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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is generally related to aerosol formulations delivered by
metered dose inhalers (MDIs). More particularly, the invention is directed
to aerosol formulations which include vasoconstricting agents and the
local anesthetic agent lidocaine in its base form dissolved in
hydrofluorocarbon propellants.
2. Description of the Prior Art
Vasoconstriction of blood vessels is achieved by stimulation of the alpha
receptors in the smooth muscle cells of the blood vessel wall.
Vasoconstriction is desirable in some clinical situations both
systemically to correct hypotension and locally to reduce regional blood
flow. The alpha-1 adrenergic recepters, found in the smooth muscle cells
of the peripheral vaculature of the coronary arteries, skin, uterus,
intestinal mucosa and splanchnic beds, mediate vasoconstriction. These
receptors serve as postsynaptic activators of vascular and intestinal
smooth muscles as well as endocrine glands. Their activation results in
either decreased or increased tone, depending upon the effector organ. The
response in resistance and capacitance blood vessels is constriction.
Alpha-1 adrenergic agonists include the natural catecholamines,
epinephrine, norepinephrine and dopamine, and the synthetic
noncatecholamines such as ephedrine, mephentermine, amphetamines,
metaraminol, phenylephrine and methoxamine.
Phenylepherine is considered a potent pure alpha-1 agonist drug which
increases venous as well as arterial constriction. Phenylephrine is used
intravenously in small doses of approximately 1 .mu.g/kg body weight to
cause systemic vasoconstriction and elevation of blood pressure. It is
also used regionally to cause vasoconstriction when injected with local
anesthetic agents to provide prolonged nerve conduction block.
Phenylephrine has been found to provide excellent decongestion of the nasal
mucosa by exerting its alpha-1 mediated vasoconstricting effect on the
mucosal blood vessels. This directly opposes the histamine-mediated
vasodilation and reduces mucosal oedema and vascularity. Other agents that
have been used for this effect are ephedrine and cocaine.
Cocaine possesses both anesthetic and vasoconstricting properties. These
properties make it suitable to provide both topical anesthesia and
vasoconstriction of the nasal mucosa to improve patient tolerance of nasal
catheterization during nasotracheal intubation, nasogastric tube
insertion, or fiberoptic examination of the nose. Vasoconstriction results
in shrinking of the nasal mucosa with enlargement of the nasal passage and
reduced bleeding during nasal procedures.
Although cocaine provides good vasoconstriction and is well tolerated by
most patients, there are significant problems with its use. One such
problem is that even small doses (approximately 30 mg for example) may
cause systemic toxicity. Another problem relates to the potential
diversion and illicit use of cocaine by medical personnel. The handling
and storage of controlled substances involves additional administrative
costs and risks.
Lidocaine is similar to cocaine in effectiveness as a local anesthetic, but
it does not vasoconstrict the mucosa and thus dilate the nasal passage.
For this reason, phenylephrine has been combined with lidocaine to reduce
nasal congestion. The combination of lidocaine and phenylephrine has been
advocated as an alternative to cocaine and its efficacy evaluated in a
number of studies.
Currently, lidocaine and phenylephrine are required to be mixed by the
clinician before applying the solution. Suitable recommended combinations
are 3-4% lidocaine hydrochloride in water mixed with 0.25-1% phenylephrine
hydrochloride, also in water. The aqueous solution is then delivered to
nasal mucosa as a spray using a conventional manual atomizer or a
multi-orificed cannula and syringe delivery system. The optimum dose used
with this spray application is 1.25-1.5 mg phenylephrine hydrochloride and
12-15 mg lidocaine hydrochloride per nostril of adult patients.
The methods of delivery and efficacy of lidocaine and phenylephrine are
discussed and evaluated in the following studies: Curtis N. Sessler et
al., Anesthesiology 64:274-277 (1986); Jeffrey Gross et al., Anesthesia &
Analgesia 63:915-918 (1984); and Robert M. Middleton et al., Chest
99:5:1093-1096 (1991).
Drug deposition in the nasal cavity is reviewed in Volume 39 of the "Drugs
and the Pharmaceutical Sciences" series titled Nasal Systemic Drug
Delivery, edited by Yie W. Chien, Kenneth S. E. Su and Shyi-Feu Cheng and
published by Marcel Dekker, Inc. in 1989.
"The deposition of aerosols in the respiratory tract is a function of
particle size and respiratory patterns. The density, shape and
hygroscopicity of the particles and the pathological conditions in the
nasal passage will influence the deposition of particles, whereas the
particle size distribution will determine the site of deposition and
affect the subsequent biological response in experimental animals and
man."
"A uniform distribution of particles throughout the nasal mucosa could be
achieved by delivering the particles from a nasal spray using a
pressurized gas propellant."
Factors related to the dosage form of the drug found to affect the
pharmacokinetics of nasal absorption include concentration of active drug,
physiological properties of active drug, density/viscosity properties of
the formulation, pH/toxicity of dosage form, and pharmaceutical excipients
used.
Highly concentrated drugs which are lipid soluble at nasal pH of 5.5 to 6.6
and, when dissolved in a minimal amount of excipient, will be rapidly and
extensively absorbed.
Lidocaine base is freely lipid soluble and will cross mucous membranes
readily. It is insoluble in water and thus not suitable for use in an
aqueous suspension, requiring ethanol or the like to obtain a liquid
solution. Some way to produce a fine spray of lidocaine base would be
advantageous for delivery to the nose.
Vasoconstricting agents such as phenylephrine are usually used in their
salt forms which are water soluble and thus suitable for intravenous
injection.
MDIs have been used extensively and have proven to be an effective means of
producing a reproducible preselected dose of medicament in a predictable
spray pattern and droplet size. This is particularly advantageous when
delivering potent drugs where the need for reliable drug delivery is
important and where overdoseage leads to dangerous clinical side-effects.
A problem with the use of MDIs relates to the chlorofluorocarbon (CFC)
propellants which have been used in MDIs. All chlorine-containing
halohydrocarbons have been implicated in the destruction of the earth's
ozone layer with subsequent adverse effects on human and animal life.
World-wide treaties have called for a ban on these propellants due to
their alleged impact on the earth's ozone layer. The most widely
recognized CFC alternatives are hydrofluorocarbon (HFC) propellants, such
as 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane, and
these propellants have been readily adopted in the refrigeration, polymer
foam blowing, and electronic cleaning industries. However, HFC propellants
have been found to behave differently than CFC propellants in the MDI
environment. In particular, it has been found to be very difficult to
solubilize or disperse pharmaceuticals in HFCs. Without solubilization or
uniform dispersability in the propellant, the MDI cannot provide a
reproducible and efficacious dose of medicament. Much work has been
performed in the area of designing new surfactants and identifying
co-solvents that can be used to solubilize or disperse pharmaceuticals in
HFC propellants.
To date, no MDI pharmaceutical products that utilize HFC propellants have
been approved for use by any industrialized country. Although, reports on
recent submissions to regulatory agencies suggest that
1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoroethane based MDIs
are the most likely CFC-alternative MDIs to gain approval in the near
future.
The object of aerosolized medication delivery by MDI is to provide the
medicament in stable suspension or solution form in the propellant in a
suitable concentration for clinical effect, with minimal or no additives.
The droplet size is predictable and is a function of the suspended
particle size in a suspension formulation or the relative volume of drug
and its cosolvents to the propellant volume in a solution formulation. The
propellant should constitute at least about 45% of the total formulation
weight and preferably about 60-98% of the formulation weight.
Lidocaine and phenylephrine have been shown to exert independent effects on
the nasal mucosa that result in vasoconstriction and topical anesthesia.
Both of these effects have been found to be helpful during procedures
involving manipulation or examination of the nose. The clinical effect is
similar and considered superior in efficacy to cocaine, but the need to
premix the solution and also to provide a suitable way to deliver a
solution or suspension thereof has prevented their combined use from
gaining universal acceptance as well as from being employed for all nasal
manipulations such as nasogastric tube insertion, where its use should be
advantageous to the patient.
Other clinical situations where a combined lidocaine/vasoconstricting agent
formulation, such as lidocaine/phenylephrine, would be in providing
topical anesthesia and vasoconstricting in the upper airway, open skin
wounds, the urethra, anus, and the cervix and vagina.
The present invention provides a solution to this long-standing shortcoming
or deficiency of the art.
SUMMARY OF THE INVENTION
An object of this invention is to provide novel formulations of lidocaine
and topically acting vasoconstricting agents suitable for use in an MDI.
Another object of this invention is to provide an MDI formulation which
includes one or more HFC propellants that includes lidocaine in its
lipid-soluble free base form and one or more vasoconstricting agents.
Yet another object of this invention is to provide a method of solubilizing
vasoconstricting agents in HFC propellants wherein the lidocaine is used
to both improve the absorption of vasoconstricting agents into the HFC
propellants.
Still another object of this invention is to provide compositions
incorporating vasoconstricting agents, such as phenylephrine, as stable,
pharmacologically acceptable acid addition salts such s hydrochloride or
bitartrate salts, dissolved in suitable solvents in an HFC propellant.
According to the invention, vasoconstricting agents, such as phenylephrine,
ephedrine, epinephrine, norepinephrine, dopamine, pseudo-ephedrine,
mephentermine, amphetamines, metaraminol, methoxamine,
phenylpropanolamine, B-hydroxyphenethylamine, 3,4-dihydroxynorephedrine,
etc. have been found to be more easily dissolved in therapeutic
concentrations in HFC propellants such as 1,1,1,2-tetrafluoroethane
(HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), when lidocaine
free base is added. Experiments have shown that solubility of the
vasoconstricting agents can be achieved with less organic solvent when
lidocaine base is present than is possible in the absence of lidocaine
base. An example of this is phenylephrine hydrochloride and ethyl alcohol
where almost 50% more ethyl alcohol is required to maintain a solution of
phenylephrine hydrochloride in HFC-134a in the absence of lidocaine base.
Examples of organic solvents considered useful in these formulations are
ethyl alcohol, benzyl alcohol, propylene glycol, diethyl ether,
dimethoxyethane, etc. Some of these solvents are not soluble when
lidocaine base is present. Some of the vasoconstricting agents, such as
ephedrine, which do not have hydroxyl groups on the benzene ring
structure, have been found to have limited solubility in the HFC
propellant alone. The addition of lidocaine base improved the solubility
of these agents to allow therapeutic concentrations to be achieved. In
essence, the lidocaine base is acting as both a solubilizing agent as well
as a thereapeutic agent in aerosol formulations prepared with
vasoconstricing agents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
Vasoconstricting agents, such as phenylephrine hydrochloride, have been
found to be insoluble in HFC propellants such as HFC-134a and HFC-227. In
addition, when the vasoconstricting agents were dissolved in EtOH in
clinically useful concentrations (e.g., approximately 2.0-2.5%) and then
mixed with HFC-134a or HFC-227, the vasoconstricting agents precipitated
out of solution in the alcohol.
Lidocaine base has been found to be extremely soluble in HFC propellants.
Table 1 shows the solubility of lidocaine base in selected media.
TABLE 1
______________________________________
Solubility
Propellant Weight % mg/ml
______________________________________
HFC-134a 58 759
HFC-227 45 602
Water 0 0
______________________________________
Vasoconstricting agents such as phenylephrine are usually used in their
salt forms which are water soluble and thus suitable for intravenous
injection. These agents are very potent and rapid acting and the base form
is not considered to be a major clinical advantage in this formulation,
but where improved solubility of the base form is shown, the base is
preferred.
When the vasoconstricting agents were combined with lidocaine base and the
HFC propellant, they were found to be either more soluble or soluble with
proportionally less organic solvent to keep them in a stable solution.
These observations demonstrate that the lidocaine acts as an adjuvant to
assist and maintain the solubility of the vasoconstricting agents. Thus,
this invention particularly contemplates using lidocaine base in solution
in HFC propellants such as HFC-134a or HFC-227 or combinations thereof, to
more readily dissolve pharmacologically active concentrations of
vasoconstricting agents, such as phenylephrine, in the HFC propellants
with either no organic solvent requirement for the formulation or
significantly less organic solvent than would be required if no lidocaine
were present.
The Example section below demonstrates that different vasoconstricting
agents can be solubilized into HFC propellants using lidocaine base. In
addition, the Example section shows that several different organic
solvents which are not soluble in HFC propellants, can be made soluble
when combined with lidocaine base. Moreover, the Example section
demonstrates that vasoconstricting agents may be dissolved in HFC
propellants without an organic solvent and using lidocaine base solely as
a solubilizing agent.
Preferably, an aerosol formulation according to this invention will
comprise lidocaine free base at 1-30% by weight, vasoconstricting agent at
0.01-10% by weight, and HFC propellant or propellant blend at 45-99% by
weight. Most preferably, the lidocaine free base will be present at 5-20%
by weight, the vasoconstricing agent will be present at 0.01-2% by weight,
and the HFC propellant or propellant blend will be present at 60-98% by
weight. Solvents such as ethanol (EtOH or ethyl alcohol), benzyl alcohol,
propylene glycol, polyethylene glycol, diethylether, and dimethoxyethane
may be included in the formulation. Preferably, the solvent will comprise
between 1-40% w/w of the formulation, and most preferably between 1-20%
w/w. Other constituents such as valve lubricants (e.g., polyethylene
glycol, sorbitan trioliate, lecithin, glycerol trioleate, etc.),
preservatives (e.g., benzalkonium chloride, cetyl pyridinium chloride,
etc.), and the like may also be included, and preferably would constitute
less than 20% w/w of the formulation. The vasoconstricting agents which
may be solubilized by this include phenylephrine, ephedrine, epinephrine,
norepinephrine, dopamine, 3,4-dihydroxynorephedrine, pseudo-ephedrine,
mephentermine, amphetamines, metaraminol, methoxamine,
phenylpropanolamine, B-hydroxyphenethyl amine, etc., and these agents can
be included in the formulation in salt form (e.g., hydrochloride salt,
bitartrate salt, tris salt, etc.) or base form or any other
pharmocologically acceptable derivative. The metered dose inhaler in which
the formulation is packaged will preferably deliver small quantities of
drug per actuation (e.g., 25-100 .mu.l doses), wherein each action will
dispense approximately 1-20 mg of lidocaine free base and 0.01-1 mg of
vasoconstricting agent. Most preferably, a dose of 2.5-10 mg lidocaine
base and 0.05-0.2 mg vasoconstricting agent will be delivered per
actuation.
An inhalable metered dose dispensable lidocaine and vasoconstricting agent
combination provides excellent delivery to the nose and upper airway
causing rapid onset of topical anesthesia and intense vasoconstriction of
the mucous membrane targeted. This is advantageously achieved when
preparing a patient's nose for examination or for passing a nasogastric
feeding tube or a nasotracheal breathing tube. This drug combination
delivery system is also advantageous in the acute treatment of upper
airway oedema, swelling and bleeding as may occur in the presence of acute
epiglottitis, inflammation, anaphylaxis and glottic tumors, etc.
Additional uses can include topical application of prolapsed hemmorrhoids
where topical anesthesia and vasoconstriction are the desired therapeutic
goals. Further, application to the labia, vaginal mucosa, cervix and
uterine endometrium will advantageously provide excellent topical
anesthesia and reduced bleeding in the treatment of local lesions or in
the preparation for therapeutic procedures such as cervical dilation and
uterine curretage.
Manufacturing of MDI solution formulations is considered easier and cheaper
than suspension formulations. Solution formulations do not require prior
micronization of the delivered medicament to the desired particle size.
Expensive surfactants are not required, thus reducing the patient's
exposure to potentially irritant and harmful substances.
The formulations of this invention can be manufactured in different ways.
In one method, the lidocaine and vasoconstricting agent are dissolved in
the organic solvent and place in the aluminum canister which is then
capped and pressure filled with propellant. Where an organic solvent is
not required, the lidocaine and vasoconstricting agent are dissolved in
the propellant which is then pressure filled into the closed empty
aluminum canister. The stability and ready solubility of these solutions
allow for a variety of organic solvents and filling techniques to be used.
EXAMPLE
Lidocaine USP in free base form, of the formula
2-(diethylamino)-2',6'-acetoxylidide [137-58-6] C.sub.14 H.sub.22 N.sub.2
O (MW 234.34), was obtained from Astra Pharmaceutcals, Inc., in
Mississuage, Ontario, Canada.
Phenylepherine hydrochloride of the formula
(R)-3-hydroxy-alpha-[(methylamino)methyl]benzene methanol hydrochloride
C.sub.9 H.sub.14 ClNO.sub.3 (MW 203.67), as well as the other chemicals,
including ephedrine, metaraminol, methoxyamine, diethylene glycol, benzyl
alcohol, and propylene glycol were obtained from Sigma Chemicals.
The aerosol propellants used in the formulations were HFC-134a, available
from the E. I. du Pont de Nemours and Company under their trademark
Dymel.RTM., and HFC-227 supplied by Great Lakes Chemical under their
trademark FM 200.RTM.. Both propellants are nonflammable vapor at room
temperature and atmospheric pressure. Neither contains chlorine atoms and,
as such, neither are implicated in stratospheric ozone destruction by
chlorofluorocarbons or other chlorinated hydrocarbons.
In a comparative test, phenylephrine hydrochloride was dissolved in ethyl
alcohol to produce a 2.5% w/w solution. This solution was placed in a
glass bottle designed for pressure filling with liquid propellant. When
HFC-134a was added to this solution, the phenylephrine hydrochloride was
precipitated out of solution. In contrast, using the same phenylephrine
hydrochloride in ethanol solution but where the solution also contained
lidocaine free base, both the lidocaine base and the phenylephrine
hydrochloride remained in solution after the addition of HFC-134a. This
comparative test demonstrates that lidocaine is a useful adjuvant for
solubilizing vasoconstricting agents such as phenylephrine in HFC-134a.
Several formulations have been prepared which demonstrate the utility and
advantages of the invention. These formulations are presented for
exemplary purposes only and by no means limit the scope and content of the
invention defined by the claims.
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Formulation 1
Phenylephrine hydrochloride
43 mg 0.86% w/w
Lidocaine free base
350 mg 7.0% w/w
Ethanol (density 0.81 g/ml)
1650 mg 33.0% w/w
HFC-134a (density 1.22 g/ml)
2957 mg 59.14%
w/w
Formulation 2
Phenylephrine hydrochloride
25 mg 0.5% w/w
Lidocaine free base
500 mg 10.0% w/w
Ethanol 1000 mg 20.0% w/w
HFC-134a 3475 mg 69.5% w/w
Formulation 3
Phenylephrine hydrochloride
40 mg 0.8% w/w
Lidocaine free base
1000 mg 20.0% w/w
Ethanol 1550 mg 31.0% w/w
HFC-134a 2410 mg 48.2% w/w
Formulation 4
Phenylephrine base 17 mg 0.37% w/w
Lidocaine free base
229 mg 5.0% w/w
Ethanol 767 mg 16.7% w/w
HFC-134a 3576 mg 77.93%
w/w
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Formulations 1-4 were all stable formulations which had and maintained both
the lidocaine free base and the phenylephrine in solution. Formulations
1-4 show that small quantities of lidocaine are very effective at
solubilizing phenylephrine in HFC-134a, and that the solubilizing property
was not affected by whether the phenylephrine was in hydrochloride salt or
base form. Formulations which include alternative acid addition salts
(bitartrate, tris, etc.) of phenylephrine, as well as other derivatives of
phenylephrine will also provide satisfactory results.
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Formulation 5
Phenylephrine hydrochloride
32 mg 0.64% w/w
Lidocaine free base
320 mg 6.4% w/w
Ethanol 1600 mg 32.0% w/w
HFC-227 3048 mg 60.96%
w/w
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Formulation 5 was a stable formulation which maintained both phenylephrine
and lidocaine in solution. Formulation 5 demonstrates that lidocaine free
base can be effectively used to solubilize phenylephrine in a different
HFC propellant from that used in formulations 1-4. Specifically,
formulation 5 demonstrates the use of lidocaine free base to solubilize
phenylephrine in HFC-227. Lidocaine free base should be effective in
solubilizing other compounds in other HFC propellants, as well as
combinations of HFC propellants.
______________________________________
Formulation 6
Ephedrine base 9 mg 0.8% w/w
HFC-134a 1104 mg 99.2% w/w
maximum solubility
Formulation 7
Ephedrine base 29 mg 6.9% w/w
Lidocaine base 133 mg 31.0% w/w
HFC-134a 260 mg 62.1% w/w
Solubilized
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Formulations 6 and 7 show that lidocaine base can be used to improve the
solubility of vasoconstrictive agents other than phenylephrine in
HFC-134a. In addition, contrasting Formulations 6 and 7, it can be seen
that some vasoconstrictive agents can be solubilized in HFC-134a without
other co-solvents being present (e.g., no ETOH, etc.)
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Formulation 8
Phenylephrine hydrochloride
1 mg 0.02% w/w
Lidocaine base 40 mg 0.8% w/w
Benzyl alcohol 219 mg 4.3% w/w
HFC-134a 4,753 mg 94.88%
w/w
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Benzyl alcohol and phenylephrine hydrochloride was not soluble in HFC-134a.
Phenylephrine hydrochloride remained in solution in the benzyl alcohol,
but the alcohol was not soluble in HFC-134a. However, with the addition of
lidocaine as shown in formulation 8, a clear and stable solution in
HFC-134a was formed. The stability of Formulation 8 demonstrates that
organic solvents other than ethyl alcohol can be used in conjunction with
lidocaine to solubilize vasoconstrictive agents.
______________________________________
Formulation 9
Phenylephrine hydrochloride
3 mg 0.14% w/w
Lidocaine base 150 mg 7.3% w/w
Diethylene glycol 102 mg 5.1% w/w
HFC-134a 1775 mg 87.46%
w/w
______________________________________
Diethylene glycol, like benzyl alcohol, was not readily soluble in
HFC-134a. While phenylephrine hydrochloride was soluble in diethylene
glycol, the combination was not soluble when combined with HFC-134a.
However, the addition of lidocaine base, as shown in Formulation 9,
produces a clear and stable solution of the phenylephrine
hydrochloride/diethylene glycol/lidocaine base/HFC-134a formulation. Clear
and stable solutions also resulted when phenylephrine base was substituted
for phenylephrine hydrochloride in formulation 9. Thus, formulation 9
shows another example of an organic solvent/vasoconstrictive agent
combination which can become soluble in HFCs when lidocaine base is used
as an adjuvant.
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Formulation 10
Phenylephrine hydrochloride
3 mg 0.44% w/w
Lidocaine base 80 mg 11.46%
w/w
propylene glycol 69 mg 9.88% w/w
HFC-134a 546 mg 78.22%
w/w
______________________________________
Like diethylene glycol and benzyl alcohol, propylene glycol also was not
soluble in HFC-134a. While phenylephrine hydrochloride was soluble in
propylene glycol, the combination was not soluble when combined with
HFC-134a. However, the addition of lidocaine base, as shown in Formulation
10, produces a clear and stable solution of the phenylephrine
hydrochloride/propylene glycol/lidocaine base/HFC-134a formulation.
______________________________________
Formulation 11
Methoxamine base 17 mg 0.6% w/w
Lidocaine base 92 mg 3.3% w/w
Ethanol 144 mg 5.2% w/w
HFC-134a 2351 mg 90.9% w/w
Formulation 12
Phenylpropanolamine base
35 mg 0.9% w/w
Lidocaine base 350 mg 9.1% w/w
Ethanol 191 mg 4.9% w/w
HFC-134a 3261 mg 85.1 w/w
______________________________________
Formulations 11 and 12 show that methoxamine and phenylpropanolamine both
in base form dissolved in ethanol are readily soluble in a lidocaine
base/HFC-134a solution.
While the invention has been described in terms of its preferred
embodiments, those skilled in the art will recognize that the invention
can be practiced with modification within the spirit and scope of the
appended claims.
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