U.S. patent application number 11/709525 was filed with the patent office on 2007-08-30 for method for a supplemental dietary composition having a multi-phase dissolution profile.
Invention is credited to Shan Chaudhuri, Ken Clement, Marvin Heuer, James Ramsbottom.
Application Number | 20070202165 11/709525 |
Document ID | / |
Family ID | 38433828 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070202165 |
Kind Code |
A1 |
Heuer; Marvin ; et
al. |
August 30, 2007 |
Method for a supplemental dietary composition having a multi-phase
dissolution profile
Abstract
The present invention relates to a method and composition for
achieving a multi-phasic dissolution prolife through the process of
fine-milling to increase the rate of dissolution of ingredients.
The ingredients to be fine-milled are ingredients suitable for use
in supplemental dietary compositions.
Inventors: |
Heuer; Marvin; (Mississauga,
CA) ; Clement; Ken; (Mississauga, CA) ;
Chaudhuri; Shan; (Mississauga, CA) ; Ramsbottom;
James; (Mississauga, CA) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
38433828 |
Appl. No.: |
11/709525 |
Filed: |
February 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60776325 |
Feb 23, 2006 |
|
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Current U.S.
Class: |
424/464 |
Current CPC
Class: |
A23L 33/16 20160801;
A61P 25/20 20180101; A61K 31/122 20130101; A61K 31/205 20130101;
A61K 36/53 20130101; A23V 2002/00 20130101; A61K 31/197 20130101;
A61K 33/24 20130101; H01L 29/788 20130101; A61K 31/4045 20130101;
A23L 2/52 20130101; A61K 36/185 20130101; A61K 36/889 20130101;
A23L 33/105 20160801; A61K 31/555 20130101; A61K 33/24 20130101;
A61K 36/84 20130101; A61K 36/539 20130101; A61K 36/889 20130101;
A23V 2002/00 20130101; A61K 31/205 20130101; A61K 9/2072 20130101;
H01L 29/7884 20130101; A61K 31/385 20130101; A61P 3/02 20180101;
A61K 36/752 20130101; A23V 2002/00 20130101; A61K 36/185 20130101;
A23L 33/175 20160801; A61K 31/197 20130101; A23L 33/10 20160801;
A61K 36/539 20130101; H01L 29/42324 20130101; A61K 31/185 20130101;
A23L 33/18 20160801; A61K 33/42 20130101; A61P 43/00 20180101; A61K
31/122 20130101; A61K 31/185 20130101; Y10S 514/923 20130101; A61K
31/198 20130101; A61P 21/06 20180101; A61K 9/14 20130101; A61K
31/4045 20130101; A61K 31/385 20130101; A61K 36/76 20130101; H01L
29/40114 20190801; A61K 31/455 20130101; A61K 31/715 20130101; A61K
36/752 20130101; A61K 36/84 20130101; A61K 9/20 20130101; A61K
36/76 20130101; A61K 9/0095 20130101; A61K 31/555 20130101; A61K
33/42 20130101; A61K 36/53 20130101; A61K 31/715 20130101; A23V
2250/21 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A23V 2200/316 20130101; A23V 2250/06 20130101; A23V 2250/0644
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A23V
2250/0606 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A23V 2200/20
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A23V 2250/7046 20130101; A61K 2300/00
20130101; A23V 2200/326 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/464 |
International
Class: |
A61K 9/20 20060101
A61K009/20 |
Claims
1. A method for achieving a multi-phasic rate of dissolution of a
supplemental dietary composition in a mammal comprising:
administering to said mammal said composition comprising a series
of one or more fine-milled and unprocessed supplemental dietary
ingredients, wherein the fine-milled and unprocessed supplemental
dietary ingredients are identical in composition and said one or
more fine-milled ingredients vary from each other in the degree of
milling.
2. The method of claim 1, wherein said multi-phasic rate of
dissolution comprises a first-phase and a second-phase; whereby
said first-phase has a first rate of dissolution and said
second-phase has a second rate of dissolution.
3. The method of claim 2, further comprising a third-phase, whereby
said third-phase has a third rate of dissolution.
4. The method of claim 3, further comprising a fourth-phase,
whereby said fourth-phase has a fourth rate of dissolution.
5. A multi-phase dissolution composition comprising a first
ingredient and a second ingredient, wherein said composition is
characterized by a first-phase corresponding to said first
ingredient and a second-phase corresponding to said second
ingredient such that said first-phase has a first rate of
dissolution and said second-phase has a second rate of
dissolution.
6. The composition of claim 5, wherein said composition further
comprises a third ingredient corresponding to a third-phase,
wherein said third-phase has a third rate of dissolution.
7. The composition of claim 6, wherein said composition further
comprises a fourth ingredient corresponding to a fourth-phase,
wherein said fourth-phase has a fourth rate of dissolution.
8. A method for manufacturing a supplemental dietary composition
suitable for ingestion by a mammal, the method comprising the step
of: providing in the supplemental dietary composition a series of
one or more fine-milled and unprocessed supplemental dietary
ingredients, wherein each of the one or more fine-milled
ingredients comprises a segment of said supplemental dietary
composition, such that each segment has a different degree of
milling.
9 The method of claim 8, wherein a first segment has a rate of
dissolution that is different from a rate of dissolution of a
second segment.
10. The method of claim 8, further comprising the step of
fine-milling the ingredient so as to obtain the first segment of
the ingredient.
11. The method of claim 10, wherein the second segment of the
ingredient is provided in a regular form.
12. The method of claim 10, further comprising the steps of:
fine-milling the ingredient so as to obtain a second segment of the
ingredient.
13. The method of claim 8, further comprising the step of providing
in the supplemental dietary composition the ingredient in a third
segment, the third segment having a range of particle sizes that is
different from the ranges of particle sizes of the first and second
segment of the ingredient.
14. The method of claim 13, wherein the third segment of the
ingredient has a rate of dissolution that is different from the
rates of dissolution of the first and second segment of the
ingredient.
15. The method of claim 13, further comprising the steps of:
fine-milling the ingredient so as to obtain the third segment of
the ingredient.
16. The method of claim 13, further comprising the step of
providing in the supplemental dietary composition the ingredient in
a fourth segment, the fourth segment having a range of particle
sizes that is different from the ranges of particle sizes of the
first, second and third segment of the ingredient.
17. The method of claim 16, wherein the fourth segment of the
ingredient has a rate of dissolution that is different from the
rates of dissolution of the first, second and third segment of the
ingredient.
18. The method of claim 16, further comprising the steps of:
fine-milling the ingredient so as to obtain the fourth form of the
ingredient.
19. A supplemental dietary composition suitable for ingestion by a
mammal, comprising: a first form of an ingredient; and a second
segment of the ingredient, wherein the first segment of the
ingredient has a range of particle sizes that is smaller than a
range of particle sizes of the second segment of the
ingredient.
20. The supplemental dietary composition of claim 19, wherein the
first segment of the ingredient has a rate of dissolution that is
different from a rate of dissolution of the second segment of the
ingredient.
21. The supplemental dietary composition of claim 19, wherein the
first segment of the ingredient is fine-milled.
22. The supplemental dietary composition of claim 21, wherein the
second segment of the ingredient is in a regular segment.
23. The supplemental dietary composition of claim 21, wherein the
second segment of the ingredient is fine-milled.
24. The supplemental dietary composition of claim 19, further
comprising the ingredient in a third segment, the third segment
having a range of particle sizes that is different segment the
ranges of particle sizes of the first and second segment of the
ingredient.
25. The supplemental dietary composition of claim 24, wherein the
third segment of the ingredient has a rate of dissolution that is
different from the rates of dissolution of the first and second
segment of the ingredient.
26. The supplemental dietary composition of claim 24, wherein the
third segment of the ingredient is fine-milled.
27. The supplemental dietary composition of claim 24, further
comprising the ingredient in a fourth segment, the fourth segment
having a range of particle sizes that is different segment the
ranges of particle sizes of the first, second and third forms of
the ingredient.
28. The supplemental dietary composition of claim 27, wherein the
fourth segment of the ingredient has a rate of dissolution that is
different segment the rates of dissolution of the first, second and
third segment of the ingredient.
29. The supplemental dietary composition of claim 16, wherein the
fourth segment of the ingredient is fine-milled.
Description
RELATED APPLICATIONS
[0001] The present application is related to and claims benefit of
priority to U.S. Provisional Application No. 60/776,325, entitled
"Compositions and method for increasing the rate of bioavailability
of supplemental dietary ingredients" filed Feb. 23, 2006, the
disclosure of which is hereby fully incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to the process of particle milling
(micronization) for the purposes of producing a supplemental
dietary composition characterized by a multi-phase dissolution
profile. Based upon the resultant particle dimensions the ultimate
rate of dissolution is affected, wherein the combination of
multiple differently sized ranges of dimensioned particles achieves
a multi-phased, multiple-term of dissolution of like particles. An
aspect of the present invention is to provide an increase in the
rate of dissolution of poorly-soluble compounds as compared to
conventional oral dosage formulations. Another aspect of the
present invention is to provide a substantially immediate
dissolution of the compositional ingredients in a first phase.
BACKGROUND OF THE INVENTION
[0003] Poorly-soluble compounds are described as either sparingly
soluble or insoluble in polar or non-polar solvents depending on
the hydrophilicity of lipophilicity of said compounds. Many
compounds, particularly in the dietary supplement industry, fall
into the class of low solubility. This not only presents a problem
in terms of bioavailability but also in terms of reducing or
preventing toxicity and irregular absorption in the intestinal
tract (Shekunov BY, Chattopadhyay P, Seitzinger J, Huff R.
Nanoparticles of poorly water-soluble drugs prepared by
supercritical fluid extraction of emulsions. Pharm Res. 2006 Jan.
23(1):196-204). Therefore, it is a challenge to make these
compounds, which will be used in a biological system, e.g., orally
ingested by a human, such that they will be more readily
bioavailable and at desired rates of dissolution. Various methods
have been explored to achieve this in the pharmaceutical industry
including chemical methods, physiological procedures, and
pharmaceutical methods (Muller RH, Benita S, Bohm B (eds.).
Emulsions and Nanosuspensions for the Formulation of Poorly Soluble
Drugs, pp 15, 16, 20. Medpharm GmbH Scientific Publishers,
Stuttgart, Germany. 1998).
[0004] Additionally, various methods have been employed to regulate
the release of active ingredients in dietary supplements such as,
enteric coating. For Example, U.S. Pat. No. 6,905,707 entitled
"Controlled Release Arginine Alpha Ketoglutarate" discloses a
controlled release formulation "characterized by protecting the
active ingredients from chemical degradation in a patient's
gastrointestinal tract and releasing the active ingredients in a
controlled manner." However, nothing in U.S. Pat. No. 6,905,707
addresses the problem associated with the rate of dissolution of
poorly-soluble compounds. Furthermore, U.S. Pat. No. 6,905,707 only
discloses conventional oral dosage formats and a chemically
time-extended release format for conventionally size compounds. As
such, it is advantageous to increase the rate of dissolution in a
liquid medium or gastric juices of poorly-soluble compounds as a
method to increase substantially immediate and subsequent
bioavailability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 is a schematic representation of overlapping
multi-phased rates of dissolution in relation to
bioavailability.
[0006] FIG. 2 is a schematic representation or non-overlapping
multi-phased rates of dissolution in relation to
bioavailability.
SUMMARY OF THE INVENTION
[0007] The present invention relates to a method and composition
for achieving a multi-phasic rate of dissolution comprising
administering to a mammal a composition comprising a series of
decreasingly fine-milled and unprocessed supplemental dietary
ingredients, wherein the fine-milled and unprocessed supplemental
dietary ingredients are of like molecules. The plurality of
dissolution rates of the composition is the result of the rates of
dissolution corresponding to the specific ingredient types and
degree of micronization for each ingredient. An aspect of the
present invention is to provide an increase in the rate of
dissolution of poorly-soluble compounds as compared to conventional
unprocessed oral dosage formulations. A further aspect of the
present invention is to provide a substantially immediate
dissolution of the compositional ingredients in a first phase.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0008] For the purposes of the present invention, the terms
micronization, milling, particle-milling, and fine-milling are used
interchangeably, wherein they refer to a technology, process and
end-products involved in or leading to a narrowing of particle size
range and a concomitant reduction in the average particle size. For
the purposes of the present invention, acceptable milled-particle
sizes are in the range of from about 1 nanometer to about 500
microns.
[0009] Although it is understood by the inventors that dietary
supplements from natural sources must inherently undergo a degree
of processing prior to use, as used herein the term `unprocessed`
refers to the physical state of ingredients or compounds which have
not been subjected to a micronization process.
[0010] As used herein, the term `bioavailability` refers to the
amount of a substance available at the site of physiological
activity after administration. It is generally assumed that
substances administered intravenously have a bioavailability of
100%. Bioavailability of a given substance is affected by a number
of factors including but not limited to degradation and absorption
of that substance. Orally administered substances are subject to
excretion prior to complete absorption, thereby decreasing
bioavailability as compared to other administration routes.
[0011] As used herein, the term `molecule` refers to the smallest
size attainable of a given substance wherein the chemical
properties of said substance are retained. It is understood that
such molecules are themselves comprised of smaller atoms, however,
the forces required and involved in reductions beyond the molecule
scale are not the subject the of the present invention.
[0012] As used herein, the term `particle` refers to chunks or
clumps of a substance of varying size wherein said chunks or clumps
are comprised of varying numbers of molecules of a given substance.
By way of example, the term `particle of ice` is used to refer to a
block of ice. Said particle of ice is comprised of several
individual water molecules. The block of ice may be incrementally
broken into smaller chunks or particles of ice still comprised of
water molecules.
[0013] As used herein, the term `solubility` refers to the amount
of or degree to which a substance or solute will dissolve within a
given solvent. Several factors affect the solubility of a given
substance. These factors include but are not limited to:specific
properties of the solute and the solvent, polarity of the solute,
the polarity of the solvent, the temperature and the pressure. The
term `absolute solubility`, as used herein, refers to the
solubility of a given substance under conditions in which time is
not a factor, i.e. infinite time. It is understood that a substance
may be in `suspension` rather than solution but will appear to be
in solution.
[0014] As used herein, the term `dissolution` refers to the process
of a solute going into solution or solubilizing. Dissolution is
dependent upon several factors including but not limited
to:temperature, agitation and surface area of a given particle.
[0015] As used herein, the term "multi-phasic" refers to the
dissolution rate characteristics of a given composition comprising
like particles of varying sizes.
Multi-Phased Dissolution Technology
[0016] Conventional oral dosage formulations are bound by the rate
of dissolution of the unprocessed substance, thereby limiting the
rate of bioavailability of the substance upon oral administration.
This is particularly problematic for poorly-soluble compounds which
have an inherently low rate of dissolution in that they may be
excreted prior to first-pass. Thus one aspect of the present
invention is to increase the rate of dissolution of a compound in
order to reduce the time to dissolution of the compound or
substance in a given solvent thus increasing the likelihood of
absorption.
[0017] It is herein understood that, due to the relationship
between solubility and dissolution, the amount of a substance in
solution at any given time is dependent upon both dissolution and
solubility. Furthermore, it is understood by way of extension that
increasing the rate of dissolution of a given substance acts to
reduce the time to dissolution of a given solute or substance in a
given solvent. However, the absolute solubility of said solute does
not increase with infinite time. Thus, increasing the rate of
dissolution of a substance will increase the amount of said
substance in solution at earlier points in time, thus increasing
the rate of bioavailability of said substance at earlier times upon
oral administration.
[0018] As it relates to this invention, micronization techniques
are employed to increase the rate of bioavailability of said poorly
soluble supplemental dietary ingredients. The increase in the rate
of bioavailability will allow better and quicker compound transfer
to the systemic parts of the body, and thus increase efficacy of
the compositions comprising such supplemental dietary
ingredients.
[0019] Micronization is a technique which has been used as a method
of sizing solid compounds to fine powders. Following a
micronization process, compounds and more specifically poorly
soluble compounds are transformed into fine powders which can then
be transformed into suitable, stable and patient-compliant dosage
forms. These forms, for the purposes of the present invention, are
derived for oral administration.
[0020] Micronization techniques are preferred in the present
invention in that they offer an advantage over larger forms of
compounds and poorly soluble compounds--following micronization,
compounds have higher surface area to volume ratio. This provides
for, as compared to physically coarse compounds, an ultrafine
micronized powder that has a significantly increased total surface
area. Mathematically, cross-sectional surface area increases with
the square of the radius, while volume increases with the cube of
the radius. Therefore, as a particle becomes smaller, the volume of
the particle decreases at a faster rate than the surface area
leading to an increase in the ratio of surface area to volume. By
way of theoretical calculations, decreasing the size of a particle
can increase its rate of dissolution via increasing the surface
area to volume ratio. In the case of solubility, this increase in
relative surface area allows for greater interaction with
solvent.
[0021] For example, consider 1 cm.sup.3 of coarse compound
occupying a virtually spherical volume (V), for demonstration
purposes, a single particle of any given substance. The surface
area (SA) of this 1 cm.sup.3 particle is calculated using Formula I
to solve for the radius (r). This value for r is used to calculate
SA with Formula II: V=(4/3) pi r.sup.3 (I) SA=4pi r.sup.2 (II)
Therefore, a particle with V of 1 cm.sup.3 has SA of approximately
4.8 cm.sup.2. If this substance were milled to several particles
each having a V of 0.5 mm.sup.3, each particle would have SA of
approximately 0.03 cm.sup.2. In this example, the volume of a
single 1 cm.sup.3 particle could contain 2000 of the particles
fine-milled to a size of 0.5 mm.sup.3 with a total SA of 2000
particles.times.0.03 cm.sup.2 per particle which equals 60 cm.sup.3
and therefore corresponds to a 60-fold increase in total SA. This
increase in total SA would allow for greater access of solvent
molecules to solute molecules, thus leading to a greater rate of
dissolution.
[0022] In the present invention, a multi-phased dissolution
technology is achieved through utilization of micronization
technologies. As opposed to conventional chemical means or the use
of excipients materials to regulate the amounts of a given compound
being released into the body of an individual, multi-phased
dissolution technology utilizes the surface-area to volume concept
and micronization. The smallest particle will have the highest
surface-area to volume ratio, and thus will have the greatest rate
of dissolution, followed by the second smallest, and then third
smallest, and so on, thus leading to multi-phased dissolution
technology wherein several particle size ranges are incorporated
together into a single dosage. In an oral formulation, like
ingredients are milled to several particular and distinct size
ranges. Each particle size range having a substantially unique rate
of dissolution, such that when they are incorporated into a single
dosage, a multi-phased dissolution profile is achieved without the
need for chemical modifiers or excipients materials.
[0023] The overlapping of the particular and distinct rates of
dissolution based on the respective sizes of the particles, forms
the phases of the multi-phased dissolution technology, and provides
a substantially linear and extended bioavailability of the given
compounds. For example, the design of a multi-phased dissolution
rate cycle as herein noted may be used in the design of sustained
energy dietary supplement formulations. With reference to FIG. 1, a
schematic representation of this embodiment can be observed.
[0024] FIG. 1 illustrates a substantially linear and consistent
dissolution rate of a dietary supplement formulation. In order to
achieve the substantially linear and consistent dissolution of a
formulation as illustrated in FIG. 1, the particle size ranges are
sequentially arranged in an increasing manner such that the upper
limit of a first phase particle range abuts the succeeding particle
size range of the following phase. For example, phase 1 may include
particles of size 2-20 microns, phase 2 includes particles of size
20-40 microns and phase 3 includes particles of size 40-60
microns.
[0025] FIG. 2 illustrates a sigmoidal dissolution rate pattern of a
dietary supplement formulation. A sigmodial dissolutation rate is
characterized by an initial substantial increase in the
bioavailability of a given compound after ingestion, and subsequent
decrease in the bioavailability of said given compound, followed by
a second substantial increase in bioavailability based on the
relative rates of solubility of a given ingredient compound based
on the surface-area to volume ratio. The preceding sigmoidal
dissolution rate pattern may continue for an infinite number of
like cycles. The design of a multi-phased dissolution rate cycle as
herein noted may be used in the design of dietary supplement
product to coincided with natural body rhythms and increase the
bioavailability of compounds at time when the body is lacking and
decrease the bioavailability of compound at times when the body is
not in need. With reference to FIG. 2, a schematic representation
of this embodiment can be observed.
Micronization
[0026] Micronization or particle-milling is preformed by a variety
of methods. Dry milling or nanosuspensions are often made by air
jet milling and wet milling in pearl mills and rotor-stator mills
as commonly known in the art as part of the micronization
process.
[0027] Methods of milling particles can also be those such as
hammer mills, cryogenic hammer mills, fluid and air jet milling,
jaw crushing, and high-pressure dispersion milling. These are
methods of medialess milling. Hammer milling produces particles of
typically 30-500 microns. At ambient temperatures, rotating hammers
which strike the particles repeatedly reduce the particle size to a
point where they can pass through a screen having a given mesh
size. If required, the process can also be done at lower
temperatures in cases where a reduces temperature is required to
fracture a given particle.
[0028] During the process of jet milling, particles are suspended
in flowing streams of air where they are targeted at either
themselves or a stationary target. This results in a fine grind
with a particle size of typically 1-10 microns being produced.
[0029] A further type of medialess milling which may be employed in
the present invention is high pressure dispersion milling in which
dispersions are pressurized to 10,000-50,000 psi. At this point,
the pressure is rapidly released. This release in pressure causes
cavitation and grinding. Particles of 0.5 to 1 micron are typically
produced via this method (The Aveka Group, Specialists in Particle
Processing. Grinding and Classification.
www.aveka.com/grinding_and_classification.htm).
[0030] In the process known as media milling, balls, pebbles or
other media such as sand are added in with material to be ground in
order to reduce particle size. The collisions of the media with
material to be ground results in the fracture of the large
particles into smaller such particles. Using media milling,
particles can be milled to average sizes of 0.1 micron with
relative ease. Through control of the grinding time and force with
which the material is ground, virtually any particle size can be
obtained. Media mill can be used with or without any liquids
additives, although water or other solvents are commonly used to
produce the finest particle.
[0031] Until recently, the actual quantitation of milling in terms
of size distribution and the effects of process variables have been
complicated. Mathematical models predicting the size and size
distribution of milled particles have been developed (Pierre
Chapelle, Nicholas Christakis, Hadi Abou-Chakra, Ian Bridle, M. S.
A. Bradley, Mayur Patel, Mark Cross. Computational model for
prediction of particle degradation during dilute phase pneumatic
conveying: Modelling of dilute phase pneumatic conveying. Advanced
Powder Technology, 2004 Vol 15, pp. 31-50) and deemed valid by the
demonstrated agreement with laboratory results. For jet milling for
example, it is now known how variables such as feed rate, angle of
inlet nozzle and air flow rate affect the process of micronization.
This allows for a much greater control over resultant particle size
with narrower size distribution.
[0032] Examples of mills and techniques for milling particles for
the purposes of size reduction are disclosed in e.g. U.S. Pat. Nos.
4,006,025, 4,294,916, 4,294,917, 4,490,654 and 4,950,586 and
4,927,744.
[0033] U.S. Pat. No. 6,604,698, fully incorporated herein by
reference, discloses a process for preparing a dispersion of solid
particles of a milled substrate in a fluid carrier comprising the
use of both large and small milling media in a media mill,
separating the produced fine particles from the milling media by
the use of a screen in the fluid carrier. The product then remains
in the fluid carrier or can be removed via the evaporation of the
fluid carrier.
[0034] U.S. Pat. No. 6,634,576, fully incorporated herein by
reference, discloses a process for milling a solid substrate in the
milling chamber of a dispersion or media mill in the presence of
two or more compositions of milling media bodies, wherein the
milling media bodies contribute to the grinding of the solid
substrate and wherein at least one composition of media bodies
provides fragments of milling media bodies that are retained with
the milled substrate particles in a synergistic commixture produced
in the milling process.
[0035] For the purposes of various embodiments herein disclosed,
but not limited to existing embodiments, the process of
micronization is referred to as fine-milling. As used herein,
fine-milling is a process employing current micronization
techniques whereby the size of a particle is reduced to a range
between 2 to 50 microns. However, milling techniques to produce
particle in the range from about 1 nanometer to about 500 microns
are acceptable to the purposes of the present invention.
Preferably, jet milling is used to produce fine-milled particles
involving the steps of feeding the material into a hopper. The
material to be fine-milled is then gravity fed into a pipe which
employs an auger to propagate the material into the jet mill.
Utilizing two opposing forces; free vortex resulting from
centrifugal force imparted on the particles by the nozzles and drag
force, created by the gas-flow as it spirals towards the centre of
the mill, the particles are reduced in size as the nozzles are
arranged tangentially in the peripheral wall of the grinding
chamber. As the particle size is reduced, said particles are drawn
to the centre of the mill where they leave the mill via a pneumatic
conveyor and are collected in a bag filter. The gas is vented to
waste.
[0036] Therefore, the present invention is directed at the use of a
process of fine-milling of supplemental dietary ingredients leading
to a method of increasing the rate of bioavailability at given
phases following oral administration of dietary supplements. The
increased rate of dissolution ensures an increased number of
molecules in solution and variable number of particle sizes ranges
incorporated into a single dosage confer the ability to vary the
times following administration in which a given dietary supplement
goes into solution, thereby creating distinct bioavailability
phase. Since a given amount of will be available in a readily
absorbable state at a given time point, the method of the present
invention thereby improves bioavailability in phase release dietary
supplements.
Experiments
[0037] Experiments relating to fine-milling and bioavailability
were undertaken by the inventors. Outlines and the result of said
experiments are given below.
[0038] In order to determine the effect of fine-milling on the
dissolution rate, initial testing was performed to examine the rate
of dissolution of common supplemental dietary ingredients. For the
purposes of this disclosure, the term "regular" as used herein
makes reference to non-fine-milled particles.
Experimental Procedure
[0039] 100 mL of water was placed into a 250 mL beaker and a
magnetic stirrer bar was added to the beaker. The beaker was then
placed on a magnetic stirrer was set to constant speed. Increments
of 2 g of regular ingredients were quickly added wherein the next
increment was added after the previous increment visually appeared
to dissolve until the mixture appeared saturated. The time required
to dissolve was estimated by visual inspection. Equal amounts of
the fine-milled ingredients were then added to the water and the
time required to dissolve was estimated by visual inspection. The
supplemental dietary ingredients used were Zinc Acetate, L-Arginine
base, Creatine Ethyl Ester and Creatine Monohydrate.
[0040] Results TABLE-US-00001 TABLE 1 Time taken Powder Amount
Added to dissolve Sample Name Type (g) (min) Zinc Acetate Regular
18 >10 Fine-milled 18 <10 Arginine Regular 16 >10
Fine-milled 16 <10 Creatine Ethyl Regular 22 >10 Ester
Fine-milled 22 <10 Creatine Regular 2 <5 Monohydrate
Fine-milled 2 <5
[0041] Table 1 presents the observations made examining the time to
dissolve for non-milled and fine-milled ingredients. In all cases,
the fine-milled ingredients dissolved faster then the regular
ingredients with the exception of Creatine Monohydrate. The
Creatine Monohydrate sample dissolved at the same rate in both the
fine-milled and regular formats.
Discussion:
[0042] In three of the four cases examined, the fine-milled
ingredients took less time to dissolve according to visual
inspection. For Zinc Acetate, Arginine and Creatine Ethyl Ester the
fine-milled samples dissolved within 10 minutes, whereas the
non-milled versions of these ingredients all required greater than
10 minutes. Creatine Monohydrate, which is known to be of
relatively low solubility, did not display a difference dependent
on particle size.
[0043] A second experiment relating to fine-milling and potential
increase in bioavailability was conducted. In order to test the
capacity of fine-milling to improve the rate bioavailability of
substances, a simple test was performed. The test was conceived to
mimic various elements involved in the processes of oral
administration of a nutritional supplement. The key parameters
involved were rate of dissolution and solubility, as it is
understood that an ingested nutrient must be dissolved or reduced
to a bio-transportable size in order to be utilized biochemically
by the body.
[0044] Digestion converts complex foods into nutrients useable by
cells. As such, digestion can be divided into distinct processes
including ingestion, mechanical digestion, chemical digestion and
absorption. Orally consumed substances are first broken down in the
mouth by a combination of physical forces (chewing) and salivary
enzymes. In the stomach, substances are further broken down by
churning and mixing with more enzymes and acid. Partially digested
substances then pass to the small intestine where more enzymes
complete digestion. In the case of many supplemental dietary
ingredients enzymatic digestion does not occur, therefore another
method of bioavailability must occur. In the present invention,
bioavailability of these substances is improved by fine-milling.
The increase in the dissolution rate, it is understood by the
inventors, to lead to and increase in bioavailability by increasing
the likelihood a given molecule is absorbed by the body of an
individual prior to excretion. In the case of poorly-soluble
substances, the substance may be excreted before it is absorbed if
it is not fine-milled, thereby decreasing bioavailability.
Absorption of digested substances begins in the stomach and occurs
mainly in the small intestine and is facilitated by diffusion and
active transport. Water is an important component of these
processes as the enzymatic reactions require that substances be in
solution i.e. dissolved.
Experimental Procedure
[0045] The rates of dissolution and solubility of regular common
nutritional supplements were compared to fine-milled versions
within a fixed time. The substances tested were whey protein
concentrate, creatine monohydrate, L-arginine, and
glycine-L-arginine-alpha-ketoisocaproic acid calcium.
[0046] 100 mL of water was added to a 250 mL beaker and a magnetic
stirring bar was placed in the beaker. The beaker was placed on a
magnetic stirrer and stirred with low speed. 1 g of a given
supplemental dietary ingredient powder was added incrementally to
the beaker with the stirring speed constant until the solution
visually appeared saturated. The solution was filtered by gravity
through a pre-weighed filter paper. The filter paper was allowed to
dry completely and weighed to measure the amount of substance
remaining on the filter paper.
[0047] Results TABLE-US-00002 TABLE 2 Max Dry Amount Powder Approx.
Sample Powder Dissolved On Filter Molecular Mass Name Type (g) (g)
Fold Change (g/mol) Whey Protein Regular 12 0.79 NA Fine-milled 12
0.15 5.3 Creatine Regular 2 0.19 149 Monohydrate Fine-milled 2 0.01
19.0 glycine-L- Regular 18 0.42 418 arginine- Fine-milled 18 0.31
1.4 alpha- ketoisocaproic acid calcium Arginine Regular 16 0.36 174
Fine-milled 16 0.25 1.4
[0048] Table 2 presents the results of the solubility test designed
to mimic bioavailability to compare regular substances to their
fine-milled counterparts. The `Fold Change` represents the change
in the amount of substance unable to pass through the filter as
calculated by the amount of unfiltered regular substance divided by
the amount of unfiltered fine-milled substance and represents the
potential theoretical improvement in bioavailability. The
approximate molecular weight is also shown for comparison.
Discussion
[0049] In analogy to digestion, the experimental test system
employed herein assesses bioavailability in relation to rate of
dissolution and solubility on the premise that undissolved
substances will be excreted from the body of an individual and not
be absorbed. The mixing of the samples with a magnetic stir bar is
analogous to mechanical digestion in the mouth and stomach. The
passage of the samples through the filter paper is likewise
analogous to the absorption of nutrients through cell membranes. In
both cases (digestion and the current experimental test system),
the rate of dissolution and solubility are factors. It is important
to understand that molecules in solution are individual molecules.
Those substances in powder form, and by extension substances in
solid forms derived from powdered substances such as tablets and
capsules, typically must be dissolved before they can effectively
pass through a membrane. Furthermore, it is important to understand
that substances in powder form are present in chunks or clumps of
molecules with a distribution of particle sizes. The goal of
micronization or milling for the purposes of the present invention
is to reduce the average particle size, ideally to the smallest
size attainable, e.g., a single molecule. It is understood that the
absolute solubility is not affected by reduced particle size
whereas the rate of dissolution is drastically increased or
improved by a fine-milling process.
[0050] Therefore, sample material remaining on the filter paper
represents two non-mutually exclusive cases. One case is that
soluble molecules are too large to pass through the pores of the
filter. In this case, if the solution is homogeneous, then none of
the solubilized molecules will pass through the pores of the filter
paper. The second case is that the material represents insoluble or
yet-undissolved sample material present as particles that are too
large to pass through the pores of the filter. It is understood
that insoluble particles comprised of numerous single molecules in
suspension may be deemed to be in solution by the naked eye under
visual inspection, however, they are in fact not actually in
solution.
[0051] In all cases the fine-milled samples passed through the
filter paper more readily and effectively than did the regular
samples, i.e. more of the regular samples remained on the filter
than the fine-milled samples. It was also observed that in all
cases the regular samples took more time to filter than the
fine-milled samples (data not shown). These data suggest that the
dissolution rate of the substances was increased by fine-milling
via decreasing average particle size.
[0052] It is interesting to note that the `Fold Change` appears to
be correlated to two parameters. The substance that was least
soluble (creatine) showed the most significant improvement
(19-fold), while the most soluble
(glycine-L-arginine-alpha-ketoisocaproic acid calcium and
L-arginine) showed the least improvement (1.4-fold). Also, the
molecular weight may contribute to the efficacy afforded by
fine-milling as evidenced by the lowest molecular weight substance
(creatine) showing the largest improvement. It should be noted that
the molecular weight of the whey protein concentrate is not listed
as it is a distribution of multiple protein fractions but the
average is most likely significantly larger than the other
substances tested and does not therefore likely follow this second
potential correlate. However, the theoretical smallest size of a
protein particle is the size of an individual amino acid e.g.
L-arginine, which constitutes the protein. Therefore, significant
improvement for whey protein (5.3-fold) is not surprising.
[0053] Further to improving bioavailability, it is understood by
the inventors that increased solubility resulting from fine-milling
will lead to improvements in characteristics in which solubility
and reduced particle size likely play a role. For example, a
fine-milled ingredient used in the formulation of a nutritional bar
will be less course in texture and more palatable than a
non-fine-milled ingredient. Likewise, a fine-milled ingredient used
in the formulation of a nutritional beverage will be less `gritty`
due to reduced particle size and increased rate of dissolution.
[0054] In order to expand on the results of the aforenoted
experiments, a kinetic experiment was conducted to examine the
change in the dissolution rate over short time periods.
Experimental Procedure
[0055] Following the same method as immediately above experiment,
the solubility of non-milled or regular Creatine monohydrate was
compared to that of fine-milled Creatine monohydrate. 1 g of sample
was added to 50 mL water in a flask with a magnetic stir bar on a
stirrer set at constant speed. Separate samples were filtered at 1
and 5 minutes. The pre-weighed filter papers (Whateman 41, particle
retention 20-25 .mu.m) were allowed to dry and the amount of sample
remaining on the filter paper was determined.
Results
1-Minute Interval:
[0056] Regular Creatine monohydrate [0057] weight of empty filter
paper=2.30 g [0058] weight of filter paper after=2.62 g [0059]
weight of unfiltered sample=0.32 g [0060] time to filter=2
minutes
[0061] Fine-milled Creatine monohydrate [0062] weight of empty
filter paper=2.26 g [0063] weight of filter paper after=2.59 g
[0064] weight of unfiltered sample=0.33 g [0065] time to filter=3.5
to 4 minutes 5-Minute Interval:
[0066] Regular Creatine monohydrate [0067] weight of empty filter
paper=2.29 g [0068] weight of filter paper after=2.69 g [0069]
weight of unfiltered sample=0.40 g [0070] time to filter=1 to 1.5
minutes
[0071] Fine-milled Creatine monohydrate [0072] weight of empty
filter paper=2.22 g [0073] weight of filter paper after=2.49 g
[0074] weight of unfiltered sample=0.27 g [0075] time to filter=2
to 2.5 minutes Discussion
[0076] At the 1-minute interval, essentially equal amounts of
regular and fine-milled creatine were retained by the filter paper
(0.33 g and 0.32 g). However, at the 5-minute interval, more of the
regular creatine was retained by the filter paper than fine-milled
creatine (0.40 g versus 0.27 g). This suggests that more of the
fine-milled creatine was able to pass through the filter paper
after 5 minutes i.e. more was in solution. The time to filter was
consistently longer for the fine-milled samples. This may be
explained by the ability of the smaller fine-milled particles to
become entrapped within the pores of the filter paper, thus slowing
the rate of solvent passage. It is commonly known in the area of
column chromatography that molecules too large to enter the pores
of the separation matrix do not usually impede the rate of flow of
solvent, while molecules small enough to enter the porous matrix
become trapped and may impede the solvent flow rate.
[0077] In the present invention as a first example embodiment of a
supplemental dietary composition that comprises the use of a
ketoacid in combination with one or more monobasic amino acids as
disclosed in U.S. application Ser. No. 11/595,170 incorporated
herein in its entirety by reference, is provided. With respect to
the instant composition, poorly-soluble monobasic, dibasic, and
tribasic amino acids and ketoacid are treated fine-milled to
increase solubility and thus bioavailability. An embodiment
comprising the present invention is set forth in greater detail in
Example 1.
[0078] Furthermore, the present disclosure provides a second
example embodiment of a supplemental dietary composition that
comprises the use of a ketoacid in combination with one or more
cationic or dibasic amino acids as disclosed in U.S. Pat. No.
6,100,287 incorporated herein in its entirety by reference wherein
at least one of the components is fine-milled. With respect to this
composition, cationic and dibasic amino acids and ketoacids are
fine-milled to increase solubility, and thus bioavailability. An
embodiment comprising present invention is set forth in greater
detail in Example 2.
[0079] Additionally, the present disclosure provides a third
example embodiment of a supplemental dietary composition that
comprises the use of Creatine-Ethyl Ester, Creatine
Alpha-ketoglutarate and Alpha-lipoic acid as disclosed in U.S.
application Ser. No. 11/399,885 incorporated herein in its entirety
by reference. With respect to this composition, the components
which comprise this example are fine-milled to increase solubility
and thus bioavailability. An embodiment comprising present
invention is set forth in greater detail in Example 3.
[0080] An aspect of the present invention is the inclusion of
fine-milled supplemental dietary ingredients as part of a greater
composition comprising like and additional ingredients. As part of
the greater composition the fine-milled ingredients may be present
in ratios from about 50:1 to about 4:1. Advantageously, this
results in multi-phasic dissolution rate, thereby broadening the
supplemental dietary ingredients' period of bioavailability due to
a multi-phasic dissolution profile.
[0081] Although the following examples illustrate the practice of
the present invention in three of its embodiments the examples
should not be construed as limiting the scope of the invention.
Other embodiments will be apparent to one skilled in the art from
consideration of the specification and the following examples.
EXAMPLE 1
In Powdered Form
[0082] A dietary supplement comprising the following ingredients
per serving is prepared for consumption one time per day per
individual:
[0083] about 2.0 ng of fine-milled Glycine, about 2.0 g of regular
Glycine, about 5.0 ng of fine-milled L-Arginine, about 5.0 g of
regular L-Arginine, about 3.0 ng of fine-milled Calcium-KIC, about
3.0 g of regular Calcium-KIC, about 2.0 g of Maltodextrin, about
1.5 g of Citric Acid, about 80 g of Dextrose, about 0.5 g of Sodium
Citrate, about 0.3 g of Sodium Gluconate, about 0.4 g of
Polyvinylyrolidone, about 0.1 g of Modified Food Starch, about 0.4
g of Syurp Solids, about 0.03 g of Gum Acacia , about 0.05 g of
Silicon Dioxide, about 0.027 g of Acesulfame-Potassium, and about
0.01 g FD&C Red #40.
[0084] Preferably, the nutritional composition is consumed in
accordance with the following directions:
[0085] Directions: As a dietary supplement, take one serving (35 g)
of product before a high-intensity workout. Mix in a shaker cup
with 8 oz. of water. Serve immediately. Consume ten 8 oz. glasses
of water daily for general good health.
In Caplet Form
[0086] A dietary supplement comprising the following ingredients
per serving is prepared for consumption one time per day per
individual.
[0087] about 2.0 ng of fine-milled Glycine, about 2.0 g of regular
Glycine, about 5.0 ng of fine-milled L-Arginine, about 5.0 g of
regular L-Arginine, about 3.0 ng of fine-milled Calcium-KIC, about
3.0 g of regular Calcium-KIC, about 1.5 g Microcrystalline
Cellulose, about 0.88 g Hydroxypropyl Cellulose, about 0.6 g
Coating [Partially Hydrolyzed Polyvinyl Alcohol, Polyethylene
Glycol, Hydroxypropyl Cellulose, Titanium Dioxide, Talc, Soy
Lecithin, Polysorbate 80, Colourings], about 0.176 g Croscarmellose
Sodium, about 0.176 g Stearic Acid, about 0.088 g Magnesium
Stearate , about 0.044 g Silica and about 0.43 mg
Acesulfame-potassium.
[0088] Preferably, the nutritional composition is consumed in
accordance with the following directions:
[0089] Directions: As a dietary supplement, take one serving (8
caplets) per day before a high-intensity workout. Do not exceed one
serving in a 24-hour period. Consume ten 8 oz. glasses of water
daily for general good health.
EXAMPLE 2
[0090] A dietary supplement comprising the following ingredients
per serving is prepared for consumption one to four times per day
per individual.
[0091] about 7.5 g Leucine, about 0.0004 g fine-milled Leucine,
about 0.05 g Calcium-KIC, about 0.45 g Hydroxyprpoyl Cellulose,
about 1.75 g Microcrystalline Cellulose, about 0.18 g
Croscarmellose Sodium, about 0.03 g Calcium Carbonate, about 0.12 g
Vegetable Stearine, about 0.06 g Magnesium Stearate, about 0.06 g
Silica, about 0.03 g Magnesium Silicate, about 0.306 g Coating
[Polyvinyl Alcohol, Polyethylene Glycol, Talc, Titanium Dioxide,
Riboflavin, Soy Lecithin, Polysorbate 80, Hydroxypropyl
methylcellulose, Colorings], about 0.001 g Lysine Ketoisocaproic
Acid and about 0.0004 g Sweeteners.
[0092] Preferably, the nutritional composition is consumed in
accordance with the following directions:
[0093] Directions: As a dietary supplement, take 1 serving (6
caplets) first thing in the morning. On workout days, take 1
serving immediately before your workout. For extreme results, take
twice a day. Consume ten 8 oz. glasses of water daily for general
good health.
EXAMPLE 3
[0094] A dietary supplement comprising the following ingredients
per serving is prepared for consumption one to four times per day
per individual.
[0095] about 2.0 g regular Creatine-Ethyl Ester HCI, about 0.001 g
fine-milled Creatine-Ethyl Ester HCI, about 0.1 g Creatine
Alpha-ketoglutarate and about 0.1 g Alpha-lipoic Acid.
[0096] Preferably, the nutritional composition is consumed in
accordance with the following directions:
[0097] Directions: As a dietary supplement, take two servings per
day, e.g., one serving (2 caplets) in the morning and one serving
(2 caplets) in the afternoon. Consume 10 8 oz. Glasses of water
daily. To maximize results, use in conjunction with weight
training.
* * * * *
References