U.S. patent application number 10/827485 was filed with the patent office on 2005-10-20 for system and a method for pharmaceutical dosage preparation using jettable microemulsions.
Invention is credited to Gore, Makarand P..
Application Number | 20050232974 10/827485 |
Document ID | / |
Family ID | 34966372 |
Filed Date | 2005-10-20 |
United States Patent
Application |
20050232974 |
Kind Code |
A1 |
Gore, Makarand P. |
October 20, 2005 |
System and a method for pharmaceutical dosage preparation using
jettable microemulsions
Abstract
A jettable solution includes an oil, the oil being one of a
naturally occurring oil, an edible oil, or a removable oil, an
edible surfactant, an edible aqueous solution, and a pharmaceutical
solubilized into the naturally occurring oil, wherein the naturally
occurring oil, the pharmaceutical, the surfactant, and the aqueous
solution form a microemulsion.
Inventors: |
Gore, Makarand P.;
(Corvallis, OR) |
Correspondence
Address: |
HEWLETT PACKARD COMPANY
P O BOX 272400, 3404 E. HARMONY ROAD
INTELLECTUAL PROPERTY ADMINISTRATION
FORT COLLINS
CO
80527-2400
US
|
Family ID: |
34966372 |
Appl. No.: |
10/827485 |
Filed: |
April 19, 2004 |
Current U.S.
Class: |
424/439 ;
424/450 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61K 47/00 20130101 |
Class at
Publication: |
424/439 ;
424/450 |
International
Class: |
A61K 047/00; A61K
009/127 |
Claims
What is claimed is:
1. A jettable solution comprising: an oil, said oil being one of a
naturally occurring oil, an edible oil, or a removable oil; an
edible surfactant; an edible aqueous solution; and a pharmaceutical
solubilized into said oil; wherein said oil, said pharmaceutical,
said surfactant, and said aqueous solution form a
microemulsion.
2. The jettable solution of claim 1, wherein said pharmaceutical
comprises a water insoluble pharmaceutical.
3. The jettable solution of claim 2, wherein said pharmaceutical
comprises one of or a derivative of a water insoluble peptides an
antimicrobial, a proton pump inhibitor, a calcium channel blocker,
a beta blocker, an anesthetic, a steroid, an antioxidant, a rennin
inhibitor, an alkaloid, a cytostatica, an anti-coagulant, a lipid
regulating agent, an anti-depressant, a neuroleptic, an
immunosuppressant, an immunomodulator, an antibiotic, an
anti-inflammatory agent, an anitneoplastic, a paclitaxel, a taxol,
a tyloxapol, a docetaxel, a lovastatin, an indometacine, a
diclofenac, a naproxen, a dexibuprofen, a rofecoxib, a celecoxib, a
celecoxib nitrendipine, a flurbiprofen, a diclofenac, a ketoprofen,
a piroxicam, a tenoxicam, a vincristine, a vinblastine, an insulin,
a calcitonin, an erythropoietin, a cephalosporin, a desmopressin,
an etoposide, a leuprolide, or a cyclosporin such as cyclosporin A,
dihydrocyclosporin C, dihydrocyclosporin D, cyclosporin D.
4. The jettable solution of claim 1, wherein said oil and said
surfactant form a plurality of micelles in said aqueous
solution.
5. The jettable solution of claim 1, wherein said naturally
occurring oil comprises one of a castor oil, an oleic acid and an
oleyl alcohol, a coconut oil, a mineral oil, a cottonseed oil, a
squalene, a safflower oil, or a fatty ester.
6. The jettable solution of claim 1, wherein said removable oil is
configured to be evaporated under the influence of heat or
vacuum.
7. The jettable solution of claim 6, wherein said removable oil
comprises one of an alcohol, a cyclic alcohol, a terpene, an
aromatic side chain alcohol, a ketone, or an ester.
8. The jettable solution of claim 1, wherein said aqueous solution
comprises water.
9. The jettable solution of claim 8, wherein said aqueous solution
and said surfactant form a plurality of micelles in said naturally
occurring oil.
10. The jettable solution of claim 1, wherein said surfactant
comprises one of a lecithin, a sphingolipid, a galacto lipid, an
ethoxylated castor oil, a polyoxyl 40 hydrogenated castor oil, an
ethoxylated fatty ester, a sucrose fatty ester, a sorbitol, a
sorbitan, a polyoxyelhylene derivative, an alkyl glucoside, an
alkyl polyglucoside, an ethoxylated mono-hydroxy stearic acid, a
bile salt, a polyoxyethylene-sorbitan monooleate, a
polyoxyethylene-sorbitan monopalmitate, a polyoxyethylene-sorbitan
monolaurate, nicotinamide or a nicotinamide derivative, a
polyoxyethylene sorbitan monostearate, cholic acid or bile salts,
nicotinic acid and nicotinamide derivatives, acetylininc alcohols,
polyhydroxylated alcohols, aromatic sulfonate salts such as xylene
sulfonates, naphthalene sulfonates, cymene sulfonate, or Ethylene
Oxide-Propylene Oxide block (pluronic) polymers.
11. The jettable solution of claim 1, wherein said surfactant
comprises an ion-pair formation between an amino acid and a fatty
acid.
12. The jettable solution of claim 11, wherein: said amino acid
comprises one of an L-arginine or an L-lysine; and said fatty acid
comprises one of a stearic acid or an oleic acid.
13. The jettable solution of claim 1, further comprising an edible
solvent.
14. The jettable solution of claim 13, wherein said edible solvent
comprises a salt.
15. The jettable solution of claim 1, further comprising one of a
biocide a viscosity modifier, a humectant, an antifoaming agent, a
surface tension adjusting agent, a rheology adjusting agent, a pH
adjusting agent, a drying agent, a color, an acrylic polymer, or a
non-acrylic polymer.
16. The jettable solution of claim 1, wherein said solution
comprises a viscosity of less than approximately 5 centipoise and a
surface tension approximately between 25 to 60 dynes per
centimeter.
17. The jettable solution of claim 1, wherein a pharmaceutical
release rate of said solution is varied by varying said naturally
occurring oil.
18. The jettable solution of claim 1, further comprising:
approximately 5% L-arginine by volume; approximately 6% stearic
acid by volume; approximately 15% soy bean oil by volume; and
approximately 74% aqueous solution by volume.
19. A method for forming a jettable pharmaceutical based
microemulsion comprising: preparing a microemulsion; and dispensing
a water insoluble pharmaceutical into said microemulsion; said
microemulsion being configured to be selectively dispensed from an
inkjet material dispenser.
20. The method of claim 19, wherein said preparing a microemulsion
comprises: combining an oil, an edible surfactant, and an aqueous
solution; wherein said oil comprises one of a naturally occurring
pharmaceutical solubilizing oil or a removable oil; and said
combination resulting in a formation of a plurality of micelles
emulsified in a solution.
21. The method of claim 20, wherein said preparing a microemulsion
further comprises agitating said combination.
22. The method of claim 20, wherein said preparing a microemulsion
further comprises adding thermal energy to said combination.
23. The method of claim 20, wherein said naturally occurring
pharmaceutical solubilizing oil comprises one of a castor oil, an
oleic acid and an oleyl alcohol, a coconut oil, a mineral oil, a
cottonseed oil, a squalene, a safflower oil, or a fatty ester.
24. The method of claim 19, wherein said pharmaceutical comprises
one of or a derivative of a water insoluble peptides an
antimicrobial, a proton pump inhibitor, a calcium channel blocker,
a beta blocker, an anesthetic, a steroid, an antioxidant, a rennin
inhibitor, an alkaloid, a cytostatica, an anti-coagulant, a lipid
regulating agent, an anti-depressant, a neuroleptic, an
immunosuppressant, an immunomodulator, an antibiotic, an
anti-inflammatory agent, an anitneoplastic, a paclitaxel, a taxol,
a tyloxapol, a docetaxel, a lovastatin, an indometacine, a
diclofenac, a naproxen, a dexibuprofen, a rofecoxib, a celecoxib, a
celecoxib nitrendipine, a flurbiprofen, a diclofenac, a ketoprofen,
a piroxicam, a tenoxicam, a vincristine, a vinblastine, an insulin,
a calcitonin, an erythropoietin, a cephalosporin, a desmopressin,
an etoposide, a leuprolide, or a cyclosporin such as cyclosporin A,
dihydrocyclosporin C, dihydrocyclosporin D, cyclosporin D.
25. The method of claim 20, wherein said aqueous solution comprises
water.
26. The method of claim 20, wherein said edible surfactant
comprises one of a lecithin, a sphingolipid, a galacto lipid, an
ethoxylated castor oil, a polyoxyl 40 hydrogenated castor oil, an
ethoxylated fatty ester, a sucrose fatty ester, a sorbitol, a
sorbitan, a polyoxyelhylene derivative, an alkyl glucoside, an
alkyl polyglucoside, an ethoxylated mono-hydroxy stearic acid, a
bile salt, a polyoxyethylene-sorbitan monooleate, a
polyoxyethylene-sorbitan monopalmitate, a polyoxyethylene-sorbitan
monolaurate, a polyoxyethylene sorbitan monostearate, cholic acid
or bile salts, nicotinic acid and nicotinamide derivatives,
acetylininc alcohols, polyhydroxylated alcohols, aromatic sulfonate
salts such as xylene sulfonates, naphthalene sulfonates, cymene
sulfonate, or Ethylene Oxide-Propylene Oxide block (pluronic)
polymers.
27. The method of claim 20, wherein said edible surfactant
comprises an ion-pair formation between an amino acid and a fatty
acid.
28. The method of claim 27, wherein: said amino acid comprises one
of an L-arginine or an L-lysine; and said fatty acid comprises one
of a stearic acid or an oleic acid.
29. A method for forming a jettable pharmaceutical based
microemulsion comprising: dissolving a pharmaceutical in a
naturally occurring pharmaceutical solubilizing oil; and combining
said dissolved pharmaceutical in a naturally occurring oil with an
aqueous solution and an edible surfactant.
30. The method of claim 29, wherein said dissolving further
comprises mixing said pharmaceutical and said naturally occurring
pharmaceutical solubilizing oil until a semi transparent or
transparent liquid results.
31. The method of claim 29, further comprising agitating said
combination to facilitate a formation of said microemulsion.
32. The method of claim 29, further comprising adding thermal
energy to said combination to expedite a formation of said
microemulsion.
33. A method for forming an oral medication comprising: presenting
an edible structure adjacent to an inkjet material dispenser; and
selectively dispensing a jettable pharmaceutical based
microemulsion from said inkjet material dispenser onto said edible
structure.
34. The method of claim 33, wherein said inkjet material dispenser
comprises one of a thermally actuated inkjet dispenser, a
mechanically actuated inkjet dispenser, an electrostatically
actuated inkjet dispenser, a magnetically actuated dispenser, a
piezo-electrically actuated inkjet dispenser, or a continuous
inkjet dispenser.
35. The method of claim 33, wherein said selectively dispensing
comprises dispensing a predetermined dosage of said jettable
pharmaceutical based microemulsion.
36. The method of claim 33, wherein said edible structure comprises
one of a polymeric or paper organic film former.
37. The method of claim 33, wherein said a jettable pharmaceutical
based microemulsion comprises: an aqueous solution; and an
naturally occurring oil based micelle, said micelle including a
pharmaceutical payload.
38. The method of claim 33, further comprising dividing said edible
structure into a plurality of single oral doses.
39. The method of claim 33, further comprising selectively
dispensing a plurality of a jettable pharmaceutical based
microemulsions onto said edible structure, said plurality of
aqueous pharmaceuticals forming a combination therapy.
40. A system for dispensing an oral medication comprising: an
edible structure; and a jettable pharmaceutical based microemulsion
configured to be dispensed onto said edible structure.
41. The system of claim 40, wherein said edible structure comprises
one of a rice starch based paper, a potato starch based paper, or
an edible polymer.
42. The system of claim 40, further comprising: a computing device
disposed adjacent to said edible structure; an inkjet material
dispenser communicatively coupled to said computing device; and a
material reservoir fluidly coupled to said inkjet material
dispenser, said material reservoir being configured to supply said
a jettable pharmaceutical based microemulsion to said inkjet
material dispenser.
43. The system of claim 42, wherein said computing device comprises
one of a personal computer, a laptop computer, a personal digital
assistant, or a cellular telephone.
44. The system of claim 42, wherein said inkjet material dispenser
comprises one of a thermally actuated inkjet dispenser, a
mechanically actuated inkjet dispenser, an electrostatically
actuated inkjet dispenser, a magnetically actuated dispenser, a
piezo-electrically actuated inkjet dispenser, or a continuous
inkjet dispenser.
45. A jettable solution comprising: a water insoluble
pharmaceutical payload; and a means for emulsifying said
pharmaceutical payload into a jettable solution.
46. The jettable solution of claim 45, wherein said jettable
solution further comprises a means for stably dispersing said
encapsulated pharmaceutical payload.
47. A system for dispensing an oral solution comprising: an edible
means for receiving a pharmaceutical payload solution; and a
jettable pharmaceutical based microemulsion configured to be
dispensed onto said means for receiving a pharmaceutical payload
solution.
48. The system of claim 47, wherein said edible means for receiving
a pharmaceutical payload solution comprises one of a rice starch
based paper, a potato starch based paper, or an edible polymer.
49. The system of claim 47, further comprising: a means for
computing disposed adjacent to said edible structure; a means for
selectively dispensing said pharmaceutical payload solution
communicatively coupled to said means for computing; and a material
reservoir fluidly coupled to said means for selectively dispensing
said pharmaceutical payload solution, said material reservoir being
configured to supply said a jettable pharmaceutical based
microemulsion to said inkjet material dispenser.
Description
BACKGROUND
[0001] Traditional oral dosage drug formulations include both
active pharmaceutical ingredients (API) and inactive ingredients.
The inactive ingredients, also called excipients, are components of
the final formulation of a drug that are not considered active
pharmaceutical ingredients (API) in that they do not directly
affect the consumer in the desired medicinal manner.
[0002] Traditional oral dosage forms have several inactive
ingredients. Among the traditional inactive ingredients included in
oral dosage forms are binders that hold the tablet together,
coatings configured to mask an unpleasant taste, disintegrants
configured to make the tablet break apart when consumed, enteric
coatings, fillers that assure sufficient material is available to
properly fill a dosage form, enhancers configured to increase
stability of the active ingredients, preservatives aimed at
preventing microbial growth, and the like.
[0003] Traditionally, the formation of an oral dose drug often
included combining a desired pharmaceutical product with a number
of the above-mentioned materials designed to control the release
rate of the API when consumed. While the traditional method is
effective for a number of soluble drugs, there are a number of
highly water insoluble drugs that are not well suited to sustained
or controlled delivery. The formulation of these highly water
insoluble APIs into controlled or modified-release dosage forms
using traditional formulation methods is both expensive and
challenging due to the APIs insolubility and unknown stability.
[0004] Microemulsion formulations potentially offer a variety of
desirable properties for pharmaceutical delivery, namely, high
solubility, high absorption, and improved pharmacokinetics.
However, precise dispensing and distribution of the microemulsions
formed for pharmaceutical product delivery has proven to be
somewhat problematic as noted in the following publications: Using
microemulsions for drug delivery, Pharmaceutical Technology, 1987;
Improved drug delivery using microemulsions: Rationale, recent
progress, and new horizons, Critical Reviews in Therapeutic Drug
Carrier Systems, 2001; and Microemulsions: an overview and
pharmaceutical applications, Critical Reviews in Therapeutic Drug
Carrier Systems, 1999.
SUMMARY
[0005] A jettable solution includes a naturally occurring, edible,
or removable oil, an edible surfactant, an edible aqueous solution,
and a pharmaceutical solubilized into the naturally occurring oil,
wherein the oil, the pharmaceutical, the surfactant, and the
aqueous solution form a microemulsion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The accompanying drawings illustrate various embodiments of
the present system and method and are a part of the specification.
The illustrated embodiments are merely examples of the present
system and method and do not limit the scope thereof.
[0007] FIG. 1 is a simple block diagram illustrating a system used
to deposit a jettable pharmaceutical based microemulsion onto an
edible substrate, according to one exemplary embodiment.
[0008] FIG. 2 is a magnified side view illustrating the structure
of a surfactant molecule, according to one exemplary
embodiment.
[0009] FIG. 3 is a magnified view illustrating an oil-based
micelle, according to one exemplary embodiment.
[0010] FIG. 4 is a magnified view illustrating a water-based
micelle, according to one exemplary embodiment.
[0011] FIG. 5 is a flow chart illustrating a method for forming a
jettable pharmaceutical based microemulsion, according to one
exemplary embodiment.
[0012] FIG. 6 is a simple block diagram illustrating a method for
dispensing a jettable pharmaceutical based microemulsion, according
to one exemplary embodiment.
[0013] Throughout the drawings, identical reference numbers
designate similar, but not necessarily identical, elements.
DETAILED DESCRIPTION
[0014] A number of exemplary systems and methods for producing an
ink jettable pharmaceutical based microemulsion are disclosed
herein. More specifically, a jettable pharmaceutical based
microemulsion is disclosed that may contain a number of
water-immiscible pharmaceuticals. Moreover, an exemplary method for
forming and dispensing the ink jettable pharmaceutical based
microemulsion to form an oral dosage form is disclosed herein.
[0015] As used in the present specification and the appended claim,
the term "edible" is meant to be understood broadly as any
composition that is suitable for human consumption and is
non-toxic. Similarly, the phrase "suitable for human consumption"
is meant to be understood as any substance that complies with
applicable standards such as food, drug, and cosmetic (FD&C)
regulations in the United States and/or Eurocontrol experimental
centre (E.E.C.) standards in the European Union. Additionally, the
term "ink" is meant to be understood broadly as meaning any
jettable fluid configured to be selectively emitted from an inkjet
dispenser, regardless of whether the jettable fluid contains a
pharmaceutically active ingredient or an oil containing solubilized
pharmaceutically active ingredient. The term "jettable" is meant to
be understood both in the present specification and in the appended
claims as any material that has properties sufficient to allow the
material to be selectively deposited by any digitally addressable
inkjet material dispenser.
[0016] Additionally, in the present specification and in the
appended claims, the term "amphiphile" or "hydrotrope" is meant to
be understood as relating to, or being a compound such as a
surfactant that includes molecules having a polar "hydrophilic"
group attached to a hydrophobic hydrocarbon chain or cluster.
Consequently, an amphiphile may include any of many organic
compounds such as a surfactant, a detergent, a bile salt, or a
phospholipid that is composed of hydrophilic and hydrophobic
portions. Moreover, the term "micelle" is meant to refer to any
electrically charged particle built up from polymeric molecules or
ions and oils that occurs in particular colloidal electrolytic
solutions.
[0017] As used in the present specification, and the appended
claims, the term "microemulsion" is meant to be understood as a
thermodynamically equilibrium colloid system comprising two
liquids. Typical microemulsion particle size is 5-150 nm.
Microemulsions are normally transparent or slightly bluish because
of the very small particle size.
[0018] In the following description, for purposes of explanation,
numerous specific details are set forth in order to provide a
thorough understanding of the present system and method for forming
and controllably dispensing a jettable pharmaceutical based
microemulsion. It will be apparent, however, to one skilled in the
art, that the present method may be practiced without these
specific details. Reference in the specification to "one
embodiment" or "an embodiment" means that a particular feature,
structure, or characteristic described in connection with the
embodiment is included in at least one embodiment. The appearance
of the phrase "in one embodiment" in various places in the
specification are not necessarily all referring to the same
embodiment.
[0019] Exemplary Structure
[0020] FIG. 1 illustrates an exemplary formulation system (100)
that may be used to apply a jettable pharmaceutical based
microemulsion (160) to an edible structure (170) according to one
exemplary embodiment. As shown in FIG. 1, the present system
includes a computing device (110) controllably coupled through a
servo mechanism (120) to a moveable carriage (140) having an inkjet
dispenser (150) disposed thereon. A material reservoir (130) is
also illustrated as fluidly coupled to the inkjet material
dispenser (150). Moreover, a substrate (180) is located adjacent to
the inkjet dispenser (150) having an edible structure (170)
disposed thereon. The edible structure (170) is configured to
receive a jettable pharmaceutical based microemulsion (160). The
above-mentioned components of the present formulation system (100)
will now be described in further detail below.
[0021] The computing device (110) that is controllably coupled to
the servo mechanism (120), as shown in FIG. 1, controls the
selective deposition of the jettable pharmaceutical based
microemulsion (160) onto the edible structure. According to one
exemplary embodiment, a digital representation of the desired
deposition of jettable pharmaceutical based microemulsion (160) may
be generated on an application hosted by the computing device
(110). The generated representation may then be converted into
servo instructions that are housed in a processor readable media
(not shown). When accessed by the computing device (110), the
instructions housed in the processor readable media are used to
control the servo mechanisms (120) as well as the movable carriage
(140) and the inkjet dispenser (150), causing them to selectively
deposit the jettable pharmaceutical based microemulsion (160). The
computing device (110) illustrated in FIG. 1 may be, but is in no
way limited to, a workstation, a personal computer, a laptop, a
personal digital assistant (PDA), or any other processor containing
device.
[0022] The moveable carriage (140) of the present formulation
system (100) illustrated in FIG. 1 is a moveable material dispenser
that may include any number of inkjet material dispensers (150)
configured to dispense the present jettable pharmaceutical based
microemulsion (160). The moveable carriage (140) may be controlled
by a computing device (110) and may be controllably moved by, for
example, a shaft system, a belt system, a chain system, etc. making
up the servo mechanism (120). As the moveable carriage (140)
operates, the computing device (110) may inform a user of operating
conditions as well as provide the user with a user interface.
[0023] As a desired quantity of the jettable pharmaceutical based
microemulsion (160) is printed, the computing device (110) may
controllably position the moveable carriage (140) and direct one or
more of the inkjet dispensers (150) to selectively dispense the
jettable pharmaceutical based microemulsion at predetermined
locations as digitally addressed drops. The inkjet material
dispensers (150) used by the present formulation system (100) may
be any type of inkjet dispenser configured to perform the present
method including, but in no way limited to, thermally actuated
inkjet dispensers, mechanically actuated inkjet dispensers,
electrostatically actuated inkjet dispensers, magnetically actuated
dispensers, piezo-electrically actuated inkjet dispensers,
continuous inkjet dispensers, etc.
[0024] The material reservoir (130) that is fluidly coupled to the
inkjet material dispenser (150) houses the jettable pharmaceutical
based microemulsion (160) prior to printing. The material reservoir
(130) may be any sterilizeable container configured to hermetically
seal the jettable pharmaceutical based microemulsion (160) prior to
printing and may be constructed of any number of materials
including, but in no way limited to, metals, plastics, composites,
ceramics, or appropriate combinations thereof.
[0025] FIG. 1 also illustrates the components of the present system
that facilitate reception of the jettable pharmaceutical based
microemulsion (160) and the edible structure (170). As shown in
FIG. 1, a substrate (180) may receive and/or positionally secure an
edible structure (170) during a printing operation. The edible
structure (170) configured to receive the jettable pharmaceutical
based microemulsion (160) may be any number of edible substrates.
According to one exemplary embodiment, the edible structure (170)
includes, but is in no way limited to, polymeric and/or paper
organic film formers. Non-limiting examples of such edible
structures include, but are in no way limited to, starch (natural
and chemically modified); glycerin based sheets with or without a
releasable backing, and the like; proteins such as gelatin, wheat
gluten, and the like; cellulose derivatives such as
hydroxypropylmethylcellulose, methocel, and the like; other
polysaccharides such as pectin, xanthan gum, guar gum, algin,
pullulan (an extracellular water-soluble microbial polysaccharide
produced by different strains of Aureobasidium pullulans), and the
like; sorbitol; seaweed; synthetic polymers such as polyvinyl
alcohol, polymethylvinylether (PVME), poly-(2-ethyl 2-oxazoline),
polyvinylpyrrolidone, and the like. Further examples of edible
delivery substrates are those that are based on milk proteins, rice
paper, potato wafer sheets, and films made from restructured fruits
and vegetables. It should be understood that one or more of the
above listed substrate materials, as well as other substrate
materials, may be used in combination in some embodiments. The
formation and composition of the jettable pharmaceutical based
microemulsion (160) will now be described in detail below.
[0026] According to one exemplary embodiment, the jettable
pharmaceutical based microemulsion (160) is made possible by the
inclusion of a number of surfactant "amphiphile" or "hydrotrope"
molecules (200) similar to that illustrated in FIG. 2. As
illustrated in FIG. 2, the exemplary surfactant molecule (200)
includes a polar head (210) and a hydrophobic tail (220) typically
made of hydrocarbons. The surfactant molecules (200) may be formed
as a result of the formation of an interfacial ion-pair formed
between an amino acid and a fatty acid. Due to the varying affinity
for aqueous solutions exhibited by the surfactant molecules (200),
the surfactant molecules facilitate the formation of micelles or
bicontinuous phases within the microemulsion as will be described
in further detail below with reference to FIGS. 3 and 4.
[0027] FIG. 3 illustrates an oil-based micelle (300) including a
number of surfactant molecules (200), according to one exemplary
embodiment. As illustrated in FIG. 3, the surfactant molecules
(200), when forming micelles, position themselves at the phase
boundary between the oil droplet (310) and the aqueous solution
(320). As illustrated in FIG. 3, during the formation of oil-based
micelles (300), the hydrophobic tails (220) of the surfactant
molecules (200) position themselves away from the aqueous solution
(320) into the oil droplet (310) while the hydrophilic polar heads
(210) of the surfactant molecules (200) are oriented in the aqueous
solution (320). This interaction between the surfactant molecules
and the dispersed fluids enables the formation of a microemulsion.
According to one exemplary embodiment illustrated in FIG. 3, the
oil-based micelle (300) is configured to confine any entrapped or
dissolved material until the micelle (300) adheres to the outer
membrane of a target cell. Consequently, when the oil-based
micelles are applied to a pharmaceutical delivery application, drug
efficacy may be increased while overall toxicity is reduced due to
the direct delivery of the pharmaceutical to the needed cells.
[0028] In addition, as illustrated in FIG. 4, the ratio of aqueous
solution to oil may be varied to form water-based micelles (400) in
a water-in-oil type microemulsion. As illustrated in FIG. 4, a
number of water-based micelles (400) may be formed out of aqueous
droplets (410) containing the polar head portion (210) of the
surfactant molecule (200) while the hydrophobic tail portion (220)
is extended into the oil solution (420) of the microemulsion. As
illustrated above, the pharmaceutical payload may be solubilized
within the oil solution (420) and evenly dispensed by an inkjet
material dispenser. The exemplary composition of the jettable
pharmaceutical based microemulsion (160; FIG. 1) will now be
described in further detail below.
[0029] Exemplary Composition
[0030] According to one exemplary embodiment, the present jettable
pharmaceutical based microemulsion (160; FIG. 1) includes an edible
surfactant such as a hydrotope; one of a naturally
occurring-pharmaceutical solubilizing oil, an edible oil, and/or an
oil that can be subsequently removed by evaporation; and an aqueous
solution which may include co-solvents. Exemplary embodiments of
the jettable pharmaceutical based microemulsion components, as well
as additional additives, are described below.
[0031] As noted above, the present jettable pharmaceutical based
microemulsion (160; FIG. 1) includes an amphiphile surfactant
configured to modify the surface tension of the interface between
the aqueous solution and the naturally occurring pharmaceutical
solubilizing oil, thereby enabling the formation of the present
microemulsion. While those skilled in the art will readily identify
a number of edible surfactants, the surfactant may include, but is
in no way limited to hydrophobic surfactants such as lecithin,
sphingolipids, and galacto lipids, or hydrophilic surfactants such
as ethoxylated castor oil; polyoxyl 40 hydrogenated castor oil;
ethoxylated fatty esters; sucrose fatty esters; mono-, di-, and
trimesters of sorbitol and sorbitan and polyoxyelhylene derivatives
thereof; alkyl glucosides or alkyl polyglucosides; ethoxylated
mono-hydroxy stearic acid, bile salts, polyoxyethylene-sorbitan
monooleate, polyoxyethylene-sorbitan monopalmitate,
polyoxyethylene-sorbitan monolaurate, polyoxyethylene sorbitan
monostearate, cholic acid or bile salts, nicotinic acid and
nicotinamide derivatives, acetylininc alcohols, polyhydroxylated
alcohols, aromatic sulfonate salts such as xylene sulfonates,
naphthalene sulfonates, cymene sulfonate, Ethylene Oxide-Propylene
Oxide block (pluronic) polymers, and appropriate mixtures thereof.
Additionally, the surfactants may be formed due to an ion-pair
formation between any edible yet basic amino acid including, but in
no way limited to, L-arginine and L-lysine and a fatty acid
including, but in no way limited to, stearic acid and oleic acid.
According to this exemplary embodiment, the emulsions may be formed
as the amino acid groups of the amino acids react with the
carboxylic acid group of the fatty acids to form an interfacial
ion-pair. The amino acids and the fatty acids may be present in the
aqueous solution or naturally occurring pharmaceutical solubilizing
oil as illustrated below. According to one exemplary embodiment,
the surfactant comprises up to 15% by weight of the total
microemulsion.
[0032] Additionally, the present system and method may be formed
using a number of naturally occurring pharmaceutical solubilizing
oils, edible silicone oils or removable oils. While there are
several edible, environmentally benign, non toxic, non corrosive,
biodegradable, and FDA approved oils available for pharmaceutical
use, the incorporation of naturally occurring pharmaceutical
solubilizing oils ensures that the resulting jettable
pharmaceutical based microemulsion is edible and contains
ingredients approved by the FDA. According to one exemplary
embodiment, the present naturally occurring pharmaceutical
solubilizing oils may include, but are in no way limited to, castor
oil, oleic acid and oleyl alcohol, coconut oil, mineral oil,
cottonseed oil, squalene, safflower oil, and fatty esters such as
triolein (glyceryl trioleate) and ethyl oleate. According to
another exemplary embodiment, the oils are removable oils that can
be evaporated under the influence of heat or vacuum after the
precision dosing process. Examples of such oils are aliphatic
alcohols such as pentanol, butanol, and hexanol; cyclic alcohols
such as cyclopentanol and 4-methyl cyclohexanol; terpenes such as
hydroxycitronellal, alpha-terpeniol and eugenol; aromatic side
chain alcohols such as cinnamoyl alcohol and benzyl alcohol;
ketones such as cyclopentanone and cyclohexanone; and esters such
as diethyl malonate.
[0033] The aqueous solution that forms the vehicle portion of the
jettable pharmaceutical based microemulsion may include, but is in
no way limited to, water and a solvent or amino acid. The aqueous
vehicle component of the present system and method is included in
the present jettable pharmaceutical based microemulsion (160; FIG.
1) for stable dispersion and transport of the pharmaceutical
payload component contained within the micelle forming component as
well as any other additives. The aqueous vehicle imparts a jettable
viscosity to the jettable pharmaceutical based microemulsion (160;
FIG. 1) while evaporating at a rate sufficient to make a dispensed
dosage resistant to smudging soon after it is deposited.
Additionally, as noted previously, the aqueous vehicle component
may or may not include a solvent. According to one exemplary
embodiment, the aqueous vehicle comprises water. In addition to
having a low cost, water is effective as a solvent for many
additives, greatly reduces inkjet dispenser compatibility issues,
effectively suspends oral drug formulations and colorants, and
effectively controls drying rates of the aqueous vesicle
pharmaceutical. In another exemplary embodiment, the aqueous
vehicle component of the present jettable pharmaceutical based
microemulsion (160; FIG. 1) includes a mixture of water and an
edible solvent, amino acid, or fatty acid such as salts, stearic
acid, oleic acid, L-arginine, L-lysine, etc.
[0034] The pharmaceutical payload component of the present jettable
pharmaceutical based microemulsion (160; FIG. 1) is a finely ground
pharmaceutical particle receptive to solubilization by an edible
and naturally occurring oil. According to one exemplary embodiment,
the pharmaceutical payload component is pre-processed to a size of
less than 1 micron average dimensions to aid in its dissolution
into the present microemulsion. Additionally, the pharmaceutical
payload component may take the form of any number of immiscible and
non-immiscible pharmaceutical products including, but in no way
limited to, water insoluble peptides, antimicrobials, proton pump
inhibitors, calcium channel blockers, beta blockers, anesthetics,
steroids, antioxidants, rennin inhibitors, alkaloids, cytostaticas,
anti-coagulants, lipid regulating agents, anti-depressants,
neuroleptics, immunosuppressants, immunomodulators, antibiotics,
anti-inflammatory agents, anitneoplastics, paclitaxel, taxol,
tyloxapol, docetaxel, lovastatin, indometacine, diclofenac,
naproxen, dexibuprofen, rofecoxib, celecoxib, celecoxib
nitrendipine, flurbiprofen, diclofenac, ketoprofen, piroxicam,
tenoxicam, vincristine, vinblastine, insulin, calcitonin,
erythropoietin, cephalosporin, desmopressin, taxol, etoposide,
leuprolide, cyclosporins such as cyclosporin A, dihydrocyclosporin
C, dihydrocyclosporin D, cyclosporin D, and/or derivatives
thereof.
[0035] In addition to the above-mentioned components of the present
jettable pharmaceutical based microemulsion (160; FIG. 1), a number
of additives may be employed to optimize the properties of the ink
composition for specific applications. For example, as is
well-known to those skilled in the art, biocides may be used in the
ink composition to inhibit growth of microorganisms. Other known
additives such as viscosity modifiers, humectants, antifoaming
agents, surface tension adjusting agents, rheology adjusting
agents, pH adjusting agents, drying agents, colors, and other
acrylic or non-acrylic polymers may be added to improve various
properties of the ink compositions as desired.
[0036] As noted previously, the present system and method may be
used to vary the release rate of the desired pharmaceutical
product. According to the present exemplary system and method, the
release rate determining factor for the absorption of the desired
pharmaceutical product in the pharmaceutical based microemulsion is
not the enzymatic metabolism of triglycerides, rather the
determining factor rests primarily in the breakdown of the
naturally occurring oil globules into microparticles since the
enzymes acting on the pharmaceutical based microemulsion act mainly
at the surface of the oil globules. Consequently, the release rate
of the pharmaceutical product may be selectively adjusted by
varying the naturally occurring oil used.
[0037] According to one exemplary formulation, a pharmaceutical
based microemulsion was formed by combining L-arginine (5%),
stearic acid (6%), and soy bean oil (15%) in an aqueous solution.
After formulation, an observation and subsequent testing was
performed illustrating that the above-mentioned combination forms
very stable microemulsions that manifest excellent ink-jet material
dispenser jetting characteristics.
[0038] While a number of exemplary formulations and ingredients for
the present jettable pharmaceutical based microemulsion are given
above, they are in no way meant to limit the present system.
Rather, they are presented for exemplary purposes only.
[0039] Exemplary Implementation and Operation
[0040] FIG. 5 illustrates an exemplary method for the formation of
the jettable pharmaceutical based microemulsion (160; FIG. 1)
according to one exemplary embodiment. As illustrated in FIG. 5,
the formation method begins by preparing a microemulsion (step
500). Once the microemulsion is prepared, a desired pharmaceutical
component is solubilized into the formed microemulsion (step 510).
Each of the above-mentioned steps will now be explained in further
detail below.
[0041] As shown in FIG. 5, the present formation method begins by
preparing a desired microemulsion (step 500). According to one
exemplary embodiment, the desired microemulsion may be prepared by
combining the naturally occurring, edible, or removable
pharmaceutical solubilizing oil, the edible surfactant, and the
aqueous solution, as well as any additional additives, as discussed
above. Once the materials are combined into an aqueous solution,
the hydrophobic groups (the naturally occurring pharmaceutical
solubilizing oil and the hydrophobic tails of the surfactant
molecules) self-associate and form one or more micelles in the
aqueous solution. While slight agitation and/or heat may be
introduced to the mixture to further facilitate the formation of
the micelles, it is not required. Rather, because microemulsions
are thermodynamically equilibrium systems, they form spontaneously,
requiring little or no mechanical work in their formation.
[0042] Once the desired microemulsion is prepared, a desired
pharmaceutical product may be solubilized into the microemulsion
(step 510). Again, a mere combination of the microemulsion and the
desired pharmaceutical product will self-associate into the desired
micelles. According to this exemplary embodiment, due to the
insolubility of the desired pharmaceutical in water, it will
equilibrate over a period of time into the oil droplet (310; FIG.
3) portion of the microemulsion.
[0043] Alternatively, the jettable pharmaceutical based
microemulsion may be formed by first dissolving the desired
pharmaceutical product into the naturally occurring-pharmaceutical
solubilizing oil to form an oil-in-water microemulsion. According
to this exemplary embodiment, the desired pharmaceutical product is
dissolved in the naturally occurring pharmaceutical solubilizing
oil until a transparent or semi-transparent liquid results.
Dissolution of the desired pharmaceutical product may be
facilitated by the use of slight agitation and/or thermal energy
and rolling in a container over a roller mill to cause through
mixing. Complete dissolution of the desired pharmaceutical product
may then be confirmed by microscopy.
[0044] After the desired pharmaceutical product has been completely
dissolved in the naturally occurring pharmaceutical solubilizing
oil, the edible surfactant and the aqueous solution may be added
with slight agitation to form the desired jettable pharmaceutical
based microemulsion. According to this exemplary embodiment, the
desired pharmaceutical product remains in solution in the naturally
occurring pharmaceutical solubilizing oil during the production of
the microemulsion. Consequently, the naturally
occurring-pharmaceutical solubilizing oil and the dissolved
pharmaceutical product are distributed throughout the aqueous phase
of the microemulsion as very tiny particles that may then be
readily taken up by the human body.
[0045] Once the jettable pharmaceutical based microemulsion has
been satisfactorily formed, it will exhibit a number of desirable
properties. According to one exemplary embodiment, the jettable
pharmaceutical based microemulsion will be suitable for inkjet
printing from an inkjet material dispenser (150; FIG. 1). According
to this exemplary embodiment, the resulting pharmaceutical based
microemulsion has a viscosity that is no more than approximately 5
centipoise, under the operating temperature and conditions,
although the value may be outside of this range. In addition, the
surface tension of the final microemulsion is typically between
about 25 to about 60 dynes per centimeter.
[0046] Once the above-mentioned jettable pharmaceutical based
microemulsion (160; FIG. 1) is formed, it may be selectively jetted
onto an edible structure (170; FIG. 1) or other substrate to form a
solid drug dosage, to prepare a drug dosage designed for
combination therapy, or in a gradient structure to form both high
and low load zones in certain sub areas of the edible structure.
FIG. 6 illustrates an exemplary method for selectively jetting a
pharmaceutical based microemulsion onto an edible structure to
specific areas and shapes image-wise corresponding to the desired
dosage shape according to one exemplary embodiment. As shown in
FIG. 6, the present method begins by depositing the formed
pharmaceutical based microemulsion into the material reservoir of a
formulation system (step 600). Once the pharmaceutical based
microemulsion is deposited, an edible structure (170; FIG. 1) is
positioned adjacent to the inkjet material dispenser (150; FIG. 1)
of the present formulation system (step 610). When positioned, the
inkjet material dispenser (150; FIG. 1) selectively deposits the
jettable pharmaceutical based microemulsion (160; FIG. 1) onto the
edible structure (step 620). Upon deposition of the jettable
pharmaceutical based microemulsion onto the edible structure, a
determination is made as to whether the present formulation system
(100; FIG. 1) has completed its formulation dispensing operation
(step 630). If it is determined that the pharmaceutical formulation
dispensing is not complete (NO, step 630), the formulation system
again selectively jets a jettable pharmaceutical based
microemulsion onto the edible structure (step 620). If, however,
the pharmaceutical dispensing operation is complete (YES, step
630), the printed media is optionally examined for defects (step
640). If no defects are found (NO, step 450), the jettable
pharmaceutical based microemulsion dispensing process is complete.
In subsequent steps, the media may be processed by dicing, slicing
and treating to heat or vacuum and packaging (step 670). If,
however, printing defects are found on the printed media (YES, step
650), the edible structure may be discarded (step 660) or otherwise
re-processed. The above-mentioned steps will now be described in
further detail below.
[0047] As shown in FIG. 6, the present method for printing a
jettable pharmaceutical based microemulsion on an edible structure
begins by depositing the formed jettable pharmaceutical based
microemulsion into a material reservoir (step 600). The deposition
of the jettable pharmaceutical based microemulsion into a material
reservoir may be performed by a user or alternatively by a fluid
channeling system disposed between a jettable pharmaceutical based
microemulsion forming apparatus and the formulation system (100;
FIG. 1).
[0048] After the formed jettable pharmaceutical based microemulsion
is deposited into a material reservoir (step 600), an edible
structure is positioned adjacent to the inkjet material dispenser
(150; FIG. 1) of the present formulation system (step 610). As
shown in FIG. 1, the edible structure (170) may be positioned under
the formulation system (100) by a moveable substrate (180).
Alternatively, an operator or a number of mechanical transportation
apparatuses may manually place the edible structure (170) adjacent
to the formulation system (100).
[0049] Once the edible structure (170) is correctly positioned, the
present formulation system (100) may be directed by the computing
device (110) to selectively jet the jettable pharmaceutical based
microemulsion (160) onto the edible structure (step 620; FIG. 6).
As was mentioned previously, the desired dosage of the jettable
pharmaceutical based microemulsion to be printed on the edible
structure (170) may initially be determined on a program hosted by
the computing device (110). The program created dosage may then be
converted into a number of processor accessible commands, which
when accessed, may control the servo mechanisms (120) and the
movable carriage (140), causing them to selectively emit a
specified quantity of jettable pharmaceutical based microemulsion
(160) onto the edible structure (170).
[0050] The precise metering capability of the inkjet material
dispenser (150) along with the ability to selectively emit the
metered quantity of aqueous vesicle pharmaceutical (160) onto
precise, digitally addressed locations makes the present system and
method well suited for a number of pharmaceutical delivery
applications. According to one exemplary embodiment, the precision
and addressable dispensing provided by the present inkjet material
dispenser (150) allows for one or more compositions to be dispensed
on a single edible structure (170). According to this exemplary
embodiment, a combination therapy may be produced in a customized
dosage for a patient. Combination therapy is to be understood as
any dosage including two or more pharmaceutical products combined
to achieve desired results. According to another exemplary
embodiment certain regions of the dosage may be printed with a
gradient to allow for an initial high concentration "burst" and a
low concentration slow release zone. This gradient deposition will
vary both the concentration and temporal release rate of the
dispensed pharmaceutical. Precision of the resulting oral drug
deposition may be varied by adjusting a number of factors
including, but in no way limited to, the type of inkjet material
dispenser (150) used, the distance between the inkjet material
dispenser (150) and the edible structure (170), and the dispensing
rate. Once the jettable pharmaceutical based microemulsion (160)
has been selectively deposited onto the edible structure (170),
according to the desired dosage, the deposited jettable
pharmaceutical based microemulsion may be absorbed by the edible
structure or remain in a fixed state on top of the edible
structure. Consequently, the jettable pharmaceutical based
microemulsion is affixed to the edible structure until consumption
initiates a selective release thereof.
[0051] Upon deposition of the aqueous vesicle pharmaceutical, it is
determined whether or not the jettable pharmaceutical based
microemulsion dispensing operation has been completed on the edible
structure (step 630; FIG. 6). Completion of the jettable
pharmaceutical based microemulsion dispensing operation may be
evaluated by a system operator or by the coupled computing device
(110). According to one exemplary embodiment, the computing device
(110) determines whether sufficient jettable pharmaceutical based
microemulsion (160) has been dispensed to produce the desired
dosage on the edible structure (170). If sufficient jettable
pharmaceutical based microemulsion (160) has not been dispensed
(NO, step 630; FIG. 6), the formulation system (100) continues to
selectively deposit jetted pharmaceutical based microemulsion onto
the edible structure (step 620; FIG. 6). If, however, sufficient
jettable pharmaceutical based microemulsion (160) has been
dispensed (YES, Step 630; FIG. 6), the dispensed quantity may
optionally be, checked for defects (step 640; FIG. 6).
[0052] In order to check the printed media for defects (step 640;
FIG. 6), according to one exemplary embodiment, the edible
structure (170) or other image receiving substrate may be analyzed
according to weight, volume, or optical properties for obvious
defects that may make the resulting substrate unacceptable.
According to one exemplary embodiment, the edible structure (170)
is subject to a series of optical scans configured to detect any
alignment or deposition defects. Additionally, adequacy of the
volume of jettable pharmaceutical based microemulsion (160)
dispensed onto an edible structure (170) may be evaluated by a
number of flow-rate sensors (not shown) disposed on the inkjet
material dispenser (150).
[0053] According to one exemplary embodiment, if defects are
discovered on the edible structure (YES, step 650; FIG. 6), the
edible structure may be discarded (step 660; FIG. 6) and the system
adjusted. If, however, no image defects are discovered (NO, step
650; FIG. 6) the edible structure (270) may be packaged or
otherwise distributed. Distribution of the edible structure
includes applying the proper coating, cutting, sizing, and/or
packaging the edible structure (step 670; FIG. 6). According to one
exemplary embodiment, the above-mentioned system and method may be
performed on a large edible structure that is then sliced or
otherwise divided into smaller individual dosages. Additionally,
evaporation processes, such as thermal or vacuum treatments, may be
performed on the edible structure to remove an oil according to one
exemplary embodiment.
[0054] In conclusion, the present system and method for producing
and dispensing a jettable pharmaceutical based microemlusion allows
for precision dispensing of insoluble or low-solubility
pharmaceuticals. More specifically, the insoluble or low-solubility
pharmaceuticals are solubilized into a jettable microemulsion based
on naturally occurring oils such as soybean oil. The system
consists of aqueous microemulsions, with or without a co-solvent
and a "pay load" pharmaceutical agent. Moreover, the use of an
inkjet material dispenser allows a high precision of dosage forms.
In addition, the jettable pharmaceutical based microemlusions
exhibit a number of desirable properties such as excellent
jettability, stability, uniform drop formation, fine particle size,
ability to form individual, gel-drops of nanometer size, and
precise control over the dosage amount. Additionally, the systems
and methods disclosed are cost effective when compared to
traditional formulation methods while being able to precisely
deliver and prepare custom dosages without special treatments,
modifications, or use of special equipment.
[0055] The preceding description has been presented only to
illustrate and describe exemplary embodiments of the present system
and method. It is not intended to be exhaustive or to limit the
system and method to any precise form disclosed. Many modifications
and variations are possible in light of the above teaching. It is
intended that the scope of the system and method be defined by the
following claims.
* * * * *