U.S. patent number 3,811,444 [Application Number 05/318,891] was granted by the patent office on 1974-05-21 for bioerodible ocular device.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Richard W. Baker, Jorge Heller.
United States Patent |
3,811,444 |
Heller , et al. |
May 21, 1974 |
BIOERODIBLE OCULAR DEVICE
Abstract
An ocular insert for the continuous controlled administration of
a predetermined therapeutically effective dosage of drug to the eye
over a prolonged period of time. The insert comprises a drug
formulation dispersed through a body of selected hydrophobic
polycarboxylic acids which erode in the environment of the eye over
a prolonged period of time to dispense the desired amount of
drug.
Inventors: |
Heller; Jorge (Palo Alto,
CA), Baker; Richard W. (Mountain View, CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23240002 |
Appl.
No.: |
05/318,891 |
Filed: |
December 27, 1972 |
Current U.S.
Class: |
424/428 |
Current CPC
Class: |
A61K
9/0051 (20130101); A61K 9/2027 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 9/20 (20060101); A61m
031/00 () |
Field of
Search: |
;128/272,156,260,127
;424/19,22,365,33 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
David R. Powell and Gilbert S. Banker; "Chemical Modification of
Polymeric Film Systems in the Solid State I: Anhydride Acid
Conversion", Journal of Pharmaceutical Sciences, Vol. 58, Nov.
1969, pp. 1,335-1,340. .
C. R. Willis, Jr. and Gilbert S. Banker; "Polymer-Drug Interacted
Systems in the Physicochemical Design of Pharmaceutical Dosage
Forms I - Drug Salts with PVM/MA and with a PVM/MA Hemi-Ester",
Journal of Pharmaceutical Sciences, Vol. 57, Sept. 1968, pp.
1,598-1,603..
|
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Ciotti; Thomas E. Mandell; Edward
L. Sabatine; Paul L.
Claims
What is claimed is:
1. A bioerodible ocular device for the controlled continuous
administration of drug to the eye comprising a body of bioerodible
drug release rate controlling material shaped and sized with a
length of from 4 to 20 mm, a width of from 1 to 12 mm and a
thickness of from 0.1 to 2 mm to be retained captive within the sac
of the eye and containing a drug dispersed within, the material
comprising a hydrophobic poly(carboxylic acid) represented by the
formula: ##SPC11##
wherein the R's are organic radicals independently selected to
provide an average of from eight to 22 total carbon atoms for each
carboxylic hydrogen and n has a value providing an average
molecular weight of from about 10,000 to about 800,000, which
material bioerodes at a controlled rate over a prolonged period of
time. in response to the environment of the eye by a process of
carboxylic hydrogen ionization, thereby releasing the dispersed
drug at a controlled rate over a prolonged period of time.
2. The ocular device defined in claim 1 wherein the R's are
hydrocarbons.
3. The ocular device defined in claim 1 wherein the R's are
4. The ocular device defined in claim 3 wherein the oxyhydrocarbon
R's
5. The ocular device defined in claim 3 wherein the oxyhydrocarbon
R's
6. The ocular device defined in claim 3 wherein the drug is an
7. The ocular device is defined in claim 1 wherein the hydrophobic
poly(carboxylic acid) comprises a polymer of an acid selected from
the group consisting of maleic acid, acrylic acid and lower alkyl
acrylic acids of from four to six carbon atoms, in which from about
20 to about 70 percent of the acid groups have been esterified with
an alkanol of from
8. The ocular device defined in claim 1 wherein the hydrophobic
poly(carboxylic acid) comprises a copolymer of an acid selected
from the group consisting of maleic acid, acrylic acid, and lower
alkyl acrylic acids of from four to about six carbon atoms, with a
copolymerizable olefinically unsaturated material selected from the
group consisting of ethylene, propylene, butadiene, isoprene and
styrene and the lower alkyl vinyl ethers, in which from about 20 to
about 90 percent of the acid groups have been esterified with an
alkanol of from one to about 10 carbon
9. The ocular device defined by claim 8 wherein the drug is an
10. The ocular device defined by claim 1 wherein the hydrophobic
poly(carboxylic acid) comprises a hydrophobic partially esterified
copolymer of acrylic acid, methacrylic acid or maleic acid with
from 0.2 to 1.5 moles, per mole of acid, of ethylene or lower one
to four carbon alkyl vinyl ether having from about 40 to 60 percent
of its total carboxyl groups esterified with lower alkanol of from
three to 10 carbon atoms.
11. The ocular device defined by claim 10 wherein the drug
comprises a drug selected from the group consisting of pilocarpine,
hydrocortisone alcohol and acetate and chloroamphenicol.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method and device for the
administration of drug to the eye over a prolonged period of time.
Still more particularly, this invention relates to an ocular drug
delivery device which bioerodes in the environment of the eye
concurrently with the controlled continuous dispensing of drug.
2. The Prior Art
It is known to treat diseases of the eye by the repeated periodic
application of ophthalmic drugs in glycerinated gelatin lamellae
form or more conventionally in liquid or ointment form. While these
methods of administration are suitable in many instances, a serious
shortcoming is the failure of these types of dosage formulations to
dispense the drug in a controlled or continuous manner. Periodic
application of these dosage forms, even though they be carried out
at intervals during the day and night, results in the eye receiving
a massive but unpredictable amount of drug at each time of
application. This conventional method of application leads to a
surging of drug level to a peak, often surpassing the toxic
threshold of the drug, at the time the drug is applied, followed by
a rapid decline in drug level, commonly to a level below the
critical point needed to achieve the desired therapeutic effect, as
tear fluid washes away the drug. This regimen of drug
administration is especially disadvantageous for ocular conditions
characterized by constant deterioration, i.e., glaucoma, wherein
any period without medication is detrimental.
Recognizing these disadvantages of conventional dosage forms, there
have recently been disclosed drug dispensing ocular inserts which,
when placed in the environ-ment of the eye, slowly release drugs to
the eye for prolonged periods of time. In this regard, see U.S.
Pat. No. 3,416,530 granted Dec. 17, 1968 to Ness entitled "Eyeball
Medication Dispensing Tablet" and U.S. Pat. No. 3,618,604 granted
Nov. 9, 1971 to Ness entitled "Ocular Insert".
The ocular inserts disclosed in these patents are fabricated of
materials which are biologically inert and insoluble in tear
liquid. When such an ocular insert is placed in the upper or lower
sac of the eye bounded by the surfaces of the sclera of the eyeball
and conjunctiva of the lid it retains its integrity and remains
intact, acting as a reservoir to continuously release drug to the
eye at a controlled rate. Such devices offer the marked advantage
of permitting a controlled and continuous release of drug. However,
since they are insoluble in the environment of the eye, they
present the problem of requiring removal at the completion of
therapy, a procedure which may present difficulty or discomfort to
some patients. In rare instances, the removal is made more
difficult by unwanted migration of the insert to the upper fornix
where it may remain long after the entire drug supply has been
released to the eye. Also, such devices have only limited
applicability with high molecular weight drugs. These devices
generally effect drug release by a diffusion mechanism. It is often
difficult or impossible to obtain useful rates of drug release with
slowly diffusing high molecular weight drugs.
In pending U.S. Patent application Ser. No. 179,129 of Higuchi et
al., filed Sept. 9, 1971, ocular devices are disclosed which are
formed of materials that bioerode in the environment of the eye
concurrent with the delivery of drugs and which thus obviate the
problems associated with the removal of ocular inserts from the
eye.
The choice of erodible materials for use in devices for releasing
drugs in the eye has shown to be most difficult. Unlike other areas
of the body, such as the gastrointestinal tract, which is highly
durable due to the tough mucosal lining and substantially protected
by large flows of highly buffered fluid, and the like, the eye is
most easily damaged or at least severely irritated by erosion
products.
Acidic erosion products which lower the eye pH below about pH 5.5
can cause serious eye irritation while products yielding pH's below
about 4.0 can cause permanent corneal burns. Similarly, erosion
products which cause an ocular tonicity imbalance cause irritation
and in many instances clouding of the colloidal gel which makes up
the cornea. Many other erosion products such as aromatic fragments,
organonitrates and the like can cause unacceptable degrees of eye
irritation. Additionally, the relatively rigid type structure of
the eye and the fragile nature of the conjunctival lining of the
eye make critical to the selection of material, the property of
freedom from crystallinity and abrasiveness. The present invention
relates to a class of bioerodible materials and compositions which
operate most advantageously in erodible ocular delivery devices
permitting controlled release of drugs to the eye while producing
erosion by-products which are highly compatible with ocular
tissue.
OBJECTS OF THE INVENTION
Accordingly, it is a primary object of this invention to provide an
improved erodible drug dispensing ocular insert for the controlled
and continuous administration of drugs to the eye over a prolonged
period of time.
Another object of the invention is to provide an improved material
for use in drug dispensing ocular inserts which is capable of
bioeroding at controlled rates in the environment of the eye and
providing a uniform sustained rate of release of drug in
therapeutically effective amounts.
Still another object of this invention is to provide improved
materials for use in drug dispensing ocular inserts; which
materials bioerode in the environment of the eye at rates dependent
upon their chemical composition.
A still further object of this invention is to provide a drug
dispensing ocular device formed of an improved bioerodible material
which can be adapted to drugs having either relatively high or
relatively low solubilities in eye fluids.
These objects, as well as other objects, features and advantages,
will become more readily apparent from the following detailed
description, the drawings and the accompanying claims.
STATEMENT OF THE INVENTION
In accomplishing these objects, a major aspect of this invention
resides in an ocular insert for the controlled and continuous
administration of a predetermined dosage of drug to the eye over a
prolonged period of time comprising a drug formulation confined
within a body of bioerodible drug release rate controlling
material, the material being hydrophobic poly(carboxylic acid)
having, on average, one ionizable carboxylic hydrogen for each 8 to
22 total carbon atoms. These poly(carboxylic) acids are polymers
represented by the general formula: ##SPC1##
wherein:
the R's (R.sup.1, R.sup.2,...R.sup.n) are organic radicals
independently selected to impart a hydrophobic character to the
polymer and to provide an average of from eight to 22 total carbon
atoms for each carboxylic hydrogen.
In another aspect, the present invention resides in an improvement
in bioerodible ocular devices for the controlled and continuous
administration of a predetermined dosage of drug to the eye wherein
the drug is enclosed within a body of bioerodible drug release rate
controlling material, said improvement comprising employing as
bioerodible drug release rate controlling material a hydrophobic
poly(carboxylic acid) having, on average, one carboxylic hydrogen
for each eight to 22 total carbon atoms.
One embodiment of this invention resides in an ocular insert for
the controlled administration of a controlled dosage of drug to the
eye over a prolonged period, which insert comprises a body of drug
release rate controlling material containing a drug formulation
confined therein, the body being of an initial shape which is
adapted for insertion and retention in the sac of the eye and of a
material comprising a hydrophobic poly(carboxylic acid) having an
average of one carboxylic hydrogen for each eight to 22 total
carbon atoms wherein the body continuously meters the flow of a
therapeutically effective amount of drug to the eye by bioeroding
and releasing confined drug at a controlled rate over a prolonged
period of time.
Another embodiment of this invention resides in an ocular insert
for the controlled administration of a predetermined variable
dosage of drug to the eye over a prolonged period comprising a
layered body of drug release rate controlling material containing
variable amounts of drug formulation confined in the separate
layers, the body being of an initial shape which is adapted for
insertion and retention in the eye and the layers of the body
comprising a hydrophobic poly(carboxylic acid) having an average of
one carboxylic hydrogen for each eight to 22 total carbon atoms
wherein the body continuously meters the flow of a therapeutically
effective variable amount of drug to the eye as the layers
sequentially bioerode and release at controlled rates over
prolonged periods of time the variable amounts of drug formulation
which they confine.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a view partly in front elevation and partly diagrammatic
of a human eye illustrating an ocular insert in accord with this
invention in an operative position after insertion in the eye.
FIG. 2 is a view partly in vertical section and partly diagrammatic
of an eyeball and the upper and lower eyelids associated therewith
showing the ocular insert of this invention in operative
position.
FIGS. 3, 4 and 5 are diagrammatic cross-sectional views of several
embodiments of ocular inserts of this invention.
FIGS. 6 and 7 are graphs illustrating the linearity of drug release
attainable with ocular inserts of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The term "bioerodible", as used in this specification and claims,
is defined as the property or characteristic of a body of material
to innocuously disintegrate or break down as a unit structure or
entity over a prolonged period of time in response to a biological
environment in which it is placed. Likewise, the term "bioerode" is
defined as the method by which such disintegration or breakdown
occurs.
The terms "hydrophobic" and "hydrophobicity" broadly refer to the
property of a substance to not absorb or adsorb appreciable amounts
of water. As used in this specification and claims, a more precise
meaning of these terms is intended; a hydrophobic material is
defined as one which absorbs or adsorbs water in a maximum amount
not substantially exceeding 10 percent of its dry weight.
In accordance with the present invention there is provided a
delivery device for the controlled continuous dispensing of a
predetermined dosage of drug to the eye over a prolonged period of
time comprising a body of bioerodible drug release rate controlling
material containing a drug formulation therein, the material being
selected from 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 hydrogens.
Suitable poly(carboxylic acids) are the hydrophobic polyacids which
are represented by the general formula: ##SPC2##
wherein:
the R's are organic radicals independently selected to provide an
average of from eight to 22 total carbon atoms for each carboxylic
hydrogen. Variations of this ratio within this range can vary the
erosion and drug release rates of ocular devices 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.
While not wishing to limit the scope of the polyacids intended to
be employed in accord with this invention, and while alternative
materials and preparative schemes are set forth in the description
of suitable polyacids which follows, a preferred method for
introducing a carboxylic acid function, as well as other
hetero-atom functions, into a polymeric material of the type
employed in this invention, is to proceed through monomers having a
carbon skeleton of at least two carbon atoms. These monomers
contain polymerizable olefinic carbon-carbon double bonds. At least
a portion of these monomers will have appended thereto one or more
carboxyl radicals, or suitable precursors thereof and optionally
also other hetero atom radicals. The polymer is formed by effecting
addition of these monomers, one to another, across the
polymerizable double bonds. This general method for forming
polyacids is well known and does not comprise a part of the present
invention. This preparative method may be generally represented by
the reaction: ##SPC3##
wherein:
A represents hydrogen or a hydrocarbon and ##SPC4##
represents a carboxyl group (or carboxyl group
precursor)-containing monomer also containing a polymerizable
olefinic double bond. Such monomers include, for example, acrylic
acid, substituted acrylic acid, maleic acid, maleic anhydride,
crotonic acid and the like. ##SPC5##
represent organic monomers containing a polymerizable double bond
which may be the same or different from ##SPC6##
This preparative technique can be employed to prepare
poly(carboxylic acids) in accord with General Formula I having
hydrocarbon R's either by polymerizing suitable hydrocarbon
substituted olefinically unsaturated acids such as substituted
acrylic acids and crotonic acids or by copolymerizing olefinically
unsaturated acids, such as acrylic acid or hydrocarbon-substituted
acrylic acids or the crotonic acids, with unsaturated hydrocarbons.
Suitable poly(carboxylic acids) having hydrocarbon R's prepared by
polymerizing substituted acrylic acids may be represented by the
general formula: ##SPC7##
wherein:
R.sub.(hc) represents hydrocarbon substituents averaging from five
to 15 carbon atoms in size, for example n-pentyl, cyclohexyl,
phenyl, n-decyl, 2,2-diethyldecyl, combinations of butyl and hexyl,
and the like. Such materials may be prepared by polymerizing the
corresponding hydrocarbon substituted acrylic acid monomers with
free radical initiators as described in U.S. Pat. No. 2,904,541
issued Sept. 15, 1959.
Also useful are poly(carboxylic acids) prepared by copolymerizing
unsaturated carboxylic acids such as acrylic acid (or substituted
acrylic acid) with a polymerizable hydrocarbon. These acids may be
represented by the general formula: ##SPC8##
wherein: R.sub.(HC) is a hydrocarbon radical, of up to about 12
carbons, or hydrogen; and R.sub.(CP) is a copolymerized hydrocarbon
group. The hydrocarbons which may be copolymerized with unsaturated
carboxylic acids include terminally olefinically unsaturated
hydrocarbons and olefinically unsaturated hydrocarbons having a
conjugated carbon-carbon double bond. Thus typical hydrocarbon
groups represented by R.sub.(CP) include ethyl, propyl, butyl,
isopentyl, and phenylethyl as result when ethylene, propylene,
butadiene, isoprene and styrene are, respectively, copolymerized
with unsaturated acids. Such preparations are set forth in J. Poly.
Sci. 10, 441, (1946 Series) and J. Poly. Sci. 10, 597 (1946
Series).
Poly(carboxylic acids) in accord with General Formula I having
hydrocarbon R's may also be prepared by other known techniques,
such as for example by oxidizing terminal methyl groups on suitable
hydrocarbon polymers to carboxyl groups with alkaline permanganate
as described in Cram and Hammond Organic Chemistry, 2nd Ed., p.
525-6; or by carboxylating olefinically unsaturated hydrocarbon
polymers by contacting them with carbon monoxide, water and
optionally some hydrogen under conditions of elevated temperature
and pressure in the presence of strongly acidic catalysts, for
example, HF, BF.sub.3, H.sub.2 SO.sub.4 and the like.
Poly(carboxylic acids) useful in the devices of the invention and
illustrated by General Formula I may suitably incorporate oxygen
atoms in their R's. Oxyhydrocarbon R's include ester groups or
ether groups. Poly(carboxylic acids) represented by Formula I
incorporating ester groups as R's are especially suitable in
devices of this invention. They may be readily prepared by
partially esterifying acid polymers or copolymers, which are
themselves easily obtained. They offer the advantage of permitting
simple variation of the ratio of carbons to acidic ionizable
carboxylic hydrogens by varying the extent of partial
esterification or the esterifying alcohol employed. As a result
easy adjustment of drug release rate and erosion characteristics of
the polycarboxylic acid product is obtained.
As an example of this easy control, poly(acrylic acid) is available
commercially or may be easily prepared for example by mixing 167
parts of 60 percent acrylic acid, 232 parts of water, 0.50 parts of
potassium peroxydisulfate and 0.25 parts of potassium metabisulfite
and heating the mixture to 60.degree.C. Poly(acrylic acid) per se,
however, is not a suitable poly(carboxylic acid) for use in devices
of this invention as it is substantially hydrophilic and water
soluble and does not have the carbon to ionizable hydrogen ratio
necessary to give suitable erosion and drug release characteristics
in the environment of the eye.
When half the carboxyl groups of poly(acrylic acid) are esterified
by reaction with a hexanol, the resulting partial ester is
hydrophobic and has a carbon to ionizable hydrogen ratio within the
range necessary for materials employed in the devices of this
invention (i.e., 12:1). A similarly suitable material would result
if two-thirds of the poly(acrylic acid) carboxyl groups were
esterified with ethanol.
This partial esterification technique is of course not limited to
poly(acrylic acid). Any organic lower poly (carboxylic acid) may be
partially esterified when necessary to achieve the required
hydrophobicity and carbon to acidic hydrogen ratio. Other polyacids
suitable for esterification include homopolymers of unsaturated
lower carboxylic acid such as acrylic acid, the lower alkyl acrylic
acids, such as methacrylic and ethacrylic acid, crotonic and
propiolic acid; maleic acid and fumaric acid: or suitable
poly(amino acids) such as poly(glutamic acid). Polymers of acid
precursors such as poly(maleic anhydride) may be hydrolyzed and
partially esterified as well. Also suitable for esterification are
acids or precursors copolymerized with lower unsaturated
hydrocarbons of from two to eight carbons such as ethylene,
propylene, butadiene, styrene and the like, or with lower
unsaturated oxyhydrocarbons such as unsaturated ethers of from
three to eight carbon atoms. Many of these polymers and copolymers
are available commercially. Others can be prepared by bulk,
solution, emulsion or suspension polymerization using free radical
initiators at 40-100.degree.C, all methods well known in the art.
The partial esterification may be conveniently effected by
contacting the acid-containing polymers with a controlled quantity
of the esterifying alcohol at elevated temperature, optionally in
the presence of an acidic esterification catalyst. Alcohols
suitable for partially esterifying the above-noted polyacids
include the hydrocarbon alcohols, preferably the alkanols of from
about one to about 16 carbon atoms, for example methanol, ethanol,
isopropanol, n-butanol, cyclohexanol, octanol, the decanols and
n-dodecanol. Combinations of alcohols may also be employed.
In addition to being included in partially esterified
poly(carboxylic acids), as noted above, ether linkages may be
included generally in the polymers employed in this invention; that
is, they may be oxyhydrocarbon R's. Ether groups may be
incorporated by copolymerizing an unsaturated carboxylic acid with
an unsaturated ether, for example, acrylic acid, maleic acid,
crotonic acid and the like with the vinyl ethers of from about
three to about 10 carbon atoms such as methyl vinyl ether, ethyl
vinyl ether, butyl vinyl ether, hexyl vinyl ether and the like, for
example, by the method described in U.S. Pat. No. 2,927,911.
Because of the small number of carbon atoms in many of these
unsaturated ethers and acids it may be desireable to achieve the
required carbon/acidic hydrogen ratio, to terpolymerize these
materials with a non-carboxylic hydrogen-containing material, most
suitably an unsaturated terpolymerizable unsaturated hydrocarbon of
from two to eight carbon atoms such as ethylene, butadiene, or
styrene.
The R's of General Formula I, as oxyhydrocarbons, may contain
alcohol linkages. The employment of alcohol linkage containing
oxyhydrocarbons as R's can pose a problem, however, as the alcohol
linkages generally decrease the hydrophobicity of the polyacid,
often to below the extent of hydrophobicity required of polyacids
for employment in this invention. It is usually possible to
incorporate up to about 10 percent, basis total polymer, of alcohol
linkage containing R's in the polyacids.
Nitrogen, sulfur and phosphorous atoms may also be incorporated in
R groups employed in the polymers represented by General Formula I.
Nitrogen may be present as cyano groups, amide groups or imide
groups. Amine groups are generally not suitable as they can result
in internal salts being formed between the polymerized acid and
amine groups. Sulfur atoms may be present as mercaptan or disulfide
linkage while phosphorous atoms may be present as phosphate
linkages.
A preferred group of materials from which to fabricate the ocular
drug dispensing devices of this invention comprise hydrophobic
polymers of an acid selected from acrylic acid, lower alkyl acrylic
acids of from four to six 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 (one to four carbon) alkyl vinyl
ethers wherein from about 20 to 90 percent of the acid groups have
been esterified with an alkanol of from one 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 (one to four carbon) alkyl vinyl
ether having from about 35 to about 70 percent of their total
carboxylic groups esterified with lower alkanol of from about three
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 in accord
with the present invention comprise hydrophobic 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 four to eight carbon atoms, wherein the carbon to acidic
carboxylic hydrogen ratio has a value of from about 10:1 to about
14:1.
The poly(carboxylic acids) employed in the devices of this
invention are soluble in organic solvents. Accordingly, the
polyacids may be conveniently formed or shaped by film casting
techniques. An organic solvented solution of the polyacid,
optionally containing drug, is prepared and cast or drawn to a
film. The solvent is then evaporated to yield a continuous film of
the polyacid. The ocular inserts, which are generally in the shape
of thin discs and the like, are then punched or cut from this
film.
A wide range of organic solvents may be used for the casting
solutions. With poly(carboxylic acid) materials having total carbon
to carboxylic hydrogen ratios at the lower end of the range
specified for this invention, such as ratios in the range of about
8:1 to about 11:1, it is generally preferred to use relatively
polar organic solvents, that is, organic solvents having dielectric
constants, as listed in the 51st edition of the Chemical Rubber
Company "Handbook of Chemistry and Physics" at pages E-62 through
E-64, of greater than about 15, for example; lower alkanols such as
methanol, ethanol, the propanols, 1 and 2-butanol; lower alkanones
such as acetone, diethyl ketone, ethyl methyl ketone and
cyclohexanone and halogenated and nitrogenated solvents such as
2-chloroethanol, and nitrobenzene. Poly(carboxylic acids) having
higher ratios of total carbon atoms to ionizable hydrogens, such as
from 14:1 to 22:1 it is generally preferred to use less polar
organic solvents, such as those having dielectric constants of less
than about 15, especially less than about 10, for example; ethers
such as diethyl ether, isopropyl ether and the like; hydrocarbons
such as cyclohexane, benzene and toluene, and other low dielectric
materials such as ethyl acetate. With the intermediate ratio
poly(carboxylic acids) either group of solvents may be used with
the alkanols and alkanones generally being favored.
The casting and drying are carried out at moderate conditions such
as at ambient temperature and pressure. Solvent removal may be
facilitated by the use of vacuum or slightly elevated temperatures.
However, substantially elevated temperatures, such as above
100.degree.C for lengthy periods, such as for several hours, may be
deleterious to some drugs or poly(carboxylic acids).
It is often desired to incorporate plasticizers in the
poly(carboxylic acid) materials to improve or vary their physical
properties, such as to make them more flexible. Exemplary
plasticizers suitable for employment for the present purpose are
the pharmaceutically acceptable plasticizers conventionally used,
such as acetyl tri-n-butyl citrate, epoxidized soy bean oil,
glycerol monoacetate, polyethylene glycol, propylene glycol
diluarate, deconol, dodecanol, 2-ethyl hexanol 2, 2-butoxyethanol
and the like. The proportion of optional plasticizer used will vary
within broad limits depending upon the characteristics of the
poly(carboxylic acid) involved. In general, from about 0.01 parts
to about 0.2 parts by weight of plasticizer for each part by weight
of the poly(carboxylic acid) can be used.
When plasticizers are included in the poly(carboxylic acid)
materials they are most suitably added prior to shaping the final
formed structure, such as by dissolving or dispersing them in the
solution from which the film is cast.
The certain poly(carboxylic acids) may be employed in all types of
devices for delivering drugs to the eye. While not intending to
restrict the scope of this invention, certain embodiments of
bioerodible drug releasing devices employing these poly(carboxylic
acids) and their use in dispensing drug to the eye are exemplified
in the drawings, some of which are exaggerated in size for purposes
of illustration.
Referring particularly to FIGS. 1 and 2, a human eye is shown in
each figure, more or less diagrammatically, comprising an eyeball 1
and upper and lower eyelids 2 and 3, respectively, the eyeball 1
being covered for the greater part of its area by the sclera 4 and
at its central portion by the cornea 5. The eyelids 2 and 3 are
lined with an epithelial membrane or palpebral conjunctiva. The
sclera 4 is lined with the bulbar conjunctiva which covers the
exposed portion of the eyeball. The cornea 5 is covered with an
epithelial layer which is transparent. That portion of the
palpebral conjunctiva which lines the upper eyelids 2 and the
underlying portion of the bulbar conjunctiva defines the upper sac
7 and that portion of the palpebral conjunctiva which lines the
lower eyelid 3 and the underlying portion of the bulbar conjunctiva
defines the lower sac 11. Upper and lower eyelashes are indicated
as 8 and 9, respectively.
A bioerodible ocular insert 12 in accord with this invention is
shown in operative position in the lower sac 11 of the eye. Other
details of the eyeball 1 are not directly concerned with the
structure of the instant invention and are omitted from the Figures
in the interest of brevity. To use the ocular insert of the
invention, it is inserted in the eye, preferably within the upper
sac 7 or lower sac 11, bounded by the surfaces of the sclera of the
eyeball and the conjunctiva of the lid. Insertion of the insert 12
into the eye can be satisfactorily accomplished by mounting or
grasping the device by means of a suitable holder, which optionally
may include a minute suction cup for engaging the outer surface of
the insert. The holder may be one of the several types commonly
used to insert and remove corneal contact lenses, artificial eyes,
and the like. Once in place, the ocular insert functions to
administer a metered amount of drug from the reservoir to the eye
and surrounding tissues over a prolonged period of time. The amount
and nature of the products which result when the hydrophobic
poly(carboxylic acid) bioerodes are such that they may be
innocuously passed from the eye either by discharge through the
punctum or by collecting at the junction of the eyelid from where
they may be easily periodically removed by wiping, for example.
FIGS. 3 to 5 inclusive, illustrate in diagrammatic cross-sectional
views, exemplary types of bioerodible drug dispensing ocular
inserts which employ the poly(carboxylic acids) in accord with this
invention. FIG. 3 illustrates generally, by reference numeral 20,
an embodiment of this invention wherein the bioerodible ocular
insert is comprised of a continuous matrix 22 formed of ionizable
hydrophobic poly(carboxylic acid) that has particles of drug 21
dispersed therethrough. When ocular device 20 is placed in the
environment of the eye, matrix 22 gradually bioerodes and releases
drug 21 to the eye and surrounding tissues.
The mechanism by which drug is released by the poly(carboxylic
acid) bodied devices of this invention offers distinct
advantages.
In general, when a body of erodible material having drug dispersed
therethrough is placed in the environment of the eye the following
release mechanisms can occur depending upon the nature of the
erodible material: if the erodible enclosing material is
hydrophilic, it will absorb tear liquid and swell. Drug can then
diffuse out through channels of absorbed tear fluids at rates which
are often uneven, unpredictable, difficult to control and highly
dependent upon the solubility of the drug in the tear fluids. If
the drug is soluble in tear fluids to an extent greater than about
50 parts per million weight, release is rapid and substantially
uncontrolled. If the erodible enclosing material is hydrophobic but
porous, it gives similar diffusion controlled rates, with the same
problems. If the enclosing material is hydrophobic and non-porous,
as are the certain poly(carboxylic acids) employed in the present
invention, the rate of drug release is controlled by the rate at
which the enclosing material (matrix 21 in FIG. 3) is eroded or
solubilized and enclosed drug (22 in FIG. 3) is uncovered. Such a
mechanism offers the advantages of being more easily controlled and
of providing a more uniform rate of drug release.
The poly(carboxylic acids) employed in the devices of this
invention have proven especially advantageous for
erosion-controlled release of drugs to the eye. Though not
understood with certainty and without intent to limit the scope of
this invention by theoretical considerations, it is believed that
the uniform and controllable rates of bioerosion observed when
devices comprising hydrophobic poly(carboxylic acids) having an
average of eight to 22 carbons for each ionizable acidic-carboxylic
hydrogen are placed in the eye are the result of a unique mating of
equilibriums inherent in the erosion of these poly(carboxylic
acids) with the dynamics of the environment of the eye.
As shown in General Formula I, the poly(carboxylic acids) of this
invention may be represented as: ##SPC9##
The carboxyl groups are weak acids which, in their unionized form,
are hydrophobic. When placed in tear fluid a portion of the
carboxyl groups ionize to yield hydrophilic ##SPC10##
groups and hydronium ions (H.sub.3 O.sup.+). As more of the
carboxyl groups in an initially hydrophobic polymer chain ionize,
the chain assumes an increasingly hydrophilic character and
eventually goes into solution in the tear fluid. This
solubilization by ionization occurs only on the outer surfaces of
the poly(carboxylic acid bodies). Even if minor amounts of tear
fluid do penetrate the surface of the bodies insignificant
ionization can occur there since the inner carboxyl groups, being
surrounded by an essentially organic medium exhibit a far higher
pKa than do the carboxyl groups on the surface which are in a more
aqueous medium.
The bioerosion by surface ionization is a reversible reaction, the
equilibrium of which is highly sensitive to pH, and thus, in the
environment of the eye, self-limiting. Tear fluids are only weakly
alkaline (pH 7.4 - 7.8), slightly buffered (26
meg/1HCO.sub.3.sup.-), of small volume (0.01 cc per eye) and flow
(16 percent replacement per minute) and, in the eye, poorly
stirred. Under these conditions when hydronium ions are generated,
they tend to cluster about the polymer body from which they were
generated, lower the pH in the area of the body, and prevent
further solubilization by ionization. Some of the clustered
hydronium ions gradually disperse or are consumed by the buffers in
the tear fluid and are replenished via further ionization. The
overall erosion rate which results, with the poly(carboxylic acids)
of this invention, is surprisingly slow, perfectly suited for
employment in bioerodible ocular devices such as device 20 designed
to release drugs over prolonged periods such as periods of from
about 8 hours to about 60 days.
The self-limiting pH control inherent with these certain
poly(carboxylic acids) offers the further advantage of preventing
the pH of the tear fluids from dropping, by reason of excess
hydronium ion release, to a level which would be irritating to the
tissues of the eye.
The exact rate of erosion is in part dependent upon the chemical
makeup of the poly(carboxylic acid). The more hydrophobic the poly
acid is, the greater the number of ionized carboxyl groups
necessary to solubilize it and the slower its erosion rate. Thus,
by changing the hydrophobicity of the certain polyacids as may be
done by varying their ratio of total carbon atoms to ionizable
carboxylic hydrogens within the range in accord with this
invention, the rate of erosion may be controlled.
The ocular insert as illustrated in FIG. 3 can be fabricated in any
convenient shape for comfortable retention in the sac of the eye.
Thus, the marginal outline of the ocular insert can be ellipsoid,
donut-shape, bean-shape, banana-shape, circular, rectangular, etc.
In cross-section, it can be doubly convex, concavo-convex,
rectangular, etc. as the ocular insert in use will tend to conform
to the configuration of the eye, the original cross-sectional shape
of the device is not of controlling importance. Dimensions of the
device can vary widely. The lower limit on the size of the device
is governed by the amount of the particular drug to be supplied to
the eye and surrounding tissues to elicit the desired pharmacologic
response, as well as by the smallest sized device which
conveniently can be inserted in the eye. The upper limit on the
size of the device is governed by the geometric space limitations
in the eye, consistent with comfortable retention of the ocular
insert. Satisfactory results can be obtained with an ocular device
for insertion in the sac of the eye of from 4 to 20 millimeters in
length, 1 to 12 millimeters in width, and 0.1 to 2 millimeters in
thickness. A preferred pattern of erosion and drug release results
when the thickness of the ocular device is substantially smaller
than the length or width of the device, preferably the width is
less than 10 percent of the length or width. With such a
configuration, an essentially constant surface area is presented
during erosion. Since erosion rate and drug release rate are
proportional to surface area, a constant, or zero order, rate of
drug release results. Exemplary shapes of such "zero order release
devices" would be an 8 mm disc and a 6 mm by 12 mm ellipsoid, each
punched out of 0.4 mm thick drug-containing poly(carboxylic acid)
sheet.
FIG. 4 illustrates, by reference numeral 30, an embodiment of this
invention with which a variable rate of drug release may be
achieved, wherein the bioerodible ocular insert is comprised of a
series of three concentric layers. The outer layer comprises a
matrix 22 of ionizable hydrophobic poly(carboxylic acid) of this
invention that has particles of drug 21 dispersed therethrough.
Matrix 22 erodes and releases drug 21 at a controlled rate over a
prolonged period, in the same manner that the matrix in device 20
released drug. When the outer layer comprising matrix 22 and drug
21 has eroded away, middle layer 31 is exposed, and begins to
erode. Layer 31 is formed from a bioerodible material, very
suitably either the same or different hydrophobic poly(carboxylic
acid) employed in matrix 22. Layer 31, as illustrated, contains no
drug and thus during the erosion provides a period where no drug
would be released. When layer 31 has been eroded the innermost
layer is exposed comprising ionizable hydrophobic poly(carboxylic
acid) matrix 22a that has particles of drug 21a dispersed
therethrough. As matrix 22a erodes, drug 21a is released at a
controlled rate for a prolonged period of time. Many variations of
the device of FIG. 4 will be apparent to those skilled in the art
of drug delivery. For example, a greater number of layers must be
employed, a variety of drugs or dosages may be employed in the
several layers, or poly acids having different erosion rates may be
used in different layers.
FIG. 5 illustrates, by reference numeral 40, an ocular insert
embodying this invention which demonstrates how several variables
may be manipulated to control the rate and period of drug release.
Ocular insert 40 comprises six layers, identified as layers A-F.
Layers A-E inclusive each comprise a matrix 22 of hydrophobic
poly(carboxylic acid) in accord with the present invention having
dispersed therethrough particles of drug 21. Layer F comprises a
slowly eroding poly(carboxylic acid) which contains no drug. The
rate of erosion of layer F is slow enough such that it will not be
eroded away until after the top six layers have disappeared. Thus
the erosion shall proceed sequentially, with layer A eroding first,
layer B eroding second, etc. The thickness, drug loading, expressed
in arbitrary "units", and the erosion rate expressed in mm of
thickness eroded per day, of the particular poly(carboxylic acid)
employed in each layer are given in the following Table 1.
TABLE 1
Characteristics of Device of FIG. 5
Rate of Drug Thickness, Erosion, Loading Layer mm mm per day
"Units" per mm
__________________________________________________________________________
A 0.04 0.04 100 B 0.02 0.02 200 C 0.06 0.06 67 D 0.04 0.02 200 E
0.04 0.02 200 F 0.01 0.001 0
__________________________________________________________________________
when device 40 is placed in the environment of the eye, layer A
first erodes, releasing 4 units of drug to the eye at a uniform
rate for a period of one day. Then layer B erodes. Although the
rate of erosion of layer B is half that of layer A, by making layer
B half as thick as layer B and by doubling the drug loading of
layer B, the same drug release rate and period as was obtained with
layer A, is achieved. The same release rate and period is obtained
when layer C erodes as it is made thicker and with a lower drug
loading to compensate for a faster erosion rate. Layer D, which is
the same as layer B except that it is twice as thick, releases drug
at the same rate as the prior layers but does so for a two day
period instead of for one day. Layer E, identical to layer A except
for a doubled drug loadng, releases drug for the same length of
time as layer A (1 day). but at twice the rate (8 units per
day).
Any of the drugs used to treat the eye and surrounding tissues can
be incorporated in the ocular insert of this invention. Also, it is
practical to use the eye and surrounding tissues as a point of
entry for systemic drugs or antigens that ultimately enter
circulation in the blood stream, or enter the nasopharyngeal area
by normal routes, and produce a pharmacological response at a site
remote from the point of application of the ocular insert. Thus,
drug or antigens which will pass through the eye or the tissue
surrounding the eye to the blood stream or to the nasal-pharyngeal,
esophageal or gastrointestinal areas, but which are not used in
therapy of the eye itself, can be incorporated in the ocular
insert.
Suitable drugs for use in therapy of the eye with the ocular insert
of this invention consistent with their known dosages and uses are
without limitation: antibiotics such as tetracycline,
chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,
oxytetracycline, chloramphenicol, gentamycin, and erythromycin;
antibacterials such as sulfonamides, sulfacetamide, sulfamethizole
and sulfisoxazole; antivirals including idoxuridine; and other
antibacterial agents such as nitrofurazone and sodium propionate;
antiallergenics such as antazoline, methapyriline,
chlorpheniramine, pyrilamine and prophenpyridamine;
anti-inflammatories such as hydrocortisone, hydrocortisone acetate,
dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,
prednisolone, methylprednisolone, predisolone 21-phosphate,
prednisolone acetate, fluoromethalone, 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.
Drugs can be in various forms, such as uncharged molecules,
components of molecular complexes, or non-irritating,
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulfate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, etc. For acidic drugs, salts of
metals, amines, or organic cations (e.g., quaternary ammonium
salts) can be employed. Furthermore, simple derivatives of the
drugs such as ethers, esters, amides, etc., which have desirable
characteristics, but which are easily hydrolized by body pH,
enzymes, etc., can be employed.
Ocular devices comprising the hydrophobic poly(carboxylic acids) of
this invention may be used to deliver drugs which are substantially
insoluble in water as well as those which are essentially
water-soluble. It is preferred, however, that the drugs employed in
the ocular devices of this invention not be highly water soluble.
Best results are obtained when the drugs are in a form which is not
soluble in tear fluids to an extent greater than about 20,000 ppm
by weight.
In accord with this invention, the ocular insert is intended to
provide a complete dosage regimen for eye therapy over this
prolonged period. Therefore, the amount of drug to be incorporated
in the device is determined by the fact that sufficient amounts of
drug must be present to maintain the desired dosage level over the
therapeutic treatment period. Typically, from 100 micrograms to
about 0.05 gram or more of drug is incorporated in the ocular
insert. The exact amount of course depends upon the drug used and
treatment period. Illustratively, in order to treat glaucoma in an
adult human, the daily release dosage should be in the range of
between 100 micrograms to 20,000 micrograms of pilocarpine per day.
Thus, for example, using pilocarpine with a device intended to
remain in place for 7 days, and with a release rate of 500
micrograms of drug per day, 3.5 milligrams of pilocarpine will be
incorporated in the device. Other devices containing different
amounts of drug for use for different time periods and releasing
drug at higher or lower controlled rates are also readily made by
the invention.
Further, in practicing this invention one can employ any of the
afore-listed drugs, consistent with their known dosages and uses,
to establish an optimum release rate. It has been found, however,
that the present continuous mode of administration surprisingly
operates to significantly improve the therapeutic efficacy when
compared with conventional treatments so that dosages may often be
significantly reduced. Exemplary of the dosages to be used with the
devices of the present invention are:
Antibiotics, such as polymixin: 200-4000 micrograms/insert/day
Antivirals, such as idoxuridene: 100-1000 micrograms/insert/day
Anti-inflammatories, such as hydrocortisone acetate 3000-60,000
micrograms/insert/day or prednisolone 3000-150,000 "
The amount of drug incorporated in devices in accord with this
invention can vary considerably depending upon the drug, its
dosage, and the length of time the device remains in the eye.
Generally, devices may contain up to about 50 percent by weight,
basis the poly(carboxylic acid) of drug, with drug loadings of from
about 0.01 to about 40 percent generally being preferred.
To provide compatibility with the eye and surrounding tissues, at
least for the initial period after insertion, the surface of the
ocular insert in contact with the eye can be coated with a thin
layer, e.g., from 1 to 2 microns thick, of bioerodible hydrophilic
material. Exemplary of the suitable materials for this purpose are
the water soluble hydrophilic polymers of vinyl alcohol and vinyl
pyrrolidone, gelatin, non-cross-linked polysaccharides, e.g., agar
and gum arabic, and the like.
The ocular inserts are suitably packaged using a drug and moisure
impermeable packaging material such as the foil-polylaminates,
e.g., aluminum foil-polyethylene laminate or aluminum
foil-polyester (Mylar)-laminate.
The ocular devices are preferably sterilized prior to insertion in
the eye. The sterilization can be effected prior to packaging or
after packaging. Suitable sterilization methods such as the use of
heat, radiation or ethylene oxide can be satisfactorily employed.
Details for these methods and other are set forth in Remington's
Pharmaceutical Sciences, Vol. XIV, 1970, pp. 1,501-1,518.
The rate of bioerosion and drug release of materials employed in
the invention can be determined experimentally in vitro by testing
them under simulated ocular environmental conditions. For example,
the rate of ocular bioerosion of a material may be measured by
placing a small weighed sample of the material in a 0.026 M
HCO.sub.3.sup.- solution of pH about 7.4 (simulated tear fluids) at
body temperature (37.degree.C), agitating for a timed interval, and
periodically measuring the amount of material eroded into the
solution. To accurately predict in vivo results, it is necessary to
multiply the in vitro rates by an experimentally determined
constant which takes into account differences in stirring rate and
eye fluid volumes between the eye and the in vitro test apparatus.
This constant may be derived by first placing a plurality of small
weighed samples of material in a plurality of eyes and
sequentially, over a period of time, removing and weighing the
samples. The rate thus determined, divided by the rate of erosion
observed in vitro with the same material, equals the necessary
constant.
For a more complete understanding of the nature of this invention,
reference should be made to the following examples which are given
merely as further illustrations of the invention, and are not to be
construed in a limiting sense. All parts are given by weight,
unless stated to the contrary.
EXAMPLE 1
A bioerodible ocular insert employing a hydrophobic poly(carboxylic
acid) having on an average from eight to 22 total carbon atoms for
each ionizable acidic carboxylic hydrogen and containing
hydrocortisone is prepared in the following manner.
A. Preparation of poly(carboxylic acid). 12.6 grams (0.10
equivalents) of ethylene-maleic anhydride copolymer (Monsanto EMA,
Grade 31) is stirred with 50 ml (0.4 moles) of n-hexyl alcohol at
120-125.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 vol. 3l). The precipitate is thoroughly leached with
the methylene chloride. The solvent is decanted and the product
dissolved in 75 ml warm acetone. Methylene chloride is added to the
cloud point. Then more methylene chloride is added to precipitate
the product (total vol. 2l ). The precipitate is then thoroughly
leached with the methylene chloride. The solvent is decanted and
the product dissolved in 75 ml acetone. The solution is transferred
to a polypropylene container and solvent is removed under vacuum at
50.degree.C to yield the polymer product. The infrared spectrum of
the polymer shows broad bands at 1,680 and 1,780 cm.sup.-.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. A
sample of the polymer is tested for hydrophobicity by measuring its
water absorption and is found to pick up only 6 percent by weight
of water.
B. Preparation of hydrocortisone-containing ocular insert.
1.8 Grams of the half ester polymer of part A is dissolved in 5 ml
of acetone, with stirring at 25.degree.C. 0.2 Grams of micronized
hydrocortisone are dispersed in the solution with stirring. The
resulting viscous dispersion is drawn on a polyethylene film to a
wet thickness of about 0.75 mm. The cast plate is allowed to dry
thoroughly to yield a 0.3 mm thick dry film. The resulting film is
removed from the polyethylene film by stripping, and is punchcut
into desired shapes and sizes. A 6 mm diameter circular disc weighs
7 mg and contains 0.7 mg of hydrocortisone.
C. Testing of inserts.
A series of 0.3 mm thick ocular inserts prepared in part B are each
placed in 60 ml portions of simulated tear fluids (water containing
0.1 moles of K.sub.2 HPO.sub.4 per liter and having a pH of 7.4)
and agitated at 37.degree.C for 40 minutes. Sequentially the ocular
inserts are retrieved, dried and weighed. The samples of simulated
tear fluids are analyzed by ultraviolet absorption at 248
millimicrons wave length for hydrocortisone content. The results of
these tests indicate that the inserts erode in this solution of
simulated tear fluids in 40 minutes at a uniform rate and that the
drug release parallels the erosion. The erosion rate in vitro could
be decreased almost 2 orders of magnitude by decreasing the buffer
concentration and the rate of stirring. The most reproducible
results are obtained at the buffer concentration and rapid stirring
rate employed. FIG. 6 illustrates by a graph drug release rates
observed when several series of these inserts are tested in
vitro.
A series of these ocular inserts are placed in rabbits' eyes, where
they exhibit a similarly uniform but slower rate of erosion and
drug release to that observed in the simulated (in vitro)
experiments. About 175+ hours are required for complete erosion.
The factor (In vivo)/(In vitro) equals 0.01. FIG. 7 illustrates by
a graph the linearity of the in vivo drug release as measured by
insert weight loss.
During the in vivo test, the rabbits are carefully watched for
evidence of ocular irritation. In accordance with the Draize method
of measuring ocular irritation, the following conditions are
watched for: hyperemia of the lids; hyperemia and chemosis of the
conjunctiva; tearing, and exudate from the conjunctiva. The
presence or absence of these conditions is indicated by assigning a
rating of 0, 1, 2, 3 or 4 to each eye examined for each of these
conditions. 0 means no evidence of the condition, 1 means very mild
presence of the condition, while 4 means serious irritation. A
total score is obtained for each eye, and an average for all eyes
is derived. An average rating of less than 2.5 is indication of
mild irritation at worst. An overall rating of 2.0 or less
indicates virtually no irritation.
The excellent irritation results achieved with the present
invention are as follows:
---------------------------------------------------------------------------
CONTROL EYES (No inserts)
Total Irritation Score Type of Number of Observations/ Total
Irritation Hour of Observation Mean 24 48 72 96 96
__________________________________________________________________________
Conjunctival hyperemia 2/4 0/1 -- -- -- 2/5=0.4 Conjunctival
chemosis 0/4 0/1 -- -- -- 0/5=0 Lid hyperemia 0/4 0/1 -- -- -- 0/5=
Tearing 0/4 0/1 -- -- -- 0/5=0 Exudate 0/4 0/1 -- -- -- 0/5=0
__________________________________________________________________________
TOTAL 2/4 0/1 -- -- -- 2/5=0.4
__________________________________________________________________________
---------------------------------------------------------------------------
TEST EYES (with inserts of Example I)
Conjunctival hyperemia 40/46 22/28 8/17 2/6 0/10 72/107=0.7
Conjunctival chemosis 6/46 0/28 0/17 0/6 0/10 6/107=0.1 Lid
hyperemia 2/46 14/28 6/17 4/6 12/10 38/107=0.4 Tearing 0/46 2/28
0/17 0/6 0/10 2/107=0.2 Exudate 20/46 12/28 4/17 0/6 8/10
44/107=0.4
__________________________________________________________________________
TOTAL 68/46 50/28 18/17 6/6 20/10 162/107=1.5
__________________________________________________________________________
EXAMPLES 2-6
The ocular insert preparation of Example 1, parts A and B, is
repeated 5 times with one variation. The molar excess of n-hexanol
employed in Example 1 is replaced with a similar amount of other
alkanols as follows:
Example Alkanol 2 n-butanol 3 n-pentanol 4 n-heptanol 5
n-octanol
The ratio of total carbon atoms to ionizable carboxylic hydrogens
in each of the resulting half esters is as follows:
Example Ratio: Carbons Ionizable Hydrogens 2 10 3 11 4 13 5 15 6
16
Water absorption tests show the products to be increasingly
hydrophobic, with the product of Example 2 giving the greatest
water pick up and the product of Example 6 giving the smallest
water pick up.
Erosion tests under the simultated conditions of Part C of Example
1 are carried out. Constant erosion rates and release rates are
noted for each of the materials. The results of these tests, as
well as the in vivo results which would be predicted using the
factor derived in Part C of Example 1 are as follows:
---------------------------------------------------------------------------
Time to Time to Completely Erode Completely Erode Example In Vitro,
min. In Vivo, hrs.
__________________________________________________________________________
2 10 10-15 3 20 30 4 50 90 5 300 550 6 450 800-900
__________________________________________________________________________
EXAMPLE 7
A. Preparation of Polymer
A mixture of 5 grams of poly(vinyl methyl ethermaleic anhydride)
1:1 molar ratio copolymer (GAF Corp. Gantrez AN 169) and 30 ml of
n-pentyl alcohol is stirred at 120.degree.C for 16 hours to yield a
viscous product. This product is poured into 500 ml of 2% Na.sub.2
CO.sub.3 solution. The resulting solution is extracted twice with
400 ml volumes of hexane and acidified to pH 1-2 with HCl. The
precipitated polymer is collected, washed with slightly acidulated
water and dried. The product is found to be the n-pentyl half ester
of maleic acid. The product is hydrophobic, exhibiting an
equilibrium water pick up of 9 percent by weight. It has an average
of 12 carbon atoms for each ionizable carboxylic hydrogen.
B. Preparation of Ocular Inserts
A 5 gram portion of the half ester product of part A is dissolved
in 10 grams of acetone with stirring. Micronized hydrocortisone
(0.5 grams) is added to the syrupy ethanol solution of ester. The
hydrocortisone does not dissolve in the ester solution but forms a
uniform suspension. The suspension is drawn to a wet thickness of
1.0 mm. on silicone release paper. The film is dried in moist air
at 25.degree.C for 72 hours and stripped from the release paper as
a cloudy film having a final dry thickness of 0.3 mm.
Although the film is somewhat brittle, it is easily punch-cut into
a variety of shapes suitable for ocular inserts including
ellipsoids and 6 mm diameter circles.
C. Testing of Inserts
The circular inserts are tested by the methods of Example 1 part C
to determine their rate of bioerosion and drug release. In the
simulated ocular environment the polymer erodes and releases its
drug at a constant rate for about 30 minutes when the final portion
of the device dissolves. When placed in rabbit eyes, the same
devices require about 20 hours to completely erode.
EXAMPLES 8 - 13
A. Preparation of Inserts
A series of ocular inserts are prepared using poly(carboxylic
acids) similar to that employed in Example 7. The poly acids
employed are the commercially-available half esters of poly(vinyl
methyl ether-maleic acid) marketed by GAF Corporation as Gantrez
ES-225 (the ethyl half ester), Gantrez ES-335 I (the isopropyl half
ester) and Gantrez ES-425 (the n-butyl half ester).
The ocular insert production method of part B of Example 7 is
repeated using these polymers and as drug, hydrocortisone,
pilocarpine hydrochloride and chloroamphenicol. Hydrocortisone
yields suspensions in the polymers while chloroamphenicol and
pilocarpine dissolve in the polymer at this drug loading (10
percent). The poly(carboxylic acid) drug ocular insert combinations
produced in these Examples were as follows:
---------------------------------------------------------------------------
Drug Poly(carboxylic Drug and amount, thickness Example acid) %,
Basis Polymer of Insert, microns
__________________________________________________________________________
8 Ethyl ester hydrocortisone 300 10% 9 isopropyl ester
hydrocortisone 300 10% 10 butyl ester hydrocortisone 300 10% 11
butyl ester hydrocortisone 300 5% 12 butyl ester pilocarpine hy-
300 drochloride 10% 13 butyl ester chloroamphenicol 300 10%
__________________________________________________________________________
B. Testing of Inserts
The inserts of Part A are tested for bioerosion and drug release
rate by the simulated ocular environment method of Example 1. In
accord with the results observed in Example 7, smooth rates of
erosion and constant, essentially zero order rates of drug release
are noted with the inserts of Examples 8-13 inclusive.
The results of the tests of inserts of Examples 8-13 are as
follows:
---------------------------------------------------------------------------
In vitro Time to complete erosion rate, erosion in the eye, Example
microns/minute hours
__________________________________________________________________________
8 120 3 9 100 4 10 60 8 11 60 8 12 60 8 13 60 8
__________________________________________________________________________
It should be noted that the rates of erosion of the inserts of
Examples 8, 9 and 10 decrease as the hydrophobicity of the polymer
increases. Also by comparing the erosion rate of the insert of
Example 10 with that of the insert of Example 11, it is seen that
rate of erosion is independent of drug loading. The rate of release
of highly water-soluble pilocarpine hydrochloride is substantially
the same with the insert of Example 12 as are the rates of release
of less soluble drugs from the inserts of Examples 10 and 13.
During the in vivo test of the material of Example 8, some edema is
noted as a result of the amount of the acidity generated by the
rapid ionization of the polymer. No serious ocular damage is noted,
however.
EXAMPLE 14
The preparation of the ocular insert of Example 7 is repeated with
one modification. Instead of a 1 mm wet thickness film, a 2 mm wet
thickness film is produced which gave a dry film with a thickness
of about 0.6 mm. When placed in the simulated ocular environment it
requires about 60 minutes to erode.
EXAMPLES 15 - 17
The preparation of the ocular inserts of Example 7 is repeated with
one modification. Plasticizers are added to the casting solution
and a thicker film is cast to compensate. The plasticizers improve
the flexibility of the films, as expected. They do not seriously
interfere with the erosion of the polymer or the controlled release
of drug.
The plasticizers and the amounts added are as follows:
---------------------------------------------------------------------------
Average Release Rate Example Plasticizer mg/hour
__________________________________________________________________________
15 dodecanol 5% 16 *acetal tri n-butyl 5% citrite 17 " 10%
__________________________________________________________________________
*Charles Pfizer and Son -- Brand name "Citroflex A-4."
EXAMPLE 18
The polymer preparation of Example 7, part A, is repeated with one
variation--2-pentanol was substituted for n-pentanol. The rate of
esterification is somewhat slower so the reaction is continued for
about 60 hours. The resulting polymer is blended with
hydrocortisone and formed into ocular inserts which yield similar
erosion and drug release to those observed in Example 7.
EXAMPLE 19
The polymer preparation of Example 7 is repeated employing as
esterifying alcohol 5 ml of n-octanol per gram of Gantrez Brand AN
169 methyl vinyl ether maleic anhydride. The reaction period is 22
hours. The half ester is precipitated in a large volume of
petroleum ether and then washed.
EXAMPLE 20
The polymer preparation of Example 19 is repeated employing as
methyl vinyl ether maleic anhydride polymer a material marketed by
GAF Corporation as GantreZ AN 119. The Gantrez AN 119 is a low
molecular weight material having a specific viscosity of 0.1-0.5.
The Gantrez AN 169, as employed in Example 19, was a high molecular
weight material having a specific viscosity of 2.6-3.5. Four ml of
octanol is employed per gram of anhydride. The reaction period is
26 hours. The product does not precipitate from petroleum ether but
is separated when the excess n-octanol is evaporated off.
The product of this Example and the product of Example 19 are
tested for water pick-up. Both are hydrophobic.
Inserts are prepared by adding 10 percent (basis polymer) of
hydrocortisone acetate to each polymer in ethanol solutions,
casting 1.0 mm films, drying, and stripping the films and
punch-cutting 6 mm diameter circular ocular inserts from the
films.
The erosion and drug release rates of these inserts are measured in
a sophisticated simultated ocular environment. The inserts are
placed in small net bags and suspended in isothermal 37.degree.C
chambers of circulating synthetic tear fluids, the dissolved
polymer and drug content of the tear fluids are continuously
monitored by an ultraviolet absorbance technique. The insert made
with high molecular weight polymer erodes at a uniform rate over
31/2 hours. The low molecular weight polymer insert erodes somewhat
faster (3 hours to total erosion) but never-the-less at a uniform
smooth rate. Drug release follows erosion with both inserts. An
earlier experiment has determined the (In Vivo)/(In Vitro) factor
for this new apparatus to be 0.01. Thus, these two inserts would be
expected to erode in the eye over periods of about 350 hours and
about 300 hours respectively.
EXAMPLE 21 - 22
A. Preparation of Half Esters of N-Vinyl Pyrrolidine-Maleic
Anhydride Copolymers
A mixture of 11.6 g (0.118 mole) of maleic anhydride (Aldrich
Chemical Co.), 12.7 ml (0.121 mole) of N-vinyl pyrrolidone (Aldrich
Chemical Co), 0.12 g bis- azodiisobutyronitrile and 140 ml benzene
is stirred under dry nitrogen at 60.degree.C for 42 hours. The
mixture is cooled to room temperature and the product 17.3 g (71
percent) collected by filtration and characterized as follows: mp
260-270.degree.C: .lambda. KBr max 1,680, 1,780, 1,850
cm.sup.-.sup.1 ; soluble H.sub.2 O, DMF; insoluble CH.sub.3 OH,
acetone.
The n-hexyl and n-decyl half esters of the poly N-vinyl
pyrrolidone-maleic anhydride copolymer are prepared according to
the procedure for the preparation of the half esters of (methyl
vinyl either-maleic anhydride) copolymer given in Part A of Example
7. Both materials are hydrophobic.
B. Production of Inserts
Hydrocortisone (10 percent, basis polymer) is added to the polymer
and the mixture formed into a viscous solution in acetone. This
solution is cast into a 1.0 mm thick film which is dried, recovered
and punch-cut into shapes suitable for ocular inserts.
C. Testing
The inserts of Part B are tested in the simulated ocular
environment described in Example 1. The n-hexyl half ester insert
bioerodes and releases drug at a constant rate over a 20-minute
period. The n-decyl ester insert bioerodes in about 20+ hours.
EXAMPLE 23
A. Preparation of N-Butyl Acrylate-Methacrylic Acid Copolymer
A solution of 14.4 ml (0.10 mole) of n-butyl acrylate, 8.51 ml
(0.10 mole) of methacrylic acid, 0.10 g of benzoyl peroxide, and 50
ml of ethanol is stirred under nitrogen at 50 - 53.degree.C for 27
hours. The product is isolated by precipitation into petroleum
ether and triturated with ethyl ether.
B. Preparation of Inserts
In a stirred flask, polymer product of part A and 10 percent of
hydrocortisone are blended. The mixture is cast and formed into 0.3
mm. thick inserts in accord with the procedures of Example 1 part
B.
C. Testing of Inserts
The inserts are tested in the simulated ocular enviroment of
Example 20 and found to bioerode and deliver drug at a constant
rate over a period of 70 minutes.
EXAMPLE 24
A. Preparation of N-Butyl Acrylate-Acrylic Acid Copolymer
A solution of 14.4 ml (0.10 mole) of n-butyl acrylate, 6.85 ml
(0.10 mole) of acrylic acid, 0.10 g benzoyl peroxide, and 50 ml
ethanol is stirred under nitrogen at 48 to 52.degree.C for 40
hours. The product is isolated by precipitation into petroleum
ether.
B. Insert Production
In acetone, polymer product of part A and 10 percent of
hydrocortisone are blended. The mixture is cast and formed into
inserts in accord with the procedures of Example 1, Part B. The
final inserts are 0.3 mm. thick.
C. Testing of Inserts
The inserts of Part B are tested in the simulated ocular
environment test of Example 1, and found to give a uniform rate of
erosion and drug release, eroding over a period of 15 minutes.
EXAMPLES 25 - 27
The preparation and simulated environment testing of inserts in
accord with Example 24 is repeated 3 times, varying the drug
content of the inserts, with the following in vitro results:
---------------------------------------------------------------------------
Example Hydrocortisone, % Erosion time, minutes
__________________________________________________________________________
25 2% 15 26 25% 15 27 40% 25
__________________________________________________________________________
The slower erosion of the product of Example 27 is probably due to
the large amount of drug interfering with the erosion process.
EXAMPLE 28
The preparation and simulated environment testing of inserts in
accord with Example 24 is repeated substituting 20 percent by
weight tetracycline hydrochloride as drug. 12 mm by 7 mm oval
inserts 0.3 mm. thick are prepared which give a linear drug release
in vitro over a period of 35 minutes at which time they are
completely eroded.
EXAMPLE 29
A. Preparation of Polymer
The preparation of Example 7, part A, is repeated with one
modification. Instead of 30 ml of n-pentyl alcohol, 30 ml of a
50:50 mole mixture of n-pentyl alcohol and n-hexyl alcohol is used.
The resulting ester product is hydrophobic and contains an average
10.5 carbon atoms for each ionizable carboxylic hydrogen.
B. Preparation of Inserts
Drug-containing ocular inserts are prepared in accord with Part B
of Example 7.
C. Testing of Inserts
The inserts are tested by the method of Example 1, part C. In the
simulated ocular environment they give a linear drug release and
erosion. In 45 minutes the insert is completely eroded and has
completely released its drug load.
EXAMPLE 30
A. Preparation of Polymer
one hundred grams of benzene, 10.4 grams of styrene and 10.0 grams
of maleic anhydride are stirred in the presence of 0.1 grams of
bis-azodiisobutyronitrile at 70.degree.C overnight. The mixture is
cooled and the product is separated by filtration and washed.
Characterization and analysis shows that it is the 1:1 mole ratio
copolymer of styrene and maleic anhydride. Ten grams of this
polymer is refluxed in ethanol for 10 hours to yield a viscous
product. Analysis shows the product to be the ethyl half ester of
styrene-maleic acid copolymer, a product which is hydrophobic and
has an average of 14 carbon atoms for each ionizable acidic
carboxylic hydrogen.
B. Preparation of Ocular Inserts
Ten percent by weight hydrocortisone ocular inserts are prepared by
the casting method of Example 7, part B. Acetone is used as solvent
for the casting solution. The finished inserts are 0.5 mm
thick.
C. Testing of Inserts
The inserts of part B are tested by the method of Example 1, part C
and found to give a linear erosion and drug release.
EXAMPLE 31
A. Preparation of Polymer
The preparation of polymer of Example 3 is repeated with one
variation; instead of an excess of pentanol only 0.8 moles of
pentanol per mole of anhydride copolymer is employed. After all the
added alcohol has reacted, 0.2 moles of water is added and the
mixture is stirred until the remaining anhydride groups have been
converted to diacids. The resulting polymer contains 40 percent of
its original anhydride groups as esters and the remaining 60
percent as acids. The product is hydrophobic.
B. Preparation of Inserts
Ocular inserts containing 10 percent by weight of hydrocortisone
acetate are prepared in accord with the method of Example 1.
C. Testing of Inserts
The inserts of part B are hydrophobic. When tested in the simulated
ocular environment test described in Example 1, they give an
essentially constant rate of drug release over a period of 10
minutes.
EXAMPLE 32
A. Preparation of Polymer
The preparation of polymer of Example 1 is repeated with the
variation that instead of an excess n-hexanol, 1.2 moles of hexanol
per mole of anhydride, is employed. One drop of H.sub.2 SO.sub.4 is
added to catalyze the reaction of the alcohol with the anhydride
and cause all the alcohol to react. The resulting product contains
60 percent of its carboxyls as esters and 40 percent as acids. The
ratio of total carbon atoms to carboxylic hydrogens is 16.5:1.
B. Production of Inserts
Ocular inserts containing 10 percent by weight of hydrocortisone
acetate are prepared in accord with the method of Example 1.
C. Testing of Inserts
The inserts of part B are hydrophobic. They erode and release drug
in the in vitro test of Example 1 part C at a uniform rate over a
period of 65 minutes.
EXAMPLES 33 - 34
Two 25.2 gram portions of ethylene maleic anhydride copolymers
(Monsanto EMA, Grade 31) are each dissolved in acetone. To one
portion is added 20 grams of water and the mixture is warmed for 4
hours to yield a fully hydrolyzed ethylene-maleic acid copolymer
having a (total carbon)/(carboxylic hydrogen) ratio of 3. To the
other portion is added 6.2 grams of absolute methanol. The mixture
is refluxed for 10 hours. Titration analysis indicates that the
original maleic anhydride groups are present in the form of methyl
half esters. Thus the (total carbon)/(carboxylic hydrogen) ratio is
about 7. Prior to preparing drug containing ocular inserts of
either of these materials, films of the polymers themselves are
tested in the simulated ocular environment. Both prove to be
substantially hydrophillic and to erode essentially
uncontrollably.
* * * * *