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Description  |
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This invention relates to a new pharmaceutical vehicle for carrying a
pharmaceutically active material, i.e., a drug or medicament, and
delivering it to mucous membranes. More specifically, the present
invention is directed to a clear, liquid, water-miscible pharmaceutical
vehicle which thickens to a gel at human body temperatures. In other
aspects, the present invention relates to a pharmaceutical composition
useful for therapeutic or protective application to mucous membranes
comprising a pharmacologically effective amount of a drug or medicament
dissolved in said pharmaceutical vehicle and to a method of delivering a
drug or medicament to a mucous membrane by applying the pharmaceutical
composition to the site to be treated.
BACKGROUND OF THE INVENTION
There are many drugs known to be useful for treatment of afflictions or
protection of mucous membranes, e.g., for ocular diseases. A practical
problem in connection with therapeutic or protective application of
pharmaceutically active chemicals to afflicted mucous membranes resides in
the delivery of the chemical or drug to the affected area in need of
treatment. Various formulations and techniques have been attempted to
deliver medicaments to mucous membranes, but there is a need for improved
pharmaceutical vehicles for delivery of drugs, and it is this need to
which the present invention is addressed.
For example, drugs have been formulated into aqueous solutions. However,
the fleeting presence and poor contact of aqueous solutions applied to
mucous membranes has been a disadvantage. The only adequate application of
medication in solution form to mucous membranes is usually accomplished by
employing continuous lavage or interrupted irrigation. This approach is
often wasteful of expensive drugs and poses a major problem of
inconvenience. Thus, treatment of severe keratoconjunctivitis sicca with
isotonic salt solutions requires ocular instillation every 15-30 minutes.
The use of viscous aqueous solutions is usually more convenient. For
example, the aforementioned isotonic salt solutions can often be applied
every 1-2 hours and accomplish the same therapeutic objective if the
solution is made viscous. Drugs have been formulated into aqueous
suspensions made viscous by the addition of gums or cellulose-modified
synthetic derivatives or incorporated into oleaginous vehicles or bases
consisting of natural plant or animal fats or modifications thereof or
petroleum-derived hydrocarbons.
Indeed, aqueous vehicles which are thickened by the addition of selected
gums or cellulose-derived viscosity building agents are perhaps the most
commonly used media for delivery of drugs or medicaments to mucous
membranes. Generally, the viscosity of such preparation ranges from about
25 cps to indeterminate values in stiff gels. Nearly uniform drug delivery
is possible with such vehicles, and they frequently provide desirable
protection to the mucous membranes.
In contrast, non-viscous aqueous suspensions have many disadvantages and
are not typically used. A major problem is rapid settling of the suspended
drug. This gives rise to undesirable need for continuous stirring during
administration in order to deliver a uniform dose.
While thick gels would seem to offer the best potential in terms of
protection as well as holding and delivering medication, they in fact have
some disadvantages. In some instances, they are difficult to apply from
their respective commercial containers. Moreover, thick gels do not spread
readily over the area being treated, and possibly painful spreading and
rubbing may be necessary. Also, on evaporation of the water from the
vehicle, a cosmetically unappealing hard granular or flaky residue often
results at the site of the application.
Attempts to use oily vehicles to increase drug delivery and prolong ensuing
pharmacologic action have not met with uniform success. The use of
oleaginous vehicles, whether anhydrous or in emulsion form (oil-in-water
or water-in-oil), may have advantages for certain therapeutic indications,
if the vehicle will adhere. However, since normal mucous membranes are
always moist with aqueous tissue fluids, and water does not mix readily
with oil bases, application, uniform spreading, and retention all become
difficult. Perhaps the only time oily or emulsion vehicles are used
successfully is when the mucous tissue is abnormally dry because of
disease.
Another approach to the delivery of drugs or medicaments to mucous
membranes is the recent development of silicone plastic devices which
deliver drugs at predetermined, nearly uniform, zero order rates extending
from a few days to several years. However, the usefulness of such devices
depends upon a constant supply of tissue fluid or glandular secretion; in
the absence of fluid, plastic devices are not operative. Such devices are
not designed to offer any protection to an inflamed mucous membrane.
Discomfort often associated with the devices, and inadvertent loss of the
devices, are additional problems.
The existence of all these disparate approaches to drug delivery to mucous
membranes evidences the need for new pharmaceutical vehicles. Against the
background of this array of formulations and devices with all their
attendant problems, the present invention fills that need.
SUMMARY OF THE INVENTION
In its broadest sense, the present invention provides a pharmaceutical
vehicle useful for delivering a compatible, pharmacologically active
chemical, i.e., drug or medicament, to a mucous membrane which consists of
a clear, water-miscible, physiologically-acceptable, liquid composition
which gels to a thickened, non-flowing and adhering consistency at human
body temperature. Pharmaceutical vehicles in accordance with the invention
are liquid at ambient room temperatures below about 30.degree., preferably
about 25.degree. C and below. They have a sol-gel transition temperature
in the range of from about 25.degree. to about 40.degree. C, preferably
from about 25.degree. , to about 35.degree. C, and most preferably from
about 29.degree. to about 31.degree. C.
In accordance with the present invention, it has been discovered that
aqueous solutions of certain polyoxyethylene-polyoxypropylene block
copolymers are useful pharmaceutical vehicles having the properties set
forth above. In particular, the present invention provides a
pharmaceutical vehicle or base for carrying a pharmaceutically active
material, i.e., a drug or medicament, which comprises:
(a) from about 10% to about 26%, preferably from about 17% to about 26%, by
weight of a polyoxyethylene-polyoxypropylene block copolymer in which the
number of polyoxyethylene units is at least about 50%, preferably about
70%, of the total number of monomeric units in the total molecule, the
block copolymer having an average molecular weight of from about 7500 to
about 15,500, preferably about 11,500, a room temperature solubility in
water of greater than about 10 grams per 100 ml. of water, and a cloud
point in 1% aqueous solution of at least about 100.degree. C.; and
(b) from about 74% to about 90% by weight water, the vehicle having a
sol-gel or gel transition temperature in the range of from about
25.degree. to about 40.degree. C., preferably from about 25.degree. to
about 35.degree. C., and especially from about 29.degree. to about
31.degree. C.
The pharmaceutical vehicle may also include various additives, such as
auxiliary non-ionic surfactants, salts to adjust osmotic pressure, buffer
systems to control pH, and preservatives. Preferably, the vehicle contains
at least one water-soluble compatible salt for adjustment of osmotic
pressure in sufficient amount to provide a solution salt content
equivalent to from about 0.1% to about 10.0%, especially from about 0.5%
to about 6.0%, sodium chloride. It is also preferred that the vehicle
contain a compatible preservative or germicide in an amount effective to
afford protection to the vehicle against bacterial contamination.
In accordance with this invention, the pharmaceutical vehicle preferably
has a pH in the range of 3.5 to 9.5. Particularly preferred is a pH in the
range of from about 6.0 to about 8.5, and especially from about 6.2 to
about 7.8.
In keeping with the concept of the present invention, there is also
provided a pharmaceutical composition useful for protective or therapeutic
application to mucous membranes comprising a solution of a
pharmacologically effective amount of a pharmaceutically active material,
i.e., drug or medicament, in a pharmaceutical vehicle as described above.
The concept of this invention is not dependent on the nature of the drug,
and any compatible pharmaceutically active material may be used.
Preferably, the drug is water-soluble. However, drugs which are not
ordinarily soluble in water may also be employed, and where needed,
auxiliary nonionic surfactants, which are typically well tolerated by
mucous membranes, can be added to increase the solvent action, while
maintaining the vehicle gel transition temperature within the required
range.
It has been discovered that a wide variety of useful pharmaceuticals which
are not ordinarily soluble in water and are presently marketed only in
suspension form can in fact be dissolved in the
polyoxyethylene-polyoxypropylene vehicles of the present invention. In
some instances, the addition of auxiliary nonionic surfactants was found
necessary. However, the critical gel transition temperature is maintained.
An important aspect of this invention is that the pharmaceutical vehicles
and compositions are liquid at ambient room temperatures and can be
applied to the affected mucous membrane area by conventional liquid
depositing means, including dispensation to the area of treatment from
standard plastic squeeze bottles or in drop form. At body temperatures
above 30.degree. C., the vehicle or base passes through the sol-gel
transition temperature and gels to a thickened, non-flowing and adhering
consistency, holding and delivering the medication as required and for
prolonged periods of time.
Thus, in accordance with the present invention, there is also provided a
method of delivering a drug or medicament to a mucous membrane comprising
the steps of providing a pharmaceutical composition which comprises a
solution of the pharmaceutically active material in the pharmaceutical
vehicle; and applying the pharmaceutical composition to the mucous
membranes. The composition is applied to the mucous membrane in an amount
sufficient to deliver a non-toxic, pharmacologically effective amount of
the drug to the intended site of treatment.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention, the pharmaceutical vehicle consists of a
clear, water-miscible, physiologically-acceptable medium which is liquid
at ambient temperature below about 30.degree. C. and thickens to a gel at
body temperatures above about 30.degree. C. In practice, it has been found
that a vehicle having a sol-gel transition temperature in the range of
from about 25.degree. to about 40.degree. C. satisfies this requirement
and is useful in the practice of the present invention. Preferably, the
sol-gel transition temperature will be in a range of from about 25.degree.
to about 35.degree. C., and excellent results have been obtained using
vehicles having a sol-gel transition temperature in the range of from
about 29.degree. to about 31.degree. C.
The capacity of the liquid pharmaceutical vehicle to gel at human body
temperature is the critical feature of the invention for it is in this
property that many of the disadvantages of previous approaches are
overcome. Thus, the dissipative quality of aqueous solutions is avoided
since the vehicles herein gel at the site of treatment. Moreover, the
problems of formulation, handling and application of viscous aqueous
vehicles or gels are overcome since at the time of application the present
pharmaceutical vehicle and composition are free-flowing liquids.
The pharmaceutical vehicle of this invention is clear and water-miscible.
These are especially important requirements for usefulness in therapeutic
and protective ocular applications. Water-miscibility of the vehicle
overcomes major problems faced in attempts to use oily vehicles.
The vehicle of this invention must be physiologically acceptable so that no
adverse reaction occurs when the pharmaceutical composition comes in
contact with human tissue or fluids. Thus, the vehicles must be inert when
tested for ocular tolerance in human and rabbit eyes.
A suitable pharmaceutical vehicle in accordance with this invention
comprises an aqueous solution of a selected
polyoxyethylene-polyoxypropylene block copolymer. It has been found that
polyoxyethylene-polyoxypropylene block copolymers in which the number of
polyoxyethylene units is at least about 50% of the number of units in the
total molecule, the block copolymer having an average molecular weight of
from about 7500 to about 15,500, a room temperature solubility in water
greater than about 10 grams per 100 ml. of water, and a cloud point in 1%
aqueous solution of at least about 100.degree. C., can be used to form a
vehicle composition having a sol-gel transition temperature in the range
of from about 25.degree. to about 40.degree. C.
Such block copolymers are included in a series of nonionic surface-active
agents sold under the trademark "Pluronic" by Wyandotte Chemical Corp. The
"Pluronics" are closely related block copolymers that may be generically
classified as polyoxypropylene-polyoxyethylene condensates terminating in
primary hydroxyl groups. They are formed by the condensation of propylene
oxide into a propylene glycol nucleus followed by the condensation of
ethylene oxide onto both ends of the polyoxypropylene base. The
polyoxyethylene hydrophilic groups on the ends of the molecule are
controlled in length to constitute anywhere from 10% to 80% by weight of
the final molecule.
The "Pluronic" series of products may be represented empirically by the
formula:
##STR1##
wherein a and c are statistically equal. They have been available in
average molecular weights of from about 1100 to about 15,500.
A preferred polyoxyethylene-polyoxypropylene block copolymer for use in the
pharmaceutical vehicle of this invention is one in which the number of
polyoxyethylene units is about 70% of the total number of monomeric units
in the molecule and where the copolymer has an average molecular weight of
about 11,500. "Pluronic F-127" is such a material, and it has a solubility
greater than 10 gms./100 ml. water as well as a cloud point in 1% aqueous
solution higher than 100.degree. C.
The concentration of the polyoxyethylene-polyoxypropylene condensate is an
important parameter. Significantly, by ready adjustment of the
concentration of the copolymer to accommodate other solutes present in the
vehicle, any desired gel transition temperature in the critical range of
above ambient temperature and below body temperature can be achieved.
Thus, the principal consideration is the selection of a concentration
which, in conjunction with all of the constituents of the vehicle
composition, will provide a sol-gel transition temperature in the required
range.
It has been found that a useful block copolymer concentration is from about
10% to about 26% by weight, particularly from about 17% to about 26%.
Excellent results have been obtained using aqueous solutions of from about
17% to about 26% by weight of "Pluronic F-127". The water content is
generally from about 74% to about 90% by weight of the vehicle
composition, and is typically from about 74 to about 85% by weight. The
water used in forming the aqueous solution is preferably purified, as by
distillation, filtration, ion-exchange or the like.
The polyoxyethylene-polyoxypropylene pharmaceutical vehicles of this
invention have been unexpectedly found to increase drug absorption by the
mucous membrane. Moreover, it has also been found that the pharmacologic
response is unexpectedly prolonged. Drug action is typically both
increased and prolonged by a factor of 2 or more. At the same time,
protection is afforded to the involved tissues.
Another advantage is that they are compatible with the therapeutic bandage
semi-hard (silicone) and soft or flexible contact lenses. In contrast to
drug suspensions in which suspended particles could be lodged in the
surfaces of the lenses and cause focal points of irritation or blurred
vision, and in contrast to oily vehicles or bases which could adversely
affect lens clarity, degree of hydration, and the physical parameters of
therapeutic lenses, the present vehicles, when used in conjunction with
therapeutic contact lenses, markedly increased wearing comfort, provided
cleaner lenses, and gave more rapid healing responses than without the
instillation of the vehicle.
The liquid pharmaceutical vehicles of this invention preferably include at
least one water-soluble compatible salt to adjust osmotic pressure.
Frequently, the vehicle would be formulated to be isotonic with human
serum and tear fluid, the normal tonicity of which is 0.9% (9.0 grams of
sodium chloride per liter of vehicle). Isotonic solutions contain about
0.9% sodium chloride, or other salt or mixture of salts having a salt
content equivalent to about 0.9% sodium chloride in their osmotic effect.
In general, the vehicles may contain a sufficient amount of at least one
salt to provide up to about 10%, especially from about 0.5% to about 6.0%,
sodium chloride equivalent salt content. Polyoxyethylene-polyoxypropylene
vehicles with as high as 10% sodium chloride equivalent salt content can
be made in accordance with this invention having the requisite gel
transition temperature. Such compositions are markedly hypertonic, and can
be advantageously used where commercially available hypertonic solutions
are presently employed.
Generaly, it was found that each additional increment of salt
proportionately lowered the gel transition temperature.
Any soluble salt or mixture of salts compatible with mucous membrane tissue
can be used to provide the desired tonicity. Sodium chloride, potassium
chloride, or mixtures thereof, are presently preferred. However, one or
more essentially neutral, water soluble alkali metal salts can be
substituted in whole or in part for the sodium or potassium chloride in
the vehicles of this invention. Thus, other alkali metal halides, such as
sodium bromide, potassium fluoride or potassium bromide can be used. Other
salts, such as sodium sulfate, potassium sulfate, sodium nitrate, sodium
phosphate, potassium nitrate or potassium phosphate can also be used.
Preferably, the pharmaceutical vehicle contains a compatible preservative
or germicide in an amount effective to afford protection to the vehicle
against bacterial contamination. Any conventional preservative system may
be used.
Quaternary germicides, particularly benzalkonium chloride, are presently
preferred. Benzalkonium chloride is an alkyl substituted
dimethylbenzylammonium chloride in which the alkyl substituents comprise a
mixture of C.sub.8 to C.sub.18 alkyl radicals. Exemplary of other
preservatives which can be desirably used are salts of
ethylenediaminetetraacetic acid, known as edetates, such as disodium
edetate and trisodium edetate, sorbic acid, salts of sorbic acid, boric
acid, and salts of boric acid, such as sodium borate. Still other useful
preservatives or germicides are thimerosal sodium, phenylmercuric acetate,
methyl, ethyl and propyl para-aminobenzoic acid esters, and the like.
The preservatives can be used individually or in combination. They are used
in effective amount to afford protection against contamination. For
example, amounts of from about 0.001% to about 0.03% by weight of a
quaternary or organic mercurial germicide are known to be effective and
can be used in the present invention. Sorbic acid NF XIII is known to be
useful in amounts of from about 0.01% to about 0.5% by weight and may be
so used in the present vehicles.
The pH of the pharmaceutical vehicles of this invention may be adjusted as
desired. In general, the pH can range from about 3.5 to about 9.5.
Preferably, the pH is from about 6.0 to about 8.5, and especially from
about 6.2 to about 7.8 the range of the human tear. In some instances, the
stability of certain preservatives is maximized by pH adjustment. For
example, acid to neutral pH is optimal for the alkyl para-aminobenzoic
acid esters.
Compatible, conventional buffers, i.e., weak acids, weak bases, and their
corresponding salts, may be used to adjust pH as desired. A sodium
biphosphate, disodium phosphate system is exemplary of useful buffering
systems. An effective amount of buffer is used to achieve the desired pH.
For example, a combination of from about 0.2% to about 0.6% sodium
biphosphate and from about 0.2% to about 0.7% disodium phosphate may be
used to adjust to a pH in the 6.2 to 7.2 range. Certain preservatives also
affect pH, such as trisodium edetate. By selection and simple correlation
of the desired additives, one having ordinary skill in the art can readily
adjust the pH as desired, while retaining the gel transition temperature
in the required range.
Compatible and physiologically-acceptable auxiliary nonionic surfactants
may optionally be used to improve solvation of the drug or medicament.
Exemplary of conventional surfactants which may be used are Polysorbate 80
and polyoxyl 40-stearate employed in conventional amounts.
Any pharmaceutically active material may be admixed in a pharmacologically
effective amount with the pharmaceutical vehicle to form the
pharmaceutical compositions of this invention. Preferably, the drug is
water-soluble. However, drugs which are not ordinarily soluble in water
may also be employed, and it has been found that a wide variety of useful
drugs which are currently marketed in suspension form can be dissolved in
the polyoxyethylene-polyoxypropylene vehicles of the present invention.
Where necessary or desirable, auxiliary nonionic surfactants may be
included in the pharmaceutical composition.
The drug or medicament is selected on the basis of the treatment indicated
for the patient. Exemplary of drugs which have been used in connection
with the pharmaceutical vehicles herein are pilocarpine HCl for glaucoma,
phenylephrine for red eyes and Dexamethasone U.S.P.. for inflammatory
ocular conditions. Various anti-microbial pharmaceuticals for treatment of
fungal and viral diseases of mucous membranes may be used, such as
Clofazimine, pimaricin, amphotericin, neomycin sulfate, choramphenical,
bacitracin, sulfacetamide, gentamycin, polymix in B sulfate, and the like.
The pharmaceutical vehicles and compositions of this invention can be
readily prepared. Essentially, any solution forming technique may be used.
The vehicle may be prepared separately and the pharmaceutical added
thereto, or preferably, the pharmaceutical composition is formulated
without separate preparation of the vehicle. For example, in the use of
the polyoxyethylene-polyoxypropylene block copolymer vehicles, the
pharmaceutical composition is desirably prepared by fusing the block
copolymer, adding the pharmaceutically active material to the fused
copolymer, and dissolving the pharmaceutical by simple stirring. A water
solution of the remaining ingredients is prepared, and the solution of
pharmaceutical in the block copolymer is mixed with the aqueous solution
to form a solution of all components. The pH may then be adjusted as
desired, e.g., by addition of a basic or acidic solution as desired. It is
generally preferred to add copolymer or a solution of a pharmaceutically
active material in the copolymer to the water or aqueous solution rather
than adding the water or aqueous solution to the copolymer or
copolymerpharmaceutical mixture.
The pharmaceutical composition is a liquid at ambient temperatures and
therefore may be employed in any manner conventionally used to apply
free-flowing liquid pharmaceuticals to mucous membranes. Preferably,
application is in drop form in the manner typically used, for example, to
apply eye drops. Thus, the normal squeeze-type liquid drop application
devices are perfectly suitable for use in applying the pharmaceutical
compositions of this invention to the site intended for treatment. The
amount of pharmaceutical composition should be sufficient to deliver a
pharmacologically effective amount of the active pharmaceutical to the
mucous membrane treatment area.
In addition to overcoming major disadvantages of previous techniques for
delivering drugs and medicaments to mucous membranes, the present
invention has been found to increase drug absorption by the affected
tissue and prolong pharmacologic response. Many other advantages will be
apparent to those skilled in the art. The general and detailed
descriptions of the invention presented above are not intended to be
restrictive of the scope of the invention. Rather, in conjunction with the
illustrative examples which follow, the description is intended to
illustrate the principles of the present invention and specific modes
encompassed thereby.
EXAMPLES
The following examples illustrate the compositions of the present
invention, and their preparation and utility, but are not limitative of
the invention. All percentages are standard weight in volume (W/V) %
expressions. In each instance, the formulations were made sterile by using
standard heat and pressure techniques, as well as aseptic techniques.
EXAMPLE I
The pharmaceutical vehicle of this invention is exemplified by the
composition:
Pluronic F-127 -- 18%
sodium chloride -- 0.75%
potassium chloride -- 0.25%
disodium edetate -- 0.025%
benzalkonium chloride -- 0.004%
purified water, enough to make 100% (adjust pH to 7.4 with dilute sodium
hydroxide solution)
It is most easily prepared by mixing all the ingredients in 95% of the
required water and allowing the polyoxyethylene-polyoxypropylene copolymer
(Pluronic F-127) to hydrate and completely dissolve overnight with gentle
stirring at temperatures below 20.degree. C. Once a clear solution is
obtained, the pH is adjusted to pH 7.4; and the balance of the water is
added. The sol-gel transition temperature was found to be at
29.degree.-30.degree. C.
This vehicle formulation was evaluated on rabbit eyes according to the
Draize scoring technique. On a scale having a maximum of 110 possible
units of irritation or ocular trauma, experimental values were
consistently at or near zero indicating that it produces no adverse ocular
effects.
The vehicle itself has pharmacologic utility. It was tested for use in
alleviating ocular symptoms of Sjogren's syndrome. Two ophthalmologists
treated 11 patients and reported that almost instant relief was obtained.
EXAMPLE II
A variation of the Example I composition was prepared for testing in
bullous keratopathy as follows:
Pluronic F-127 -- 17%
benzalkonium chloride -- 0.0075%
disodium edetate -- 0.0125%
trisodium edetate -- 0.025%
sodium chloride -- 3.75%
potassium chloride -- 1.0%
purified water, enough to make 100%
The desired pH is achieved and maintained by the use of the acidic and
basic salts of ethylenediaminetetraacetic acid. This formulation contains
approximately five times the amount of salt present in isotonic sodium
chloride solution. The solgel transition temperature was about 30.degree.
C.
When the formulation was tried in 6 patients, with and without soft contact
lenses, and all with corneal edema associated with bullous keratopathy,
very significant improvement was noted. In several other instances where
corneal swelling was associated with prolonged hard contact lens wear, as
well as other edematous conditions of unrelated problems, the product was
found efficacious. When compared to Adsorbonac 5 (Burton Parsons, Inc.,
Washington, D.C.), a commercially available hypertonic solution, the new
invention was preferred in all instances. The test preparation caused
significantly less discomfort upon eye instillation.
EXAMPLE III
The following vehicle was prepared:
Pluronic F-127 -- 16%
sorbic acid -- 0.1%
disodium edetate -- 0.1%
sodium borate -- 0.23%
sodium chloride -- 0.5%
potassium chloride -- 0.2%
purified water, enough to make 100%
The pH was 7.5, and the sol-gel transition temperature was 34.degree. C.
With the advent of continous wear therapeutic soft contact lenses, and
more recently continuous wear cosmetic lenses, there is a frequent need
for innocuous eye drops that loosen the accummulated mucoid deposits on
the lenses, reequilibrate the lenses and add to the overall comfort of
wear. The composition of this Example was evaluated by an opthalmologist
for this purpose by eye drop application on 14 patients. Without
exception, all of the patients found that this eye drop was the best
product which they had used. The ophthalmologist was also impressed with
the clinical response.
Examples I, II and III illustrate compositions which may be used as
pharmaceutical vehicles in accordance with the invention, and
significantly, have protective and therapeutic usefulness in themselves
without further addition of drugs or medicaments. The following Examples
demonstrate preparation and utility of pharmaceutical compositions in
accordance with the invention.
EXAMPLE IV
The following pharmaceutical composition containing the drug Dexamethasone
as the added active pharmaceutical material was prepared to test
corticosteroid anti-inflammatory solubilization and stability:
Dexamethasone U.S.P. -- 0.05%
Pluronic F-127 -- 19%
thimerosal sodium U.S.P. -- 0.005%
disodium edetate U.S.P. -- 0.1%
sodium chloride U.S.P. -- 0.9%
purified water U.S.P., enough to make 100%
To prepare this formulation, the Pluronic F-127 was first fused at about
50.degree.-60.degree. C., at which point the Dexamethasone was added and
dissolved by simple stirring. The remainder of the ingredients were
dissolved in water and added. Then the pH was adjusted to 7.0 with a
dilute solution of sodium hydroxide. The solution, observed over a period
of 5 months, remained crystal clear. The sol-gel transition temperature
was about 26.degree. C. On warm days, refrigeration was required to
maintain the product in the liquid state. However, this turned out to be
advantageous for when the cooled product was tried on 2 patients with a
severe inflammatory ocular condition resulting from chemical burns, the
cooling sensation upon instillation provided added relief. Other clinical
tests of this formulation verified its utility and demonstrated that the
concentration herein employed, which is half of the amount normally used
in the commercially available product Decadron (Merck, Sharpe & Dohme),
was at least as effective. Using half as much of an expensive raw material
could mean a significant saving to the patient.
EXAMPLE V
The following pharmaceutical composition containing pilocarpine HCl as the
added active pharmaceutical was prepared for treatment of glaucoma:
pilocarpine HCl -- 0.5%
Pluronic F-127 -- 18%
sodium chloride -- 0.3%
potassium chloride -- 0.1%
disodium phosphate -- 0.5%
sodium biphosphate -- 0.08%
benzalkonium chloride -- 0.01%
purified water, enough to make 100%
pH - 6.8
This formulation was compared to 2% pilocarpine (commercially available in
an aqueous solution) normally prescribed for glaucoma in 4 patients. In
all instances, the reduction in intra-ocular pressure by treatment with
the present formulation was found to be as good as or better than the
product having four times the concentration.
EXAMPLE VI
The following composition containing phenylephrine HCl as the added
pharmaceutically active material was prepared:
phenylephrine HCl -- 0.1%
Pluronic F-127 -- 18%
sodium chloride -- 0.9%
benzalkonium chloride -- 0.008%
purified water, enough to make 100%
This formulation was compared to an aqueous 0.5% solution in a small series
of patients with red eyes. The rate of vasoconstriction (scleral
blanching) in both instances was about the same. Two of the 3 volunteer
patients reported better comfort in the eye treated with the present
formulation. In all 3 patients, the paired eyes treated with this product
looked much better than the 0.5% phenylephrine solution when examined with
a slit lamp 20 minutes after treatment. Residual amounts of the
pharmaceutical vehicle were still apparent in the treated eyes, whereas
all of the more concentrated 0.5% aqueous solution had dissipated in the
opposite eyes. This observation demonstrates the added ocular protection
and duration of the new drug form of this invention.
EXAMPLE VII
The following pharmaceutical solution containing the antimicrobial agent
Clofazimine was prepared:
Clofazimine -- 0.1%
Pluronic F-127 -- 12%
Polysorbate 80 -- 20%
sodium chloride -- 0.6%
benzalkonium chloride -- 0.1%
purified water, enough to make 100% pH - 6.8, sol-gel transition at
35.degree. C.
This pharmaceutical composition was tested in vitro and found to exhibit
good activity.
EXAMPLE VIII
The following pharmaceutical solution containing the antimicrobial agent
pimaricin was prepared:
______________________________________
pimaricin 0.3%
Pluronic F-125 10%
(average molecular
weight of about 8000,
polyoxyethylene units
about 50% of total units
in molecule)
polyoxyl 40-stearate 20%
sodium chloride 0.6%
benzalkonium chloride 0.1%
purified water enough to make
100%
pH - 6,5, sol-gel transition
at 31.degree. C.
______________________________________
This formulation was also tested in vitro and was likewise found to exhibit
good activity.
Pharmaceutical compositions containing antimicrobial agents other than
those of Examples VII and VIII have similarly been prepared and tested
with success. Suitable vehicles for antimicrobial agents have been a
recognized problem, and the usefulness of the vehicles of this invention
in connection with antimicrobial agents represents a particularly
significant and advantageous aspect of this invention.
It will be readily apparent to those skilled in the art that the features,
advantages and uses of this invention are many. Those skilled in the art
will recognize that many modifications and adaptations of the invention
can be made without departing from the scope or spirit of the invention.
* * * * *
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