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BACKGROUND OF THE INVENTION
Field of Invention
The vasoconstricting agent phenylephrine in acid addition salt form is
combined with a particular local anaesthetic, lidocaine base, and
dissolved in a solvent and then in a selected HFC propellant to produce a
stable solution suitable for metered dose aerosol delivery.
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 receptors, found in the smooth muscle cells
of the peripheral vasculature of the coronary arteries, skin, uterus,
intestinal mucosa and splanchnic beds, mediate vasoconstriction. These
receptors serve as postsynaptic activators of vascular and intestinal
smooth muscle 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.
Phenylephrine is considered a potent pure alpha agonist drug which
increases venous as well as arterial constriction. Phenylephrine is used
intravenously in small doses of 1.mu.g/kg to cause systemic
vasoconstriction and elevation of blood pressure. It is also used
regionally to cause vasoconstriction when injected with local anaesthetic
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 edema and vascularity. Other agents that
have been used for this effect are ephedrine and cocaine.
Cocaine possesses both anaesthetic and vasoconstricting properties. These
properties make it suitable to provide both topical anaesthesia 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 (30mg) may cause systemic toxicity and
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 anaesthetic,
but it does not vasoconstrict the mucosa and thus dilate the nasal
passage. For this reason, phenylephrine is often 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
the 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 are listed:
a) concentration of active drug
b) physicochemical properties of active drug
c) density/viscosity properties of the formulation
d) pH/toxicity of dosage form
e) 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.
Phenylephrine base is also lipid soluble, but this molecule is unstable and
rapidly oxidizes to phenylephrine oxide. For this reason the more stable
water-soluble hydrochloride or bitartrate salts are preferred for clinical
use.
Metered dose inhalers (MDI) 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 overdosage leads to
dangerous clinical side-effects. A problem with the use of MDIs relates to
the chlorofluorocarbon (CFC) propellants which have been used to date. 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.
A class of propellants referred to as hydrofluorocarbons has been
reintroduced for use and will completely replace the CFC propellants by
1996. These agents have zero Ozone Depletion Potential and are not
Volatile Organic Compounds (VOC), i.e., they have negligible photochemical
reactivity.
Hydrofluorocarbons 1,1,1,2-tetrafluoroethane (CF.sub.3 CH.sub.2 F) HFC-134a
and 1,1,1,2,3,3,3-heptafluoropropane (CF.sub.3 CHFCF.sub.3) HFC-227 have
been the subject of extensive toxicological testing over the last few
years. Both are soon expected to be approved for use in delivery of
medicaments to humans in metered dose aerosol form.
A major problem with both of these propellants is their poor solubility
characteristics, making formulations of solutions and suspensions of
medicaments in these propellants very difficult. Difficulty in finding
suitable cosolvents and surfactants to promote stable suspensions of
medicaments in these HFC propellants is slowing development of new aerosol
formulations and threatens to prolong the period of phasing out of the CFC
propellants.
Most of the metered dose formulations using the HFC propellants are
suspensions of finely ground medicament with the use of surfactant agents
like oleic acid, sorbitan trioleate and soya lecithin (e.g.,
isoproterenol-phenylephrine CFC aerosol of Riker/3M - Duomedihaler.RTM.).
The object of aerosolized medication delivery is to provide the medicament
in stable suspension and preferably 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 as well as the relative volume of drug and its cosolvents to
the propellant volume. The propellant should constitute at least about 45%
of the total formulation weight and preferably about 50-95% of the
formulation weight.
Lidocaine and phenylephrine have been shown to exert independent effects on
the nasal mucosa that result in vasoconstriction and topical anaesthesia.
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 would
clearly be advantageous to the patient.
Other clinical situations where a combined lidocaine-phenylephrine
formulation, preferably in the form of a metered dose aerosol spray of
lidocaine base and phenylephrine salt to provide topical anaesthesia and
vasoconstriction, could advantageously be used include delivery to 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.
OBJECTS OF THE INVENTION
An object of the invention is to provide a novel formulation of lidocaine
and phenylephrine salt suitable for and/or in metered dose aerosol form.
It is a further object to provide a formulation embodying lidocaine in its
lipid-soluble free base form to improve absorption and solubility of the
phenylephrine salt in the propellant. It is an additional object to
provide such compositions incorporating phenylephrine as a stable
pharmacologically-acceptable acid addition salt, e.g., the hydrochloride
or bitartrate salt, dissolved in a suitable solvent such as anhydrous
ethyl alcohol (ethanol). It is another object to incorporate in such
compositions only certain selected HFC propellants in accordance with
concerns related to use of CFC propellants and ozone depletion. Still
further objects will become apparent as this description proceeds and yet
additional objects will be apparent to one skilled in the art.
SUMMARY OF THE INVENTION
What I therefore believe and claim to be my invention, inter alia, singly
or in combination, is as follows:
An aerosol-dispensable pharmaceutical composition consisting essentially of
a combination of lidocaine free base, a pharmacologically-acceptable
phenylephrine acid addition salt, and a pharmacologically-acceptable
organic solvent, all dissolved in a propellant selected from the group
consisting of 1,1,1,2-tetrafluoroethane of the formula CF.sub.3 CH.sub.2 F
(HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane of the formula CF.sub.3
CHFCF.sub.3 (HFC-227) or a combination of the said propellants; such a
composition wherein the amount of solvent is between that amount sufficient
to dissolve the phenylephrine salt and about 50% w/w, the amount of
lidocaine free base is about 1-20% w/w, the amount of phenylephrine acid
addition salt is about 0.1-2% w/w, and the amount of propellant is about
45%-95% w/w; such a
composition wherein the amount of solvent is about 5-40% w/w, the amount of
lidocaine free base is about 5-20% w/w, the amount of phenylephrine acid
addition salt is about 0.25-2% w/w, and the amount of propellant is about
50%-80% w/w; such a
composition wherein the solvent is ethanol and the phenylephrine acid
addition salt is the hydrochloride; such a
composition wherein the amount of phenylephrine hydrochloride is about 1%
w/w; and such a
composition wherein the solvent is selected from the group consisting of
ethanol, polypropylene glycol, polyethylene glycol, diethylether, and
dimethoxyethane.
Moreover, such a composition under pressure in a metered-dosage valve
canister which dispenses about 25-100 microliters per metered dosage,
preferably 25 or 50 microliters per unit dosage; such a
composition wherein the amount of lidocaine free base dispensed per metered
dosage unit dispensed is about 1-20 mg and the amount of phenylephrine
acid addition salt dispensed per metered dosage unit is about 0.05-1 mg;
such a
composition wherein the amount of lidocaine free base dispensed per metered
dosage unit is between about 1 and 10 mg, and the amount of phenylephrine
acid addition salt dispensed per unit dose is between about 0.1 and 1 mg;
such a
composition wherein the amount of lidocaine free base dispensed per metered
dosage unit is about 2.5-5 mg, and the amount of phenylephrine acid
addition salt dispensed per metered dosage unit is about 0.1-0.5 mg; such
a
composition wherein the solvent is ethanol and the phenylephrine acid
addition salt is the hydrochloride; and such a
composition wherein the amount of lidocaine free base dispensed per metered
dosage unit is about 2.5-5 mg and the amount of phenylephrine
hydrochloride is about 0.2 mg and the ethanol solvent is about 30% w/w.
THE INVENTION IN GENERAL
The present invention relates to lidocaine free base and a
pharmacologically-acceptable phenylephrine acid addition salt, e.g., the
hydrochloride or bitartrate, in a solution as a formulation suitable for
aerosol delivery together with one or more of certain specified HFC
propellants.
Phenylephrine hydrochloride is water soluble and was found to be insoluble
in propellants HFC-134a and HFC-227. Moreover, when dissolved in ethyl
alcohol in clinically useful concentrations and then mixed with HFC-134a
or 227, the phenylephrine hydrochloride was precipitated out of solution
in the alcohol.
Lidocaine base has surprisingly been found to be extremely soluble in the
HFC propellants of interest. See Table.
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Solubility of Lidocaine in Selected Propellants
Solubility
Propellant Weight % mg/ml
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Dymel .RTM. 134a CF.sub.3 CH.sub.2 F
58 759
FM 200 .RTM. CF.sub.3 CHFCF.sub.3
45 602
Water Ins. --
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When lidocaine base was added to the crystalline phenylephrine
hydrochloride and the mixture then added to propellant HFC-134a or 227,
the phenylephrine hydrochloride did not dissolve. However, again
surprisingly, when phenylephrine hydrochloride was dissolved in ethyl
alcohol and admixed with lidocaine base before the addition of HFC134a or
227, or vice versa, the phenylephrine remained in solution in the
resulting formulation. The lidocaine free base obviously acts as an
adjuvant to assist and maintain the solubility of the phenylephrine salt.
The formulation of this invention is therefore lidocaine base with a
phenylephrine acid addition salt, preferably the hydrochloride, dissolved
in a suitable solvent such as ethyl alcohol in solution in HFC-134a or
HFC-227 or a combination thereof.
DETAILED DESCRIPTION OF THE INVENTION
The formulation of the present invention and suitable for topical nasal
anaesthesia and vasoconstriction is free base lidocaine plus phenylephrine
hydrochloride or other acid addition salt, dissolved in anhydrous ethyl
alcohol or other suitable solvent, in solution in the selected non-CFC
hydrofluorocarbon propellant HFC-134a (1,1,1,2-tetrafluoroethane: CF.sub.3
CH.sub.2 F) or HFC-227 (1,1,1,2,3,3,3-heptafluoropropane; CF.sub.3
CHFCF.sub.3) or a combination thereof, preferably under pressure in a
predetermined metered-dosage-releasing aerosol delivery container.
Lidocaine USP in free base form, of the formula
2-(Diethylamino)-2',6'-acetoxylidide [137-58-6]C.sub.14 C.sub.22 N.sub.2 O
(MW 234.34), was obtained from Astra Pharmaceuticals, Inc. in Mississuaga,
Ontario, Canada.
Phenylephrine hydrochloride of the formula
(R)-3-Hydroxy-alpha-[(methylamino)methyl]benzenemethanol hydrochloride
C.sub.9 H.sub.14 ClNO.sub.2 (MW 203.67) was obtained from Sigma Chemicals.
The aerosol propellants employed are HFC-134a, available from E. I. du Pont
de Nemours and Company under their Trademark Dymel 134a (CF.sub.3 CH.sub.2
F), and HFC-227 (CF.sub.3 CHFCF.sub.3), supplied by Great Lakes Chemical
under their Trademark FM 200.
Both propellants are a 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.
Phenylephrine hydrochloride crystalline, both alone and in combination with
lidocaine, was determined to be insoluble in both of the propellants
employed.
PROCEDURE
The general procedure employed was as follows:
Phenylephrine hydrochloride was dissolved in ethyl alcohol (ethanol) to
produce a 2.5% w/w solution. This solution was placed in a glass bottle
designed for pressure filing with liquid propellant. When HFC-134a was
added to this solution, the phenylephrine hydrochloride was precipitated
out of solution. Then, using the same phenylephrine hydrochloride in
ethanol solution, lidocaine free base was added. With the addition of
HFC-134a under pressure, the lidocaine went into solution in the 134a as
expected, but it also served to place and keep the phenylephrine
hydrochloride in solution. HFC-227 acted the same. The following Examples
are given by way of illustration only and are not to be construed as
limiting.
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Example 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
Example 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
Example 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
Example 4
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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The solutions of all examples are advantageously useful and effective for
their intended purpose.
Formulations incorporating other pharmacologically-acceptable organic
solvents and other pharmacologically acceptable phenylephrine acid
addition salts are equally operative and give utilizable solutions.
Thus, the possibility of a combination of lidocaine and phenylephrine salt,
e.g., the hydrochloride, in a stable solution in the selected HFC
propellant, suitable for topical delivery to the nose, was discovered and
has now been realized. This formulation provides lidocaine in
lipid-soluble base form and phenylephrine as a stable salt, preferably the
hydrochloride, and dissolved in a suitable organic solvent, preferably
anhydrous and preferably ethyl alcohol, in combination with one of the
non-CFC propellants HFC-134a or HFC-227 or combinations thereof.
Other suitable pharmacologically-acceptable organic solvents may be used to
place the phenylephrine salt, e.g., bitartrate or hydrochloride, into
solution such as propylene glycol, polyethylene glycol, diethylether, and
DME (dimethoxyethane or ethylene glycol dimethyl ether-Monoglyme.RTM.).
These solvents, as well as ethanol, serve additionally as a valve
lubricant, preventing a metered-dose valve from sticking during use.
Higher concentrations of solvent, e.g., ethanol, may also be used and will
produce and maintain a solution, but the less solvent the better both from
a most effective concentration and a most effective aerosol particle size
standpoint.
Preferably about 1-20% weight/weight (w/w) of lidocaine free base and
0.1-2% w/w of phenylephrine salt, hydrochloride or bitartrate, in e.g.
anhydrous ethyl alcohol, are employed to provide about 1-20 mg lidocaine
and 0.05-1mg of phenylephrine salt, e.g., hydrochloride, per metered dose.
This combination under pressure in a canister with a 25-100, usually 25-50,
and preferably about 25 microliter metered dose valve and appropriate
intranasal delivery catheter or other device representatively releases
25-50 microliters of solution per metered dose. This most preferably
provides 1-10 mg lidocaine and 0.1-1 mg phenylephrine hydrochloride or
other pharmacologically-acceptable acid addition salt per metered dose.
The preferred combination is preferably chosen to limit the solvent and
preferably ethanol to a maximum of about 35% and preferably 33% w/w to
limit nasal irritation and ensure small enough droplet size to achieve
adequate intra-nasal dispersion. A concentration of about 5-40%,
preferably 15-35% w/w, and especially about 30% solvent, e.g., ethanol,
w/w is considered optimal. This limitation on solvent, e.g., ethanol,
limits the amount of phenylephrine hydrochloride able to be dissolved but
still allows an ideal therapeutic dose of 0.1-1 and preferably 0.1-0.5 mg
per metered dose to be realized.
The high solubility of lidocaine base in the selected HFC propellants
allows a wide range of concentrations and dosages to be achieved. In the
therapeutic concentrations considered desirable, lidocaine free base
unpredictably enables solubility of the phenylephrine salt, e.g., the
hydrochloride, and keeps it in solution in the HFC propellant employed.
The present formulation of lidocaine free base and a phenylephrine salt in
aerosol form is also useful for delivery to the airway (specifically
epiglottis, larynx and trachea), open wounds (broken skin), and other
mucosal structures such as the urethra, prostatic urethra, bladder, anus,
cervix, and vagina. The formulation of the present invention is moreover
well adapted for all of its uses and applications in the field of
veterinary medicine as will immediately be recognized by one skilled in
the art.
It is therefore seen from the foregoing that a novel and valuable solution
of a pharmacologically-acceptable acid addition salt of phenylephrine and
lidocaine free base and a pharmacologically-acceptable solvent in a
selected non-CFC propellant, namely, HFC-134a or HFC-227 or a combination
thereof, which is suitable for aerosol application, has been provided,
thereby remedying an obvious shortcoming in the art. The acid addition
salt of phenylephrine is preferably the hydrochloride or the bitartrate
and the solvent employed is preferably ethyl alcohol, although other salts
and other solvents may be employed with facility as described in the
foregoing. As already set forth in the foregoing, the amount of solvent
employed is that amount which is required to place the phenylephrine acid
addition salt into solution and the maximum amount of solvent present in
the composition of the invention may be as great as 50% w/w but is
optimally about 15-40% w/w and preferably about 30% w/w and in any event
an excess of solvent over that amount required to place the phenylephrine
acid addition salt into solution is not recommended, inasmuch as it
reduces the concentration of active ingredients and makes it more
difficult to place effective amounts of solution into maximally-effective
small-sized aerosol spray particles, e.g., 5-25 microns in size, when the
amount of solvent employed is greater than necessary.
The amount of lidocaine free base in the composition of the invention is
between about 1 and 20% w/w, preferably between about 5 and 20% w/w. Per
unit dose as administered in spray form and preferably by means of an
aerosol spray as set forth hereinbefore, the amount of lidocaine is
usually between about 1 and 20 mg per dose, preferably between about 1 and
10 mg per dose, and optimally about 2.5-5 mg per dose.
Correspondingly, the amount of phenylephrine acid addition salt in the
composition is between about 0.1 and 2% w/w, preferably between about 0.25
and 2% w/w, and optimally about 1% w/w. Per unit dose, especially when
administered by aerosol but also when administered by simple spray device,
the dose of phenylephrine acid addition salt administered is usually
between about 0.05 and 1 mg per unit dose, preferably between about 0.1
and 0.5 or 1.0 mg per unit dose, and optimally about 0.2 mg per unit dose.
For optimal aerosol delivery, the amount of the aerosol propellent HFC-134a
or HFC-227 should be between about 50% and 95% w/w and, as indicated by
the foregoing examples, percentages of about 60% w/w for HFC-227 and
50-70% w/w for HFC-134a are quite satisfactory.
With the combination composition of the invention under pressure in a
canister with a metered dose valve providing between about 25 and 100
microliters per metered dose, usually between about 25 and 50 microliters
per unit dose, and most preferably about 25 microliters per metered dose,
no problem is encountered in delivering effective amounts of the
phenylephrine acid addition salt and the lidocaine free base in
sufficiently small aerosol particle size and in accord with and within the
foregoing enumerated dosage ranges. Numerous metered-dosage delivering
canisters of the type employed are readily available in the art, for
example, the one employed with the Riker/3M-Duomedihaler product, or the
representative such device disclosed in my U.S. patent application Ser.
No. 07/949,445, allowed Mar. 8, 1994.
The advantages of having the phenylephrine acid addition salt and the
lidocaine free base available in aerosol form together with a suitable HFC
and non-CFC propellant all in solution in a minimal amount of
pharmacologically-acceptable solvent and all dissolved in the propellant
will be readily appreciated by medical practitioners and others skilled in
the art.
It is to be understood that the present invention is not to be limited to
the exact details of operation, or to the exact compounds, compositions,
methods, procedures, or embodiments shown and described, as various
modifications and equivalents will be apparent to one skilled in the art,
wherefore the present invention is to be limited only by the full scope
which can be legally accorded to the appended claims.
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