U.S. patent application number 16/331733 was filed with the patent office on 2019-09-19 for suspensions and diluents for metronidazole and baclofen.
This patent application is currently assigned to CutisPharma, Inc.. The applicant listed for this patent is CutisPharma, Inc.. Invention is credited to Priya Capila, Ken Fallin, Neal Muni, Zeus Pendon.
Application Number | 20190282500 16/331733 |
Document ID | / |
Family ID | 61562345 |
Filed Date | 2019-09-19 |
United States Patent
Application |
20190282500 |
Kind Code |
A1 |
Fallin; Ken ; et
al. |
September 19, 2019 |
SUSPENSIONS AND DILUENTS FOR METRONIDAZOLE AND BACLOFEN
Abstract
Suspensions of metronidazole or baclofen and/or salts or ester
derivative thereof, such as metronidazole benzoate, are disclosed.
The suspension may include metronidazole or baclofen, and/or a salt
or ester derivative thereof a hydrocolloid stabilizer, simethicone
emulsion, a buffer, such as sodium citrate, (dihydrate), a
preservative, a thickening agent, a sweetener, and water.
Inventors: |
Fallin; Ken; (Diamondhead,
MS) ; Pendon; Zeus; (Woburn, MA) ; Capila;
Priya; (Wellesley, MA) ; Muni; Neal;
(Wellesley, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CutisPharma, Inc. |
Woburn |
MA |
US |
|
|
Assignee: |
CutisPharma, Inc.
Woburn
MA
|
Family ID: |
61562345 |
Appl. No.: |
16/331733 |
Filed: |
September 8, 2017 |
PCT Filed: |
September 8, 2017 |
PCT NO: |
PCT/US2017/050714 |
371 Date: |
March 8, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62385325 |
Sep 9, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02A 50/491 20180101;
Y02A 50/30 20180101; A61K 47/38 20130101; A61K 31/197 20130101;
A61K 9/0095 20130101; A61K 31/4164 20130101; A61P 31/04 20180101;
A61K 47/36 20130101; A61K 9/10 20130101; A61K 47/46 20130101; A61K
47/12 20130101; A61K 47/34 20130101; A61P 33/02 20180101; A61K
47/26 20130101 |
International
Class: |
A61K 9/10 20060101
A61K009/10; A61K 31/4164 20060101 A61K031/4164; A61K 47/38 20060101
A61K047/38; A61K 47/12 20060101 A61K047/12; A61K 47/34 20060101
A61K047/34; A61K 47/26 20060101 A61K047/26; A61K 47/46 20060101
A61K047/46 |
Claims
1. A suspension of metronidazole or a salt or ester derivative
thereof, comprising metronidazole or a salt or ester derivative
thereof; a hydrocolloid stabilizer, simethicone emulsion; sodium
citrate, (dihydrate); a preservative, a thickening agent, a
sweetener, and water.
2. The suspension of claim 1, wherein the hydrocolloid stabilizer
is microcrystalline cellulose and/or carboxymethylcellulose
sodium.
3. The suspension of claim 1, wherein the thickening agent is
xanthan gum.
4. The suspension of claim 1, wherein the suspension comprises
metronidazole benzoate.
5. The suspension of claim 1, wherein the sweetener is selected
from the group consisting of ammonium glycyrrhizate, sucralose, and
saccharin sodium.
6. The suspension of claim 1, wherein the preservative is sodium
benzoate.
7. The suspension of claim 1, wherein the preservative is citric
acid.
8. The suspension of claim 1, further comprising flavor grape
59.266/A.
9. The suspension of claim 1, wherein the pH of the formulation is
between 3.6 and 4.6.
10. The suspension of claim 1, wherein the formulation retains
homogeneity of less than +/-5% of assay for active pharmaceutical
ingredient after at least 30 days.
11. The suspension of claim 1, wherein the suspension includes the
following: a. 0.05% (w/v) ammonium glycyrrhizate, (magnasweet 100);
b. 1.50% (w/v) Avicel RC591; c. 0.50% (w/v) citric acid,
(anhydrous); d. 0.05% (w/v) flavor grape 59.266/A; e. 0.03% (w/v)
saccharin sodium; f. 0.2% (w/v) simethicone emulsion, (30%); g.
0.15% (w/v) sodium benzoate, NF; h. 0.20% (w/v) sodium citrate,
(dihydrate); i. 0.10% (w/v) sucralose; j. 0.10% (w/v) xanthan gum;
and k. purified water,
12. The suspension of claim 1, wherein the suspension includes the
following: a. 0.12% (w/v) citric acid, (anhydrous); b. 0.0002%
(w/v) D&C Yellow No. 10; c. 0.000038% (w/v) FD&C Red No.
40; d. 0.0500% (w/v) flavor grape 59.266/A; e. 0.5000% (wv)
hydroxyethyl cellulose; f. 5.000% (w/v) propylene glycol; g.
0.1500% (w/v) simethicone emulsion, (30%); h. 0.1000% (w/v) sodium
benzoate; i. 0.2000% (w/v) sucralose; j. purified water.
13. A liquid diluent comprising: 0.03-0.08% (w/v) ammonium
glycyrrhizate; 1.0-2.0% (w/v) Avicel RC591; 0.1-0.9% (w/v) citric
acid; 0.01-0.10% (w/v) flavoring; 0.01-0.05% (w/v) saccharin
sodium; 0.1-0.3% (w/v) simethicone emulsion; 0.1-0.2% (w/v) sodium
benzoate; 0.1-0.3% (w/v) sodium citrate, (dihydrate); 0.05-0.2%
(w/v) sucralose; 0.05-0.2% (w/v) xanthan gum; and purified
water.
14. The liquid diluent of claim 12, comprising: 0.05% (w/v)
ammonium glycyrrhizate, (magnasweet 100); 1.50% (w/v) Avicel RC591;
0.50% (w/v) citric acid, (anhydrous); 0.05% (w/v) flavor grape
59.266/A; 0.03% (w/v) saccharin sodium; 0.2% (w/v) simethicone
emulsion, (30%); 0.15% (w/v) sodium benzoate; 0.20% (w/v) sodium
citrate, (dihydrate); 0.10% (w/v) sucralose; 0.10% (w/v) xanthan
gum; and purified water.
15. A suspension of metronidazole, comprising a salt or ester
derivative of metronidazole; simethicone emulsion; sodium
bicarbonate; and sodium citrate, (dihydrate), wherein the
suspension is stable for at least 30 days when stored at 2-8
degrees celsius.
16. The suspension of claim 1, wherein the suspension comprises a
pH of no more than pH 4.6.
17. The suspension of claim 1, wherein the formulation retains
homogeneity of less than +/-5% of assay for active pharmaceutical
ingredient after at least 30 days.
18. The suspension of claim 1, wherein the formulation maintains
homogeneity of the active pharmaceutical ingredient for at least 30
days after reconstitution.
19-28. (canceled)
29. A liquid diluent comprising: citric acid; flavoring;
hydroxyethyl cellulose; simethicone emulsion; propylene glycol;
sodium benzoate; sucralose; and purified water.
Description
RELATED APPLICATIONS
[0001] This application is a national stage filing under 35 U.S.C.
371 of International Patent Application Serial No.
PCT/US2017/050714, filed Sep. 8, 2017, entitled "SUSPENSIONS AND
DILUENTS FOR METRONIDAZOLE AND BACLOFEN", which claims the benefit
of U.S. Provisional No. 62/385,325 filed on Sep. 9, 2016, the
entire contents of each of which are incorporated by reference
herein.
BACKGROUND OF THE INVENTION
[0002] Medications are often prescribed in a solid dosage form
which many patients are unable to swallow, requiring these
medications to be administered in an oral liquid form. The
populations unable to swallow solid dosage forms and are in need of
liquid formulations include pediatric patients, older patients with
dysphagia, ICU patients and patients on enteral nutrition.
SUMMARY OF THE INVENTION
[0003] Disclosed herein are suspensions of metronidazole or
baclofen and/or salts thereof. The suspensions may comprise
metronidazole or baclofen or a salt thereof, such as metronidazole
benzoate, a hydrocolloid stabilizer, simethicone emulsion, sodium
citrate, (dihydrate), a preservative, a thickening agent, a
sweetener, and water. In some embodiments, the suspension comprises
metronidazole or baclofen. In some embodiments, the hydrocolloid
stabilizer is microcrystalline cellulose and/or
carboxymethylcellulose sodium. In one embodiment, the hydrocolloid
stabilizer is Avicel RC591. In some embodiments, the thickening
agent is xanthan gum.
[0004] A variety of sweeteners and flavorings can be used to
improve palatability of the disclosed formulations. In some
embodiments, the sweetener is one or more of ammonium
glycyrrhizate, sucralose, and saccharin sodium. In some
embodiments, the formulation comprises flavor grape 59.266/A. In
some embodiments, the preservative is sodium benzoate and/or citric
acid.
[0005] In some aspects of the invention, the pH of the formulation
is between 3.6 and 4.6. In other aspects of the invention, the pH
of the formulation is 3.4 and 4.0, 3.0-4.0, 3.0-5.0, or 3.0-6.0. In
some embodiments, the formulation retains homogeneity of less than
+/-5% of assay for active pharmaceutical ingredient after at least
30 days, at least 40 days, at least 45 days, at least 60 days, at
least 75 days, at least 100 days, each up to alternatively 100
days, 200 days, 1 year or two years. In other embodiments, the
formulation retains homogeneity of less than +/-10% of assay for
active pharmaceutical ingredient after at least 30 days, at least
40 days, at least 45 days, at least 60 days, at least 75 days, at
least 100 days, each up to alternatively 100 days, 200 days, 1 year
or two years. In some embodiments the homogeneity is assessed for
samples stored at room temperature.
[0006] One embodiment of the liquid formulations as taught by the
invention comprises ammonium glycyrrhizate (magnasweet 100), Avicel
RC591, citric acid (anhydrous), grape flavor, saccharin sodium,
simethicone emulsion, sodium benzoate, sodium citrate, sucralose,
xanthan gum, and water.
[0007] In a specific embodiment a liquid formulation of the
invention comprises:
[0008] a. 0.05000% (w/v) ammonium glycyrrhizate, (magnasweet
100);
[0009] b. 1.500% (w/v) Avicel RC591;
[0010] c. 0.500% (w/v) citric acid, (anhydrous);
[0011] d. 0.0500% (w/v) flavor grape 59.266/A;
[0012] e. 0.0300% (w/v) saccharin sodium;
[0013] f. 0.2000% (w/v) simethicone emulsion, (30%);
[0014] g. 0.1500% (w/v) sodium benzoate;
[0015] h. 0.2000% (w/v) sodium citrate, (dihydrate);
[0016] i. 0.1000% (w/v) sucralose;
[0017] j. 0.1000% (w/v) xanthan gum;
[0018] k. purified water.
[0019] Another embodiment of the liquid formulations as taught by
the invention comprises citric acid, D&C Yellow No. 10,
FD&C Red No 40, grape flavor, hydroxyethyl cellulose, propylene
glycol, simethicone emulsion, sodium benzoate, sucralose, and
water.
[0020] In a specific embodiment a liquid formulation of the
invention comprises:
[0021] a. 0.12% (w/v) citric acid, (anhydrous);
[0022] b. 0.0002% (w/v) D&C Yellow No. 10;
[0023] c. 0.000038% (w/v) FD&C Red No. 40;
[0024] d. 0.0500% (w/v) flavor grape 59.266/A;
[0025] e. 0.5000% (wv) hydroxyethyl cellulose;
[0026] f. 5.000% (w/v) propylene glycol;
[0027] g. 0.1500% (w/v) simethicone emulsion, (30%);
[0028] h. 0.1000% (w/v) sodium benzoate;
[0029] i. 0.2000% (w/v) sucralose;
[0030] j. purified water.
[0031] In some embodiments a liquid formulation of the invention
comprises 0.12-0.6% (w/v) citric acid; 0.1500-0.250% (w/v)
simethicone emulsion; 0.1000-0.1550% (w/v) sodium benzoate;
sweetener and water.
[0032] Disclosed herein are diluents for reconstituting
metronidazole or baclofen or a salt thereof. In some embodiments,
the liquid diluent comprises 0.03-0.08% (w/v) ammonium
glycyrrhizate; 1.0-2.0% (w/v) Avicel RC591; 0.1-0.9% (w/v) citric
acid; 0.01-0.10% (w/v) flavoring; 0.01-0.05% (w/v) saccharin
sodium; 0.1-0.3% (w/v) simethicone emulsion; 0.1-0.2% (w/v) sodium
benzoate; 0.1-0.3% (w/v) sodium citrate, (dihydrate); 0.05-0.2%
(w/v) sucralose; 0.05-0.2% (w/v) xanthan gum; and purified
water.
[0033] In a specific embodiment, the liquid diluent comprises 0.05%
(w/v) ammonium glycyrrhizate, (magnasweet 100); 1.50% (w/v) Avicel
RC591; 0.50% (w/v) citric acid, (anhydrous); 0.05% (w/v) flavor
grape 59.266/A; 0.03% (w/v) saccharin sodium; 0.2% (w/v)
simethicone emulsion, (30%); 0.15% (w/v) sodium benzoate; 0.20%
(w/v) sodium citrate, (dihydrate); 0.10% (w/v) sucralose; 0.10%
(w/v) xanthan gum; and purified water.
[0034] Further disclosed herein are suspensions of metronidazole or
baclofen or a salt thereof, comprising metronidazole or baclofen or
a salt of metronidazole or baclofen;
[0035] simethicone emulsion; sodium bicarbonate; and sodium
citrate, (dihydrate), where the suspension is stable for at least
30 days when stored at 2-8 or 15-30 degrees celsius. In some
embodiments, the suspension is stable for at least 30 days when
stored at 38-42 degrees celsius. In some embodiments, the
suspension comprises a pH of no more than pH 4.6, 5.5, or 6.5. In
some embodiments, the suspension comprises a pH of 4.
[0036] In some embodiments, the formulations described herein
retain homogeneity of less than +/-2%, +/-5%, or +/-10% of assay
for active pharmaceutical ingredient after at least 30 days, 60
days or 90 days. In some embodiments, the formulations described
herein maintain homogeneity of the active pharmaceutical ingredient
at room temperature for at least 30 days, at least 40 days, at
least 45 days, at least 60 days, at least 75 days, at least 100
days, each up to alternatively 100 days, 200 days, 1 year or two
years after reconstitution. In some embodiments the formulations
described herein maintain homogeneity of the active pharmaceutical
ingredient for 30 days-two years 40 days-two years, 90 days-two
years, 1-2 years, 11/2 years-2 years or up to 2 years.
[0037] In any of the metronidazole suspensions described herein the
suspension may be prepared with micronized metronidazole.
[0038] In some aspects the invention is a suspension of baclofen or
a salt thereof, that includes baclofen or a salt thereof; a
hydrocolloid stabilizer, simethicone emulsion; sodium citrate,
(dihydrate); a preservative, a thickening agent, a sweetener, and
water.
[0039] In some embodiments the hydrocolloid stabilizer is
microcrystalline cellulose and/or carboxymethylcellulose sodium. In
other embodiments the thickening agent is xanthan gum. In other
embodiments the pH of the formulation is between 3.6 and 4.6. In
yet other embodiments the formulation retains homogeneity of less
than +/-5% or less than +/-10% or any percentage there between of
assay for active pharmaceutical ingredient after at least 30
days.
[0040] In a specific embodiment a liquid formulation of the
invention comprises baclofen plus: [0041] 0.05000% (w/v) ammonium
glycyrrhizate, (magnasweet 100); [0042] 1.500% (w/v) Avicel RC591;
[0043] 0.500% (w/v) citric acid, (anhydrous); [0044] 0.0500% (w/v)
flavor grape 59.266/A; [0045] 0.0300% (w/v) saccharin sodium;
[0046] 0.2000% (w/v) simethicone emulsion, (30%); [0047] 0.1500%
(w/v) sodium benzoate; [0048] 0.2000% (w/v) sodium citrate,
(dihydrate); [0049] 0.1000% (w/v) sucralose; [0050] 0.1000% (w/v)
xanthan gum; [0051] purified water.
[0052] A suspension of baclofen, comprising a salt of baclofen;
simethicone emulsion; sodium bicarbonate; and sodium citrate,
(dihydrate), wherein the suspension is stable for at least 30 days
when stored at 2-8 degrees celsius is provided in other aspects of
the invention.
[0053] In some embodiments the suspension comprises a pH of no more
than pH 4.6. In other embodiments the formulation retains
homogeneity of less than +/-5% of assay for active pharmaceutical
ingredient after at least 60 days.
[0054] Each of the embodiments of the invention can encompass
various recitations made herein. It is, therefore, anticipated that
each of the recitations of the invention involving any one element
or combinations of elements can, optionally, be included in each
aspect of the invention.
DETAILED DESCRIPTION
[0055] The invention encompasses liquid compounded formulations of
metronidazole or baclofen and salts or ester derivatives thereof
such as metronidazole benzoate, diluents that can be used by a
pharmacist to reconstitute metronidazole or baclofen or a salt or
ester derivative thereof, and related compounding kits. In some
embodiments, the invention encompasses liquid compounded
formulations of metronidazole or baclofen, diluents that can be
used by a pharmacist to reconstitute metronidazole or baclofen, and
related compounding kits.
[0056] Commonly, pediatric and geriatric populations encounter
difficulty being administered solid oral dosage forms such as
capsules and tablets which may lead to noncompliance with the
recommended pharmacotherapy with the solid oral dosage forms and
likely results in rendering the therapy ineffective. Solid oral
dosage forms are usually not favorable for pediatric and geriatric
populations due to the potential risk of choking. Additionally,
certain solid oral dosage forms of medications cannot be
administered simply by crushing (e.g., patients requiring various
types of feeding tubes) because of the coating or drug delivery
mechanism by which the drug is released.
[0057] For most community pharmacies (retail/chain and
independent), compendial metronidazole oral formulations do not
provide ease of use, flavoring, flexible dosing, or a uniform
formulation. Commercially available dosage forms include many gels,
lotions, tablets, capsules, and solutions for injections, including
170 marketing authorizations currently recognized in the United
States by the U.S. National Library of Medicine, DailyMed listing,
however none of these are liquids for oral dosing.
[0058] The liquid formulations of the invention is stable for at
least 30 days, at least 40 days, at least 45 days, at least 60
days, at least 75 days, at least 100 days, each up to alternatively
100 days, 200 days, 1 year, or two years or for 30 days-two years
40 days-two years, 90 days-two years, 1-2 years, 11/2 years-2 years
or up to 2 years. under room temperature storage conditions. The
liquid formulations of the invention have improved palatability
compared to the compendial formulation, and when compared to
previously described oral formulations or compounded formulations.
The liquid formulations disclosed herein have improved homogeneity
when compared to commercially available liquid formulations.
[0059] Metronidazole is an antibiotic and antiprotozoal drug with a
broad range of indications, many of which require or benefit from
oral dosing, including bone and joint infections, endocarditis,
various gynecologic infections, intra-abdominal infections,
meningitis, and other CNS infections, infections of the respiratory
tract, septicemia, infections of the skin and skin structure,
amebiasis, bacterial vaginosis, Balantiadiasis, Blastocystis
hominis infection, Clostridium difficile-associated diarrhea (CDAD)
and associated conditions, Crohn's Disease, including refractory
perianal Crohn's Disease, infection by Dientameoba fragilis,
infection by Dracunculus medinensis (Guinea Worm), giardiasis,
Helicobacter pylori infection and associated duodenal ulcer
disease, non-gonococcal urethritis, pelvic inflammatory disease,
Rosacea, infection by Clostridial bacteria, especially C. tetani,
and trichomoniasis.
[0060] In addition, metronidazole can be used as perioperative
prophylaxis where there is a risk of anaerobic bacterial infection,
for example in colorectal surgery or appendectomy. Furthermore,
metronidazole is used as a component of anti-infective,
post-exposure prophylaxis in sexual assault victims. In many of
these conditions, patients may, as a result of the conditions, or
as a result of comorbidities, have difficulty in taking drug, or be
unwilling or unable to take drug in tablet or capsule
presentations. The disclosed liquid formulations provide clinicians
and patients with convenient and palatable alternative dosing
formats that allow precise adjustment of dose, and enhance patient
compliance with clinician orders.
[0061] In specific patient populations, such as those with hepatic
impairment, a clinician may need to adjust the dose of
metronidazole and monitor serum concentrations to balance
therapeutic benefit against risk in subjects with reduced liver
function. The liquid formulations disclosed herein provide
clinicians with a tool to make fine adjustments to oral dosing is
such patients. Similarly, in geriatric patients, the age-related
changes in the pharmacokinetics of metronidazole can require
clinicians to adjust dosage. The liquid formulations disclosed
herein provide clinicians with a tool to make fine adjustments to
oral dosing is such patients in order to maximize therapeutic
benefit while managing patient risk in a way that cannot be
efficiently achieved by dosing with fractional tablets or
capsules.
[0062] Baclofen (.beta.-(4-chlorophenyl)-GABA) is a muscle relaxer
and an antispastic agent that is often used to treat muscle
symptoms caused by multiple sclerosis, including spasm, pain, and
stiffness. Baclofen acts on the central nervous system to relieve
spasms, cramping, and tightness of muscles caused by spasticity. It
is a GABA receptor agonist (derivative of .gamma.-aminobutyric acid
(GABA)) that acts specifically on the GABA-B receptors. Baclofen is
believed to block mono-and-polysynaptic reflexes by acting as an
inhibitory neurotransmitter, blocking the release of excitatory
transmitters.
[0063] The liquid formulations disclosed herein maintain stability
and homogeneity for at least thirty days. With respect to
stability, samples of the disclosed formulations show greater than
90%, or greater than 95%, or greater than 97.5% of the nominal
concentration or starting concentration of metronidazole when
measured in an assay compliant with the assay for Metronidazole
benzoate, thirty days after the liquid is formulated. Alternately,
when assayed thirty days after the liquid is formulated, samples
average to greater than 90%, or greater than 95%, or greater than
97.5%, or greater than 98%, or greater than 99% of the nominal
concentration or starting concentration of metronidazole or
baclofen. With respect to homogeneity, samples of the disclosed
formulations taken from the top, middle, and bottom of the
container of formulated drug show greater than 90%, or greater than
95%, or greater than 97.5% of the nominal concentration or starting
concentration of metronidazole, when measured in an assay compliant
with the assay for metronidazole or baclofen thirty days after the
liquid is formulated. Alternately, when assayed thirty days after
the liquid is formulated, samples taken from the top, middle, and
bottom of the container of formulated drug show less than 10%, less
than 5%, less than 2%, less than 1% or less than 1% but greater
than 0.5% variation from each other, or from the average
concentration measured thirty days after formulation or from the
nominal concentration of metronidazole or baclofen.
[0064] An advantage of the invention is the flexibility of dose
that can be prescribed by the physician. The ability to
reconstitute metronidazole or baclofen or a salt or ester
derivative thereof, in a liquid formulation to be dosed orally to a
patient later in the day, over the course of several days, over the
course of a week, or over the course of several weeks, provides
ease of use to the compounding pharmacist, physician, and patient.
This provides a time saving and cost effective method of producing
multiple drug doses in the pharmacy for a single patient. In
addition, as the method described utilized bulk API rather than
recycling final dosage forms of licensed drug products (i.e.
recovering granules of drug from drug capsules) the invention
provides additional consistency over alternative compounding
formulation methods. In some embodiments, the formulations
described and the preparation methods disclosed produce comparably
stable and homogenous liquid formulations from more than one source
of bulk API, demonstrating the broad applicability of the methods
disclosed.
[0065] The ability to use the liquid formulations of the invention
also offers advantages to physicians, as it provides the ability to
prescribe with more flexibility for a range of challenging and
otherwise vulnerable patients. The palatability of the disclosed
formulations improves patient compliance and minimizes patient
distress. The liquid nature of the formulations disclosed allows
the dosing of metronidazole or baclofen and salts or ester
derivatives thereof, to children who are unable to reliably swallow
capsules. In addition, the liquid nature of the formulations
disclosed allows the dosing of metronidazole or baclofen and salts
or ester derivatives thereof, to elderly patients who are unable to
reliably swallow capsules. Furthermore, the liquid nature of the
formulations disclosed allows the dosing of metronidazole or
baclofen to critical care patients who are otherwise unable to
swallow capsules due to intubation or other injuries, pathologies,
or interventions that inhibit the ability to receive or take
medication in solid format.
[0066] The liquid formulations disclosed provide a vehicle for the
delivery of a suspension of metronidazole or baclofen or salts or
ester derivatives thereof, within a diluent comprising
microcrystalline cellulose, simethicone emulsion, a buffer system
(for example sodium bicarbonate and/or sodium citrate), one or more
preservatives, one or more thickening agents, one or more
sweeteners and/or flavorings, and water. While not excluding the
possibility that other ingredients contribute to the stability of
the formulation, microcrystalline cellulose and/or
carboxymethycellulose sodium are included to stabilize the active
ingredient. Similarly, the use of simethecone contributes to
stability by minimizing the formation of foam on mixing or
agitation during formulation, or incidentally during transport,
use, and storage. The formation of foam could be associated with
conditions denaturing the API or conditions that would diminish the
patient's ability to measure an exact dose. sodium bicarbonate
and/or sodium citrate can be used to provide a buffered diluent
that promotes the maintenance of a constant pH during liquid
storage after formulation. Thickening agents and sweeteners are
included to improve the handling, appearance, and palatability of
the finished dosage.
[0067] Other buffers that can be used in the suspensions and
diluents described herein include pharmacologically acceptable
combinations of cations selected from sodium, potassium, magnesium,
calcium, and aluminum and anions selected from bicarbonate,
hydroxide, gluconate, glycinate, and other appropriate amino acid
salts. Additional buffering agents can include other forms of
citrate, tartrates, acetates, carbonates, phosphates,
metaphosphates, glycerophosphates, polyphosphates, pyrophosphates,
and certain oxides in pharmacologically and pharmaceutically
acceptable combinations of anions and cations providing buffering
capacity as known in the art.
[0068] Preservatives that can be used in the formulations disclosed
herein include anti-microbials, anti-oxidants, and agents providing
biocidal or biostatic activity, such that a low bioburden is
maintained in the formulation of the invention from preparation
through storage, and during routine use by patients and clinicians.
Exemplary preservatives include benzyl alcohol or other
pharmaceutically acceptable alcohol, ascorbic acid, ascrobyl
palmitate or other pharmaceutically acceptable ascorbate salts,
BHA, BHT, citric acid or other citrate salts, sodium benzoate,
benzoic acid or other pharmaceutically acceptable benzoate salts,
sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens,
potassium sorbate or other pharmaceutically acceptable sorbate
salts, or vanillin.
[0069] Sweeteners or sweetening agents may include any compounds
that provide a sweet taste to enhance the palatability of the
formulation, including natural and synthetic sugars and natural and
synthetic sweeteners (i.e., non-sugar sweetening agents). These
could include glucose, fructose, sucrose, or other pharmaceutically
acceptable monosaccharide and disaccharides or sugar alcohols, such
as xylitol. Also, sweeteners may include maltodextrin, polydextrose
and the like. Other sweeteners may include glycerin, inulin,
maltol, salts of acesulfame, alitame, aspartame, neotame, cyclamate
salts, saccharin and its salts, and other artificial and
naturally-occurring agents providing sweetness either singly or in
combination.
[0070] In other embodiments, the liquid formulations comprise a
flavoring agent or flavorant to enhance the flavor or aroma of the
dose, and to improve general palatability of the dose, thus helping
to mask the flavor of the metronidazole or baclofen, or salt or
ester derivative thereof, active ingredient which patients may find
unpleasant. This provides an improved experience for patients, and
better compliance with the drug regimen desired by clinicians.
Suitable natural or artificial flavors can be selected from
pharmaceutically acceptable options as described in standard
pharmacy references which are known to those skilled in the art. In
a particular embodiment, grape flavor is used. The use of grape
flavor has been found to be effective in helping to mask the
unpleasant flavor of metronidazole or baclofen and salts or ester
derivatives thereof. Natural and synthetic flavors can be used and
adapted to the palate of diverse patient populations, including but
not limited to, age- and culturally-related flavor preferences (for
example bubble gum flavor for pediatric patients).
[0071] In further embodiments, the liquid formulation may contain a
pharmaceutically acceptable coloring agent. Many such agents are
approved for use by the U.S. Food and Drug Administration, and are
well known to those skilled in the art of compounding pharmacy. The
use of color can enhance the aesthetic appearance of the dose as
well as providing confirmation of the identity of the drug in a
context where more than one oral formulation is being prepared,
stored, transported, or used. Enhancing the aesthetic appearance of
the dose increased the overall palatability of the dose, which
provides benefits to patients and clinicians in terms of improved
patient experience and improved compliance with the drug regimen.
The ability to unambiguously identify the medication in the
pharmacy, clinical, and patient context provides benefits to the
patient by reducing the scope for errors in the preparation,
storage, handling, transport, and use of the medication. In
addition, the use of color in the formulations can mask color
changes in the formulation lacking additional color agents. For
example, uncolored formulations may change color due to chemical
changes taking place during storage that do not affect the safety,
potency, or efficacy of the medication, but that might confuse a
patient or clinician, or that might lead to a lack of compliance
with a prescribed drug regimen.
[0072] A key problem in devising oral liquid formulations that are
practical, safe, and effective to make and use, is the balance
required between palatability and the handling requirements of the
dose form on the one hand, and the stability of the formulation and
the homogeneity of the doses on the other. Where, as in the present
invention, it is desired to produce a liquid medication for oral
delivery in a series of doses spread over time, it is critical to
provide a formulation in which the potency of the API remains
acceptably constant over the time that the formulation is to be
used, so that from the first dose to last dose, the same dose of
active drug is delivered per unit volume of the formulation dosed
to the patient. In addition, as in the case of the present
invention where the API is presented as a suspension in a liquid
formulation, it is necessary that the formulation is capable of
providing homogenous doses. That is, that the API does not clump,
settle to the bottom, float to the top, or stick to the sides of
the container or any dosing or manufacturing device in a manner
that would cause the dose of API contained in unit volume doses
obtained from the preparation to vary unacceptably. It is generally
desirable for the formulation to be sufficiently pleasant for the
patient to consume and assure compliance with the regimen
prescribed by the clinician, where the dose is delivered orally. It
is generally desirable for the viscosity of the liquid formulation
to be low enough to facilitate handling of the formulation in the
manufacture, storage, and dosing in a manner such that there are
not unacceptable losses of drug, i.e., material adhering to the
containers or equipment used for manufacture and storage or by
adherence or clumping within the drug delivery device such as a
nasogastric feeding tube. If too much drug adheres to and clumps on
equipment and containers used to make, store, and deliver doses,
then the delivery of API to the patient becomes unreliable, which
undermines the consistency, efficacy, and safety of therapy.
[0073] Specific examples are provided below of pharmaceutically
acceptable formulations that achieve appropriate homogeneity and
stability in useful, practical, and palatable presentations.
[0074] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one
skilled in the art. Although any methods and materials similar or
equivalent to those described herein can be used in the practice of
testing of embodiments described herein, certain preferred methods,
devices, and materials are now described.
[0075] As used herein, active pharmaceutical ingredient (or "API")
refers to metronidazole or baclofen and/or a salt or ester
derivative thereof, for example, metronidazole benzoate.
[0076] As used herein and in the appended claims, the singular
forms "a", "an", and "the" include plural reference unless the
context clearly dictates otherwise. Thus, for example, reference to
"an excipient" is a reference to one or more excipients and
equivalents thereof known to those skilled in the art, and so
forth.
[0077] The term "about" is used to indicate that a value includes
the standard level of error for the device or method being employed
to determine the value. The use of the term "or" in the claims is
used to mean "and/or" unless explicitly indicated to refer to
alternatives only or the alternatives are mutually exclusive,
although the disclosure supports a definition that refers to only
alternatives and to "and/or". The terms "comprise", "have", and
"include" are open-ended linking verbs. Any forms or tenses of one
or more of these verbs "comprises," "comprising," "has," "having,"
"includes," and "including" are also open-ended. For example, any
method that "comprises," "has" or "includes" one or more steps is
not limited to possessing only those one or more steps and also
covers other unlisted steps.
[0078] "Optional" or "optionally" may be taken to mean that the
subsequently described structure, event or circumstance may or may
not occur, and that the description includes instances where the
events occurs and instances where it does not.
[0079] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent or improve an
unwanted condition or disease of a patient. In some embodiments, a
therapeutic agent is a bactericide, amebicide or trichomonacide. In
some embodiments the therapeutic agent direct anti-inflammatory
effects, effects on neutrophil motility, effect on lymphocyte
transformation, and effects on cell-mediated immune function. In
some embodiments the therapeutic agent is bactericidal or
bacteriostatic against gram positive anaerobes and gram negative
anaerobes. In some embodiments the therapeutic agent is active
against Helicobacter pylori, Entamoeba hystolytica, Trichomonas
vaginalis, Giardia lambalia, or Balantidium coli.
[0080] As used herein, the terms "patient," "subject" and
"individual" are intended to include living organisms in which
certain conditions as described herein can occur. Examples include
humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and
transgenic species thereof. In a preferred embodiment, the patient
is a primate. In certain embodiments, the primate or subject is a
human. In certain instances, the human is an adult. In certain
instances, the human is a child. In certain instances, the human is
elderly. Other examples of subjects include experimental animals
such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.
[0081] By "pharmaceutically acceptable", it is meant the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not deleterious to the recipient
thereof.
[0082] The term "pharmaceutical composition" shall mean a
composition comprising at least one active ingredient, whereby the
composition is amenable to investigation for a specified,
efficacious outcome in a mammal (for example, without limitation, a
human). Those of ordinary skill in the art will understand and
appreciate the techniques appropriate for determining whether an
active ingredient has a desired efficacious outcome based upon the
needs of the artisan.
[0083] A "therapeutically effective amount" or "effective amount"
as used herein refers to the amount of active compound or
pharmaceutical agent that elicits a biological or medicinal
response in a tissue, system, animal, individual or human that is
being sought by a researcher, veterinarian, medical doctor or other
clinician, which includes one or more of the following: (1)
preventing the disease; for example, preventing a disease,
condition or disorder in an individual that may be predisposed to
the disease, condition or disorder but does not yet experience or
display the pathology or symptomatology of the disease, (2)
inhibiting the disease; for example, inhibiting a disease,
condition or disorder in an individual that is experiencing or
displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., arresting further development of the
pathology and/or symptomatology), and (3) ameliorating the disease;
for example, ameliorating a disease, condition or disorder in an
individual that is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (i.e.,
reversing the pathology and/or symptomatology). As such, a
non-limiting example of a "therapeutically effective amount" or
"effective amount" of a composition of the present disclosure may
be used to inhibit, block, or reverse the activation of gastric
acid secretion.
[0084] The terms "treat," "treated," "treatment," or "treating" as
used herein refers to both therapeutic treatment in some
embodiments and prophylactic or preventative measures in other
embodiments, wherein the object is to prevent or slow (lessen) an
undesired physiological condition, disorder or disease, or to
obtain beneficial or desired clinical results. For the purposes
described herein, beneficial or desired clinical results include,
but are not limited to, alleviation of symptoms; diminishment of
the extent of the condition, disorder or disease; stabilization
(i.e., not worsening) of the state of the condition, disorder or
disease; delay in onset or slowing of the progression of the
condition, disorder or disease; amelioration of the condition,
disorder or disease state; and remission (whether partial or
total), whether detectable or undetectable, or enhancement or
improvement of the condition, disorder or disease. Treatment
includes eliciting a clinically significant response without
excessive levels of side effects. Treatment also includes
prolonging survival as compared to expected survival if not
receiving treatment. A prophylactic benefit of treatment includes
prevention of a condition, retarding the progress of a condition,
stabilization of a condition, or decreasing the likelihood of
occurrence of a condition. As used herein, "treat," "treated,"
"treatment," or "treating" includes prophylaxis in some
embodiments.
[0085] Various aspects of the embodiments described above may be
used alone, in combination, or in a variety of arrangements not
specifically discussed in the embodiments described in the
foregoing, and is therefore not limited in its application to the
details and arrangement of components set forth in the foregoing
description or illustrated in the drawings. For example, aspects
described in one embodiment may be combined in any manner with
aspects described in other embodiments.
[0086] The present invention is further illustrated by the
following Examples, which in no way should be construed as further
limiting. The entire contents of all of the references (including
literature references, issued patents, published patent
applications, and co-pending patent applications) cited throughout
this application are hereby expressly incorporated by
reference.
EXAMPLES
Example 1
[0087] An exemplary formulation of a liquid diluent of the present
invention was prepared. In order to make a relative high viscosity
formulation with approximately 255 cP viscosity in a preparation at
batch size of 2 liters, the following method was successfully used.
For reference purposes, this formulation is referenced herein as
Formula 6 in some embodiments. [0088] 1. 1700 mL of purified water,
was added to a suitable container. [0089] 2. 30.0 grams of Avicel
RC-591 was added while mixing the preparation. [0090] 3. 2.00 grams
of xanthan gum, was added to the preparation while continuing to
mix. [0091] 4. The preparation was mixed for 30 to 60 minutes.
[0092] 5. 1.00 grams of ammonium glycyrrhizate, (also known as
magnasweet 100) was added to preparation while continuing to mix.
[0093] 6. 0.600 grams of saccharin sodium, was added to the
preparation while continuing to mix. [0094] 7. 4.00 grams of sodium
citrate, (dihydrate) was added to the preparation while continuing
to mix. [0095] 8. 3.00 grams of sodium benzoate, was added to the
preparation while continuing to mix. [0096] 9. 2.00 grams of
sucralose, was added to the preparation while continuing to mix.
[0097] 10. Mixing was continued for 10 to 20 minutes. [0098] 11.
10.0 grams of citric acid, (anhydrous) was added to the preparation
while continuing to mix. [0099] 12. 4.00 grams of simethicone
emulsion, (30%) was added to the preparation while continuing to
mix. [0100] 13. 1.00 grams of flavor grape 59.266/A was added to
the preparation while continuing to mix. [0101] 14. Mixing was
continued for 10 to 20 minutes. [0102] 15. The mixing was stopped
and sufficient purified water, was added to make the final volume
up to 2000 mL. [0103] 16. The diluent was mixed for a further 10-15
minutes. [0104] 17. The batch was transferred to containers using
bottle B325-38-BLA-WHT and cap 8040-A.
[0105] Properties of the diluent, an off-white liquid with a grape
odor, were determined. The dynamic viscosity (30 RPM at 25.degree.
C.) was found to be 255 cP, the density was found to be 1.01 g/mL,
and the pH was 3.72 at 25.1.degree. C.
Example 2
[0106] Physicochemical properties and data characterizing the
stability and homogeneity of metronidazole formulated to 50 mg/ml
and 100 mg/mL in the liquid diluent described above as Formula 6
were determined. Suspensions produced with micronized versus
non-micronized metronidazole were compared. The metronidazole
suspension was prepared using a suspension kit at 40.degree. C. and
75% RH. The suspension was then stored at 25.degree. C. and 60% RH
for an extended period of time. Samples were tested for stability
after 15 and 30 days of storage. The concentration of the API
(metronidazole benzoate) in samples obtained from the top, middle
(meaning midway between the surface of the liquid and the bottom of
the container) and bottom of the container containing the
formulated drug were measured. The metronidazole assay was run on a
HPLC with samples of 5.00 .mu.L, for 18 minutes. The data for the
50 mg/ml suspension produced from micronized metronidazole is shown
in Table 1 and the data for the 100 mg/mL suspension produced from
micronized metronidazole is shown in Table 2.
TABLE-US-00001 TABLE 1 Time Point: Kits Initial Initial Initial
Initial Initial 3 M Pull Date: Kits for Compounding N/A N/A N/A N/A
N/A Time Point: Compounded Solution (in-use) Testing Method
Specification Initial 15 days 30 days 60 days 90 days Initial
Appearance of ATM- A slightly A slightly A slightly A slightly
Suspension 1095 hazy, white hazy, slightly hazy, slightly hazy,
slightly to slightly yellow liquid yellow liquid yellow liquid
yellow liquid with a grape with a grape with a grape with a grape
odor odor odor odor pH USP<791> Report 3.7 3.7 3.7 Results
Assay USP 90.0%- Top: 97.9% 97.9% Top: 97.2% 110.0% of Middle:
98.2% Middle: 97.4% label claim Bottom: 98.1% Bottom: 97.1%
TABLE-US-00002 TABLE 2 Time Point: Kits Initial Initial Initial
Initial Initial 3 M Pull Date: Kits for Compounding N/A N/A N/A N/A
N/A Time Point: Compounded Solution (in-use) Testing Method
Specification Initial 15 days 30 days 60 days 90 days Initial
Appearance of ATM- A slightly A slightly A slightly A slightly
Suspension 1095 hazy, white hazy, slightly hazy yellow hazy,
slightly to yellow yellow liquid liquid with a yellow liquid liquid
with a with a grape grape odor with a grape grape odor odor odor pH
USP<791> Report 3.7 3.7 3.7 Results Assay USP 90.0%- Top:
95.2% 95.5% Top: 94.3% 110.0% of Middle: 95.3% Middle: 95.5% label
claim Bottom: 94.9% Bottom: 94.5%
[0107] In contrast to the micronized metronidazole the data for a
50 mg/ml suspension produced from non-micronized metronidazole is
shown below. The non-micronized metronidazole benzoate still shows
a gradient from the top to the bottom. The suspensions were stored
at 25.+-.2.degree. C./60.+-.5% RH.
Metronidazole Benzoate Suspension Assay Results Using
Non-Micronized Metronidazole
TABLE-US-00003 [0108] Time Point Sample Assay Average RSD Initial
Top 99.6% 109.9% 8.3% Middle 113.3% Bottom 116.9%
Example 3
[0109] Physicochemical properties and data characterizing the
stability and homogeneity of baclofen formulated to 1 mg/ml and 5
mg/mL in the liquid diluent described above as Formula 6 were
determined. Suspensions were produced at a 2 oz or 4 oz sample size
using several baclofen batches and the relative stability with
storage time was compared. The baclofen suspension was prepared
using a suspension kit at 40.degree. C. and 75% RH. The suspension
was then stored at 25.degree. C. and 60% RH for an extended period
of time. Samples were tested for stability after 15, 30, and 60
days of storage. The concentration of the API in samples obtained
from the top, middle (meaning midway between the surface of the
liquid and the bottom of the container) and bottom of the container
containing the formulated drug were measured. The baclofen assay
was run on a HPLC with samples of 5.00 .mu.L for 18 minutes. The
data for the 1 mg/ml suspension produced in a 4 oz sample using
different batches of baclofen is shown in Tables 3 and 4
respectively and the data for the 5 mg/mL suspension produced in a
4 oz or 2 oz sample is shown in Tables 5 and 6 respectively.
TABLE-US-00004 TABLE 3 Time Point: Kits Initial 3 M Pull Date: Kits
for Compounding N/A N/A N/A N/A Time Point: Compounded Solution
(in-use) Testing Method Specification Initial 15 days 30 days 60
days Initial Appearance of ATM- A slightly A slightly A slightly A
slightly A slightly Suspension 1095 hazy, white hazy, white hazy,
white hazy, white hazy, white liquid with a liquid with a liquid
with a liquid with a liquid with a grape odor grape odor grape odor
grape odor grape odor Assay USP 90.0%- Top: 96.7% 97.4% Top: 97.2%
97.2% 110.0% of Middle: 97.0% Middle: 96.8% label claim Bottom:
96.7% Bottom: 96.8% pH USP<791> Report N/A 3.8 3.8 3.8
results
TABLE-US-00005 TABLE 4 Time Point: Kits Initial Initial Initial
Initial 3 M Pull Date: kits for Compounding N/A N/A N/A N/A Time
Point: Compounded Solution (in-use) Testing Method Specification
Initial 15 days 30 days 60 days Initial Appearance of ATM- A
slightly A slightly A slightly A slightly A slightly Suspension
1095 hazy, white hazy, white hazy, white hazy, white hazy, white
liquid with a liquid with a liquid with a liquid with a liquid with
a grape odor grape odor grape odor grape odor grape odor Assay USP
90.0%- Top: 95.9% 97.3% Top: 97.1% 97.6% 110.0% of Middle: 96.5%
Middle: 96.7% label claim Bottom: 96.6% Bottom: 95.8% pH
USP<791> Report N/A 3.8 3.8 3.8 results
TABLE-US-00006 TABLE 5 Time Point: Kits Initial Initial Initial
Initial 3 M Pull Date: Kits for Compounding N/A N/A N/A N/A Time
Point: Compounded Solution (in-use) Testing Method Specification
Initial 15 days 30 days 60 days Initial Appearance of ATM- A
slightly A slightly A slightly A slightly A slightly Suspension
1095 hazy, white hazy, white hazy, white hazy, white hazy, white
liquid with a liquid with a liquid with a liquid with a liquid with
a grape odor grape odor grape odor grape odor grape odor Assay USP
90.0%- Top: 101.7% 100.9% Top: 101.1% 101.7% 110.0% of Middle:
102.5% Middle: 100.7% label claim Bottom: 100.9% Bottom: 103.8% pH
USP<791> Report N/A 4.0 4.0 4.0 results
TABLE-US-00007 TABLE 6 Time Point: Kits Initial Initial Initial
Initial 3 M Pull Date: Kits for Compounding N/A N/A N/A N/A Time
Point: Compounded Solution (in-use) Testing Method Specification
Initial 15 days 30 days 60 days Initial Appearance of ATM- A
slightly A slightly A slightly A slightly A slightly Suspension
1095 hazy, white hazy, white hazy, white hazy, white hazy, white
liquid with a liquid with a liquid with a liquid with a liquid with
a grape odor grape odor grape odor grape odor grape odor Assay USP
90.0%- Top: 98.0% 96.8% Top: 97.0% 96.9% 110.0% of Middle: 98.3%
Middle: 97.1% label claim Bottom: 96.8% Bottom: 97.1% pH
USP<791> Report N/A 4.0 4.0 4.0 results
[0110] The diluent of the invention produced highly superior
stability of the metronidazole and baclofen suspensions.
[0111] The foregoing written specification is considered to be
sufficient to enable one skilled in the art to practice the
invention. The present invention is not to be limited in scope by
examples provided, since the examples are intended as a single
illustration of one aspect of the invention and other functionally
equivalent embodiments are within the scope of the invention.
Various modifications of the invention in addition to those shown
and described herein will become apparent to those skilled in the
art from the foregoing description and fall within the scope of the
appended claims. The advantages and objects of the invention are
not necessarily encompassed by each embodiment of the
invention.
Example 4
[0112] An exemplary liquid formulation present invention was
prepared. For reference purposes, this formulation is referenced
herein as Formula R9990, in some embodiments.
[0113] Methods for preparing the formulation can be found below:
[0114] 1. 5 L of colorant solution was prepared in a suitable
container. [0115] 2. 400.0 grams of sucralose was prepared in a
suitable container. [0116] 3. 200.0 grams of sodium benzoate, was
added to the preparation while continuing to mix. [0117] 4. 240.0
grams of citric acid, was added to the preparation while continuing
to mix. [0118] 5. 1000.0 grams of Baclofen, was added to the
preparation while continuing to mix. [0119] 6. 10000.0 grams of
propylene glycol was transferred into a suitable container and
1000.0 grams of hydroxyethyl cellulose was added. The mixture was
then added to the preparation while continuing to mix. [0120] 7.
300.0 grams of simethicone emulsion was added to the preparation
while continuing to mix. [0121] 8. The preparation was mixed for 30
to 60 minutes. [0122] 9. The colorant solution was added to the
preparation while continuing to mix. [0123] 10. 100.0 grams of
flavor grape 59.266/A was added to the preparation while continuing
to mix.
[0124] Physicochemical properties and data characterizing the
stability of the baclofen solution 1 mg/ml and baclofen suspension
5 mg/mL using Formula R9990 above were determined. Suspensions were
produced at a 4 oz or 10 oz sample size and the relative stability
with storage time was compared. The stability data for the 1 mg/ml
solution produced in a 10 oz sample at 38-42 degrees Celsius is
shown in Tables 7 and the data for the 5 mg/mL suspension produced
in a 4 oz sample at 38-42 degrees Celsius is shown in Tables 8.
TABLE-US-00008 TABLE 7 Time Point: Testing Method Specification
Initial 1 M Appearance of Organoleptic A slightly hazy, A slightly
hazy, A slightly hazy, Solution yellow to orange yellow to orange
white liquid with liquid with liquid with a grape odor a grape odor
a grape odor Baclofen Assay In-house 90.0%-110.0% of label 100%
100% claim Sodium Benzoate In-house 80.0%-120.0% of label 101% 101%
Assay claim pH USP<791> Report results 4.0 4.0 Density
In-house Report results 1.00 1.00
TABLE-US-00009 TABLE 8 Time Point: Testing Method Specification
Initial 1 M Appearance of Organoleptic A slightly hazy, A slightly
hazy, A slightly hazy, Solution yellow to orange yellow to orange
white liquid with liquid with liquid with a grape odor a grape odor
a grape odor Baclofen Assay In-house 90.0%-110.0% of label 101%
102% claim Sodium Benzoate In-house 80.0%-120.0% of label 102% 102%
Assay claim pH USP<791> Report results 4.2 4.3 Density
In-house Report results 1.00 1.01
* * * * *