U.S. patent number 3,914,402 [Application Number 05/369,916] was granted by the patent office on 1975-10-21 for ophthalmic dosage form, for releasing medication over time.
This patent grant is currently assigned to ALZA Corporation. Invention is credited to John W. Shell.
United States Patent |
3,914,402 |
Shell |
October 21, 1975 |
Ophthalmic dosage form, for releasing medication over time
Abstract
A dosage form for ophthalmic drugs is disclosed. The dosage form
is a suspension of 10 to 300 micron particles in a liquid medium.
The particles are made up of drug enclosed within a drug release
rate-controlling material which bioerodes in the environment of the
eye.
Inventors: |
Shell; John W. (Los Altos,
CA) |
Assignee: |
ALZA Corporation (Palo Alto,
CA)
|
Family
ID: |
23457473 |
Appl.
No.: |
05/369,916 |
Filed: |
June 14, 1973 |
Current U.S.
Class: |
424/428 |
Current CPC
Class: |
A61K
9/1635 (20130101); A61K 9/1647 (20130101); A61K
9/0051 (20130101); A61K 9/1658 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 9/16 (20060101); A61K
027/12 () |
Field of
Search: |
;424/19-22,32-38
;128/260,272 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Speiser, P., Chem. Abst. 67 No. 14813n, 1967..
|
Primary Examiner: Rose; Shep R.
Attorney, Agent or Firm: Sabatine; Paul L. Benz; William H.
Mandell; Edward L.
Claims
I claim:
1. An ophthalmic dosage form comprising substantially dry solid
particles of ophthalmic drug enclosed within a bioerodible release
rate controlling material formed of a hydrophobic poly(carboxylic
acid) having a molecular weight of about 10,000 to about 800,000
and containing 8 to 22 carbon atoms for each carboxylic hydrogen
with the particles consisting of about 8 parts drug up to 1 part
material to about 1 part drug up to about 3 parts material, said
particles being from 10 to 300 microns in largest dimensions and
forming a suspension of 1 part up to 50 parts when admixed prior to
administration with up to 100 parts of an ophthalmically acceptable
isotonic aqueous carrier having a pH acceptable to the eye, with
drug released in the eye as the particles erode in response to the
ocular environment in a controlled and continuous rate over a
prolonged period of time.
2. An ophthalmic dosage form according to claim 1 wherein the
ophthalmic drug is a member selected from the group consisting of
idoxuridine, phenylephrine, pilocarpine and its acceptable salts,
eserine, carbachol, phospholine iodine, demecarium bromide,
cyclopentolate, homatropine, scopolamine and epinephrine.
3. An ophthalmic dosage form according to claim 1 wherein the drug
is an ophthalmic steroid selected from the group consisting of
hydrocortisone, hydrocortisone acetate, dexamethasone,
dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone,
methylprednisolone, prednisolone 21-phosphate, prednisolone
acetate, fluorometholone, betamethasone and triamcinoline.
4. An ophthalmic dosage form according to claim 1 wherein te drug
is an ophthalmic antibiotic selected from the group consisting of
tetracycline, chlorotetracycline, bacitracin, neomycin, polymyxin,
gramicidin, oxytetracycline, chloramphenicol, gentamycin, pencillin
and erythromycin.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an improved dosage form for ophthalmic
drugs. More particularly it relates to a new ocular dosage form
which is easy to use and which achieves a controlled release of
drug to the eye over a prolonged period of time.
2. The Prior Art
Most ocular treatments call for the administration of medicaments
topically to the tissues of the ocular cavity. These medicaments
have, in the prior art, assumed a wide range of forms.
The most common dosage form for ophthalmic medicaments is liquid
drops. Liquid drops may be found for example, in over-the-counter
ocular decongestants, such as Murine, and Visine, and in
anti-glaucoma solutions, such as 1/2 percent, 1 percent and 2
percent aqueous solutions of pilocarpine salts. The liquid drop
dosage form is easy to use, but suffers from the disadvantage that
the medication it contains is rapidly washed from the ocular cavity
by tear flow, so that a continuous sustained level of medication is
not achieved. Also, periodic application of eye drops results in
the eye receiving a massive, but unpredictable, amount of
medication at each time of application. The result of this
intermittent administration and rapid washing is that the level of
medication surges to a peak at the time the drops are applied --
then the drug concentration drops rapidly. Thus, a plot of
medication concentration in the eye versus time has the appearance
of a series of peaks of drug level which may surpass the toxic
threshold of the drug separated by extended valleys of drug level
below the critical level needed to achieve the desired therapeutic
effect.
Suspensions of particles of drug in liquids have been widely used
as well; for example, hydrocortisone acetate and prednisolone
acetate are typical of drugs presently marketed as suspensions.
These suspensions usually contain preservatives, isotonicity
adjusters, and suspending and dispersing agents. Present day
suspensions present a variety of problems. First, they generally
may only be made with relatively water-insoluble drugs, since
soluble drugs form saturated solutions which have higher tonicities
than the eye can easily adapt to. Also, the rate of release from
the particles of the suspension is related to the rate of
solubility of the drug so that one dosage rate along may be
obtained with a given drug. In the majority of cases this one rate
of delivery is not ideal.
Other dosage forms have been proposed, most on the basis that they
give a more prolonged release of drug to the eye. These dosage
forms include ointment; lamellae of glycerinated gelatin, such as
described in U.S. Pat. No. 273,410 issued Mar. 6, 1883; and other
similar dosage forms. These dosage forms give an only marginally
more sustained drug release than do liquid drops and most
particularly, do not give a constant release pattern; additionally
they suffer the disadvantages of being difficult to sterilize and
apply and often causing blurring of vision.
Recently developed ophthalmic drug delivery systems, such as
described in U.S. Pat. No. 3,416,530 patented Dec. 17, 1968 and in
U.S. Pat. No. 3,618,604 patented Nov. 9, 1971, do give true
controlled deliveries of drug. The ophthalmic drug delivery systems
of these patents are unitary ocular inserts, several millimeters in
size which are placed in the upper or lower sac of the eye to
deliver a complete ophthalmic dosage regimen for a period of 24
hours or longer.
While these ocular inserts do deliver drug to the eye continuously
and in a controlled manner, there remain improvements to be made.
Many patients, especially the farsighted elderly have difficulty
inserting or removing ocular inserts. Also the large unitary ocular
inserts are at times accidentally ejected from the ocular cavity by
the blinking action of the eyelids.
It would indeed by desirable to provide a dosage form which
combined the ease of administration of liquid drops with the
improved drug release characteristics of ocular inserts.
STATEMENT OF THE INVENTION
In accordance with the present invention, a new ophthalmic dosage
form is provided which combines the ease of administration of
liquid drops with the improved drug release characteristics of drug
releasing ocular inserts. This new dosage form for ophthalmic drugs
comprises a suspension of solid particles in a liquid medium, said
particles comprising ophthalmic drug enclosed within a bioerodible
drug release rate controlling material. These particles are from 10
to 300 microns in largest dimension.
In one embodiment, the particles each comprise a body of
drug-impermeable bioerodible release rate-controlling material
containing a drug dispersed throughout, which material bioerodes at
a controlled rate over a prolonged period of time in response to
the environment of the eye, thereby releasing the dispersed drug at
a controlled rate over a prolonged period of time.
In another embodiment, the particles each comprise single depots of
drug microencapsulated by a drug-impermeable bioerodible drug
release rate controlling material which material bioerodes at a
controlled rate over a prolonged period of time in response to the
environment of the eye, thereby releasing the microencapsulated
drug at a controlled rate over a prolonged period of time.
In yet other embodiments, the particles comprise either a
drug-containing body or microcapsule made of a bioerodible material
through which the drug is permeable at a controlled rate for a
prolonged period of time.
Although the solid particles of the suspension are small enough to
be passed from the ocular cavity through the punctum, this does not
in fact happen. Instead the particles of the suspension painlessly
disperse and lodge in the soft tissues which line the surfaces of
the palpebral and bulbar conjunctiva.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawing contains four drawings.
FIG. 1 is a magnified view of ophthalmic suspension in accord with
this invention showing in partial crosssectional view one type of
useful particle.
FIG. 2 is a view like FIG. 1 showing in partial cross-sectional
view another type of useful particle.
FIG. 3 is a view like FIG. 1 showing in perspective view yet
another type of useful particle.
FIG. 4 is a cross-sectional view of a container for mixing and
administering the suspensions of this invention.
DETAILED DESCRIPTION OF THE INVENTION
In its simplest form, the present dosage form includes a liquid
medium and a substantial plurality of 10 to 300 micron sized
particles containing drug and a drug release rate-controlling
substance. The liquid medium employed in the present suspension
dosage form may be an aqueous or non-aqueous ophthalmically
acceptable sterile liquid. Suitable non-aqueous liquid media
include the physiologically acceptable oils such as silicone oil,
USP mineral oil, white oil, and vegetable oils, for example corn
oil, peanut oil, or the like. An aqueous medium is generally
preferred.
The dosage form optionally contains a variety of other materials to
adjust pH, render the medium isotonic, preserve the dosage form and
the like. Preservative agents include benzalkonium chloride in a
concentration of from 1:15,000 to 1:30,000; chlorobutanol, in a
concentration of from 0.3 percent to 0.8 percent; thimerosol, in a
concentration of from 0.001 percent to 0.003 percent; and phenyl
mercuric nitrate, in a concentration range of from 1:60,000 to
1:80,000. Agents may be added to increase viscosity, promote
suspension and/or improve ocular compatibility, such as methyl
cellulose in an amount of from 0.1 percent to 0.7 percent or
poly(vinyl alcohol) in an amount of from 0.4 percent to 2 percent.
These and other additive materials are known in the art and are
generally described in the book Contact Lens Practice by Robert B.
Mandell (Charles C. Thomas, 1965) at pages 159-165, which
description is herein incorporated by reference.
The particles which are suspended in the liquid medium contain at
minimum, drug surrounded by a bioerodible drug release
rate-controlling material. As used herein, a "drug release
rate-controlling material" is defined to be a material which, when
fully surrounding a particle of physiologically active drug,
prevents the drug from exhibiting its physiological activity or
limits the rate at which the drug may diffuse into the ocular
environment. Only when the surrounding drug release
rate-controlling material is disrupted or when the drug diffuses
through the rate-controlling material may the enclosed drug be
released. As used herein the term "drug release rate-controlling
material" is intended to include only those materials which truly
function as just set forth. Fillers, binders and the like, known to
the art are not included within these materials. If the particles
are to painlessly lodge in the ocular tissues and to deliver drugs
at a controlled rate they must be of a size of from 10 microns to
300 microns in largest dimension, preferably from 20 microns to 200
microns in largest dimension. The particles should also be sized
such that a substantial plurality of particles (such as 100 or
more) are delivered with each administration, to ensure a uniform
delivery.
The drug release rate-controlling material must be bioerodible,
that is, it must innocuously disintegrate or break down from a unit
structure or enclosure over a prolonged period of time in response
to the environment of the eye by one or more physical or chemical
degradative processes, for example, enzymatic action, hydrolysis,
ion exchange, or dissolution by solubilization, emulsion formation
or micelle formation.
Likewise the term "bioerode" is defined as the method by which such
disintegration takes place. Bioerosion of the release
rate-controlling material serves two purposes, not only may it
release enclosed drug at a controlled rate but also it prevents a
build-up of particles in the tissues of the ocular cavity.
In the particles of the suspensions of this invention are employed
bioerodible materials which are non-toxic and compatible with the
drug used, and which are capable of forming films which wholly
surround and enclose drug particles. Exemplary of the materials
which can be employed are:
1. Polyesters
Polyesters of the general formula:
and mixtures thereof, wherein:
W is a radical of the formula --CH.sub.2 --; or ##EQU1## Y has a
value such that the molecular weight of the polymer is from about
4,000 to 100,000 may be employed as release rate-controlling
materials.
These polymers are polymerization condensation products of
monobasic hydroxy acids of the formula:
wherein n has a value of 1 or 2, especially lactic acid and
glycolic acid. Also included are copolymers derived from mixtures
of these acids. The preparation of polymers of the formula I per se
forms no part of the present invention. Several procedures are
available and reported by Filachione, et al, Industrial and
Engineering Chemistry, Vol. 36, No. 3, pp.223-228, (March 1944;
Tsuruta, et al, Macramol. Chem., Vol 75, pp.211-214 (1964) and in
U.S. Pat. Nos. 2,703,316; 2,668,162; 3,297,033; and 2,676,945.
These polymers are hydrophobic and substantially impermeable to
most drugs. Thus, they function best in particles which release
encapsulated drug by an erosion mechanism. This application is
related to copending U.S. application Ser. No. 248,168 filed on
Apr. 27, 1972, now U.S. Pat. No. 3,867,519 issued on Feb. 18, 1975
and assigned to the same assignee as this application. Application
Ser. No. 248,168 disclosed bioerodible ocular devices of polylactic
acid microencapsulated chloramphenicol which erode in the eye. 2.
Cross-Linked Gelatin
Gelatin is obtained by the selective hydrolysis of collagen, as is
well known, and comprises a complex mixture of high molecular
weight water soluble proteins. As used herein, the term
cross-linked gelatin means the reaction product of gelatin or a
gelatin derivative with a cross-linking agent which is reactive
with either the hydroxyl, carboxyl or amino functional groups of
the gelatin molecule but is substantially unreactive with the
peptide linkages of the gelatin molecule. The product of
cross-linking reaction preferably has an average molecular weight
of from 20 to 50,000 between cross-links, while higher values can
also be employed. These reaction products bioerode in the
environment of the eye over a prolonged period of time.
Cross-linked gelatin materials and their preparations are well
known. The degree of gelatin cross-linking is dependent upon te
processing conditions employed and markedly affects the gelatin's
bioerodibility. This application is related to copending U.S.
application Ser. No. 179,129 filed on Sept. 9, 1971 which
application is assigned to the same assignee as this application
and discloses ocular devices made of cross-linked gelatin.
Application Ser. No. 179,129 is cross-referenced in U.S. Pat. No.
3,867,519.
Exemplary cross-linking agents are: aldehydes, such as
monoaldehydes, e.g. C.sub.1 - C.sub.4 aldehydes, dialdehydes,
epoxides, para-benzene quinone, and aqueous peroxydisulfate.
Aldehydes and ketones, especially the 1 to 4 carbon aldehydes and
ketones are preferred, with formaldehyde being a most preferred
across linking agent.
Irradiation is another suitable method for cross-linking gelatin;
see for example Y. Tomoda and M. Tsuda, J. Poly. Sci., 54,321
(1961).
The reactive hydroxyl, carboxyl and amino groups are respectively
present in gelatin in the appropriate amounts of 100, 75 and 50 meq
per 100 grams. These quantities may serve as a general guide in
determining the amount of cross-linking agent to be used.
Cross-linked gelatin is relatively permeable to ocular fluid so
that diffusion of drug through gelatin may take place to some
extent. Thus, cross-linked gelatin is a good example of a release
rate-controlling material which releases drug by a diffusion
mechanism.
3. Polyacids
A third typical group of drug release rate-controlling materials is
made up of a certain class of poly(carboxylic acids). These
polyacids are characterized as being hydrophobic when unionized and
compatible with the tissues of the eye and as having a specified
proportion of carboxylic hyrogens.
Suitable poly(carboxylic acids) are the hydrophobic polyacids which
are represented by the general formula: ##EQU2## wherein: the R's
are organic radicals independently selected to provide an average
of from 8 to 22 total carbon atoms for each carboxylic hydrogen.
Variations of this ratio within this range can vary the bioerosion
and drug release rates of drug particles prepared from these
polymeric acids. Organic radicals represented by R.sup.1, R.sup.2,
. . .R.sup.n may be selected from hydrocarbon radicals and
hetero-atom containing organic radicals. Suitable hetero-atoms for
employment in R.sup.1, R.sup.2, . . . R.sup.n can include oxygen,
nitrogen, sulfur and phosphorous as well as other hetero-atoms so
long as the required hydrophobicity and carbon to carboxylic
hydrogen average ratio is maintained. The value of n and hence the
average molecular weight of the polymer is not critical and may
vary over a wide range. Suitable molecular weights, for example,
range from about 10,000 to about 800,000. Materials within this
range bioerode to products which may be easily and innocuously
passed from the environment of the eye. Preferred molecular weights
are from about 15,000 to about 500,000. These poly(carboxylic
acids) materials and their preparation and fabrication are more
fully described in U.S. patent application Ser. No. 318,891 of
Heller and Baker, filed Dec. 27, 1972, and now U.S. Pat. No.
3,811,444 dated May 21, 1974 which application is herein
incorporated by reference. U.S. Pat. No. 3,811,444 and this
application Ser. No. 369,916 are assigned to the same assignee. The
patent pertains to ocular inserts containing different ocular drugs
in varying amounts, with the insert having varying dimensions and
prepared from many reagents. The patent discloses the in vivo
erosion rates for inserts and the examples numbers in the Table
below correspond to the example numbers in the patent. In the
Table, number 1 through 5 are alkanol half esters of maleic acid.
Examples 7 through 14 are the alkanol half esters of poly(vinyl
methyl ether maleic acid). The patent also discloses other inserts
prepared from different reagents with the erosion rates measured in
vitro and in simulated ocular environments. These examples are
incorporated herein by reference.
TABLE ______________________________________ Example Ester Time to
complete erosion in eye, hrs ______________________________________
1 n-hexyl 175 2 n-butyl 10 - 15 3 n-pentyl 30 4 n-heptyl 90 5
n-octyl 550 6 -- -- 7 n-pentyl 20 8 ethyl 3 9 isopropyl 4 10 butyl
8 11 butyl 8 12 butyl 8 13 n-pentyl 1 14 2-pentyl 60
______________________________________
A preferred group of polyacid release rate-controlling materials
comprise hydrophobic polymers of an acid selected from acrylic
acid, lower alkyl acrylic acids of from 4 to 6 carbon atoms per
monomeric unit, and maleic acid either alone or copolymerized with
up to about 2 moles, per mole of acid, of a copolymerizable
olefinically unsaturated group such as ethylene or lower (1 to 4
carbon) alkyl vinyl ethers wherein from about 20 percent to 90
percent of the acid groups have been esterified with an alkanol of
from 1 to about 10 carbon atoms and wherein the ratio of total
carbon atoms to acidic carboxylic hydrogens is in the range of from
about 9:1 to about 20:1.
An even more preferred group of poly(carboxylic acids) comprise the
hydrophobic partially esterified copolymers of acrylic acid,
methacrylic acid or maleic acid with from 0.2 to 1.5 moles, per
mole of acid, of ethylene or lower (1-4 carbon) alkyl vinyl ether
having from about 35 percent to about 70 percent of their total
carboxylic groups esterified with lower alkanol of from about 3 to
about 10 carbon atoms, said copolymers having a carbon to acidic
carboxylic hydrogen ratio of from about 10:1 to about 15:1.
A group of poly(carboxylic acids) most preferred for use as rate
controlling materials in accord with the present invention comprise
hdyrophobic copolymers of maleic acid with about one mole, per mole
of maleic acid, of ethylene or methyl vinyl ether, said copolymer
having about half of its total carboxyl groups esterified with a
lower monoalkanol of from 4 to 8 carbon atoms, wherein the carbon
to acidic carboxylic hydrogen ratio has a value of from about 10:1
to about 14:1. These poly(carboxylic acids) are generally
drug-impermeable and thus are another example of a material which
releases drug at a controlled rate by erosion.
These materials are considered illustrative. Any bioerodible
material which is compatible with the drug, non-toxic and which has
the desired encapsulation, diffusion and erosion properties might
also be used. The polyesters, cross-linked gelatins and polyacids
set forth herein are preferred as release rate-controlling
materials.
Drugs suitable for incorporation in the particles of the
suspension, consistent with their known dosages and uses, are
without limitation solid ophthalmic drugs including: antibiotics
such as tetracycline, chlortetracycline, bacitracin, neomycin,
polymyxin, gramicidin, oxytetracycline, chloramphenicol,
gentamycin, penicillin, and erythromycin; antibacterials such as
sulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole;
antivirals, including idoxuridine; and other antibacterial agents
such as nitrofurazone and sodium propionate; anti-allergenics such
as antazoline, methapyriline, chlorpheniramine, pyrilamine and
prophenpyridamine; anti-inflammatories such as hydrocortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, medrysone, prednisolone, methylprednisolone,
prednisolone 21-phosphate, prednisolone acetate, fluorometholone,
betamethasone and triamcinolone; decongestants such as
phenylephrine, naphazoline, and tetrahydrazoline, miotics and
anticholinesterases such as pilocarpine, eserine salicylate,
carbachol, di-isopropyl fluorophosphate, phospholine iodide, and
demecarium bromide; mydriatics such as atropine sulfate,
cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,
and hydroxyamphetamine; and sympathomimetics such as
epinephrine.
The solid drug and drug release rate-controlling material are
combined in any fashion which enables small (10 to 300 micron)
particles of enclosed drug to be formed which have the predominant
portion of the drug fully enclosed within rate-controlling
material.
One suitable manner for combining drug and rate-controlling
material is illustrated in FIG. 1. FIG. 1 is a magnification of a
suspension containing particles 10 in a liquid medium not expressly
shown. Particles 10, when cut away, can be seen to comprise drug 11
microencapsulated within drug release rate-controlling material 12.
As the figure illustrates, the particles 10 are of variable size.
Also, it should be noted that the thickness of the coatings of drug
release rate-controlling material varies (compare coating 12 with
coatings 12a and 12b). This variation in erodible coating
substantially prolongs the release of drug. Light coatings will
erode through rapidly, while heavier coatings will take longer. By
varying the relative proportions of various coating thicknesses a
variable release rate may be achieved as well. Also, by varying the
coating material among a group of differently eroding materials,
some rapid -- some slow, a controlled prolonged release may be
obtained. It can also be seen, how, by adjusting the proportions of
coated particles, a constant rate of drug release could be
obtained, that is, a release rate having a zero order dependence on
time.
Any of the standard encapsulation techniques known in the art can
be used to prepare the microcapsule particles 10. The drug can be
added to the drug release rate-controlling encapsulating material
while it is in liquid or particle form, the mixture being reduced
to fine microcapsules by grinding, or the like. Alternatively, fine
particles of the drug can be coated such as by suspending dry
particles of the drug in an air stream and contacting that stream
with a stream of rate-controlling material that coats the drug with
a wall of rate-controlling material.
Another suitable microencapsulation method is the co-ascervation
technique. The co-ascervation technique of fabrication consists
essentially of the formation of three immiscible phases, a liquid
manufacturing phase, a core material phase and a liquid coating
phase. Liquid coating is deposited on the core material and
rigidized usually be thermal, cross-linking or desolvation.
Techniques for preparing microcapsules, such as the Bungenberg, de
Jong and Kaas method are reported in Biochem, Z., Vol. 232, (1931)
pp. 338-345; and J. Pharm. Sci., Vol. 59, No. 10 (1970) pp.
1367-1376.
A second typical configuration which particles may assume is
illustrated in FIG. 2. There, a variety of particles 20 are
illustrated which each contain a number of depots or drug 11
dispersed through a body 12 of ratecontrolling material. As the
rate-controlling material erodes, it gradually exposes and releases
the drug from the depots.
These type of particles could be easily formed by admixing 0.5 to 5
micron drug particles and release rate-controlling material in a
fluid phase and casting and settling a solid piece of drug and
rate-controlling material. This piece could then be micronized,
such as in a CRC Micromill, to give the desired 10 to 300 micron
particles of rate-controlling material containing drug.
FIG. 3 illustrates an embodiment of the invention which can yield a
more constant rate of release. The particles of the suspension of
FIG. 3 are all flat discs, essentially having only two dimensions.
That is, one of each disc's dimensions is less than 10 perent of
either of its other dimension. While round discs are shown in FIG.
3, clearly other two dimensional shapes could also be used. These
two dimensional particles present an essentially constant surface
area throughout their period of bioerosion. The particles
internally are similar to particles 20 of FIG. 2, that is, they
contain a plurality of drug depots dispersed through a body of
release rate-controlling material.
Another way to obtain a constant rate of drug release with an
ophthalmic suspension in accord with this invention is to employ
particles of the type shown in FIG. 1 (particles 10) having
accurately controlled proportions of rate-controlling wall
material. By providing an accurately graded range of thickness of
rate-controlling material, a smooth flow of drug can be
achieved.
The suspension dosage forms of this invention permit a uniform rate
of ophthalmic drug delivery. Also, by their ability to prolong drug
release, they permit the time periods between drop instillation to
be greatly prolonged, such as to well over 4 hours, for example up
to 4 to 5 days or even a week. Preferably suspensions are used to
prolong drug release over periods of from 18 to 72 hours per
instillation.
The suspension must therefore contain enough drug to satisfy the
dosage requirements for these prolonged periods.
It is generally preferred to adjust the amount of drug in the
suspensions so that from about 2 to 10 drops of suspension contains
the required complete dosage regimen.
Typical dosages for drugs administered in the improved dosage form
are:
Antibiotics, such as polymixin: 250 micrograms/day Sulfonamides,
such as sulfacetamide: 500 micrograms/day Antivirals, such as
idoxuridine: 5 micrograms/day Anti-inflammatories, such as
hydrocortisone acetate or prednisolone: 500 micrograms/cay
Philocarpine: 25-500 micrograms/day
The proportion of drug and drug release rate-controlling material
can range from about 8 parts drug to 1 part rate-controlling
material to about 1 part drug to about 3 parts rate-controlling
material. The particles shall contain sufficient drug for the
entire dosage regimen. The proportion of drug-containing particles
to liquid medium of the suspension can range from about 1 part
particles to 100 parts liquid to about 1 part particles to about 2
parts liquid.
In summary, the suspensions of this invention generally contain the
following proportions of components:
Liquid medium 100 parts Particles 1-50 parts Drug 0.3-45 parts
Rate-controlling material 0.1 to 33 parts Preservatives and the
like (as required)
When an aqueous medium is employed in the suspension, it is often
desirable to take precautions to prevent undue erosion of the
particles in the medium prior to use. This may be done chemically,
for example, by saturating the medium with dissolved drug release
rate-controlling material in cases where bioerosion proceeds
through solubilization, or by adjusting the solution pH, in cases
where the ratecontrolling material's erosion is pH dependent, to
nonerodible ranges. It may also be done physically by separating
the solid particles from the liquid medium until immediately prior
to application of the suspension. In a most elementary fashion,
this may be carried out by adding a few drops of liquid to the
particles prior to use. A more accurate, more controlled addition
of liquid can be carried out using a multi-chambered drug container
such as shown in cross-sectional form in FIG. 4 as container 40.
Container 40 grossly is in the form of a single dosage dropper
bottle of the type often used for ophthalmic preparations. It has
an outer wall 41, generally of flexible plastic. The top of wall 41
terminates in a small dropper tip having a hole. It may be a part
of wall 41, as shown, or it may be as second separate insert plug.
The latter configuration facilitates filling the container. The tip
is equipped with a cover to keep dirt, germs, and the like out and
maintain sterility of the contents of container 40. Container 40
contains a measured amount of 20 to 200 micron enclosed solid drug
particles 44 in a second upper chamber. The two chambers are
separated from one another by a barrier 45 carrying a valve 46. By
squeezing the lower portion of device 40 the liquid there contained
is forced upward through the valve into the upper chamber and mixed
with particles 44. A variation of this configuration could employ a
rupture disc between the two chambers. The resulting suspension
would have an accurately determined composition and would be easily
administered to a patient's eye via the dropper tip.
EXAMPLES I and II
Two ocular suspensions in accord with this invention are
prepared.
A. First, a drug release rate-controlling material is prepared as
follows: 126 grams (1.0 equivalents) of ethylene-maleic anhdyride
copolymer (Monsanto EMA, Grade 31) is stirred with 500 ml (4.0
moles) of n-hexyl alcohol at 120.degree.-125.degree. C for 7 hours.
The solution is cooled to room temperature and methylene chloride
is gradually added to the cloud point. Then more methylene chloride
is added to precipitate the product (total volume 20l). The
precipitate is thoroughly leached with the methylene chloride. The
solvent is decanted and the product dissolved in 750 ml warm
acetone. Methylene chloride is added to the cloud point. Then more
methylene chloride is added to precipitate the product (total
volume 15l). The precipitate is then thoroughly leached with
methylene chloride. The solvent is decanted and the product
dissolved in 750 ml acetone. The solution is transferred to a
polypropylene container and solvent is removed under vacuum at
50.degree.C to yield the drug release rate-controlling polymer
product. The infrared spectrum of the polymer shows broad bands at
1680 and 1780 cm-.sup.1 indicative of ester carboxyl. Titration
with base shows that the hexyl half ester of maleic acid has been
formed, and thus the ratio of total carbons to ionizable hydrogens
on average is 12:1.
B. Preparation of hydrocortisone-containing particles. 1.8 Grams of
the half ester polymer of part A is dissolved in 5 ml of acetone,
with stirring at 25.degree.C. 0.6 Grams of hydrocortisone acetate
micronized to 4 to 10 microns are dispersed in the solution with
stirring. The resulting viscous dispersion is cast on a
polyethylene film. The casting is allowed to dry thoroughly to
yield a dry film. The resulting film is removed from the
polyethylene film by stripping, and is micronized and screened to a
size of from 20 to 200 microns. 20 Mg of these particles containing
5 mg of hydrocortisone acetate suspended in 40 drops of sterile
water (about 2 cc).
A 4 drop portion of this suspension is added to a small shaken
vessel having a liquid volume and liquid turnover simulating a
human eye. The rate of hydrocortisone acetate release is measured
by infrared spetroscopy and compared with the rate of release of
hydrocortisone acetate observed when 0.5 mg of 4 to 10 micron
hydrocortisone acetate particles are placed in the same vessel
under the same conditions. The coated particles present a release
which is substantially more prolonged than that of the uncoated
particles.
C. Alternative preparation. 30 Grams of hydrocortisone acetate are
micronized to 5 micron average size and screened to separate out a
1 to 10 micron range of sizes. These separated particles are then
microencapsulated in 50 grams of the poly(acid) of part A by
dissolving the poly(acid) in 500 cc's of acetone and spraying the
acetone solution using a Wurster air suspension technique. The
spray coating varies from 5 to 40 microns in thickness. When these
particles are suspended in an aqueous medium and tested in accord
with part B of this example, they too give a sustained release of
drug.
EXAMPLE III
Five hundred grams of chloramphenicol of a particle size of from 20
to 40 microns is encapsulated with polylactic acid polymer of
molecular weight 50,000, according to the following procedure: 250
grams of the polylactic acid is dissolved in 2 liters of
chloroform. The chloramphenicol particles are coated with the
polylactic acid using a Wurster air suspension technique. The coat
thickness is determined to vary from 8 to 60 microns thick.
Three grams of the chloramphenicol microcapsules are dispersed in
50 cc's of an aqueous medium containing preservatives and salts to
achieve ocular isotonicity. When drops of this dispersion are
placed in the eye, the poly (lactic acid) coated particles imbed in
the soft tissues lining the eyelids. They gradually release their
chloramphenicol over a prolonged (48 hour) period. After about 96
hours, no residual poly (lactic acid) is noted in the ocular
cavity.
EXAMPLE IV
The procedures of Example III are repeated, substituting 250 grams
of crystalline pilocarpine nitrate for the chloramphenicol. The
pilocarpine has an average particle size of 15 to 30 microns. The
polylatic acid coating has a thickness ranging from 10 to 50
microns. When 3 - 4 drops of the resulting liquid suspension are
added each day for a week to a patient's ocular cavities, it is
noted that the patient's ocular pressures are continuously reduced
from their normal levels, indicative of a prolonged controlled
release of pilocarpine. This release pattern is especially
effective as it avoids periods where no drug is being
delivered.
EXAMPLE V
A suspension of cross-linked gelatin particles containing
hydrocortisone acetate for the treatment of eye inflammation is
prepared as follows:
A phosphate buffer is prepared from one liter of distilled water,
7.1 grams of disodium hydrogen phosphate and 6.9 grams of sodium
dihydrogen phosphate monohydrate. The pH of 6.8. 40 Ml of the
phosphate buffer and 0.15 grams chlorobutanol as combined with
heating and stirring. Nine grams of gelatin (Atlantic Pharmagel 250
Bloom Type A USP) is added slowly with stirring to the 40 grams of
buffer solution at 90.degree.C. Alternatively, the gelatin can be
added to the buffer solution after it is cooled to room temperature
and the mixture then heated to 90.degree.C until solution is
complete.
3.1 Grams of micronized (10 micron) hydrocortisone and 10
microliters of Tween 80 (Atlas, USP grade) are ground together and
suspended in 5 ml of phosphate buffer. The resultant mixture is
added immediately to the stirred gelatin solution as it cools to
approximately 50.degree.C. The final mixture is stirred thoroughly
for four minutes until the temperature falls to 40.degree.C and
poured onto a sheet of polyvinyl chloride. The resulting film is
dried at room temperature for one day.
A solution of formaldehyde (1% by weight) is prepared by addition
of 13.1 grams of 38 percent formaldehyde reagent to 487 grams
phosphate buffer (pH 6.8). The gelatin films are submerged in this
buffered formaldehyde solution for 20 minutes at room temperature,
quickly rinsed with water and soaked in ice water for 2 hours. The
films are removed from the ice water and dried overnight. The dried
film is then micronized to a particle size of about 100
microns.
A liquid medium consisting of sterile distilled water, 1 percent w.
poly(vinyl alcohol) and 0.004 percent benzalkonium chloride is
prepared.
A suspension of about 2 parts particles in 100 parts liquid medium
is prepared. When drops of this suspension are administered to the
eye, the particles lodge in the linings of the ocular cavity.
Ocular fluid permeates the gelatin of the particles and drug
diffuse out through the ocular fluid at a controlled rate over a
prolonged period of time. The gelatin erodes as well in the ocular
environment.
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