U.S. patent number 3,870,791 [Application Number 05/435,475] was granted by the patent office on 1975-03-11 for solid state ophthalmic medication delivery method.
Invention is credited to Heskel M. Haddad, Spiro P. Loucas.
United States Patent |
3,870,791 |
Haddad , et al. |
March 11, 1975 |
Solid state ophthalmic medication delivery method
Abstract
A method of delivering a medicament to the eye in solid form is
described. The duration of miotic, mydriatic or other
pharmacological activity is prolonged by the direct insertion of
solid dosage forms of pharmacologically active compounds in the
cul-de-sac of the conjunctiva.
Inventors: |
Haddad; Heskel M. (New York,
NY), Loucas; Spiro P. (Plainview, NY) |
Family
ID: |
26938131 |
Appl.
No.: |
05/435,475 |
Filed: |
January 22, 1974 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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246661 |
Apr 24, 1972 |
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Current U.S.
Class: |
424/427; 514/54;
424/484; 514/57 |
Current CPC
Class: |
A61K
9/0051 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61k 027/12 () |
Field of
Search: |
;128/260
;424/14,16,19-22,180,361,362,273 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Iakovlov, Vistn. Oftal, Nov.-Dec., 1966, pp. 40-42, The Use of
Pilocarpine in a Polyvinyl Alcohol Film for the Treatment of
Glaucomators. .
Krishna et al., Am. J. Ophthal 57; 94-106, (1964), Polyvinyl
Alcohol as an Opthalmic Vehicle. .
Maichuk, Antibiotik 112(5); 432-435, (1967), Polyvinyl Alcohol
Films with Antibiotics in the Therapy of Lye Infections. .
Anderson et al., Am. J. Ophthal 51; 1200-1203, (1961), Tissue
Response to Polyvinyl Alcohol Implants in Rabbits. .
Haas et al., Am. J. Ophthal 54; 21-23, (1962), The Effect of
Methylallulose on Responses to Solutions of Piloarpine. .
Dohlman et al., Annals. Ophthal, Oct., 1972, pp. 823-832, A New
Ocular Insert Device for Continuous Constant Rate Delivery of
Medication to the Eye. .
Loucas et al., J. Pharm. Sci. 61(6), pp. 985-986, June, 1972,
Solid-State Ophthalmic Dosage Systems in Effecting Prolonged
Release of Pilocarpine in the Cul de Sac. .
Haddad, et al., Bull. et Mem. Soc. Fr. Opthalm. 84; 621-624,
(1971), Les Derives de l'Acide Polyuronique Prolongeant le
Transport de la Pilocarpine..
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Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Fitzpatrick, Cella, Harper &
Scinto
Parent Case Text
This is a continuation application of Ser. No. 246,661, Filed Apr.
24, 1972.
Claims
What is claimed is:
1. A complete ophthalmic dosage of medicament in solid form for
insertion into the cul-de-sac of the eye between the eyeball and
lid to dispense the medicament to the eye over a prolonged period
and leave the cul-de-sac free from tear insoluble residue,
comprising a solid matrix of a non-irritating pharmacologically
acceptable polyuronic acid or carboxymethylcellulose salt of a
medicament, said matrix adapted to form a gel-matrix after
insertion into the cul-de-sac to slowly diffuse said dosage of
medicament to the eyeball, said matrix being free from tear
insoluble carriers.
2. The product of claim 1 in the form of a disc capable of assuming
essentially the configuration of the curvature between the eyeball
and the lid.
3. The product of claim 1, wherein the medicament is employed in
the form of a salt of a polyuronic acid.
4. The product of claim 3, wherein the polyuronic acid is alginic
acid.
5. The product of claim 1, wherein the medicament is a miotic.
6. The product of claim 5, wherein the miotic is selected from the
group consisting of pilocarpine, eserine and carbachol.
7. A complete ophthalmic dosage of medicament for treating
glaucoma, in solid form, for insertion into the cul-de-sac of the
eye between the eyeball and lid to dispense the medicament to the
eye over a prolonged period and leave the cul-de-sac free from tear
insoluble residue, comprising a solid matrix of a non-irritating
pharmacologically acceptable polyuronic acid or
carboxymethylcellulose salt of a medicament, said matrix adapted to
form a gelmatrix after insertion into the cul-de-sac to slowly
diffuse said dosage of medicament to the eyeball, said matrix being
free from tear insoluble carriers.
8. The product of claim 7, wherein the medicament is employed in
the form of a disc having a marginal outline and cross section
adapted to assume essentially the configuration of curvature
between the eyeball and the lid.
9. The product of claim 8, wherein the medicament is in the form of
a disc having a thickness of about 0.3 mm, a diameter of about 3 to
7 mm, and a weight of about 3-8 milligrams.
10. The product of claim 7, wherein the medicament is present in
the form of a salt of a polyuronic acid.
11. The product of claim 10, wherein the polyuronic acid is
selected from the group consisting of alginic acid, galactouronic
acid and glucouronic acid.
12. The product of claim 7, wherein the medicament is selected from
the group consisting of pilocarpine, eserine or carbachol.
13. The product of claim 12, wherein the salt is pilocarpine
alginate.
Description
BACKGROUND OF THE INVENTION
This invention relates to a method of dispensing drugs to the eye
over a prolonged period of time.
At the present time, drugs of various kinds are frequently employed
in ophthalmic practice for the treatment of eye diseases. Since
these drugs are rapidly excreted from the body or diffuse from any
site of local application, repeated or numerous administration of
the drug during the crucial period is generally necessary.
Therapeutic substances may be introduced into the eye by various
methods. The methods generally used are instillation into the
conjunctival sac, subconjunctival injection, iontophoresis,
systemic administration and direct injection into the globe itself.
The most common route is by instillation into the conjunctival sac
in the form of drops or ointments. In this method, drugs enter the
eye largely through the cornea but to be effective, in many cases,
the application of the drug must be substantially continuous. At
the present time, it is not possible to obtain continuous delivery
of a given drug through the use of drops or ointments even though
they are applied at intervals during a given period. Periodic
application of such dosage forms generally results in the eye
receiving a large but uncertain amount of the drug at the moment it
is applied, but the drug is washed away rapidly by tears, thus
leaving the eye without medication until the next application. For
example, persons suffering from glaucoma, a symptomatic condition
characterized by an increase in intra-ocular pressure, must use
eyedrops in large quantities and at frequent intervals in order to
maintain the base pressure below a reasonable level. Pilocarpine is
generally used in the treatment of glaucoma, but frequent
administration is required due to the fact that the hypotensive
action of the drug is not of long duration. Thus, there still
remains a need to find better methods of delivering drugs to the
eye so as to obtain the maximum effect from the drug without the
need for frequent administration.
One method which has been proposed for the treatment of acute
glaucoma, for example, is to deliver the drug to the eye enclosed
in a polyvinyl membrane. This method was proposed by Vropaeva &
Indeikin in Oftal. Zh., 24: 543 (no. 7) 1969. The membrane
containing the drug is applied to the eyelid. However, it was found
that the inclusion of the drug in a membrane did not increase the
effectiveness of the drug in the general treatment of acute attacks
of glaucoma. An additional drawback is the need to remove the
membrane which contains the drug from the eye after each
application.
U.S. Pat. No. 3,618,604 describes an ocular insert which is used to
dispense drugs to the eye. The insert is comprised of a polymeric
material which is insoluble in tear liquid, the body of which
contains the drug. The drug is then dispensed to the eye by
diffusion through the polymeric material. This method has an
inherent disadvantage in that the insert must be removed from the
eye each time after application of the drug. In addition, the
polymeric insert must be so fashioned that it will not irritate the
sensitive tissues of the eye.
U.S. Pat. No. 3,630,200 describes an ocular insert made up of an
inner core having an affinity for a given drug and a soft
hydrophilic outer layer. U.S. Pat. No. 3,626,940 also describes an
ocular insert fabricated from polymeric materials, but the insert
contains a magnetically attractable substance to permit insertion
and removal of the insert by magnetic means. Thus, each of the drug
dispensing methods described in the above patents requires removal
of the insert after each application of the drug.
Other methods include the use of vehicles such as methylcellulose
in the preparation of ophthalmic solutions because of the apparent
ability of this compound to prolong the action of medicaments which
have been dissolved in such solutions. Although the use of
methylcellulose solutions prolongs the action of the medicament,
frequent application of eyedrops made from such solutions is still
required in order to bring a sufficient quantity of the drug in
contact with the eye. Other agents have been added to ophthalmic
solutions for the purpose of prolonging the effect of the drug, but
each of these methods requires the use of solutions which must be
placed in the eye at frequent intervals.
The object of the present invention is to provide a method of
delivering a therapeutic drug to the eye in solid form which
results in a continuous controlled release of the medicament and
obviates the need for frequent administration of the drug.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to a method of treating diseases of
the eye which comprises delivering a medicament in solid form to
the eye. The drug, in the form of a disc, pellet, flake, wafer,
etc., is placed in the cul-de-sac of the conjunctiva between the
eyeball and the eyelid. While the disc can be inserted under either
the upper lid or the lower lid, it is preferred to place the disc
under the lower lid. Once the disc is in place, the drug
disintegrates slowly causing it to be released into the tear
fluids. The drug is transported to the eyeball by the flow of tear
fluid or by the blinking action of the eyelids. A slow diffusional
process controls the rate of loss of the drug from its solid
matrix; thus, the drug is held in reserve and is available for
prolonging the duration of a desired pupillary response. Due to the
slow diffusional process, a means is thus provided for controlling
the release of a given drug from its dosage form in which
availability for absorption from the cul-de-sac is more uniform
than is the case with ophthalmic solutions containing the drugs.
Thus, a single disc can provide the complete ophthalmic dosage
requirement for a particular time period depending upon the
concentration of the drug in a given disc. Moreover, frequent
repeated applications of the drug are unnecessary, which is not the
case with solutions and ointments. For the purpose of lessening any
irritation which may result from the initial contact of the solid
with the eye, the solid may be dipped in an isotonic solution which
causes the solid to assume a semi-plastic consistency. Generally,
physiological salt solutions are suitable for this purpose.
Any drug normally used to treat diseases of the eye and the
surrounding tissues can be employed which is a solid or can be made
into a solid derivative. Also, within the comtemplation of the
present invention is the use of drugs which will pass through the
eye or the tissue surrounding the eye into the bloodstream, but
which may not be used in treatment of the eye itself.
Some examples of drugs used in ophthalmic therapy which may be
employed in the present invention are: anti-infectives: such as
antibiotics, including tetracycline, chlortetracycleine,
bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline,
chloramphenicol, and erthromycin; sulfonamides, including
sulfacetamide, sulfamethizole, and sulfisoxazole; antivirals,
including idoxuridine; and other anti-infectives including
nitrofurazone and sodium propionate; antiallergenics such as
antazoline, methapyrilene, chlorpheniramine, pyrilamine and
prophenpyridamine; anti-inflammatories such as hydrocortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate
and prednisolone acetate; decongestants such as phenylephrine,
naphazoline, and tetrahydrazoline; miotics and anticholinesterases
such as pilocarpine, eserine salicylate, carbachol, diisopropyl
fluorophosphate, phospholine iodide, and demacarium bromide;
mydriatics such as antropine sulfate, cyclopentolate, homatropine,
scopolamine, tropicamide, eucatropine, and hydroxyamphetamine and
sypathomimetics such as epinephrine. The drugs can be in various
forms such as uncharged molecules, componenets of molecular
complexes, or nonirritating, pharmacologically acceptable salts,
such as the hydrochloride, hydrobromide, sulfate, phosphate,
nitrate, borate, acetate, maleate, tartrate, salicylate, salts of
polyuronic acids such as alginic acid, galactouronic acid and
glucouronic acid, and salts prepared from carboxymethylcellulose.
Furthermore, simple derivatives of the drugs such as ethers,
esters, amides, etc., which have desirable retention and release
characteristics but which are easily hydrolyzed by body pH,
enzymes, etc. can be employed. The amount of drug used to make up
the solid dosage form will vary widely depending upon the
particular drug, the desired therapeutic effect, and the time span
for which the solid dosage form will be used There is no critical
upper limit on the amount of the drug used since the solid dosage
is intended to provide the complete dosage requirement for a given
period. The lower limit will depend on the activity of a given drug
and its rate of diffusion in the tear fluids. Therefore, it is not
practical to define a particular range for a therapeutically
effective amount to be used to make up the solid dosage. However,
generally about 1-50 mg. will be employed in the usual solid form,
depending upon the particular drug employed. The preferred range is
from about 1-10 mg.
The solid dosage form can be prepared by any conventional method
used to prepare discs, pellets, wafers, etc., from solids. One
method, for example, involves dissolving the medicament in a
solvent such as water, placing the solution in a suitable container
or vessel and removing the solvent by evaporation. Where desired,
the semi-solid mass left upon partial evaporation can be sectioned
into the desired shape by means of various size cutting tools. The
solid is then dried to ensure the removal of all of the solvent. In
this manner, it is possible to vary the dimensions of a respective
dose by simply replacing the size of the cutting tool or changing
the volume of the liquid used in preparation of the disc. The disc
can be fabricated in any convenient shape, keeping in mind that it
must be comfortably retained in the cul-de-sac of the eye. The
shape, however, must not have sharp, jagged or rough edges which
may irritate the sensitive tissues of the eye. The actual shape
used presents little problem to eye tissue since the initial form
is changed upon coming into contact with the eye fluids. The solid
form of the drug may be a disc, pellet, flake, etc.; it can be
concave, convex, rectangular, etc. The original shape of the solid
drug form is not of critical importance. The actual size of the
solid dosage form will vary widely. The lower limit will be
governed by the amount of the particular drug to be applied to the
eye to obtain the desired ophthalmic response. The upper limit will
be governed by the smallest sized solid which can be conveniently
inserted into the cul-de-sac. Generally, the solid form will be
about 1-8 mm. in length, about 1-4 mm. in width, having a thickness
of about 0.2-1 mm. The preferred shape is a disc having a thickness
of about 0.3 mm., a diameter of 3-7 mm., and a weight of about
3.0-8 mg.
Although the duration of the pharmacological effect of the drug in
the eye will depend upon the particular drug employed and the
amount used, solid form delivery of the drug generally results in a
pupillary response of up to 7-8 hours in the animal and longer in
humans.
Those compounds which are normally solids may be delivered in the
form of a disc or pellet, etc., without the aid of an additive.
Those compounds which are normally liquid may be used in the form
of a pharmacologically acceptable solid derivative. Also
contemplated is the use of a diluent or vehicle in conjunction with
the solid dosage form. Suitable vehicles include, for example,
methylcellulose, hydroxypropylmethylcellulose,
diethylaminoethylcellulose, polyvinylpyrrolidone and
pharmacologically acceptable cationic or anionic resins.
The treatment of eye diseases by delivering the medicament directly
to the cul-de-sac of the eye in solid form has general application
to various diseases of the eye. Any condition where prolonged drug
administration is required may be treated in this manner. For
example, it is possible to treat in this manner such eye disorders
as uveitis, glaucoma, diseases of the cornea such as, for example,
purulent keratitis, herpes simplex keratitis, herpes zoster, acne
rosacea, interstitial keratitis, and the like, diseases of the
orbit such as exophthalmas and periostitis and diseases of the
conjunctiva such as mucopurulent conjunctivitis and ophthalmia. The
present mode of drug delivery may also be used when postoperative
treatment is required such as after retinal and cataract
surgery.
An additional disadvantage related to the use of solutions of drugs
in the treatment of diseases of the eye is the instability of most
drugs in solution. Drug solutions generally contain a preservative
to prevent bacterial growth. The pH of eye fluids is about 7.4
while the pH of commercial pilocarpine solutions is about 5.3-5.5.
It is known that acidic solutions tend to cause discomfort to the
eye. The administration of the drug in solid form, however,
circumvents the problems relating to stability and eye discomfort
since the drug in solid form is stable for an indefinite
period.
In a specific example of the method of delivering a drug to the
cul-de-sac in solid form, in accordance with the present invention,
pilocarpine is prepared in the form of a disc and used to treat the
symptoms of glaucoma. Glaucoma is a clinical condition which is
characterized by an increase in intra-ocular pressure. The tension
which is associated with chronic simple glaucoma requires careful
study and repeated observation. In cases of chronic simple
glaucoma, miotic treatment is generally instituted. The most
commonly used miotic is pilocarpine which is administered several
times a day. A solution of about 0.5-4 percent is used in early
cases, but stronger solutions are used when necessary to control
the condition. Eserine can be used generally in an 0.025-1.0
percent solution if necessary and, in certain instances, stronger
cholinergic drugs such as echothiophate iodide (phospholine iodide)
may be employed.
In treating glaucoma, pilocarpine is generally administered in the
form of an aqueous solution, but it may also be administered in the
form of an ointment or by injection. The eye drops commonly used to
make up the solution generally consist of an aqueous solution of
pilocarpine hydrochloride. The present inventors have found that
delivery of the drug, pilocarpine in the present example, to the
cul-de-sac of the eye in the form of a solid disc provides a means
for controlling the release of the drug from a given dosage form.
The availability of the drug for absorption from the cul-de-sac is
more uniform than that obtained from inorganic salt type ophthalmic
solutions.
The effectiveness of the administration of the drug in solid form
is illustrated by the following example. The acid salts used in the
example are prepared by conventional methods used to prepare acid
addition salts from compounds containing a base nitrogen.
EXAMPLE 1
A. Preparation of ophthalmic solid dosage forms
a. Pilocarpine alginate ophthalmic discs are prepared by dissolving
pilocarpine alginate powder (7 percent w/v) in a small quantity of
sterile water with stirring. The solution is placed in a
flat-bottom petri dish and evaporated under reduced pressure at
30.degree.C. in a thermostatic water bath assembly. When the
colloidal solution reaches a semi-solid consistency, the mass is
sectioned into circular flakes (0.3 mm. thickness, 3-7 mm.
diameter, 3.1-7.8 mg.) by means of various size trephines and the
sections are dried to the point of solidification at 30.degree.C.
The solid is dried for an additional 24 hours at room temperature
and the discs are removed and stored in light-resistant
containers.
b. Pilocarpine hydrochloride -- A disc was prepared in the same
manner as in (a) above using 14.7 mg. of pilocarpine hydrochloride
and 100 mg. of methylcellulose 4000 cps in sterile water for
injection. A disc weighing 4.6 mg. was obtained.
c. Pilocarpine alginate -- A disc was prepared in the same manner
as in (a) above using 22 mg. of pilocarpine alginate and 0.23 mg.
of methylcellulose in sterile free water for injection. A disc
weighing 22.23 mg. was obtained.
d. Pilocarpine -- A disc was prepared as in (a) above using 4 mg.
of pilocarpine. A disc weighing 4 mg. was obtained.
B. Preparation of ophthalmic solutions
a. Pilocarpine alginate (3.34 percent w/v) solution was prepared
from sterile Sorensen phosphate buffer stock solutions mixed in
varying proportions to give a final pH of 6.14. The solution was
adjusted for toxicity with sodium chloride.
b. Pilocarpine hydrochloride solution (2.00 percent w/v) in the
presence of methylcellulose 4000 cps required to adjust the
viscosity to that of the alginate in a) above (72 cps, Brookfield
viscosimeter, model LVT, 25.degree.C.) was prepared from sterile
Sorensen phosphate buffer stock solutions mixed in varying
proportions to give final pH of 6.14 and adjusted for toxicity with
sodium chloride.
Preparation A
1. Pilocarpine alginate -- Pilocarpine free base (5 g.) and alginic
acid powder (5 g.) are mixed together in 50 ml. of sterile,
distilled water with stirring. The mixture is heated in a water
bath at 50.degree.C. and the stirring is continued for 1 hour. The
resulting gel is cooled to room temperature and the stirring is
continued for 24 hours under reduced light. The mixture is then
diluted to 100 ml. with distilled water and the resulting solution
is stirred for 12 hours at room temperature. The solution is then
transferred to a dessicator-water bath assembly and evaporated to
dryness under reduced pressure at 30.degree.C. The dry powder left
upon removal of the water is used directly to prepare the disc and
the solution of pilocarpine alginate.
Albino male rabbits are allowed to equilibrate under constant
conditions of illumination for 24 hours prior to treatment with
liquid and solid dosages of pilocarpine.
Each solution is delivered from a micrometer syringe (0.075 ml.)
into the lower cul-de-sac of one eye. Aqueous alginic acid or
aqueous hydrochloric acid is placed in the other eye as a control.
The disc is soaked in isotonic sodium chloride solution and then
deposited into the lower cul-de-sac with the aid of forceps. The
alginic acid and methylcellulose disc is used as a control. The
size of each pupil is measured just before the test drug is applied
by means of a Optiker Ryer pupillary gauge fixed at a distance of 6
inches from the globe. During measurement, the animals are confined
in a wooden box which provides free head and neck motion. Prior to
taking measurements, a waiting period of one minute is exercised
from the time the gauge is brought within the above distance. At
specified time intervals, at least six pupillary diameter readings
are made at each point.
Pupillary responses indicate (FIG. 1) that, in the liquid state,
pilocarpine alginate exhibits essentially comparable miotic
activity as pilocarpine hydrochloride following single dose
treatment. No pupillary contraction is noted in both liquid and
solid dose control eyes. The results derived from solid pilocarpine
alginate deposition show the magnitude of maximum pupil size
constriction to be enhanced, with duration of miosis significantly
increased over that of both liquid dosage systems. Restoration of
normal pupillary diameter for the solid state dose is observed to
occur between 7 and 8 hours in contrast to 3-3 1/2hours for the
ophthalmic solution.
In FIG. 2, data for repetitive pilocarpine alginate disc
application are given. In this study phase, miotic activity is
monitored after repeating the dose at maximum pupil constriction,
50 percent and 100 percent recovery of pupillary diameter.
Repeating the treatment at 50 percent pupil recovery gives about a
two-fold increase in miotic duration relative to both single dose
deposition and normal pupillary diameter and multiple treatments at
the points of maximum constriction. When a second and third disc is
applied at recovery (7 mm.), the behavior is additive with
restoration of pupil size being reached after seven, twelve and
about seventeen hours.
Overall duration of miosis in the case of triplicate liquid
treatments (FIG. 3) at recovery shows that activity derived from
solutions of pilocarpine alginate and pilocarpine hydrochloride
methylcellulose is essentially equal. Recovery from the first,
second and third drop instillations is reached at about four, seven
and ten hours, respectively.
The availability of the medicament in the cul-de-sac from solid
form doses appears to be more uniform as a consequence of
diminished diffusion through the gel matrix where the drug is held
in reserve in contrast to liquid dosage forms when the dose is
immediately released in the conjunctival fluids. Although the rate
of diffusion of the solid drug will depend on the given drug
employed, the concentration of a given disc can be controlled so as
to allow maximum dosage over a given period once the rate of
diffusion of a given drug is known. The use of solid ophthalmic
dosages in the treatment of diseases of the eye is more effective
than conventional methods and requires less frequent administration
of the drug to produce prolonged physiological activity.
While a preferred embodiment of the present invention has been
described, it is apparent that numerous variations and additions
may be made to the invention without departing from the spirit
thereof. It is the intention, therefore, to be limited only by the
scope of the following claims:
* * * * *