U.S. patent application number 11/048368 was filed with the patent office on 2005-06-16 for fluid-jet medicament delivery.
Invention is credited to Childers, Winthrop D., Lee, Brian Craig, Samii, Mohammad M., Steinfield, Steven W., Van Veen, Mark A..
Application Number | 20050129746 11/048368 |
Document ID | / |
Family ID | 21843509 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050129746 |
Kind Code |
A1 |
Lee, Brian Craig ; et
al. |
June 16, 2005 |
Fluid-jet medicament delivery
Abstract
A method of applying an orally-ingestible medicament to an
orally-ingestible carrier comprising the steps of controlling a
relative position between a fluid ejector and the carrier, and
ejecting a plurality of drops of solution onto the carrier, wherein
the plurality of drops includes a desired therapeutic quantity of
the orally-ingestible medicament.
Inventors: |
Lee, Brian Craig;
(Corvallis, OR) ; Steinfield, Steven W.; (San
Diego, CA) ; Childers, Winthrop D.; (San Diego,
CA) ; Van Veen, Mark A.; (Cardiff by the Sea, CA)
; Samii, Mohammad M.; (La Jolla, CA) |
Correspondence
Address: |
HEWLETT PACKARD COMPANY
P O BOX 272400, 3404 E. HARMONY ROAD
INTELLECTUAL PROPERTY ADMINISTRATION
FORT COLLINS
CO
80527-2400
US
|
Family ID: |
21843509 |
Appl. No.: |
11/048368 |
Filed: |
January 31, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11048368 |
Jan 31, 2005 |
|
|
|
10028450 |
Oct 24, 2001 |
|
|
|
Current U.S.
Class: |
424/443 ;
427/2.14 |
Current CPC
Class: |
A61K 9/2095 20130101;
B41J 2/17513 20130101; A61J 3/00 20130101; B41J 3/407 20130101;
A61K 9/7007 20130101; B41J 29/393 20130101; A61K 9/209 20130101;
A61K 9/2086 20130101; G16H 20/13 20180101; A61K 9/2072
20130101 |
Class at
Publication: |
424/443 ;
427/002.14 |
International
Class: |
A61K 009/70; B01J
013/00 |
Claims
What is claimed is:
1. A method of applying an orally-ingestible medicament to an
orally-ingestible carrier, the method comprising: controlling a
relative position between a fluid ejector and the carrier; and
ejecting a plurality of drops of solution onto the carrier, wherein
the plurality of drops includes a desired therapeutic quantity of
the orally-ingestible medicament.
2. The method of claim 1, wherein each of the plurality of drops
has substantially the same volume as each other drop of the
plurality of drops.
3. The method of claim 2, wherein each of the plurality of drops
has a volume at most 10% different than a volume of each other drop
of the plurality of drops.
4. The method of claim 2, wherein each of the plurality of drops
has a volume at most 6% different than a volume of each other drop
of the plurality of drops.
5. The method of claim 2, wherein each of the plurality of drops
includes substantially equal amounts of orally-ingestible
medicament.
6. The method of claim 5, wherein each of the plurality of drops
has an amount of orally-ingestible medicament at most 10% different
than an amount of orally-ingestible medicament of each other drop
of the plurality of drops.
7. The method of claim 5, wherein each of the plurality of drops
has an amount of orally-ingestible medicament at most 6% different
than an amount of orally-ingestible medicament of each other drop
of the plurality of drops.
8. The method of claim 1, wherein ejecting a plurality of drops
includes ejecting a number of drops selected to yield the desired
therapeutic quantity of the orally-ingestible medicament.
9. The method of claim 1, wherein the desired therapeutic quantity
is within a range no more than 1% greater or less than a target
dose.
10. The method of claim 1, further comprising printing information
onto the orally-ingestible sheet.
11. The method of claim 10, wherein printing includes printing the
information onto the orally-ingestible sheet in a machine
detectable form.
12. The method of claim 10, wherein printing includes printing the
information onto the orally-ingestible sheet in a human-perceptible
form.
13. The method of claim 1, further comprising sealing the
orally-ingestible medicament on the orally-ingestible sheet.
14. The method of claim 13, wherein sealing includes activating a
fluid ejector to eject a barrier component fluid over the
orally-ingestible medicament.
15. An edible dosage form produced by the method of claim 1.
16. A method of applying an orally-ingestible medicament on an
orally-ingestible sheet, comprising: advancing the
orally-ingestible sheet to a dispense position; and activating a
fluid ejector to eject the orally-ingestible medicament onto the
orally-ingestible sheet.
17. The method of claim 16, further comprising printing information
onto the orally-ingestible sheet.
18. The method of claim 17, wherein printing includes printing the
information onto the orally-ingestible sheet in a machine
detectable form.
19. The method of claim 17, wherein printing includes printing the
information onto the orally-ingestible sheet in a human-perceptible
form.
20. The method of claim 17, wherein printing includes ejecting an
orally-ingestible ink from at least one ink ejector fluidically
coupled to an ink reservoir onto the orally-ingestible sheet.
21. The method of claim 16, wherein activating includes activating
the fluid ejector to eject a predetermined number of ejections of
the orally-ingestible medicament.
22. The method of claim 16, further comprising sealing the
orally-ingestible medicament on the orally-ingestible sheet.
23. The method of claim 21, wherein sealing includes activating a
barrier fluid ejector to eject a barrier component fluid over the
orally-ingestible medicament.
24. An edible dosage form produced by the method of claim 16.
25. A method of applying an orally-ingestible medicament on an
orally-ingestible sheet, comprising: receiving a fluid ejection
cartridge into a fluid dispensing system, the cartridge holding a
mixture of an orally-ingestible ink and an orally-ingestible
medicament; advancing the orally-ingestible sheet to a dispense
position; and printing a user message on the orally-ingestible
sheet using the mixture of the orally-ingestible ink and the
orally-ingestible medicament.
26. An edible dosage form produced by the method of claim 25.
27. A method of manufacturing an orally-ingestible dose,
comprising: advancing an orally-ingestible sheet having at least
one dosage region to a dispense position; and activating a fluid
ejector to eject a two-dimensional array of an orally-ingestible
medicament onto the dosage region of the orally-ingestible sheet,
wherein the dosage region includes a first edge and a second edge,
and wherein a density of the two-dimensional array of the
orally-ingestible medicament varies between the first edge and the
second edge, forming a two-dimensional gradient of
orally-ingestible medicament.
28. The method of claim 27, further comprising coating a deposited
array of ingestible medicament with an ingestible coating
material.
29. The method of claim 28, wherein coating the deposited array
includes activating a second fluid ejector to eject an ingestible
barrier component fluid over the deposited array of ingestible
medicament.
30. An edible dosage form produced by the method of claim 27.
31. A method of manufacturing an orally-ingestible dosage form,
comprising: advancing an orally-ingestible sheet having at least
one dosage region to a dispense position; activating a fluid
ejector to eject a first two-dimensional array of an
orally-ingestible medicament onto the dosage region of the
orally-ingestible sheet; dispensing an orally-ingestible barrier
layer on the first two-dimensional array of orally-ingestible
medicament; and activating the fluid ejector to eject a second
two-dimensional array of orally-ingestible medicament on the
orally-ingestible barrier layer, thus forming a three-dimensional
array of orally-ingestible medicament on the orally-ingestible
sheet.
32. An edible dosage form produced by the method of claim 31.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/028,450, filed Oct. 24, 2001.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present disclosure relates to fluid-jet medicament
delivery. More particularly, the present disclosure relates to
applying precise doses of medicament onto an edible sheet using
fluid-jet technology.
[0004] 2. Description of the Art
[0005] Oral administration of pharmaceuticals is one of the most
widely used methods to provide effective therapy for a variety of
illnesses. Many powdered medications are typically administered
orally to a person in a dosage form such as tablets or capsules,
while still others are in liquid form. The release of orally
administered medications falls into two broad categories, buccal or
sublingual administration, and oral dissolution. For example,
enteric coated tablets that release the medication in the
intestinal tract of the patient. Further, many individuals suffer
from chronic health problems that require the regular
administration of medicaments. Diseases such as diabetes,
allergies, epilepsy, heart problems, AIDS, and even cancer requires
the regular delivery of precise doses of medicaments if patients
are to survive over long periods of time. Such chronic treatment
creates the need to regularly obtain additional medication. This
can be extremely troublesome for those patients that lack the
mobility to easily travel to a pharmacist to refill medications,
such as the elderly and infirm. Thus, a method and a dosage form
that provides the ability to make custom doses, outside of the
large pharmaceutical manufacturing plants, is desirable.
[0006] Most pharmaceuticals involve dosage units in the microgram
to milligram range of the purified active ingredient or
ingredients. Thus, many pharmaceutical doses in tablet or liquid
form are made in formulations of a predetermined quantity of
pharmaceutical units in each dose. Such pharmaceutical doses are
frequently available in fixed different strengths, such as 50 mg,
100 mg, etc.
[0007] Unfortunately, such conventional oral dosage forms suffer
from a number of disadvantages. Typically, to effectively handle
and dispense small doses a considerable amount of adjuvant material
must be added in order that the final dosage form is of a
manageable size. Thus, typical methods for manufacturing include
the mixing of the pure drug with various other substances commonly
referred to as excipients or diluents that are therapeutically
inert and acceptable by regulatory bodies, such as the FDA.
Excipients may also protect the drug from deterioration by
oxidation, humidity, and light. Palatability can be improved
through the addition of flavorants and identification by use of
colorants. This mixing process often requires the use of
sophisticated, complex expensive machinery. Certain excipients may
be needed to improve the flowability of the drug and diluents
through the mixing machinery. Therefore, a method and dosage form
that reduces the mixing of the active drug with other substances,
and utilizes less complex and expensive machinery would also be
desirable.
[0008] These therapeutically inactive or inert materials also have
the disadvantage that each such material must be evaluated before
use in terms of potential incompatibilities with the medicaments
present. For example, some of these materials, such as lubricants
or disintegrants, may present problems concerning the
bioavailability of the active ingredient. Further, the
certification of new drugs is a lengthy and costly process
involving animal studies followed by chemical trials to establish
both the efficacy and safety of the new drug. Because a
pharmaceutical's characteristics may be affected by changes in
manufacturing and/or packaging, the approval process limits the
approval to a particular manufacturing and packaging process. Thus,
the ability to rapidly and easily change dosage units is extremely
limited in conventional pharmaceutical manufacturing processes.
[0009] Drugs with a narrow therapeutic range must also be precisely
dosed. If the patient falls below the range, the desired effect
will not occur. However, if the patient is above the range then the
risk of toxic effects increases. Clinicians assume the dose units
manufactured are uniform and that generic equivalents have equal
bioavailability. The many FDA generic formulation rejections and
recalls for pharmaceuticals that have too high or low of a drug
level, however, are evidence that accuracy and precision are still
challenges for pharmaceutical manufacturing.
[0010] The ability to easily make a custom dose using tablets or
capsules utilizing current technology is also difficult. It is
virtually impossible to split or divide a capsule to decrease the
dose administered requiring that the smallest dose be
predetermined. Further, in the case of tablets a patient or
pharmacist may often encounter difficulty in splitting or dividing
even relatively large tablets that have a notch or groove at a
predetermined breaking point to form a lower dosage unit. The
splitting or breaking often results in fragments of unequal size.
Thus, a method and dosage form that allows for variable doses to be
formed outside the pharmaceutical manufacturing plant is
desirable.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1a is a perspective view of a fluid cartridge
containing an orally-ingestible medicament;
[0012] FIG. 1b is a perspective view of fluid ejection cartridges
held within a carriage;
[0013] FIG. 1c is a perspective view of fluid ejection cartridges
and an image acquisition system held within a carriage;
[0014] FIG. 2a is a perspective view of a orally-ingestible
medicament dispensing system;
[0015] FIG. 2b is a perspective view of a orally-ingestible
medicament dispensing system with an ingestible sheet tray;
[0016] FIG. 3 is a cross-sectional view of a fluid ejection
cartridge;
[0017] FIG. 4 a perspective view of an ingestible sheet;
[0018] FIG. 5a is a plan view of an ingestible sheet;
[0019] FIG. 5b is a cross-sectional view of the ingestible sheet
shown in FIG. 5a.
[0020] FIG. 6a is a cross-sectional view of a method for generating
a dosage form;
[0021] FIG. 6b is a cross-sectional view of a method for generating
a dosage form;
[0022] FIG. 6c is a cross-sectional view of a method for generating
a dosage form;
[0023] FIG. 6d is a cross-sectional view of a method for generating
a dosage form;
[0024] FIG. 7a is a perspective view of a process for manufacturing
a dosage form;
[0025] FIG. 7b is a perspective view of an encapsulated and
unitized single dose;
[0026] FIG. 7c is a plan view of a process for manufacturing a
dosage form;
[0027] FIG. 8a is a perspective view of a dosage form to vary the
amount of the medicament released over time;
[0028] FIG. 8b is a perspective view of a dosage form to vary the
amount of the medicament released over time;
[0029] FIG. 8c is a perspective view of a dosage form to vary the
amount of the medicament released over time;
[0030] FIG. 9a is a plan view of a dosage form containing user
information;
[0031] FIG. 9b is a plan view of a dosage form containing user
information and manufacturing information;
[0032] FIG. 10a is a cross-sectional view of a process for
manufacturing a dosage form;
[0033] FIG. 10b is a cross-sectional view of a dosage form
manufactured using the process shown in FIG. 10a;
[0034] FIG. 11 is a block diagram of a medicament dispensing system
for the interactive dispensing of a medicament on an ingestible
sheet;
[0035] FIG. 12 is a flow diagram of an interactive method for
generating a dosage form;
[0036] FIG. 13a is a flow diagram showing a more detailed view of
the steps for loading materials shown in FIG. 12;
[0037] FIG. 13b is a flow diagram showing a more detailed view of
the steps for reading information from materials shown in FIG.
12;
[0038] FIG. 13c is a flow diagram showing a more detailed view of
the steps for requesting information shown in FIG. 12;
[0039] FIG. 13d is a flow diagram showing a more detailed view of
the steps for specifying information shown in FIG. 12;
[0040] FIG. 13e is a flow diagram showing a more detailed view of
the steps for verifying information shown in FIG. 12;
[0041] FIG. 13f is a flow diagram showing a more detailed view of
the steps for applying the medicament on the ingestible sheet shown
in FIG. 12;
[0042] FIG. 13g is a flow diagram showing a more detailed view of
the steps for printing information shown in FIG. 12.
DETAILED DESCRIPTION
[0043] The present invention advantageously uses the multi-drop
deposition capability of a fluid-jet ejection system to dispense
medicaments on an ingestible carrier such as an ingestible sheet.
Although one embodiment describes the use of a thermally activated
fluid-jet ejection cartridge to dispense medications in the form of
drops on an ingestible media, other methods of activating fluid-jet
ejection, such as piezoelectric or acoustic activation, may also be
used in the present invention. The fluid ejection system of the
present disclosure includes a drop-on-demand type fluid dispenser.
The present disclosure provides greater control of the drug dose
than a typical diluting and mixing apparatus by producing precise
and repeatable doses onto an ingestible carrier. Another feature of
the present invention is the ability to dispense multiple different
pharmaceuticals in varied quantities onto an ingestible
carrier.
[0044] For purposes of this description, the term "medicament"
shall mean a substance that treats or prevents or alleviates a
disease or illness and/or the symptoms of the disease or illness.
An example of a medicament is a pharmaceutical substance, such as a
drug. The term "medicament" can be used to refer to such a
substance in pure form, a mixture of the substance with other
substances, and/or a solution including the substance. An
"orally-ingestible medicament" is a medicament intended for intake
into the digestive track via the mouth, as opposed to a medicament
that is intended to be injected or surgically implanted. An
orally-ingestible medicament may be configured to be digested
and/or otherwise act in one or more of the mouth, throat, stomach,
intestines, or any other portion of the alimentary canal.
[0045] Referring to FIG. 1a, an exemplary embodiment of a fluid
ejection cartridge 102 is shown in a perspective view. In this
embodiment, a fluid reservoir 128, in the body portion of the fluid
ejection cartridge 102, typically contains a medicament used to
generate the pharmaceutical dose and/or an ingestible ink used to
generate an image or characters on an ingestible sheet or other
carrier used to make a dosage form. The fluid reservoir 128 is
fluidically coupled, preferably through internal passageways, to a
substrate (not shown) that is attached to the back of a nozzle
layer 126. The substrate (not shown) normally contains an
energy-generating element or fluid ejector (not shown) that
generates the force necessary for ejecting the fluid held in the
reservoir. Two widely used energy generating elements are thermal
resistors and piezoelectric elements. The former rapidly heats a
component in the fluid above its boiling point causing vaporization
of the fluid component resulting in ejection of a drop of the
fluid. While the latter utilizes a voltage pulse to generate a
compressive force on the fluid resulting in ejection of a drop of
the fluid. For more information on various transducers utilized in
drop-on-demand fluid ejection cartridges see Stephen F. Pond, Ph.D.
Inkjet Technology and Product Development Strategies, ch 4 (Torrey
Pines Research, 2000); and more particularly for thermal inkjet
technology see J. Stephen Aden et al., The Third-Generation HP
Thermal InkJet Printhead, Hewlett-Packard Journal, vol. 45, no. 1,
pg. 41-45, February 1994.
[0046] The substrate (not shown), the nozzle layer 126, nozzles
124, and a flexible circuit 125 form what is generally referred to
as an ejector head 122. In other embodiments the ejector head 122
includes the substrate (not shown), the nozzle layer 126 and the
nozzles 124. The nozzle layer 126 contains one or more nozzles 124
through which fluid, that is contained in a chamber around the
fluid ejectors, is ejected by activation of the fluid ejectors (not
shown) located in close proximity to the nozzles 124. Each
activation of a fluid ejector results in the ejection of a precise
quantity of fluid in the form of a fluid drop; thus, the number of
activations of the fluid ejector controls the number of drops
ejected. For more information on drop formation see for example
Jaime H. Bohorquez et al., Laser-Comparable Inkjet Text Printing,
Hewlett-Packard Journal, vol. 45, no. 1, pg. 9-17, February 1994;
or William A. Buskirk et al., Development of a High Resolution
Thermal Inkjet Printhead, Hewlett-Packard Journal, vol. 39, no. 5,
pg. 55-61, October 1988.
[0047] The fluid ejection cartridge 102 described in the present
invention can reproducibly and reliably eject drops in the range of
from about ten femto-liters to about ten micro-liters depending on
the parameters of the fluid ejection cartridge such as the size and
geometry of the chamber around the fluid ejector, the size and
geometry of the fluid ejector, and the size and geometry of the
nozzle. Thus, the present invention has the ability to accurately
dispense a medicament solution with a part per million to a part
per billion accuracy. This is particularly advantageous when
dispensing expensive medicaments, such as certain hormones,
antibiotics, and medicaments derived from some natural products in
scarce supply. The accuracy and precision is advantageous when
dispensing concentrated substances with high potency. In addition,
a further advantage of utilizing the fluid ejection cartridge 102
of the present invention is a reduction, to less than one percent
by weight, in the amount of excess medicament that is dispensed to
assure proper label dosage. In other words, medicament can be
accurately applied to a carrier in the form of a plurality of
closely sized drops, which include substantially equal amounts of
medicament. By controlling the number of drops that are applied,
the total amount of medicament can be controlled. As used herein,
"target dose" shall mean the exact amount of medicament that is to
be placed onto a carrier, and "therapeutic quantity" is a range of
acceptable doses that includes the target dose. This embodiment is
also advantageous for utilizing a mixture of the medicament and an
ingestible ink contained in the fluid reservoir 128.
[0048] Fluid ejection cartridge 102, can utilize a method of
creating discrete sized drops that are independently ejected from a
particular nozzle utilizing a particular fluid ejector while
maintaining a narrow drop volume distribution. In addition, the
narrow drop volume distribution can be maintained over multiple
nozzles each having a separate fluid ejector and fired
independently or simultaneously. Such a cartridge can be
characterized by a very narrow distribution of drop volumes and may
have anywhere from a 2.times., 3.times. or even more narrower drop
volume distribution than conventional fluid ejector devices such as
hydraulic, air assisted, or ultrasonic nozzles that form a spray of
fluid having varying drop sizes. The range in drop volume is
generally within 10 percent of the targeted or specified value and
under steady state conditions can be within about 6 percent or less
of the targeted value. Thus, a medicament can be accurately
dispensed with a part per million to a part per billion
accuracy.
[0049] The nozzle layer 126 may be formed of metal, polymer, glass,
or other suitable material such as ceramic. Preferably, the nozzle
layer 126 is formed from a polymer such as polyimide, polyester,
polyethylene naphthalate (PEN), epoxy, or polycarbonate. In an
alternate embodiment, the nozzle layer 126 is formed from a metal
such as a nickel base enclosed by a thin gold, palladium, tantalum,
or rhodium layer. Preferably, the components of the ejector head
122 and the fluid reservoir are formed of materials that are inert
to the medicament and/or the ingestible ink which are to be
dispensed therefrom. Thus, inert materials such as glass, ceramic,
stainless steel, noble metals, and polymers inert to the medicament
are preferred.
[0050] The fluid is selectively expelled from the one or more of
the nozzles 124 by electrical signals communicated through
electrical contacts 130 and associated conductive traces 132
disposed on the flexible circuit 125. In the preferred embodiment,
the flexible circuit 125 is typically bent around an edge of the
fluid ejection cartridge 102 and secured. The electrical traces 132
are routed from the electrical contacts 130 to bond pads on the
substrate (not shown) to provide electrical connection for the
fluid ejection cartridge 102. Thus, by communicating the proper
electrical signal through the electrical contacts 130 a fluid
ejector is activated the appropriate number of times to eject a
predetermined number of drops.
[0051] An information storage element 133 is disposed on cartridge
102. Preferably, the information storage element 133 is coupled to
a flexible circuit such as the flexible circuit 125 as shown in
FIG. 1a. The information storage element 133 is any type of memory
device suitable for storing and outputting information that may be
related to properties or parameters of the medicament contained
within the fluid reservoir 128. Preferably, the information storage
element 133 is a memory chip mounted on the flexible circuit 125
and electrically coupled through the electrical traces 132 to the
electrical contacts 130. Alternatively, the information storage
element 133 can be encapsulated in its own package with
corresponding separate electrical traces and contacts.
[0052] When the fluid ejection cartridge 102 is either inserted
into, or utilized in, a dispensing system the information storage
element 133 is electrically coupled to a controller that
communicates with the information storage element 133 to use the
information or parameters stored therein. However, other forms of
information storage can also be utilized for the information
storage element 133, such as a bar code or other device that allows
storage of information. Further, the information storage element
133 can be mounted elsewhere on or within the body of the fluid
ejection cartridge 102 with appropriate contacts and electrical
connections to access the storage element depending on the
particular application. In addition, the information storage
element 133 can also be placed on an off-axis container utilized
with semi-permanent ejector heads or cartridges.
[0053] The information storage element 133 may contain information
such as the particular medicament or other material contained in
the fluid reservoir 128; the quantity of material remaining in the
fluid reservoir 128 based on the number of drops dispensed or the
number of times the fluid ejector has been activated. Other
information can include the date of manufacture, inspection dates,
quality control information, dispensing system parameters, and
customer/patient information.
[0054] The fluid ejection cartridge 102, or more preferably a set
of individual fluid ejection cartridges 102 and 103, capable of
ejecting drops of medicament and/or ingestible ink or a combination
thereof from ejector heads 122 and 123 are held within a carriage
111, as illustrated in a perspective view in FIG. 1b. Alternative
embodiments can include one or more semi-permanent ejector heads
that are replenished from one or more fluidically-coupled off-axis
fluid containers, or a single fluid ejection cartridge having one
or more fluids available within the fluid ejection cartridge and
fluid ejecting nozzles designated for each fluid integrally coupled
with each fluid reservoir, or a single fluid ejection cartridge
having a mixture of the medicament and ingestible ink. The present
invention can be satisfactorily employed by at least these
alternatives.
[0055] An alternate embodiment of the present invention where a
carriage 111' contains an image acquisition system 150 is shown in
FIG. 1c. In this embodiment, the image acquisition system 150
contains a camera 151 and a light source 152. As the cartridge 102
ejects drops of a medicament onto the ingestible sheet, the drops
may exhibit spots on the sheet having various visual or otherwise
detectable geometric aspects, such as area extent, shape, and
position. Preferably, the light source 152 is positioned relative
to the camera 151 so that the camera 151 can image these detectable
geometric aspects. Although as depicted in FIG. 1c the light source
152 comprises a single source, multiple sources can also be used.
The light source 152 is preferably a light emitting diode (LED),
although other light sources such as light bulbs or lasers can also
be utilized.
[0056] The image acquisition system 150 also contains, a camera and
light source, controller 153 that is preferably coupled to a
drop-firing controller 214 as shown in FIG. 2a. When either fluid
ejection cartridge 102 or 103 is activated by the drop-firing
controller 214, to dispense medicament or ingestible ink on an
ingestible sheet, the camera controller 153 is correspondingly
triggered by the drop-firing controller 214; thus activating the
camera 151 to gather image information pertaining to a portion of
the surface of an ingestible sheet on which either a medicament or
ingestible ink has been deposited. The camera 151 as shown in FIG.
1c can be any camera that can image the desired qualities on an
ingestible sheet such as a camera that captures 2 dimensional
images or line scan cameras that capture a narrow-stripped portion
of the surface being imaged and these narrow-stripped portions are
combined to for a complete two dimensional image.
[0057] In addition to capturing images of either the medicament or
ingestible ink or other material dispensed on the ingestible sheet
the image acquisition system 150 can also be utilized to capture
images of information that has been placed on an ingestible sheet
prior to deposition of the medicament or ingestible ink. Examples
of such information are the composition of the ingestible sheet or
results of quality control testing; data on compatibility with the
medicaments, i.e. whether the ingestible sheet is compatible or
incompatible with medicament being dispensed; patient information
such as height, weight, name, age, prescribed dose etc.; expiration
dates, temperature and/or humidity sensors, indicating that the
ingestible sheet is no longer effective or it has been exposed to
an extreme which could hinder its effectiveness. Although the image
acquisition system 150, as depicted in FIG. 1c, is mounted in
carriage 111', other arrangements can also be utilized such as
mounting the image acquisition system 150 on a separate carriage,
or locating the image acquisition system in a different portion of
a medicament dispensing system 200 shown in FIG. 2a.
[0058] The essential parts of a medicament dispensing system 200
according to an embodiment of the present invention is shown in a
block diagram in FIG. 2a. In this embodiment, a platen to which an
ingestible sheet 204, such as a starch or glycerin based paper, is
transported by mechanisms that are known in the art. The carriage
111 is typically supported by a slide bar 213 or similar mechanism
within the system 200 and physically propelled along the slide bar
213 to allow the carriage 111 to be translationally reciprocated or
scanned back and forth across the ingestible sheet 204. The scan
axis, X, is indicated by an arrow in FIG. 2a.
[0059] Under control of the drop firing controller 214 and a
position controller 218, the carriage 111 scans across the
ingestible sheet 204, and fluid drops are selectively ejected from
fluid ejectors disposed within the fluid ejection heads of the set
of fluid ejection cartridges 102 and 103 onto the ingestible sheet
204. The power to activate the fluid ejectors is supplied by a
power supply 215. The drops are ejected to form predetermined dot
matrix patterns, forming both the pharmaceutical dose from the
cartridge containing the medicament, and images or alphanumeric
characters from the cartridge containing the ingestible ink.
[0060] Rasterization of the data can occur in a host computer such
as a personal computer or PC (not shown) prior to the rasterized
data being sent, along with the system control commands, to the
system, although other system configurations or system
architectures for the rasterization of data are possible. This
operation is under control of system driver software resident in
the system's computer. The system interprets the commands and
rasterized data to determine which drop ejectors to fire. An arrow
in FIG. 2a indicates the fluid drop trajectory axis, Z, directed
from the fluid ejection cartridges 102 and 103 toward the
ingestible sheet 204. When a swath of fluid ejection has been
completed, the ingestible sheet 204 is moved an appropriate
distance along the ingestible sheet axis, Y, indicated by the
arrow, in preparation for the next swath. This invention is also
applicable to medicament dispensing systems employing alternative
means of imparting relative motion between the fluid ejection
cartridges and the ingestible sheet, such as those that have fixed
fluid ejection cartridges and move the ingestible sheet in one or
more directions, and those that have fixed ingestible sheet and
move the fluid ejection cartridges in one or more directions.
[0061] As can be appreciated from a preferred embodiment shown in
FIG. 2a, the ingestible sheet 204 is advanced into a fluid ejection
area beneath the ejector heads 122 and 123 (shown in FIG. 1b) by a
sheet positioning mechanism commonly referred to as a sheet
positioner or sheet advancer including rollers 217, a platen motor
216, and traction devices (not shown). In a preferred embodiment,
the fluid ejection cartridges 102 and 103 are incrementally drawn
across the ingestible sheet 204 on the platen by a carriage motor
212 in the .+-.X direction, perpendicular to the Y direction of
entry of the medium. The platen motor 216 and the carriage motor
212 are typically under the control of the sheet and cartridge
position controller 218. An example of such a positioning and
control apparatus may be found described in U.S. Pat. No.
5,070,410. Thus, the ingestible sheet 204 is positioned in a
location so that the fluid ejection cartridges 102 and 103 may
eject drops of fluid onto the ingestible sheet 104 as required for
the particular dose being generated, and the particular data being
written that is input to the drop-firing controller 214 of the
medicament dispensing system 200. These drops of fluid are expelled
from selected orifices in the ejector heads 122, 123 (as shown in
FIG. 1b) in a band parallel to the scan direction as the fluid
ejection cartridges 102 and 103 are translated across the
ingestible sheet 204 by the carriage motor 212. Once the fluid
ejection cartridges 102 and 103 have reached the end of their
traverse in the X direction on the slide bar, they are either
returned back along the support mechanism while continuing to eject
fluid or returned without fluid ejection.
[0062] When the fluid ejection cartridges 102, 103 reach the end of
their travel at an end of a fluid ejection swath on the ingestible
sheet 204, the ingestible sheet 204 is conventionally incrementally
advanced by the position controller 218 and the platen motor 216.
Once the fluid ejection cartridges have reached the end of their
traverse in the X direction on the slide bar 213 or similar support
mechanism, they are either returned back along the slide bar 213
while continuing to eject fluid or returned without ejecting. The
ingestible sheet 204 may be advanced by an incremental amount
equivalent to the width of the fluid-ejecting portion of the
fluid-ejecting head or some fraction thereof related to the spacing
between the nozzles. Control of the ingestible sheet 204,
positioning of the fluid ejection cartridge, and selection of the
correct fluid ejectors for creation of both the medicament dose and
the image or character written is determined by the position
controller 218 and the drop-firing controller 214. The controllers
may be implemented in a conventional electronic hardware
configuration and provided operating instructions from conventional
memory 219.
[0063] The medicament dispensing system 200 can also contain a
heater 221 coupled to a heater controller 220 as shown in FIG. 2a.
The heater 221 heats the ingestible sheet 204 to remove water and
other solvents deposited on the ingestible sheet 204 after
deposition of the medicament or ingestible ink. The heater also
contains a temperature sensor (not shown) that is coupled to the
heater controller 220 to maintain the ingestible sheet 204 at the
appropriate temperature. The particular temperature that the
temperature sensor maintains depends on the particular medicament
or ingestible ink being dispensed, and on the particular ingestible
sheet 204 being utilized. Although the heater 221 is located above
the rollers 217 as depicted in FIG. 2a the heater can also be
located in other portions of the medicament dispensing system 200
such as underneath the ingestible sheet 204 in front of the rollers
217.
[0064] A perspective view of an alternate embodiment of the present
invention where the medicament dispensing system 200 includes an
ingestible sheet tray 299 is shown in FIG. 2b. In this embodiment,
the tray 299 holds separate ingestible sheets 204' that are
advanced into the fluid ejection area beneath ejector heads (not
shown) by rollers 217' and other mechanisms as described above in
FIG. 2a. Preferably the tray 299 holds from 1 to about 250 sheets,
however, depending on the particular system, ingestible sheet, and
medicament being utilized, the tray 299 may hold more than 250
sheets.
[0065] The apparatus described above makes unique use of an
automated fluid ejecting device, having at least one medicament
supply in a reservoir or chamber and at least one, and preferably,
a plurality of fluid ejectors in an array, each ejector dispensing
a precise volume of fluid in essentially individual droplets on
each activation of the fluid ejector. This arrangement enables the
quantity of the medicament dispensed to be varied in a specified
area of the ingestible sheet thereby enabling either custom, or a
wide range of doses to be more easily prepared. The apparatus or
system as depicted in FIGS. 2a and 2b may be used in a
manufacturing environment, a pharmacy, or even in other dispensing
locations such as in a hospital, home etc. to automatically prepare
pharmaceutical doses in response to patients needs.
[0066] A cross-sectional view of an alternate embodiment of the
present invention where a fluid ejection cartridge 302 includes
three fluid reservoirs 327, 328, and 329 contained within a
cartridge body 334 is shown in FIG. 3. In this embodiment, a
substrate 336 is attached to the outer surface of the cartridge
body 334, and includes three groups of fluid ejectors 346, 346' and
346", in fluid communication with the three fluid reservoirs 327,
328, and 329 via three fluid routing channels 337, 338, and 339
respectively. Three fluid filters 340, 341, and 342, are mounted
within the fluid reservoirs 327, 328, and 329, respectively. These
filters are preferably constructed from stainless steel wire mesh
of a desired porosity to provide good filtration of solid particles
and air bubbles when fluid passes from the three fluid reservoirs
327, 328, and 329 into the three fluid routing channels 337, 338,
and 339.
[0067] Attached to the substrate 336 is a firing chamber layer 344
that defines the volume around each fluid ejector. Attached to the
firing chamber layer 344 is a nozzle layer 326 that contains three
groups of nozzles 324, 324' and 324". The fluid will flow from the
three fluid reservoirs 327, 328, and 329 through the three fluid
filters 340, 341, and 342 into the three fluid output ports 337,
338, and 339 through the substrate 336. A firing chamber layer 344
includes fluid channels (not shown) and a firing chamber (not
shown) formed into the layer that feeds fluid to the ejectors 346,
346' and 346". Upon appropriate activation, the ejectors 346, 346'
and 346" initiate the ejection of fluid out of the fluid ejection
cartridge 302 through the three groups of nozzles 324, 324' and
324". Preferably, each group of nozzles is in a column and more
preferably in staggered columns, however other patterns, such as
circular patterns can also be utilized. This embodiment is
particularly advantageous when the user desires a self-contained
cartridge or integral replaceable unit containing the medicament,
the ingestible ink, and a protective coating that is dispensed over
the dispensed medicament. This embodiment is also advantageous when
the user has three compatible medicaments that can be dispensed on
the same sheet.
[0068] Although the properties of the ingestible sheets used in
accordance with the present invention depend both on the particular
medicament being dispensed and on the particular materials utilized
in the sheet, it is generally preferable that the sheets are safely
edible or ingestible, and do not have an objectionable "feel" in
the mouth. In addition, the sheets preferably dissolve or degrade
in body fluids and/or enzymes. However, the sheets can be made of
non-degradable materials that are readily eliminated by the body.
Preferably the sheets are hydrophilic and readily disintegrate in
water and more preferably the dissolution or disintegration of the
sheets is enhanced at the pH of the fluids in the stomach or upper
intestine. Further, ingestible sheets that minimize unintended
interactions with the medicament dispensed on the sheets and sheets
that minimize the release of any sheet component that would cause
unintended interactions with the medicament upon dissolution of the
sheet, are also desirable.
[0069] Additional properties of the ingestible sheet that are
desirable are the ability to remain stable over extended periods of
time, at elevated temperatures, and at high or low levels of
relative humidity. In addition, it is also preferable that the
ingestible sheets are generally a poor medium for the growth of
microorganisms to reduce spoilage. Further, ingestible sheets that
possess reasonable mechanical properties such as tensile strength
and tear strength are desirable to allow the sheets to be processed
through the various steps of fabrication of the final dosage form
using methods such as are recognized in the art.
[0070] Ingestible sheets that can be utilized in the present
invention can be one or a mixture of organic film formers generally
classified into two broad categories, i.e. polymeric and paper.
Examples of such film formers are starch (i.e. both natural and
chemically modified) and glycerin based sheets with or without a
releasable backing. Other examples include, proteins such as
gelatin, cellulose derivatives such as hydroxypropylmethylcellulose
and the like; other polysaccharides such as pectin, xanthan gum,
guar gum, algin and the like; synthetic polymers such as polyvinyl
alcohol, polyvinylpyrrolidone and the like. Examples of ingestible
sheets or edible films that can be utilized are those that are
based on milk proteins, rice paper, potato wafer sheets, and films
made from restructured fruits and vegetables.
[0071] In particular, sheets or films made from restructured fruits
and vegetables are advantageous were it is desirable to mask or
modify the taste or smell of the medicament being delivered.
Further, these restructured fruit and vegetable films also provide
a convenient approach to encourage children to take various
medications as well as providing a more pleasing and varied taste
for various medications taken by adults. For more information on
restructured fruit and vegetable films, see for example U.S. Pat.
No. 5,543,164 and U.S. Pat. No. 6,027,758.
[0072] Dispensing the medicament on an ingestible sheet containing
a water-expandable foam is preferable for those applications
desiring rapid release of the medicament once ingested. Examples of
such materials are an oxidized regenerated cellulose commercially
available from Johnson and Johnson under the trademark
SURGICEL.RTM., and a porcine derived gelatin powder commercially
available from Pharmacia Corporation under the trademark
GELFOAM.RTM..
[0073] The form of the ingestible sheet that can be utilized in the
present invention can be any of the forms generally recognized in
the art such as those used for paper, cardboard or polymeric films.
The ingestible sheet or roll preferably is uniform in thickness and
in width. Although the thickness of the ingestible sheet will
depend on the particular medicament being dispensed, the particular
ingestible sheet being utilized, and the particular method of
manufacture used; the thickness of the ingestible sheet preferably
ranges from about 10 to about 350 microns and more preferably from
about 25 to about 100 microns thick.
[0074] The dosage forms produced in accordance with the present
invention are eminently suited to span the range of production from
individualized doses made in a home or hospital environment to the
high speed high volume production in a pharmaceutical manufacturing
environment. Thus, the particular width and length will not only
depend on both the particular medicament being dispensed and the
particular ingestible sheet being utilized, but more particularly
on the particular method of manufacture used. Thus, the ingestible
sheet can be in roll or individual sheet forms with widths varying
from approximately one centimeter to several meters, and lengths
from a few centimeters to several thousand meters, although other
lengths and widths can also be utilized.
[0075] An embodiment of an ingestible sheet that is preferable for
both high speed high volume manufacturing as well as for custom,
individualized dispensing is illustrated in a perspective view in
FIG. 4. In this embodiment, an ingestible sheet 404 is in the form
of a roll that contains perforations 447 that delineates each
dosage form 405 and 405'. In this embodiment, a medicament is
dispensed preferably in a two-dimensional array, although other
patterns can also be utilized, onto a first portion of the
ingestible sheet 404. A sheet advancer (not shown) then advances
the ingestible sheet 404 and a second two dimensional array or
alternate pattern is dispensed on a second portion of the
ingestible sheet. The first and second portions form dosage forms
405 and 405' respectively.
[0076] Preferably, after the medicament is dispensed on the dosage
form 405 the user or system separates the dosage form 405 from the
dosage form 405' by tearing, by cutting along the perforations 447,
or by punching out the dispensed areas of the sheet. The user or
system can also separate the dosage form 405 from the dosage form
405' before dispensing of the medicament. This embodiment is
particularly advantageous for systems such as those that have fixed
fluid ejection cartridges; however, it can also be utilized in
other systems as well. Preferably, the ejector head is
approximately the width of the ingestible sheet 404 and the platen
(not shown) moves the ingestible sheet in the direction of arrow
448 allowing both the dispensed dose of medicament as well as the
appropriate characters or symbols utilizing the ingestible ink to
be formed.
[0077] An alternate embodiment of an ingestible sheet that can also
be used for custom, individualized pharmaceutical doses is shown in
a plan view in FIG. 5a and in a cross-sectional view in FIG. 5b. In
this embodiment, an ingestible sheet 504 is in the form of a sheet
with a plurality of dosage forms 505 where each dosage form 505
contains dosage form separators 547 around its peripheral edge.
Preferably, after the medicament is dispensed on the plurality of
the dosage forms 505 contained in the ingestible sheet 504 the user
or system separates the dosage form 505 from the dosage forms 505'
and 505" by bending or, by pushing up in the center of the dosage
form 505, or some other convenient method and peeling the dosage
form 505 from a releasable backing 549 shown in FIG. 5b. This
embodiment is particularly advantageous for systems used to
dispense custom pharmaceutical doses at home, in a hospital or a
pharmacy; however, it can also be utilized in other systems as
well. Although FIG. 5a shows the ingestible sheet 504 utilizing
dosage form separators 547, the ingestible sheet 504 can utilize
any convenient means of separation such as perforations shown in
FIG. 4.
[0078] An embodiment of a method for generating a dosage form where
the medicament is dispensed onto the ingestible sheet is shown in a
cross-sectional view in FIG. 6a. In this embodiment, a drop-firing
controller in a fluid dispensing system (not shown) activates one
and, typically, a plurality of fluid ejectors, of a fluid ejection
cartridge (not shown), to eject fluid drops 650, 650', and 650" of
the medicament onto an ingestible sheet 604 forming deposits 651,
651', and 651", respectively. For clarity in understanding the
invention, the fluid drops 650, 650', and 650" are shown as being
deposited on the surface of the ingestible sheet 604. Although this
will occur for non-porous, non-absorbing ingestible sheets,
typically, the ingestible sheet 604 will be a porous and absorbing
material which will allow the medicament to be absorbed into the
interior of the ingestible sheet 604. A dosage form 605 is
generated when the required number of fluid drops of the
medicament, to create the desired pharmaceutical dose, have been
dispensed on a portion of the ingestible sheet 604. Preferably, the
dosage form 605 contains a two-dimensional array of the deposits
651, 651' and 651" of the medicament on the ingestible sheet 604.
However, other arrangements can also be utilized, such as
overlapping deposits forming a layer, or a different geometrical
arrangement of the deposits 651, 651', and 651".
[0079] An alternate embodiment of the present invention where the
process used for generating a dosage form includes a barrier
material deposited over the medicament is shown in a
cross-sectional view in FIG. 6b. In this embodiment, the
drop-firing controller activates one and, typically, a plurality of
fluid or barrier ejectors, to eject fluid drops of a barrier
material over the deposits 651, 651', and 651" of the medicament to
form barrier deposits 652, 652", and 652". The barrier deposits
652, 652', and 652" and deposits 651, 651', and 651" of the
medicament on the ingestible sheet 604 form dosage form 606. The
barrier material acts to seal the medicament from the environment.
Depending on the particular medicament dispensed, and the
particular ingestible sheet used, the barrier material provides
various protective properties, such as humidity protection,
protection from oxidation, inactivation, or contamination. The
barrier material is an edible coating made from a suitable
polymeric material such as a water-soluble polyoxyethylene or
cellulose ether derivative. In addition, preferably the barrier
material is an inert material, which will not interact with the
deposited medicament. Further, the barrier material may also act as
an adhesive as will be discussed later. In this embodiment, the
fluid ejectors activated by the drop-firing controller are either,
a different subgroup of fluid ejectors on the fluid ejection
cartridge used to dispense the medicament, or a different fluid
ejection cartridge.
[0080] An alternate embodiment of the present invention where the
process used for generating a dosage form includes ingestible ink
deposited over the medicament is shown in a cross-sectional view in
FIG. 6c. In this embodiment, after the medicament and the barrier
material has been deposited onto the surface of the ingestible
sheet 604, as described above, the drop-firing controller activates
one and, typically, a plurality of ink ejectors, to eject fluid
drops of an ingestible ink at various locations on the ingestible
sheet 604 to form dots 654, 654' and 654". The dots 654, 654' and
654" are deposited in patterns using dot matrix manipulation or
other means to generate an image, alphanumeric characters, or a
machine understood code such as a one or two dimensional bar code,
on the ingestible sheet 604. The dots 654, 654' and 654", the
barrier deposits 652, 652", and 652" and deposits 651, 651', and
651" of the medicament on the ingestible sheet 604 form dosage form
607.
[0081] An alternate embodiment of the present invention where the
process used for generating a dosage form includes deposition of
more than one medicament onto the ingestible sheet 604' is shown in
a cross-sectional view in FIG. 6d. In this embodiment, the deposits
651, 651', and 651" of the medicament and the deposits 652, 652'
and 652" of the barrier material have been formed on the ingestible
sheet 604' as described above. Next, the drop-firing controller
activates one and, typically, a plurality of fluid ejectors, to
eject fluid drops of a second medicament on the ingestible sheet
604' to form deposits 656, 656' and 656". In this embodiment, the
fluid ejectors activated by the drop-firing controller to eject the
second medicament are either, a different subgroup of fluid
ejectors on the fluid ejection cartridge used to dispense the first
medicament, or a different fluid ejection cartridge.
[0082] After the second medicament has been dispensed, a second
barrier is then formed over the deposits 656, 656' and 656" forming
barrier deposits 658, 658' and 658" forming dosage form 608.
Preferably the second barrier material is the same as the first,
however, depending on the properties and compatibilities of the
first and second medicaments as well as the first barrier material
the second barrier material may be different from the first barrier
material. Although FIG. 6d depicts two different medicaments
deposited on the ingestible sheet, more than two medicaments can be
deposited on an ingestible sheet.
[0083] FIGS. 6a-6d depict isolated deposits of the medicament and
barrier material being deposited onto the ingestible sheet;
however, by depositing overlapping deposits of, either or both, the
medicament and barrier material layers of each material can be
formed. In addition, the order of deposition can also be varied
depending on the particular application. For example, the
ingestible ink can be deposited before the medicament and the
barrier material. Further, the ingestible sheet 604 or 604' shown
in FIGS. 6a-6d can have, either or both, a releasable backing (not
shown) or barrier material (not shown) coated on the surface
opposite to the surface on which the medicament is dispensed.
[0084] An alternate embodiment of the present invention of a
process for manufacturing a dosage form containing more than one
medicament is shown in a perspective view in FIG. 7a. In this
embodiment, multiple ingestible sheets 704, 706, and 707 each
having multiple portions 760, 761, 762 respectively that have a
medicament deposited thereon. The center ingestible sheet 704 is
then sandwiched between the outer sheets 706 and 707 to form a
laminated structure 764 where each of the multiple portions 760,
761, 762 are positioned where the portion 761 is above the portion
760 which is above the portion 762. This arrangement forms a dosage
form 705 that contains multiple medicaments.
[0085] Although FIG. 7a depicts three layers of ingestible sheet
being laminated, laminated structures containing two or more layers
can be utilized. The ingestible sheets 704, 706, and 707 can be
formed from the same or different materials. In addition, the
various processes and resultant structures depicted in FIGS. 6a-6b
can also be utilized. Further, other films such as a barrier film
or ingestible adhesive film can also be laminated or coated on the
different ingestible sheets 704, 706, and 707 to improve various
properties such as water vapor transmission rate or adhesion
depending on the particular medicaments and the particular
ingestible sheets being utilized. Subsequent to the lamination
process the laminated structure 764 can further be encapsulated and
unitized to form single dose 766 as shown in perspective view in
FIG. 7b.
[0086] An alternate embodiment of the present invention of a
process for manufacturing a dosage form containing more than one
medicament is shown in a plan view in FIG. 7c. In this embodiment,
an ingestible sheet 704' contains multiple portions 760', 761',
762', and 763 each containing a different medicament deposited
thereon. The four multiple portions form a dosage form 705' that
contains multiple medicaments. Although FIG. 7c depicts four
multiple portions, the ingestible sheet 704' containing two or more
multiple portions can be utilized. The various processes and
resultant structures depicted in FIGS. 6a-6b can also be utilized
in this embodiment. In addition, other films such as a barrier film
or ingestible adhesive film can also be laminated or coated on the
ingestible sheet 704' to improve various properties such as water
vapor transmission rate, acid resistance, or drug release rate
depending on the particular medicaments and the particular
ingestible sheet being utilized. Further the multiple portions
760', 761', 762' and 763 can also be utilized in the laminated
structure 764 shown in FIG. 7a by either making a larger dosage
form or by folding.
[0087] As noted above an expandable foam may be desirable for the
rapid release of a medicament once ingested, however, some
applications may want to vary the amount of the medicament released
over time. An advantage of the present invention is the ability to
make dosage forms that can vary the amount of medicament or drug
released over time as shown in FIGS. 8a-8c. In an alternate
embodiment, shown in FIG. 8a, a fluid ejection cartridge (not
shown) containing at least a medicament ejects the medicament onto
an ingestible sheet 804 to form deposits 808 of the medicament
dispensed in a two dimensional array over the surface of the
ingestible sheet 804. In this embodiment, a dosage form 805
contains a first edge 806 having a greater density of the deposits
808 than a second edge 807 where the density of the deposits 808
between the first edge 806 and second edge 807 varies, forming a
gradient of the medicament dispensed on the ingestible sheet.
Although as shown in FIG. 8a the medicament is dispensed in the
form of deposits 808 over the entire surface of dosage form 805
other forms can also be utilized such as centering the two
dimensional array of deposits 808 in a narrower strip in the center
of the dosage form 805 running from the edge 806 to the edge 807.
The dosage form 805 is wound into a coil, where the edge 806 having
the higher dot density forms the edge contained in the center of
the coil and the edge 807 having the lower dot density forms the
outer edge of the coil.
[0088] As the ingestible sheet 804 dissolves the radius of the
coiled dosage form 805 decreases, resulting in a smaller surface
area, thus the amount of medicament released can be varied or
maintained constant. For example as shown in FIG. 8a a gradient
that increases as the surface area decreases can be used to
maintain a constant or increasing release rate depending on the
particular gradient used. Thus, in this example the medicament is
deposited in a gradient adapted to provide a dosage form that,
after being ingested, the amount of the medicament released
increases over time. Further, the medicament can also be deposited
in a gradient adapted to provide a dosage form that, after being
ingested, the amount of the medicament released remains constant
over time However, as shown in FIG. 8b, a dosage form 805' that is
coiled in the opposite direction where the edge 807, having the
lower dot density, forms the center of the coil and the edge 806,
having the higher dot density, forms the exterior surface of the
coil; generates a gradient that decreases as the surface area
decreases. Such a dosage form can be used to decrease the release
rate as a function of time creating a loading dose. Thus, in this
example the medicament is deposited in a gradient adapted to
provide a dosage form that, after being ingested, the amount of the
medicament released decreases over time.
[0089] A perspective view of an alternate embodiment of the present
invention where repeat dosages are formed is shown in FIG. 8c. In
this embodiment a fluid ejection cartridge (not shown) containing
at least one medicament ejects the medicament onto the ingestible
sheet 804 to form the deposits 808 of the medicament dispensed in a
two dimensional array over discrete portions 809 on the surface of
the ingestible sheet 804. The dosage form 805" is wound into a coil
where each of the discrete portions 809 will release the deposited
medicament at different times depending on the thickness of the
ingestible sheet 804, the rate of dissolution of the ingestible
sheet 804 and the particular placement of each discrete portion 809
among other variables. This embodiment provides a dosage form where
a discrete amount of the medicament is released at either
repeatable times or discrete amounts of the medicament is released
at different times. Although each of the alternative embodiments
shown in FIGS. 8a-8c are described in terms of fixed dot size and
varying the dot density, other methods can also be utilized such as
varying the drop size and keeping the dot density constant. This
ability to vary the dosage release rate over time is an advantage
over a conventionally formed tablet, which would release less
medicament as the diameter of the tablet decreases. Thus, the
present disclosure allows for a dosage form where the amount of
medicament released over time, increases, decreases, remains
constant, is repeatable, or a discrete dose is released at
different times.
[0090] Referring to FIGS. 9a-9b, an alternate embodiment of the
present invention is shown where the dosage form 905 contains user
information 970 to be conveyed to the user or patient. For example,
FIG. 9a depicts the user information 970 as a clock showing the
time the dose is to be taken or administered. In this particular
example the user information 970 is deposited over the two
dimensional array of the deposits 908 of the medicament. However,
depending on the particular medicament and the particular
ingestible sheet being utilized the medicament can also be
deposited over the user information. Another example is shown in
FIG. 9b where the information is a message indicating the name,
date, and time to take the medicament. However, the user
information 970 can be any symbol, icon, image, or text or
combinations thereof, such as a company logo or cartoon character.
Other examples of the type of information that can be conveyed to
the user are the name of the medicament, the expiration date, the
flavor of the ingestible sheet, or information having some
marketing value. In addition, the dosage form 905 can also contain
manufacturing information 972 to be used by the manufacturer and/or
distributor. For example, FIG. 9b depicts the manufacturing
information 972 as a two-dimensional bar code. The manufacturing
information 972, however, can be any symbol, icon, image, or text
or combinations thereof. Examples of various forms are a
one-dimensional bar code, a text message, a code, or hologram.
Examples of the various types of information that can be utilized
in the manufacturing information 972 would be the composition of
the ingestible sheet or results of quality control testing, data on
compatibility with medicaments, expiration dates, or part tracking
information.
[0091] A cross-sectional view of an alternate embodiment of the
present invention where a dosage form 1005 is encapsulated in a
tablet 1079 is shown in FIG. 10b. In this embodiment, a lower die
chamber 1074 and an upper die chamber 1076 are substantially filled
with an excipient powder 1078 as shown in FIG. 10a. Dosage form
1005, which contains the medicament deposited on an ingestible
sheet 1004, is positioned between the two die chambers such that
the excipient powder formulation encases or encloses the dosage
form 1005. Compressing the lower die chamber 1074 against the upper
die chamber 1076 forms the tablet 1079. Preferably, the tablet is
cylindrical with convex outer surfaces typically about 5 to 15 mm.
in diameter and about 5 mm. in thickness. However, a variety of
regular and irregular shapes and sizes can be utilized, such as
elliptoids, cuboids, indentations, polygonoids and other convex and
concave surfaces. Optional subsequent processes including
dedusting, drying, and coating may be performed.
[0092] Depending on the desired pharmacokinetic characteristics of
the medicament dispensed on the ingestible sheet 1004, the
excipient formulation may be similar to the ingestible sheet 1004
or one may select excipients that are dissimilar to the ingestible
sheet to obtain tabletting or pharmacokinetic characteristics
unlike the ingestible sheet 1004. For example microcrystalline
sugar (97% sucrose and 3% maltodextrin) or cellulose, calcium
phosphate, and sodium carboxymethylcellulose can be used with a
cellulosic-based ingestible sheet. Sugars and corn, wheat, or rice
starches can be used with starch-based ingestible sheets. Whereas
silica added to improve flowability, stearates for lubrication, and
guar gum or gelatin as binders are examples of dissimilar
materials.
[0093] A preferable excipient formulation for direct compression
tabletting of a dosage form made from an ingestible sheet which
does not include the weight of the ingestible sheet nor the weight
of the medicament dispensed is: about 70 weight percent lactose,
about 25 weight percent microcrystalline cellulose, about 2 weight
percent di-calcium phosphate dihydrate, 2 weight percent sodium
carboxymethylcellulose, about 0.3 weight percent fumed silica and
about 0.5 weight percent magnesium stearate. However, excipient
ranges in formulations for direct compression tabletting of a
dosage form made from an ingestible sheet which does not include
the weight of the ingestible sheet nor the weight of the medicament
dispensed are 0 to about 80 weight percent sugar, 0 to about 25
weight percent microcyrstalline cellulose, 0 to about 90 weight
percent calcium phosphate, about 5 to about 25 weight percent
starch, about 1 to about 2 weight percent sodium
carboxymethylcellulose, about 0.2 to about 0.3 weight percent
silica and about 0.5 to about 1 weight percent magnesium stearate
can also be utilized.
[0094] In addition to improve adhesion between the excipient powder
formulation and the ingestible sheet the excipient formulation can
be modified by adding natural or synthetic polymers such as
proteins, carboxymethylcellulose, polyvinylacetate, gelatins, or
dextrins can be utilized to improve the adhesive properties of the
excipient powder. It is also contemplated that an ingestible
adhesive can be dispensed between the two die chambers prior to
applying pressure to form the tablet. For example, a monomeric
methyl or ethylcyanoacrylate type adhesive can be utilized.
Alternatively, the ingestible sheet 1004 of the dosage form 1005
can be perforated to allow greater contact area between excipient
powder 1078 contained in the upper die chamber 1076 and the lower
die chamber 1074 or the dosage form 1005 can be formed in the shape
of a ring containing an area in the center of the dosage form 1005
that allows the excipient powder in the two chambers to bond.
[0095] The process described above for compression tabletting of an
ingestible sheet containing a medicament is advantageous over
conventional tabletting in that the number of mixing steps can be
reduced as well as the need to assure thorough mixing of the
excipient with the pharmaceutical material to ensure proper
dilution. In addition, flowability and drying criteria of the
excipient formulation can also be relaxed.
[0096] An exemplary system 1100 for the interactive dispensing of a
medicament on an ingestible sheet is shown as a schematic diagram
in FIG. 11. In this embodiment a processor 1180 is coupled to a
drop-firing controller via dispense interface 1182. The processor
1180 converts a specified quantity of the medicament to be
dispensed into a number of drops or ejections to be activated by
the drop-firing controller. This number is transmitted via the
dispense interface 1182 to the drop-firing controller of the
medicament dispensing system 200. The specified quantity of the
medicament is then ejected onto the ingestible sheet forming a
dosage form. The system 1100 also includes a storage device 1186
and a display device 1184 coupled to the processor 1180 to store
and display information. For example user input information, system
parameters, information and parameters associated the ingestible
sheet can all be stored on storage device 1186 and/or displayed on
display device 1184.
[0097] The system 1100 having the processor 1180, display device
1184, and storage device 1186 is advantageous over current methods
of forming pharmaceutical doses in that it allows a user such as a
doctor or pharmacist to generate variable doses as well as custom
doses in the convenience of a hospital, pharmacy, or home
environment. Further, such a system can also be utilized as a point
of sale machine, in such locations as a pharmacy or a supermarket,
to allow customers to create variable or custom doses of vitamins,
nutritional supplements, or other over-the-counter medications.
[0098] In addition, the system 1100 also includes a user interface
1188 or signal receiver that is coupled to the processor 1180 and
is also coupled via communication channel 1193 to an external
communication network 1190 as shown in FIG. 11. Preferably, the
external communication 1190 is a digital network such as what is
commonly referred to as the Internet. Other communication channels
such as wireless communication, wireline telephone, digital cable
television, as well as other point-to-point, point-to-multipoint,
and broadcast communications methods can also be used. The user
interface or signal receiver 1188 receives a signal from a remote
signal source specifying information to be utilized by system 1100.
For example, the remote signal source can specify the quantity of
medicament to be dispensed or an authorization code verifying the
authority of the user to dispense the medicament. As shown in FIG.
11, the system 1100 can also be coupled to a provider system 1192
via network 1190.
[0099] The provider system 1192 includes a provider processor 1181,
coupled to a provider display 1185, a provider storage device 1187,
and a provider interface 1189. The provider interface 1189 is
coupled via provider channel 1194 to the external communication
network 1190. The provider system 1192 is utilized, for example, by
a health care provider such as a doctor, a pharmacist, a nurse,
appropriate insurance personnel, or other appropriate health care
professional. Although FIG. 11 shows a single provider coupled to
the system 1100 it also preferable to have multiple providers, such
as doctors, pharmacists, nurses, insurance providers, and
pharmaceutical manufacturers all coupled to the system 1100 over
the external network 1190. This is particularly advantageous where
system 1100 is located in a home where the patient can request
information on the medicament and appropriate dosage information
from a pharmacist, request information on the ingestible sheet from
the manufacturer, and current health information from a doctor or
nurse over the network; to form the appropriate pharmaceutical dose
for that time or multiple doses to cover a period of the next day
to several days or weeks. Such a system also allows potentially
adverse drug interactions and individual allergies or intolerances
and sensitivities to be flagged.
[0100] An exemplary embodiment of an interactive method for
generating a dosage form where the medicament is dispensed onto the
ingestible sheet is shown as flow diagrams in FIGS. 12-13. An
overview of the method is shown in FIG. 12. In step 1200, the
various materials such as the medicament and the ingestible sheet
are loaded or inserted into a medicament dispensing system. In Step
1210, information indicative of the materials is read either by the
system or by a user who then manually enters the information into
the system, such as the composition of the ingestible sheet and the
active ingredients of the medicament. In step 1220, various forms
of information are requested by the system such as requesting from
the doctor or pharmacist the quantity or dose of the medicament to
be dispensed. In step 1230, various forms of information are
specified and then transmitted and received by the system, such as
the doctor or pharmacist specifying the quantity or dose of the
medicament to be dispensed. Various forms of information are
verified in step 1240 such as verifying that the dose is within the
correct range. The medicaments as well as other materials such as
the barrier material are dispensed on the ingestible sheet in step
1250 providing all of verification steps were successfully
completed. In optional step 1260, appropriate user and
manufacturing information is printed on the ingestible sheet.
[0101] A more detailed view of the various steps associated with
the loading step 1200 is shown in FIG. 13a. In step 1301, an
off-axis medicament container is inserted into the dispensing
system where the container, after insertion is fluidically coupled
to a medicament reservoir of a semi-permanent cartridge. Either a
replaceable or semi-permanent medicament ejection cartridge is
inserted in the dispensing system in step 1302. An off-axis
ingestible ink container, and either a replaceable or
semi-permanent ingestible ink ejection cartridge, are inserted into
the dispensing system in steps 1303 and 1304 respectively, where
the off-axis ink container is fluidically coupled to an ink
reservoir in a semi-permanent ink cartridge. Depending on the
particular ingestible sheet, and medicament utilized, a cartridge
containing a mixture of the medicament and the ingestible ink can
be inserted into the system in step 1305. In step 1306, an
ingestible sheet is loaded into the dispensing system.
[0102] A more detailed view of the various steps associated with
the reading step 1210 is shown as a flow diagram in FIG. 13b. In
step 1311, information is read from the ingestible sheet. For
example, the composition or the expiration date of the ingestible
sheet can be read by the system utilizing an image acquisition
system scanning a bar code. Preferably this information is stored
in a machine readable form, however, a human perceptible form can
also be utilized. In steps 1312 and 1314 information from the
medicament cartridge and from the medicament container is accessed
or read respectively. Preferably this information is stored in a
memory chip that this accessed, however, other means can also be
utilized such as printing the information on the cartridge in a
machine readable or human perceptible form.
[0103] A more detailed view of the various steps associated with
the requesting step 1220 is shown as a flow diagram in FIG. 13c. In
step 1321 the quantity of the medicament to be dispensed is
requested by the medicament dispensing system. For example, this
could be displayed on a display device located in the vicinity of
the dispensing system or it can be displayed on a remote display
device such a doctor's or pharmacist's office. User information is
requested by the system in step 1322. This information is any
information about the user, i.e. typically the patient, that can be
utilized for example in determining the appropriate dose, such as
the patient's height, weight, age, etc. or information that is used
by the user in administering the dosage form. In step 1324,
manufacturer's information is requested by the system. This
information is any information from the manufacturer of the
medicament and/or the ingestible sheet. For example, this
information can be the same or similar to that obtained in steps
1311, 1312, 1314 and can be used in conjunction with that
information to act as a verification.
[0104] A more detailed view of the various steps associated with
the specifying step 1230 is shown as a flow diagram in FIG. 13d. In
step 1331, the quantity of the medicament to be dispensed is
specified, for example by a doctor or pharmacist, transmitted to
and received by the medicament dispensing system. In step 1332,
dosage information, such as dosage forms that vary the amount of
medicament released over time as shown in FIG. 8, is specified,
transmitted to and received by the system. User information is
specified transmitted to and received by the system in step 1334.
This information is any information about the user, i.e. typically
the patient, that can be utilized for example in determining the
appropriate dose, such as the patient's height, weight, age, etc.
or information that is used by the user in administering the dosage
form. In step 1336, manufacturer's information is specified. This
information is any information from the manufacturer of the
medicament and/or the ingestible sheet. For example, this
information can be the same or similar to that obtained in steps
1311, 1312, 1314 and can be used in conjunction with that
information to act as a verification.
[0105] A more detailed view of the various steps associated with
the verifying step 1240 is shown as a flow diagram in FIG. 13e. In
step 1341, the dosage quantity is verified. Step 1341 verifies
information obtained in a previous step such as step 1331 or
multiple steps is used to verify the dosage specified, is either
correct or within an acceptable range. For example, the information
accessed from the medicament cartridge in step 1312 is compared to
the specified quantity to be dispensed in step 1331. Another
example would be the use of a third party authorization key where
the dosage quantity is verified utilizing the key that is located
on the user's system or is accessed via a network such as the
Internet. The dosage information specified in step 1332 is verified
in step 1342. For example, if the information has been previously
entered then the information specified in step 1332 can be verified
from stored information stored on a storage device. However, if
step 1332 is being performed for the first time with a given user
then either the information can be retransmitted back to the person
specifying or the information can be verified by a third party such
as a doctor or an insurance agent via a network such as the
Internet. In step 1344, user information is verified. This step can
also be carried out using either previously stored information or a
third party as described above in step 1342. The manufacturer's
information is verified in step 1346. This step can also be carried
out using either previously stored information or a third party as
described above in step 1342. The manufacturer's information is any
information from the manufacturer of the medicament or the
ingestible sheet obtained in steps 1336 or step 1210.
[0106] A more detailed view of the various steps associated with
dosing of the medicament on the ingestible sheet in step 1250 is
shown as a flow diagram in FIG. 13f provided the verification steps
described above have been successfully completed. In step 1351, the
quantity of medicament to be dispensed is converted on a processor
into a number of activations of a fluid ejector. The ingestible
sheet is advanced into a fluid ejection area beneath the ejector
head or heads in step 1352. The dosing data preferably in the form
of the number of activations of a fluid ejector is transmitted from
the processor to the dispense system in step 1354. In step 1356,
the fluid ejectors are activated to produce the pharmaceutical
dose. Preferably, the drops are ejected in a predetermined fluid
swath pattern using dot matrix manipulation, forming the
pharmaceutical dose from the cartridge containing the medicament,
however other processes of firing the fluid ejectors can also be
utilized. In addition, a custom medicament dose can also be
generated by inputting the user information, the manufacturing
information, dosage information, as well as appropriate information
from the medicament cartridge into a dose algorithm. The dose
algorithm then combines this information in a predetermined manner
to generate a custom medicament dose.
[0107] A more detailed view of the various steps associated with
printing information on the ingestible sheet, in step 1260, is
shown as a flow diagram in FIG. 13g. In step 1361, appropriate
manufacturing information, such as the composition of the
ingestible sheet and the name or the medicament, is printed on the
ingestible sheet. The manufacturing information printed in step
1361 can be printed either in a machine understood form in step
1363 or it can be printed in a human perceptible form in step 1362
or in some combination thereof. The user information, such as the
name of the user or patient and the date and time for administering
the dosage form, is printed on the ingestible sheet in step 1364.
In step 1366, preferably the barrier material is dispensed over the
medicament previously dispensed in step 1356. However, depending on
the particular ingestible sheet, medicament, and dosage structure
(e.g. capsule or laminated structure) being utilized, the barrier
material may be dispensed before the medicament is dispensed.
[0108] The present invention can advantageously reduce the number
of therapeutically inactive materials, the number of dilutions, and
the number of mixings in the manufacture of unit dosage forms. In
addition, the medicament cartridge and the medicament dispensing
system of the present invention provides for the custom dispensing
of pharmaceutical unit dosage forms where the type of
pharmaceutical and the quantity of the selected drug can be easily
varied to meet a specific prescription. The medicament cartridge
and the medicament dispensing system of the present invention
provides the ability of dispensing multiple, different
pharmaceuticals in varied, selected quantities to a single
receiving medium thus simplifying the taking of drugs, especially
combinations of different drugs by providing multiple drugs in one
dose.
* * * * *