Note: Descriptions are shown in the official language in which they were submitted.
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BACKGROUND OF THE INVENTION
1. Pield of the Invention
This invention relates to the use of gums as adjuvants in ophthalmic compositions
to potenffate the miotic response of cholinergic agents, particularly echothiophate
iodide whioh is used in treatment of glaucoma; this allows the administtation of lower,
more eff ctive dosages of said cholinergic agents, thereby slleviating side effects. In a
further aspect this invention relates to a drug delivery system that is a gel and is useful
for topioal applications.
In this application the term "adjuvant" is defined as found in Stedman Medical
Dlctionary, 22nd 13dition as "that which aids or sists; denoting a remedy that is added
to a pres¢ription to sist or inorease the action of the main ingredient".
2. Descrlption o- the Prior Art
The prior art discloses a variety of gums and polymers used as adjuvQnts in
ophthalmic compositions.
For example, C. Rosenblum et. al. in Arch Ophthal, 77:234-237,1967, disclosed
the use of hydroxyethyl cellulose to increase the systemic absorption by ocular tissues
of dexamethasone. With drugs such as erythromycin propionate and sulfapyridazinesodium, Y.~. Malchuk, Am. J Ophthal, 74:694, 1972 taught the use of polyvinyl alcohol
to potentiate their pharmacological response. Similarly, guar gum was found to
increase the corneal absorption of tropicamide as reported by Lee et al, J. Pharm. Sci.
63:721, 1974.
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A~IP-6B60/6664
The use of gum and polymer combinQtions is also disclos~d, such ~s their
application as a bactericidal cleanser, lubricant, and wetting agent. German Patent
2,051,369 is illustrative, wherein is disclosed a solution containing polyethylene glycol, poly
(ethyleneoxide), and an ophthalmic medicine. British Patent 1,337,105 teaches a different
5 combination of polymers for use in eye wash sol~ltion containing hydroxyethyl cellulose and
polyvinyl alcohol. Still another example is presented by British Patent 1,340,518 which
discloses ophthalmic compositions containing an ophthalmic medicament, a polyalkylene
glycol, a cellulosic derivative or mixture of such derivatives, and, optionally, polyvinyl-
pyrrolidone. See also U.S. Patents 3,944,427 and 3,700,451 which disclose gelable and
10 gelled compositions containing agar, xanthan gum, and locust bean gum in a liquid medium
for use as a carrier of therapeutic solutions, but particularly as a carrier for photo-
processing solutions. These compositions, however, are rigid gels at room temperature.
SUMMARY OF THE INVENTION
In accordance with the present invention, xanthan gum or locust bean gum is
15 incorporated in ophthalmic compositions of cholinergic agents, particularly echothiophate
iodide, to enhance the drug's therapeutic activity thereby allowing a reduction in dosage
and a concomitant reduction in toxicity while retaining an effective level of antiglaucoma
activity.
An important embodiment of the invention relates to a composition consisting
20 essentially of a therapeutically effective dosage of a topically effective ophthalmic drug
and about 0.01% to 2.5% weight per volume of xanthan gum or l~lcust bean gum in a
pharmaceutically acceptable liquid carrier.
The xanthan gum or locust bean gum, incorporated in ophthalmic solutions of
echothiophate iodide, acts as an adjuvant and thus promotes the activity of the drug. The
25 xanthan gum or locust bean gum adjuvant is prepared by dissolving the gum in the solution
i.e. the pharmaceutically acceptable liquid vehicle followed by dissolution of the
echothiophate iodide.
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DETAILED DESCRIPTION OP THE INVENTION
Echothiophate iodide is described in U.S. Patent 2,911,430 granted Nov. 3, 1959 to
5 H.M. Fitch.
In this application "xanthan gum" means Xanthomonas hydrophilic colloid produced
by bacteria of the genus Xanthomonas. Illustrative of such a colloid is the xanthan gum sold
under the Keltrol trademark (Kelco Co., Clark, N.Y.). It may be described as a high
molecular wright natural carbohydrate, or more specifically polysaccharide. The generic
10 term xanthan gum defines exocellular biopolysaccharides which are produced in a pure culture
ferm ntation process by the microorganism Xanthaomonas campestris. Three diîferent
monosaccharides are found in the basic structure - mannose, glucose and glucuronic acid (as a
mixed potassium, sodium and calcium salt). Each repeating block within the polymer contains
sixteen sugar units. The linear portion consists of five B, 1~3 4-linked ~glucose units,
15 four ~,1~4-linked ~mannose units and four~, 1~2-linked ~gluouronic acid units. At
C-3 of two glucose units there are mannose branches and at some other position, as yet
undetermined, in the repeating unit is a side chain derived from wruvic acid and glucose i.e.
- 4,6-O-(carboxyethylidine~glucose. Each repeating unit contains an average of 3.4 acetyle
groups which are believed to be connected at C6 of mannose.
Locust bean gum is a high molecular weight polysaccharide derived from ceratonia
siliqua. Chemically, locust bean gum is a galactomannan best illustrated with galactose units
locflted on every fourth mannose unit, with the smaller amounts of pentoglycan, protein,
cellulose and ash. A detailed description of the composition, physical and chemical
25 properties, preparation, etc. of locust bean gum is given in Industrial Gums (Polysaccharides
and Their Derivatives), Academic Press, (1959) at pp. 361-376.
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In the compositions of this invention, the concentration o~ xanth~n gum or locust
bean gum is from about 0.01% to about 2.5% weight by volume. It will be appreciated that as
the concentration of the gum is increased, it is accompanied by an increase in viscosity.
Thus, at concentrations of gum above about 1.0% and up to about 2.5%, a gel like consistency
5 is attained. This gel like consistency permits various topical applications of drug such that
the drug is maintained at the site of administration over a longer period than is possible by a
liquid composition. By a gel it is meant a colloid in which the disperse phase has combined
with the continuous phase to produce a simi-solid such as a jelly.
The preferred concentration of xanthan gum or locust bean gum for dropwise
10 ophthalmic applications is from about 0.02% to about 1.0% weight/volume. When echo-
thiophate iodide, a drug used in the treatment of glaucoma, is the ophthalmic drug incor-
porated in said gum composition, its concentration can vary from about 0.005 to about 0.25%
weight/volume. An advantage of this invention is that the systemic side effects observed at
higher concentrations of echothiophate iodide may be reduced due to the potentiation of the
15 drug's pharmacological response by xanthan gum or locust bean gum thereby permitting the
administration of reduced concentrations of drug. Illustratively, it was observed that a
composition containing 0.03% echothiophate iodide and 0.2% xanthan gum or locust bean gum
potentiated a greater pharmacological response than one containing 0.25% echothiophate
iodide and no gum.
Potentiation of pharmacologic response was observed to increase with increasing
concentrations of xanthan gum or locust bean gum. Also required or preferred concentrations
of gum needed to achieve optimum results will vary from drug to d~ug. Thus, while with
echothiophate iodide a concentration of xanthan gum or locust bean gum from about 0.02% to
about 1.0% is preferred; with the aldose reductase inhibitor, 1,3-dioxo-lH-benz[de] iso-
25 9uinoline-2(3H)-acetic acid a concentration of xanthan gum or locust bean gum from about
0.5% to about 1.5% is preferred. The xanthan gum or locust bean gum composition has also
been found suitable as a vehicle for widely varied concentrations of drug. For example,
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10~3467 AHP-6660/6664
these compositions have been found su~table for delivering QS little as 0.005 weight/volume of
echothiophate iodide or as much as 12.0% of Alrestatin. The choice i8 usually limited only by
the need to incorporate a therapeutically effective dosage of drug within the compositions OI
this invention.
An advantage of the herein disclosed invention is its superiority as an adjuvant over
such previously art known adjuvants as polyvinyl alcohol, hydroxyethyl cellulose, and ethylene
oxide polymer as demonstrated in tests conducted with echothiophate iodide. Also, while the
compositions of this invention may be prepared in an aqueous solvent, these compositions are
also feasiMe in liquid vehicles containing water and water miscible solvents; thus, it will be
appreciated that these compositions are equally well adapted to the delivery of drugs with
vsrying degrees of solubility. By way of illustration, the xanthan gum compositions are stable
in the presence of such non-aqueous solvents as ethanol, propylene glycol, 1,3-butanediol,
glycerin, sorbitol and the like when such solvents Compose up to about 1/2 by volume of the
carrier system, i.e. the liquid vehicle comprises 50-100% water. The locust bean gum
compositions are stable in the presence of such non-aqueous solvents as ethanol up to 6%
volume/volume, propylene glycol up to 25% volume/volume and the like when such solvents
are incorporated within the carrier system, i.e. the pharmaceutically acceptable liquid
vel~icle comprises 75 -100% water.
The compositions of this invention can be designed first by selecting the drug to be
used and the pharmacological response desired. A composition can then be designed to
produce that pharmacological response comprising the xanthan gurn or locust bean gum
adjuvant and the selected drug in a pharmaceutically acceptable liquid vehicle.
Any of the drugs used to treat the eye and surrounding tissues can be incorporated in
the ophthalmic compositions of this invention.
Although the use of the xanthan gum or locust bean gum adjuvant has principally
been described with respect to drug delivery systems for the administration of ophthalmic
drugs, it will be appreciated that each gum may be employed as well in a
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5 wide variety of bioerodable compositions for administering drugs to the other areas of the
body. Thus, the pharmaceutical delivery systems o~ this invention may be employed to
advantage in external ~nd internal erodable drug delivery compositions such as, for example,
topical, oral, nQsal and buccal preparations. In each instance, the composition employs
xanthan gum or locust bean gum in combination with the selected drug and is of a shape or
1 aform appropriate for implantation or insertion in the described body tissues or cavities
respectively or for application to a particular body area.
Suitable drugs for use in therapy with the compositions of the invention include
antibacterials, such as bacitracin, chloramphenicol, gentamycin, gramicidin, polymyxin,
sulfacetamide, sulfisoxazole, and tetracycline; antiglaucomatous agents, such as, aceta-
15 zolamide, epinephrine, and echothiophate iodide; sympathomimetic agents, such as epin-
ephrine, phenylephrine, cocaine, and ephedrine; parasympathiolytics, such as, atropine,
homatropine, scopolamine, tropicamide and cyclopentolate; parasympathomimetics, such as
carbachol, echothiophate, pilocarpin, and isoflurophate; sympatholytics, such as, dibenamine
and tolazoline; anti-inflammatory agents, such as, cortisone, hydrocortisone, prednisolone,
20 prednisone, and dexamethasone; and others, such as antiwrine, antazoline, LH-RH, LH-FSH,
and 1,3-dioxo-lH-benz[de] isoquinoline-2(3H~acetic acid.
The term "drug" as used herein is intended to be interpreted in its broadest sense as
including any compositon or substance that will produce a pharmacologic response, either at
the site of application or at a site remote therefrom.
Additionally, the compositions of the invention may include a variety of additives
including preservatives, buffers, electrolytes, antioxidants, stabilizers, and pharmaceutically
acceptable liquid vehicles as described earlier.
The invention may be illustrated in part through the following examples.
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AHP-6660/6664
E X A M P L ~ 1
Ingredients A B C D E F G H
Echothiophate
Iodide 0.3g 0.3g 0.3g 0.3g 0.3g 0.3g 2.5g 0.3g
Xanthan Gum -- 2.0g 5.0g 0.4g 0.2g 2.0g -- --
Locust Bean -- -- -- ~ 2.0g
Gum
Boric Acid,
Reagent Grade 0.6g 0.6g 0.6g 0.6g 0.6g -- 0.6g
Sodium Phosphate
Dried 0.26g 0.26g 0.26g 0.26g 0.26g -- 0.26
Mannitol 12.0g 12.0g 12.0g 12.0g 12.0g -- 12.0g
Chlorbutanol
Anhydrous 5.0g 5.0g 5.0g 5.0g 5.0g -- 5.0g
Potassium Acetate 8.0g 8.0g 8.0g 8.0g 8.0g -- 8.0g
15 Phenylethyl
Alcohol -- -- -- -- -- 5.0ml -- 5.0ml
Hydrochloric Acid,
lN q.s. to pH 3
Distilled Water
20 q.s. to 1 L 1 L 1 L 1 L 1 L 1 L 1 L 1 L
These formulations were prepared by dissolving sodium phosphate, boric
acid, mannitol, chlorobutanol or phenylethyl alcohol in distilled water; dispersing the
gum in the solution; autoclaving the solution at 121C for 60 minutes; adjusting the
solution's pH to 3 where noted and filtering. Then, dissolve echothiophate iodide to
25 prepare the test solution.
Rabbits' eyes were treated with 2 drops of the test solutions of
example 1 and pupillary diameters were measured with a cathetometer. The miotic
response intensity was computed by taking the difference in pupillary diameters at zero
time and time "T" (i.e. hours after instillation) and dividing it by the pupillary diameter
30 at zero time. The table below illustrates the average miotic response for all eyes as
a function of hours after instillation.
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AHP-6660/6664
~AMI @ HOURS AFTER INSTILLATION
2 3 7 24 25
A 0.02 0.02 0.06 0.04 0.14 0.19
B 0.27 0.37 0.53 0.52 0.25 0.25
C 0.47 0.68 0.74 0.54 0.30 0.32
D 0.17 0.35 0.37 0.27 0.25 0.25
E 0.11 0.16 0.17 0.13 0.19 0.17
1~ F 0.66 0.68 0.69 0.60 0.32 0.33
,~ G 0.19 0.39 0.34 0.24 0.19 0.19
H 0.44 0.53 0.57 0.39 0.28 0.26
By comparing Formulations B-E and H with formulation A and G, it is clear that
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~ ~ the former group potentiated significantly higher miotic response intensities than those
i- formulations not having xanthan gum or locust bean gum. Thus, it was observed that
the dosage level of gum containing formulations can be reduced. It was also observed
f 15 that the gum containing formulations could be used to deliver a sustained and controlled
l dosage regimen of echothiophate iodide over a 24 hour period.
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AHP-6660/6664
EXAMPLE 2
Ingredients I J K L M N
Echothiophate Iodide O.lOg O.lOg O.lOg 0.30g 0.30g 0.30g
Locust Bean Gum - 2.0g 5.0g - 3.0g 5.0g
Boric Acid, Reagent Grade 0.60g - - 0.60g 0.60g 0.60g
Sodium Phosphate, Dried 0.26g - - 0.26g 0.26g 0.26g
Mannitol 12.0g - - 12.0g 12.0g 12.0g
Chlorobutanol, Anhydrous 5.0g - - 5.0g 5.0g 5.0g
Potassium Acetate 2.80g - - 8.0g
Phenylethyl Alcohol - 5.0ml 5.0ml
Hydrochloric Acid, lN
q.s. to pH 3
- Distilled Water q.s. to 1 L 1 L 1 L 1 L 1 L 1 L
_g _
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AHP-6660/6664
Formulations D-G were prepared and evaluated as in Example 1. The table
below illustrates the average miotic response intensity for all eyes as a function of
hours after instillation.
AMI @ HOURS AFTER INSTILLATION
1 2 3 7 24 25
0.030.09 0.040.02 0.08 0.08
J 0.190.33 0.370.32 0.17 0.16
K 0.500.64 0.580.32 0.16 0.05
L 0.010.02 0.060.05 0.13 0.18
M 0.080.18 0.250.28 0.17 0.13
N 0.470.68 0.730.54 0.30 0.32
The tests on formulations I-K were done simultaneously but separately from
the tests on formulations L-N which were also run simultaneously. These results
indicate, as in Example 1, that locust bean gum containing formulations potentiate
significantly higher miotic response intensities than those form~ations not having the
gum adjuvant. It WRS observed that as the concentration of gum adjuvant increases, the
degree of potentiation also increases. Thùs, it was observed that lower concentrations
of the drug may be administered and that a sustained and controlled dosage of
echothiophate iodide over a 24 hour period is feasible with the use of the gum
ao containing formulation.
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EXAMPLE 3
Ingredients O P Q R
Pilocarpine Hydrochloride 0.01g 0.01g 0.05g 0.01g
Xanthan Gum - 0.50g
Locust Bean Gum - - - 0.05g
Boric Acid 1.24g 1.24g 1.24g 1.24g
Potassium Chloride 0.04g 0.04g 0.04g 0.04g
Phenylethyl Alcohol - 0.50ml 0.50ml 0.50ml
Sodium Carbonate 2.12%
solution in water or 0.1NHCl,
q.s. to pH 5.3
Distilled Water q.s. to 100ml 100ml 100ml 100ml
* Avg. Miotic Response Intensity
Formulations containing pilocarpine hydrochloride were prepared as in Example 1.
Rabbits' eyes were treated and tested as in Example 1 and the results are listed
in the following table.
AMI @ HOURS AFTER INSTILLATION
Hours =~> 0.3 0.7 0.8 1 2
O -- 0.01 0.01 0.01
P 0.01 0.09 0.09 0.09
Q 0.12 0.2 0.19 0.18 0.15
R -- 0.01 0.02 0.04 0.03
These results indicated that xanthan gum or locust bean gum potentiates the
miotic response of pilocarpine hydrochloride. It therefore appears that the dose of
pilocarpine can be reduced when use in combination with xanthan gum or locust bean
gum.
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EXAMPLE 4
Formulations containing the aldose reductase inhibitor, 1,3-dioxo-lH-benz[de] iso-
quinoline-2~3H)-acetic acid, Alrestatin were prepared as in example 1:
S T U
AlrestRtin 12.0g 12.0g 12.0g
Potassium Hydroxide 3.25g 3.40g 3.30g
:
Xanthan Gum -- 1.0g
10 Locust Bean Gum -- -- 1.0g
BenzaL~conium Chloride 17% 0.06ml 0.06ml 0.06ml
EDTA acid 0.10g 0.10g 0.10g
' ~ Potassium Hydroxide q.s. to pH 6 ~/ ~/ J
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Phenylethyl Alcohol -- 1.0ml 1.0ml
Distilled Water q.s. to 100ml 100ml 100ml
Potentistion of the aldose reductase inhibitor was demonstrated by measuring its
ocular penetration following instillation m the eyes of unaesthesized rabbits, see below:
OCULAR PENETRATION OF ALRESTATIN
S T U
20 Aqueous Humor (mcg/ml) 8.5 14.2 10.8
Cornea (mcg/ml) 78 173 142
Lens (mcg/ml) 0.5 0.6 0.4
These results illustrate increased ocular penetration informulations containing xanthan
~um or locust bean gum in combination with aldose reductase inhibitor.
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AHP-6660/6664
EXAMPLE 5
Manufactured as described in Example 1, formulations containing carbachol,
2-[ (Aminocarbonyl)oxy ]-N,N,N-trimethylethanaminium chloride were prepared.
Formula per 50 ml V W X
Carbachol 0.50g 1.50g1.50g
Xanthan Gum 0.25g 0.25g
Locust Bean Gum -- -- 0.25g
Phenylethyl Alcohol 0.125ml 0.125ml 0.125ml
Distilled Water q.s. to 50 ml50 ml 50 ml
The stability of carbachol containing formulations was evaluated and found to
be satisfactory.
EXAMPLE 6
A formulation containing the polypeptide, gonadorelin also known as luteinizing
hormone - releasing hormone was prepared as in Example 1 for intranasal or intramuscular
15 application.
LH-RH l.Og
Locust Bean Gum 0.5g
Phenylethyl Alcohol 0.5ml
Distilled Water q.s. to 100 ml
The stability of this LH-RH formulation was evaluated over a one year period
and found to be satisfactory.
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