U.S. patent application number 14/016259 was filed with the patent office on 2014-03-06 for bioactive dose having containing a material for modulating ph of a bodily fluid to help or hinder.
The applicant listed for this patent is Joseph M. FUISZ, Richard C. FUISZ. Invention is credited to Joseph M. FUISZ, Richard C. FUISZ.
Application Number | 20140065216 14/016259 |
Document ID | / |
Family ID | 45352785 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140065216 |
Kind Code |
A1 |
FUISZ; Richard C. ; et
al. |
March 6, 2014 |
Bioactive Dose Having Containing a Material for Modulating pH of a
Bodily Fluid to Help or Hinder
Abstract
A bioactive dose for delivering a bioactive agent to a mammal,
includes a solid bioactive dosage unit containing at least one
bioactive agent and a rapid release coating provided on at least
one outer surface of the solid bioactive dosage unit, the rapid
release coating containing a material having a property of rapidly
modulating a pH of bodily fluids in which the material comes in
contact in a direction towards an ideal absorptive pH or towards an
ideal pH to hinder absorption of the at least one bioactive agent
given the pKa that least at one bioactive agent. A modified liquid
that is administered prior to, contemporaneous with, or following
the delivery of a bioactive agent is also described. The liquid
includes a pH modifier selected to control the pH of the liquid to
a predetermined range so that the modified liquid rapidly modulates
the pH of bodily fluids to enhance or hinder absorption of the
bioactive agent.
Inventors: |
FUISZ; Richard C.; (Beverly
Hills, CA) ; FUISZ; Joseph M.; (Surfside,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FUISZ; Richard C.
FUISZ; Joseph M. |
Beverly Hills
Surfside |
CA
FL |
US
US |
|
|
Family ID: |
45352785 |
Appl. No.: |
14/016259 |
Filed: |
September 3, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12874632 |
Sep 2, 2010 |
8529914 |
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14016259 |
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12824803 |
Jun 28, 2010 |
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12874632 |
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Current U.S.
Class: |
424/474 |
Current CPC
Class: |
A61K 36/81 20130101;
A61K 36/185 20130101; A61K 9/2806 20130101; A61K 31/465
20130101 |
Class at
Publication: |
424/474 |
International
Class: |
A61K 9/28 20060101
A61K009/28 |
Claims
1. A bioactive dose for delivering a bioactive agent to a mammal,
comprising a solid bioactive dosage unit containing a bioactive
agent provided in a pouch and a rapid release coating provided on
substantially all of the pouch material or in substantially all of
the pouch material, the rapid release coating comprising a material
having a property of moving a pH of bodily fluids with which the
material comes in contact in a direction towards an ideal
absorptive pH of the at least one bioactive agent given the pKa of
that the bioactive agent.
2. The bioactive dose according to claim 1, wherein the bioactive
agent comprises a botanical.
3. The bioactive dose according to claim 1, wherein material in the
rapid release coating is acidic.
4. The bioactive dose according to claim 1, wherein material in the
rapid release coating is basic.
5. The bioactive dose according to claim 1, wherein the rapid
release coating dissolves in 30 seconds or less.
6. The bioactive dose according to claim 1, wherein the rapid
release coating dissolves in 20 seconds or less.
7. The bioactive dose according to claim 1, wherein the rapid
release coating dissolves in 10 seconds or less.
8. The bioactive dose according to claim 1, wherein the rapid
release coating is provided on the pouch material.
9. The bioactive dose according to claim 1, wherein the rapid
release coating is provided in the pouch material.
10. A bioactive dose for delivering a bioactive agent to a mammal,
comprising a solid bioactive dosage unit containing at least one
bioactive agent, the at least one bioactive agent not categorized
as a drug by the U.S. Food and Drug Administration, and a rapid
release coating provided on at least one outer surface of the solid
bioactive dosage unit, the rapid release coating containing a
material having a property of moving a pH of bodily fluids with
which the material comes in contact in a direction towards an ideal
absorptive pH of the at least one bioactive agent given the pKa of
that at least one bioactive agent.
11. The bioactive dose according to claim 10, wherein the at least
one bioactive agent comprises a botanical.
12. The bioactive dose according to claim 10, wherein the rapid
release coating is provided on an outermost surface of the
bioactive dose.
13. The bioactive dose according to claim 10, further comprising an
outer enteric coating provided on an outer surface of the rapid
release coating.
14. The bioactive dose according to claim 10, wherein material in
the rapid release coating is acidic.
15. The bioactive dose according to claim 10, wherein material in
the rapid release coating is basic.
16. The bioactive dose according to claim 10, wherein the rapid
release coating dissolves in 30 seconds or less.
17. The bioactive dose according to claim 10, wherein the rapid
release coating dissolves in 20 seconds or less.
18. The bioactive dose according to claim 10, wherein the rapid
release coating dissolves in 10 seconds or less.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of application Ser. No.
12/874,632, filed Sep. 2, 2010, which is a continuation-in-part
application of U.S. application Ser. No. 12/824,803, filed Jun. 28,
2010.
BACKGROUND OF THE INVENTION
[0002] It is well known in the art that from a pharmacological
standpoint pH has a significant effect on drug absorption. It is
generally accepted that non-parenterally, non-ionized drug is best
absorbed compared to its ionized version. A common term in
pharmaceuticals is the pKa, which is the pH at which 50% is ionized
and 5% is non-ionized, and therefore a critical pH with respect to
absorption relative to whether the drug is a weak acid or a weak
base, keeping the Henderson Hasselbach equation in mind (see
http://manuelsweb.com/pka.htm). The sum of pKa and pKb equals 14 at
25.degree. C. in an aqueous solution. As set forth in
http://www.sciencechatforum.com/viewtopic.php?f=38&t=11464, the
contents of which are incorporated herein by reference, most drugs
are weak organic acids or bases, existing in un-ionized and ionized
forms in an aqueous environment. The un-ionized form is usually
lipid soluble and diffuses readily across cell membranes. The
ionized form cannot penetrate the cell membrane easily because of
its low lipid solubility and high electrical resistance, resulting
from its charge and the charged groups on the cell membrane
surface. Thus, drug penetration may be attributed mostly to the
un-ionized form. Now this pKa applies at all areas of drug
absorption, whether mucosally, in the mouth, or in the later
regions of the GI tract. It is also applicable to vaginal, nasal,
rectal and ophthalmic, aural, respiratory and other sites of drug
delivery which are non-parenteral. This is subject to absorption
principles relative to lipid solubility and water solubility.
Generally the pH is controlled by the internal dosage form's
dynamic buffer systems. By internal, we mean that one or more
buffering agents are included in the original composition (e.g.
tablet granulation, sheet extrusion mass, film casting liquid,
capsule and liquigel contents etc.) and are uniformly present
throughout the dosage form. As a result, such buffering agents are
released at the same rate as the active ingredient and other
excipients as the dosage form disintegrates which of coarse it must
do to be absorbed.
DISCLOSURE OF THE INVENTION
[0003] The present invention relates to a bioactive dose for
delivering a bioactive agent to a mammal includes a solid bioactive
dosage unit containing at least one bioactive agent and a rapid
release coating provided on at least one outer surface (or
functioning as a non-enteric outer layer) of the solid bioactive
dosage unit. The rapid release coating contains a material having a
property of rapidly modulating a pH of bodily fluids in which the
material comes in contact in a direction towards a pH which is most
suitable for absorption considering the pKa of the at least one
bioactive agent or alternatively towards a pH which is most
suitable for retardation of absorption. This pH modifier precedes
any internal dynamic buffer system which is typically used.
[0004] In another embodiment, e.g., to aid oral quick dissolve
forms, such as quick dissolve films which are intended to dissolve
in the mouth but for which it may not be desirable to absorb the
bioactive in the mouth, the pH coating can condition to hinder the
absorption. In this embodiment, the rapid release coating contains
a material having a property of rapidly modulating a pH of bodily
fluids in which the material comes in contact in a direction toward
the least effective absorptive pH in keeping with the Henderson
Hasselbach equation. On the other hand the pH coating can condition
to increase the absorption in the mouth. In this embodiment, the
rapid release coating contains a material having a property of
rapidly modulating a pH of bodily fluids in which the material
comes in contact in a direction toward the most effective
absorptive pH in keeping with the Henderson Hasselbach
equation.
[0005] Furthermore, this invention relates to the use of a modified
liquid that contains an immediately acting pH modifier for use
either contemporaneously with, prior to, or following the
administration of a solid dosage form, with a view towards
facilitating (or retarding) absorption. This liquid can be a base
or water or a liquid which aids in swallowing (Fuisz U.S. Pat. No.
6,337,083, the contents of which are incorporated herein by
reference) or in some cases the use of a flavorant liquid such as
Flavorx.RTM. to which a pH modifying agent has been added.
[0006] One aspect of this invention is to further aid absorption by
using saliva and/or other mucosal fluids to be the immediate
carrier of the pH modifier and, using a rapidly dissolving coating
on the exterior or near the exterior of the dosage units,
precondition the surrounding saliva and fluids to near a pH level
determined with reference to the pKa of the given drug, thereby
establishing an initial pH prior to the availability of
conventional buffer systems. In this way, absorption is facilitated
almost immediately. This methodology would apply to all solid
dosage units including without limitation capsules, liquigels,
tablets, thin film, sheet, orally dissolving tablets, vaginal
rings, suppositories, pessaries, topicals, microparticles,
particles and the like. This would also apply to nasal, ophthalmic,
aural, rectal and vaginal dosage units.
[0007] Similarly, the same method may be used according to another
aspect of the present invention to adjust pH so as to retard
absorption, including in a specific area. As noted above, it may be
desirable to retard absorption of an antagonist which could be
absorbed sublingually in the mouth (e.g. naloxone).
[0008] To date, the coating art has been used in the pharmaceutical
field principally as a way of delaying the disintegration of a
dosage form and or for the protection of the bioactive agent in
vivo until absorbed. For example an enteric coating is a barrier
applied to oral medication that controls the location in the
digestive system where it is absorbed. Enteric refers to the small
intestine; therefore enteric coatings prevent release of medication
before it reaches the small intestine. Most enteric coatings work
by presenting a surface that is stable at the highly acidic pH
found in the stomach, but breaks down rapidly at a less acidic
(relatively more basic) pH. Materials used for enteric coatings
include fatty acids, waxes, shellac and plastics, plant fibers,
etc. (see, e.g. Sands et al US 2004/0162263 A1; Herbig et al U.S.
Pat. No. 6,609,590; Lew U.S. Pat. No. 5,364,634; Oshlack et al
6,387,404; Ullah et al U.S. Pat. No. 6,331,316 (each of which is
incorporated herein by reference). When enteric coatings are used
the PH modification layer is immediately under the enteric coating.
If further assurance of non-buccal absorption is required then the
pH modifying layer can be exterior to the enteric coating. The pH
modifier of this invention is not part of the granulation in a
solid dosage form as this granulation would include the usual
internal dynamic buffer system that is known in the art.
[0009] Coatings may be applied to either to the dosage form or to
the drug particles themselves. In taste masking, a light coating
may be applied such that the taste of the drug is masked when in
the mouth (in the case of a quick dissolve dosage form), but is
quickly released in the gastrointestinal tract.
[0010] One aspect of the present invention is to allow for the
application of a rapid release and rapid acting pH modulating
coating for the saliva or mucosal fluid, on a solid dosage form. In
one embodiment, a pH agent (either an acid or base or neutral
agent) together with a rapidly dissolving polymer is coated on the
exterior of the dosage form. The polymer dissolves promptly when
wetted by saliva and rapidly releases the pH agent and thereby
rapidly modulates the pH of the saliva. By immediately optimizing
pH for drug absorption, delivery of the bioactive agent is enhanced
or, in the case of multiple bioactives in one dosage unit, it may
enhance one and retard one or more others. The use of multiple
bioactives is seen in many opiate drugs that are taken orally and
include an antagonist. The goal here is to use the pH to absorb the
active and little if any of the antagonist when the oral dose is
taken orally. If the oral dose is abused intravenously, the
antagonist blocks the opiates actions.
[0011] This invention applies to all dosage forms. It has
particular application to oral mucosally absorbed forms as well as
others. It can also serve to aid oral quick dissolve forms, such as
quick dissolve films, which are to be swallowed but in which it is
not desirable to absorb the bioactive in the mouth. In this case
the pH coating can condition to hinder the absorption. In this
embodiment, the rapid release coating contains a material having a
property of rapidly modulating a pH of bodily fluids in which the
material comes in contact in a direction toward the least effective
absorptive pH in keeping with the Henderson Hasselbach equation
relating to a particular drug.
[0012] It is expressly contemplated that one or more pH agents may
be incorporated into the rapid release coating. It is also
contemplated that an acid/base combination--referred to in the art
as a "dynamic buffering system" may be included in the rapid
release coating (see Fuisz U.S. Patent Application Publication No.
2009/0098192 A1 discussing dynamic buffering and incorporated
herein by reference). The pH agent may include any material--or
combination of materials--useful to modify pH; however since the
role of this coating is as a "strike force" it may not need the
reserve amounts of the dynamic equation in a true dynamic buffering
system.
[0013] It is further contemplated that the rapid release coating of
the present invention may be applied as a pre-coating prior to a
coating that is aimed, like an enteric coating, at delaying
disintegration of the dosage form. An enteric coating is a barrier
applied to oral medication that controls the location in the
digestive system where it is dissolved; enteric coatings prevent
release of medication before it reaches the small intestine.
[0014] In such an embodiment, after the enteric coating (or similar
coating) dissolves, the rapid release coating would then rapidly
release the pH modulating agent. Of course, in this embodiment, the
pH modulating agent would be acting upon gastric juices as distinct
from saliva as is the case in the primary embodiment. Other
mammalian uses, such as and without limitation vaginal or nasal or
respiratory or ophthalmic or aural use would involve the local
fluids.
[0015] It is further contemplated that the enteric coating and pH
modulating agent can be combined.
[0016] By "rapid release" is meant that the coating will dissolve
rapidly in the intended medium--within approximately ninety
seconds, preferably within approximately thirty seconds, more
preferably within approximately 20 seconds and most preferably
within 10 seconds. The effect on pH will be nearly instantaneous
with the release of the pH agent.
[0017] As used herein the method of "coating" may include spray
coating, spray drying, dip coating or any other currently known or
future developed coating method. For film use the "coating" may
well be applied during the drying process. For sheet use it may be
applied as it leaves an extruder or similar device.
[0018] The coating may be a polymer or a saccharide but is not
limited to them because anyone skilled in the art can use whatever
coating material that functions well. Various combinations of
materials may be used for the coating material.
[0019] It is important to state here that an internal buffer system
which is in common use, is part of the recipe of the granulation
and is therefore released "in part" as the dosage form dissolves
whereas the "coating" which is referenced here is on the front
line--dissolving rapidly and in its entirety and therefore having a
quick and optimal pH effect on the surrounding fluids. Thus, the
coating can contain a material having a property of rapidly
modulating a pH of bodily fluids in which the material comes in
contact in a direction towards an ideal absorptive pH (or in
another aspect of the invention towards an ideal pH for hindering
absorption) of the at least one bioactive agent that one desires to
be absorbed. By "rapidly modulating a pH," we mean changing the pH
by at least 1.5, preferably at least 2, more preferably at least 3,
most preferably at least 4, in 20 seconds. By "in a direction
towards an ideal absorptive pH of the at least one bioactive agent
that one desires to be absorbed," we mean that the pH moves (i.e.,
lower or higher) at the start of release from the starting pH of
the bodily fluid (without the core dose in contact therewith) in a
direction of an ideal absorptive pH (or in another aspect of the
invention tan ideal pH for hindering absorption) given the pKa of
the at least one bioactive agent and considering whether the at
least one bioactive agent is acidic or basic (e.g., weak acid or
weak base), and may, with continued release, approach, reach and
exceed the ideal absorptive pH of the at least one bioactive agent,
the absorption of which one wants to maximize (or hinder). Thus,
the goal would be to modulate the pH near the ideal absorptive pH
for a given drug and then let the internal dynamic buffer system
take over and fine-tune the pH; however, as with any medication,
patient size, individual physiology, other medications, foods,
drink, etc. may cause an overshoot or undershoot.
[0020] While the present application refers to "pKa," since the sum
of pKa and pKb equals 14 at 25.degree. C. in an aqueous solution,
reference to pKa should be taken as a short-hand reference to
either pKa or pKb, since if one is known, the other can be easily
calculated.
[0021] The ideal absorptive pH is the pH at which 50-70%,
preferably at least 80%, more preferably at least 90%, most
preferably at least 99% of the bioactive is nonionized. The ideal
pH for hindering absorption is the pH at which 50-70%, preferably
at least 80%, more preferably at least 90%, most preferably at
least 99% of the bioactive is ionized.
[0022] While the primary embodiment is directed at rapidly
controlling the pH of the saliva, the invention may equally apply
to vaginal fluids, gastric juices, ophthalmic fluids, nasal fluids,
respiratory fluids and other bodily fluids of a mammal.
[0023] It is expressly contemplated that the present invention may
be applied to drug particles or microparticles, wherein each
particle or microparticle is functioning and structured as an
individual dosage unit. In this case the microparticle may be
coated with a pH modulator even though the particle itself may
contain an accessory dynamic buffer system. This is directly
applicable to certain new approaches that deposit bioactive
particulates and vapors on the nasal mucosa. It also has an
important application to topical absorption wherein the pH
modulation enhances the activity or hinders the activity of one or
more bioactives.
[0024] This application applies to all bioactive forms including
nicotine, tobacco, materials derived from tobacco and any type
container or vehicle containing same, including a pouch type
delivery vehicle. The pouch of the tobacco pouch delivery system is
an ideal vehicle to modify buccal pH towards that which favors
nicotine absorption. In a pouch tobacco product the pH modifier as
described above may be on the pouch, or in the pouch material or on
the tobacco or nicotine therein.
[0025] If the dosage unit contains more than one bioactive agent,
e.g., an opiate and an antagonist, the material having the property
of rapidly modulating a pH of bodily fluids in which the material
comes in contact rapidly can modulate a pH of bodily fluids towards
an ideal absorptive pH of one bioactive agent given the pKa (e.g.,
the opiate) and rapidly modulate a pH of bodily fluids away from an
active pH range, given the pKa, of another bioactive agent (e.g.,
the antagonist).
[0026] In another embodiment, the pH system may be delivered in a
modified liquid that is taken prior to, at the same time, or
following the administration of a solid dosage form (see Fuisz U.S.
Pat. No. 6,337,083 (Oral delivery method and composition for solid
medications or dietary supplement)) in which one of the current
inventors teaches a swallowing aid, the full text of which is
incorporated herein by reference as if fully stated).
[0027] This liquid pH system may be combined with the invention of
U.S. Pat. No. 6,337,083 in a single liquid.
[0028] The liquid system embodiment is, in a sense, the ultimate
embodiment of the rapid release coating--with the liquid, the pH
system has already been released into the liquid medium.
[0029] Special mention must be made that in U.S. Pat. No.
6,337,083, the liquid is modified to aid in the swallowing of a
solid oral dosage unit and by adding pH modification of this
invention, it becomes a new entity in terms of advancing absorption
or in the case of say the bisphosphonates which are excoriating to
the esophagus and which are active at a very acidic pH so that
modifying the saliva to a neutral or basic pH serves to retard any
absorption in the esophagus. This pH modifier can also be added to
a product like Flavorx.RTM., which is used in compounding a liquid
dosage unit in order to improve the taste profile and therefore
also serve to modify or retard absorption.
[0030] In addition to modifying the pH of liquids such as that
described in U.S. Pat. No. 6,337,083 and Flavorx.RTM., the present
invention contemplates modifying the pH of any liquid, whether used
for ease of swallowing of solid dosage forms or for flavoring or
other purposes, such that the modified liquid directly, indirectly
or by dilution provides a pH which promotes (or hinders in another
embodiment) the bioactive dose.
[0031] As with the rapid release coatings for solid dosage forms
disclosed herein, the liquid pH system may be used to enhance
absorption or hinder absorption as set forth herein. For example,
one application is to use with a product like Fosamax.RTM. to
retard absorption of the drug in the esophagus by modifying the pH
of the esophageal mucosa so as to discourage or hinder drug
absorption. The liquid may further act through an alternate
modality by modifying pH to prevent or hinder disintegration of the
tablet (or other solid dosage form) itself, where the dosage form
disintegrates less quickly at certain pHs.
[0032] Additionally, the liquid system may be used to treat the pH
of the oral cavity and GI tract prior to, during or after the
administration of a bioactive, e.g., a solid bioactive dose to
promote or hinder absorption of the bioactive.
[0033] Because of the sheer mass of the liquid system, the liquid
may be preferable to the rapid release coating where large changes
in the GI tract pH are desired.
[0034] It is expressly contemplated that the liquid may be
premanufactured and bottled, or made on demand using a package of
ingredients. For example, the pH of the liquid may be controlled at
the same time a flavor package is inserted, such as those made by
Flavorx.RTM..
[0035] Thus, the modified liquid is one the pH of which has been
modified, e.g., during its production at or prior to bottling or at
the time of administration by including a pH modifier particularly
selected to control the effective pH of the liquid in a
predetermined range to help or hinder absorption.
[0036] The most common method of administration of the liquid or
solid composition of the present invention will be to the oral
mucosa. However, the pharmaceutical composition may be administered
in the vagina, rectum, ophthalmic, aural, nose, topically,
respiratory tree, within the GI tract or any other drug delivery
location. The pH modifier may also be used in a douche type product
which will affect the absorption of a gel or solid dosage form then
used vaginally.
[0037] The pH modifier may be any material that has the required pH
and can be safely administered to a mammal. Examples of such
materials include but are not limited to malic acid, caustic soda,
etc. Other materials useful as a pH modifier would be known to
those skilled in the art based on the teachings in the present
specification.
[0038] The pH modifier may be present in an amount that brings
about the rapid modulation of the pH of bodily fluids in which the
material comes in contact in a direction towards (or away from) an
ideal absorptive pH of the at least one bioactive agent that one
desires to be absorbed given the pKa of the bioactive agent. That
amount will vary depending on the type of administration, the
bioactive agent, the dosage form, etc. but can be determined by
those skilled in the art by routine experimentation based on the
teachings provided in this specification.
[0039] While the invention is primarily directed at drug
application, it is expressly contemplated that the invention may be
used within any bioactive agent. The bioactive agent of the present
invention may be any pharmaceutical, biological, antigenic,
antibody, botanical, tobacco, food or nutraceutical, cosmaceutical
or other active agent.
[0040] Examples of pharmaceutical bioactive agents include, but are
not limited to ace inhibitors, such as Benazepril, Captopril,
Enalapril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril
and Trandolapril; acne treatments, such as adapalene, azelaic acid,
BenzaClin, Benzamycin, Benzoyl Peroxide, clindamycin, Duac,
Erythromycin, Glycolic Acid, Isotretinoin, Sulfacetamide with
sulfur, Tazarotene and Tretinoin; actinic keratosis, such as
declofenac, fluorouracil; addiction aids, such as buprenorphine,
Disulfiram, Naltrexone, Suboxone and varenicline; aldosterone
antagonists, such as eplerenone and spironolactone; alpha-1
adrenergic blockers, such as alfuzosin, doxazosin, prazosin,
tamsulosin and terazosin; ALS agents, such as riluzole; Alzheimer's
Disease medications, such as donepezil, Galantamine, rivastigmine,
tacrine and memantine; anesthetics, such as dexmedetomidine,
etomidate, ketamine, methohexital, pentobarbital, propofol and
thiopental; angiotensin II receptor blockers, such as candesartan,
eprosartan mesylate, irbesartan, losartan, olmesartan, telmisartin
and valsartan; antacids, such as Aluminum hydroxide, AlOH and
magnesium trisilicate; anti-arrhythmics, such as adenosine,
amiodarone, Atropine, Bretylium, digoxin-Immune Fab, disopyramide,
dofetilide, epinephrine, Esmolol, flecainide, ibutilide,
isoproterenol, lidocaine, mexiletine, moricizine, procainamide,
propafenone, quinidine, sotalol, tocainide and verapamil;
antibiotics, such as Aztreonam, TMP/SMX, Chloramphenicol,
Clindamycin, Dapsone, Daptomycin, Ertapenem, Imipenem/cilastatin,
Linezolid, Meropenem, Metronidazole, Nitrofurantoin,
Quinupristin/Dalfopristin, Rifaximin, Tigecycline, Telithromycin
and Tinidazole; anticholinergic acids, such as Dicyclomine,
Donnatal, Flavoxate, Glycopyrrolate, Hyoscyamine, Oxybutynin,
Propantheline and Tolterodine; anticonvulsants, such as
carbamazepine, clonazepam, diazepam, ethosuximide, felbamate,
fosphenytoin, gabapentin, levetiracetam, lamotrigine, lorazepam,
Oxcarbazepine, Phenobarbital, phenytoin, pregabalin, primidone,
tiagabine, topiramate and valproic acid; antidepressants, such as
amitriptyline, buproprion, citalopram, desipramine, doxepin,
duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine,
mirtazapine, nefazodone, nortriptyline, nortriptyline, sertraline,
trazodone and venlafaxine; anti-diarrheals, such as
dephenoxylate+atropine, Imodium and bismuth subsalicylate;
anti-emetics, such as Aprepitant, dolasetron, droperidol,
granisetron, metoclopramide, ondansetron, prochlorperazine,
scopolamine and trimethobenzamide; antifungals, such as Ampho B,
Ampho B lipid, anidulafungin, caspofungin, Clotrimazole
fluconazole, flucytosine, Griseofulvin, Itraconazole, ketoconazole,
Micafungin, nystatin, Posaconazole, terbinafine, voriconazole,
butenafine, ciclopirox, clotrimazole, enconazole, ketoconazole,
Miconazole, naftifine, nystatin, oxiconazole terbinafine and
Tolnaftate; anti-hepatitis, such as adefovir, entecavir,
lamivudine, peginterferon alfa-2a, peginterferon alfa-2b, Rebetron
and ribavirin; anti-herpetic agents, such as Acyclovir,
famciclovir, valacyclovir, acyclovir, docosanol and penciclovir;
antihistamines, such as cetirizine, desloratadine, fexofenadine,
loratadine, chlorpheniramine, clemastine, cyproheptadine,
dimenhydrinate, diphenhydramine, hydroxzine and promethazine;
anti-hypertension, such as Benazepril & HCTZ, Captopril &
HCTZ, Enalapril & HCTZ, Lisinopril & HCTZ, Moexipril &
HCTZ, Losartan & HCTZ, Valsartan & HCTZ, Atenolol &
chlorthalidone, Bisoprolol & HCTZ, Metoprolol & HCTZ,
Nadolol & bendroflumethazide, Propranolol & HCTZ, Timolol
& HCTZ, Amlodipine & benazepril, Verapamil &
trandolapril, Amiloride & HCTZ, Spironolactone & HCTZ,
Triamterene & HCTZ, Clonidine & chlorthalidone, Hydralazine
& HCTZ, Methyldopa & HCTZ and Prazosin & polythiazide;
anti-hypertensives, such as Aliskiren, Aliskiren, epoprostenol,
fenoldopam, hydralazine, minoxidil, nitroprusside, phentolamine and
treprostinil; anti-influenza agents, such as amantadine,
oseltamivir phosphate, rimantadine and zanamivir;
anti-malarials/anti-protozoals/amebicides, such as Atovaquone,
Chloroquine, Iodoquinol, Mefloquine, Primaquine, Pyrimethamine,
Pyrimethamine-Sulfadoxine and Quinine Sulfate; anti-platelet
agents, such as abciximab, dipyridamole/ASA, anagrelide,
cilostazol, clopidogrel, dipyridamole, eptifabatide, ticlopidine
and tirofiban; antipsychotics, such as aripiprazole,
chlorpromazine, Clozapine, fluphenazine, haloperidol, loxapine,
molindone, olanzepine, perphenazine, pimozide, quetiapine,
risperidone, thioridazine, thiothixine, trifluoperazine,
ziprasidone and Lithium; antispasmotics, such as Dicyclomine,
Donnatal Extentabs, Propantheline, Simethicone, hyoscyamine,
Librax, tegaserod and Bellergal-S; anti-tussives/expectorants, such
as Benzonatate and guaifenesin; atopic dermatitis medications, such
as pimecrolimus and tacrolimus; benzodiazepines and
non-benzodiazepine sedatives, such as alprazolam, buspirone,
chlordiazepoxide, chlorazepate, clonazepam, diazepam, estazolam,
eszcpiclone, flurazepam, lorazepam, midazolam, Oxazepam, ramelteon,
temazepam, triazolam, zaleplon and zolpidem; beta blockers, such as
atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol,
metoprolol, nadolol, pindolol, propranolol, sotalol and timolol;
bile acid sequestrants, such as cholestyramine, colesevelam and
colestipol; bisphosphonates, such as alendronate, etidronate,
pamidronate, risedronate, tiludronate and Zoledronic acid,
Raloxifene and Teriparatide; bladder spasm medications, such as
flavoxate, hyoscyamine, darifenacin, oxybutynin, solifenacin,
tolterodine and trospium; benign prostatic hypertrophy medications,
such as alfuzosin, doxazosin, dutasteride, finasteride, tamsulosin
and terazosin; burn preparations, such as mafenide acetate and
silver sulfadiazine; calcium channel blockers, such as amlodipine,
bepridil, diltiazem, felodipine, isradipine, nicardipine,
nifedipine and nisoldipine; calcium supplements, such as Calcium
and Hypocalcemia; cephalosporins, such as Cefadroxil, Cefazolin,
Cephradine, Cephalexin, Cefaclor, Cefotetan, Cefoxitin, Cefprozil,
Cefuroxime, Cefuroxime, Ioracarbef, Cefdinir, Cefixime,
Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten,
Ceftizoxime and Cefepime; colony stimulating factors, such as
darbepoietin alfa, erythropoietin, filgrastim, oprelvekin,
pegfilgrastim and sargramostim; corticosteroids, such as
Budesonide, cortisone acetate, dexamethasone, fludrocortisones,
hydrocortisone, methylprednisolone and prednisone; corticosteroids
Intra-articular, such as Depo-Medrol and Triamcinolone Acetonide;
cystitis, such as pentosan polysulfate, Bethanecol and Alum
irrigation; decongestants, such as Phenylephrine and
Pseudoephedrine; anti-diabetic agents, such as acarbose, Miglitol
and metformin, Avandamet.RTM., Glucovance, Metaglip, Metaglip,
rosiglitazone, osiglitazone, repaglinide, Chlorpropamide,
glimepiride, glyburide, glipizide, Tolazamide, Tolbutamide,
Glucagon, extenatide and pramlintide; direct thrombin inhibitors,
such as argatroban, Bivalirudin and lepirudin; disease modifying
agents, such as adalimumab, anakinra, auranofin, azathioprine,
etanercept, hydroxychloroquine, infliximab, leflunomide,
methotrexate and sulfasalazine; diuretics, such as Acetazolamide,
Amiloride, Amiloride and HCTZ Bendroflumethiazide, Bumetanide,
Chlorothiazide, Chlorthalidone, Dichlorphenamide, Eplenerone,
Ethacrynic acid, Furosemide, Hydrochlorothiazide,
HCTZ/Triampterene, Hydroflumethiazide, Indapamide, Methazolamide,
Methyclothiazide, Methyclothiazide, Metolazone, Polythiazide,
Spironolactone, Spironolactone, HCTZ Torsemide, Trichlormethiazide
and Triamterene; endocrine agents, such as bromoc cinacalcet
cosyntropin, riptine, cabergoline, calcitonin, desmopressin,
Leuprolide, octreotide and vasopressin; erectile dysfunction
agents, such as Sildenafil, tadalafil, vardenafil; fever
medications, such as allopurinol, antihistamines, azathioprine,
barbiturates, carbamazepine, cephalosporins, cimetidine, folic
acid, hydralazine, hydroxyurea, ibuprofen, isoniazid, methyldopa,
nitrofurantoin, penicillins, phenytoin, phenytoin, procainamide,
prophylthiouracil, quinidine, streptomycin sulfonamides, sulindac,
triamterene and vancomycin; fibrates, such as clofibrate,
fenofibrat and gemfibrozil; fluoroquinolones, such as
Ciprofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin,
Norfloxacin and Ofloxacin; gastrointestinal agents, such as
Alosetron, infliximab, Mesalamine, misoprostol, Neomycin,
octreotidev, osalazine, Orlistat, sucralafate, Sulfasalazine and
vasopressin; gout treatments, such as allopurinol, colchicine,
probenecid, Rasburicase and sulfinpyrazone; H2 receptor blockers,
such as cimetidine, famotidine, nizatidine and ranitidine;
aAnti-herpetic agents, such as Acyclovir, famciclovir,
valacyclovir, acyclovir, docosanol and penciclovir; hypertensive
urgency, such as Captopril, Clonidine and Labetalol; hypertensive
emergency, such as Enalaprilat, Esmolol, Fenoldopam mesylate,
Hydralazine, Labetalol, Nicardipine, Nitroglycerin and Sodium
nitroprusside; hemorrhoidal preparations, such as Anusol HC, Anusol
Suppository, Dibucaine, pramoxine 1%, Proctofoam-HC and
Analpram-HC; inflammatory bowel disease agents, such as
balsalazide, budesonide, infliximab, mesalamine, olsalazine and
sulfasalazine; Interferon, such as Interferon Alfa-2A, Interferon
Alfa-2b, Interferon Alfa-2b and Ribavirin combo Pack, Interferon
Alfa-N3, Interferon Beta-1A, Interferon Beta-1B (Betaseron);
intermittent claudication, such as cilostazol and pentoxifylline;
immunizations, such as Comvax, diphtheria-tetanus toxoid, Hepatitis
A vaccine, Hepatitis B vaccine, Influenza vaccine, Fluzone, Lyme
disease vaccine, PNEUMOVAX* 23; laxatives, such as Bisacodyl,
Cascara, Docusate, Fleet Phospho-Soda, Glycerin, Lacalutose,
lubiprostone, Magnesium citrate, Magnesium hydroxide--MOM, Mineral
Oil, Pericolace, Psyllium and Senna; low molecular weight heparins,
such as dalteparin, danaparoid, enoxaparin, tinzaparin,
fondaparinux; macrolides, such as Azithromycin, Clarithromycin and
Erythromycin; magnesium, such as magnesium salt; migraine
treatments, such as almotriptan, eletriptan, frovatriptan,
naratriptan, rizatriptan, sumatriptan, zolmitriptan, Cafergot.RTM.,
Cafergot.RTM., dihydroergotamine and Midrin.RTM.; mouth and lip
treatments, such as amlexanox, Benzocaine, carbamide, peroxide,
Kenalog in Orabase.RTM., Phenol, chlorhexidine gluconate,
clotrimazole, Nystatin, Penciclovir, docosanol, Gelclair, lidocaine
viscous, BMX Cocktail, Pilocarpine and Artificial saliva; multiple
sclerosis treatments, such as glatiramer, interferon beta-1A and
interferon beta-1B; muscle relaxants, such as baclofen,
carisprodol, cyclobenzaprine, cyclobenzaprine, Diazepam,
Metaxalone, Methocarbamol, Orphenadrine; nasal preparations, such
as azelastine, beclomethasone, budesonide, cromolyn, desmopressin
acetate, flunisolide, fluticasone, Ipratropium bromide, mometasone,
oxymetazoline, phenylephrine, Saline nasal spray, Sumatriptan,
triamcinolone and Zolmitriptan; urology treatments, such as
Belladonna and opium, flavoxate, hyoscyamine, hyoscyamine,
oxybutynin, solifenacin, tolterodine and trospium; neuromuscular
blockers, such as Atracurium, Cisatracurium, doxacurium,
mivacurium, pancuronium, Rocuronium, Succinylcholine, vecuronium,
Mivacurium, Rapacuronium, Rocuronium, Succinylcholine, Atracurium,
Cisatracurium, Pancuronium, Vecuronium, Doxacurium, Pipecuronium
and Tubocurarine; nitrates, such as Isosorbide dinitrate,
Isosorbide mononitrate, Nitroglycerin ointment, Nitrobid and
Nitroglycerin transdermal; NSAID's, such as Arthrotec, diclofenac,
Etodolac, indomethacin, Ketorolac, Sulindac, Tolmentin Diflunisal
Salsalate Meloxicam, piroxicam, Nabumetone Flurbiprofen, Ibupropen,
Ketoprofen, Naproxen, Oxaprozin, celecoxib, Rofecoxib and
Valdecoxib; ophthalmic agents, such as, proparacaine, tetracaine,
Ciprofloxacin, Erythromycin, Gentamcyin, levofloxacin,
levofloxacin, norfloxacin, Ofloxacin, Polysporin.RTM., Polytrim,
Sulfacetamide, Tobramycin, Blephamide.RTM., Blephamide.RTM.,
Maxitrol.RTM., Pred G.RTM. and TobraDex.RTM., Dexamethasone,
Fluorometholone, Loteprednol, Prednisone, Rimexolone, azelastine,
Cromolyn sodium, emedastine, Epinastine, Ketotifen Fumarate
Ophthalmic Solution 0.025%, Levocabastine, Lodoxamide tromethamine,
Naphazoline, Naphcon-A.RTM., nedocromil, Olopatadine, pemirolast,
Betaxolol, Betaxolol, Levobunolol, Timolol, Brinzolamide,
Dorzolamide, Pilocarpine, bimatoprost, Latanoprost, travoprost,
unoprostone, Apraclonidine, Brimonidine, Cosopt.RTM. and
Cosopt.RTM., Atropine, Cyclopentolate, Homatropine, Phenylephrine,
Phenylephrine, Diclofenac, Flurbiprofen and Ketorolac; ear (otic)
preparations, such as Auralgan.RTM., carbamide peroxide,
CIPRODEX.RTM., Ciprofloxacin and hydrocortisone, Cortisporin.RTM.,
Ofloxacin, Triethanolamine and Vosol Otic.RTM.; opiates, such as
Codeine Fentanyl Hydrocodone Hydrocodone, Meperidine Methadone,
morhphine, xycodone, Propoxyphene, Darvon.RTM., Fioricet, Fiorinal,
Soma compound, Tramadol, Anexsia, Darvocet, Darvon Compound,
Lorcet, Lortab, Percocet, Percodan, Roxicet, Tylenol with Codeine,
Tylox, Vicodin, Wygesic, Buprenorphene, Butorphanol, Dezocine,
Nalbuphine, Pentazocine, Nalmefene Naloxone, Suboxone.RTM. and
Ziconotide; parkinson's disease treatments, such as amantadine,
benztropine, bromocriptine, entacapone, pergolide, pramipexole,
ropinirole, selegiline, Sinemet.RTM., tolcapone and
trihexyphenidyl; PCA--Patient Controlled Analgesia, such as
Fentanyl, Hydromorphone, Meperidine and Morphine; penicillin's,
such as Ampicillin, Ampicillin/sulbactam, Amoxicillin,
Amoxicillin/Clavulanate, Cloxacillin, Dicloxacillin, Nafcillin,
Penicillin G, Penicillin VK, Piperacillin,
Piperacillin/Tazobactamm, Ticarcillin, and Ticarcillin/Clavulanate;
phosphate supplementation, such as, K-Phos.RTM. Neutral Tablets,
K-PHOS.RTM. ORIGINAL, Neutra-Phos.RTM.; potassium supplementation,
such as K-LOR, Klor-Con.RTM., Potassium depletion; prostate cancer
medications, such as bicalutamide, flutamide, goserelin, leuprolide
and nilutamide; proton pump inhibitor's, such as esomeprazole,
Lansoprazole, Omeprazole, Pantoprazole and Rabeprazole Sodium;
psoriasis medications, such as acitretin, alefacept, Anthralin,
Calcipotriene, efalizumab and Tazarotene; renal failure
medications, such as Aluminum Hydroxide, Calcium acetate,
Calcitriol, Doxercalciferol, Ferric Sodium Gluconate, paricalcitol
and sevelamer; pulmonary medications, such as ipratropium,
tiotropium, albuterol, bitolterol, levalbuterol, pirbuterol,
metaproterenol, formoterol, salmeterol, Advair.RTM.,
Symbicort.RTM., beclomethasone, budesonide, flunisolide,
fluticasone, Mometasone furoate, triamcinolone, montelukast
Singulair.RTM., zafirlukast, cromolyn sodium, nedocromil,
acetylcysteine and aminophylline/theophylline; disease modifying
agents, such as adalimumab, anakinra, auranofin, azathioprine,
etanercept, hydroxychloroquine, infliximab, leflunomide,
methotrexate and sulfasalazine; HMG COA reductase inhibitors, such
as Atorvastatin, Fluvastatin, Lovastatin, Pravastatin,
Rosuvastatin, Simvastatin, Advicor.RTM., Vytorin.RTM. and
ezetimibe; stimulants, such as atomoxetine, benzphetamine,
Caffeine, dexmethylphenidate, Dextroamphetamine, diethylpropion,
Methylphenidate, Modafinil, Pemoline, phendimetrizine, phentermine
and sibutramine; tetracyclines such as Doxycycline, Minocycline and
Tetracycline; thrombolytic agents such as Alteplase; anti-thyroid
agents such as methimazole and propylthiouracil; toxicology related
medications such as acetylcysteine, Charcoal, deferoxamine, digoxin
immune fab, flumazenil, fomepizole, methylene blue, naloxone,
sodium polystyrene sulfonate and Sorbitol; anti-mycobacterial
agents such as Ethambutol, Isoniazid, Pyrazinamide, rifabutin,
Rifamate, Rifampin, Rifapentine and Rifater; topical products such
as Alitretinoin, Becaplermin, Calamine, Capsaicin, Doxepin,
lidocaine/prilocaine, fluorouracil, Masoprocol, Pimecrolimus,
Selenium sulfide and Tacrolimus; topical anti-viral agents such as
acyclovir, docosanol, imiquimod, penciclovir, podofilox and
podophyllin; topical antibacterials such as bacitracin,
metronidazole, mupirocin, bacitracin/neomycin/polymyxin,
bacitracin/polymyxin and silver sulfadiazine; topical antifungals
such as butenafine, ciclopirox, clotrimazole, econazole,
ketoconazole, miconazole, naftifine, nystatin, oxiconazole,
terbinafine and tolnaftate; topical anti-parasitic agents such as
Crotamiton, Lindane, Permethrin, pyrethrins and piperonyl butoxide;
topical burn preparations such as mafenide acetate and silver
sulfadiazine; topical corticosteroids such as Aclometasone
diproprionate, Desonide, Flucinolone acetonide, Hydrocortisone,
Betamethasone dipropionate, betamethasone valerate, clocortolone
pivalate, desoximetasone, fluocinolone acetonide, flurandrenolide,
fluticasone propionate, Chydrocortisone butyrate, hydrocortisone
valerate, mometasone furoate, prednicarbate, triamcinolone,
amcinonide, augmented betamethasone dipropionate, betamethasone
dipropionate, desoximetasone, diflorasone diacetate, fluocinolone
acetonide, fluocinonide, halcinonide, clobetasol propionate,
diflorasone diacetate and halobetasol propionate; urology
medications such as pentosan polysulfate, Bethanecol and
phenazopyridine; vaginal preparations such as clindamycin,
metronidazole, butoconazole, clotrimazole, miconazole, terconazole
and tioconazole; vasodilators such as Fenoldopam mesylate,
Hydralazine, Nesiritide, Nicardipine, Nitroglycerin, and Sodium
Nitroprusside; and vasopressors and inotropes such as Dobutamine,
Dopamine, Epinephrine, inamrinone, Milrinone, Norepinephrine,
Phenylephrine, and Vasopressin.
[0041] Examples of food or nutraceutical bioactive agents include,
but are not limited to, constituents in foods or dietary
supplements that are responsible for changes in health status, such
as components of plants, especially fruits and vegetables, e.g.,
soy which contains isoflavones and phytoestrogens, tomatoes which
contain lycopene that may have anticancer properties, berries such
as blueberries and raspberries which contain flavonoids like
anthocyanins that may act as antioxidants, green tea which contains
epigallocatechin gallate (EGCG) that may have anticancer
properties, resveratrol from red grape products as an antioxidant,
soluble dietary fiber products, such as psyllium seed husk for
reducing hypercholesterolemia, broccoli (sulforaphane) as a cancer
preventative, and soy or clover (isoflavonoids) to improve arterial
health. Flavonoids, antioxidants, alpha-linolenic acid from flax
seeds, extracts such as ginseng, garlic oil, etc. Ph modifier
coating may be applied in foods for better nutrient absorption as
well as for improvement of flavor.
[0042] Examples of biological bioactive agents include, but are not
limited to biologically active substances in plants that have
proven (e.g. cholesterol lowering effects of phytosterols) or
potential beneficial effects on health, i.e., phytochemicals or
phytonutrients, in particular phytochemicals in leaves, stems,
roots, tubers, buds, fruits, seeds and flowers, and plant derived
foods and drinks (such as tea, coffee, alcoholic beverages), such
as flavonoids found in a range of plant derived foods including
tea, wine, onions, apples and berries, glucosinolates from
Cruciferous vegetables, phenolic acids in tea and coffee for
example, and carotenoids (some of which are precursors of vitamin
A) prevalent in red, green and orange fruits and vegetables.
[0043] Examples of antigen bioactive agents include, but are not
limited to exogenous antigens, endogenous antigens, autoantigens
and tumor antigens. Exogenous antigens are antigens that have
entered the body from the outside, for example by inhalation,
ingestion, or injection. By endocytosis or phagocytosis, these
antigens are taken into the antigen-presenting cells (APCs) and
processed into fragments. APCs then present the fragments to T
helper cells (CD4.sup.+) by the use of class II histocompatibility
molecules on their surface. Some T cells are specific for the
peptide:MHC complex. They become activated and start to secrete
cytokines. Cytokines are substances that can activate cytotoxic T
lymphocytes (CTL), antibody-secreting B cells, macrophages, and
other particles. Endogenous antigens are antigens that have been
generated within the cell, as a result of normal cell metabolism,
or because of viral or intracellular bacterial infection. The
fragments are then presented on the cell surface in the complex
with MHC class I molecules. If activated cytotoxic CD8.sup.+T cells
recognize them, the T cells begin to secrete various toxins that
cause the lysis or apoptosis of the infected cell. In order to keep
the cytotoxic cells from killing cells just for presenting
self-proteins, self-reactive T cells are deleted from the
repertoire as a result of tolerance (also known as negative
selection). They include xenogenic (heterologous), autologous and
idiotypic or allogenic (homologous) antigens. An autoantigen is
usually a normal protein or complex of proteins (and sometimes DNA
or RNA) that is recognized by the immune system of patients
suffering from a specific autoimmune disease. These antigens
should, under normal conditions, not be the target of the immune
system, but, due to mainly genetic and environmental factors, the
normal immunological tolerance for such an antigen has been lost in
these patients. Tumor antigens or Neoantigens are those antigens
that are presented by MHC I or MHC II molecules on the surface of
tumor cells. These antigens can sometimes be presented by tumor
cells and never by the normal ones. In this case, they are called
tumor-specific antigens (TSAs) and, in general, result from a
tumor-specific mutation. More common are antigens that are
presented by tumor cells and normal cells, and they are called
tumor-associated antigens (TAAs). Cytotoxic T lymphocytes that
recognize these antigens may be able to destroy the tumor cells
before they proliferate or metastasize. Tumor antigens can also be
on the surface of the tumor in the form of, for example, a mutated
receptor, in which case they will be recognized by B cells.
[0044] Examples of botanical bioactive agents include, but are not
limited to PMI-004 (advanced botanical formulation for type II
diabetes that represents a multi-mechanism bioactive that: 1) in
adipocytes increases adiponectin secretion, 2) in the liver lowers
PEPCK expression, and 3) in muscle cells increases cellular
signaling through the insulin receptor pathway, increasing glucose
uptake, glycogen synthase, and glycogen accumulation), PMI-005
(botanical bioactive, derived from a common vegetable, that
inhibits gene expression of a variety of pro-inflammatory cytokines
(including a-TNF, i-NOS, IL-1b, and COX-2) that are currently
undergoing a human clinical trial in osteoarthritis may also may
have utility in the management of severe/life threatening
inflammatory conditions, such as in the management of the septic
patient), PMI-006 (botanical bioactive, derived from a spice, that
inhibits a range of inflammation-related enzymes (including a-TNF
and COX-2) and also possesses range of novel bioactivities related
to both lipid and glucose metabolism (RXR receptors)), PMI-007 (a
powerful, centrally acting, botanical appetite suppressor which
acts via a unique central pathway in the nutrient-sensing
hypothalamic neurons by increasing ATP content/production,
possesses potent anorectic activity without typical CNS appetite
suppressor side effects and pre-clinical data for which has shown
that the agent suppresses both appetite and reduces weight in
animal models, while there is supporting clinical evidence of human
efficacy), PMI-008 (botanical bioactive, derived from an
agricultural waste processing stream, that blocks fat
accumulation/absorption and promotes weight loss via interaction
with a variety of lipases including PL, LPL, and HSL), and PMI-016
(a powerful, plant-derived anabolic/ergogenic agent, with no
androgenic side effects; could be used in a range of human muscle
wasting disorders, including those associated with both cancer and
AIDS, as well as general aging (sarcopenia); has been shown to
induce protein synthesis in muscle cells (similar to IGF) and
promote a reduction in protein degradation, while it has also been
shown to increase growth hormone gene transcription and decrease in
ubiquitin protein ligase gene transcription; and shows no binding
to testosterone receptor in contrast to anabolic steroids).
Examples of botanical bioactive agents also include tobacco and all
tobacco extracts, as well as nicotine itself.
[0045] The FDA defines drugs as products that "cure, treat,
mitigate or prevent disease or that affect the structure or
function of the human body." Cosmetic products are defined by the
FDA as "articles intended to be rubbed, poured, sprinkled, or
sprayed on, introduced into, or otherwise applied to the human body
. . . for cleansing, beautifying, promoting attractiveness, or
altering the appearance." Although cosmaceutical products have
properties of both groups, the FDA lumps them under the definition
of cosmetics, and they are not recognized as a distinct category.
Because cosmaceutical products are not included in the FDA's
definition of drugs, they are not subject to the same regulations,
restrictions, and testing.
[0046] The following materials were used in each of the examples
below: Hydroxypropylmethylcellulose (HPMC) 4,000 cps, Spectrum
Chemical; Malic Acid Powder from Spectrum Chemical; Caustic soda
liquid 50% concentration Rayon grade from Tilley Chemical; Calcium
carbonate powder, (brand name CalEssence 80) from Specialty
Mineral; Calcium silicate (brand name Hubersob 600) from Akrochem;
Malic acid from Spectrum Chemicals; Prehydrated Xantham Gum from
Tic Gums; Confectioner sugar from Domino; and Corn starch from
Market Pantry. We used a pH meter pH 5 Acorn series from
Oakton.
EXAMPLE A
[0047] Example A comprises an orally dissolvable tablet (i.e. a
quick dissolve tablet) that was coated with a rapid release coating
to rapidly modulate saliva pH.
[0048] We started with Children's Benadryl Allergy FastMelt Cherry
flavor that had a starting mass of 605 mg. This was simply a test
mule. We then created an acid dipping solution comprised of: water
87%, malic acid 12%, HPMC 1%. Using an Oakton pH meter, this pH of
this solution was measured at pH 2.03. We also created an acid
powder coating comprising confectioner sugar 50% and malic acid
50%.
[0049] Separately, we created a base dipping solution, comprised of
water 91%, caustic soda 8%, HPMC 1% (pH 13.1). We also created a
base powder coating compromised of calcium carbonate 29%, calcium
silicate 29%, caustic soda 42%
[0050] To make the foregoing, the following mixing procedures were
used.
[0051] For liquid dipping solutions: weigh and add ingredients to
water and mix vigorously until HPMC is completely dissolved and
wait until solution is clear without lumps and bubbles.
[0052] For powder coating mixes: weigh and add ingredients together
and mix until ingredients are well dispersed.
[0053] In the base powder coating, calcium silicate is used as an
absorbent for the liquid caustic soda.
[0054] We then employed the following coating procedure. First, dip
tablet in liquid solution and remove quickly, shake off excess
liquid and allow dry at room temperature. Second before tablet is
completely dry, roll tablet in powder coating, shake off excess
coating and let dry fully. The weight of tablets after coating was
640 to 650 mg.
[0055] The following test was then made by a healthy male
volunteer: 1) rinse mouth with water. 2) Accumulate saliva in
mouth. 3) Insert tablet in mouth and let stand for 10 seconds to
mix with saliva. 4) Insert pH meter probe in mouth and take
reading.
[0056] The results were as follows. Saliva in mouth at starting
point: pH 6.4 Saliva with non-coated tablet after ten seconds: pH
6.22. Saliva with acid coated tablet after ten seconds: pH 2.94.
Saliva with base coated tablet after ten: pH 9.13
[0057] Thus, it was demonstrated that a quick dissolve tablet could
be effectively coated with a rapid release coating that will
rapidly modulate the pH of saliva. This coating worked by to
increase and decrease pH (in separate embodiments).
EXAMPLE B
[0058] Example B comprises a conventional tablet that was coating
with a rapid release coating to modulate pH.
[0059] The tablet used was Tylenol 8 hr muscle aches and pain.
Again, this was simply used as a test mule and not for its
Henderson Hasselbach absorptive profile.
[0060] Using the same procedures as with Exhibit A, we made a base
coating solution comprising: water 91%, caustic soda 8%, HPMC (4000
cps) 1%. The resulting base coating solution pH was: 13.1.
[0061] The procedures followed were: 1) Add caustic soda and HPMC
to water (water pH 7.5). 2) Mix vigorously to dissolve HPMC 3) Wait
until caustic coating solution is clear without bubbles and lumps.
4) Dip tablet in solution and remove immediately. 5) Drain extra
solution off tablet. 6) Let tablet dry in ambient room
conditions.
[0062] A healthy male volunteer tested the tablet as follows: 1)
Rinse mouth with water. 2) Accumulate saliva in mouth. 3) Insert pH
meter probe in mouth and take reading: pH 6.8. 4) Insert tablet in
mouth and let stand for 10 seconds to mix with saliva. 5) Insert pH
meter probe in mouth and take reading : pH 8.9
EXAMPLE C
[0063] Example C comprises a thin film coated with a rapid release
coating to rapidly modulate pH.
[0064] We purchased Novartis Triaminic thin strips for children,
cough & runny nose. Again, this was simply used as a test mule
dosage unit. We weighed the unmodified thin film and found a mass
of 50 mg. To determine a pH, we dissolved two strips in 5 grams of
water and obtained a reading using an Oakton pH meter of 9.05.
[0065] We first attempted to use a liquid coating as was used in
Example A but we experienced difficulty in that we were tending to
dissolve the strip. So we decided instead to use only a simple
powder coating, comprising 50% confectioner sugar and 50% malic
acid. Using a healthy male volunteer and an Oakton pH meter, we
determined an initial pH saliva in mouth: 6.30. The pH of saliva in
mouth was found to be 6.46 after dissolving one virgin piece in
mouth (i.e., a strip without coating). The pH of saliva in the
mouth was measured at: 4.68 ten seconds after dissolving one
slightly coated piece (coated film weight: 65 grams). The pH of
saliva in the mouth was measured at 4.14 ten seconds after
dissolving one heavier coated piece (coated film weight: 90
grams).
EXAMPLE D
[0066] For Example D, we purchased Swedish Snus brand General
original with no flavor. This was a test mule. We made a coating
solution by mixing the following ingredients: water 91%, caustic
soda 8%, HPMC 1% (after mixing, we measured the solution's pH to be
13.06). For reference the city water used had a pH of: 7.45.
[0067] The Snus pouch weight as purchased was 0.973 gram. We dipped
two Snus pouches in the coating solution, after which they each
weighed approximately 1.364 g (they were measured without being
dried).
[0068] We used the following testing method: 1) put 2 virgin
pouches in container and add 10 gram of city water; 2) soak for 10
minutes while squeezing pouches without braking them, Temp: 22.4
centigrade; 3) repeat same procedure with 2 coated pouches, Temp:
22.9 centigrade.
[0069] The test results were as follows: for the uncoated pouches:
pH: 7.94; and for the coated pouches: pH: 11.02.
[0070] The above test was done for matters of convenience in a way
that was different from the Examples of A, B, and C. However, it
was concluded that coating a tobacco pouch would have the same
rapid effect on pH that was seen in the other examples.
[0071] It is readily seen from the tobacco example that the present
invention can be applied to various cannabis products, whether
through the use of loose cannabis in a pouch used in the mouth, or
the use of cannabis or a cannabis derived extract or by product
contained in a conventional solid dosage form.
EXAMPLE E
[0072] A liquid solution was made by combining 100 grams water and
1 gram Swallow Easy.TM. formula, comprised of 4 parts sugar and one
part Tic xantham gum. To this solution was added 1 gram of malic
acid. The pH of the solution was measured at 2.77. A healthy male
volunteer measured his saliva pH for a baseline measurement of
6.81. Then, he allowed the solution to soak in his mouth akin to a
mouthwash rinse for 5 seconds. He then measured the pH of his
saliva at 4.59.
* * * * *
References