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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)
Appl. No.: 05/318,891
Filed: December 27, 1972


Current U.S. Class: 424/428
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

U.S. Patent Documents
3143472 August 1964 Lappas et al.
3608063 September 1971 Banker
3629392 December 1971 Banker
3618604 November 1971 Ness
2935449 May 1960 Bavley
3279996 October 1966 Long, Jr. et al.
3551556 December 1970 Kliment et al.
R27401 June 1972 Wichterle et al.
3674902 July 1972 Kalopissis
3630200 December 1971 Higuchi
3710795 January 1973 Higuchi
3737521 June 1973 Born

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.

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