U.S. patent application number 13/842414 was filed with the patent office on 2013-08-22 for customized polypills having high drug loads.
This patent application is currently assigned to Tailorpill Technologies, LLC. The applicant listed for this patent is Kenneth Mimnaugh Alfano. Invention is credited to Kenneth Mimnaugh Alfano.
Application Number | 20130216616 13/842414 |
Document ID | / |
Family ID | 46314713 |
Filed Date | 2013-08-22 |
United States Patent
Application |
20130216616 |
Kind Code |
A1 |
Alfano; Kenneth Mimnaugh |
August 22, 2013 |
CUSTOMIZED POLYPILLS HAVING HIGH DRUG LOADS
Abstract
Patient-specific polypills, or similar drug products with
potential to benefit from reduced need for bulking agent and
preferably having multiple active ingredients, producible via
appropriately adapted "micro-dosing" technologies not requiring
fluid-jet or like substrate and solvent dependent approaches,
having less need for excipient, particularly filler, so that the
products may contain a larger number of different drug substances
having a lower overall number or amount of excipient materials
and/or may contain drug substances having comparatively less need
for formulation development or pre-production processing and/or may
contain fewer potential causes of side effects.
Inventors: |
Alfano; Kenneth Mimnaugh;
(Canton, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alfano; Kenneth Mimnaugh |
Canton |
MI |
US |
|
|
Assignee: |
Tailorpill Technologies,
LLC
Canton
MI
|
Family ID: |
46314713 |
Appl. No.: |
13/842414 |
Filed: |
March 15, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13757828 |
Feb 3, 2013 |
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13842414 |
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PCT/US2011/062167 |
Nov 26, 2011 |
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13757828 |
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61426576 |
Dec 23, 2010 |
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Current U.S.
Class: |
424/451 ;
424/463; 424/484 |
Current CPC
Class: |
G16H 20/10 20180101;
A61J 3/06 20130101; A61J 3/074 20130101; A61J 1/00 20130101; A61J
3/07 20130101; G16H 20/13 20180101; A61K 9/0087 20130101; G05D
11/134 20130101; B65B 1/34 20130101 |
Class at
Publication: |
424/451 ;
424/463; 424/484 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1. A customized multiple-unit-dose drug product, comprising: two or
more solid-form drug substances combined in one directly or
indirectly ingestible drug product, at respective dose levels
specific to one particular patient, wherein at least one drug
substance is not blended or otherwise formulated with a
non-functional diluent, said non-functional diluent being an
ingredient for augmenting mass or volume to accommodate ease of
processing and accuracy of measurement, and wherein said at least
one drug substance is not on a sheet or other substrate; and a
barrier limiting contact between at least two of said two or more
drug substances.
2. The product of claim 1, wherein said drug substances are
contained within respective compartments of a multi-compartment
capsule, thereby achieving said barrier.
3. The product of claim 1, wherein a drug substance(s) is contained
within a first capsule shell that is contained within a second
capsule shell containing another substance(s), thereby achieving
said barrier.
4. The product of claim 1, wherein a drug substance(s) is
formulated with an excipient whose presence reduces contact between
drug substances, thereby achieving said barrier.
5. The product of claim 1, wherein said at least one drug substance
is present as encapsulated granule or bead particles comprising
functional excipient(s), the encapsulation achieving said
barrier.
6. The product of claim 1, wherein said at least two of said two or
more drug substances are present as solidified beads, such that
contact between said at least two of said two or more drug
substances is limited to essentially said beads' surfaces, thereby
achieving said barrier.
7. The product of claim 6, wherein said beads are of a kind
producible by any known fluid bed pelletization or spray-drying
technolog(ies).
8. The product of claim 7, wherein said beads are at least about 75
percent active ingredient.
9. The product of claim 8, wherein said beads comprise matrix-type
pellets.
10. The product of claim 9, wherein said pellets are microspheres
having a functional coating, and wherein said drug substances are
encapsulated in a capsule shell or other envelopment that is
directly ingestible.
11. A customized multiple-unit-dose drug product, comprising: two
or more drug substances whose respective identities and dose levels
are customized for a particular patient and combined in a single
ingestible or otherwise orally-administrable drug product, wherein
at least one of said drug substances is not in formulation with a
non-therapeutic excipient, said non-therapeutic excipient being an
ingredient that is not intended to directly or indirectly
facilitate pharmacokinetics or pharmacodynamics in vivo, and
wherein said at least one of said drug substances is not on a sheet
or other substrate; and a barrier for limiting in vitro contact
between at least two of said two or more drug substances.
12. The product of claim 11, wherein at least one drug substance is
combined with an excipient that was selected for said particular
patient.
13. The product of claim 11, wherein at least one drug substance is
a solid, and wherein the drug product is designed to be directly
swallowable without chewing or mixing or sprinkling or dissolving,
and wherein the drug product is packaged in compliance
packaging.
14. The product of claim 11, wherein at least one drug substance is
a pure raw active pharmaceutical ingredient.
15. The product of claim 11, wherein no drug substance is
formulated with a glidant or flow enhancer.
16. A customized multiple-unit-dose drug product, comprising: two
or more drug substances at dose levels essentially as prescribed
for a particular patient, combined in one drug product having an
enteral or otherwise non-intravenous route of administration,
wherein at least one drug substance is present without significant
functional or non-functional excipient, said at least one drug
substance not having been deposited as a liquid onto an
intermediary substrate; and a barrier for restricting contact
between at least two drug substances.
17. The product of claim 16, wherein said at least one drug
substance is in particles having sufficient uniformity such that
each particle contributes an approximately equal amount of active
ingredient to the drug product.
18. The product of claim 16, wherein an inactive pharmaceutical
ingredient or a nutriceutical ingredient is present in the drug
product but not in formulation with any active pharmaceutical
ingredient.
19. The product of claim 16, wherein a drug substance(s) exists in
formulation with an excipient that is medically appropriate for at
least a portion of patients who use said drug substance(s), and
wherein the drug product is prepared for an oral route of
administration.
20. The product of claim 16, wherein a drug substance(s) is
formulated with at least one functional excipient serving either a
bioavailability-enhancing purpose in vivo or a stability-enhancing
purpose in vitro.
Description
CROSS-REFERENCE
[0001] This filing is a US continuation application claiming
priority to (and reiterating select portions of) U.S. continuation
application Ser. No. 13/757,828, filed on Feb. 3, 2013, which
claims priority to international patent application
PCT/US2011/062167, filed on Nov. 26, 2011, which claims priority to
U.S. provisional application 61/426,576, filed on Dec. 23, 2010,
all of which are hereby incorporated by reference in their
entireties.
FIELD
[0002] This application relates to pharmaceuticals, and more
particularly, relates to patient-specific drug products having high
drug loads achievable by "micro-dosing" dispensing technology with
filler-free capability for reducing diluent used.
BACKGROUND
[0003] This section provides background information related to the
present disclosure, which is not necessarily prior art. Separate
and distinct topics addressed for background in this section
include: 1) the traditional and current practice of pharmaceutical
"compounding," 2) benefits and challenges of combination drugs or
"polypills," 3) "inkjet" based dispensing approaches for
customizing drug oral dosage forms, and 4) current "micro-dosing"
technologies for expediting manufacturability of pills for clinical
trials.
[0004] Pharmaceutical "compounding" is when a pharmacist prepares
medication uniquely for a particular patient, based on a
physician's prescription. Before the prevalence of mass-produced
drugs, this was a very common practice, but now it has largely been
relegated to special cases where a mass-produced version of a drug
is either unavailable or unsuitable for a patient. Provided that
each compounded medication is uniquely prepared for an individual
patient pursuant to a physician's order, compounding generally
falls outside the jurisdiction of the FDA and instead within the
regulation of the practice of Pharmacy under relevant state
law.
[0005] Most compounding is either manual or partially-automated
with the help of certain tools or equipment. So-called Automated
Compounding Devices (ACDs), having full automation, exist at this
time only for parenteral/intravenous (I.V.) medications, which are
prepared as comparatively high-volume liquid solutions administered
from bags (typically in a hospital). There is a noteworthy
distinction between "reconstitution" which is performed according
to a manufacturer's instruction versus "compounding" which is
performed according to a doctor's prescription. Compounding of
solid oral dosage forms is relatively rare today for several
reasons, including the time and skill involved compared to the
relative logistical ease of using mass-produced products
instead.
[0006] "Polypills" or "combopills" are pills (capsules or tablets)
containing multiple medications, manufactured to have combinations
and dosages that would get prescribed together. For example, one
particular "5-in-1 polypill" is targeted for heart-disease patients
and it contains three blood pressure medications, a cholesterol
reducer, and aspirin. Polypills are not presently
common--especially for more than two drugs--partly because each
permutation of drugs and dosages to be marketed must first be
developed (including blends with appropriate inactive ingredients),
trialed (for a suitable population), FDA-approved, manufactured,
and stocked. To be worthwhile for a drug manufacturer, a particular
drug/dosage permutation would need to prove suitable for a large
number of people. Hence, manufactured polypills lack much
personalizability. Alternatively, personalized polypills are
possible via custom-compounding by a pharmacist, but very few
pharmacies offer such service.
[0007] Much research has been done over many years on the potential
to use inkjet printing based technologies for producing oral drug
dosage forms, which may have applicability for facilitating
patient-customized pills or polypills, including with customized
formulations; Hewlett-Packard has published and patented
significantly on inkjet-related approaches (e.g. U.S. Pat. Nos.
6,962,715, 7,727,576, and 7,707,964), which can offer precision and
accuracy for spraying or jetting liquid drops of fluid
API-in-solution onto an ingestible substrate such as a sheet or
film, as well as for facilitating layer-by-layer deposition of
powder substances (which is useful in making controlled-release
tablets, via binding agents for "3-dimensional printing." Ink-jet
principles have also been adapted for dispensing liquid drugs into
vials, or onto porous tablet substrates. All such ideas have been
suggested to offer benefits for R&D, mass production, and
customized dosage forms--including for multiple drugs. However,
their dispensation is restricted to liquids, and to work with
capsules they require an intermediary substrate.
[0008] In another development which is wholly unrelated to
compounding or polypills, there have emerged some technologies to
aid the manufacturability of new drugs for clinical trials. To
manufacture drug capsules for clinical trial patients,
traditionally this had required a choice between either developing
a formulation with appropriate excipient(s) to permit automated
manufacture (which was not precise enough to accurately handle raw
drug substance without bulking), or else manually weighing the
active pharmaceutical ingredient (API) for each capsule (requiring
much time and skill, especially for potent substances). In recent
years, certain manufacturing equipment has solved this dilemma and
thus expedited many candidate drugs' manufacturability.
[0009] In order to allow automated manufacture without needing to
develop a formulation, certain capsule filling machines have been
developed which possess ability for "micro-dosing" very small
amounts of powder with great precision, speed, and reliability.
These are utilized to place raw API directly into capsules, in
order to postpone the need to develop blends until initial studies
can be done. This can save several months of delays before trials,
thereby allowing failures to occur faster and with less sunk-cost.
Simple formulations or select excipients can be included as well
when desired, which may still involve significantly less mass than
would otherwise be needed without micro-dosing. The most successful
of such systems have used a "pepper-shaker" means (e.g. U.S. patent
application Ser. Nos. 11/571,169 and 12/035,037).
[0010] For example, the "Xcelodose" line of products by Capsugel
can produce "API only" capsules--thus enabling sooner human trials
without needing to first develop a formulation or perform
compatibility or preformulation studies. Precise "micro-dosing" or
"micro-filling" can be accurate to 100 micrograms, with minimal
waste/attrition owing partly to the lack of a powder bed. Also,
capsule type/size and powder properties can vary significantly.
Other systems featuring similar capability, using significantly
different technological means, are available from other companies:
Mettler-Toledo has the "Quantos" and Symyx has the "Powdernium,"
which employ other precision-dispensing mechanisms. Known usage and
exploitation of all such capabilities has only extended to research
and development (R&D) applications & clinical trial product
manufacturing--and only for single-drug products.
SUMMARY
[0011] This section is not a comprehensive disclosure of the
invention's scope or features.
[0012] The present invention involves medications prescribed for
individual patients. Aspects of inventive items and processes
herein include precision micro-dosing technology, which enables
very small amounts of drug substance to be reliably and accurately
dispensed without requiring non-therapeutic diluent.
[0013] Applications include custom-prescribed polypills in
pharmacies (e.g., hospital, retail, or mail-order), including
customized dosage levels (beyond the mass-produced options). This
could facilitate use of compliance-packaging, and potentially
reduce medication error by reducing pill-burden.
[0014] Further inventive details and areas of applicability will
become apparent from the description provided herein. The
description, drawings, and examples in this specification are
intended for purposes of illustrative purposes only and are not
intended to limit the scope of the present disclosure.
DRAWINGS
[0015] The drawings described herein are for illustrative
purposes.
[0016] FIG. 1 is an example of a simple and generalized
conceptual-relational diagram of a polypill-capable micro-dosing
compounding system. It features a base unit comprising micro-dosing
capsule-filling instrumentality as a central component of the
overall system 105 which allows the inputs of patient information
via user interface 101 and ingredient substances 104 via various
possible logistical approaches to result in the output of said
patient's pills 106 being produced in the specified quantity.
Appropriately programmed software 102 could feasibly reside in
various locations and it controls a plurality of dispensing
mechanisms such as heads 103 which are operationally integrated
with each other as well as said central instrumentality. Optional
integrated accessories 107 may facilitate the system itself
processing select ingredient material(s) among other functions.
Capsule shells are not shown, but would of course be an input
also.
[0017] The remaining figures depict a particular example for
dispensing, using the "salt/pepper-shaker" approach.
[0018] Specifically, in FIG. 2 there is an overall view of such a
system, including a monitor for display 201, a keyboard 202 for
entry or retrieval of information such as a given patient's drug(s)
and dosage(s), and a casing 203 with internal components of the
dispensing mechanism. A separate cartridge tray 204 holds
dispending heads/cartridges not being used in a given run.
[0019] FIG. 3 shows a view of this same system without the casing
to reveal the central processing unit or CPU 301, a pill rack tray
302, and a rotor to hold and position dispensing heads/cartridges
303.
[0020] FIG. 4 zooms further to show the tips of dispensing heads
401, the solenoid 402 having a pointed rod to tap the head, rubber
padding 403 to isolate vibration from other heads not being tapped,
and a highly-sensitive scale or micro-balance such as a Zeta scale
404 under the capsule being filled to provide continuous feedback
during filling to influence the rate of tapping.
[0021] FIG. 5 shows a cross-sectional cutaway of a dispensing head
secured to the rotor via magnets 501 built in to the rotor holder
and configured to pull and hold the head against said rubber
padding with sufficient force to be stable without being so tight
as to defeat the isolative function of the rubber padding.
[0022] FIG. 6 shows a pill rack 601 which slides within in said
pill rack tray, and which contains enough holes 602 for a
particular prescription run.
[0023] FIG. 7 shows a cross-sectional cutaway of a portion of the
pill rack tray showing how example capsule pieces 701 may fit
therein. Moreover, in this particular configuration, the curvature
of the capsule shell bottom 702 is exploited as it partially
protrudes through a comparatively smaller hole in the bottom of the
pill rack (not large enough in diameter to let the full capsule
fall through), which in turn facilitates weighing each pill from
below--as the rack slides/advances between capsules going over the
scale.
DESCRIPTION
[0024] Important characteristics are provided so that this
disclosure will convey the full inventive scope to those skilled in
the art. It will be apparent to those of ordinary knowledge of
existing relevant technologies that some details need not be
employed, that some attributes may be embodied in many different
forms, and that neither should be construed to limit the scope.
[0025] The present invention encompasses pills tailored to
individual patient needs. Embodiments combine the principle of
pharmaceutical compounding with the technology of precision
micro-dosing.
[0026] While most embodiments are expected to be for solid-form
APIs, the invention encompasses embodiments for semi-solid (i.e.
lipid-based, poorly water-soluble compounds) and some fluidic
means--as well as applications for the output produced. Likewise,
most embodiments are expected to be for non-biological
("small-molecule") drugs, however, some biopharmaceuticals are
feasible to incorporate--such as peptides/proteins suitable for
oral delivery via appropriate formulations under development
capable of preventing enzymatic degradation in vivo, and overcoming
their unique obstacles to dissolution and intestinal permeation.
Furthermore, while the primary uses and benefits of the invention
are expected to focus on human patients, many concepts are readily
adaptable to analogous veterinary applications (where legally
permitted).
[0027] The ability to avoid the need for diluents (also sometimes
known as "fillers" or "bulking agents"), made possible by the
micro-dosing/insertion features presently being directed at
clinical-trial pill manufacture--is an aspect of making it
practical to have automated compounding of multi-drug polypills
and/or personalized-dosage pills. For example, grinding tablets to
put into capsules would be prohibitively voluminous for many
polypills, and likewise for using powder blends that fail to omit
much unnecessary material. (Often such "non-functional" excipients
are used now to facilitate handling, measuring, manufacturability,
controllability, etc.--and a significant part of their role is to
add volume or mass.) This is partly because of the space-saving
consequences of limiting unnecessary content, along with the
reduced need for usage or validation of formulations, reduced
waste, and the net overall reduction of ingredient processing and
preparation. By contrast, pharmacologically functional excipients,
or stability-enhancing or inter-substance barrier excipients could
add relatively little mass or volume and thus can still be usefully
employed where appropriate. Of course, any remaining free space in
a capsule may optionally be filled with diluent if desired.
[0028] Embodiments cover API or formulation in sufficiently small
and exact quantities as to substantially eliminate need for
non-therapeutic diluent, along with packaging for enhancing patient
adherence.
[0029] Existing technical approaches found in today's automated
capsule-filling machines may be used. Such operational principles
can be adapted directly from existing micro-dosing machines such as
by Capsugel ("Xcelodose"), Mettler-Toledo ("Quantos"), and Symyx
("Powdernium").
[0030] Some feasible ways to adapt current micro-dosing design
principles toward multi-drug capability involve coordinating
multiple dispensing arms and heads, for multiple frequently-used
APIs/drugs, some of which could remain on "stand-by" during any
given prescription when not among the APIs being selected--for
embodiments where supplies of all available ingredients need not be
loaded by the operator between every use. This could be arranged
such that the chosen heads travel to each capsule--or vice versa.
With these approaches, a microbalance weighing the capsules being
filled may provide only an aggregate reading for total accumulated
content dispensed, hence the feedback algorithm might also
continuously calculate the subset of weight attributable to each
additional drug being dispensed in succession (or re-tare between).
Additional coordination and control algorithms could be included to
handle issues of sequence management, non-interference, etc. Many
such adaptations are possible, with varying degrees of complexity
but with comparable feasibility as for many similar
electro-mechanical pharmaceutical devices.
[0031] Embodiments may comprise barriers between APIs that should
not be in contact within capsules (i.e. for inter-drug stability
concerns in vitro). One way to achieve intra-capsule separation is
a "capsule-in-capsule" approach: preparing a small capsule 703
containing API(s) 704 to be segregated from other(s), for
subsequent insertion into a larger capsule 705 containing said
other(s) 706. This would require a machine amenable to varying
capsule sizes (and perhaps capsule substances), and could
incorporate a mechanism for automated insertion of the smaller
capsule into the larger capsule--performed along with
API-dispensing into the larger capsule. Micro-encapsulated API
particles 707 may instead provide separation on the particle-level,
and could also be utilized to achieve sustained/delayed release
characteristics if desired. (Note that controlled-release or
inter-drug separation might be achieved inherently if excipient
blending or granulation is employed for some simple formulation.
Alternatively, delayed-release and/or multi-compartment capsules
708 could be used.) Such possibilities could also help control
taste, when capsules are expected to be re-opened for consumption
rather than being swallowed whole. Embodiments may use current or
later-developed means of achieving sufficient separation, such as
exploiting hydrophobicity/hyrdophilicity, microcapsules 709, or
nanoparticles.
[0032] Implementation methods include usage of custom polypills for
outpatients with high pill-burden, including compliance packaging
for outpatients, as well as hospital or long-term-care
inpatients--for whom medication dispensation and administration
errors occur in correlation to the quantity and frequency of
medication.
[0033] Another related use is in conjunction with blister-packing
or the like (which is often required for pills of nursing-home
patients) or other unit-dose packaging or even specialized
dispensing apparatuses; or, in the case of health-system
pharmacies, the small plastic packets/pouches that hold one or more
pills designated for inpatients (often with printed labeling on the
outside). Note that inpatients' drugs and dosages are often not
"settled" and can thus change often, so adaptation there would
require having low pill quantities per machine run.
[0034] A preferred embodiment of the immediate output of the system
and methods, where applicable, is a capsule containing multiple
drugs of patient-customized selection and dosage, which may be
granulated blends, encapsulated particles, or microspheres. A
preferred embodiment of the eventual ultimate output of the system
and methods herein, for nursing-home patients or hospital
outpatients having high pill-burden, is compliance-package
blister-packs designating a single pill to be taken at particular
time(s) or with a particular meal(s) each day. The latter requires
combined implementation with appropriate packaging equipment.
[0035] Some notable advantages which help to elucidate how to
target and apply the invention include (without limitation)
enabling more pharmacies to offer prescription-compounded capsules
suited to individual patients, thereby expanding access to
personalized drug dosages and combinations thereof such as via
customized polypills--with resultant benefits to patient
convenience, compliance, and health. This can facilitate adherence
to multi-drug regimens, whether for different conditions or
combination therapy for a single condition. When using unsealed or
re-openable capsules, this also facilitates subsequent mixing or
dissolving the dispensed powder with food or drink or other
solvent. And in contrast to inkjet methods, the invention notably
entails the ability to custom-compound by placing pharmaceutical
materials into capsules without necessarily requiring first
dissolution into solvent and deposition onto a substrate/sheet.
[0036] One safety application and benefit especially applicable to
hospitals or long-term care facilities or the like is the potential
to reduce inpatient medication errors (particularly dispensation or
administration errors pertaining to incorrect drugs or dosages,
including omission and wrong-dose and wrong-time errors) by
significantly reducing the number of pills needing to be
administered, handled, etc., which is a significant factor in
medication error risk. Medication errors among highly-medicated
patients have been documented to account for many injuries and
costs. High rates of medication errors in assisted-living
facilities and the like occur with the following medication
classes: cardiovascular, anti-convulsant, anti-psychotic,
anti-infective, anti-platelet, anti-diabetic, laxative,
anti-hyperlipidemic, anti-depressant, and others.
[0037] Regarding outpatients, important applications involve
patient compliance, and thus safety, as patient noncompliance among
high pill-burden patients has been documented to account for many
injuries and costs. High pill-burden outpatient groups often
include transplant, HIV, cancer, mental-health, and others.
Extensions of the drug-consolidation potential of polypills
include, for example, the ability to prescribe two separate
polypills (perhaps using labeled capsules) for morning and night,
with compatible medications being clustered and incompatible
medications separated for patient safety (certain drugs could also
overlap between them). Another variation on this could include four
daily polypills--in conjunction with "compliance packaging" or the
like--as some highly medicated patient groups require multiple
medications with breakfast, lunch, dinner, and at bedtime. (Of
course, such packaging could also be useful for nursing home
inpatients, where blister-packing is often a legal requirement.)
Furthermore, select niche patient groups may be targeted who are at
unique risk of error (e.g., blind patients).
[0038] An additional niche application/advantage lies in being able
to gradually increase or decrease a patient's dosage of any
particular drug in small increments, such as when tapering or
phasing one off of a drug to discontinue a therapy no longer
needed--while also avoiding withdrawal adverse events.
[0039] Institutional settings whose principal purposes is not
healthcare but which nonetheless provide healthcare, such as prison
facilities, are another context in which consolidating and
streamlining medications could provide organizational efficiencies
as well as patient benefits.
[0040] Practitioners' options may also be broadened to more often
prescribe drugs whose manufactured forms may be discontinued or
unavailable. In some cases it could in effect ease drug
shortages--whose causes include production delays, forecasting
uncertainties, inventory planning issues, or manufacturing
problems--by eliminating intermediary steps or bottlenecks in the
supply chain. It can also address drugs whose mass-produced dosage
levels are not optimal for a patient's weight, age (e.g.
pediatrics), size, genetic profile, or condition severity--as
mass-produced drug products have few dosing options, often based
upon clinical trials which can have limited subject demographics
(e.g. due to difficulty in patient recruitment, which has been
notably documented regarding cancer drug trials). Further, custom
dosing reduces demand for pill splitting--a practice which presents
various safety and efficacy concerns, as has been advised against
by the FDA.
[0041] While the text and drawings herein describe to and enable
those of ordinary skill, such persons will also understand and
appreciate the existence of enumerable variations. Hence the
foregoing description is not intended to be exhaustive, and any
references herein to the "invention" are intended in such a
spirit.
* * * * *