U.S. patent application number 15/662175 was filed with the patent office on 2018-03-15 for oral dosage forms for oxygen-containing active agents and oxyl-containing polymer.
This patent application is currently assigned to Spriaso LLC. The applicant listed for this patent is Spriaso LLC. Invention is credited to Chandrashekar Giliyar, Satish Kumar Nachaegari, Chidambaram Nachiappan, Mahesh V. Patel, Srinivansan Venkateshwaran.
Application Number | 20180071277 15/662175 |
Document ID | / |
Family ID | 48695315 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180071277 |
Kind Code |
A1 |
Giliyar; Chandrashekar ; et
al. |
March 15, 2018 |
ORAL DOSAGE FORMS FOR OXYGEN-CONTAINING ACTIVE AGENTS AND
OXYL-CONTAINING POLYMER
Abstract
The disclosed invention is drawn to pharmaceutical tablets that
provide delivery of active agents having at least three
oxygen-containing groups, a tri-oxy active agent, as well as a
second active ingredient. Non-limiting examples of three
oxygen-containing group active agents include guaifenesin, codeine,
hydrocodone, and their pharmaceutically acceptable salts. In one
embodiment, a pharmaceutical tablet for oral administration once
every 12 hours is provided. The tablet includes a first active
agent that is a tri-oxy active agent, a second active agent, and a
release rate controlling non-ionic oxyl-containing hydrophilic
polymer. The total oxyl content of the hydrophilic polymer in the
tablet is from about 4.times.10.sup.-4 moles to about
2.0.times.10.sup.-3 moles. The tablet is a matrix tablet and a
single-dose administration of one or more tablets to a subject
under fasted conditions provides a mean C.sub.max for each of the
first active agent and the second active agent that is 70% to 135%
of a respective mean C.sub.max provided by administering an
immediate release oral dosage form to a subject under fasted
conditions every 4 to 6 hours over a 12 hour time period, wherein
cumulative dosage amounts administered over the 12 hour time period
of each active agent is equivalent to the respective amount of each
active agent in the pharmaceutical tablet.
Inventors: |
Giliyar; Chandrashekar;
(Plymouth, MN) ; Nachaegari; Satish Kumar;
(Holladay, UT) ; Nachiappan; Chidambaram; (Sandy,
UT) ; Patel; Mahesh V.; (Salt Lake City, UT) ;
Venkateshwaran; Srinivansan; (Salt Lake City, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Spriaso LLC |
Salt Lake City |
UT |
US |
|
|
Assignee: |
Spriaso LLC
Salt Lake City
UT
|
Family ID: |
48695315 |
Appl. No.: |
15/662175 |
Filed: |
July 27, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15062443 |
Mar 7, 2016 |
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15662175 |
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13342883 |
Jan 3, 2012 |
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15062443 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/194 20130101;
A61K 31/485 20130101; A61K 9/2054 20130101; A61K 31/137 20130101;
A61K 31/4402 20130101; A61P 11/00 20180101; A61P 11/02 20180101;
A61P 11/14 20180101; A61K 31/09 20130101; A61K 45/06 20130101; A61K
9/0053 20130101; A61K 31/485 20130101; A61K 2300/00 20130101; A61K
31/09 20130101; A61K 2300/00 20130101; A61K 31/137 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20; A61K 45/06 20060101 A61K045/06; A61K 31/194 20060101
A61K031/194; A61K 31/4402 20060101 A61K031/4402; A61K 31/09
20060101 A61K031/09; A61K 31/137 20060101 A61K031/137 |
Claims
1. A pharmaceutical matrix tablet for oral administration once
every 12 hours: a first active agent that is a tri-oxy active
agent, a second active agent, and a release rate controlling
non-ionic oxyl-containing hydrophilic polymer the total oxyl
content of the hydrophilic polymer in the tablet is from about
4.times.10.sup.-4 moles to about 2.0.times.10.sup.-3 moles, and
wherein a single-dose administration of one or more tablets to a
subject under fasted conditions provides a mean C.sub.max for each
of the first active agent and the second active agent that is 70%
to 135% of a respective mean C.sub.max provided by administering an
immediate release oral dosage form to a subject under fasted
conditions every 4 to 6 hours over a 12 hour time period, wherein
cumulative dosage amounts administered over the 12 hour time period
of each active agent in the immediate release oral dosage is
equivalent to the respective amount of each active agent in the
pharmaceutical tablet.
2. The pharmaceutical tablet of claim 1, wherein the hydrophilic
polymer is a cellulose polymer.
3. The pharmaceutical tablet of claim 2, wherein the cellulose
polymer is hydroxypropyl methyl cellulose (HPMC).
4. The pharmaceutical tablet of claim 3, wherein the hydroxypropyl
methyl cellulose has an average methoxy content of about 15 mole %
to about 30 mole %.
5. The pharmaceutical tablet of claim 3, wherein the hydroxypropyl
methyl cellulose has an average methoxy content of about 18 mole %
to about 25 mole %.
6. The pharmaceutical tablet of claim 3, wherein the hydroxypropyl
methyl cellulose is present in the tablet in an amount of 40 mg to
about 175 mg.
7. The pharmaceutical tablet of claim 3, wherein the hydroxypropyl
methyl cellulose is present in the tablet in an amount of 60 mg to
about 150 mg.
8. The pharmaceutical tablet of claim 1, wherein the first active
agent is selected from the group consisting of guaifenesin,
codeine, hydrocodone, and their pharmaceutically acceptable
salts.
9. The pharmaceutical tablet of claim 8, wherein the mean C.sub.max
of the first active agent does not vary by more than 40% when
administered with food as compared to administration under fasted
condition.
10. The pharmaceutical tablet of claim 1, wherein the second active
agent is a tri-oxy active agent.
11. The pharmaceutical tablet of claim 1, wherein the second active
agent is a non-tri-oxy active agent.
12. The pharmaceutical tablet of claim 11, wherein the second
active agent is selected from the group consisting of
chlorpheniramine, cyclopentamine, dexchlorpheniramine,
diphenhydramine, brompheniramine, dexbrompheniramine,
dextromethorphan tripolidine, desloratadine, cyproheptadine,
phenylephrine, pyrallamine, pseudoephedrine, azalastin, loratidine,
theophyline and their salts or esters thereof and combinations
thereof.
13. The pharmaceutical tablet of claim 11, wherein the second
active agent is chlorpheniramine or its acceptable salt.
14. The pharmaceutical tablet of claim 1, wherein the tablet
further includes a third active agent.
15. The pharmaceutical tablet of claim 14, wherein the third active
agent is a decongestant.
16. The pharmaceutical tablet of claim 1, wherein the first active
agent is codeine.
17. The pharmaceutical tablet of claim 16, wherein the ratio of
total molar content of the oxyl groups in the hydrophilic polymer
to the total molar content of the oxygen-containing groups in the
codeine is about 2.5 to about 9.
18. The pharmaceutical tablet of claim 16, wherein the codeine
comprises about 25 wt % to about 30 wt % of the tablet.
19. The pharmaceutical tablet of claim 16, wherein the second
active agent is chlorpheniramine or pharmaceutically acceptable
salts thereof.
20. The pharmaceutical tablet of claim 19, wherein when placed in a
USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N
hydrochloric acid solution in water at 37.degree. C., about 30% to
about 40% of the amount of codeine is released in the first 0.5 to
1 hour and the amount of chlorpheniramine released in the same time
is between 80% and 120% of the amount of codeine released.
21-100. (canceled)
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/062,443, filed Mar. 7, 2016, which, is a
continuation of U.S. patent application Ser. No. 13/342,883, filed
Jan. 3, 2012, each of which is herein incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to oral dosage forms
containing combination of pharmaceutical active agents for treating
cough and associated methods of treatment and manufacture.
Accordingly, this invention involves the fields of chemistry,
pharmaceutical sciences, medicine and other health sciences.
BACKGROUND OF THE INVENTION
[0003] Tri-oxy active agents (drugs having at least three different
oxygen-containing groups) such as guaifenesin, codeine and
hydrocodone are used to treat cold and cough as well as other
related symptoms. Often, cold, cough, allergies, and other similar
conditions can require treatment with multiple active agents in
order to simultaneously alleviate multiple symptoms. For example,
combinations of active agents such as codeine or hydrocodone with a
mucolytic or a decongestant or an anti-tussive have been used for
management of cold, cough and flu symptoms. However, these
combinations are primarily available as inconvenient liquids which
are prone to dosing errors and which require frequent dosing in
order to provide consistent and continuous symptom relief.
Commercially available combination products tend to be short-acting
and often require dosing every four, six or eight hours. The need
for frequent dosing and the re-emergence of symptoms between doses
often make sleeping difficult, which in turn can delay the recovery
process. Moreover, the combination dosage forms must meet each
active agent's own unique pharmacokinetic requirement for symptom
or co-symptom relief.
[0004] Guaifenesin (glyceryl guaiacolate, GGE) is a widely used
expectorant that assists in loosening phlegm (mucus) and thins
bronchial secretions to make cough more productive. The structure
of guaifenesin is generally shown as:
##STR00001##
Guaifenesin is thought to act by increasing the volume and reducing
the viscosity of secretions in the trachea and bronchi. It is also
reported to stimulate the flow of respiratory tract secretions
allowing ciliary movement to carry the loosened secretions upward
toward the pharynx. Guaifenesin has a plasma half-life of about one
hour. GGE is commonly available as an immediate release tablet (200
mg and 400 mg strengths) requiring frequent dosing such as once
every four hours.
[0005] Codeine (3-methylmorphine) is an opiate used widely for its
antitussive (cough suppression) and analgesic properties. Its
structure is generally shown as:
##STR00002##
Codeine helps in temporary control of cough caused by minor throat
and bronchial irritation as occurs with common cold or inhaled
irritants. The recommended antitussive codeine dose in adults and
children 12 years of age and above is 10 to 20 mg codeine
administered every 4 to 6 hours not to exceed 120 mg/day. The
reported a plasma half-life for codeine is about 2.5-3 hours. It is
more commonly available as immediate release dosage form that
requires frequent dosing.
[0006] Hydrocodone is a narcotic pain reliever and a cough
suppressant and its structure is generally shown as:
##STR00003##
Hydrocodone is an opioid derived from codeine and is recognized as
both an effective analgesic and antitussive agent. It is generally
considered to be one of the potent and effective antitussive drugs
and is believed to act, at least in part, by a direct depressant
effect on a cough center in the medulla and to a lesser degree the
respiratory center. The recommended adult hydrocodone bitartrate
dosage for the symptomatic relief of cough is 5 mg (as hydrocodone
bitartrate) every 4 to 6 hours as needed, not to exceed 30 mg in 24
hours. Children 6 to 12 years of age should be administered 1/2 the
adult dose, not to exceed a total of 15 mg drug in 24 hours. It is
reported to have a plasma half-life of about 3.8 to 6 hours. It is
more commonly available as immediate release dosage form that
requires frequent dosing.
[0007] Pseudoephedrine is a sympathomimetic drug of the
phenethylamine and amphetamine chemical classes. It is found as a
hydrochloride or sulfate salt in many over-the-counter preparations
more commonly as a single ingredient formulation. It is generally
indicated for temporary relief of nasal and/or sinus congestion due
to the common cold, hay fever or other upper respiratory allergies.
The typical dose for adults and children 12 years of age is 60 mg
to 120 mg.
[0008] Chlorpheniramine is a propylamine antihistamine
(H.sub.1-receptor antagonist) that also possesses anticholinergic
and sedative activity. It prevents released histamine from dilating
capillaries and causing edema of the respiratory mucosa.
[0009] Chlorpheniramine maleate is commonly available in immediate
release dosages as an over-the-counter anti-allergy drug. Following
oral administration of chlorpheniramine the peak plasma
concentration is reached in 2-3 hours and its duration of effect
lasts for 4-6 hours, therefore requiring frequent dosing. The oral
dose in adults and children 12 years of age and older is typically
4 mg chlorpheniramine maleate every 4 to 6 hours.
[0010] Dextromethorphan hydrobromide monohydrate
(C.sub.18H.sub.25NO.HBr.H.sub.2O) is a centrally acting antitussive
agent which elevates the threshold for coughing. It has no
analgesic or addictive properties. Its dose is 10 to 30 mg every 4
to 8 hours. Dextromethorphan exerts its effect in 15 to 30 minutes
after oral administration and its duration of action is for
approximately three to six hours, hence requiring frequent
dosing.
[0011] Phenylephrine is a potent decongestant agent commonly used
for temporary relief of nasal congestion associated with allergy or
head colds symptoms, etc. Following oral administration,
phenylephrine exerts its effect in 15 to 30 minutes and its effect
persists for up to 4 hours, therefore requiring frequent dosing.
The usual adult dose of phenylephrine is 10 to 20 mg orally every 4
hours as needed.
[0012] Most long acting oral dosage forms currently available to
treat the above-recited conditions contain only one active agent,
and typically require coating or bi-layering to enable various
controlled or sustained release including biphasic release of the
active.
[0013] Oxyl-containing polymers (having oxygen-containing groups)
such as methacrylates, carbomers, hypromellose (HPMC), etc. have
been used to enable slow release dosage forms having a single
tri-oxy or non-tri-oxy active. As reported for a single-layer
matrix tablet of a non-tri-oxy active such as chlorpheniramine, an
HPMC polymer (Methocel K4M) to active ratio of about 1:1 provides a
time to 50% in vitro drug release of about 3.5 hours. However, such
very slow release profile is unsuitable for a 12 hour dosing
therapy of tri-oxy actives to allow sleeping through the night and
without excessive daytime grogginess.
[0014] Use of oxyl-containing non-ionic hydrophilic polymers (e.g.
HPMC) have also been reported to formulate a single di-oxy active
(having two different oxygen-containing groups) such as propranolol
HCl into a matrix tablet, wherein a HPMC (Methocel K4M) to active
agent ratio is 1:0.3 by weight, and which provides a time to 50%
drug release in vitro of about 4 hours. However, such a slow
release profiles for tri-oxy actives is unsuitable for a 12 hour
dosing therapy.
[0015] Due to tremendous safety liability associated with
deviations from acceptable peak blood concentrations, many tri-oxy
active agents, such as narcotics like codeine and hydrocodone,
require stable blood levels upon oral dosing. For a solid dosage
form (tablet, capsules etc.) containing multiple actives with a
hydrophilic polymer, the design and management of the dosage form
performance for a given intended use becomes increasingly
challenging. This is especially true with regards to efficacy,
release, and pharmacokinetic requirements, which can be further
complicated for each active due to its distinct physiochemical and
biological properties. Additionally, food interactions with an oral
dosage form upon ingestion can produce unacceptable higher blood
concentrations of actives, especially from a longer acting product
which has higher active strength per dosage unit relative to an
immediate release dosage form. It is noteworthy that regulatory
concerns related to food effects of a bilayer tablet containing
ionic polymer of guaifenesin and codeine have been reported in the
literature.
[0016] To date, there appear to be no known teachings that enable a
combination matrix tablet containing at least one tri-oxy active,
such as guaifenesin or a codone, that upon single administration of
the combination tablet of two pharmacologically different actives
are released in an optimal manner, individually and collectively,
and that enables optimal blood levels of each active as required
for twice-a-day dosing therapy for regulatory approval
purposes.
SUMMARY OF THE INVENTION
[0017] The present inventors have recognized a benefit to providing
a tri-oxy active containing pharmaceutical tablet that is a matrix
tablet formulated for dosage every twelve hour and which does not
have negative food effects. Moreover, it has been surprisingly
found that by including certain levels of at least one tri-oxy
active agent in an oxyl-containing non-ionic hydrophilic polymer
based matrix tablet, there exists a unique optimal oxyl content
composition that enables a 12 hour product having no food
effect.
[0018] Accordingly, the present disclosure is drawn to combination
pharmaceutical solid dosage forms comprising at least one tri-oxy
active agent, a second active agent, and optionally, a third active
agent. The dosage form is formulated for oral dosing once every 12
hours. The tablet can include a first active agent that is a
tri-oxy active agent, a second active agent, and a release rate
controlling non-ionic oxyl-containing hydrophilic polymer. The
total oxyl content of the hydrophilic polymer in the tablet is from
about 4.times.10.sup.-4 moles to about 2.0.times.10.sup.-3 moles.
In one embodiment, a pharmaceutical matrix tablet for oral
administration once every 12 hours is provided. Related methods of
use and treatment are also provided. In one aspect, a single-dose
administration of one or more tablets to a subject under fasted
conditions can provide a mean C.sub.max for each of the first
active agent and the second active agent that is about 70% to about
135% of a respective mean C.sub.max provided by administering an
immediate release oral dosage, as a combination or respective
single active dosage form, to a subject under fasted conditions
every 4 to 6 hours over a 12 hour time period, wherein cumulative
dosage amounts administered over the 12 hour time period of each
active agent from the immediate release dosage forms are equivalent
to the respective amount of each active agent in the pharmaceutical
tablet.
[0019] In another embodiment, a combination pharmaceutical solid
dosage forms is provided that includes at least one tri-oxy active
agent, a second active agent, and optionally, an third active
agent. The dosage form is formulated for oral dosing once every 12
hours. The tablet can include a first active agent that is a
tri-oxy active agent, a second active agent, and a release rate
controlling non-ionic oxyl-containing hydrophilic polymer. The
total oxyl content of the hydrophilic polymer in the tablet is from
about 4.times.10.sup.-4 moles to about 2.0.times.10.sup.-3 moles.
In one embodiment, a pharmaceutical matrix tablet for oral
administration once every 12 hours is provided. Related methods of
use and treatment are also provided. In one aspect, a single-dose
administration of one or more tablets to a subject under fasted
conditions can provide a mean C.sub.max for each of the first
active agent and the second active agent that is about 70% to about
135% of a respective mean C.sub.max provided by administering the
same oral dosage to a subject under fed over a 12 hour time period,
wherein cumulative dosage amounts administered over a 12 hour time
period.
[0020] In another embodiment, a pharmaceutical solid dosage form
for dosing once every 12 hours is provided. The solid dosage form
is a matrix tablet and can include a first active agent that is a
tri-oxy active agent, a second active agent, and a release rate
controlling non-ionic oxyl-containing hydrophilic polymer. The
tablet is formulated such that when placed in a USP Type 2
dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric
acid solution in water at 37.degree. C., about 50 wt % of the first
active agent is released in about 1.5 hours to about 3.2 hours. The
ratio of the amount of first active released from the tablet to the
amount of second active agent released at 1 hour and at 4 hours is
between about 0.7:1 and about 1.3:1.
BRIEF DESCRIPTION OF DRAWINGS
[0021] FIG. 1 is a plot of the release profile of several
embodiment formulations of the present invention as well as a
comparative example.
[0022] FIG. 2 is a plot release profiles of the actives from some
of the representative examples as well as a comparative
example.
[0023] FIG. 3 is a plot of release profiles of the actives from
some representative examples and comparative examples.
DETAILED DESCRIPTION
[0024] Before the present pharmaceutical tablets and related
methods of use are disclosed and described, it is to be understood
that this invention is not limited to the particular process steps
and materials disclosed herein, but is extended to equivalents
thereof, as would be recognized by those ordinarily skilled in the
relevant arts. It should also be understood that terminology
employed herein is used for the purpose of describing particular
embodiments only and is not intended to be limiting.
[0025] It should be noted that, the singular forms "a," "an," and,
"the" include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to "an excipient" includes
reference to one or more of such excipients, and reference to "the
carrier" includes reference to one or more of such carriers.
Definitions
[0026] As used herein, the term "treatment," when used in
conjunction with the administration of oral dosage forms containing
guaifenesin and a codone (such as codeine, hydrocodone etc), refers
to the administration of the oral dosage forms to subjects who are
either asymptomatic or symptomatic. In other words, "treatment" can
both be to reduce or eliminate symptoms associated with a condition
or it can be prophylactic treatment, i.e. to prevent the occurrence
of the symptoms. Such prophylactic treatment can also be referred
to as prevention of the condition.
[0027] As used herein, the terms "formulation" and "composition"
are used interchangeably and refer to a mixture of two or more
compounds, elements, or molecules. In some aspects the terms
"formulation" and "composition" may be used to refer to a mixture
of one or more active agents with a carrier or other excipients.
Furthermore, the term "dosage form" can include one or more
formulation(s) or composition(s) provided in a format for
administration to a subject. When any of the above terms is
modified by the term "oral" such terms refer to compositions,
formulations, or dosage forms formulated and intended for oral
administration to subjects.
[0028] A temperature processing aid is a compound that, when added
to the formulations of the present disclosure, can act to impart
handling flexibility with respect to processing temperature.
[0029] As used herein, "active agent," "bioactive agent,"
"pharmaceutically active agent" and "drug" may be used
interchangeably to refer to an agent or substance that has
measurable specified or selected physiologic activity when
administered to a subject in an effective amount. More
specifically, as used herein, a "tri-oxy active agent" or "tri-oxy
active" has at least three different types of oxygen-containing
groups in the "parent" or basic molecular structure. The
oxygen-containing group can be a carbonyl or ketone (C.dbd.O)
group, a methoxy or methoxyl (--OCH.sub.3) group, an ether (--O--)
group, or hydroxy or hydroxyl (--OH) group. For example, in one
embodiment the tri-oxy active can have at least one methoxyl group,
at least one ether group, and at least one carbonyl or hydroxyl
group.
[0030] In one embodiment, the tri-oxy active suitable for this
invention is selected from the group comprising guaifenesin,
codeine, hydrocodone, guaiacolsulfonate, carbetapentane,
methscopolamine, and their pharmaceutical acceptable salts,
hydrates, solvates and polymorphs. In a specific embodiment, the
tri-oxy active suitable for this invention is selected from the
group comprising guaifenesin, codeine, hydrocodone,
guaiacolsulfonate and their pharmaceutical acceptable salts,
hydrates, solvates and polymorphs.
[0031] Similarly, as used herein, a "non-tri-oxy" active agent is a
pharmaceutically active agent that contains less than three
different oxygen-containing groups. In one embodiment, the
non-tri-oxy active can have only one oxygen-containing group. In
another embodiment, the non-tri-oxy active does not have any
oxygen-containing group.
[0032] As used herein, "decongestants" are a class of active agents
that induces vasoconstriction of the blood vessels in the nose,
throat, and paranasal sinuses, which results in reduced
inflammation (swelling) and mucus formation in these areas. These
actives are commonly used in the treatment of cough/cold symptoms.
Non-limiting examples of suitable decongestants of are ephedrine,
levo-methamphetamine, phenylephrine, phenylpropanolamine,
propylhexedrine, pseudoephedrine, synephrine, levonordefrin,
mephentermine, tuaminoheptane, tymazoline, and their
pharmaceutically acceptable salts.
[0033] As used herein, the term "non-ionic oxyl-containing
hydrophilic polymer" is an uncharged polymer that contains at least
hydroxyl (--OH) and methoxyl (--OCH.sub.3) groups in its basic
monomer structure; the polymer swells/gels and eventually dissolves
in water. The number of each of these groups in the polymer
determines the rate and extent of its hydration/gelling in an
aqueous medium.
[0034] Accordingly, the "methoxyl content" or "methoxy content" of
the polymer is the total methoxyl groups in the polymer and can be
expressed as moles percent (moles %). Similarly, the "hydroxyl
content" of the polymer is the total hydroxyl groups in the polymer
and can be expressed as moles %. For example, one mole of the
Hypromellose 2208, is reported to contain approximately 22 mole %
methoxyl groups and 8 mole % hydroxyl groups. In other words, the
methoxyl groups and hydroxyl groups constitute about 22% and 8% of
the molecular weight, respectively.
[0035] As used herein, the "total oxyl content of the polymer" is
the sum of the methoxyl and hydroxyl contents in the molecule, and
can be expressed in terms of moles. It can also be expressed in
terms of moles per dosage unit (example, a tablet), which is
calculated based on the amount of that specific polymer present per
dosage unit.
[0036] The total oxyl content, methoxyl and hydroxyl contents of
the non-ionic oxyl-containing hydrophilic cellulose polymer in the
tablet of the current invention can be calculated by the following
equations:
Total Oxyl Content , in moles = ( Weight of polymer in tablet in
grams Molecular Wt of the Polymer ) * [ 3 + { Dp * ( A + 1 ) } ]
##EQU00001## Total Methoxyl Content , in moles = ( Weight of
polymer in dosage form in grams Molecular Wt of the Polymer ) * ( D
p * A ) ##EQU00001.2## Total Hydroxyl Content , in moles = ( Weight
of polymer in dosage form in grams Molecular Wt of the Polymer ) *
( D p + 3 ) ##EQU00001.3##
Wherein, Dp=Degree of Polymerization depending on the grade of
polymer, A=degree of substitution of Methoxyl group in the polymer
and A=1.4 and 1.9 for Hypromellose 2208 and Hypromellose 2910,
respectively. The above values for Dp and A is typical for a given
type of hypromellose and can be obtained from the manufacturer's
technical sheets/certificates.
[0037] By way of example, consider a tablet containing 100 mg of a
Hypromellose 2208 of 4000 cP viscosity grade. The total oxyl,
methoxyl and hydroxyl contents for the polymer can be calculated as
shown below:
[0038] From the literature, Hypromellose 2208 has a methoxyl
substitution of 1.4, a degree of polymerization of 460 and a
molecular wt of 86,000 g/mol. Using these values in the above said
equations, the following results are obtained:
Total oxylcontent = ( 0.1 86 , 000 ) * [ 3 + { 460 * ( 1.4 + 1 ) }
] = 1.29 * 10 - 03 moles ##EQU00002## Total Methoxyl Content = (
0.1 86 , 000 ) * ( 460 * 1.4 ) = 7.49 * 10 - 04 moles
##EQU00002.2## Total Hydroxyl Content = ( 0.1 86 , 000 ) * ( 460 +
3 ) = 5.38 * 10 - 04 moles ##EQU00002.3##
[0039] As used herein, the "total molar oxygen containing groups of
the active" is the sum of the oxygen containing groups in the
molecule, and can be expressed in terms of moles. It can also be
expressed in terms of moles per dosage unit (example, a tablet),
which is calculated based on the amount of the oxygen containing
groups for that specific active present per dosage unit.
[0040] The "total molar oxygen containing groups of the active" in
the tablet of the current invention can be calculated by the
following equations:
Total molar oxygen containing groups of the active = ( Weight of
Active in dosage form in grams Molecular Wt of the Active ) * A
##EQU00003##
Wherein A is the number of oxygen containing groups in the "parent"
or basic molecular structure. For example, for guaifenesin, A=4;
for codeine phosphate, A=3; for hydrocodone bitartrate, A=3. The
weight of active in the dosage form is the actual weight of the
active used. The molar weight is the weight of one mole of the
active expressed in grams. For the purpose of the above
calculation, if a salt form is used in the dosage form, the weight
of active used and the molar weight should be of the corresponding
salt only.
[0041] As an example, for a tablet having 30 mg (0.03 g) of Codeine
Phosphate, (molecular weight=397.37; number of oxygen-containing
groups in the "parent" or basic molecular structure=3) the total
molar content of oxygen containing groups can be calculates as
Total molar oxygen containing groups in 30 mg Codeine Phosphate = (
0.03 397.37 ) * 3 = 2.26 * 10 - 04 Moles ##EQU00004##
Similarly, for a tablet having 600 mg (0.6 g) of Guaifenesin
(molecular weight=198.22; number of oxygen-containing groups in the
"parent" or basic molecular structure=4), the total molar content
of oxygen containing groups can be calculated as:
Total molar oxygen containing groups in 600 mg Guaifenesin = ( 0.6
198.22 ) * 4 = 1.21 * 10 - 02 Moles ##EQU00005##
[0042] Calculation of ratio of the total molar content of oxyl
groups in the hydrophilic polymer to the total molar content of the
oxygen containing groups in an active can be calculated as shown
below:
( Total Oxyl moles for a given weight of polymer in the dosage form
Total molar oxygen containing groups in Active in the dosage form )
##EQU00006##
[0043] As used herein, "solid dosage form" of the present invention
refers to the unitary dispensable solid dosage comprising a
pre-determined amount of the actives in the composition of the
invention wherein the dosage form is intended to deliver one
therapeutic dose per administration. Examples of known solid dosage
forms include without limitation, tablets, capsules, caplets, mini
tablets, powders, pellets, granules, triturates, solid solutions
etc. In one embodiment the tablet, mini tablet, powder, pellets,
and granules may be coated with a suitable a conventional coating
material to achieve, for example, greater shelf-life stability
(photo-stability, chemical stability, moisture-stability etc), or
to enhance identification (color coating) or to enhance the
organoleptic perceptions (include flavor and/or sweetener, prevent
bad taste and/or odor, etc.). Tablets and caplets may be scored to
facilitate division of dosing. The capsules containing powder,
pellets or granules or tablets or mini tablets can be also
coated.
In a specific embodiment, the tablet is a matrix tablet wherein,
the two or more actives of the invention can be present as a
homogenous admixture within a matrix and presented as a monolithic
tablet.
[0044] The term "guaifenesin" refers to the expectorant compound
(3-(2-methoxyphenoxy)-1, 2-propanediol). For the purpose of the
current invention, guaifenesin can be used in the form of a 100%
pure powder or as a pre-granulate form (for example, for direct
compression process) or its equivalent form. It should also be
noted that a mixture of the said guaifenesin forms can be used.
[0045] The term "codeine" refers to the narcotic as classified
under schedule II of DEA controlled substances and refers to the
compound itself as well as its pharmaceutically acceptable salts,
hydrates, polymorphs, solvates, isomers and the like. Non-limiting
examples of pharmaceutically acceptable codeine salts include, but
are not limited to, codeine phosphate, codeine hydrochloride,
codeine phosphate, codeine sulfate, codeine citrate, and
combinations thereof. In one embodiment codeine is in the form of
codeine, codeine sulphate, codeine phosphate or combinations
thereof. In a specific embodiment, codeine is in the form of
codeine sulphate, or codeine phosphate or combinations thereof.
[0046] The term "hydrocodone" refers to the narcotic as classified
under Schedule II of DEA controlled substances and refers to the
compound itself as well as its pharmaceutically acceptable salts,
hydrates, polymorphs, solvates, isomers and the like. Non-limiting
examples of pharmaceutically acceptable hydrocodone salts include,
but are not limited to, hydrocodone bitartrate, and combinations
thereof
[0047] The term "substantially free" of a particular component or
compound, such as "substantially free of ionic polymer" should be
understood as meaning less than 5 wt %, or less than 3 wt % of less
than 2 wt % of the total composition. In another aspect,
substantially free can refer to less than 1 wt % of the designated
component. For example, a composition that is said to be
substantially free of ionic polymer can have less than 5 wt %, or
less than 3 wt/o, or less than 2 wt %, or less than 1 wt % of the
ionic polymer. In some embodiments, the compositions and oral
dosage forms of the present invention can be free of ionic
polymer.
[0048] As used herein, the terms "release" and "release rate" are
used interchangeably to refer to the discharge or liberation of a
substance, including without limitation a drug, from a dosage form
into a surrounding environment such as an aqueous medium either in
vitro or in vivo.
[0049] As used herein, the term "immediate release" refers to the
release of active from a dosage form, wherein, T.sub.25% release is
less than 0.3 hour, T.sub.50% release is less than 0.5 hour and
T.sub.75% release is less than 0.7 hour and wherein the release of
dosage form is determined using a USP Type II (paddle) Dissolution
Apparatus set at 50 rpm in about 900 mL of 0.1N hydrochloric acid
solution in water at about 37.degree. C. The immediate release
dosages (for example, in the form of tablet) are used herein to
compare with the dosage forms of the current invention. The
immediate release dosage form can comprise a single active or a
combination of actives that are being compared. In one aspect, the
dosage forms of the current invention does not contain any of the
actives as an immediate release layer or component or portion, or
fraction, nor is a combination of immediate release and sustained
release components.
[0050] The terms "release rate controlling agent", "release
modifying agent", "release modulating agent", and "release
modifiers" are used interchangeably and refer to pharmaceutically
acceptable agents or devices that are able to alter, delay, target,
increase or decrease, or otherwise customize, the release rates of
at least one of the contents of the dosage form, when exposed to an
aqueous use environment. In one embodiment, the release rate
controlling agent is a non-ionic oxyl-containing hydrophilic
polymer.
[0051] As referred to herein, resistance to "alcohol extraction" or
"alcohol associated dose dumping" in presence of alcohol can be
tested for the dosage forms of this invention, by subjecting the
dosage form to Simulated Gastric Fluid (SGF) with 20% ethanol. A
typical manner in order to obtain 900 ml of Simulated Gastric Fluid
(SGF) with 20% ethanol is by mixing 800 ml of SGF with 210 ml of
95% ethanol/water (which provides 200 ml ethanol) and taking 900 ml
of the mixture. Resistance to alcohol extraction can also be tested
using an aqueous solution comprising 400 ethanol and performing a
drug release testing in presence of alcohol, the results can be
compared to the release of drug from the same release medium
without alcohol added.
[0052] Unless otherwise specified, a drug release rate obtained at
a specified time refers to the in vitro drug release rate obtained
at the specified time following implementation of an appropriate
release testing. The mean time at which a specified percentage of
the drug within a dosage form has been released to the medium of
test may be referenced as the "T.sub.x %" value, where "x" is the
percent of drug that has been released. For example, the commonly
used reference measurement for evaluating drug release from dosage
forms is the time at which 25%, 50% and/or 75% of drug within the
dosage form has been released. This measurement is referred to as
the "T.sub.25%", "T.sub.50%", "T.sub.75%" for the dosage form.
[0053] As used herein, "subject" refers to a mammal that may
benefit from the administration of a drug composition or method of
this invention. Examples of subjects include humans, and may also
include other animals such as horses, pigs, cattle, dogs, cats,
rabbits, and aquatic mammals. In one embodiment, the subject is a
human subject.
[0054] The term "oral administration" represents any method of
administration in which an active agent can be administered by
swallowing, chewing, or sucking of the dosage form. In an
embodiment, the pharmaceutical tablet of this invention is
swallowed whole with the aid of a liquid such as water, milk, juice
and the like.
[0055] For the purpose of this invention, unless otherwise stated,
administration to a subject under fed condition ("fed treatment")
refers to administration such that following an overnight fast of
at least 10 hours, the subject starts the test meal 30 minutes
prior to administration of the dosage form. The dosage form is
administered 30 minutes after start of the test meal, wherein the
dosage form is administered with about 240 mL of water. No food is
allowed for at least 4 hours post-dose. Water can be allowed as
desired except for one hour before and after drug
administration.
[0056] Similarly, unless specifically mentioned, administration to
subjects under fasted condition ("fasted treatment") refers to
administration such that following an overnight fast of at least 10
hours, the dosage form is administered with about 240 mL of water
to the subject. No food is allowed for at least 4 hours post-dose.
Water can be allowed as desired except for one hour before and
after drug administration. A "test meal" for evaluating food-effect
refers to a high-fat (approximately 50 percent of total caloric
content of the meal) and high-calorie (approximately 800 to 1000
calories) meal. The test meal should derive approximately 150, 250,
and 500-600 calories from protein, carbohydrate and fat,
respectively.
[0057] As used herein, "no food effect", "refractory to food
intake", "absence of food effect" and the like refer to the
property such of an oral dosage form such that following single
dose administration of an oral dosage form to a subject under
either fed or fasted conditions, the variation in the
pharmacokinetic parameters for the active agents in the oral dosage
form is not more than about 40% as compared to the same
pharmacokinetic parameter measured in the same subject when the
oral dosage form is administered under the opposite condition (i.e.
fed vs. fasted). In one embodiment, the pharmacokinetic parameters,
particularly the plasma mean C.sub.max or the mean AUC.sub.0-inf or
both, for the respective actives does not vary by more than about
30% when administered under a fed versus a fasted condition.
[0058] As used herein, "steady state" or "C.sub.ss" refers to the
concentration of an active in a body fluid (usually plasma) when
the rates of drug administration and drug elimination are equal.
C.sub.ss is a value approached as a limit and is achieved,
theoretically, following the last of an infinite number of equal
doses given at equal intervals. C.sub.ss max) is the maximum value
under steady state conditions and C.sub.ss min is the minimum value
achieved under steady state conditions.
[0059] As used herein, an "effective amount" or a "therapeutically
effective amount" of a drug refers to a non-toxic, but sufficient
amount of the drug, to achieve therapeutic results in treating a
condition for which the drug is known to be effective. It is
understood that various biological factors may affect the ability
of a substance to perform its intended task. Therefore, an
"effective amount" or a "therapeutically effective amount" may be
dependent in some instances on such biological factors. Further,
while the achievement of therapeutic effects may be measured by a
physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and
response to treatments may make the achievement of therapeutic
effects a somewhat subjective decision. The determination of an
effective amount is well within the ordinary skill in the art of
pharmaceutical sciences and medicine. See, for example, Meiner and
Tonascia, "Clinical Trials: Design, Conduct, and Analysis,"
Monographs in Epidemiology and Biostatistics, Vol. 8 (1986),
incorporated herein by reference.
[0060] As used herein, the term "about" is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint. As
used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0061] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0062] Concentrations, amounts, levels and other numerical data may
be expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges or decimal units encompassed within that range as if
each numerical value and sub-range is explicitly recited. As an
illustration, a numerical range of "about 1 to about 5" should be
interpreted to include not only the explicitly recited values of
about 1 to about 5, but also include individual values and
sub-ranges within the indicated range. Thus, included in this
numerical range are individual values such as 2, 3, and 4 and
sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well
as 1, 2, 3, 4, and 5, individually. This same principle applies to
ranges reciting only one numerical value as a minimum or a maximum.
Furthermore, such an interpretation should apply regardless of the
breadth of the range or the characteristics being described.
[0063] Reference will now be made in detail to preferred
embodiments of the invention. While the invention will be described
in conjunction with the preferred embodiments, it will be
understood that it is not intended to limit the invention to those
preferred embodiments. To the contrary, it is intended to cover
alternatives, variants, modifications, and equivalents as may be
included within the spirit and scope of the invention as defined by
the appended claims.
[0064] With this in mind, the present invention provides for
pharmaceutical tablets for delivering at least two actives, at
least one of which is a tri-oxy active agent. In one embodiment, a
pharmaceutical tablet for oral administration once every 12 hours
is provided. The tablet includes a first active agent that is a
tri-oxy active agent, a second active agent, and a release rate
controlling non-ionic oxyl-containing hydrophilic polymer. The
total oxyl content of the hydrophilic polymer in the tablet is from
about 4.times.10.sup.-4 moles to about 2.0.times.10.sup.-3 moles.
The tablet is a matrix tablet and a single-dose administration of
one or more tablets to a subject under fasted conditions provides a
mean C.sub.max for each of the first active agent and the second
active agent that is 70% to 135% of a respective mean C.sub.max
provided by administering an immediate release oral dosage to a
subject under fasted conditions every 4 to 6 hours over a 12 hour
time period, wherein cumulative dosage amounts administered over
the 12 hour time period of each active agent in the immediate
release oral dosage is equivalent to the respective amount of each
active agent in the pharmaceutical tablet.
[0065] In another embodiment, a pharmaceutical tablet for oral
administration once every 12 hours is provided. The tablet includes
a first active agent that is a tri-oxy active agent, a second
active agent, and a release rate controlling non-ionic
oxyl-containing hydrophilic polymer. The total oxyl content of the
hydrophilic polymer in the tablet is from about 4.times.10.sup.-4
moles to about 2.0.times.10.sup.-3 moles. The tablet is a matrix
tablet and a single-dose administration of one or more tablets to a
subject under fed conditions provides a mean C.sub.max for each of
the first active agent and the second active agent that is 70% to
135% of a respective mean C.sub.max provided by administering an
immediate release oral dosage to a subject under fed conditions
every 4 to 6 hours over a 12 hour time period, wherein cumulative
dosage amounts administered over the 12 hour time period of each
active agent in the immediate release oral dosage is equivalent to
the respective amount of each active agent in the pharmaceutical
tablet.
[0066] In another embodiment, a pharmaceutical tablet for oral
administration once every 12 hours is provided. The tablet includes
a first active agent that is a tri-oxy active agent, a second
active agent, and a release rate controlling non-ionic
oxyl-containing hydrophilic polymer. The total oxyl content of the
hydrophilic polymer in the tablet is from about 4.times.10.sup.-4
moles to about 2.0.times.10.sup.-3 moles. The tablet is a matrix
tablet and a single-dose administration of one or more tablets to a
subject under fasted conditions every twelve hours provides a mean
C.sub.max for each of the first active agent and the second active
agent that is 70% to 135% of a respective mean C.sub.max provided
by administering the same oral dosage to the subject under fed
conditions every 12 hours. The same amount of each active agent is
administered over any given 12 hour period.
[0067] In another embodiment, a pharmaceutical tablet for dosing
once every 12 hours is provided. The tablet is a matrix tablet and
includes a first active agent that is a tri-oxy active agent, a
second active agent, and a release rate controlling non-ionic
oxyl-containing hydrophilic polymer. The tablet is formulated such
that when placed in a USP Type 2 dissolution apparatus at 50 rpm in
900 mL of 0.1 N hydrochloric acid solution in water at 37.degree.
C., about 50 wt % of the first active agent is released in about
1.5 hours to about 3.8 hours. The ratio of the amount of first
active released from the tablet to the amount of second active
agent released at 1 hour and at 4 hours is between about 0.7:1 and
about 1.3:1. In one embodiment, the tablets of the present
invention can be single layer tablets. In other words, the active
agents are present in a common tablet matrix and not separated into
distinct active agent layers.
[0068] In yet a further embodiment, the present invention provides
for a method of treating cough and/or cold symptoms in a human
subject, comprising administering to the human subject a
pharmaceutical tablet in accordance with one of the embodiments of
the present invention. In yet another embodiment, a method of
minimizing sleep disturbance for a human subject having cough
and/or cold symptoms is provided in which the method comprises
administering to the human subject a pharmaceutical tablet in
accordance with an embodiment of the present invention. In one
aspect, the methods of the present invention can be accomplished
without regard to food consumption. In one embodiment, the mean
C.sub.max of the first active agent will vary not more than 40%
when administered with food as compared to administration of the
same tablet to the same subject without food.
[0069] The oral dosage forms disclosed herein can be, but do not
have to be, administered with food (or meals). In one embodiment,
the composition or oral dosage capsule can be administered with a
meal, such as a meal that provides about 200 to about 1000 calories
of energy. In another embodiment, the oral dosage form can be
administered with a standard meal. In another embodiment, the oral
dosage form can be administered with a meal has no fat, low fat,
medium fat or high fat. The compositional make-up of the meals that
are administered can vary depending on the tastes and dietary needs
of a subject.
[0070] The oral dosage forms (e.g. tablets) disclosed herein can be
orally administered in a 12 hours' dosing regimen or as "12 hour
dosing" that is suitable to the needs of the subject. The dosage
form is also referred to as or "12 hour dosage form", or "12 hour
product". The 12 hours' dosing regimen can include administering
the dosage forms in the morning, in the evening, at about night
time or combinations thereof. The 12 hours' dosing regimen can
include dosing one or more dosage units at one or more
administration times. In one embodiment, the pharmaceutical dosage
forms of the current invention can be administered once every 12
hours. Further, the pharmaceutical dosage forms of the current
invention can be administered twice in a day (or about 24 hours)
usually about 12 hours apart. In another embodiment, the
pharmaceutical dosage form of the current invention is administered
once every 12 hours as a single oral dosage tablet.
[0071] In one embodiment, the 12 hour oral dosage forms of the
invention has no food--effect wherein, the dosage form provides
upon a single dose administration to a subject under fed and fasted
conditions, a ratios of the corresponding mean C.sub.max or
AUC.sub.0-inf, or both, for the respective actives between fed and
fasted treatments, in the range between about 0.7 and about 1.3. In
another specific embodiment, the 12 hour oral dosage forms of the
invention provides upon a single dose administration to a subject
under fed and fasted conditions, a ratio of the mean AUC.sub.0-inf
or AUC.sub.0-t or both, for the respective active between fed and
fasted treatments, in the range between 0.7 and 1.3.
[0072] The pharmaceutical tablets of the present invention include
a first active agent, which is a tri-oxy active agent. In one
embodiment, the first active agent can be codeine or its
pharmaceutically acceptable salts. In another embodiment, the first
active agent can be guaifenesin. It yet another embodiment, the
first active agent can be hydrocodone or its pharmaceutically
acceptable salts.
[0073] The pharmaceutical tablets of the present invention include
a second active agent, wherein, the second active agent can, but
does not need to, be a tri-oxy active. Thus, in some embodiments
the tablet can include a first and a second active agent that that
are each tri-oxy active agents, while in other embodiments the
second active agent can be a non-tri-oxy active agent. Non-limiting
examples of non-tri-oxy second active agents that can be used in
the tablets can include chlorpheniramine, cyclopentamine,
dexchlorpheniramine, diphenhydramine, brompheniramine,
dexbrompheniramine, dextromethorphan tripolidine, desloratadine,
cyproheptadine, phenylephrine, pyrallamine, pseudoephedrine,
azalastin, loratidine, theophylline, their salts or esters thereof,
and combinations thereof. In one embodiment, the second active
agent is a non-tri-oxy active agent. In another embodiment, the
second active agent is chlorpheniramine or its pharmaceutically
acceptable salt. Exemplary embodiments of first and second active
agent combinations include, but are not limited to, codeine and
guaifenesin, codeine and chlorpheniramine, guaifenesin and
hydrocodone, guaifenesin and chlorpheniramine, and hydrocodone and
chlorpheniramine, codeine and pseudoephedrine, guaifenesin and
pseudoephedrine, guaifenesin and dextromethorphan, codeine and
dextromethorphan, hydrocodone and chlorpheniramine; hydrocodone,
chlorpheniramine and pseudoephedrine or phenylephrine.
[0074] The pharmaceutical tablets of the present invention also
include a non-ionic oxyl-containing hydrophilic polymer. In one
embodiment, the non-ionic hydrophilic polymer is a release-rate
controlling polymer. In some embodiments, the tablets are also
free, or substantially free, of ionic polymers. Non-limiting
examples of non-ionic release-rate controlling hydrophilic polymers
that can be used include cellulose polymers such as hydroxypropyl
cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl
methyl cellulose, combinations thereof, and the like.
[0075] In one embodiment, the hydrophilic polymer is a cellulose
polymer. In another embodiment, the hydrophilic polymer is a
hydroxypropyl methyl cellulose. In a specific embodiment, the
polymer has an average methoxy content of about 15 mole % to about
30 mole %. In another specific embodiment, the polymer has an
average methoxy content of about 18 mole % to about 25 mole %. In
another embodiment, when used in a tablet dosage form of the
invention, the total oxyl content of the hydrophilic polymer in the
tablet is from about 4.times.10.sup.-4 moles to about
2.0.times.10.sup.-3 moles. In further embodiment, when used in a
tablet dosage form of the invention, the hydrophilic polymer
provides a methoxy content of about 2.2.times.10.sup.-4 to
1.2.times.10.sup.-3 moles per tablet. It should be noted that a
mixture of the said hydroxypropyl methyl celluloses can be used
wherein the requisite range of methoxyl content per dosage form
(example, tablet) is obtained.
[0076] In still further embodiments, when the cellulose polymer is
hydroxypropyl methyl cellulose, it can be present in the tablet in
an amount of about 40 mg to about 175 mg, or in an amount of about
60 mg to about 150 mg, or in an amount of about 60 mg to about 125
mg. In a specific embodiment, the hydroxypropyl methyl cellulose
can have an average apparent viscosity of about 3000 cP to about
15000 cP when determined on a 2% solution in water at 20.degree. C.
In another embodiment, the hydroxypropyl methyl cellulose can have
an average apparent viscosity of about 3000 cP to about 5000 cP
when determined on a 2% solution in water at 20.degree. C. It
should be noted that a mixture of hydroxypropyl methyl celluloses
can be used to achieve a desired viscosity within the above defined
ranges.
[0077] Without being limited by theory, it is believed that there
exists an interaction at the molecular level between the
oxyl-content of the non-ionic hydrophilic cellulose polymer and the
oxygen-containing groups in the tri-oxy actives of the invention.
It is believed that this interaction influences the rate and extent
of hydration, gelation and/or erosion of the polymer which in turn
enables the requisite performance for a matrix tablet formulated
for administration once every twelve hours. Therefore, a particular
range of the amount of the non-ionic polymer in a tri-oxy active
combination solid dosage form (e.g. matrix tablet) can provide a
release profile which enables 12 hour dosing. Accordingly,
Applicants have discovered that a total oxyl content of
4.times.10.sup.-4 moles to about 2.0.times.10.sup.-3 moles from the
polymer per dosage form (e.g. tablet) enables a 12 hour dosing
therapy of at least one tri-oxy active in combination with another
active of the invention. Applicants further believe that one or
more of the oxygen containing groups in the tri-oxy active is
responsible for the synergistic effect with the oxyl-containing
polymer. Furthermore, the levels of the oxyl-containing polymer
enabling a 12 hour solid dosage form is specific to an active that
contains at least three oxygen-containing groups; preferably at
least one of each of methoxyl group and ether groups and at least
one of carbonyl or hydroxyl groups. In contrast, as seen through
some of the experimental examples disclosed herein, a higher or
lower methoxy content of the polymer can result in an undesirably
fast or very slow release of the actives from the dosage form
thereby failing to comply with the typical requirements for the 12
hour dosing regimen.
[0078] The pharmaceutical tablets of the present invention can be
formulated such that upon single-dose administration of one or more
tablets to a subject under fasted conditions, the tablets can
provide a mean AUC.sub.inf of each of the first active agent and
the second active agent that is 70% to 135% of a respective mean
AUC.sub.inf provided by administering an immediate release oral
dosage to a subject under fasted conditions every 4 to 6 hours over
a 12 hour time period. The cumulative dosage amounts administered
over the 12 hour time period of each active agent in the immediate
release oral dosage is equivalent to the respective amount of each
active agent in the pharmaceutical tablet. Similarly, the tablets
can be formulated such that upon single-dose administration of one
or more tablets to a subject under fasted conditions provides a
mean AUC.sub.0-12 of each of the first active agent and the second
active agent that is 70% to 135% of a respective mean AUC.sub.0-12
provided by administering an immediate release oral dosage to a
subject under fasted conditions every 4 to 6 hours over a 12 hour
time period. As above, the cumulative dosage amounts administered
over the 12 hour time period of each active agent in the immediate
release oral dosage is equivalent to the respective amount of each
active agent in the pharmaceutical tablet.
[0079] In one embodiment, the first active agent is codeine or its
pharmaceutically acceptable salt. In one embodiment, the codeine
can be resin free or substantially resin free. The codeine can
comprise about 35 wt % or less, of the total tablet weight. The
codeine can comprise from about 20 wt % to about 35 wt % of the
total tablet weight. In another embodiment, the codeine can
comprise about 25 wt % to about 30 wt % of the total tablet weight.
In another embodiment, the codeine can comprise about 3 wt % to
about 5 wt % of the total tablet weight. In a further embodiment,
the codeine can comprise about 3.5 wt % to about 4 wt % of the
total tablet weight. In another embodiment, when the first active
agent is codeine, the ratio of total content of the oxyl groups in
the hydrophilic polymer to the total molar content of the
oxygen-containing groups in the codeine is from about 2.5 to about
9. In another embodiment, when the first active agent is codeine,
the ratio of total content of the oxyl groups in the hydrophilic
polymer to the total molar content of the oxygen-containing groups
in the codeine is from about 2.5 to about 4.5.
[0080] In a further embodiment, the tablet can have a first active
agent of codeine or its pharmaceutically acceptable salts and the
second active agent can be chlorpheniramine or a pharmaceutically
acceptable salt thereof. The codeine and chlorpheniramine tablet
can, upon single-dose administration to a subject under fasted
conditions, provide a mean T.sub.max for codeine of about 2.2 hours
to about 3.4 hours and a mean T.sub.max for chlorpheniramine of
about 5 hours about 14 hours. In another aspect, the codeine and
chlorpheniramine tablet can, when placed in a USP Type 2
dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric
acid solution in water at 37.degree. C., provide a release of the
active agents such that about 30% to about 40% of the amount of
codeine is released in the first 0.5 to 1 hour, and the amount of
chlorpheniramine released in the same time is between 80% and 120%
of the amount of codeine released. In another aspect, when placed
in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N
hydrochloric acid solution in water at 37.degree. C., the time to
release about 50 wt % of the codeine and chlorpheniramine is about
1.5 to about 3 hrs. In another aspect, when placed in a USP Type 2
dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric
acid solution in water at 37.degree. C., the time to release about
50 wt % of the codeine and chlorpheniramine is about 1.6 to about
2.4 hrs. In yet a further embodiment, the tablet can provide a
release of about 45-60% of the amount of codeine and about 45-60%
of the amount of chlorpheniramine in about 2 hours. In yet a
further aspect, when placed in a USP Type 2 dissolution apparatus
at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at
37.degree. C., the tablet can provide a release of the active
agents such that at least about 70% of the amount of
chlorpheniramine is released in about 3 hours to 4 hours, and the
amount of codeine released in the same time period is between 80%,
and 120% of the amount of chlorpheniramine released. In still a
further embodiment, the pharmaceutical tablet can be formulated
such that when placed in a USP Type 2 dissolution apparatus at 50
rpm in 900 mL of 0.1 N hydrochloric acid solution in water at
37.degree. C., the ratio of the amount of first active released to
the amount of second active agent released at a single time point
between 1 hour and 4 hours is about 0.8:1 and about 1.2:1.
[0081] In one embodiment, the dosage forms of the current invention
can include a third active agent. The third active agent can be a
tri-oxy active agent or a non-tri-oxy active agent. In one
embodiment, the active agent can be a decongestant. In one
embodiment, the decongestant can be pseudoephedrine, phenylephrine,
and their pharmaceutically acceptable salts. Example combinations
of first, second, and third active agents that can be combined in
the pharmaceutical tablets of the present invention include,
without limitation, 1) codeine, chlorpheniramine, and
pseudoephedrine; 2) codeine, chlorpheniramine, and phenylephrine;
3) codeine, guaifenesin, and pseudoephedrine; 4) codeine,
guaifenesin, and phenylephrine; 5) guaifenesin, hydrocodone, and
pseudoephedrine; 6) guaifenesin, hydrocodone, and phenylephrine;
and the like.
[0082] In one aspect, a single-dose administration of one or more
tablets to a subject under fasted conditions can provide a mean
C.sub.max for each of the first active agent, second active agent
and the third active agent that is about 70% to about 135% of a
respective mean C.sub.max provided by administering an immediate
release oral dosage, as a combination or respective single active
dosage form, to a subject under fasted conditions every 4 to 6
hours over a 12 hour time period, wherein cumulative dosage amounts
administered over the 12 hour time period of each active agent from
the immediate release dosage forms are equivalent to the respective
amount of each active agent in the pharmaceutical tablet. In one
aspect, the pharmaceutical matrix tablet of the current invention,
with the three actives, when placed in a USP Type 2 dissolution
apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution
in water at 37.degree. C., where in the amount of second and third
active released is within 70% to 135% of release of first active
when measured between about 1 and 4 hours.
[0083] In a further embodiment, the first active agent is codeine
and the second active agent is guaifenesin. It is noteworthy that
because both the codeine and the guaifenesin are tri-oxy active
agents and either of them could be considered as the first active
agent. The codeine can be present in the amounts discussed above,
and the guaifenesin can be present in amounts of about 600
mg/tablet to about 1200 mg/tablet. In another embodiment, the
guaifenesin can be present in an amount of 600 mg/tablet. In one
embodiment, the codeine can be present in an amount of about 30 mg,
the guaifenesin can be present in an amount of about 600 mg, and
the hydrophilic polymer can be hydroxypropyl methyl cellulose and
comprises about 8 wt % to about 20 wt % of the tablet. In a still
further specific embodiment, the hydrophilic polymer can be
hydroxypropyl methyl cellulose and comprises about 8 wt % to about
15 wt % of the tablet.
[0084] In another embodiment, the pharmaceutical tablet includes
codeine and guaifenesin and upon administration to a subject under
fasted conditions the tablet provides a guaifenesin C.sub.min of
about 3 ng/mL or more, at steady state. In another embodiment, the
tablet provides at steady state, a guaifenesin mean C.sub.max of
about 850 ng/mL to about 1700 ng/mL, and a codeine mean C.sub.max
of about 30 ng/mL to about 90 ng/mL.
[0085] In one aspect, when placed in a USP Type 2 dissolution
apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution
in water at 37.degree. C., the T.sub.25 for both codeine and the
guaifenesin is about 0.5-1 hour and the T.sub.75% for both the
codeine and the guaifenesin is about 5 hours. In another aspect,
when the tablet is placed in a USP Type 2 dissolution apparatus at
50 rpm in 900 mL of 0.1 N hydrochloric acid solution in water at
37.degree. C., about 25% to about 35% of the amount of guaifenesin
is released in the 0.5-1 hour, and the amount of codeine released
in the same time is between 70% and 130% of the amount of
guaifenesin released. In another aspect, when the tablet is placed
in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N
hydrochloric acid solution in water at 37.degree. C., about 50 wt %
of each of the guaifenesin and the codeine are released in about
1.5 to about 3 hours. In another embodiment, when the tablet is
placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of
0.1 N hydrochloric acid solution in water at 37.degree. C., about
50 wt % of each of the guaifenesin and the codeine are released in
about 1.6-2.4 hours. In still a further aspect, when the tablet is
placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of
0.1 N hydrochloric acid solution in water at 37.degree. C., at
least about 80% of the amount of codeine is released in about 8
hours, and the amount of guaifenesin released in the same time
period is between 80% and 120% of the amount of codeine released.
In one embodiment, the when the active agents are codeine and
guaifenesin and the dissolution is accomplished according to the
methodologies described above, the ratio of the amount of first
active released to the amount of second active agent released at a
single time point between 1.5 hours and 4 hours is about 0.7:1 and
about 1.3:1.
[0086] In a further embodiment, the first active agent can be
guaifenesin. The guaifenesin can be present in amounts of about 600
mg/tablet to about 1200 mg/tablet. In one embodiment, the
guaifenesin can be present in an amount of 600 mg/tablet. In one
embodiment, the ratio of the total molar content of oxyl groups in
the hydrophilic polymer to the total molar content of the oxygen
containing groups in the guaifenesin can be about 0.07 to 0.18.
When guaifenesin is the first active agent, the second active agent
can be hydrocodone. Like guaifenesin, hydrocodone is a tri-oxy
active agent and thus either of them could be considered to be the
first active agent in a tablet having both guaifenesin and
hydrocodone. In the guaifenesin--hydrocodone combination tablet, in
one embodiment the tablet can be such that upon administration to a
subject the tablet can provide a guaifenesin C.sub.min of about 3
ng/mL or more, at steady state. In one embodiment, the tablet can
be such that the guaifenesin can be present in an amount of about
600 mg to about 1200 mg, the hydrocodone can be present in an
amount of 5 mg to 10 mg, and the hydrophilic polymer can be
hydroxypropyl methyl cellulose and can be present in an amount of
55 mg to about 165 mg.
[0087] In still a further embodiment, the tablet can be such that
the guaifenesin can be present in an amount of about 600 mg/tablet,
the hydrocodone can be present in an amount of 5 mg/tablet, and the
hydrophilic polymer can be hydroxypropyl methyl cellulose and
comprises about 8 wt % to about 20 wt % of the tablet. In another
specific embodiment, the hydrophilic polymer can be hydroxypropyl
methyl cellulose and comprises about 8 wt % to about 15 wt % of the
tablet. In another embodiment, the tablet provides at steady state,
a guaifenesin mean C.sub.max of about 850 ng/mL to 1700 ng/mL, and
a hydrocodone mean C.sub.max of about 12 ng/mL to 25 ng/mL.
[0088] When the pharmaceutical tablets include guaifenesin and
hydrocodone as the first and second active agents respectively, the
tablet can be formulated such that when placed in a USP Type 2
dissolution apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric
acid solution in water at 37.degree. C., the T.sub.25% for both
guaifenesin and the hydrocodone is from about 25 minutes to about
75 minutes and the T.sub.75% for both the guaifenesin and the
hydrocodone is from about 3 hours to about 7 hours. In another
embodiment, the tablet can be formulated such that when placed in a
USP Type 2 dissolution apparatus at 50 rpm in 900 mL of 0.1 N
hydrochloric acid solution in water at 37.degree. C., about 35% or
less of the amount of guaifenesin and about 20% to 40% of the
amount of the hydrocodone are released in 0.5-1 hour. In yet a
further embodiment, the tablet can be formulated such that when
placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of
0.1 N hydrochloric acid solution in water at 37.degree. C., about
40-65% of the amount of guaifenesin and about 40-65% of the amount
of hydrocodone are released in about 2 hours. In another
embodiment, the tablet can be formulated such that wherein when
placed in a USP Type 2 dissolution apparatus at 50 rpm in 900 mL of
0.1 N hydrochloric acid solution in water at 37.degree. C., the
time to release about 50% of the amount of guaifenesin and of
hydrocodone is about 2 hours.
[0089] In another embodiment, the tablet can be formulated such
that when placed in a USP Type 2 dissolution apparatus at 50 rpm in
900 mL of 0.1 N hydrochloric acid solution in water at 37.degree.
C., about 35% or less of the amount of guaifenesin and about 20-40%
the amount of guaifenesin is released in the first 0.5-1 hour, and
the amount of hydrocodone released in the same time is between 70%
and 130% of the amount of guaifenesin released.
[0090] In still a further embodiment the tablet can be formulated
such that when placed in a USP Type 2 dissolution apparatus at 50
rpm in 900 mL of 0.1 N hydrochloric acid solution in water at
37.degree. C., at least about 80% of the amount of hydrocodone is
released in about 8 hours, and the amount of guaifenesin released
in the same time period is between 80% and 120% of the amount of
hydrocodone released. In yet another embodiment, when the active
agents are guaifenesin and hydrocodone and the release of the
actives is determined according to the methodologies described
above, the ratio of the amount of first active released to the
amount of second active agent released at a single time point
between 1.5 hours and 4 hours is about 0.7:1 and about 1.3:1.
[0091] In still a further embodiment the tablet can be formulated
such that when placed in a USP Type 2 dissolution apparatus at 50
rpm in 900 mL of 0.1 N hydrochloric acid solution in water at
37.degree. C., at least about 80% of the amount of hydrocodone is
released in about 8 hours, and the amount of guaifenesin released
in the same time period is between 80% and 120% of the amount of
guaifenesin released.
[0092] In some embodiments, the first active agent can be
hydrocodone or its pharmaceutically active salts. The hydrocodone
can comprise 0.5 wt % to about 1 wt % of the tablets and can be
present in amounts of about 5 mg/tablet to about 10 mg/tablet. In
embodiments where hydrocodone is the first active agent the
non-ionic hydrophilic polymer can be hydroxypropyl methyl cellulose
and can be present in amounts of 40 mg/tablet to about 175
mg/tablet.
[0093] In another aspect, the matrix tablet of the current
invention can be formulated such that it does not exhibit "dose
dumping" effect when tested in vitro in a USP Type 2 dissolution
apparatus at 50 rpm in 900 mL of 0.1 N hydrochloric acid solution
in water containing from about 4%-40% v/v of ethanol, at 37.degree.
C. Accordingly, in one embodiment, the tablet does not release the
entire amount of the tri-oxy active in about 2 hours or less. In
another embodiment, the amount of the tri-oxy active released from
the tablet under the said in vitro "dose dumping" release testing
conditions is about 180% or less, preferably, about 150% or less or
even more preferably 130% or less of the amount of the respective
tri-oxy active released in about 2 hours in a 900 mL 0.1 N
hydrochloric acid solution in water but without ethanol, at
37.degree. C., taken in a USP Type 2 dissolution apparatus at 50
rpm.
[0094] The compositions and the solid oral dosage forms (example,
tablets) of the current invention can also include one or more of
the pharmaceutical process aids selected from the group known in
the art, consisting of binders, bufferants, compacting aids,
diluents, disintegrants, flavors, colorants, taste-masking agents,
pH modifiers, lubricants, glidants, thickening agent, opacifying
agent, humectants, desiccants, effervescing agents, sweeteners,
plasticizing agents, wetting agents and the like. The amount of
each of these excipients per dosage form (example, matrix tablet)
can vary depending on the amount of the actives and non-ionic
oxyl-containing hydrophilic polymer in the dosage form. For
example, the tabletting aids are added in amounts typically known
to one of relevant skill in the art. Non-limiting examples of the
tabletting aids suitable for use in the pharmaceutical tablets of
the present invention include non-crystalline cellulose;
microcrystalline cellulose; dextrose; croscarmellose;
cyclodextrins; .beta.-cyclodextrins; .alpha.-cyclodextrin;
dextrates; sorbitol; lactose; sucrose; maltose; galactose;
polyvinylpyrrolidone (povidone K 12 to K120); crospovidone;
polyvinyl alcohol; glycerol; glucose; polyols such as mannitol;
xylitol or sorbitol or their combinations; polyethylene glycol
esters; alginates; sodium alginate; poly(lactide coglycolide);
gelatin; crosslinked gelatin; agar-agar; sodium dodecyl sulfate;
glycerin; polyethylene glycols of mol wt range from about 100 to
about 20,000 or their mixtures; lactose; guar gum; xanthan gum;
starches; gum arabic; dextrins; dibasic calcium phosphate;
cyclodextrins or its derivatives and their combinations; sodium
starch glycolate; croscarmellose sodium; galactomannan; tricalcium
phosphate; maltodextrin or its derivatives and their combinations;
polyoxyethylene stearate; carnuaba wax; fatty alcohols; sugar
esters; sugar ethers; shellacs; tocopherol; tocopherol
polyethyleneglycol succinate; tocopherol succinate; tocopherol
acetate; talc, magnesium stearate, stearic acid, sodium lauryl
sulphate, and the like.
[0095] The solid oral dosage forms the present invention can be
manufactured as tablet or capsule dosage forms either by dry
blending/granulation methods, or by wet granulation methods. For
example, the actives can be combined with one or more
pharmaceutically acceptable excipients/aids described above and
blended to get a homogenous mixture which can be compressed into a
tablet or into mini tablets to be disposed into a capsule. In
another embodiment, the homogenous mixture can be kneaded with a
binder solution to get a wet granulate mass which can be dried and
sized, for example by passing through ASTM mesh #30. The resulting
granules can be optionally blended with pharmaceutical aids such as
diluents, lubricants, disintegrants etc, and disposed into capsules
or compressed into tablets. In another particular case, the tablets
can be coated. Non-limiting examples of the processes that can be
used to prepare the compositions and dosage forms of this invention
include mixing melting, prilling, size reduction, melt-spray
congealing, co-precipitation, co-crystallization, encapsulation,
co-milling, spry or freeze drying, complexing, granulating,
extruding, slugging, or combinations thereof.
[0096] The solid oral dosage forms can also be formulated using
melt-extrusion processes alone or in combination with other known
processes. For example, in one embodiment, the required amounts of
the actives and non-ionic oxyl-containing hydrophilic polymer can
be homogeneously combined with a sufficient amount of one or more
pharmaceutical excipients/tableting aids prior to undergoing
extrusion.
[0097] The dosage forms of the invention provide "no food effect"
or the dosage form is "refractory to food intake". Accordingly, in
one embodiment, the pharmacokinetic parameters, particularly the
plasma mean C.sub.max and the mean AUC.sub.0-inf for the respective
actives following a single dose administration of the dosage form
under fed or fasted conditions, does not vary by more than about
400. In a preferred embodiment, the pharmacokinetic parameters,
particularly the plasma mean C.sub.max and the mean AUC.sub.0-inf
for the respective actives does not vary by more than about 300. In
another embodiment, the dosage forms of the invention has no
food--effect and the dosage form provides, upon a single dose
administration to a subject under fed and fasted conditions, a
ratio of the corresponding mean C.sub.max or AUC.sub.0-inf, or
both, for the respective actives between fed and fasted treatments,
in the range between about 0.7 and about 1.3. In still another
embodiment, the dosage form of the current invention provides, upon
a single dose administration to a subject under fed and fasted
conditions, a ratio of the mean AUC.sub.0-inf or AUC.sub.0-t, or
both, for the respective active between fed and fasted treatments,
in the range between 0.7 and 1.3.
[0098] In another aspect, the present invention discloses
pharmaceutical solid dosage form such as matrix tablet wherein, for
a given dose levels of two actives, at least one of which is a
tri-oxy active, an optimal non-ionic oxyl-containing hydrophilic
polymer level is tied to an optimal Pk of each of both the actives,
that is robust to differential dose levels of the actives for 12
hour dosing.
EXAMPLES
[0099] The following examples are provided to promote a more clear
understanding of certain embodiments of the present invention, and
are in no way meant as a limitation thereon. Unless otherwise
specified or mentioned, all the compositions provided in the
examples are by measure of weight in the final composition.
Example 1: In Vitro Release Profiles of the Actives from Dosage
Forms
[0100] The in vitro release profiles of the respective actives from
the dosage form examples of the current invention were determined
using a USP Type II (paddle) Dissolution Apparatus set at 50 rpm in
about 900 mL of 0.1N hydrochloric acid solution in water at about
37.degree. C. Aliquots sampled from the dissolution apparatus at
pre-determined time intervals varying from about 5 minutes up to
about 36 hours were analyzed for the respective actives by
employing an HPLC with a UV spectrophotometer detector and using
appropriate standard solutions. The amount of the active released
is then calculated from the concentrations of actives in the medium
and the volume of the medium, and expressed as a percentage of
their amounts originally present in the dosage form.
Example 2: In Vivo Pharmacokinetic Evaluation of the Dosage
Forms
[0101] Dosage forms of examples where indicated, were evaluated for
in vivo pharmacokinetic performance. The general study design was
an open-label, randomized, single-dose, crossover performed on
10-12 volunteers. In each treatment period, subjects were housed
from at least 12 hours before dosing until after the 24-hour blood
draw. There was at least 5-day washout between treatment periods,
during the study. The analysis of the plasma samples were carried
out for the respective drugs using LC-MS/MS.
[0102] The C.sub.max, T.sub.max, AUC.sub.0-t and AUC.sub.0-.varies.
were calculated for the first and second actives in the plasma of
the test subjects. Pharmacokinetic and statistical analyses were
performed on the data obtained from the subjects using
Pharsight.RTM. WinNonlin.RTM.. The pharmacokinetic parameters are
defined as follows: [0103] AUC.sub.0-t: The area under the plasma
concentration vs. time curve, from zero time to last measurable
concentration of the drug, as calculated by the linear trapezoidal
method. [0104] AUC (AUC.sub.0-.varies.): The area under the plasma
concentration versus time curve from time 0 to infinity. AUC was
calculated as the sum of the AUC0-t plus the ratio of the last
measurable plasma concentration of the administered drug to the
elimination rate constant. [0105] C.sub.max: The maximum measured
plasma concentration of the administered drug. [0106] C.sub.12: The
plasma concentration of the administered drug 12 hours post-dosing.
[0107] T.sub.max: The time at which the maximum measured plasma
concentration of the administered drug is achieved [0108]
C.sub.min: Minimum concentration of an active in the plasma
measured during steady state. It can be the minimum concentration
observed during the dosing period, in a single-dose study. [0109]
Mean: Average value of measured parameter of all individual
subjects.
Example 3-15: Dosage Forms Having at Least One Tri-Oxy Active and
at Least One Oxyl-Containing Non-Ionic Hydrophilic Polymer
[0110] Tablet dosage forms having the compositions as recited in
Examples 3 through 15 are prepared by using the respective
components shown in Tables I and II.
TABLE-US-00001 TABLE I EXAMPLE INGREDIENT* 3 4 5 6 7 8 9 10 First
Active (Tri-oxy active), 54 54 54 54 54 54 54 54 mg [e.g. Codeine
Phosphate, CP] Second Active (Non-oxo 8 8 8 8 8 8 8 8 active), mg
[e.g. Chlorpheniramine Maleate, CPM] Oxyl-containing non-ionic 25
75 200 450 65 85 -- 50 hydrophilic polymer, mg [e.g. Hypromellose
2208] Oxyl-containing non-ionic -- -- -- -- -- -- 57 19 hydrophilic
polymer, mg [e.g. Hypromellose 2910] Pharmaceutical Processing 65
65 105 160 75 65 73 80 Aids, mg Total Methoxyl Content of the 0.19
0.56 1.50 3.37 0.49 0.64 0.58 0.57 non-ionic hydrophilic polymer,
(mMol.) Total Hydroxyl Content of the 0.13 0.40 1.08 2.42 0.35 0.46
0.31 0.37 non-ionic hydrophilic polymer (mMol.) Total Oxyl Content
of the non- 0.32 0.97 2.57 5.79 0.84 1.09 0.89 0.94 ionic
hydrophilic polymer (mMol.) Total Molar Content of the 0.41 0.41
0.41 0.41 0.41 0.41 0.41 0.41 Oxygen Containing Groups in Codeine
(mMol.) Ratio of the total molar content 0.78 2.38 6.30 14.2 2.06
2.67 2.17 2.30 of oxyl groups in the hydrophilic polymer to the
total molar content of the oxygen containing groups in Codeine
Phosphate *Excipients shown are exemplary of the classes;
additional Pharmaceutical Processing aids known in the art can be
used.
TABLE-US-00002 TABLE II EXAMPLE 11 12 13 14 15 INGREDIENT* mg mg mg
mg mg First Active (Tri-oxy 27 54 54 54 40 active) [e.g. Codeine
Phosphate, CP] Second Active (Non-oxo 4 8 8 -- -- active) [e.g.
Chlorpheniramine Maleate, CPM] Second Active (Non-oxo -- -- -- --
120 active) [e.g. Pseudoephedrine, SUD] Second Active (Non-oxo --
-- -- 30-60 -- active) [e.g. Phenylephrine, PE] Third Active [e.g.
-- 120 -- -- -- Pseudoephedrine, SUD] Third Active [e.g. -- --
30-60 -- -- Phenylephrine, PE] Oxyl-containing non-ionic -- 70-135
70-135 70-135 70-135 hydrophilic polymer [e.g. Hypromellose 2208]
Pharmaceutical Processing 155 55-80 55-80 55-80 55-80 Aids
*Excipients shown are exemplary of the classes; additional
Pharmaceutical Processing aids known in the art can be used.
Procedure for Preparing the Tablets of Examples 1 to 15 is as
Follows:
[0111] The actives are separately sifted through a clean ASTM Mesh
No. 60 and thoroughly mixed by serial addition method. The actives
are mixed thoroughly and the non-ionic hydrophilic polymer(s) are
passed through the ASTM Mesh No. 60 and blended with the mixture of
the actives. The powder admixture is blended with the previously
sieved (ASTM mesh No. 60) and collected pharmaceutical aids
(diluents, lubricants etc) The resulting powder blend is then
compressed into tablets using 8 or 10 mm diameter round die-punch
tooling fitted to a single stroke tablet compression machine,
keeping the hardness of tablets in the range of about 4-9 kP.
[0112] Example 11 is an immediate release tablet manufactured
either by dry blending or conventional wet granulation and
compression process and wherefrom about 80% by weight or more of
both the actives was released within about 30 minutes when tested
in vitro as described above. It should be noted that the above said
compositions can be also processed to get tablets by the
conventional wet-granulation method known in the art. Accordingly,
an aqueous solution of the binder in which the wetting agent(s) may
also be included, is employed to granulate an admixture of the
actives, filler and the polymer(s). The wet granulate is dried,
sized, lubricated and compressed to tablets. The in vitro drug
release testing procedure for the above disclosed example dosage
forms is described in Example 1. The calculated release profiles of
the actives from some of the representative example dosage forms
are shown in Table III and FIG. 1.
TABLE-US-00003 TABLE III Example 3 4 5 6 11 12 ACTIVE CP CPM CP CPM
CP CPM CP CPM CP CPM CP CPM SUD Mean T.sub.25 %, hours 0.3 0.3 0.5
0.5 1.0 1.0 1.1 0.9 <0.3 <0.3 0.5 0.4 0.5 Mean T.sub.50 %,
hours 0.9 0.9 1.8 1.9 3.5 3.3 4.9 4.3 <0.5 <0.5 1.7 1.8 1.9
Mean T.sub.75 %, hours 1.9 2.0 3.9 4.0 7.3 7.1 11.3 10.1 <0.7
<0.7 3.7 4.0 4.2 CP = Codeine Phosphate; CPM = Chlorpheniramine
Maleate; SUD = Pseudoephedrine
[0113] Unlike Examples 3, 5, 6 and 11, Example 4 of the invention
provides optimal release for a 12 hour product. Notably, Example 4
has a ratio of total molar content of the oxyl groups in the
hydrophilic polymer to the total molar content of the
oxygen-containing groups in the codeine about 3.5, whereas Example
3 has the ratio less than 2.5 and Examples 5 and 6 has the ratio
greater than 9.0.
[0114] The tablet dosage forms of Examples 4, 5 and 6 were
evaluated for in vivo pharmacokinetic performance after a single
dose administration in comparison to the IR tablet of Example 11,
in 10-12 subjects. The study was carried out similar way as
presented in Example 2. The Tablets of Examples 4, 5 and 6 were
administered once, while the tablet of Example 11 was administered
every six hours, for 12 hours (i.e. twice in 12 hours). The total
dose of Codeine Phosphate was 54.3 mg in 12 hours and
chlorpheniramine maleate was 8 mg. The plasma concentration of
codeine and chlorpheniramine was determined by LC-MS/MS method.
[0115] Table IV shows the results of the pharmacokinetic parameters
for each of the actives of Examples 4, 5 and 6 expressed as a
percentage of its ratio to the corresponding parameters obtained
for respective actives given as IR tablet (Example 11) every 6
hours, twice. However it is noteworthy that the IR tablet can be
given as a single combination tablet (as Example 11) or as co
administered single active tablets.
TABLE-US-00004 TABLE IV EXAMPLE 4 5 6 ACTIVE CP CPM CP CPM CP CPM
Mean % C.sub.max (ng/ml) 88.9 85.3 64.2 70.6 53.1 64.0 Mean %
AUC.sub.0-12 101.7 95.2 83.0 73.1 70.7 65.4 (ng h/ml) Mean %
AUC.sub.inf (ng h/ml) 104.9 100.5 112.5 101.6 110.1 92.7 Mean %
C.sub.12 (ng/mL) 98.6 85.0 128.6 74.3 123.1 61.9
[0116] Unlike Examples 5 and 6, Example 4 of the invention provides
optimal pharmacokinetic parameters for a 12 hour product. Notably,
Example 4 has a ratio of total molar content of the oxyl groups in
the hydrophilic polymer to the total molar content of the
oxygen-containing groups in the codeine about 3.5, whereas Examples
5 and 6 has the ratio greater than 9.0.
Example 16-32: Dosage Forms Having at Least One Tri-Oxy Active and
at Least One Oxyl-Containing Non-Ionic Hydrophilic Polymer
[0117] Tablet dosage forms of having the compositions as recited in
Examples 16 to 32 are prepared by using the respective components
shown in Tables V to VII. The tablet dosage forms are manufactured
by a similar process as described for Examples 3 to 15. Tablet
dosage forms of Examples 23, 24 and 25 were compressed to achieve a
total Codeine Phosphate dose of 30 mg per tablet and guaifenesin to
600 mg per tablet.
TABLE-US-00005 TABLE V EXAMPLE INGREDIENT* 16 17 18 19 20 21 22
First Active (Tri-oxy active), mg 30 30 30 30 30 30 20 [e.g.
Codeine Phosphate, CP] Second Active (Tri-oxy active), 600 600 600
600 600 600 400 mg [e.g. Guaifenesin, GGE] Oxyl-containing
non-ionic 20 65 105 185 105 220 -- hydrophilic polymer, mg [e.g.
Hypromellose 2208] Pharmaceutical Processing Aids, 60-100 60-100
60-100 60-100 75-140 60-100 55 mg Total Methoxyl Content of the
0.15 0.49 0.79 1.39 0.79 1.65 -- non-ionic hydrophilic polymer
(mMol.) Total Hydroxyl Content of the 0.11 0.35 0.57 1.00 0.57 1.18
-- non-ionic hydrophilic polymer (mMol.) Total Oxyl Content of the
non- 0.26 0.84 1.35 2.38 1.35 2.83 -- ionic hydrophilic polymer
(mMol.) Total Molar Content of the 0.23 0.23 0.23 0.23 0.23 0.23 --
Oxygen Containing Groups in Codeine Phosphate (mMol.) Ratio of the
total molar content of 1.15 3.71 5.96 10.51 5.96 12.50 -- oxyl
groups in the hydrophilic polymer to the total molar content of the
oxygen containing groups in Codeine Phosphate Total Molar Content
of the 12.11 12.11 12.11 12.11 12.11 12.11 -- Oxygen Containing
Groups in Guaifenesin (mMol.) Ratio of the total molar content of
0.02 0.07 0.11 0.20 0.11 0.23 -- oxyl groups in the hydrophilic
polymer to the total molar content of the oxygen containing groups
in Guaifenesin *Excipients shown are exemplary of the classes;
additional Pharmaceutical Processing aids known in the art can be
used.
TABLE-US-00006 TABLE VI EXAMPLE 23 24 25 INGREDIENT* % w/w % w/w %
w/w First Active (Tri-oxy active) 3.8-3.9 3.2-3.7 3.0-3.1 [e.g.
Codeine Phosphate, CP] Second Active (Tri-oxy active) 76-79 64-74
59-62 [e.g. Guaifenesin, GGE] Oxyl-containing non-ionic 1-5 8-20
23-26 hydrophilic polymer [e.g. Hypromellose 2208] Pharmaceutical
Processing Aids 15-16 13-15 11-12 *Excipients shown are exemplary
of the classes; additional Pharmaceutical Processing aids known in
the art can be used.
TABLE-US-00007 TABLE VII EXAMPLE 26 27 28 29 30 31 32 INGREDIENT*
(mg) (mg) (mg) (mg) (mg) (mg) (mg) First Active (Tri-oxy active) 30
30 30 30 30 30 30 [e.g. Codeine Phosphate, CP] Second Active
(Tri-oxy active) 600 600 600 600 600 -- -- [e.g. Guaifenesin, GGE]
Second Active (Non-oxo active) -- -- -- -- -- 30 -- [e.g.
Dextromethorphan, DXM] Third Active -- -- -- -- 60 -- 60 [e.g.
Pseudoephedrine, SUD] Third Active [e.g. Phenylephrine, -- -- --
15-30 -- 15-30 -- PE] Oxyl-containing non-ionic 53 25 -- 60-125
80-150 60-150 80-150 hydrophilic polymer [e.g. Hypromellose 2208]
Oxyl-containing non-ionic 40 10 80 -- -- -- -- hydrophilic polymer
[e.g. Hypromellose 2910] Pharmaceutical Processing Aids 70-145
80-125 90-120 90-120 90-120 90-120 90-120 *Excipients shown are
exemplary of the classes; additional Pharmaceutical Processing aids
known in the art can be used.
[0118] The in vitro for drug release testing procedure for the
above example dosage forms is described in Example 1. The
calculated release profiles of the actives from some of the
representative examples are shown in Table VIII and FIG. 1I.
Example 22 is an immediate release tablet wherefrom about 80% by
weight or more of both the actives was released within about 30
minutes when tested in vitro as previously described.
TABLE-US-00008 TABLE VIII EXAMPLE 16 17 18 19 22 ACTIVE GGE CP GGE
CP GGE CP GGE CP GGE CP Mean 0.20 0.30 0.5 0.3 0.8 0.6 1.4 0.9
<0.3 <0.3 T.sub.25 %, hours Mean 0.70 0.80 2.2 1.9 3.0 2.4
4.4 3.3 <0.5 <0.5 T.sub.50 %, hours Mean 1.40 1.50 5.2 4.8
6.5 5.6 8.9 7.0 <0.7 <0.7 T.sub.75 %, hours, GGE =
guaifenesin; CP = codeine phosphate
[0119] Unlike Examples 16 and 19, Examples 17 and 18 of the
invention provides optimal release for a 12 hour product. Notably,
Examples 17 and 18 have a ratio of total molar content of the oxyl
groups in the hydrophilic polymer to the total molar content of the
oxygen-containing groups in the guaifenesin is between 0.07 about
0.18, whereas Example 16 has the ratio less than 0.07 and Example
19 has the ratio greater than 0.18. The tablet dosage forms of
Examples 17, 18 and 19 were evaluated for in vivo pharmacokinetic
performance after a single dose administration in comparison to the
IR tablet of Example 22, in 10-12 subjects. The study was carried
out in similar way as outlined in Example 2. In particular, the
dosage forms of Example 17, 18 and 19 were administered once, while
the dosage form of Example 22 was administered every four hours,
for 12 hours. (i.e. three times in 12 hours). The total dose of
guaifenesin was 1200 mg in 12 hours and codeine phosphate was 60 mg
in 12 hours. The plasma concentration of GGE and codeine were
determined by LC-MS/MS method
[0120] Table VIII shows the results of the pharmacokinetic
parameters for each of the actives of Examples 17, 18 and 19
expressed as a percentage of its ratio to the corresponding
parameters obtained for respective actives given as IR tablet
(Example 22) every 4 hours for 12 hours. The mean T.sub.max is
expressed as absolute value in hours for each active from
respective examples. However it is noteworthy that the IR tablet
can be given as a single combination tablet (as Example 22) or as
co administered single active tablets.
TABLE-US-00009 TABLE IX EXAMPLE 17 18 19 GGE CP GGE CP GGE CP Mean
% C.sub.max (ng/ml) 75.4 100.2 60.0 90.8 44.7 80.0 Mean %
AUC.sub.0-12 91.7 97.3 89.8 98.1 86.3 99.8 (ng h/ml) Mean % AUC
0-.alpha. 91.4 97.3 89.8 99.2 92.0 106.1 (ng h/ml) Mean % C.sub.12
(ng/mL) 29.3 50.5 71.2 62.5 111 68.4 Mean T.sub.max (hour) 2.0 4.0
2.0 4.0 2.0 4.0
[0121] It can be seen from Examples 17, 18 and 19, the criticality
of the type and the minimum and maximum levels of the non-ionic
oxyl-containing hydrophilic polymer that is essential for enabling
a product for delivery once every 12 hours, for oxo-actives such as
guaifenesin and codeine. Notably, Examples 17 and 18 have a ratio
of total molar content of the oxyl groups in the hydrophilic
polymer to the total molar content of the oxygen-containing groups
in the guaifenesin is between 0.07 about 0.18, whereas Example 19
has the ratio greater than 0.18. Furthermore, Table X gives the
absolute C.sub.max and C.sub.min value of the dosage forms of
invention upon steady state simulation. For the purpose of
simulations, dosage forms of Examples 17 are 18 are administered
two tablets every 12 hours.
TABLE-US-00010 TABLE X EXAMPLE 17 18 ACTIVE GGE CP GGE CP Mean
C.sub.max (ng/mL) 1342 59.2 1153 56.9 Mean C.sub.minss (ng/mL) 56
15.7 136 19.8
Examples 17 and 18 of the invention provides optimal
pharmacokinetic for a 12 hour product.
Examples 33-48: Dosage Forms Having at Least One Tri-Oxy Active and
at Least One Oxyl-Containing Non-Ionic Hydrophilic Polymer
[0122] Tablet dosage forms of having the compositions as recited in
Examples 27 through 38 are prepared by using the respective
components shown in Tables XI to XIII. The in vitro for drug
release testing procedure for the said example dosage forms is
described in Example 1. The release profiles of the actives from
some of the representative examples are shown in Table-XIV and FIG.
III. Examples 38 and 39 are immediate release tablets of
hydrocodone bitartrate (HB) and GGE respectively and which release
about 80% by weight or more of the active within about 30 minutes
when tested in vitro as previously described.
[0123] Example 38 is a commercially available hydrocodone
bitartrate IR tablet (e.g. Hycodan.RTM., Endo Pharmaceuticals) and
it contains an additional active homatropin methyl bromide. IR
Tablets of guaifenesin and hydrocodone bitartrate (Examples 38 and
39, respectively) together constitute as reference product for
comparison of the said example dosage forms of the current
invention.
TABLE-US-00011 TABLE XI EXAMPLE INGREDIENT* 33 34 35 36 37 38.sup.#
39 First Active (Tri-oxy active), mg 600 600 600 600 600 -- 400
[e.g. Guaifenesin, GGE] First Active (Tri-oxy active), mg 5 5 5 5 5
5 -- [e.g. Hydrocodone Bitartrate, HB] Homatropine Methylbromide,
mg -- -- -- -- -- 1.5 -- Oxyl-containing non-ionic 25 65 145 185
105 -- -- hydrophilic polymer, mg [e.g. Hypromellose 2208]
Pharmaceutical Processing Aids, 45 40-65 40-65 40-65 50-120 50-150
50-70 mg Total Methoxyl Content of the 0.19 0.49 1.09 1.39 0.79 --
-- non-ionic hydrophilic polymer (mMol.) Total Hydroxyl Content of
the 0.13 0.35 0.78 1.00 0.57 -- -- non-ionic hydrophilic polymer
(mMol.) Total Oxyl Content of the non- 0.32 0.84 1.87 2.38 1.35 --
-- ionic hydrophilic polymer (mMol.) Total Molar Content of the
12.11 12.11 12.11 12.11 12.11 -- -- Oxygen Containing Groups in
Guaifenesin (mMol.) Ratio of the total molar content of 0.03 0.07
0.15 0.20 0.11 -- -- oxyl groups in the hydrophilic polymer to the
total molar content of the oxygen containing groups in Guaifenesin
*Excipients shown are exemplary of the classes; additional
Pharmaceutical Processing aids known in the art can be used.
.sup.#Commercially available hydrocodone bitartrate IR tablet (e.g.
Hycodan .RTM.)
TABLE-US-00012 TABLE XII EXAMPLE 40 41 42 INGREDIENT* % w/w % w/w %
w/w First Active (Tri-oxy active) 78-82 66-76 62-63 [e.g.
Guaifenesin, GGE] First Active (Tri-oxy active) 0.7 0.5-0.6 0.5
[e.g. Hydrocodone Bitartrate, HB] Oxyl-containing non-ionic 1-5
8-20 23-27 hydrophilic polymer [e.g. Hypromellose 2208]
Pharmaceutical Processing Aids 16 13-15 11-13 *Excipients shown are
exemplary of the classes; additional Pharmaceutical Processing aids
known in the art can be used.
TABLE-US-00013 TABLE XIII EXAMPLE 43 44 45 46 47 48 INGREDIENT*
(mg) (mg) (mg) (mg) (mg) (mg) First Active (Tri-oxy active) 600 600
190 600 600 600 [e.g. Guaifenesin, GGE] First Active (Tri-oxy
active) 5 5 -- 5 5 5 [e.g. Hydrocodone Bitartrate, HB] Second
Active (Non Oxo -- -- -- 30 -- 30 Containing) (e.g.
Dextromethorphan) Third Active -- -- -- 60 -- -- [e.g.
Pseudoephedrine, SUD] Third Active [e.g. Phenylephrine, -- -- -- --
15-30 15-30 PE] Oxyl-containing non-ionic 73 -- -- 80-150 80-150
80-150 hydrophilic polymer [e.g. Hypromellose 2208] Oxyl-containing
non-ionic 55 110 -- -- -- -- hydrophilic polymer [e.g. Hypromellose
2910] Pharmaceutical Processing Aids 90-120 40-65 90-120 50-120
50-120 50-120 *Excipients shown are exemplary of the classes;
additional tableting aids known in the art can be used.
TABLE-US-00014 TABLE XIV Example 33 34 35 36 38 39 ACTIVE GGE HB
GGE HB GGE HB GGE HB HB GGE Mean 0.2 0.3 0.6 0.5 1.0 1.0 1.3 1.3
<0.3 <0.3 T.sub.25 %, hours Mean 0.6 0.7 1.9 1.5 3.1 2.9 4.0
4.1 <0.5 <0.5 T.sub.50 %, hours Mean 1.4 1.4 4.0 3.3 6.3 5.6
7.5 7.3 <0.7 <0.7 T.sub.75 %, hours, GGE = guaifenesin; HB =
hydrocodone bitartrate
[0124] Unlike Examples 33, 36, 38 and 39, Examples 34 and 35 of the
invention provides optimal release for a 12 hour product. Notably,
Examples 34 and 35 have a ratio of total molar content of the oxyl
groups in the hydrophilic polymer to the total molar content of the
oxygen-containing groups in the guaifenesin is between 0.07 about
0.18, whereas Example 33 has the ratio less than 0.07 and Example
36 has the ratio greater than 0.18
[0125] The tablet dosage forms of Examples 33, 34 and 35 were
evaluated for in vivo pharmacokinetic performance after a single
dose administration in comparison to the Guaifenesin IR tablet(s)
of Example 39 and hydrocodone bitartrate IR tablet (e.g.
Hycodan.RTM., Example 38), in 10-12 subjects. The study was carried
out as outlined in Example 2. Specifically, the dosage forms of
Examples 33, 34 and 35 were administered once, while Guaifenesin IR
tablet was given every four hours for 12 hours, and the hydrocodone
bitartrate IR reference tablet given every six hours for 12 hours.
The total dose of Guaifenesin was 1200 mg in 12 hours and of
hydrocodone bitartrate was 10 mg in 12 hours. The plasma
concentration of GGE and hydrocodone were determined by LC-MS/MS
method.
[0126] Table XV shows the results of the pharmacokinetic parameters
for each of the actives of Examples 33, 34 and 35 expressed as a
percentage of its ratio to the corresponding parameters obtained
for respective actives given as IR tablets (Examples 31 and 32
every four hours and every 6 hours respectively, for 12 hours. The
absolute minimum plasma concentrations at steady state for
guaifenesin and hydrocodone from the administered dosage forms of
some examples of this invention are shown in Table XVI.
TABLE-US-00015 TABLE XV EXAMPLE 33 34 35 ACTIVE GGE HB GGE HB GGE
HB Mean % C.sub.max (ng/ml) 75.4 100.2 60.0 90.8 44.7 80.0 Mean %
AUC.sub.0-12 95.3 108.0 90.3 102.9 74.1 94.9 (ng h/ml) Mean %
AUC.sub.inf (ng h/ml) 91.4 97.3 89.8 99.2 92.0 106.1 Mean %
C.sub.12 (ng/mL) 30.2 50.7 70.8 63.6 87.2 67.5 Mean T.sub.max (h)
1.3 2.8 2.0 4.0 2.0 4.0
[0127] Unlike Example 33, Examples 34 and 35 of the invention
provides optimal pharmacokinetic for a product formulated for
delivery once every 12 hours. Notably, Examples 34 and 35 have a
ratio of total molar content of the oxyl groups in the hydrophilic
polymer to the total molar content of the oxygen-containing groups
in the guaifenesin is between 0.07 about 0.18, whereas Example 33
has the ratio less than 0.07
TABLE-US-00016 TABLE XVI EXAMPLE 33 34 35 ACTIVE GGE GGE GGE Mean
C.sub.minss 1.85 14.1 22.8 (ng/mL)
As it can be seen from Examples 34 and 35 have acceptable Mean
C.sub.minss (ng/mL) value of greater than 3 ng/mL for 12 hour
product.
Example 49: Coated Pharmaceutical Tablets
[0128] The tablet dosage forms of Examples 3 to 10, 12 to 15,
16-21, 23-32, 33-37 and 40 to 48 can be further coated with a
coating solution having typical composition set forth in Table
XVII, using conventional tablet coating procedures known in the art
to a weight gain of about 2 to 6%.
TABLE-US-00017 TABLE XVII INGREDIENT* Composition in % w/w Film
coating polymer (e.g. Methocel E 5) 8.0 Plasticizer (e.g.
Polyethylene glycol, NF 8000) 0.6 Coating Solvent (e.g. Ethanol)
54.8 Coating Solvent Water 36.6 *Excipients shown are exemplary of
the classes; additional pharmaceutical processing aids known in the
art can be used.
Examples 50-51: In Vitro Release of Actives from Exemplary
Embodiments
[0129] Tablet dosage forms of having combination of the oxo-actives
(e.g. guaifenesin, codeine phosphate etc.) in the compositions as
recited in Examples 50 and 51 are prepared by using the respective
components shown in Tables XVIII. The in vitro drug release testing
procedure for the said example dosage forms is described in Example
1. The release profiles of the actives from some of the
representative formulations are shown in Table-XIX. Example 50
contains the oxyl-containing non-ionic hydrophilic polymer within
the range disclosed in the invention, while Example 51 does not
contain polymer within the range disclosed in the invention.
TABLE-US-00018 TABLE XVIII EXAMPLE 50 51 INGREDIENT* (mg) (mg)
First Active (Tri-oxy active) 30 30 [e.g. Codeine Phosphate, CP]
Second Active (Tri-oxy active) 600 600 [e.g. Guaifenesin, GGE]
Oxyl-containing non-ionic hydrophilic 105 -- polymer [e.g.
Hypromellose 2208] Oxyl-containing non-ionic hydrophilic -- 15
polymer [e.g. Hypromellose 2910] Pharmaceutical Processing Aids
65-100 65-105 *Excipients shown are exemplary of the classes;
additional Pharmaceutical Processing aids known in the art can be
used.
TABLE-US-00019 TABLE XIX Example 50 51 GGE CP GGE CP Mean
T.sub.25%, 0.84 0.55 1.00 0.85 hours Mean T.sub.50%, 3.01 2.40 3.90
3.60 hours Mean T.sub.75%, 6.51 5.57 8.00 7.12 hours,
[0130] Unlike Example 51, Example 50 of the invention provides
optimal release for a 12 hour product. The tablet dosage forms of
Examples 50 and 51 were evaluated for in vivo pharmacokinetic
performance after a single dose administration of two (2) tablets
each. Table XX shows the absolute values of the pharmacokinetic
parameters for guaifenesin.
TABLE-US-00020 TABLE XX EXAMPLE 50 51 GGE GGE Mean C.sub.max
(ng/ml) 1050 821
[0131] Unlike Example 51, Example 50 of the invention provides
greater C.sub.ma for a 12 hour product.
Example 52: Food Effect Pharmacokinetics
[0132] The tablet dosage forms of Example 18, the IR tablets of
Example 22 were evaluated for Effect of food on in vivo
pharmacokinetic performance after a single dose administration to
10 subjects. Accordingly, the tablet of Example 18 (Test
formulation) administered either after overnight fasting or within
30 minutes of administration of food. Similarly, in another group,
the IR tablets of Example 22 (Reference formulation) were given
either after overnight fasting or within 30 minutes of
administration of food. The plasma analysis for guaifenesin and
codeine were carried out by LC-MS/MS. The PK parameters are
expressed as a ratio to the corresponding parameters obtained for
each dosage form after administration with food or under fasted
state.
[0133] It was observed that a there was no significant food effect
seen for guaifenesin and codeine from the Example 18 tablets. On
the contrary, the IR tablets exhibited a significant food effect
wherein, the plasma guaifenesin C.sub.max was significantly low
when administered with food compared to when given under fasted
conditions, as shown in the Table XXI & XXII wherein the ratios
of the fed-to-fasted PK results for guaifenesin are given.
TABLE-US-00021 TABLE XXI Example 18 Example 22 ACTIVE GGE CP GGE
Mean % C.sub.max ratio (fed/fasted) (ng/ml) 102 127 67 Mean %
AUC.sub.last ratio (fed/fasted) (ng h/ml) 98 109 89 Mean %
AUC.sub.0-.alpha. ratio (fed/fasted) 96 104 89 (ng h/ml)
[0134] Unlike the Example 22, Example 18, containing appropriate
level of oxyl-containing non-ionic hydrophilic polymer, is less
sensitive to food effect.
Example 53-54: Effect of Oxyl-Containing Non-Ionic Polymer in
Comparison to Ionic Polymer on Food Effect Pharmacokinetic
Study
[0135] Tablet dosage forms according to the current invention
having combination of oxo-actives (e.g. guaifenesin and Codeine
phosphate) in the compositions as recited in Examples 53 and 54
shown in Table XIX were evaluated for food effect pharmacokinetics
on similar lines as described under Example 52. While dosage form
of Example 53 contains only oxyl-containing non-ionic hydrophilic
polymer within the range disclosed in the invention, the Example 54
has ionic hydrophilic polymer along with oxyl-containing non-ionic
hydrophilic polymer.
TABLE-US-00022 TABLE XXII EXAMPLE 53 54 Ingredient* (mg) (mg) First
Active (Tri-oxy active) 30 30 [e.g. Codeine Phosphate, CP] Second
Active (Tri-oxy active) 600 600 [e.g. Guaifenesin, GGE]
Oxyl-containing non-ionic hydrophilic polymer 105 15 [e.g.
Hypromellose 2208 or Hypromellose 2910] Ionic Hydrophilic Polymer
[e.g. Carbopol -- 7.5 974P] Pharmaceutical Processing Aids 75-120
65-85 *Excipients shown are exemplary of the classes; additional
Pharmaceutical Processing aids known in the art can be used.
[0136] The dosage form of Example 53 showed no food effect on
C.sub.max, AUC.sub.0-inf. On the contrary, the ionic polymer
containing formulation similar to Example 54 is prone to food
effect, probably due to the ionic nature of the polymer, which is
known to be sensitive to pH changes in the presence of food.
* * * * *