U.S. patent application number 10/653149 was filed with the patent office on 2005-02-24 for method for administering a spill resistant pharmaceutical system.
This patent application is currently assigned to Taro Pharmaceutical Industries Ltd.. Invention is credited to Mehta, Rakesh, Moros, Dan.
Application Number | 20050042237 10/653149 |
Document ID | / |
Family ID | 22217234 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050042237 |
Kind Code |
A1 |
Mehta, Rakesh ; et
al. |
February 24, 2005 |
Method for administering a spill resistant pharmaceutical
system
Abstract
A method for administering a spill-resistant pharmaceutical
formulation comprises delivery from a squeezable container of a
pharmaceutical agent in a suitable vehicle comprising a liquid base
and a thickening agent.
Inventors: |
Mehta, Rakesh; (Chestnut
Ridge, NY) ; Moros, Dan; (Larchmont, NY) |
Correspondence
Address: |
TARO PHARMACEUTICALS
5 SKYLINE DRIVE
HAWTHORNE
NY
10532
US
|
Assignee: |
Taro Pharmaceutical Industries
Ltd.
Haifa Bay
IL
|
Family ID: |
22217234 |
Appl. No.: |
10/653149 |
Filed: |
September 3, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10653149 |
Sep 3, 2003 |
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10052462 |
Jan 23, 2002 |
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6656482 |
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10052462 |
Jan 23, 2002 |
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09549148 |
Apr 13, 2000 |
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6399079 |
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09549148 |
Apr 13, 2000 |
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09089360 |
Jun 3, 1998 |
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6071523 |
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Current U.S.
Class: |
424/400 ;
424/486 |
Current CPC
Class: |
A61P 11/08 20180101;
A61J 7/0053 20130101; A61K 31/00 20130101; A61K 47/22 20130101;
A61K 9/0095 20130101; A61P 25/04 20180101; A61P 31/00 20180101;
A61P 9/00 20180101; A61K 47/02 20130101; A61P 11/10 20180101; A61K
47/32 20130101; A61J 7/0015 20130101; A61P 1/08 20180101; A61K
47/10 20130101; A61K 47/38 20130101; A61P 3/06 20180101; A61K 47/12
20130101; A61K 47/36 20130101; A61K 9/06 20130101; A61P 3/02
20180101; A61P 25/00 20180101; A61P 43/00 20180101; A61K 47/18
20130101; A61P 29/00 20180101; A61P 11/14 20180101; A61K 9/0056
20130101; A61J 7/0023 20130101; A61P 35/00 20180101; A61P 1/10
20180101 |
Class at
Publication: |
424/400 ;
424/486 |
International
Class: |
A61K 009/00; A61K
009/14 |
Claims
What is claimed is:
1. A method for administering a pharmaceutically active agent to a
patient in need of the pharmaceutically active agent, comprising
the step of administering a therapeutically effective amount of the
active agent in a pharmaceutical composition comprising an
effective amount of a pharmaceutical agent in a suitable vehicle
comprising a liquid base and a thickening agent, the formulation
consisting of mutually compatible components and having the
following properties: an initial viscosity within the range of
about 7,500 to about 12,500 cps using a Brookfield Viscometer with
a `C` spindle with Helipath movement at a spindle speed of 20 rpm
and 20-25 degrees C., a viscometric yield value of a semi-solid a
spill resistant consistency permitting the composition to be
squeezed by light manual pressure though a channel of about 1-1.5
mm, to spread in a spoon bowl sufficiently quickly for accurate
measurement, and to remain in the spoon bowl without spilling for
at least about one second and less than about 20 seconds on spoon
tilting at 90 degrees, and for at least about 30 seconds upon spoon
vibration at a frequency of about 120/minute, homogeneity such that
the components do not separate under conditions of use, and a
storage stability such that the foregoing properties are retained
for at least three months of storage at elevated temperature, with
viscosity remaining within a range of 50% less to 100% more than
the initial viscosity, wherein said thickening agent comprises
components selected from the group consisting of cellulose
derivatives in an amount of less than about 2 weight % by volume,
and water-soluble carboxyvinyl polymer in an amount less than 1
weight % by volume.
2. The method of claim 1 wherein the composition has a viscosity
between about 7,500 and about 25,000 cps after storage for three
months at a temperature of 40 degrees C. and 75% humidity.
3. The method of claim 1 wherein the composition has an initial
viscosity of between about 7500 and about 12,500 cps after
storage.
4. The method of claim 1 wherein the thickening agent is from about
0.25 to less than 1 weight % water-soluble carboxyvinyl
polymer.
5. The method of claim 1 wherein the liquid base comprises glycerin
and sorbitol.
6. The method of claim 1 wherein the thickening agent comprises
water-soluble carboxyvinyl polymer in an amount of from about 0.25
to about 1.0 weight % by volume.
7. The method of claim 1 having a spill-resistant consistency
permitting the composition to remain in the spoon bowl without
spilling for from about 1 second to about 4 seconds on spoon
inversion and on spoon tilting at 90 degrees.
8. The method of claim 1 wherein the pharmaceutical agent is
selected from the group consisting of an analgesic, non-steroidal
anti-inflammatory, antihistamine, cough suppressant, expectorant,
bronchodilator, anti-infective, CNS active drug, cardiovascular
drug, antineoplastic, cholesterol-lowering drug, anti-emetic,
vitamin, mineral supplement and fecal softener.
9. The method of claim 1 wherein the pharmaceutical agent is
selected from the group consisting of acetaminophen, aspirin,
ibuprofen, diphenhydramine, dextromethorphan, guafenesin,
pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine,
ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir,
fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically
acceptable salt or ester thereof.
10. The method of claim 1 wherein the storage stability
extrapolates to at least two years shelf life at room
temperature.
11. The method of claim 1 wherein the patient is
dexterity-impaired.
12. The method of claim 1 wherein the patient is selected from the
group consisting of young children, the infirm, and elderly adults
with motor disabilities.
13. The method of claim 1 wherein the patients have tremors.
Description
BACKGROUND OF THE INVENTION
[0001] This application is a continuation of U.S. Ser. No.
10/052,462, now issued, filed on Jan. 23, 2002 which is a
divisional of U.S. Ser. No. 09/549,148, now U.S. Pat. No.
6,399,079, filed on Apr. 13, 2000, which is a continuation of U.S.
Ser. No. 09/089,360 now U.S. Pat. No. 6,071,523, filed on Jun. 3,
1998, all of which are hereby incorporated by reference.
[0002] The invention relates to compositions for administering
pharmaceuticals orally without spilling. More specifically, the
invention relates to vehicles and devices for delivering a variety
of pharmaceutical products.
[0003] Syrups, elixirs, solutions, and suspensions are traditional
dosage forms for oral medication. These liquid formulations are
typically measured by pouring into a spoon, but this approach has
the great drawback of spillage. The risk of spillage can cause
people to underfill the spoon, leading to inaccurate dosage. With
elderly people, children, and the infirm, difficulty in filling a
spoon with a liquid and bringing it to the mouth can be a serious
impediment to administering the medicine. Solid formulations such
as pills, tablets, and capsules are also difficult for children and
for elderly, infirm people to swallow.
[0004] Tachon et al., U.S. Pat. No. 5,300,302, teaches a pump
dispenser for administering a metered dosage of a drug formulation.
This requires a complex mechanical device and formulation
properties suitable for pumping.
[0005] Gorman et al., U.S. Pat. No. 5,288,479, teaches a thickened
pharmaceutical preparation comprising a hexitol and a seaweed
polysaccharide. Such compositions tend to separate, and require a
metered dispenser.
[0006] Ross, U.S. Ser. No. 08/114,315, EP 95939059.2 (commonly
owned with this application and incorporated herein by reference),
teaches semi-solid formulations and a delivery system. However,
there remains a need for more stable compositions with improved
Theological characteristics. There is also a need for a reliable
test system for identifying optimal formulations.
SUMMARY OF THE INVENTION
[0007] The invention relates to a drug delivery system including
combination of a squeezable container, a dispenser, and a
semi-solid pharmaceutical formulation. Each of these elements of
the drug delivery system has certain characteristics so that the
combination (a) allows easy administration (b) of a measured amount
of the drug, (c) from a convenient, preferably tamper-resistant and
child-proof container, (d) with predetermined resistance to
spilling, (e) while providing a suitable storage stable
pharmaceutical composition with compatible components. These
properties result from a variety of physico-chemical
characteristics of the formulation optimized in conjunction with
the type of container and dispenser.
[0008] An embodiment of the invention is a method for obtaining a
suitable spill-resistant formulation comprising combining a
systemic pharmaceutical agent suitable for oral administration with
a semi-solid vehicle, and then conducting the following tests of
the formulation: measuring initial viscosity, measuring yield
value, extruding the formulation into a spoon from a container
through a 1 to 5 mm orifice, observing the spreading/leveling
characteristic of the formulation in the spoon, measuring spill
resistance by spill start time after at least one of spoon
vibration, spoon inversion, and spoon tilting at 90 degrees, and
measuring viscosity after storing at elevated temperature for at
least one month.
[0009] The compositions of the invention are light, water-soluble
gels, which are easy to clean from a spoon bowl, and from any other
surfaces which they may contact. The surface tensions of the
formulations are sufficiently high to provide desirable
spill-resistance, while allowing the product to be sufficiently
free-flowing. In the examples of the prior Ross application, the
viscosity was higher, providing a firm, spill-proof product. Here,
the range of viscosity is lower, providing a freer-flowing, better
leveling product, that is easier to administer with
spill-resistance, but one which is more prone to spillage than the
prior formulations. Thus, while the prior compositions may be
considered spill-proof, the compositions set forth here are
optimally "spill-resistant" but have other superior characteristics
e.g. as to measurability and dispensability.
[0010] Preferred characteristics for the formulation and the method
are as follows. The viscosity, when measured by a Brookfield
Viscometer using "C" spindle at 20 rpm and 20-25 degrees Celsius,
is between about 5,000 to 50,000 cps, preferably less than
25,000-2cps. Surprisingly, a most preferred range for a formulation
to be squeezed from a tube is between about 7,000 and about 12,500
cps. The formulation does not start to spill until after about 30
seconds when vibrated at a frequency of about 2-8 per second, and
an amplitude up to about 1 inch. The spill start time on spoon
inversion is at least about 20-30 seconds for a plastic 8 ml spoon,
longer than for a syrup, and within about 1-20 seconds on spoon
tilting at 90 degrees, which is slower than a syrup, but faster
than prior non-spill formulations.
[0011] Preferred compositions have good shelf life, meaning that
the preferred characteristics are retained after at least three
months storage at a temperature of at least about 40 degrees
Celsius at 75% humidity, which extrapolates under normal
assumptions accepted by the U.S. Food and Drug Administration to
two years shelf-life stability at room temperature. Surprisingly,
in preferred embodiments using carboxyvinyl polymers such as
Carbopol 974, stability may be accomplished by minimizing sodium
containing substances from the formulation. Also, the Carbopol has
a surprising taste masking effect for bitter drugs like
acetaminophen.
[0012] Preferred compositions have Carbopol 974 in a concentration
of from about 0.25% to below about 1%, in contrast to prior
compositions having 1% or more. Other preferred compositions have a
cellulose derivative in an amount of from about 2.5% to 3.3%, more
preferably less than about 2%. A particularly preferred composition
has about 1% microcrystalline cellulose and less than about 2.0%
sodium carboxymethylcellulose, in contrast to prior formulations
with about 2.4 to 2.8% CMC.
[0013] The configuration of the container, closure device, and
receptacle and the consistency of the formulation are selected so
that in response to pressure on the container when the channel
closure device is open, a single predetermined unit dose of the
pharmaceutical composition can be easily squeezed by manual
pressure from the container through the channel into the
receptacle, measured, and administered orally without spilling any
of the composition from the container or the receptacle. The device
may be as shown in the commonly owned Ross application or any other
suitable device available to a person of ordinary skill.
[0014] This invention succeeds where previous efforts failed to
provide a simple, stable, useful system of spill-resistant
pharmaceutical formulations. This invention solves a previously
unrecognized problem as to the Theological properties that must be
optimized for a successful spill-resistant formulation.
[0015] This invention is in a crowded and mature art of oral
medications, in which new dosage forms are constantly sought, at
great expense and at high profit. Nonetheless, no similar
composition or system has been previously discovered. Indeed,
semi-solid formulations run contrary to the conventional wisdom of
using either liquid or solid dosage forms.
[0016] This invention omits complex mechanical elements employed in
the prior art such as pumps, syringes, and elaborate measuring
vessels without loss of ability, and indeed with improved
performance. This provides advantages in manufacturing,
distribution, and waste disposal, and other economies as well.
[0017] The drug delivery system of the invention is
counter-intuitive and inventive as indicated by the lack of
commercially available embodiments of semi-solid formulations for
oral administration of pharmaceutical agents. The resistant drug
delivery system of the invention solves such longstanding problems
with liquid formulations as spillage, and resultant underfilling of
measuring spoons. The drug delivery system of the invention also
overcomes the disadvantages of solid dosage forms, such as being
hard to swallow.
[0018] The inventive formulations are semi-solid, not liquid or
solid. Palatability, stability (a long shelf life) compatibility of
components, and ease of administration of a required dose are
provided. The system allows effortless administration of
predetermined measured doses to children and adults with motor
problems, without spilling. It is easier to measure than a liquid
and easier to swallow than a solid.
[0019] A spill-resistant pharmaceutical formulation for oral
administration from a squeezable container comprises a per-unit
dose effective amount of a pharmaceutical agent in a suitable
vehicle comprising a liquid base and a thickening agent, the
formulation consisting of mutually compatible components and having
the following properties: a viscosity within the range of about
7500 to about 25,000 cps using a Brookfield Viscometer with a `C`
spindle with Helipath movement at a spindle speed of 20 rpm and
20-25.degree. C.; a viscometric yield value of a semi-solid; a
spill-resistant consistency permitting the composition to be
squeezed by light manual pressure through a channel of about 1-5
mm, to spread in a spoon bowl sufficiently quickly for accurate
measurement, and to remain in the spoon bowl without spilling for
at least several seconds on spoon inversion and tilting at 90
degrees, and for at least one minute upon spoon vibration;
homogeneity such that the components do not separate under
conditions of use, and a storage stability such that the foregoing
properties are retained for at least three months of storage at
accelerated stability conditions of elevated temperature and
humidity.
[0020] The viscosity is preferably between about 7000 and about
25,000 cps, more preferably between about 7500 and about 12,500
cps, after storage for three months at a temperature of at least 40
degrees C.
[0021] The formulation preferably comprises about 0.25 to about 1%
water-soluble carboxyvinyl polymer and is preferably essentially
free of sodium. The liquid base preferably comprises glycerin and
sorbitol, and the thickening agent preferably comprises sodium
carboxymethylcellulose in an amount of less than about 2.5% and
microcrystalline cellulose in an amount of about 0.9%. The
formulation preferably comprises glycerin and sorbitol as a
solution of about 70% in water, the concentration of glycerin and
sorbitol solution being about 40%, and microcrystalline cellulose
in an amount of about 0.9%, and carboxymethylcellulose in an amount
of about 0.9% to about 2.4%.
[0022] The pharmaceutical agent is preferably selected from the
group consisting of an analgesic, non-steroidal anti-inflammatory,
antihistamine, cough suppressant, expectorant, bronchodilator,
anti-infective, CNS active drug, cardiovascular drug,
antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin,
mineral supplement and fecal softener. The pharmaceutical agent may
be selected from the group consisting of acetaminophen, aspirin,
ibuprofen, diphenhydramine, dextromethorphan, guafenesin,
pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine,
ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir,
fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically
acceptable salt or ester thereof.
[0023] The liquid base is preferably in an amount of about 45
weight-percent to about 95 weight-percent, comprising a palatable
solvent, selected from the group consisting of water, propylene
glycol, polyethylene glycol, glycerin, and mixtures thereof, and
the thickening agent is preferably in an amount of about 1
weight-percent to about 55 weight-percent, and is selected from the
group consisting of starch, modified starch, sodium carboxymethyl
cellulose in an amount of less than about 2%, microcrystalline
cellulose, hydroxypropyl cellulose, other cellulose derivatives,
acacia, tragacanth, pectin, gelatin, polyethylene glycol, and
water-soluble carboxyvinyl polymers in a concentration of less than
1% and in the absence of a sodium component. The thickening agent
is preferably a cellulose derivative in an amount of about 0.9 to
2.5 weight % by volume.
[0024] The invention further encompasses a pharmaceutical delivery
system comprising the formulation of the invention in a squeezable
container from which a unit dose of the formulation may be
squeezed, either a single dose or multiple doses of the
formulation. The system may further comprise a spoon bowl
receptacle attachable to the container.
[0025] A method for producing a formulation for a spill-resistant
pharmaceutical composition comprises combining a per-unit dose
effective amount of a pharmaceutical agent with suitable vehicle
components comprising a liquid base and a thickening agent, testing
the formulation for acceptance criteria for a composition that can
be easily squeezed from a container into a receptacle, measured,
and administered orally without spilling the composition from the
container or the receptacle, and accepting a formulation that
satisfies the acceptance criteria, the acceptance criteria
comprising:
[0026] viscosity within the range 2500-75,000, preferably
5000-45,000 cps equivalent using a Brookfield Viscometer with a `C`
spindle with Helipath movement at 20 RPM and 20-25.degree. C.;
[0027] viscometric yield value,
[0028] ease of administration comprising (a) extrudability under
light manual pressure from a squeezable container or a proxy (e.g.
a syringe with a 5 mm orifice), and (b) spreadability in a spoon
bowl measured by extruding the formulation into a spoon bowl and
determining whether the material spreads to the edges of the spoon
bowl,
[0029] spill resistance in the spoon bowl during at least one test
period of vibrations, inversion, and tilting, while monitoring
whether the product spills from the spoon,
[0030] mutual compatibility of the components such that they do not
separate, and
[0031] shelf-life of two years at room temperatures as demonstrated
by 3-months accelerated stability testing at elevated temperature
and humidity.
[0032] The test spoon may be plastic and the test period for
vibrations at least about five minutes, the test period for
inversion at least about 30 seconds, and the test period for
tilting at least about 20 seconds. The spreadability is such that
the formulation spreads to the edge of the spoon within seconds.
The method preferably comprises testing a vehicle without the
pharmaceutical agent for at least one of the acceptance criteria,
combining the pharmaceutical agent with the vehicle, and then
testing the formulation for all acceptance criteria.
[0033] Further objectives and advantages will become apparent from
a consideration of the description and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The invention is better understood by reading the following
detailed description with reference to the accompanying figures, in
which like reference numerals refer to like elements throughout,
and in which:
[0035] FIGS. 1-4 were included in the commonly-owned Ross
application.
[0036] FIG. 1 illustrates a closed tube containing a semisolid
composition of the invention
[0037] FIG. 2 illustrates a replacement cap of the invention for
the tube of FIG. 1 equipped with a spoon for measuring and
administering a dose of the semisolid composition of the
invention.
[0038] FIG. 3 illustrates a tube containing the semisolid
composition of the invention with attached replacement cap equipped
with a spoon.
[0039] FIG. 4 shows a section of FIG. 3 along lines 4-4.
[0040] FIG. 5 illustrates inventive test equipment. FIG. 5A shows
an apparatus for measuring spill resistance on vibration. FIG. 5B
illustrates an apparatus for measuring spill resistance on tilting
at 90 degrees.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0041] In describing preferred embodiments of the present invention
illustrated in the drawings, specific terminology is employed for
the sake of clarity. However, the invention is not intended to be
limited to the specific terminology so selected, and it is to be
understood that each specific element includes all technical
equivalents which operate in a similar manner to accomplish a
similar purpose.
[0042] Oral drug delivery systems are typically either liquid or
solid dosage forms. The invention provides a new system combining a
squeezable container and a semisolid oral dosage formulation. There
has been a longstanding need for such a system, and there is
nothing like it available. This system includes a formulation that
has certain physico-chemical and Theological characteristics: such
a formulation is (a) semisolid, (b) spill-resistant, (c) easy to
administer and measure, (d) storage stable, (e) comprised of
compatible components, and (f) has viscosity within a specific
range. The meaning of these terms is apparent to one experienced
with drug formulation, and as defined herein.
[0043] Viscosity is measured using a Brookfield Viscometer with a
`C` spindle with Helipath movement at 20 RPM and 20-25.degree. C.,
or equivalent. Viscosity decreases slightly with increasing
temperature. It has been noted that viscosity measured at 10 rpm
may be significantly higher (50-100%) than measured at 20 rpm;
however for some of the formulations, it is impossible to measure
the viscosity accurately at the slower spindle speed. It was
therefore determined that the 20 rpm spindle speed gave a better
reflection of the important rheologic properties of the inventive
formulations.
[0044] Semi-solid character is used to indicate a formulation that
has a viscometric yield value determined as a relative value, e.g
using the shutting off motion of a Brookfield Viscometer with dial
gauge.
[0045] Ease of administration is intended to mean (a) extrudability
under light manual pressure from a squeezable container or a proxy
(e.g. a syringe with a 5 mm orifice), and (b) spreadability in a
spoon bowl measured by extruding the formulation into a spoon bowl
and determining whether the material spreads to the edges of the
spoon bowl.
[0046] Spill resistance is meant as something different than
non-spill characteristics. A spill-resistant formulation according
to the invention begins to spill from a spoon bowl during test
periods of vibrations, inversion, and tilting, but slowly enough to
conform with practical time limits between dispensing and
ingesting, and quickly enough to enable the product to be readily
consumed from a spoon bowl.
[0047] Mutual compatibility of the components means that they do
not separate in preparation and storage for the equivalent of two
years at room temperature (as indicated by three-months accelerated
stability testing at 40.degree. centigrade and 75% relative
humidity). Storage stability means that the materials do not lose
their desirable properties during storage for the same period.
Preferred compositions do not exhibit a drop in viscosity of more
than 50% or an increase in viscosity of more than 100% during that
period.
[0048] Only certain formulations may be prepared to have the
physico-chemical and rheological characteristics described herein
rendering them suitable for the drug delivery system of the
application. Other formulations lack the critical characteristics
and are therefore distinct.
[0049] Criteria for selecting formulations according to the
invention included the following:
[0050] they are semi-solid, in that they have a viscometric yield
value determined as a relative value, e.g using the shutting off
motion of a Brookfield Viscometer with dial gauge.
[0051] They are easy to administer--they were easily squeezed from
a tube into a teaspoon with light manual pressure such as could be
applied by an elderly or infirm person; they tended to level
themselves in the spoon by spreading to the edge of the spoon to
allow accurate measurement of a teaspoon dose; they did not spill
quickly when the spoon was shaken, tipped, or inverted; and they
had a consistency making them readily removed orally from the spoon
(when a subject inserted the spoon into his mouth, closed his lips,
and removed the spoon).
[0052] They are spill-resistant--this characteristic was quantified
in experiments emulating the behavior of elderly, infirm, and young
people, in which full teaspoon samples of the formulations were
shaken, tilted, and inverted.
[0053] They are storage-stable for an extended period, without any
evidence of separation, hardening, or softening; they retain their
preferred viscosity range.
[0054] They have attractive appearance, suitable texture and
mouthfeel.
[0055] The components are mutually compatible in that they do not
interfere with the bioactivity of the pharmaceutical agent or
physical properties of the vehicle, and the components do not
separate and retain their properties.
[0056] The formulations are suitable for a squeezable container
such as a tube, and for extrusion into a receptacle such as a spoon
bowl. The receptacle is sized to hold a unit dose, to hold it
conveniently without spilling, and to be comfortable and provide a
good fit into the mouth between the lips for oral administration.
The oval sectional shape of a typical teaspoon bowl as evolved over
history satisfies these criteria and is a suitable receptacle,
although other shapes can work as well.
[0057] These properties complement the characteristics of a simple
preferably tamper-resistant and childproof dispensing system for a
storage stable, semi-solid, spill-resistant oral systemic
pharmaceutical that is easy to administer and measure.
EXAMPLES
[0058] To compare the drug delivery system of the invention to
other technologies, experiments were conducted with the goal of
identifying and quantifying the relevant physico-chemical
characteristics of formulations according to the invention. These
were compared to characteristics of other formulations that are
commercially available or disclosed in the prior art. The results
indicate that the properties of the pharmaceutical compositions
herein have surprising advantages and critical characteristics
necessary for a non-spill drug delivery system and that the other
tested products are unsatisfactory for this system.
[0059] Materials and Methods
[0060] TEST SAMPLES (Examples 21 to 31): Laboratory scale (100
g-500 g) batches of pharmaceutical formulations were prepared
essentially according to the methods and compositions described in
examples 2-4, 7, 9, 11-13, 15-16, and 18 of the earlier Ross
application, U.S. Ser. No. 08/114,315. These compositions were
tested for the new acceptance criteria set forth herein.
[0061] These formulations have liquid bases in a concentration of
from about 45% to about 97%, and thickeners in the range of 1% for
Carbomer, 2-3% for cellulose derivative, or 45% for polyethylene
glycol (PEG).
S.N. 21
EXAMPLE 2
Pseudoephedrine HCl Formulation Thickened with Polyethylene
Glycols
[0062]
1 Ingredient % Pseudoephedrine HCl 0.6 Propylene Glycol 25.0
Polyethylene Glycols 73.5 (PEG 400:PEG 3350 3:1) Methyl Paraben
0.22 Sodium Saccharin 0.20 Strawberry Flavor 0.05 D&C Red #33
0.0057 Purified water to 100
[0063] PEG with a molecular weight less than 800 is a solid and
works as a thickener and over 800 is a liquid. Thus, in S.N. 21,
about 18% of the formulation is PEG 3350 (a liquid) and about 55.5%
is PEG 400 (a thickener).
S.N. 22
EXAMPLE 3
Acetaminophen Formulation Thickened with Carboxymethylcellulose
[0064]
2 Ingredient % Acetaminophen 3.2 Glycerin 4.0 Propylene Glycol 25.0
Sodium Saccharin 0.2 Methyl Paraben 0.22 Sodium
Carboxymethylcellulose 2.4 Purified water to 100
S.N. 23
EXAMPLE 4
Dextromethorphan Hydrobromide Formulation Thickened with
Carbomer
[0065]
3 Ingredient % Dextromethorphan HBr 0.3 Propylene Glycol 25.0
Glycerin 4.0 Carbomer 974P 1.0 Strawberry Flavor 0.05 Sodium
Saccharin 0.2 Sodium Hydroxide (10% Solution) 1.75 Purified water
to 100
S.N. 24
EXAMPLE 7
(Placebo) Formulation Thickened with Sodium
Carboxymethylcellulose
[0066]
4 Ingredient % Citric Acid 0.200 ETDA Disodium 0.020 FDC red #33
0.006 Glycerin 20.000 Sodium Carboxymethylcellulose 2.400 Sodium
benzoate 0.100 Hydrogenated glucose (a thickener) 6.5 Purified
water to 100
S.N. 25
EXAMPLE 9
(Placebo) Formulation Thickened with Sodium Carboxymethylcellulose
and Hydroxypropyl Methylcellulose
[0067]
5 Ingredient % Dibasic Sodium Phosphate 0.030 Sodium
Carboxymethylcellulose 2.400 Hydroxypropyl Methyl cellulose (F4M)
0.900 Monobasic Potassium Phosphate 0.020 Methyl Paraben 0.180
Propyl Paraben 0.500 Sodium Chloride 0.050 Sorbitol 70% 30.000
Purified water to 100
S.N. 26
EXAMPLE 11
(Placebo) Formulation Thickened with Sodium
Carboxymethylcellulose
[0068]
6 Ingredient % Sodium Benzoate 0.250 FDC Yellow #6 0.008 Sodium
Saccharin 0.220 Sodium Carboxymethylcellulose 2.800 Hydrogenated
Glucose 20.000 Purified water to 100
S.N. 27
EXAMPLE 12
(Placebo) Formulation Thickened with Sodium
Carboxymethylcellulose
[0069]
7 Ingredient % Sodium Carboxymethylcellulose 2.400 FDC Red #33
0.006 Sodium Saccharin 0.240 Sodium Chloride 0.050 Purified water
to 100
S.N. 28
EXAMPLE 13
Acyclovir Formulation Thickened with Sodium Carboxymethylcellulose
and Microcrystalline Cellulose
[0070]
8 Ingredient % Acyclovir 4.000 Methyl Paraben 0.100 Propyl Paraben
0.020 Sodium Carboxymethylcellulose 2.400 Peppermint Flavor 0.150
Glycerin 20.000 Microcrystalline Cellulose 0.900 Sorbitol 70%
20.000 Sodium Saccharin 0.30 FDC Yellow #6 0.008 Purified water to
100
S.N. 29
EXAMPLE 15
(Placebo) Formulation Thickened with Sodium Carboxymethylcellulose
and Microcrystalline Cellulose
[0071]
9 Ingredient % FDC Red #33 0.006 Microcrystalline Cellulose 0.900
Sodium Carboxymethylcellulose 2.400 Methyl Paraben 0.200 Propyl
Paraben 0.050 Sodium Saccharin 0.250 Purified water to 100
S.N. 30
EXAMPLE 16
(Placebo) Formulation Thickened with Sodium
Carboxymethylcellulose
[0072]
10 Ingredient % FDC Red #33 0.007 Saccharin Sodium 0.250 Imitation
Cherry Flavor 0.150 Sodium Carboxymethylcellulose 2.800 Methyl
Paraben 0.220 Purified water to 100
S.N.31
EXAMPLE 18
(Placebo) Formulation Thickened with Sodium Carboxymethylcellulose
and Polyethylene Glycol
[0073]
11 Ingredient % Butylhydroxy Toluene 0.200 Sodium
Carboxymethylcellulose 2.500 Polyethylene Glycol 1500 25.000 Methyl
Paraben 0.200 Purified water to 100
[0074] REFERENCE SAMPLES (Serial Nos. 32-37): The following
commercially available formulations were obtained (Ser. Nos.
32-34). These were selected as examples of thick viscous liquid
preparations suitable for pharmaceutical use.
[0075] S.N. 32: Corsym Antihistaminic Suspension: (manufactured by
Ciba, Canada), containing phenylpropanolamine hydrochloride,
chorpheniramine maleate, antifoam A, corn syrup, ethyl cellullose,
flavoring, methyl and propyl paraben, polyethylene glycol,
polysorbate 80, starch, vegetable oil, xantham gum, and water.
[0076] S.N. 33: Agarol Laxative Liquid (manufactured by Warner
Lambert Co., Canada), containing mineral oil, glycerin,
phenolphthalein, agar, sodium cyclamate, and water.
[0077] S.N. 34: Natural Honey
[0078] Also several non-commercial pharmaceutical formulations
disclosed in prior patents were also prepared (Ser. Nos. 35-37) to
determine whether the characteristics of the formulations (such as
viscosity, semisolid character, non-spillability, ease of
administration, storage stability) would be suitable for the drug
delivery system of the invention. The formulations were as
described in the patents, except the materials were prepared as
placebos (without the active ingredient). The characteristics of
the formulations should not be expected to be significantly
different with the active ingredient. As to Tachon et al. (Nos.
36-37), the two formulations selected were closest to those in the
examples herein in that they lacked xanthan gum and other
extraneous ingredients.
[0079] S.N. 35: Sterling Patent (Gorman et al., U.S. Pat. No.
5,288,479), Example, Placebo:
12 Ingredient % PEG-6-32 20.00 (PEG 300/PEG 1500 = 1:1) Propylene
Glycol 5.00 Glycerin 5.00 Sorbitol Solution, 70% 40.00 Potassium
Sorbate 0.300 Benzoic Acid 0.100 FD & C Red #33 0.010
Cherry/Raspberry Flavor 0.094 Calcium Saccharin 0.180 Carrageenan
1.50 Purified Water to 100
[0080] S.N. 36: Nestec Patent (Tachon et al., U.S. Pat. No.
5,300,302, Example 24, Placebo:
13 Ingredient % Carbomer 974P 1.0 Glycerol 15.0 Sorbitol 15.0
Methyl paraben 0.15 Sodium saccarinate 0.2 Purified water to
100
[0081] S.N. 37: Nestec Patent (Tachon et al., U.S. Pat. No.
5,300,302, Example 31, Placebo:
14 Ingredient % Carbomer 974P 1.7 Sodium hydroxide 0.79 Sodium
benzoate 0.2 Sodium saccharinate 0.2 Purified water to 100
[0082] VISCOSITY: To measure viscosity, a Brookfield Viscometer was
used with a `C` spindle with Helipath movement at 20 RPM and
20.degree. C. Further details are given in Table 1.
[0083] SEMI-SOLID CHARACTER: If a material is a semisolid then it
has a measurable yield value. Yield value was measured as a
relative value for all the samples utilizing the shutting off
motion of the Brookfield Viscometer (with dial gauge). Semisolid
products in gel or other semisolid form have a significant yield
value; thick liquids or suspensions do not. The character of the
material can be confirmed by visual and tactile observation.
[0084] EASE OF ADMINISTRATION: Ease of administration is reflected
both (a) in extrudability and (b) spreadability. Extrudability was
measured by loading 8 ml of the product into a syringe having an
orifice of about 5 mm or less, then pressing the product out
through the orifice. Extrudability is the ease of extruding a
product from a squeezable container through a small orifice onto a
spoon. A product that is difficult to extrude under these
conditions is unsuitable for administration from a squeezable
container. Extrudability also reflects the ease of ingesting the
formulation when the spoon is placed in the mouth and the tongue is
used to remove the product cleanly from the spoon. Spreadability
(levelling) was measured by observing the behavior of the product
over 5 minutes to determine whether the material remains as a heap
or tends to spread to the edges of the spoon. Spreadability is also
important to the ability to measure and administer a predetermined
dose (typically one teaspoon) of a formulation.
[0085] SPILL RESISTANCE-VIBRATION: Three components of spill
resistance measured: vibrations, inversion, and tilting. As to
vibration, a lab shaker with minor modification was used to
demonstrate, quantitatively, the extent of non-spillability of the
claimed products when shaken in the spoon. The lab shaker was
modified to exhibit controlled horizontal motion of the spoon(s)
attached. See FIG. 5A.
[0086] SPILL RESISTANCE-INVERSION: A custom-made platform was
prepared to show the comparative spilling of the product from a
spoon, when inverted (turned upside down).
[0087] SPILL RESISTANCE-TILTING: Measurements were made to
determine the time at which the products tend to come off the
spoon. The method used was to clamp spoons at a 90.degree. angle
and monitor the product sliding off the spoon. See FIG. 5B.
[0088] Results
[0089] The data generated on the above samples is presented in
Tables 1 and 2. The data emphasizes the important properties and
advantages of a semi-solid drug delivery system. Table 1 presents
the physico-chemical characteristics of the test samples and
reference samples. Table 2 presents the spill resistance data.
15TABLE 1 PHYSICO-CHEMICAL CHARACTERISTICS Viscosity Semi-solid
Ease of No. Product/Base Description (cps) Characteristics
Administration** A. Test samples (From Ross Patent Application) 21
PEG/PG Base w/Pseudoephed. 36,500 Yes + 22 CMC/PG/Gly base w/APAP
38,500 Yes ++ 23 Carbomer/NaOH w/DMH Br 13,500 Yes ++ 24
CMC/Gly/Hyd.Glucose base(Placebo) 43,500 Yes ++ 25
CMC/HPMC/Sorbitol base(Placebo) 45,000 Yes ++ 26 CMC/Hyd. Glucose
base (Placebo) 48,000 Yes +++ 27 CMC base (Placebo) 28,000 Yes ++
28 CMC/MCC/Glyc/Sorb.base w/Acyclovir 45,000 Yes +++ 29 CMC/MCC
Base (Placebo) 24,500 Yes ++ 30 CMC Base (Placebo) 38,000 Yes ++ 31
CMC/PEG Base (Placebo) 42,500 Yes ++ B. Reference Samples
(Commercial products or patented examples) 32 Corsym Suspension
3,500 No ++++ 33 Agarol Laxative Liquid 2,700 No ++++ 34 Natural
Unpasteurized Honey 22,850 No ++++ 35 PEG 6-32/Carageenen
base(Placebo): Sterling 16,500 Yes (Phase separation) Pat#
5,200,479 36 Carbomer/Glyc/Sorb: Ex# 24(Placebo), Nestec 400 No
++++ Pat# 5,300,302 37 Carbomer/Glyc/Sorb/NaOH: Ex#31(Placebo), Yes
Yes -- Nestec Pat# 5,300,302 *Viscosity measurements done by
Brookfield Viscometer, Model BVII, using `C` spindle at 20 rpm and
20 deg C. except in Nos. 8 & 17, where the `C` spindle could
not be used due to instrumental error. The viscosity result shown
above are extrapolated from measurements using `D` spindle. **Ease
of administration is demonstrated through the extrudability of the
product from tube onto spoon and then measurability/spreadibility
of the product in the spoon, as discussed in the text. Grades `+`
to `+++` indicate the products have acceptable #
extrudability/measurability, whereas product marked `++++` behave
like a thick # liquid which has a tendency to spill off the spoon
on overfilling. Products marked `--` indicate the products do not
extrude as uniform gel and also do not have # spreading
characteristics.
[0090] A summary of the results of Table 1 is as follows:
[0091] (a) The test samples (S.N. 21-31) all had a viscosity when
made within the range of 13,500-45,000 at 20 degrees C. and 20 rpm.
Reference sample S.N. 32, 33, and 36 all had very low viscosity,
below 3500 cps.
[0092] (b) The test samples all had semisolid characteristics.
Reference samples S.N. 32-34 and 36 did not. Viscosity was
independent of yield value (semi-solid character) so that a product
with the same viscosity can be distinguished as a liquid or
semi-solid.
[0093] (c) The test samples all rated "+" to "+++" for ease of
administration (extrudability and spreadability). The samples of
S.N. 21-31 have a semi-solid gel-like consistency which can be
squeezed out of a tube to the spoon. However, they are thick and
the leveling is somewhat slow. This represents an intermediate
level of ease of administration and measurability of dosage by
spoon-leveling indication. Reference samples S.N. 35 and 36 lacked
ease of administration. Ease of administration was also observed to
be a characteristic somewhat independent of the other measured
characteristics. For example, it may be difficult to administer a
unit dose of a thick liquid because the liquid will dribble from
the container instead of extrude as a cohesive mass.
16TABLE 2 SPILL RESISTANCE DATA Time to Spill (min) Non-spill No.
Product/Base Composition On Vibration On Inversion On Tilting at
90.degree. Characteristics A. Test Samples (From Ross Patent
Application) 21 PEG/PG base w/Pseudoephed. 15 >20 1:30 yes 22
CMC/PG/Glyc base w/APAP >60 2:40 3:51 yes 23 Carbomer/NaOH base
w/DMH Br 30 >20 0:40 yes 24 CMC/Glyc/Hyd.Glucose base (Placebo)
>60 3:40 0:58 yes 25 CMC/HPMC/Sorbitol base (Placebo) >60
>20 7 yes 26 CMC/Hyd.Glucose base (Placebo) >60 4:10 0:56 yes
27 CMC base (Placebo) >60 0:31 0:22 yes 28 CMC/Glyc/MCC/Sorb.
base w/Acyclovir >60 >20 >20 yes 29 CMC/MCC base (Placebo)
>60 0:27 0:20 yes 30 CMC Base (Placebo) >60 >1:15 0:45 yes
31 CMC PEG Base (Placebo) >60 >20 >20 yes B. Reference
Samples (commercial products or patented examples) 32 Corsym
Suspension 1 Immediately Immediately no 33 Agarol Laxative Liquid
0.5 Immediately Immediately no 34 Natural Unpasteurized Honey 31
Immediately Immediately no 35 PEG6-32/Carageenen base(Placebo)
Sterling 33 Immediately 0:11 no # 5,288,479 36 Carbomer/Glyc/Sorb
base: Ex# 24(Placebo) Immediately Immediately Immediately no Nestec
# 5,300,302 37 Carbo./Glyc/Sorb/NaOH base: Ex# 31(placebo) >60
>20 15 yes, but too stiff Nestec # 5,300,302 Equipment Used: Lab
Shaker, Model: BURREL WRIST SHAKER, modified to provide horizontal
shaking. Frequency: 28 per minute Speed setting:Amplitude: Speed
#1:0.5", #2:0.75, #3:1:0, #4:1.25, #5:1.5 Vibrating Time: 10
minutes on each speed beginning from speed #2 Spoon: White plastic
spoon round, deep (dia. = 11/2" (4 cm) depth. = 7/16 (1.2 cm) with
8 ml capacity. Inversion and tilting resistance were monitored for
20 minutes.
[0094] The results of Table 2 are summarized as follows: The Ross
test samples all had non-spill characteristics. Reference samples
S.N. 32-36 lacked non-spill characteristics and lacked spill
resistance. These characteristics were observed to be largely
independent of those reported in Table 1. In particular, for the
test samples, the spill start time on vibration was 15 minutes or
more, the spill start time on inversion was half a minute or more,
and the spill start time on tilting at 90 degrees was at least
about 30 seconds. The only prior art reference sample that matched
this non-spill characteristic was S.N. 37, but it was too stiff for
ease of administration (see above).
[0095] a) By Vibration: The Ross examples are non-spilling for as
much as 15-60 minutes at a shaking speed of 1.5" amplitude w/28 per
sec. frequency. In contrast, the marketed products like Corsym
(thick suspension), Agarol Laxative Liquid (gel like product), and
natural honey tend to spill-off the spoon in less than one to about
30 minutes.
[0096] b) By Inversion and Tilting: Many of the Ross test non-spill
base products do not spill off the spoon when inverted upside down
for as long as 20 minutes, whereas most of the other prior art
samples spill off immediately. It was also observed that the test
products do not leave residual content of the drug product on the
spoon, and are not likely to do so when ingested by mouth. This can
be correlated to the assurance of full dosage administration. In
contrast, the thick liquids do not come off cleanly.
[0097] As to S.N. 35 (Gorman et al.), the preparation when
completed as per the process mentioned in the patent does not form
a uniform gel. Instead, water starts separating out on storage
within a few hours. This renders the product not suitable for
uniform dosage when the active component will be incorporated, nor
is it physically stable. Also, the spill resistance qualities are
not met, with special reference to vibration and invertibility.
This is different than the qualities covered for the non-spill
formulations of the invention.
[0098] As to Tachon et.al., S.N. 36 turned out to be a thick liquid
and not a semisolid gel, and it lacked spill-resistance as claimed
here. S.N. 37 on the other hand yielded a very stiff consistency
product which is not easily squeezable from a tube/dispenser and is
also non-spreading. Thus this product is inconsistent, and is not
easy to administer or measure as to dose.
[0099] CONCLUSION: Non-spill formulations according to the Ross
invention and the prior art products exhibit particular rheological
properties which may be measured as a proxy for administration to
dexterity-impaired patients. The test methods described herein are
a useful way to determine whether a formulation is suitable for use
as a spill-resistant formulation according to the invention, as a
non-spill formulation or otherwise. Examples 21-31 are very thick,
and examples 32-37 have other properties that make them unsuitable
as a drug delivery system for children and geriatric and
motor-disordered patients. These patients find it difficult to keep
the hands steady and hence are likely to spill the drug product
from the spoon before ingesting. In formulations according to the
Ross application, the non-spill base and pharmaceutical
formulations offer an absence of spilling despite
invertibility.
EXAMPLES 38-45
[0100] In these experiments, spill resistant formulations were
prepared containing dextromethorphan hydrobromide (DM), guafenesin
(GU), acetaminophen (AC), or pseudoephedrine hydrochloride (PE), in
a cellulose-based gel and in a carbomer gel according to the
invention. The formulations are given in Table 3.
17 TABLE 3 EXAMPLES INGREDIENT % 38 39 40 41 42 43 44 45 Active DM
GU AC PE DM GU AC PE 0.30 2.00 3.20 0.60 0.30 2.00 3.20 0.6 Sodium
Carboxymethylcellulose 0.90 0.90 0.90 0.90 Microcrystalline 0.90
0.90 0.90 0.90 cellulose Propylene glycol 25.00 25.00 25.00 25.00
Carbopol 974 0.50 0.25 0.25 1.00 Glycerin 30.00 30.00 30.00 30.00
50.00 50.00 50.00 50.00 FD&C Yellow #6 0.01 0.01 0.01 0.01
FD&C Red #40 0.005 0.005 0.005 0.005 Sodium 0.30 0.30 0.30 0.30
saccharin Methyl paraben 0.20 0.20 0.20 0.20 0.22 0.22 0.22 0.22
Sorbitol 70% 10.00 10.00 10.00 10.00 Purified water 57.39 55.69
54.49 57.09 23.975 22.525 21.325 23.175 pH 6.08 6.06 6.08 6.41 6.72
6.63 6.55 6.25 Storage Data Viscosity (initial) 11950 11100 12175
11975 7050 9550 9800 10625 Viscosity (40.degree.) 20560 22250 9520
19354 8370 9350 8650 12100
[0101] Each of these formulations had suitable characteristics of
viscosity, spill-resistance, and ease of administration. They were
semi-solids. They were freer-flowing gels than the compositions of
Ross. They all had pH between about 6 and about 7. Examples 42-45
were essentially free from sodium except for small quantities of
sodium oxide used to adjust the pH.
[0102] In addition, the formulations were subjected to stability
testing for several months at room temperature and accelerated
stability conditions with elevated temperature and elevated
humidity (40 degrees C., 75% relative humidity). In all cases, the
formulations homogeneous at the outset and after stability testing.
Viscosity remained suitably constant. Table 3 gives the viscosity
data for stored formulation after storage for 3 months at elevated
temperature (40 degrees C.) and 75% humidity.
[0103] An additional unexpected advantage of Example 44 was that
the Carbopol had a very effective taste-masking effect, making the
formulation palatable despite the bitterness of acetaminophen. This
feature permits the avoidance of other taste-masking agents.
18 TABLE 4 Spill time Active (sec) No. Agent Thickener 90.degree.
Invert Spreadability Semisolid? 38 DM CMC/MCC 3 4 +++++ Yes 39 GU 3
4 +++++ Yes 40 AC 2 3 +++++ Yes 41 PE 2 3 +++++ Yes 42 DM Carbopol
1 2 +++++ Yes 43 GU 2 3 +++++ Yes 44 AC 2 3 +++++ Yes 45 PE 2 3
+++++ Yes
[0104] Spreadability is given on a scale where:-- means very stiff
semi-solid, + means less stiff semi-solid, 2+, 3+, 4+, and 5+
indicate increasing spreadability.
[0105] As can be seen from Table 4, the inventive formulations are
semi-solids, unlike the liquid formulations of the prior art. The
inventive formulations have very high spreadability, at least as
high as honey. They do not spill from a spoon immediately on
tilting or inversion, as do the liquids, but they do come off
within several seconds, much faster than the non-spill formulations
of Ross.
[0106] In addition, the formulations were tested at high frequency
vibration similar to the tremors of Parkinsonian patients. At
amplitudes of 1 to 2 inches, and frequency of 120-240 per minute
(4/sec), the inventive formulations do not spill. This
spill-resistance is better than honey at room temperature.
[0107] Each reference cited herein is incorporated by reference in
its entirety as if specifically incorporated by reference. The
embodiments illustrated and discussed in this specification are
intended only to teach those skilled in the art the best way known
to the inventors to make and use the invention. Nothing in this
specification should be considered as limiting the scope of the
present invention. Modifications and variations of the
above-described embodiments of the invention are possible without
departing from the invention, as appreciated by those skilled in
the art in light of the above teachings. It is therefore to be
understood that, within the scope of the claims and their
equivalents, the invention may be practiced otherwise than as
specifically described.
* * * * *