U.S. patent number 3,608,073 [Application Number 04/745,175] was granted by the patent office on 1971-09-21 for emulsion of pilocarpine for ophthalmic use.
This patent grant is currently assigned to Barnes-Hind Pharmaceuticals, Inc.. Invention is credited to Hans H. Kaspar, Russell E. Phares, Jr..
United States Patent |
3,608,073 |
Phares, Jr. , et
al. |
September 21, 1971 |
EMULSION OF PILOCARPINE FOR OPHTHALMIC USE
Abstract
An easy to apply, stable and effective form of pilocarpine is
provided by an oil-in-water emulsion of pilocarpine.
Inventors: |
Phares, Jr.; Russell E.
(Sunnyvale, CA), Kaspar; Hans H. (Sunnyvale, CA) |
Assignee: |
Barnes-Hind Pharmaceuticals,
Inc. (N/A)
|
Family
ID: |
24995569 |
Appl.
No.: |
04/745,175 |
Filed: |
July 16, 1968 |
Current U.S.
Class: |
514/397; 514/939;
514/913 |
Current CPC
Class: |
A61K
9/0048 (20130101); Y10S 514/913 (20130101); Y10S
514/939 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61k 027/00 () |
Field of
Search: |
;424/273,168 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Chem. Abstracts, Vol. 63, 1965 p. 2856g. .
Remington, "Remingtons Pharmaceutical Sciences," 13th Ed. 1965 p.
884, 979..
|
Primary Examiner: Friedman; Stanley J.
Assistant Examiner: Turner; Vincent D.
Claims
We claim:
1. An oil-in-water emulsion of a pilocarpine useful in the
treatment of glaucoma containing on a weight basis from about 0.25
to 8 percent of a pilocarpine selected from the group consisting of
pilocarpine hydrochloride, pilocarpine borate and pilocarpine
nitrate, from about 10 to 80 percent of a physiologically
acceptable oil selected from the group consisting of mineral oil,
silicone oil and a vegetable oil, an emulsifying amount of a
physiologically acceptable emulsifier selected from the group
consisting of acacia, gum tragacanth, methyl cellulose, lecithin,
cholesterol, polyoxyethylene (40 units) stearate, polyoxyethylene
cetyl ether, sorbitan, sorbitan trioleate and polyoxyethylene (20)
sorbitan trioleate and the balance of the composition being
essentially water.
2. The composition of claim 1 wherein the oil is mineral oil.
3. The composition of claim 1 wherein pilocarpine nitrate is
employed.
4. The composition of claim 1 wherein the pH of the aqueous phase
of the emulsion is from 4.5 to 7.
5. The composition of claim 4 wherein the pH is about 6.
Description
SUMMARY OF THE INVENTION
Pilocarpine is used as an antiglaucoma agent over long periods of
time. Generally the condition is such that it must be used for the
rest of the patient's life. Since many of the users are old and
infirm, they find great difficulty instilling medicine into the
eye. The easiest form of application of this medicine is a liquid
drop while the most effective form of medication previously known
is an ointment of semisolid material. The ointment is more
effective both from the depth and duration of clinically
significant response. However, many patients have difficulty in
applying an ointment and it also obscures the vision for prolonged
period of time. It is also difficult for the patient to judge when
he has instilled an effective amount of either the aqueous drop or
the solid ointment in his eye since a drop may catch just the
corner of the eye and be rinsed out by tear fluid while the
ointment can obscure vision even though it is applied only to the
eyelid and the eyelashes. For these reasons, ophthalmologists
normally restrict the use of ointment to bedtime, if at all,
despite the advantage of less frequent instillation and better
effect.
In accordance with the present invention, a fluid emulsion is
provided which combines the ease of administration of aqueous drops
with the depth and duration of an ointment. With the emulsion of
the present invention there is a brief obscuring of vision but this
brief obscuring is actually an advantage because the patient can
then judge whether he has instilled an effective amount of the
medication on the surface of the eye itself.
It is surprising that the effectiveness of pilocarpine in the
formulation of the present invention is virtually the same as the
ointment since the pilocarpine is contained exclusively in the
aqueous phase of the emulsion. Although the invention is not based
on any theory of its operation, it is believed that this unexpected
result comes from the effect of immobilizing the aqueous phase by
the oil droplets, thereby permitting longer contact of the
pilocarpine with the surface of the eye before it is normally
drained.
Another advantage of the present invention is that the chemical
decomposition of pilocarpine is retarded when in the emulsion of
the present invention so that it can be formulated and have a
substantial shelf life.
Further advantage of the present invention is that the emulsion can
be produced in sterile form while ointments are not available as
sterile products because of processing difficulties.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph comparing the stability of an emulsion formulated
in accordance with the present invention with that of an aqueous
solution. This is under accelerated aging conditions at 50.degree.
C.
FIG. 2 shows the effect on pupil dilation of 0.5 percent and 1
percent formulations made in accordance with the present invention
compared with a 1 percent aqueous solution of the prior art.
FIG. 3 is similar to FIG. 2, showing the availability of 2 percent
formulation of the present invention, of an ointment, and of a
solution.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In its simplest form the formulation of the present invention
includes pilocarpine, water, a physiologically acceptable oil and a
physiologically acceptable emulsifying agent. Other materials are
advantageously added to adjust the pH, to act as buffering agents
and to render the emulsion isotonic. Fungicidal and sterilizing
agents as well as a chelating agent may also be employed.
The formulation of the present invention contains from 0.25 to 8
percent pilocarpine and from 10 to 80 percent of oil. The balance
of the formulation is water plus any of the minor ingredients
mentioned above. Normally the pH is adjusted in the range of 4.5 to
7 and preferably is about 6.
Pilocarpine can be employed as the base material itself or its
salts such as pilocarpine hydrochloride, pilocarpine borate or
pilocarpine nitrate can be employed. Preferably the salts are
employed because of their greater stability.
Various oils can be used such as mineral oil, U.S.P., silicone oils
or vegetable oils such as corn oil, peanut oil, olive oil or the
like. Preferably mineral oil is employed because of its acceptance
by the medical profession, superior stability and low cost.
In preparing the formulations of the present invention, the
emulsifying agent or agents are added to the oil and the mixture is
then heated to about 60.degree. C. This warm mixture is added with
rapid stirring to water which also is about 60.degree. C. and which
contains the pilocarpine as well as any of the minor ingredients
mentioned above. The resulting oil-in-water emulsion is then
allowed to cool slowly to room temperature while it is slowly
stirred. The formulation is then ready for use.
A large number of emulsifying agents are suitable for use with the
present invention. The requirements are that the material form
oil-in-water emulsions and that it be nontoxic in the concentration
employed. Thus suitable materials include carbohydrates such as
acacia, gum tragacanth and methylcellulose; alcohols and esters of
alcohol such as lecithin and cholesterol and its esters;
polyoxyethylene derivatives such as polyoxyethylene (40 units)
sterate, polyoxyethylene cetyl ether, ethylene oxide reaction
product of wool fat, and polyethylene oxide sorbitan reaction
product of wool fat as well as sorbitan and sorbide derivatives
such as sorbitan trioleate and polyoxyethylene (20) sorbitan
trioleate.
As been mentioned above, various additional materials can be added.
These include sodium acid phosphate, disodium acid phosphate as
buffering agents, benzalkonium chloride as a fungicide and
sterilizing agent, chelating such as sodium ethylene diamine
tetra-acetic acid and salts such as sodium chloride or sodium
nitrate to render the emulsion isotonic.
Pilocarpine and its salts, like many drugs, are chemically unstable
in aqueous solution and will therefore lose potency with time. The
loss of pilocarpine nitrate from a conventional solution and the
product of the present invention when both samples were stored
under identical accelerated conditions, is shown in FIG. 1. As can
be seen, a higher concentration of the therapeutically effective
form of the drug is always present in the emulsion than is in an
equivalent conventional dosage from. At the end of 30 days the
emulsion has 88 active drug as compared to 79.5 percent in the
aqueous solution. These results are since in both samples, of the
drug was contained in the water.
An accepted method of comparing the biological availability of a
drug from various dosage forms is to compare the areas under their
biological and neither the disadvantages solution and human
efficacy formulations of response versus time plots. Applying this
method to the data in FIGS. 2 and 3, it is found that the emulsion
of the present invention has more than twice the biological
availability or activity of an equivalent conventional dosage form.
The release or availability of the drug from the emulsion is as
good as from an ointment but the emulsion has the advantages of a
solution and neither the disadvantages of a solution or an
ointment. The availability results shown in FIGS. 2 and 3 are
surprising in view of the fact that the drug is present in the
water in both dosage forms. Assay has shown that none of the drug
in the emulsion is present in the oil phase of the preparation.
Although this particular work was done with rabbits, pilocarpine is
an old drug and the correlation in pupil response between rabbits
and human beings is well established. Further, tests on human
beings have been made and have established the efficacy and safety
of the formulations of the present invention.
The following nonlimiting examples illustrated preferred
embodiments of the invention. All percentages are being weight.
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EXAMPLE I
% Pilocarpine nitrate 3.0 Mineral Oil (U.S.P.) 30.0 Tween-40 (a)
2.52 Arlacel-40 (b) 5.48 NaH.sub.2 PO.sub.4.H.sub.2 O 0.26 Na.sub.2
HPO.sub.4 0.045 Benzalkonium chloride 0.004 EDTA (c) 0.02 NaC1 0.26
Water to make 100.0 pH 5.5
__________________________________________________________________________
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EXAMPLE II
% Pilocarpine (free base) 1.0 Silicone Oil 100 c.p.s. 10.0 Polawax
(d) 2.4 NaH.sub.2 PO.sub.4 .H.sub.2 O qs. pH 6 Thimerosal (e) 0.01
NaC1 0.26 Water to make 100.0
__________________________________________________________________________
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EXAMPLE III
% Pilocarpine nitrate 4.0 Mineral Oil (U.S.P.) 30.0 Polawax 2.1
NaH.sub.2 PO.sub.4.H.sub.2 O 0.04 Na.sub.2 HPO.sub.4 0.04 PMA
(Phenylmercuric acetate) 0.004 Sodium nitrate 0.38 Water to make
100.0 pH 6.0
__________________________________________________________________________
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EXAMPLE IV
% Pilocarpine nitrate 2.0 Corn Oil 50.0 Polawax 1.8 NaH.sub.2
PO.sub.4.H.sub.2 O 0.19 Na.sub.2 HPO.sub.4 0.46 Thimerosal 0.01
NaC1 0.26 Water to make 100.0 pH 7.0
__________________________________________________________________________
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EXAMPLE V
% Mineral Oil (U.S.P.) 30.0 Polyoxyethylene (40) Stearate 2.4
Pilocarpine nitrate 8.0 Water to make 100.0
__________________________________________________________________________
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EXAMPLE VI
% Mineral Oil (U.S.P) 80.0 Polyoxyethylene (20) Sorbitan 7.5
Monolaurate Pilocarpine (hydrochloride) 0.25 Water to make 100.0
__________________________________________________________________________
a. Tween 40 is Polyoxyethylene Sorbitan Monopalmitate
b. Arlacel 40 is Sorbitan Monopalmitate
c. Ethylenediaminetetraacetate sodium
d. Polawax is Polyoxyethylene Stearate
e. Thimerosal is Sodium Ethylmercurithiosalicylate
* * * * *