent
amount of force to the pharmaceutical composition with a large
degree of sensitivity. The heater element in 12 may be used to heat
the stamp if desired to aid the stamping process.
[0150] FIG. 14 further shows in a perspective view the apparatus
including the press support structure 18, which holds the ram
bearing 11.
[0151] The apparatus may be operated manually by a user, or it may
be operated by electronic, computer, or automatic control in a
production environment. Preferably, the load cell is used to apply
a consistent amount of force. Specifically, the force applied to
the pharmaceutical composition preferably should be a specific
amount held for some set period of time or released immediately
once the predetermined force is applied. The desired force will
vary depending on the pharmaceutical composition to be stamped. One
skilled in the art can perform experiments to find an optimal force
profile for stamping depending on the characteristics of the
pharmaceutical composition being stamped. Production rate can be
another important factor in selecting stamp conditions.
[0152] In many circumstances, it may be desirable to use heat in
combination with force to stamp. For this reason, in some
embodiments, as shown in FIG. 15, the apparatus can have a heating
element 19 that may be used to heat the stamp directly through the
heat/stamp holder 12. FIG. 15 shows how the heating element (19)
can be mounted on the heater/stamp holder to heat the stamp. Heat
can also be applied to the pharmaceutical composition via an
environmental chamber or via the pharmaceutical composition mount
14 which is shown as jaws in FIG. 15. Like the force, the
desirability of heat and the amount and duration of heat to apply
will vary with the pharmaceutical composition. Exemplary stamping
temperatures and pressures are described above. One skilled in the
art can perform experiments to find optimal heating conditions for
stamping. Cold stamping can be carried out.
[0153] The pharmaceutical composition mount 14 may hold non-wafer
form pharmaceuticals, such as cylindrical pills and capsules. FIG.
15 shows one embodiment where the pharmaceutical composition mount
is constructed from parallel plates placed on top of one another.
The parallel plates are split down the middle to create a space to
hold a pharmaceutical form. Each of these parallel plates may be
adjusted independently to hold a variety of shapes including
cylinders, disks, and other non-wafer shapes. This ability to hold
pharmaceutical forms of varying shapes is valuable, because
pharmaceutical compositions are manufactured in a number of
different forms. Any number of other mechanisms to suitably hold
non-wafer pharmaceutical forms can be used by one skilled in the
art and considered within the scope of the invention. Such
alternative mechanisms can hold non-wafer pharmaceutical forms
securely enough to allow stamping. At the same time, such
alternative mechanisms should minimize damage to the pharmaceutical
form. Preferably, a user can adjust the pharmaceutical composition
mount to accommodate a variety of pharmaceutical forms. Such
alternative mechanisms, for example, could use vacuum suction to
hold the pharmaceutical form. In another embodiment a cut-out shape
can be used to hold the pharmaceutical form using mechanical
pressure from the stamp side.
[0154] The press base spring 16 can add sensitivity to the
apparatus by dampening the force applied to the pharmaceutical form
by the pressure ram. Thus, breakage and other damage to the
pharmaceutical forms to be stamped may be reduced or eliminated.
The tension of the spring may be selected by one skilled in the art
to provide the proper amount of dampening. In some embodiments, the
single spring may be replaced by multiple springs or other
dampening members. For example, the single spring illustrated in
FIG. 13 may be replaced by a hydraulic member in some embodiments.
This hydraulic member may provide a similar dampening function as
the spring illustrated in FIG. 13. The apparatus can contain
dampening members readily selected by one of ordinary skill in the
art to dampen the force applied to the pharmaceutical form being
stamped.
[0155] FIG. 16 shows the stamp in motion to contact the
pharmaceutical composition, wherein the stamp is smaller than the
pharmaceutical composition.
[0156] Other modifications may be made to the apparatus described
above by one of ordinary skill in the art. For example, the
pharmaceutical composition mount may hold more than one
pharmaceutical composition. This modification may allow multiple
pharmaceutical compositions to be stamped simultaneously, or it may
allow multiple pharmaceutical compositions to be stamped without
needing to remount additional pharmaceutical compositions. In
another embodiment, the heater/stamp holder may hold more than one
stamp so that multiple pharmaceutical compositions may be stamped
simultaneously. In the alternative, the multiple stamps may be used
to allow a user to switch stamps without needing to manually
replace the existing stamp. In another embodiment, the pressure ram
or the pharmaceutical form mount may be designed to move in the x-y
plane. This modification may allow pharmaceutical compositions
positioned at different locations on the pharmaceutical form mount
to be stamped. These and other modifications may be made by one
skilled in the art and are within the scope of the present
invention.
[0157] In a preferred embodiment, the instrument shown in FIGS.
13-16 comprises the stamps described above and are operated in
continuous, automated mode under computer control at high
production speeds.
[0158] Additional embodiments for the stamping instrument can be
found in U.S. provisional patent application Ser. No. 60/637,007
filed Dec. 20, 2004 to Cruchon-Dupeyrat et al. "Apparatus and
Methods for Preparing Identification Features" (attny docket no.
083847-0261), which is completely incorporated by reference in the
present specification in its entirety including the specification,
figures, and claims.
IX. Further Literature to Enable Practice of the Invention
[0159] No admission is made that any technical literature noted
herein is prior art. One skilled in the art can refer to prior
technical literature in the practice of the present invention and
can use selected features therein in the practice of this
invention.
[0160] For example, U.S. Pat. No. 5,700,998 to Palti is
incorporated by reference in its entirety. It describes a drug
coding and delivery system in which a machine readable code is
placed on the outer surface of drug pills. The code can be a linear
bar code, a radial bar code, a code on the outer peripheral edge of
the tablet, or a coaxial code. In addition, U.S. Pat. No. 5,845,264
to Nelhaus is incorporated by reference in its entirety and
describes bar code identification of drugs. U.S. Pat. No. 5,992,742
to Sullivan is incorporated by reference in its entirety and
purports to describe an identification code which has patterns
whose resolution is too small for the unaided eye to discern. U.S.
Pat. No. 6,543,692 to Nelhaus et al. is incorporated by reference
in its entirety. It discloses a schema for identification of solid
form drugs, which include a drug identification system comprising a
composite pill imprint formed of a human-readable symbol and a
machine-readable bar code.
[0161] Methods of nanolithographic and microlithographic
fabrication are also known including use of etching. For example,
the text Fundamentals of Microfabrication, The Science of
Minitaturization, 2.sup.nd Ed., Marc J. Madou, describes micro and
nanotechnologies including additive and subtractive methods, for
example, lithography (Chapter 1), pattern transfer with dry etching
methods (Chapter 2), pattern transfer with additive methods
(Chapter 3), and wet bulk micromachining (Chapter 4). Also, the
text Direct-Write Technologies for Rapid Prototyping Applications:
Sensors, Electronics, and Integrated Power Sources (Eds. A. Pique
and D. B. Chrisey), describes micro and nanotechnologies including
additive and subtractive methods. For example, bulk micromachining
and etching are described on pages 617-619. DPN printing on the
Sub-100 nanometer length scale is described in Chapter 10.
Self-assembled monolayers, etching, and microfabrication are
further described in, for example, U.S. Pat. Nos. 5,618,760 to Soh
et al; 5,620,850 to Bamdad et al.; and 5,512,131 to Kumar et
al.
[0162] References on stamping and molding include: (i) Harmening
Backer Bley et al. Proceedings IEEE Micro Electro Mechanical
Systems 202 (1992), (ii) "Molding of Plastic Components Using
Micro-Dem Tools", Electronics Manufacturing Technology Symposium,
Hong Li and Stephen D. Senturia, 1992, pp. 145-149, and (iii) I.
Rubin Injection Molding (Wiley, N.Y) 1992.
[0163] All references cited in this application are incorporated by
reference in their entirety.
XI. Working Examples
[0164] To further describe the invention, additional description is
provided on process steps and variables including figures and
working examples. The following points relate to the working
examples and are important potential steps and variables in
carrying out the invention:
1. Stamp fabrication [0165] Substrate cleaning [0166] Thermal
evaporation of adhesion layers such as chromium or titanium (x nm)
and then a metal, e.g., gold (x nm) onto substrate using an
electron beam evaporator [0167] DPN printing patterns on gold
surface using NSCRIPTOR and InkCAD software with MHA ink [0168]
Redundant patterns using multiple parallel pen assemblies [0169]
Wet chemical etching to remove gold from around patterns, remove
titanium [0170] RIE etching to create high aspect ratio patterns in
the silicon 2. Optional coating of stamp with a release layer, e.g.
Teflon-like layer, or durable coating [0171] Use of amorphous
fluorocarbon polymer, e.g., Cytop spin on polymer [0172] Use of
polymer, Paralene CVD coating and release layer [0173] Diamond-like
carbon (DLC), with or without fluorine [0174] Nickel
electroplating
3. Stamping Variables
[0174] [0175] Stamping apparatus [0176] Temperature [0177] Time
[0178] Pressure 4. Types of Pills stamped: [0179] film coating
[0180] liquid filled capsule [0181] tablet
WORKING EXAMPLES
[0182] The invention is further described with use of the following
non-limiting working examples.
[0183] Nano-Embossing Pharmaceutical Tablets with Stamps Generated
by DPN printing
[0184] Experimental Section
[0185] Chemicals. Ammonium hydroxide, hydrogen peroxide (30%),
16-mercaptohexadecanoic acid (MHA), Na.sub.2S.sub.2O.sub.3, KOH,
K.sub.3Fe(CN).sub.6 and K.sub.4Fe(CN).sub.6. Milli-Q water (>18
M.OMEGA.cm) was used for all aqueous experiments.
[0186] Substrate preparation. A silicon wafer was cut into
1.times.1 cm.sup.2 squares. After being ultrasonicated with acetone
for 10 min and rinsed with Milli-Q water, the Si substrates were
immersed into a boiling solution of ammonium hydroxide and hydrogen
peroxide (V(NH.sub.4OH):V(H.sub.2O.sub.2):V(H.sub.2O)=1:1:5) for 1
h. The cleaned substrates were rinsed with Milli-Q water and dried
with N.sub.2, and then put into a Varian Electron Beam Evaporator
(UIC) chamber. Under vacuum conditions (pressure <10.sup.-7
Torr), the substrates were coated with a 1 nm Ti adhesion layer via
thermal evaporation and subsequently coated with Au (10 nm) to make
Au film.
[0187] Dip-pen nanolitbography (DPN Printing) and wet chemical
etching. The metal substrates were patterned with
16-mercaptohexadecanoic acid (MHA) by DPN printing, and all DPN
printing experiments were carried out under ambient conditions
(probe set point=0.5 nN, 22-24.degree. C., 30-36% relative
humidity) by using a NSCRIPTOR.TM. (NanoInk Inc., Chicago, Ill.)
with MHA-coated tips. MHA-coated tips were prepared by immersing
Si.sub.3N.sub.4 DPN parallel 3-probe assembly (k=0.004, 0.016, and
0.032 N/m for probes with the s-3, s-4 and s-5 model number,
respectively, NanoInk Inc., Chicago, Ill.) in an acetonitrile
solution saturated with MHA for .about.5 s. They were subsequently
dried with compressed difluoroethane (Dust-off, Ted Pella, Inc.,
Redding, Calif.). A2-A11 cantilevers from NanoInk also were used.
Multiple dipping including double dipping processes were used in
some cases to coat the probes.
[0188] The Au substrates, patterned with MHA, were immersed in a
ferri/ferrocyanide etching solution (a 1:1:1:1 (v:v:v:v) aqueous
mixture of 0.1 M Na.sub.2S.sub.2O.sub.3, 1.0 M KOH, 0.01 M
K.sub.3Fe(CN).sub.6 and 0.001 M K.sub.4Fe(CN).sub.6) for .about.10
min under constant stirring to remove the Au layer from the exposed
regions of the Au substrate. After rinsing with Milli-Q H.sub.2O,
the etched substrates were dried with N.sub.2.
[0189] Technical literature including experimental descriptions for
these processes can be found in the following references which are
hereby incorporated by reference in their entirety: (a) Zhang, H.;
Li, Z.; Mirkin, C. A. Adv. Mater. 2002, 14, 1472. (b) Zhang, H.;
Chung, S. W.; Mirkin, C. A. Nano Lett. 2003, 3, 43. (c) Zhang, H.;
Lee, K. B.; Li, Z.; Mirkin, C. A. Nanotechnology 2003, 14, 1113.
(d) Zhang, H.; Mirkin, C. A. Chem. Mater. Web Release Date: 24 Mar.
2004; (Article) DOI: 10.1021/cm0305507.
[0190] AFM images. All etched metal nanostructures were imaged
under ambient conditions in contact mode using a NSCRIPTOR.TM.
(NanoInk Inc., Chicago, Ill.) or an AutoProbe CP AFM (TM
Microscopes, Sunnyvale, Calif.) with a DPN Si.sub.3N.sub.4 probe
(model s-1, k=0.041 N/m, NanoInk Inc., Chicago, Ill.).
[0191] Reactive Ion Dry Etching. The patterned dice were processed
as follows: the wafers were etched for 1.5 minutes in a Technics
Micro RIE with 4 sccm SF6 gas at an RF Power=100 Watts. The
pressure was .about.70-100 mT (uncontrolled).
[0192] Release Layer Coatings. Some of the samples were coated with
fluorocarbon using a STS DRIE (deep reactive ion etching) system
operating with 85 sccm C4F8 and 8.5 sccm Ar gases for 16 seconds
under the following conditions: Platten power (substrate RF
bias)=30 Watts, coil power (ICP)=600 watts, APC (throttle valve
position)=67 degrees.
[0193] Stamping. Using the apparatus shown in FIG. 12, various pill
surfaces were imprinted with a silicon stamp. Time for stamping,
pressure, and temperature were optimized by stamping under a range
of conditions (Time=0.5 s to 30s, T=60.degree. C. to 130.degree.
C., Pressure=1 MPa to 27 MPa).
(2) Results
[0194] Results. Silicon stamps were imaged by SEM and AFM after
reactive ion etching. Stamps had relatively smooth surfaces with
relief structures making up the pattern, as shown in FIGS. 1-3. The
stamps were used without further treatment to imprint film-coated
tablets and soft, liquid-filled tablets, using a range of
temperature, pressure, and time during stamping in order to find
the optimal conditions for an imprint. After stamping pills were
examined using optical microscopy and atomic force microscopy. The
optimal conditions for film-coated tablets were as follows: time=1
to 3 s, Temp=100-110.degree. C., pressure=5-10 MPa. For soft,
liquid-filled caplets, the optimal conditions were as follows:
time=3s, Temp=80C, and Pressure=13 MPa.
[0195] After finding the optimal stamping conditions, the imprint
patterns on the stamped pills were imaged with AFM and the line
dimensions in the barcode patterns were compared to the dimensions
of the original silicon master. The line widths and depths matched
closely the original stamp pattern. However, since there was
particulate matter on the pill surface, it was decided to scan more
than one of the patterned regions to obtain a complete pattern.
[0196] Finally, additional numbered embodiments described in
priority provisional application Ser. No. 60/563,443 filed Apr. 20,
2004 include:
1. A pharmaceutical composition comprising: a pharmaceutical
composition having a surface, wherein the surface comprises at
least one identification region, the region having at least one
identification feature, the feature having a lateral dimension of
about 500 microns or less. 2. The pharmaceutical composition
according to 1, wherein the lateral dimension is about 10 microns
or less. 3. The pharmaceutical composition according to 1, wherein
the lateral dimension is about one micron or less. 4. The
pharmaceutical composition according to 1, wherein the lateral
dimension is about 500 nm or less. 5. The pharmaceutical
composition according to 1, wherein the lateral dimension is about
100 nm or less. 6. The pharmaceutical composition according to 1,
wherein the identification feature has a height dimension of about
one micron or less. 7. The pharmaceutical composition according to
1, wherein the identification feature has a height dimension of
about 500 nm or less. 8. The pharmaceutical composition according
to 1, wherein the identification feature has a height dimension of
about 250 nm or less. 9. The pharmaceutical composition according
to 1, comprising a plurality of identification features which are
separated from each other by an average distance of about 100
microns or less. 10. The pharmaceutical composition according to 1,
comprising a plurality of identification features which are
separated from each other by an average distance of about 10
microns or less. 11. The pharmaceutical composition according to 1,
comprising a plurality of identification features which are
separated from each other by an average distance of about one
micron or less. 12. The pharmaceutical composition according to 1,
comprising a plurality of features which are separated from each
other by an average distance of about 500 nm or less. 13. The
pharmaceutical composition according to 1, wherein the
identification region is about 10,000 square microns or less. 14.
The pharmaceutical composition according to 1, wherein the
identification region is about 400 square microns or less. 15. The
pharmaceutical composition according to 1, wherein the
identification region is about 4 square microns or less. 16. The
pharmaceutical composition according to 1, wherein the
identification feature comprises an indentation into the surface.
17. The pharmaceutical composition according to 1, wherein the
identification feature comprises a protrusion out from the surface.
18. The pharmaceutical composition according to 1, wherein the
identification region comprises at least one indentation into the
surface and at least one protrusion out from the surface. 19. The
pharmaceutical composition according to 1, wherein the
identification region comprises a bar code. 20. The pharmaceutical
composition according to 1, wherein the identification region
comprises a hologram. 21. The pharmaceutical composition according
to 1, wherein the identification feature is a dot. 22. The
pharmaceutical composition according to 1, wherein the
identification feature is a line. 23. The pharmaceutical
composition according to 1, wherein the surface further comprises
at least one mark outside of the identification region which is
detectable by optical microscopy. 24. The pharmaceutical
composition according to 1, wherein the pharmaceutical composition
is a pill, tablet, or capsule. 25. The pharmaceutical composition
according to 1, comprising a plurality of identification regions
each having a plurality of identification features which are
separated from each other by an average distance of about 100
microns or less, wherein the plurality of identification features
have an average lateral dimension of about one micron or less, and
an average height dimension of about one micron or less. 26. The
pharmaceutical composition according to 1, comprising a plurality
of identification features which are separated from each other by
an average distance of about 10 microns or less, wherein the
plurality of identification features have an average lateral
dimension of about 500 nm or less, and an average height dimension
of about 500 nm or less. 27. The pharmaceutical composition
according to 1, comprising a plurality of identification features
which are separated from each other by an average distance of about
1 micron or less, wherein the plurality of identification features
have an average lateral dimension of about 100 nm or less, and an
average height dimension of about 250 nm or less. 28. The
pharmaceutical composition according to 1, wherein the
identification region comprises identification features which form
a hologram or bar code, and the surface further comprises at least
one mark outside the identification region which is detectable by
optical microscopy. 29. The pharmaceutical composition according to
1, wherein the identification region comprises identification
features which form a hologram or bar code, and the surface further
comprises at least one mark outside the identification region which
is detectable my optical microscopy. 30. The pharmaceutical
composition according to 1, wherein the identification region
comprises identification features which form a hologram or bar
code. 31. An object comprising:
[0197] an object having a surface, wherein the surface comprises at
least one identification region, the region having at least one
identification feature, the feature having a lateral dimension of
about 500 microns or less.
32. The object according to 31, wherein the lateral dimension is
about one micron or less. 33. The object according to 31, wherein
the identification feature has a height dimension of about one
micron or less. 34. The object according to 31, wherein the
identification feature has a height dimension of about 250 nm or
less. 35. The object according to 31, comprising a plurality of
identification features which are separated from each other by an
average distance of about 100 microns or less. 36. The object
according to 31, wherein the identification region is about 10,000
square microns or less. 37. The object according to 31, wherein the
identification feature comprises an indentation into the surface.
38. The object according to 31, wherein the identification feature
comprises a protrusion out from the surface. 39. The object
according to 31, wherein identification region comprises
identification features which form a bar code. 40. The object
according to 31, wherein identification region comprises
identification features which form a hologram. 41. A composition
comprising:
[0198] a composition having a surface, wherein the surface
comprises at least one identification region, the region having at
least one identification feature, the feature having a lateral
dimension of about 500 microns or less.
42. The composition according to 41, wherein the lateral dimension
is about one micron or less. 43. The composition according to 41,
wherein the identification feature has a height dimension of about
one micron or less. 44. The composition according to 41, wherein
the identification feature has a height dimension of about 250 nm
or less. 45. The composition according to 41, comprising a
plurality of identification features which are separated from each
other by an average distance of about 100 microns or less. 46. The
composition according to 41, wherein the identification region is
about 10,000 square microns or less. 47. The composition according
to 41, wherein the identification feature comprises an indentation
into the surface. 48. The composition according to 41, wherein the
identification feature comprises a protrusion out from the surface.
49. The composition according to 41, wherein identification region
comprises identification features which form a bar code. 50. The
composition according to 41, wherein identification region
comprises identification features which form a hologram. 51. A
method of making a pharmaceutical composition having at least one
identification region and at least one identification feature
comprising: (i) providing a stamp which has a surface to form at
least one identification region having at least one identification
feature; (ii) providing a pharmaceutical composition having a
surface; and (iii) contacting the stamp and the pharmaceutical
composition under conditions so that the pharmaceutical composition
comprises a surface having the at least one identification region
having at least one identification feature. 52. The method
according to 51, wherein the contacting is carried out at a
temperature of about 25.degree. C. to about 400.degree. C. 53. The
method according to 51, wherein the contacting is carried out at a
pressure of about 0.01 MPa to about 1,000 MPa. 54. The method
according to 51, wherein the contacting is carried out for a time
of about 0.1 seconds to about 50 seconds. 55. The method according
to 51, wherein the contacting is carried out for a time of about
0.1 seconds to about 50 seconds, at a pressure of about 0.01 MPa to
about 1,000 MPa, and at a temperature of about 25.degree. C. to
about 400.degree. C. 56. The method according to 51, wherein the
identification feature has a lateral dimension of about 500 microns
or less. 57. The method according to 51, wherein the identification
feature has a lateral dimension of about one micron or less. 58.
The method according to 51, wherein the identification feature has
a height dimension of about one micron or less. 59. The method
according to 51, wherein the identification feature has a height
dimension of about 250 nm or less. 60. The method according to 51,
wherein the pharmaceutical composition comprises a plurality of
identification features which are separated from each other by an
average distance of about 100 microns or less. 61. The method
according to 51, wherein the identification region is about 10,000
square microns or less. 62. The method according to 51, wherein the
identification feature comprises an indentation into the surface.
63. The method according to 51, wherein the identification feature
comprises a protrusion out from the surface. 64. The method
according to 51, wherein identification region comprises a bar
code. 65. The method according to 51, wherein identification region
comprises a hologram. 66. A method of making a composition having
at least one identification region and at least one identification
feature without etching after formation of identification feature
consisting essentially of: (i) providing a stamp which has a
surface to form at least one identification region having at least
one identification feature; (ii) providing a composition having a
surface; and (iii) contacting the stamp and the composition under
conditions so that the composition comprises a surface having the
at least one identification region having at least one
identification feature. 67. The method according to 66, wherein the
contacting is carried out at a temperature of about 25.degree. C.
to about 400.degree. C. 68. The method according to 66, wherein the
contacting is carried out at a pressure of about 0.01 MPa to about
1,000 MPa. 69. The method according to 66, wherein the contacting
is carried out for a time of about 0.1 seconds to about 50 seconds.
70. The method according to 66, wherein the contacting is carried
out for a time of about 0.1 seconds to about 50 seconds, at a
pressure of about 0.01 MPa to about 1,000 MPa, and at a temperature
of about 25.degree. C. to about 400.degree. C. 71. The method
according to 66, wherein the identification feature has a lateral
dimension of about 500 microns or less. 72. The method according to
66, wherein the identification feature has a lateral dimension of
about one micron or less. 73. The method according to 66, wherein
the identification feature has a height dimension of about one
micron or less. 74. The method according to 66, wherein the
identification feature has a height dimension of about 250 nm or
less. 75. The method according to 66, wherein the pharmaceutical
composition comprises a plurality of identification features which
are separated from each other by an average distance of about 100
microns or less. 76. The method according to 66, wherein the
identification region is about 10,000 square microns or less. 77.
The method according to 66, wherein the identification feature
comprises an indentation into the surface. 78. The method according
to 66, wherein the identification feature comprises a protrusion
out from the surface.
[0199] 79. The method according to 66, wherein identification
region comprises a bar code.
80. The method according to 66, wherein identification region
comprises identification features which form a hologram. 81. An
apparatus for forming identification features to pharmaceutical
compositions comprising:
[0200] a pressure ram;
[0201] optionally, a stamp attached to the pressure ram for
imprinting at least one identification feature on a pharmaceutical
composition;
[0202] a mount for holding at least one non-wafer pharmaceutical
composition; and
[0203] a load cell for measuring the amount of force applied to the
at least one pharmaceutical composition;
[0204] wherein the pressure ram presses the stamp against the at
least one pharmaceutical composition held by the pharmaceutical
composition mount with a desired amount of force as measured by the
load cell to form at least one identification feature on the at
least one pharmaceutical composition.
82. The apparatus of 81, further comprising a dampening member
connected to the pharmaceutical form mount. 83. The apparatus of
81, further comprising a heating element in thermal contact with
the stamp. 84. The apparatus of 81, further comprising a heating
element in thermal contact with the at least one pharmaceutical
composition. 85. The apparatus of 81, wherein the pressure ram may
be moved in the x-y plane. 86. The apparatus of 81, wherein the
stamp imprints more than one identification feature. 87. The
apparatus of 81, wherein the pharmaceutical form mount holds more
than one pharmaceutical composition. 88. The apparatus of 81,
wherein the pharmaceutical composition mount may be moved in the
x-y plane. 89. A pharmaceutical composition comprising:
[0205] a pharmaceutical composition having a surface, wherein the
surface comprises at least one identification region, the region
having a plurality of identification line features, the lines
having a line width of about one micron or less and a line length
of at least one micron.
90. The pharmaceutical composition according to 89, wherein the
line width is about 500 nm or less and the line length is at least
10 microns. 91. The pharmaceutical composition according to 89,
wherein the line width is about 200 nm or less and the line length
is at least one micron. 92. A stamping instrument comprising: (i) a
device adapted for coupling with a stamp, and (ii) a mount for
holding an object or composition, wherein the device and the mount
are operably coupled for relative motion of the stamp and the
object or composition and for stamping the object or composition
with the stamp. 93. The instrument according to 92, further
comprising components for bringing the object or composition to the
mount for stamping, and components for bringing the object or
composition away from the mount after stamping.
[0206] While it is apparent that the preferred embodiments of the
inventions disclosed herein provide the advantages and features
noted above, it should be appreciated by one of skill in the art
that the invention is susceptible to modification, variation and
change without departing from the proper scope or fair meaning of
the following claims.
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