U.S. patent application number 11/255555 was filed with the patent office on 2007-04-26 for compositions and methods of making rapidly dissolving lonically masked formulations.
This patent application is currently assigned to PFab LP. Invention is credited to Russell Lee McMahen, Mark Tengler.
Application Number | 20070092553 11/255555 |
Document ID | / |
Family ID | 37985648 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070092553 |
Kind Code |
A1 |
Tengler; Mark ; et
al. |
April 26, 2007 |
Compositions and methods of making rapidly dissolving lonically
masked formulations
Abstract
The present invention includes compositions and methods for
reduce the taste of the drug in the drug resin complex. The
composition may include one or more drug-resin complexes and a
highly compressible, free-flowing pharmaceutical excipient. The
resin is present in an amount effective to reduce the taste of the
drug in the drug resin complex relative to an otherwise identical
pharmaceutical composition without the resin; and wherein the
highly compressible, free-flowing pharmaceutical excipient causes
release of the drug-resin complex in the mouth.
Inventors: |
Tengler; Mark; (Colleyville,
TX) ; McMahen; Russell Lee; (Flower Mound,
TX) |
Correspondence
Address: |
CHALKER FLORES, LLP
2711 LBJ FRWY
Suite 1036
DALLAS
TX
75234
US
|
Assignee: |
PFab LP
Grand Prairie
TX
|
Family ID: |
37985648 |
Appl. No.: |
11/255555 |
Filed: |
October 21, 2005 |
Current U.S.
Class: |
424/440 ;
424/451; 424/78.14 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 31/785 20130101; A61P 35/00 20180101; A61K 47/58 20170801;
A61K 47/59 20170801; A61K 31/137 20130101; A61P 9/00 20180101; A61K
31/4402 20130101; A61K 47/585 20170801; A61P 21/02 20180101; A61K
31/74 20130101; A61P 31/00 20180101; A61K 31/46 20130101; A61K
9/0002 20130101; A61P 29/00 20180101; A61P 11/00 20180101; A61K
47/26 20130101; A61P 25/16 20180101 |
Class at
Publication: |
424/440 ;
424/451; 424/078.14 |
International
Class: |
A61K 31/785 20060101
A61K031/785; A61K 9/68 20060101 A61K009/68; A61K 9/48 20060101
A61K009/48 |
Claims
1. A taste-masked pharmaceutical composition comprising: a
drug-resin complex and a highly compressible, free-flowing
pharmaceutical excipient, wherein the resin is present in an amount
effective to reduce the taste of the drug in the drug resin complex
by more than about 15 percent relative to an otherwise identical
pharmaceutical composition without the resin; and wherein the
highly compressible, free-flowing pharmaceutical excipient aids
release of the drug-resin complex in the mouth.
2. The composition of claim 1, wherein the composition comprises a
chewable tablet, a solid, a dissolvable or disintegrating tablet, a
liquid, a gel, a tab, a capsule, a powder, a lotion, a cream, a
gum, a lozenge and combinations thereof.
3. The composition of claim 1, wherein the drug in the drug-resin
complex comprises dextromethorphan, codeine, morphine, hydrocodone,
hyoscyamine, moguisteine, pseudoephedrine chlorpheniramine,
phenylpropanolamine, pharmaceutically acceptable salts of the same
and combinations thereof.
4. The composition of claim 1, wherein the pharmaceutical
composition is suitable for oral administration.
5. The composition of claim 1, further comprising one or more
flavorants, sweeteners, coolants, dyes, or combinations and
mixtures thereof.
6. The composition of claim 1, further comprising one or more
excipients, one or more binders or combinations and mixtures
thereof.
7. The pharmaceutical of claim 1, wherein the drug-resin complex
comprises polistirex, polyacrilex and combinations thereof.
8. The pharmaceutical of claim 1, wherein the drug-resin complex
comprises pseudoephedrine polistirex and chlorpheniramine
polyacrilex.
9. The pharmaceutical of claim 1, wherein the resin in the
drug-resin complex comprises one or more cationic exchange
resins.
10. The pharmaceutical of claim 1, wherein the drug-resin complex
comprises a divinylbenzene sulfonic acid cationic exchange
resin.
11. The pharmaceutical of claim 1, wherein the composition
comprises a hardness of between about 5 and about 15 kPa.
12. The pharmaceutical of claim 1, wherein the composition has at
least about 20 percent better mouth-feel.
13. The pharmaceutical of claim 1, wherein the drug-resin complex
comprises a diffusion barrier coating.
14. The pharmaceutical of claim 13, wherein the diffusion barrier
coating is a time release coating.
15. A rapidly dissolving or disintegrating, taste-masked
pharmaceutical composition comprising: a drug-resin complex and a
compressible, free-flowing, pharmaceutical, taste-masking
excipient, wherein the resin is present in an amount effective to
reduce the taste of the drug in the drug resin complex relative to
an otherwise identical pharmaceutical composition without the
resin; and wherein the highly compressible, free-flowing
pharmaceutical excipient causes release of the drug-resin complex
in the mouth.
16. The pharmaceutical of claim 15, wherein the drug-resin complex
comprises polistirex, polyacrilex and combinations thereof.
17. The pharmaceutical of claim 15, wherein the drug-resin complex
comprises pseudoephedrine polistirex and chlorpheniramine
polyacrilex.
18. A chewable tablet comprising: a pharmaceutically active
drug-resin complex, whereby the pharmaceutically active ingredient
is slowly released when the tablet is chewed, the tablet becoming
thixotropic when chewed but not fully dissociating for at least 30
seconds when chewed, and the tablet slowly dissociates when the
tablet is chewed, so as to completely dissociate thereafter once
swallowed; and one or more amorphous sugars.
19. The pharmaceutical of claim 18, wherein the pharmaceutically
active drug-resin complex comprises polistirex, polyacrilex and
combinations thereof.
20. The pharmaceutical of claim 18, wherein the pharmaceutically
active drug-resin complex comprises pseudoephedrine polistirex and
chlorpheniramine polyacrilex.
21. The composition of claim 18, further comprising one or more
flavorants, sweeteners, coolants, dyes, or combinations and
mixtures thereof.
22. The composition of claim 18, further comprising one or more
excipients, one or more binders or combinations and mixtures
thereof.
23. A taste-masked chewable pseudoephedrine and chlorpheniramine
pharmaceutical composition comprising: a pseudoephedrine-resin
complex; a chlorpheniramine-resin complex; one or more amorphous
sugars; and a compressible, free-flowing, pharmaceutical,
taste-masking excipient, wherein the highly compressible,
free-flowing pharmaceutical excipient aids release of the
drug-resin complex in the mouth.
24. The pharmaceutical of claim 23, wherein the
pseudoephedrine-resin complex, chlorpheniramine-resin complex or
both comprise a polistirex resin, a polyacrilex resin and
combinations thereof.
25. A rapidly dissolving, taste-masked hyoscyamine pharmaceutical
composition comprising: a hyoscyamine-resin complex, whereby the
hyoscyamine is released when the tablet disintegrates; and one or
more amorphous sugars; and a compressible, free-flowing,
pharmaceutical, taste-masking excipient.
26. The composition of claim 25, further comprising one or more
flavorants, sweeteners, coolants, dyes, or combinations and
mixtures thereof.
27. The composition of claim 25, further comprising one or more
excipients, one or more binders or combinations and mixtures
thereof.
28. A taste-masked chewable pseudoephedrine and chlorpheniramine
pharmaceutical composition comprising: a pseudoephedrine-resin
complex; a chlorpheniramine-resin complex; one or more amorphous
sugars; and a compressible, free-flowing, pharmaceutical,
taste-masking excipient, whereby the pseudoephedrine and the
chlorpheniramine are slowly released when the composition is
chewed, the composition becoming thixotropic when chewed but not
fully dissociating for at least 10 seconds when chewed, and the
composition slowly dissociates when the composition is chewed, so
as to fully dissociate after the mixture is swallowed.
Description
FIELD OF INVENTION
[0001] The invention relates to compositions and methods of making
rapidly disintegrating or chewable, sustained-release formulations,
and more particularly, to compositions and methods for making
rapidly disintegrating ionically masked formulations.
BACKGROUND OF THE INVENTION
[0002] Without limiting the scope of the invention, its background
is described in connection with ionically masked pharmaceutical
agents that are rapidly disintegrating and delivered in an extended
or sustained-release form, as an example.
[0003] Methods for sustained release are known in the art. One such
method of making sustained release particles is taught in U.S. Pat.
No. 6,120,787, issued to Gustafsson, et al., which teach a method
for preparing parenterally administrable sustained release
microparticles. The method includes preparing core particles in an
aqueous medium that is essentially free from organic solvent and
the biologically active substance is entrapped therein during or
after preparation, e.g., drying the core particles. The coating may
be the same release-controlling polymer, which is added by an air
suspension technique to create a shell on the core particles
without any detrimental exposure of the active substance to organic
solvent.
[0004] Another sustained-release composition includes an amorphous
polymer as taught in U.S. Pat. No. 6,613,358, issued to Randolph,
et al., which provides for a sustained release composition of a
pharmaceutical substance that includes: a biocompatible polymer
that is highly amorphous and a pharmaceutical substance in a
hydrophobic ion complex with an amphiphilic material. A compressed
antisolvent method for manufacturing the composition it also
taught, as are various product forms incorporating the composition
and various uses for the composition.
[0005] Yet another sustained release drug formulation is taught in
U.S. Pat. No. 5,980,945, issued to Ruiz in which a sustained
release drug formulation includes a drug; a biodegradable polymer
that is insoluble in water; and an oil vehicle in which both the
drug and the polymer are dissolved. The oil vehicle may contain
10-100% by volume of a pharmaceutically acceptable oil and 0-90% by
volume of a pharmaceutically acceptable liquid carrier for the drug
or the polymer.
[0006] Finally, U.S. Pat. No. 5,674,533 issued to Santus, et al.,
teaches pharmaceutical compositions for the controlled release of
the anti-tussive, moguisteine, in a liquid suspension designed
either as ready-to-use and time-stable liquid formulations with a
shelf-life of at least two years, or as dry formulations that are
reconstituted with water when needed and then remain stable
throughout the treatment period. Santus teaches the use of coated
microgranules for the controlled release of moguisteine having
sizes ranging from 50 to 500 .mu.m, preferably from 90 to 300
.mu.m, which are capable of remaining easily in suspension in a
liquid for extended times. The microgranules have a moguisteine
core, with one or more optional plasticizers and excipients,
granulated into microgranules having sizes smaller than 500 .mu.m,
uniform surfaces, substantially spherical shapes, apparent
densities of about 500 to 600 g/l and very low friabilities, which
are made by wet-kneading micronised moguisteine using water or a
mixture of water and other solvents. These initial microgranules
have controlled-release properties by, a first coating having
essentially hydrophilic characteristics, which isolates the
microgranules; followed by a second coating having lipophilic
characteristics on top of the first coating; and a third coating
having hydrophilic characteristics.
[0007] Orally administered drug formulations may be provided to the
patient in many dosage forms, including solid forms (e.g.,
capsules, caplets, effervescent or tablets) and liquid forms (e.g.,
solutions, syrups, emulsions or suspensions). Generally, orally
administered drug formulations administered in solid dosage form
are intended to be swallowed whole and any disagreeable taste can
be easily masked with an exterior coating. However, some
formulations are designed for rapid absorption of the active
ingredient through the oral mucosa, e.g., chewing of the tablets,
effervescent, and the like and thus result in tastes that are more
difficult to mask. A growing market for these and other products is
the pediatric and geriatric patients.
[0008] Many pharmaceutical compositions must be formulated as
liquids for use by pediatric, geriatric patients, disabled persons,
incapacitated patients and persons with dysphagia often have
trouble swallowing. To alleviate this challenge a number of drug
delivery protocols have been developed including rapid in-mouth
disintegrating tablets, tablets which disintegrate in liquid prior
to ingestion, liquids and syrups, gums and transdermal
compositions. Unfortunately, these delivery methods can pose their
own problems.
[0009] For example, immediate release compositions with rapid
absorption of the active ingredient through the oral mucosa (e.g.,
rapid in-mouth disintegrating tablets, tablets that disintegrate in
liquid prior to ingestion, liquids and syrups, gums) may have an
unpleasant texture or even an unpalatable taste associated with the
immediate release agent or other component of the composition.
SUMMARY OF THE INVENTION
[0010] The present inventors recognized that certain drugs produce
an unpalatable taste associated with the immediate release agent
that are not effectively masked by traditional taste masking
techniques. The present invention addresses the problems associated
with the delivery of one or more active agents in a solid dosage
form under controlled conditions. Solid, chewable formulations are
often preferred by many users due to the easy of delivery, namely,
natural chewing and swallowing thereby leading to increased
compliance with dosing regimens. Many children and adults fail to
comply with dosing instructions due to the size, shape, taste
and/or mouth-feel of, e.g., tablets, caplets and even gelcaps.
[0011] The present inventors further recognized that delivery of
agents in a chewable formulation is not always preferred by users
because of the taste and/or mouth feel of the active agents and/or
excipients often included with chewable formulations. What is
needed are formulations that are manufactured using commonly used
equipment, are shelf-stable have improved mouth-feel (e.g., less
grainy, bitter or slimy) and provide actual controlled, sustained,
mixed or modified release. Finally, it was recognized that despite
many decades of research and development, controlled-release
formulations have not been amenable to large-scale production in
facilities and to amounts that are permissible for industrial
applicability of controlled-release chewable formulations. However,
despite the many known techniques for eliminating the problems
commonly associated with the manufacture of chewable formulations,
and hence their widespread failure, none of these formulations have
solves the problems of patient compliance due to taste and mouth
feel.
[0012] More particularly, the present invention includes
compositions and methods for preparing a chewable,
controlled-release formulation by blending one or more controlled
release microbeads having one or more active agents with one or
more microbeads. The one or more microbeads may include an enteric
coat, a resin coat, a lacquer coat, a pH-sensitive coating, a
biodegradable polymer matrix, a water soluble matrix, an ionic
matrix, combinations and mixtures thereof. The one or more
microbeads may also include one or more polymers selected from
cellulose, ethylcellulose, methylcellulose, propylcellulose,
methoxypropylcellulose, cellulose nitrate, poly(vinyl alcohol),
poly(vinyl chloride), polystyrene, polyethylene, polypropylene,
poly(ethylene-co-vinyl acetate), poly(hydroxybutyric acid),
poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic
acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid),
poly(.epsilon.(-caprolactones),
poly(.epsilon.-caprolactone-co-DL-lactic acid), poly(maleic
anhydride), polyamides, gelatin, chitosan, collagen,
poly(hydroxyalkyl)-L-glutamines,
poly(.gamma.-ethyl-L-glutaminate-co-glutamic acid),
poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamic acid),
poly(alkyl 2-cyanoacrylates), polyurethanes, poly(methyl
methacrylate), poly(methyl methacrylate-co-methacrylic acid) and
poly(methacrylate-co-hydroxypropyl methacrylate), polystyrene,
polistirex, polacrilex and salts, combinations and mixtures
thereof.
[0013] The present invention may be, e.g., a taste-masked soluble
chewable pseudoephedrine and chlorpheniramine pharmaceutical
composition. The composition includes a pseudoephedrine-resin
complex, a chlorpheniramine-resin complex and one or more amorphous
sugars. The composition may be a compressible, free-flowing,
pharmaceutical, taste-masking excipient, wherein the highly
compressible, free-flowing pharmaceutical excipient aids the
release of the drug-resin complex in the mouth.
[0014] The present invention provides a method of masking the taste
of a rapidly disintegrating or chewable, taste-masked
pharmaceutical composition by adding one or more amorphous sugars
to a pharmaceutically active drug-resin complex. A taste-masked
soluble chewable composition may include pseudoephedrine and
chlorpheniramine in a therapeutically effective amount formed into
a pharmaceutical composition. The composition may include a
pseudoephedrine-resin complex, a chlorpheniramine-resin complex,
one or more amorphous sugars and a compressible, free-flowing,
pharmaceutical, taste-masking excipient. The pseudoephedrine and
the chlorpheniramine are slowly released as the composition is
chewed. The composition becoming thixotropic when chewed but not
fully dissolving for at least 10 seconds, so as to dissolve
thereafter in saliva during chewing.
[0015] The present invention includes a rapidly dissolving,
taste-masked hyoscyamine pharmaceutical composition. The
composition includes a hyoscyamine-resin complex, one or more
amorphous sugars and a compressible, free-flowing, pharmaceutical,
taste-masking excipient. The hyoscyamine is released slowly when
the tablet disintegrates or is chewed. The rapidly disintegrating,
taste-masked pharmaceutical composition may include any salt of
hyoscyamine, e.g., an ionically bound hyoscyamine. The composition
may be a hyoscyamine-resin complex and one or more amorphous
sugars. The hyoscyamine is released slowly when the composition is
chewed, the composition becoming thixotropic when chewed but not
fully dissolving for at least 30 seconds when chewed, and the
composition slowly dissociates when chewed, to substantially
dissociate thereafter in saliva during chewing.
[0016] The present invention includes a chewable tablet in which a
pharmaceutically active drug-resin complex is slowly released when
the tablet is chewed. As the tablet is chewed it becomes
thixotropic but not fully dissociated for at least 10 seconds. The
tablet may slowly dissociate thereafter in saliva during chewing or
once swallowed for up to 24 hours. The chewable formulation may
include a portion of the one or more beads with an immediate
release profile and another portion with a controlled or delayed
release profile. In one example, the active agent may be included
in two different salt forms or on two different resins, wherein the
active agent is differentially released or becomes dissolved and/or
bioavailable at a different rate from the second salt or released
from the second bead. When using an ion-exchange matrix, bead or
resin to retain the one or more active agents the liquid solution
will in some cases be a low-ionic strength, depending on the nature
of the ion-exchange matrix and the one or more active agents. Based
on the present disclosure, the skilled artisan may easily determine
the best matrix for a particular active, determine the amount of
loading (theoretical and empirical), and the conditions for
retention and release.
[0017] Examples of active agents that may be provided as part of
the chewable formulations of the present invention include
vitamins, minerals, nutritional supplements, herbal extracts, gums,
gels, oils, salts, mixtures and combinations thereof.
Pharmaceutical active agents may include, e.g., protein, peptide,
carbohydrate, polysaccharide, glycoprotein, lipid, hormone, growth
factor, cytokine, interferon, receptor, antigen, allergen,
antibody, antiviral, antifungal, antihelminthic, substrate,
metabolite, cofactor, inhibitor, drug, nutrient, toxin, poison,
explosive, pesticide, chemical warfare agent, biowarfare agent,
biohazardous agent, infectious agent, prion, radioisotope, vitamin,
heterocyclic aromatic compound, carcinogen, mutagen, narcotic,
amphetamine, barbiturate, hallucinogen. In some cases the chewable
may be, eg., a vaccine for against a virus, bacterium, helminth
and/or fungi, fragments, receptors or toxins thereof, e.g.,
Salmonella, Streptococcus, Brucella, Legionella, E. coli, Giardia,
Cryptosporidium, Rickettsia, spore, mold, yeast, algae, amoebae,
dinoflagellate, unicellular organism, pathogen, cell, combinations
and mixtures thereof. The one or more active agents may be a
pharmaceutical agent, an enzyme, a cytokine, a growth promoting
agent, an antibody, an antigen, a hormone, a vaccine, a cell, a
live-attenuated pathogen, a heat-killed pathogen, a virus, a
bacteria, a fungi, a peptide, a carbohydrate, a nucleic acid, a
lipid, mixtures and combinations thereof.
[0018] Specific examples of active agents include: steroids,
respiratory agents, sympathomimetics, local anesthetics,
antimicrobial agents, antiviral agents, antifungal agents,
antihelminthic agents, insecticides, antihypertensive agents,
antihypertensive diuretics, cardiotonics, coronary vasodilators,
vasoconstrictors, .beta.-blockers, antiarrhythmic agents, calcium
antagonists, anti-convulsants, agents for dizziness, tranquilizers,
antipsychotics, muscle relaxants, drugs for Parkinson's disease,
respiratory agents, hormones, non-steroidal hormones, antihormones,
vitamins, antitumor agents, miotics, herb medicines, herb extracts,
antimuscarinics, interferons, immunokines, cytokines, muscarinic
cholinergic blocking agents, mydriatics, psychic energizers,
humoral agents, antispasmodics, antidepressant drugs,
anti-diabetics, anorectic drugs, anti-allergenics, decongestants,
expectorants, antipyretics, antimigrane, anti-malarials,
anti-ulcerative, anti-estrogen, anti-hormone agents, anesthetic
agent, or drugs having an action on the central nervous system. For
example, for use in the treatment of cold/cough symptoms the active
agents may include one or more antihistamines, anti-tussives,
expectorants and the like, e.g., hyoscyamine, pseudoephedrine,
chlorpheniramine, dextromethorphan, guaifenesin, and salts thereof
or mixtures of salts thereof. The chewable formulation may also
include an analgesic or even a narcotic.
[0019] Examples of carriers for the actives of the present
invention include any degradable, partially degradable or
non-degradable and generally biocompatible polymer, e.g.,
polystirex, polypropylene, polyethylene, polacrilex, poly-lactic
acid (PLA), poly-glycolic acid (PGA) and/or poly-lactic
poly-glycolic acid (PGLA) in the form or a matrix or even a
bead.
[0020] The present invention also includes those chewable
formulations made by the methods disclosed and claimed herein. For
example, specific chewable formulation may include one or more
active agents available for immediate, modified and/or extended or
controlled release for use in treating cold/cough/allergy symptoms.
The one or more actives for cold/cough/allergy may include one or
more of the following: anti-tussives, anti-histamines, expectorants
and analgesics. For example, the actives may include hyoscyamine,
pseudoephedrine, chlorpheniramine, dextromethorphan, guaifenesin,
and salts thereof or mixtures of salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0021] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0022] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. The terminology herein is used to describe
specific embodiments of the invention, but their usage does not
delimit the invention, except as outlined in the claims.
[0023] Pharmaceutically active agents can be administered to the
patient in many forms with oral administration being the most
popular as liquid solutions, emulsions, suspensions or in solid
form such as capsules or tablets. The oral administration is
problematic for some individual (e.g., infants, children and older
persons) that are unable to swallow whole tablets and capsules.
Therefore, it is desirable to administer doses in a liquid form, a
dissolvable form, a chewable form or in a form that are absorbed
through the oral mucosa.
[0024] Unlike tablets or capsules which are intended to be
swallowed whole, forms that are absorbed through the oral mucosa
must be formulated to take into account the taste of the active
ingredient. Some therapeutic agents can cause strong negative
sensory perceptions in the mouth due to their delivery through the
mucosa. Often the sensory perceptions are so objectionable that a
patient stops taking the medicine. In such cases, the use of
conventional sweetener/flavor approach is not sufficient to mask or
hide these negative perceptions. Conventional sweeteners and/or
flavors are commonly used to prevent the taste from being apparent
during the time that the medicine is in the mouth.
[0025] The present invention may be used to taste-mask a wide range
of chemicals in a formulation depending on the predominant,
secondary and tertiary taste. The selection of two, three or more
masking agents may be modified, without undue experimentation, by
comparing the most common predominant, secondary and tertiary
flavors or taste of the one or more actives. Differences may also
be determined between children and adults (e.g., changes in
sweetness thresholds), males and females and in accordance with the
flavor of the final composition (e.g., cherry versus grape).
[0026] The sense of taste caused by the excitation of taste
receptors on the tongue. The tongue includes receptors for a large
number of specific chemicals have been identified that contribute
to the reception of taste, e.g., chemicals as sodium, potassium,
chloride, glutamate and adenosine. Despite this complexity, five
types of tastes are commonly recognized: Salty, Sour, Sweet, Bitter
and Umami. The umami taste is that of monosodium glutamate and has
recently been recognized as a unique taste, as it cannot be
elicited by any combination of the other four taste types.
Glutamate is present in a variety of protein-rich foods, and
particularly abundant in aged cheese.
[0027] The perception of taste may also be influenced by thermal
stimulation of the tongue. For example, in some people, warming the
front of the tongue produces a clear sweet sensation, while cooling
leads to a salty or sour sensation. Tastes are based on human
sensations and some physiologists believe that each animal probably
has its own perception of taste.
[0028] As used herein, the terms "extended release," "sustained
release," and "delayed release" are used to define a release
profile to effect delivery of an active over an extended period of
time, defined herein as being between about 60 minutes and about 2,
4, 6, 8 or even 12 hours. Extended release may also be defined
functionally as the release of over 80 to 90 percent (%) of the
active ingredient after about 60 minutes and about 2, 4, 6 or even
8 hours. Extended release as used herein may also be defined as
making the active ingredient available to the patient or subject
regardless of uptake, as some actives may never be absorbed by the
animal. Various extended release dosage forms may be designed
readily by one of skill in art as disclosed herein to achieve
delivery to both the small and large intestines, to only the small
intestine, or to only the large intestine, depending upon the
choice of coating materials and/or coating thickness.
[0029] As used herein, the term "USP" is used to describe the
United States Pharmacopoeia a widely recognized organization that
sets some of the standards that pharmaceutical manufacturers must
meet to sell their drugs and drug compounds in the United States.
USP standards include procedures for the physical tests that must
be performed on drugs and drug compounds to ensure compliance with
the specific requirements set forth within these standards.
[0030] As used herein, the term "pharmaceutically acceptable salts"
is used to describe those salts in which the anion (or cation) does
not contribute significantly to the toxicity or pharmacological
activity of the salt, and, as such, they are the pharmacological
equivalents of the bases of the compounds to which they refer.
Examples of pharmaceutically acceptable acids that are useful for
the purposes of salt formation include but are not limited to
hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic,
mandelic, fumaric, succinic, phosphoric, nitric, maleic, mucic,
isethionic, palmitic, tannic and others. The active salt
combinations of the pharmacologic ingredients may be the free
acids, bases or as salts having anionic functional groups such as
bitartrate, maleate, citrate, chloride, bromide, acetate and
sulfate. The source of the functional groups may be natural or
synthetic.
[0031] As used herein, the term "Controlled release" refers to the
release of an agent such as a drug from a composition or dosage
form in which the agent is released according to a desired profile
over an extended period of time. Controlled release profiles
include, for example, sustained release, prolonged release,
pulsatile release, and delayed release profiles. In contrast to
immediate release compositions, controlled release compositions
allow delivery of an agent to a subject over an extended period of
time according to a predetermined profile. Such release rates can
provide therapeutically effective levels of agent for an extended
period of time and thereby provide a longer period of pharmacologic
or diagnostic response as compared to conventional rapid release
dosage forms. Such longer periods of response provide for many
inherent benefits that are not achieved with the corresponding
short acting, immediate release preparations. For example, in the
treatment of chronic pain, controlled release formulations are
often highly preferred over conventional short-acting
formulations.
[0032] Controlled release pharmaceutical compositions and dosage
forms are designed to improve the delivery profile of agents, such
as drugs, medicaments, active agents, diagnostic agents, or any
substance to be internally administered to an animal, including
humans. A controlled release composition is typically used to
improve the effects of administered substances by optimizing the
kinetics of delivery, thereby increasing bioavailability,
convenience, and patient compliance, as well as minimizing side
effects associated with inappropriate immediate release rates such
as a high initial release rate and, if undesired, uneven blood or
tissue levels.
[0033] The present invention provides a taste-masked pharmaceutical
composition including a drug-resin complex and a highly
compressible, free-flowing pharmaceutical excipient. The resin is
present in an amount effective to reduce the taste of the drug in
the drug resin complex by patients that is significant relative to
an otherwise identical pharmaceutical composition without the
resin. The highly compressible, free-flowing pharmaceutical
excipient the formulation to be compressed, while allowing for
rapid disintegration or breakdown by chewing in the mouth. The
pharmaceutical composition includes a chewable tablet, a solid, a
liquid, an orally disintegrable tablet, a gel, a tab, a powder, a
gum, a lozenge or a combination thereof. The disintegratable
formulations may be delivered to, and adapted for, oral, nasal,
buccal, ocular, urethral, transmucosal, vaginal, topical or rectal
delivery, although oral delivery is used mostly. In addition,
conventional excipients such as colorants, anti-tack agents,
fillers, plasticizers, pore forming agents, glossing agents, etc.
can be added to the present invention.
[0034] The present invention provides a taste-masked chewable
pseudoephedrine and chlorpheniramine pharmaceutical composition.
The composition includes a pseudoephedrine-resin complex, a
chlorpheniramine-resin complex and one or more amorphous sugars.
The composition also includes a compressible, free-flowing,
pharmaceutical, taste-masking excipient, wherein the highly
compressible, free-flowing pharmaceutical excipient causes
disintegration of the tablet and liberation of the drug-resin
complex in the mouth. In some instances the resin is polistirex,
polyacrilex or a combination thereof, and more specifically
pseudoephedrine polistirex and chlorpheniramine polyacrilex. The
amorphous sugar may be the commercially available Pharmaburst or
other sugars known to the skilled artisan. However the skilled
artisan will recognize that other combinations of actives, resins
and sugars may be used.
[0035] The present invention also includes a taste-masked soluble
chewable pseudoephedrine and chlorpheniramine pharmaceutical
composition. The composition includes a pseudoephedrine-resin
complex, a chlorpheniramine-resin complex, one or more amorphous
sugars and a compressible, free-flowing, pharmaceutical,
taste-masking excipient. The pseudoephedrine and the
chlorpheniramine are slowly released when the composition is
chewed. The composition becoming thixotropic when chewed but not
fully dissolving for at least 10 seconds, so as to dissolve
thereafter in saliva during chewing.
[0036] The present invention includes a rapidly disintegrating,
taste-masked hyoscyamine pharmaceutical composition. The
composition includes a hyoscyamine-resin complex, one or more
amorphous sugars and a compressible, free-flowing, pharmaceutical,
taste-masking excipient. The hyoscyamine is slowly released as the
tablet disintegrates. In some instances the resin is polistirex,
polyacrilex or a combination thereof, and more specifically
hyoscyamine polistirex. The amorphous sugar may be the commercially
available Pharmaburst or other sugar known to the skilled
artisan.
[0037] The present invention also includes a rapidly
disintegrating, taste-masked hyoscyamine pharmaceutical
composition. The composition includes a hyoscyamine-resin complex
and one or more amorphous sugars. The hyoscyamine is slowly
released when the composition is chewed, the composition becoming
thixotropic when chewed but not fully dissolving for at least 10
seconds when chewed, and the composition slowly dissolves when the
composition is chewed, so as to completely dissociate thereafter
once swallowed. Alternatively, the active agent is slowly released
when the composition is chewed, the composition becoming
thixotropic when chewed but not fully dissolving for at least 10
seconds when chewed, and the composition slowly dissolves when the
composition is chewed; however the remaining material need not be
swallowed and may be discarded. The present invention may be
formulated in a variety of forms including a chewable tablet, a
solid, a liquid, a gel, a tab, a capsule, a disintegrating tablet,
a powder, a lotion, a cream, a gum, a lozenge or combination
thereof.
[0038] Generally, the drug-resin complex includes an exchange
resin, e.g., cationic exchange resin. The resin may be
divinylbenzene sulfonic acid cationic exchange resin, e.g.,
polistirex. In some embodiments the drug-resin complex includes
pseudoephedrine polistirex, chlorpheniramine polistirex,
hyoscyamine polistirex or a combination thereof.
[0039] The present invention includes a soluble chewable tablet
including a pharmaceutically active drug-resin complex. The
pharmaceutically active ingredient is slowly released when the
tablet is chewed. As the tablet is chewed it becomes thixotropic
but not fully dissolving for at least 30 seconds, rapidly
disintegrating during chewing but preventing the release of the
ionic drug until after the complex is swallowed
[0040] The tablet may contain other conventional ingredients,
including other fillers, which include water-soluble compressible
carbohydrates such as dextrose, sucrose, mannitol, sorbitol,
maltitol, xylitol, lactose, and mixtures thereof; other
conventional dry binders like polyvinyl pyrrolidone and the like;
sweeteners such as aspartame, acesulfame potassium, sucralose, and
saccharin; and lubricants, such as magnesium stearate, stearic
acid, talc, and waxes. The mixture may also incorporate
pharmaceutically acceptable adjuvants, including, for example,
preservatives, flavors, antioxidants, surfactants, and coloring
agents.
[0041] When in the form of a chewable tablet components include all
those substances which, alone or mixed with one another, behave
like chewing gum for at least 5 seconds when chewed, but begin to
disintegrate during this time and are then completely disintegrated
and swallowed with the saliva. The range of substances include,
inter alia, but not exclusively, gum arabic, tragacanth, guar gum,
xanthan gum, pectins; but also dry syrups, such as, for example,
dry glucose syrup and/or fructose syrup; soluble cellulose
derivatives, such as, for example, sodium carboxymethylcellulose.
Dry glucose syrup likewise exhibits partly rubber-like behavior on
chewing.
[0042] The pharmaceutical composition of the present invention also
includes an orally disintegrable composition having the amount of
disintegration agent, either effervescent or noneffervescent or the
combination thereof provided sufficient such that the composition
provides a pleasant organoleptic sensation in the mouth of the
patient. In general, the amount of effervescence disintegration
agent, noneffervescent disintegration agent or both in accordance
with the present invention should be sufficient to allow for the
rapid and complete disintegration of the composition when orally
administered. Complete disintegration of the composition does not
require dissolution or disintegration of the microparticles or
other discrete materials included.
[0043] The present invention may contain preservatives to prevent
microbial contamination. Examples of preservatives are the
alkylparabens, particularly methylparaben, propylparaben and
butylparaben. The amount of preservative generally used will vary
depending upon the preservative selected and may, for example,
range from about 0.05% to about 15% weight/volume of the final
composition. The preservative will be present in an amount from
about 0.01% to about 20% weight/volume of the final
composition.
[0044] In some instances the present invention may include a syrup
component including glucose syrup, maltodextrin solution, swollen
gelatin, but also other syrups, such as corn, sugar or invert sugar
syrup. Glucose syrup can be completely or partly replaced by other
concentrated carbohydrate, sugar alcohol, gelatin or similar
solutions.
[0045] The present invention also includes a tablet formulation
that has one or more amorphous sugars. The skilled artisan will
recognize that many amorphous sugars may be used. Generally,
amorphous sugar signifies a sugar which is materially amorphous or
which is capable of becoming amorphous. In the process of becoming
amorphous there may be states where a portion is not amorphous.
Commercially, amorphous sugars such as Mannogem EZ and Pharmaburst
(both available from SPI Pharma, Lewes, Del.) may be used to
provide fast delivery.
[0046] The skilled artisan will recognize that other amorphous
sugars and combinations of sugars may be used. Examples of
amorphous sugars include glucose, lactose, maltose, sorbitol,
trehalose, lactitol, fructose, polyols and the like. Polyols may be
used in the present invention and function as an additive,
compacting agent, filler, and/or carriers inter alia for active
pharmaceutical ingredients. Polyols have sweetening properties
which are comparable to those of sucrose and many polyols show a
cooling effect, which is felt to be pleasant, during the dissolving
process. Commonly used polyols include xylitol, mannitol, lactitol,
isomalt and sorbitol.
[0047] Generally, polyols may be used in the present invention as
they have a sweet taste and can be used to provide a cooling effect
in the mouth. Commonly-used polyols include xylitol, mannitol,
sorbitol and erythritol. However, the skilled artisan will
recognize that a variety of polyols and combinations of polyols may
be used. Xylitol is an odorless white crystalline powder that is
comparably sweet to sucrose. The heat of solution of crystalline
xylitol causes a strong cooling sensation in the mouth when the
crystals dissolve. Crystalline xylitol can also change the flavor
profiled. Erythritol is an odorless white crystalline powder with a
clean sweet taste that is similar to sucrose. The heat of solution
of crystalline erythritol also causes a strong sensory cooling
feeling in the mouth like xylitol. Sorbitol is a popular bulk
sweetener found in numerous food products. In addition to providing
sweetness, it is an excellent humectant and texturizing agent.
Mannitol is a monosaccharide polyol. Both sorbitol and mannitol are
generally stable and chemically unreactive.
[0048] In addition cellulose esters such as cellulose acetate and
cellulose acetate butyrate, and cellulose triacetate may be used as
taste masking agents since they do not dissolve in the mouth and
are tough enough to remain effectively intact during processing and
normal chewing in the mouth.
[0049] Adsorption of the active ingredient onto the ion exchange
resin particles to form the active agent-resin complex is a
well-known technique as shown in U.S. Pat. No. 2,990,332 (relevant
portions incorporated herein by reference) and demonstrated in the
examples hereinbelow. In general, the active ingredient is mixed
with an aqueous suspension of the resin and the complex is then
dried. Adsorption of the active ingredient onto the resin is
detected by a change in the pH of the reaction medium.
[0050] In accordance with the present invention the active
ingredient can be any pharmaceutically active material and can also
include vitamins, minerals, nutritional supplements and the like.
These can include, without limitation systematically distributable
pharmaceutically active materials, vitamins, minerals, dietary
supplements, as well as non-systematically distributable
pharmaceutically active materials. Drugs or pharmaceutically active
materials may include, without limitation, antacids, analgesics,
anti-inflammatories, antipyretics antibiotics, antimicrobials,
laxatives, anorexics, antihistamines, antiasthmatics,
antidiuretics, antiflatuents, antimigraine agents, antispasmodics,
sedatives, antihyperactives, antihypertensives, tranquilizers,
decongestants, beta blockers and combinations thereof.
[0051] In addition, nanoparticulate and microparticulate active
agents may be used in the present invention and may include
proteins, peptides, nucleotides, anti-obesity drugs,
nutraceuticals, corticosteroids, elastase inhibitors, anti-fungals,
oncology therapies, anti-emetics, analgesics, cardiovascular
agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives, astringents, beta-adrenoceptor blocking
agents, blood products and substitutes, cardiac inotropic agents,
contrast media, corticosteroids, cough suppressants, diagnostic
agents, diagnostic imaging agents, diuretics, dopaminergics,
haemostatics, immunological agents, lipid regulating agents, muscle
relaxants, parasympathomimetics, parathyroid calcitonin and
biphosphonates, prostaglandins, radio-pharmaceuticals, sex
hormones, anti-allergic agents, stimulants and anoretics,
sympathomimetics, thyroid agents, vasodilators, and xanthines.
[0052] Substrates include a powder that constitutes a finely
divided (e.g., milled, micronized, nanosized, precipitated) form of
an active ingredient or additive molecular aggregates or a compound
aggregate of multiple components or a physical mixture of
aggregates of an active ingredient and/or additives. Such
substrates may be formed of various materials known in the art,
such as, for example sugars (e.g., lactose, sucrose or dextrose),
polysaccharides (e.g., maltodextrin or dextrates), starches,
cellulosics (e.g., microcrystalline cellulose or microcrystalline
cellulose/sodium carboxymethyl cellulose), inorganics (e.g.,
dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or
titania) and polyols (e.g., mannitol, xylitol, sorbitol or
cyclodextrin).
[0053] Flavoring agents that may be used in the present invention
include, and are not limited to, natural flavors, natural fruit
flavors, artificial flavors, artificial fruit flavors, flavor
enhancers or mixtures thereof. Natural flavors, artificial flavors
or mixtures thereof include, and are not limited to, mint (e.g.,
peppermint or spearmint), lemon, lime, orange, strawberry, menthol,
cinnamon, vanilla, artificial vanilla, chocolate, artificial
chocolate or bubblegum. Natural fruit flavors, artificial fruit
flavors or mixtures thereof include, and are not limited to,
cherry, grape, orange, strawberry or lemon. Flavor enhancers
include, and are not limited to, citric acid. Although flavoring
agents are generally provided as a minor component of the taste
masking composition in amounts effective to provide a palatable
flavor to the liquid pharmaceutical composition, the addition of at
least one flavoring agent is preferred; and, more preferably, up to
two flavoring agents may be employed. A flavoring agent used in the
taste masking composition has a range of from about 0.01 to about
0.15 grams per 100 mL. The flavorings are generally utilized in
amounts that will vary depending upon the individual flavor, and
may, for example, range in amounts of about 0.01% to about 10% by
weight/volume of the final composition.
[0054] Examples of sweeteners include sweetening agents, artificial
sweeteners and dipeptide based sweeteners, e.g., monosaccharides,
disaccharides and polysaccharides such as xylose, ribose, glucose,
mannose, galactose, fructose, dextrose, sucrose, sugar, maltose,
partially hydrolyzed starch, or corn syrup solids and sugar
alcohols such as sorbitol, xylitol, mannitol, saccharin salts,
i.e., sodium, or calcium saccharin salts, cyclamate salts,
acesulfam-K, ammonium glycyrrhizinate, dipotassium glycyrrhizinate
and the free acid form of saccharin L-aspartylphenylalanine methyl
ester and mixtures thereof.
[0055] Generally, the sweetener will be present in an amount
corresponding to about 1 to 60% weight/volume of the total
composition, the amount depending in part upon whether other
sweetener ingredients are present and the level of sweetness
desired. Typically sugar is used it is present from about 10% to
about 50% w/v of the composition. It will be appreciated that
combinations of sweeteners can be used. The sweetening agents, when
used, may also be used alone or in combination with each other.
When an artificial sweetness enhancer is used it may be present in
an amount from about 0.05% to about 15% weight/volume of the final
composition.
[0056] The colorants useful in the present invention include
pigments such as titanium dioxide, that may be incorporated in
amounts of up to about 10% by weight/volume. The colorants may
include other dyes suitable for food, drug and cosmetic
applications, and known as F.D. & C. dyes and the like. The
materials acceptable for the foregoing spectrum of use may be
water-soluble. Illustrative examples include indigoid dye, known as
F.D. & C. Blue No. 2, which is the disodium salt of
5,5'-indigotindisulfonic acid. Similarly, the dye known as F.D.
& C. Green No. 1, includes a triphenylmethane dye and is the
monosodium salt of
4-[4-Nethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulf-
oniumbenzyl)-2,5-cyclohexadienimine].
[0057] Examples of organic acids for use with the formulations
include, e.g., citric acid, tartaric acid, succinic acid, malic
acid, fumaric acid, hydroxybenzoic acid and the like. The
hydroxybenzoic acids include paraben esters of p-hydroxybenzoic
acid (e.g., methyl paraben, ethyl paraben, propyl paraben, butyl
paraben and benzyl paraben). Salts of drugs where the anion of the
salt is acidic, such as acetate, hydrochloride, hydrobromide,
sulfate, succinate, citrate, and the like, may be used to produce
immediate disintegration and dissolution of the porous particle.
Some variation in dosage will necessarily occur depending on the
condition of the subject being treated. The person responsible for
administration will, in any event, determine the appropriate dose
for the individual subject. Moreover, for human administration,
preparations should meet sterility, pyrogenicity, general safety
and purity standards as required by FDA Office of Biologics
standards. The interaction of an acidic component with, e.g., a
porous particle of, for example, calcium hydrogen phosphate, in the
presence of water from gastric fluids accelerates dissolution of
the particle at a greater rate than gastric fluid alone, producing
a more rapid and complete release of the liquid, active agent
formulation into the environment of use. Alternatively, alkaline
components or salts of drugs may be used if the cation of the salt
is alkaline such as choline may be incorporated into the liquid,
active agent formulation to promote rapid and complete dissolution
of a porous particle which is soluble or swells at elevated pH.
Such a particle may be formed, e.g., of poly(methacrylic
acid-methyl methacrylate) 1:2 available commercially as Eudragit
S100 (Rohm America, Sommerset, N.J.).
[0058] Other additives conventionally used in pharmaceutical
compositions may be included, which are well known in the art. Such
additives include, e.g., anti-adherents (e.g, anti-sticking agents,
glidants, flow promoters, lubricants) such as talc, magnesium
stearate, fumed silica), micronized silica, polyethylene glycols,
surfactants, waxes, stearic acid, stearic acid salts, stearic acid
derivatives, starch, hydrogenated vegetable oils, sodium benzoate,
sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate. The
present invention includes purified, hydrated, magnesium silicate
(i.e., talc) which is widely used in oral solid dosage forms as a
lubricant and diluent.
[0059] Pharmaceutical compositions according to the invention may
also include one or more binding agents, filling agents,
lubricating agents, suspending agents, sweeteners, flavoring
agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents, and other excipients. Such components are
known to the skilled artisan.
[0060] Examples of filling agents include lactose monohydrate,
lactose anhydrous, and various starches. Examples of binding agents
include various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose, microcrystalline cellulose, and
silicized microcrystalline cellulose. Generally, suitable
lubricants, including agents that act on the flowability of the
powder to be compressed, are colloidal silicon dioxide, talc,
stearic acid, magnesium stearate, calcium stearate, and silica
gel.
[0061] Examples of preservatives include sorbates, and parabens,
e.g., potassium sorbate, methylparaben, propylparaben, benzoic acid
and its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic
compounds such as phenol, or quarternary compounds such as
benzalkonium chloride. In addition suitable diluents include
pharmaceutically acceptable inert fillers, such as microcrystalline
cellulose, lactose, dibasic calcium phosphate, saccharides, and/or
mixtures of any of the foregoing.
[0062] The present invention includes disintegrants which include
lightly crosslinked polyvinyl pyrrolidone, corn starch, potato
starch, maize starch, and modified starches, croscarmellose sodium,
cross-povidone, sodium starch glycolate, and mixtures thereof. Some
embodiments of the present invention are in the form of
effervescent compositions. Examples of effervescent agents include
an organic acid and a carbonate or bicarbonate. Suitable organic
acids include, for example, citric, tartaric, malic, fumaric,
adipic, succinic, and alginic acids and anhydrides and acid salts.
Suitable carbonates and bicarbonates include, for example, sodium
carbonate, sodium bicarbonate, potassium carbonate, potassium
bicarbonate, magnesium carbonate, sodium glycine carbonate,
L-lysine carbonate, and arginine carbonate. Alternatively, only the
acid component of the effervescent couple may be present
invention.
[0063] For certain actives it may be useful to provide buffering
agents, where the acid is a pharmaceutically acceptable acid, such
as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric
acid, nitric acid, boric acid, phosphoric acid, acetic acid,
acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino
acids, ascorbic acid, benzoic acid, boric acid, butyric acid,
carbonic acid, citric acid, fatty acids, formic acid, fumaric acid,
gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic
acid, maleic acid, methanesulfonic acid, oxalic acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic
acid, salicylic acid, stearic acid, succinic acid, tannic acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid and uric
acid, and where the base is a pharmaceutically acceptable base,
such as an amino acid, an amino acid ester, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide,
magnesium aluminum silicate, synthetic aluminum silicate, synthetic
hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, or a salt of a pharmaceutically acceptable
cation and acetic acid, acrylic acid, adipic acid, alginic acid,
alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid,
boric acid, butyric acid, carbonic acid, citric acid, a fatty acid,
formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,
isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid,
oxalic acid, para-bromophenylsulfonic acid, propionic acid,
p-toluenesulfonic acid, salicylic acid, stearic acid, succinic
acid, tannic acid, tartaric acid, thioglycolic acid,
toluenesulfonic acid, and uric acid. The buffer include acids and
their base salts for example, citric acid (e.g., citric acid
anhydrous), tartaric acid, malic acid, phosphoric acid and the like
and their respective salts.
[0064] The present invention may also include one or more binders.
The choice of binder for a given application may also be determined
readily by those skilled in the art. Generally, the binder must be
capable of wetting the surfaces of the particle being pelletized or
granulated. In general, binders must have sufficient wet strength
to allow agglomerates to be handled and sufficient dry strength to
make them suitable for their intended purposes. Each process,
however, makes use of a different system of forces and may require
a different agglomerate strength. The final selection of the binder
is made generally based on the type of equipment used. Factors that
affect the equipment and binder choices include: the size and size
distribution of pellets, bulk density, strength and flow
properties. Other factors that affect the performance of the
pellets, which may be adjusted by one skilled in the art by the
inclusion of additives, choice of equipment and processing
conditions.
[0065] The present invention may also include one or more coolants
that will contribute a cooling sensation to products in which it is
found without the unwanted harshness or flavor characteristics.
Generally, coolants are compounds that provide a physiological
cooling effect on the skin or on the mucous membranes of the body,
particularly the mucous membranes of the nose and bronchial tract.
For example, Menthol is well known for its physiological cooling
effect on the skin and mucous membranes of the mouth. The "cooling"
effect of menthol is a physiological effect due to the direct
action of menthol on the nerve endings of the human body
responsible for the detection of hot or cold and is not due to
latent heat of evaporation. It is believed that the menthol acts as
a direct stimulus on the cold receptors at the nerve endings, which
in turn stimulate the central nervous system. In addition, menthol
is a major constituent of oil of peppermint and may function as a
flavoring as well. Since many of the physiological cooling agents
do not have their own perceptible flavor they can be combined with
other types of flavors to offer new and unique advantages.
[0066] Physiological cooling agents that may be used in the present
invention include menthol, menthone glycerol ketal, menthyl
lactate, N-ethyl-p-menthane-3-carboxamide,
3-1-menthoxypropane-1,2,diol, 3-substituted-P-menthanes,
N-substituted-P-menthane-3-carboxamides and
3-1-menthoxypropane-1,2-diol, 3-1-menthoxypropane-1,2-diol, a ketal
combined with another coolant (e.g., menthol or carboxamides),
physiological cooling agents and reduced menthol, menthone ketals,
menthone glycerol ketals, cyclodextrin complex with physiological
cooling agents, ketoesters of menthol, sulphoxides and sulphones,
acyclic carboxamides, menthyl lactate, cyclohexanamides, carbonic
acids having free polar groups, acyclic secondary and tertiary
alkanols, menthyl succinate and carboxamides,
alpha-oxy(oxo)mercaptan alkanes, acyclic sulphonamides and
sulphinamides, substituted p-menthane-3-carboxamides, substituted
cyclohexanamides, alkyl substituted alicyclic carboxylic acids,
alkyl substituted alicyclic esters, alkyl substituted alicyclic
amides, 3-substituted p-menthanes, p-menthane-3-carboxylates,
N-acetylglycine menthyl ester, L-menthyl-3-hydroxybutyrate,
2-isopropenyl-5-methylcyclohexanol, bicyclic acids, esters, amides
and substituted menthanols, trialkyl-substituted cyclohexane
carboxamides, cyclic and acyclic amides, ureas and sulphonamides,
p-menthane carboxamide physiological cooling agent with menthol,
3-I-menthoxypropane-1,2-diol, N-substituted p-menthane carboxamides
and menthol, cyclohexanol derivatives, substituted p-menthanes,
substituted p-menthane-carboxamides (e.g.,
N-ethyl-p-menthane-3-carboxamide), acyclic darboxamides,
substituted cyclohexanamides, substituted cyclohexane carboxamides,
substituted ureas and sulphonamides, and substituted menthanols,
hydroxymethyl and hydroxyethyl derivatives of p-menthane, menthyl
succinate, 2-mercapto-cyclo-decanone,
2-isopropanyl-5-methylcyclohexanol, hydroxycarboxylic acids with
2-6 carbon atoms, menthone glycerol ketals,
3-I-menthoxypropane-1,2-diol, menthyl lactate, substituted
p-menthane carboxamides (PMC), N-ethyl-p-menthane-3-carboxamide,
acyclic carboxamides (AC), N-2,3-trimethyl-2-isopropyl butanamide,
N-ethyl-2,3-dimethyl-2-isopropyl butanamide, N,
2,3-trimethyl-2-isopropyl butanamide, menthone glycerol ketal
(MGK), menthyl lactate (ML), menthyl succinate (MS),
3-I-menthoxypropane-1,2-diol (TCA). Physiological cooling agents
may generally be of the chemical classification of ketone, hemi
ketal, ketal, acetal, or hemiacetal.
[0067] Stearic acid is commonly used in the pharmaceutical industry
primarily as a lubricant for tablets and capsules. It is typically
used in a concentration of 1% to 10% when used as a tablet
lubricant. Stearic acid is described as a mixture of stearic acid
and palmitic acid. The content of stearic acid is not less than
about 10% and the sum of the two acids is not less than about
90.0%. Stearic acid is used as an emulsifying agent; solubilizing
agent; tablet and capsule lubricant. The purpose in this
formulation is that of a lubricant of the gauifenesin so that an
adequate plug can be produced and delivered through the dosing disk
without excessive wear.
[0068] Suitable excipients are those used commonly to facilitate
the processes involving the preparation of the solid carrier, the
encapsulation coating, or the pharmaceutical dosage form. These
processes include agglomeration, air suspension chilling, air
suspension drying, balling, coacervation, comminution, compression,
pelletization, cryopelletization, extrusion, granulation,
homogenization, inclusion complexation, lyophilization,
nanoencapsulation, melting, mixing, molding, pan coating, solvent
dehydration, sonication, spheronization, spray chilling, spray
congealing, spray drying, or other processes known in the art. The
excipients may also be pre-coated or encapsulated, as are well
known in the art.
[0069] The excipient in the form of a hydrate may be selected from
organic compounds such as dextrose monohydrate, maltodextrin,
lactose monohydrate, dextrin, and citric acid monohydrate, as well
as inorganic compounds including dibasic calcium phosphate
dihydrate, dibasic sodium phosphate dihydrate, dibasic sodium
phosphate heptahydrate, dibasic sodium phosphate dodecahydrate,
monobasic sodium phosphate monohydrate, and monobasic sodium
phosphate dihydrate. Preferably, the excipient in the form of a
hydrate is an organic compound, more preferably dextrose
monohydrate.
[0070] The present invention may include calcium stearate and/or
magnesium stearate which are primarily used in pharmaceutical
formulations as a lubricant in tablet and capsule manufacture.
Calcium stearate has good anti-adherent and lubricant properties.
Maltodextrin is used in tablet formulations as a binder and diluent
in both direct compression and wet granulation process.
Maltodextrin appears to have no adverse effects on the rate of
tablet dissolution. As a binder it is typically used in
concentrations of 1% to 25%.
[0071] The pharmaceutical compositions of the present invention may
include optionally one or more solubilizers, i.e., additives to
increase the solubility of the pharmaceutical active ingredient or
other composition components in the solid carrier. It has been
recognized by the present inventors that guaifenesin, in fact, acts
as a solubilizer for phenylephrine, and is used as such in the
examples provided herein. Other solubilizers are known in the art.
Mixtures of solubilizers are also within the scope of the invention
and are readily available from standard commercial sources.
[0072] The amount of solubilizer that may be included in
compositions of the present invention is not particularly limited.
Of course, when such compositions are administered to a patient,
the amount of a given solubilizer is limited to a bioacceptable
amount, which is readily determined by one of skill in the art. In
some circumstances, it may be advantageous to include amounts of
solubilizers far in excess of bioacceptable amounts, for example,
to maximize the concentration of active ingredient, with excess
solubilizer removed prior to providing the composition to a patient
using conventional techniques, such as distillation or
evaporation.
[0073] In some formulations additives may also include chelating
agents (e.g., EDTA and EDTA salts); colorants or opaquants (e.g.,
titanium dioxide, food dyes, lakes, natural vegetable colorants,
iron oxides, silicates, sulfates, magnesium hydroxide and aluminum
hydroxide); coolants (e.g., trichloroethane, trichloroethylene,
dichloromethane, fluorotrichloromethane); cryoprotectants (e.g.,
trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran
and mannitol); and diluents or fillers (e.g., lactose, mannitol,
talc, magnesium stearate, sodium chloride, potassium chloride,
citric acid, spray-dried lactose, hydrolyzed starches, directly
compressible starch, microcrystalline cellulose, cellulosics,
sorbitol, sucrose, sucrose-based materials, calcium sulfate,
dibasic calcium phosphate and dextrose). Yet other additives may
include disintegrants or super disintegrants; hydrogen bonding
agents, such as magnesium oxide; flavorants or desensitizers.
[0074] The present invention may also include one or more surface
stabilizer selected from the group consisting of cetyl pyridinium
chloride, gelatin, casein, phosphatides, dextran, glycerol, gum
acacia, cholesterol, tragacanth, stearic acid, stearic acid esters
and salts, calcium stearate, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols, dodecyl trimethyl ammonium bromide,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl celluloses, hydroxypropyl methylcellulose,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone,
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde, poloxamers, poloxamines, a charged phospholipid,
dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate,
dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate,
alkyl aryl polyether sulfonates, mixtures of sucrose stearate and
sucrose distearate, triblock copolymers of the structure:
--(--PEO)--(--PBO--)--(--PEO--)--,
p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;
n-decyl.beta.-D-glucopyranoside, n-decyl .beta.-D-maltopyranoside,
n-dodecyl .beta.-D-glucopyranoside, n-dodecyl .beta.-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside,
n-heptyl .beta.-D-thioglucoside, n-hexyl.beta.-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl.beta.-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside,
octyl.beta.-D-thioglucopyranoside, lysozyme, a PEG derivatized
phospholipid, PEG derivatized cholesterol, a PEG derivatized
cholesterol derivative, PEG derivatized vitamin A, PEG derivatized
vitamin E, and random copolymers of vinyl acetate and vinyl
pyrrolidone, biopolymers, polysaccharides, cellulosics, cationic
lipids, benzalkonium chloride, sulfonium compounds, phosphonium
compounds, quarternary ammonium compounds,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride bromide, C.sub.12-15 dimethyl
hydroxyethyl ammonium chloride, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium
chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl
trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl
(ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium
bromide, N-alkyl(C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-diclecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12 trimethyl ammonium
bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 trimethyl
ammonium bromides, dodecylbenzyl triethyl ammonium chloride,
poly-diallyldimethylammonium chloride, dimethyl ammonium chlorides,
alkyldimethylammonium halogenides, tricetyl methyl ammonium
chloride, decyltrimethylammonium bromide, dodecyltriethylammonium
bromide, tetradecyltrimethylammonium bromide, methyl
trioctylammonium chloride, tetrabutylammonium bromide, benzyl
trimethylammonium bromide, choline esters, benzalkonium chloride,
stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl
pyridinium chloride, halide salts of quaternized
polyoxyethylalkylamines, alkyl pyridinium salts; amines, amine
salts, amine oxides, imide azolinium salts, protonated quaternary
acrylamides, methylated quaternary polymers, cationic guar,
polymethylmethacrylate trimethylammonium bromide,
polyvinylpyrrolidone-2-dimetbylaminoethyl methacrylate dimethyl
sulfate, hexadecyltrimethyl ammonium bromide,
poly(2-methacryloxyethyltrimethylammonium bromide),
poly(N-vinylpyrrolidone/2-dimethylaminoethyl methacrylate)
dimethylsulphate quarternary and
poly(2-methylacryloxyamidopropyltrimethylammonium chloride).
[0075] Pelletizers are generally classified based on the angle of
their axis as a horizontal drum or an inclined dish pelletizer.
Rotary fluidized granulators may also be used for pelletization. A
standard fluidized drier bowl may be replaced with a rotating plate
as an air distributor. For granulation, a binder liquid is sprayed
from via one or two binary nozzles located axially to the
rotational movement of the powder bed. The granulation results in
rounding of the granules to approximately spherical pellets. Such
balling or agitation techniques are generally influenced by
operating conditions, e.g., the bridging/binding liquid
requirements, the residence time of the material in the pelletizer,
the speed and angle of inclination of the pelletizer, the amount of
material fed to the pelletizer and the choice and levels of binder,
etc. Those skilled in the art may adjust readily such factors to
produce a satisfactory product.
[0076] A pelletization process typically involves preparing a
molten solution of the composition of the solid carrier or a
dispersion of the composition of the solid carrier solubilized or
suspended in an aqueous medium, an organic solvent, a supercritical
fluid, or a mixture thereof. Such solution or dispersion is then
passed through a certain opening to achieve the desired shape,
size, and other properties. Similarly, appropriate drying processes
may be used to control the level of the residual dispersing medium,
if necessary. The processes described above, the combination of the
processes, or the modification of the processes are well know in
the art.
[0077] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing, in a suitable machine, the therapeutic
ingredient in a free-flowing form such as a powder or granules,
optionally mixed with a binder, lubricant, inert diluent,
preservative, surface therapeutic or dispersing agent. Molded
tablets may be made by molding, in a suitable machine, a mixture of
the powdered compound moistened with an inert liquid diluent. The
tablets may be optionally coated or scored and may be formulated so
as to provide a slow or controlled release of the therapeutic
ingredient therein.
[0078] The tablet may be made in any manner, and a variety of
tableting methods are known in the art. Conventional methods for
tablet production include direct compression ("dry blending"), dry
granulation followed by compression, and wet granulation followed
by drying and compression. Other methods include the use of
compacting roller technology, e.g., a chilsonator (e.g., a dry
granulation/roll compactor roller press system), drop roller,
molding, casting, or extrusion technologies. All of these methods
are well known in the art. The tablets are formed by the direct
compression method, which involves directly compacting a blend of
the active ingredient, the excipient in the form of a hydrate, the
water-swellable excipient, and any other appropriate optional
ingredients. After blending, a pre-determined volume of particles
is filled into a die cavity of a rotary tablet press, which
continuously rotates as part of a "die table" from the filling
position to a compaction position. The particles are compacted
between an upper punch and a lower punch to an ejection position,
at which the resulting tablet is pushed from the die cavity by the
lower punch and guided to an ejection chute by a stationary
"take-off" bar.
[0079] Two examples of the present invention include a chewable
tablet with the following formulations:
EXAMPLE I
[0080] TABLE-US-00001 First active ingredient polistirex 100.00 mg
Second active ingredient polistirex 15.00 mg Pharamaburst 170.00 mg
Sorbitol 100.00 mg Sweetener 25.00 mg Xylisorb 30.00 mg Citric acid
10.00 mg Flavor 7.50 mg Dye 2.50 mg Talc 40.00 mg Steric acid 10.00
mg
EXAMPLE II
[0081] TABLE-US-00002 Pseudoephedrine polistrex 99.70 mg
Chlorpheniramine polyacrilex 14.70 mg Pharamaburst 170.00 mg
Sorbitol 100.00 mg Aspertame 25.00 mg Xylisorb 30.00 mg Citric acid
10.00 mg Grape Flavor 7.50 mg Purple Lake Blend 2.50 mg Talc 40.00
mg Steric acid 10.00 mg
[0082] Below is a list of actual assay results for one example of
the present invention with the composition listed as formula II
above. The dissolution profile for the release of pseudoephedrine
and chlorpheniramine are shown in Table 1, below. TABLE-US-00003
TABLE 1 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 35.1
42.7 51.6 60.8 Pseudoephedrine 27.6 37.8 59.4 82.0
[0083] Based on assay and dissolution profile 35.1% of the
chlorpheniramine is released within 30 minutes. The release of
chlorpheniramine at 1 hour is about 42.7%. The release profile
after 3 hours and 8 hours demonstrate a release of 51.6% and 60.8%
respectively. The dissolution profile also shows that 26.7% the
pseudoephedrine is released within 30 minutes. The release of
pseudoephedrine at 1 hour is about 37.8%. The release profile after
3 hours and 8 hours demonstrate a release of 59.4% and 82.0%
respectively.
EXAMPLE III
[0084] TABLE-US-00004 Pseudoephedrine polistrex 102.92 mg
Chlorpheniramine polyacrilex 15.11 mg Pharamaburst 170.00 mg
Sorbitol 86.97 mg Aspertame 25.00 mg Xylisorb 30.00 mg Citric acid
10.00 mg Grape Flavor 7.50 mg Purple Lake Blend 2.50 mg Talc 40.00
mg Steric acid 10.00 mg
[0085] Below is a list of assay results for one example of the
present invention with the composition listed as formula II above.
The dissolution profile for the release of pseudoephedrine and
chlorpheniramine are shown in Table 2, below. TABLE-US-00005 TABLE
2 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 36.4 42.1
51.0 60.7 Pseudoephedrine 27.0 36.3 53.0 78.4
[0086] Based on assay and dissolution profile 36.4% of the
chlorpheniramine is released within 30 minutes. The release of
chlorpheniramine at 1 hour is about 42.1%. The release profile
after 3 hours and 8 hours demonstrate a release of 51.0% and 60.7%
respectively. The dissolution profile also shows that 27.0% of the
pseudoephedrine is released within 30 minutes. The release of
pseudoephedrine at 1 hour is about 36.3%. The release profile after
3 hours and 8 hours demonstrate a release of 53.0% and 78.4%
respectively.
[0087] Below is a list of actual assay results for one example of
the present invention with the composition listed as formula II
above. The dissolution profile for the release of pseudoephedrine
and chlorpheniramine are shown in Table 3, below. TABLE-US-00006
TABLE 3 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 40.1
45.1 53.3 62.1 Pseudoephedrine 29.2 39.7 61.2 85.2
[0088] Based on assay and dissolution profile 29.2% of the
pseudoephedrine is released within 30 minutes. The release of
pseudoephedrine at 1 hour is about 39.7%. The release profile after
3 hours and 8 hours demonstrate a release of 61.2% and 85.2%
respectively. The dissolution profile also shows that 40.1% of the
chlorpheniramine is released within 30 minutes. The release of
chlorpheniramine at 1 hour is about 45.1%. The release profile
after 3 hours and 8 hours demonstrate a release of 53.3% and 62.1%
respectively.
[0089] In addition the composition may be in the form of a capsule.
Below is a list of actual assay results for one example of the
present invention when in the form of a capsule. The dissolution
profile for the release of pseudoephedrine and chlorpheniramine are
shown in Table 4, below. TABLE-US-00007 TABLE 4 Capsules 90 min (%)
3 Hr (%) 6 Hr (%) 12 Hr (%) Pseudoephedrine 34.8 54.1 75.4 91.7
Chlorpheniramine 21.9 35.4 55.2 78.6
[0090] Based on assay and dissolution profile of the capsule 34.8%
of the pseudoephedrine is released within 90 minutes. The release
of pseudoephedrine at 3 hour is about 54.1%. The release profile
after 6 hours and 12 hours demonstrate a release of 75.4% and 91.7%
respectively. The dissolution profile also shows that 21.9% of the
chlorpheniramine is released within 90 minutes. The release of
chlorpheniramine at 3 hour is about 35.4%. The release profile
after 6 hours and 12 hours demonstrate a release of 55.2% and 78.6%
respectively.
[0091] Generally, sorbitol is highly compressible and binds other
tablet ingredients and may be used in pharmaceutical tablets,
powders, and sachets. It may be used in direct compression
tableting have particle size distributions that make them
free-flowing. The particle size is controlled to optimize the flow
characteristics of the granulations in modern tablet presses.
Sorbitol increases the strength and integrity of a pharmaceutical
tablet. The skill artisan will recognize that other substances may
be used in place of sorbitol or in addition to sorbitol.
EXAMPLE IV
[0092] TABLE-US-00008 Pseudoephedrine polistrex 102.92 mg
Chlorpheniramine polyacrilex 15.11 mg Pharamaburst 170.00 mg
Sorbitol 86.97 mg Aspertame 25.00 mg Xylisorb 30.00 mg Citric acid
10.00 mg Grape Flavor 7.50 mg Purple Lake Blend 2.50 mg Talc 40.00
mg Steric acid 10.00 mg
EXAMPLE V
[0093] TABLE-US-00009 Active ingredient polistirex 0.33 mg
Amorphous sugar 150.00 mg Excipient/binder 10.00 mg Sweetener 5.00
mg Coolant 2.67 mg Flavor 6.00 mg Dye 0.50 mg Talc 30.00 mg Steric
acid 5.00 mg
EXAMPLE VI
[0094] TABLE-US-00010 Hyoscyamine polistirex 0.33 mg Pharmaburst
150.00 mg Povidone 10.00 mg Aspertame 5.00 mg Coolant 2.67 mg
Peppermint Flavor 6.00 mg Lake Blend Lt Green 0.50 mg Talc 30.00 mg
Steric acid 5.00 mg
EXAMPLE VII
[0095] TABLE-US-00011 Hyoscyamine polistirex 0.33 mg Mannogem .TM.
EZ 150.00 mg Povidone 10.00 mg Aspertame 5.00 mg Coolant 2.67 mg
Peppermint Flavor 6.00 mg Lake Blend Lt Green 0.50 mg Talc 30.00 mg
Steric acid 5.00 mg
[0096] When formulated with microparticles or nanoparticles, the
one or more actives the release profile can easily be adapted by
adding, e.g., a hard or soft gelatin coating, a starch coating, a
resin or polymer coating and/or a cellulosic coating. Although not
limited to microparticles or nanoparticles such dosage forms may be
further coated with, for example, a seal coating, an enteric
coating, an extended release coating, or a targeted delayed release
coating. The term "enteric coating" as used herein relates to a
mixture of pharmaceutically acceptable excipients that is applied
to, combined with, mixed with or otherwise added to the carrier or
composition. The coating may be applied to an active that is
compressed, molded or extruded and may also include: gelatin,
and/or pellets, beads, granules or particles of the carrier or
composition. The coating may be applied through an aqueous
dispersion or after dissolving in appropriate solvent. The carrier
may or may not be fully or partially biodegradable.
[0097] Carriers for use with the present invention include
permeable and semipermeable matrices or polymers that control the
release characteristics of the formulation. Such polymers include,
for example, cellulose acylates, acetates, and other semi-permeable
polymers as well as the selectively permeable polymers formed by
the coprecipitation of a polycation and a polyanioni. The carrier
of the compositions of the present invention may be a powder or a
multiparticulate, such as a granule, a pellet, a bead, a spherule,
a beadlet, a microcapsule, a millisphere, a nanocapsule, a
nanosphere, a microsphere, a platelet, a minitablet, a tablet or a
capsule. A carrier may be a finely divided (e.g., milled,
micronized, nanosized, precipitated) form of a matrix on which the
active ingredient is disposed. Such matrix may be formed of various
materials known in the art, such as, for example: sugars, such as
lactose, sucrose or dextrose; polysaccharides, such as maltodextrin
or dextrates; starches; cellulosics, such as microcrystalline
cellulose or microcrystalline cellulose/sodium carboxymethyl
cellulose; inorganics, such as dicalcium phosphate, hydroxyapitite,
tricalcium phosphate, talc, or titania; and polyols, such as
mannitol, xylitol, sorbitol or cyclodextrin. It should be
emphasized that a substrate need not be a solid material, although
often it will be a solid.
[0098] Other carriers for use with the present invention include,
e.g., starch, modified starch, and starch derivatives, gums,
including but not limited to xanthan gum, alginic acid, other
alginates, benitoniite, veegum, agar, guar, locust bean gum, gum
arabic, quince psyllium, flax seed, okra gum, arabinoglactin,
pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin,
dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange
resins, such as potassium polymethacrylate, carrageenan (and
derivatives), gum karaya, biosynthetic gum, etc. Other useful
polymers include: polycarbonates (linear polyesters of carbonic
acid); microporous materials (bisphenol, a microporous
poly(vinylchloride), micro-porous polyamides, microporous
modacrylic copolymers, microporous styrene-acrylic and its
copolymers); porous polysulfones, halogenated poly(vinylidene),
polychloroethers, acetal polymers, polyesters prepared by
esterification of a dicarboxylic acid or anhydride with an alkylene
polyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric
porous polymers, cross-linked olefin polymers, hydrophilic
microporous homopolymers, copolymers or interpolymers having a
reduced bulk density, and other similar materials, poly(urethane),
cross-linked chain-extended poly(urethane), poly(imides),
poly(benzimidazoles), collodion, regenerated proteins, semi-solid
cross-linked poly(vinylpyrrolidone).
[0099] Additional additives and their levels, and selection of a
primary coating material or materials will depend on the following
properties: resistance to dissolution and disintegration in the
stomach; impermeability to gastric fluids and drug/carrier/enzyme
while in the stomach; ability to dissolve or disintegrate rapidly
at the target intestine site, physical and chemical stability
during storage; non-toxicity; easy application as a coating
(substrate friendly); and economical practicality.
[0100] The one or more active agents that are formulated in a
self-stable manner using the present invention may include a wide
variety of uses, not just the traditional pharmaceutical agents.
Those skilled in the art will appreciate that any of these
compounds may be used in the form of their pharmaceutically
acceptable salt forms, e.g., carboxylic acids, with counter-ions,
e.g., potassium, sodium, calcium; as ionic combinations with, e.g.,
resins, polymers, beads, matrices; with sugars or sugar
derivatives, e.g., malate, tannate; amino acids, lipids, oils or
combinations, mixtures and the like. In some embodiments, the
present inventors have found that certain actives may be provided
with two different salts, each of which may have a different
solubility and/or release profile under, e.g., physiologic
conditions. In fact, liquid formulation of present invention
includes combinations of one or more of the following: immediate
release, pulsatile release, controlled release, extended release,
delayed release, targeted release, or targeted delayed release.
[0101] Some examples of active ingredients suitable for use in the
pharmaceutical formulations and methods of the present invention
include hydrophilic, lipophilic, amphiphilic or hydrophobic, and
that can be solubilized, dispersed, or partially solubilized and
dispersed, on or about a carrier. For example, the following
example may be used for the following active agents:
EXAMPLE VIII
[0102] TABLE-US-00012 Active Agent-polistirex 0.33 mg Mannogem .TM.
EZ 150.00 mg Povidone 10.00 mg Aspertame 5.00 mg Coolant 2.67 mg
Peppermint Flavor 6.00 mg Lake Blend Lt Green 0.50 mg Talc 30.00 mg
Steric acid 5.00 mg
[0103] The active agent-carrier combination may be coated further
to encapsulate the agent-carrier combination. Alternatively, an
active ingredient may also be provided separately from the solid
pharmaceutical composition, such as for co-administration. Such
active ingredients can be any compound or mixture of compounds
having therapeutic or other value when administered to an animal,
particularly to a mammal, such as drugs, nutrients, cosmaceuticals,
nutraceuticals, diagnostic agents, nutritional agents, and the
like. The active agents of the present invention may be found in
their native state; however, they will generally be provided in the
form of a salt. The active agents listed below include their
isomers, analogs and derivatives.
[0104] In one embodiment, the active ingredient agent is
hydrophobic. Hydrophobic active ingredients are compounds with
little or no water solubility. Intrinsic water solubilities for
hydrophobic active ingredients are generally less than about 15% by
weight. Suitable hydrophobic active ingredients are not limited by
therapeutic category, and can be, for example, analgesics,
anti-inflammatory agents, antihelmimthics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malariale,
anti-migrainc agents, anti-muscarinic agents, anti-neoplastic
agents, crectile dysfunction improvement agents,
immunosuppressants, anti-rotozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-Blockers, cardiac inotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastro-intestinal agents,
histamine receptor antagonists, keratolytics, lipid regulating
agents, anti-anginal agents, cox-2 inhibitors, leukotriene
inhibitors, macrolides, muscle relaxants, nutritional agents,
opioid analgesics, protease inhibitors, sex hormones, stimulants,
muscle relaxants, anti-osteoporosis agents, anti-obesity agents,
cognition enhancers, anti-urinary incontinence agents, nutritional
oils, anti-benign prostate hypertrophy agents, essential fatty
acids, non-essential fatty acids, and mixtures thereof. Salts,
isomers and derivatives of the above-listed hydrophobic active
ingredients may also be used, as well as combinations and mixtures
thereof.
[0105] Other examples of suitable hydrophobic active ingredients
include: acetretin, albendazole, albuterol, aminoglutethimide,
amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin,
atovaquone, azithromycin, baclofen, beclomethasone, benezepril,
benzonatate, betamethasone, bicalutanide, budesonide, bupropion,
busulfan, butenafine, calcifediol, calcipotriene, calcitriol,
camptothecin, candesartan, capsaicin, carbamezepine, carotenes,
celecoxib, cerivastatin, cetirizine, chlorpheniramine,
cholecalciferol, cilostazol, cimetidine, cinnarizine,
ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene,
clomipramine, clopidogrel, codeine, coenzyme Q10, cyclobenzaprine,
cyclosporin, danazol, dantrolene, dexchlorpheniramine, diclofenac,
dicoumarol, digoxin, dehydroepiandrosterone, dihydroergotamine,
dihydrotachysterol, dirithromycin, donezepil, efavirenz, eposartan,
ergocalciferol, ergotamine, essential fatty acid sources, etodolac,
etoposide, famotidine, fenofibrate, fentanyl, fexofenadine,
finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin,
frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide,
glipizide, glyburide, glimepiride, griseofulvin, halofantrine,
ibuprofen, irbesartan, irinotecan, isosorbide dinitrate,
isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac,
lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide,
loratadine, lovastatin, L-thryroxine, lutein, lycopene,
medroxyprogesterone, mifepristone, mefloquine, megestrol acetate,
methadone, methoxsalen, metronidazole, miconazole, midazolam,
miglitol, minoxidil, mitoxantrone, montelukast, nabumetone,
nalbuphine, naratriptan, nelfinavir, nifedipine, nilsolidipine,
nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin,
oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxetine,
pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone,
probucol, progesterone, pseudoephedrine, pyridostigmine,
rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine,
rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone,
saquinavir, sertraline, sibutramine, sildenafil citrate,
simvastatin, sirolimus, spironolactone, sumatriptan, tacrine,
tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene,
telmisartan, teniposide, terbinafine, terazosin,
tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran,
tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,
troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine,
verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin
K, zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of
course, salts, isomers and derivatives of the above-listed
hydrophobic active ingredients may also be used, as well
combinations and mixtures thereof.
[0106] In other embodiments, the active ingredient is hydrophilic,
however, combination of hydrophilic, hydrophobic and non-polar
agents may also be used. The water solubility for hydrophilic
active ingredients is generally greater than about 0.1% by weight,
and typically greater than about 1% by weight. Suitable hydrophilic
active ingredients include: analgesics, anti-inflammatory agents,
antihelminthics, anti-arrhythmic agents, anti-bacterial agents,
anti-viral agents, anti-coagulants, anti-depressants,
anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout
agents, anti-hypertensive agents, anti-malarials, anti-migraine
agents, anti-muscarinic agents, anti-neoplastic agents, erectile
dysfunction improvement agents, immunosuppressants, anti-protozoal
agents, anti-thyroid agents, anxiolytic agents, sedatives,
hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropic agents,
corticosteroids, diuretics, anti-parkinsonian agents,
gastro-intestinal agents, histamine receptor antagonists,
keratolytics, lipid regulating agents, anti-anginal agents, cox-2
inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,
nutritional agents, opioid analgesics, protease inhibitors, sex
hormones, stimulants, muscle relaxants, anti-osteoporosis agents,
anti-obesity agents, cognition enhancers, anti-urinary incontinence
agents, nutritional oils, anti-benign prostate hypertrophy agents,
essential fatty acids, non-essential fatty acids, and mixtures
thereof.
[0107] Other hydrophilic active ingredients include: a cytokine, a
peptidomimetic, a peptide, a protein, a toxoid, a serum, an
antibody, a vaccine, a nucleoside, a nucleotide, a portion of
genetic material, a nucleic acid, or a mixture thereof. Other
examples of suitable hydrophilic active ingredients include:
acarbose; acyclovir; acetyl cysteine; acetylcholine chloride;
alatrofloxacin; alendronate; aglucerase; amantadine hydrochloride;
ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid;
amphotericin B; antihemophilic factor (human), antihemophilic
factor (porcine); antihemophilic factor (recombinant), aprotinin;
asparaginase; atenolol; atracurium besylate; atropine;
azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin;
belladona; bepridil hydrochloride; bleomnycin sulfate; calcitonin
human; calcitonin salmon; carboplatin; capecitabine; capreomycin
sulfate; cefamandole nafate; cefazolin sodium; cefepime
hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan
disodium; cefotaxime; cefoxitin sodium; ceftizoxime; ceftriaxone;
cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine;
chorionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium
bromide; clindamycin and clindamycin derivatives; ciprofloxacin;
clodronate; colistimethate sodium; colistin sulfate; corticotropin;
cosyntropin; cromolyn sodium; cytarabine; dalteparin sodium;
danaparoid; desferrioxamine; denileukin diflitox; desmopressin;
diatrizoate meglumine and diatrizoate sodium; dicyclomine;
didanosine; dirithromycin; dopamine hydrochloride; domase alpha;
doxacurium chloride; doxorubicin; etidronate disodium; enalaprilat;
enkephalin; enoxaparin; enoxaprin sodium; ephedrine; epinephrine;
epoetin alpha; erythromycin; esmolol hydrochloride; factor IX;
famciclovir; fludarabine; fluoxetine; foscarnet sodium;
ganciclovir; granulocyte colony stimulating factor,
granulocyte-macrophage stimulating factor; growth
hormones--recombinant human; growth hormone-bovine; gentamycin;
glucagon; glycopyrolate; gonadotropin releasing hormone and
synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin;
haemophilus B conjugate vaccine; Hepatitis A virus vaccine
inactivated; Hepatitis B virus vaccine inactivated; heparin sodium;
indinavir sulfate; influenza virus vaccine; interleukin-2;
interleukin-3; insulin-human, insulin lispro; insulin procine;
insulin NPH; insulin aspart; insulin glargine; insulin detemir;
interferon alpha; interferon beta; ipratropium bromide; ifosfamide;
Japanese encephalitis virus vaccine; lamivudine; leucovorin
calcium; leuprolide acetate, levofloxacin; lincomycin and
lincomycin derivatives; lobucavir; lomefloxacin; loracarbef;
mannitol; is measles virus vaccine; meningococcal vaccine;
menotropins; mepenzolate bromide; mesalamine; methenamine;
methotrexate; methscopolamine; metformin hydrochloride; metoprolol;
mezocillin sodium; mivacurium chloride; mumps viral vaccine;
nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;
neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate;
oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;
perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline;
periciclovir; pentagastrin; pentholamine mesylate; phenylalanine;
physostigmine salicylate; plague vaccine; piperacillin sodium;
platelet derived growth factor-human; pneumococcal vaccine
polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live
(OPV); polymyxin B sulfate; pralidoxime chloride; pramlintide,
pregabalin; propafenone; propenthaline bromide; pyridostigmine
bromide; rabies vaccine; residronate; ribavarin; rimantadine
hydrochloride; rotavirus vaccine; salmeterol xinafoate; sinealide;
small pox vaccine; solatol; somatostatin; sparfloxacin;
spectinomycin; stavudine; streptokinase; streptozocin;
suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate;
thiopeta; ticarcillin; tiludronate; timolol; tissue type
plasminogen activator; TNFR:Fc; TNK-tPA; trandolapril; trimetrexate
gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride;
tumor necrosis factor; typhoid vaccine live; urea; urokinase;
vancomycin; valacyclovir; valsartan; varicella virus vaccine live;
vasopressin and vasopressin derivatives; vecuronium bromide;
vinblastine; vincristine; vinorelbine; vitamin B12; warfarin
sodium; yellow fever vaccine; zalcitabine; zanamivir; zolendronate;
zidovudine; pharmaceutically acceptable salts, isomers and
derivatives thereof; and mixtures thereof.
[0108] A wide variety of therapeutically active agents can be used
in conjunction with the present invention. The therapeutically
active agents (e.g. pharmaceutical agents) which may be used in the
compositions of the present invention include both water soluble
and water insoluble drugs. Examples of such therapeutically active
agents include antihistamines (e.g., dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),
analgesics (e.g., aspirin, codeine, morphine, dihydromorphone,
oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g.,
naproxyn, diclofenac, indomethacin, ibuprofen, sulindac),
anti-emetics (e.g., metoclopramide), anti-epileptics (e.g.,
phenyloin, meprobamate and nitrezepam), vasodilators (e.g.,
nifedipine, papaverine, diltiazem and nicardirine), anti-tussive
agents and expectorants (e.g., codeine phosphate), anti-asthmatics
(e.g. theophylline), antacids, anti-spasmodics (e.g., atropine,
scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,
ethacrynic acid, bendrofluazide), anti-thypotensives (e.g.,
propranolol, clonidine), antihypertensives (e.g, clonidine,
methyldopa), bronchodilators (e.g., albuterol), steroids (e.g.,
hydrocortisone, triamcinolone, prednisone), antibiotics (e.g.,
tetracycline), antihemorrhoidals, hypnotics, psycho-tropics,
antidiarrheals, mucolytics, sedatives, decongestants, laxatives,
vitamins, stimulants (including appetite suppressants such as
phenylpropanolamine), as well as salts, hydrates, and solvates of
the same. The above list is not meant to be exclusive.
[0109] In certain embodiments, the therapeutically active agent
include hydromorphone, oxycodone, dihydrocodeine, codeine,
dihydromorphine, morphine, buprenorphine, salts, hydrates and
solvates of any of the foregoing, mixtures of any of the foregoing,
and the like. In other embodiments, the active agent is a locally
active therapeutic agent and the environment of use may be, e.g.,
the gastrointestinal tract, or body cavities such as the oral
cavity, periodontal pockets, surgical wounds, the rectum or vagina.
The liquid formulations of the present invention may be provided
orally, topically, subcutaneously, intramuscularly,
intraperitoneally, intraocularly, intraossealy, nasally,
urethrally, mucosally, vaginally, rectally, intradurally,
epidurally and the like. The liquid formulation of the present
invention may also be provided as a mist, e.g., to the deep lung
(alveolarly).
[0110] Locally active pharmaceutical agents of use with the present
invention include antifungal agents (e.g., amphotericin B,
clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic
agents (penicillins, cephalosporins, erythromycin, tetracycline,
aminoglycosides, etc.), antiviral agents (e.g, acyclovir,
idoxuridine, etc.), breath fresheners (e.g. chlorophyll),
antitussive agents (e.g., dextromethorphan hydrochloride),
anti-cariogenic compounds (e.g. metallic salts of fluoride, sodium
monofluorophosphate, stannous fluoride, amine fluorides), analgesic
agents (e.g., methylsalicylate, salicylic acid, etc.), local
anesthetics (e.g., benzocaine), oral anti-septics (e.g.,
chlorhexidine and salts thereof, hexylresorcinol, dequalinium
chloride, cetylpyridinium chloride), anti-flammatory agents (e.g.,
dexamethasone, betamethasone, prednisone, prednisolone,
triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol),
antiplaque agents (e.g, hlorhexidine and salts thereof, octenidine,
and mixtures of thymol, menthol, ethysalicylate, eucalyptol),
acidity reducing agents (e.g., buffering agents such as potassium
phosphate dibasic, calcium carbonate, sodium bicarbonate, sodium
and potassium hydroxide, etc.), and tooth desensitizers (e.g.,
potassium nitrate). This list is not meant to be exclusive.
[0111] The examples herein include pharmaceutically active
compounds useful in the practice of the present invention, e.g.,
antihistamines, decongestants, antitussives and/or expectorants.
Other actives for use with the present invention include, but are
not limited to: non-steroidal anti-inflammatory drugs (NSAIDs) and
other analgesic drugs such as acetominophen and phenacetin. These
materials are incorporated into the immediate or controlled release
formulations of the invention in amounts governed by the desired
release characteristics of the material in such excipient base and
such that conventional dosages comply with applicable federal Food
and Drug Administration (FDA) or other regulations.
[0112] Decongestants useful with the present invention (along with
a salt form) are phenylephrine (bitartrate, tannate, HBr, HCl),
phenylpropanolamine (HCl) and pseudoephedrine (HCl). Furthermore, a
number of herbal and/or natural decongestants are known in the art,
all of which may be used with the present invention.
[0113] Expectorants for use with the present invention include,
e.g., guaifenesin, terpin hydrate, (glyceryl guaiacolate),
potassium (iodide, citrate) and potassium guaicolsulfonate. Other
expectorants, whether individual ingredients or combinations of
ingredients may be used with the present invention. Furthermore, a
number of herbal and/or natural expectorants are known in the art,
all of which may be used with the present invention.
[0114] Examples of antihistamines for use with the present
invention (e.g., in salt form) are chlorpheniramine (maleate),
brompheniramine (maleate), dexchlorpheniramine (maleate),
dexbrompheniramine (maleate), triprolidine (HCl), diphenhydramine
(HCl), doxylamine (succinate), tripelennamine (HCl), cyproheptatine
(HCl), bromodiphenhydramine (HCl), phenindamine (tartrate),
pyrilamine (maleate, tannate) and azatadine (maleate). Antitussives
that may be used with the present invention (with salt form)
include: caramiphen (edisylate), dextromethorphan (HBr) and codeine
(phosphate, sulfate). A number of herbal and/or natural
antihistamines are known in the art, all of which may be used with
the present invention.
[0115] Other actives may also be included with the present
invention, e.g., non-steroidal anti-inflammatory drugs (NSAIDs)
such as propionic acid derivatives; acetic acid derivatives;
fenamic acid derivatives; biphenylcarboxylic acid derivatives; and
oxicams. Examples of propionic acid derivatives include: ibuprofen,
naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen, fenbufen,
and fluprofen may be mentioned as preferred compounds. Acetic acid
derivatives derivatives include: tolmetin sodium, zomepirac,
sulindac and indomethacin. Fenamic acid derivatives derivatives
include: mefenamic acid and meclofenamate sodium. Diflunisal and
flufenisal are biphenylcarboxylic acid derivatives, while oxicams
include piroxicam, sudoxicam and isoxicam. Other analgesics for use
with the present invention include acetominophen and phenacetin.
Naproxen may be present in amounts of about 50 to about 250
milligrams per dose, however, naproxen may be used in amounts of
between about 100 and about 150 milligrams per liquid dose.
[0116] Phenylephrine may be present in amounts of between about 15
and about 60 milligrams per liquid dose. Phenylephrine is generally
in amounts of about 5 to about 30 milligrams per liquid dose, with
half or less of that amount used in a pediatric form of the
formulation. In one example of the present invention, phenylephrine
is provided in the amount of about 15 mg for extended release.
Phenylephrine hydrochloride is an orally effective nasal
decongestant. Chemically it is (S)-3-hydroxy-.alpha.[(methylamino)
methyl]benzenemethanol hydrochloride. Phenylepherine is a
synthetic, optically active sympathomimetic amine that has one
hydroxyl group on the benzene ring. The hydroxyl group is placed in
the position meta to the aliphatic side chain. The meta position
affords optimal activity and phenylepherine (neo-synephrine)
replaced an older preparation, synephrine, in which the hydroxyl
was in the para position.
[0117] Phenylephrine hydrochloride is available in the form of the
levorotatory isomer, a white, odorless, non-hygroscopic,
crystalline compound possessing a bitter taste. Phenylephrine
hydrochloride has a melting point of 140-145 degrees C. and is
freely soluble in water and alcohol. Decongestant compounds in the
form of their free bases as well as their salts, e.g.,
hydrochloride, citrate, maleate, tannate, etc., are well known.
[0118] Dextromethorphan may be present in amounts of between about
5 and about 20 milligrams per liquid dose, with a general range of
about 10 to about 15 milligrams. Brompheniramine may be present in
amounts of between about 0.5 and about 4.0 milligrams per liquid
dose with a general range of about 2.0 milligrams per liquid dose.
Half or less of that amount may be used in a pediatric form of the
formulation.
[0119] The present invention may also include chlorpheniramine,
which is an antihistamine used to relieve, e.g., allergic rhinitis
(seasonal allergy). The symptoms of allergic rhinitis include:
sneezing, runny nose, itching, and watery eyes. Chlorpheniramine
may also be used to treat immediate allergic reactions.
Chlorpheniramine may be provided alone and in combination with
other prescription or nonprescription drugs, e.g., to treat
symptoms of allergy, colds, and upper respiratory infections.
[0120] The pharmaceutical composition and/or the solid carrier
particles can be coated with one or more enteric coatings, seal
coatings, film coatings, barrier coatings, compress coatings, fast
disintegrating coatings, or enzyme degradable coatings. Multiple
coatings may be applied for desired performance. Further, some
actives may be provided for slow release, pulsatile release,
controlled release, extended release, delayed release, targeted
release, synchronized release, or targeted delayed release. For
release/absorption control, solid carriers can be made of various
component types and levels or thicknesses of coats, with or without
an active ingredient. Such diverse solid carriers can be blended in
a dosage form to achieve a desired performance. The compositions
may be formulated for oral, nasal, buccal, ocular, urethral,
transmucosal, vaginal, topical or rectal delivery, although oral
delivery is used mostly.
[0121] The present invention may also contain a plasticizer and
possibly other coating excipients such as colorants, talc, and/or
magnesium stearate, which are well known in the art. Suitable
plasticizers include: triethyl citrate (citroflex 2), triacetin
(glyceryl triacetate), acetyl triethyl citrate, carbowax 400
(polyethylene glycol 400), diethyl phthalate, tributyl citrate,
acetylated monoglycerides, glycerol, fatty acid esters, propylene
glycol, and dibutyl phthalate. In particular, anionic carboxylic
acrylic polymers usually will contain about 5-25% by weight of a
plasticizer, especially dibutyl phthalate, polyethylene glycol,
triethyl citrate and triacetin. Conventional coating techniques
such as spray or pan coating are employed to apply coatings. The
coating thickness must be sufficient to ensure that the oral dosage
form remains intact until the desired site of topical delivery in
the lower intestinal tract is reached.
[0122] It should be appreciated that there is considerable overlap
between the above-listed additives in common usage, since a given
additive is often classified differently by different practitioners
in the field, or is commonly used for any of several different
functions. Thus, the above-listed additives should be taken as
merely exemplary, and not limiting, of the types of additives that
can be included in compositions of the present invention. The
amounts of such additives may be readily determined by one skilled
in the art, according to the particular properties desired.
[0123] Additives may be include, e.g., pre-mixed propylene glycol,
glycerin, citric acid, sodium benzoate, povidone (kollidon 30),
sorbitol solution and the like. Flavorants, sweeteners,
preservatives, bitter masking agent, thickeners and the like may
also be added to the blender. In one example, the flavorants may be
lemon, bubble gum, grape, wild cherry or other flavors, with
sweeteners including saccharin or honey. In addition, a glycerin
solution may be added in addition to water, e.g., double deionized
water.
[0124] In addition the present invention may be in the form of a
chewing gum formulation based on natural rubber have been widely
used in the pharmaceutical industry. The advantages are the
pleasant and popular dosage form and rapid, sublingual absorption
of an active ingredient. When in the form of a chewing gum the
present invention may include waxes, such as, for example, beeswax,
solid paraffin, ozocerite, polyols, cellulose esters,
pharmaceutically active materials, flavoring agents, sweeteners,
colorants, stearic acid, calcium stearate, magnesium stearate,
solubilizers, chelating agents, surface stabilizer, additives, or
similar substances, may be used to ensure a longer chewing time,
have proven particularly advantageous with regard to the
chewability.
[0125] In yet another embodiment, the formulation may be a
combination of a soft-gel or liquid interior coated with a more
firm exterior. For example, certain agents may be provided for
immediate release in a thixotropic gel in the interior of a gel or
chewing-gum-like exterior.
[0126] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims.
[0127] All publications and patent applications mentioned in the
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0128] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
* * * * *