JPS5820930B2 - Method for manufacturing biodegradable ophthalmic devices - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a device for administering drugs to the eye at a continuous and controlled rate over an extended period of time.
e).

More particularly, the present invention relates to drug-containing inserts that are biodegradable in the periphery of the eye, either simultaneously with drug delivery or at some appropriate time after the desired amount of drug has been delivered.

Currently, eye diseases are treated by the administration of eye medications in the form of liquids or ointments.

In many cases, ophthalmic drugs must be used constantly to be properly effective.

Such continuous delivery of drugs, even if administered at intervals throughout the day and night, is impossible to achieve with liquid or ointment drug dosage forms.

With this type of interspaced administration of drugs, a large, unpredictable amount of drug is given to the eye at once at the time of administration, and this is rapidly flushed out with tears, effectively leaving the eye with no fluid until the next dose. He is not receiving any medication.

When the amount of drug in the eye and its surrounding tissues is plotted against time when a typical ocular drug dosage form is administered, there are peaks above the drug's toxicity threshold and peaks below the critical concentration required to achieve the desired therapeutic effect. The valleys that fell into the sky appear alternately.

Continuous administration, which avoids this peak and trough effect, has very important therapeutic benefits, especially in certain eye diseases where there is a constant deterioration phenomenon, such as glaucoma.

Moreover, the ointment forms currently in use are largely not sterile and are generally difficult to use without obstructing vision.

At the end of the last century, it was proposed to use water-soluble drug-containing gels of glycerinated gelatin formed into thin films or discs.

Films of this type are applied to the eye to deliver drugs to the eye.

However, when used, the glycerinated gelatin carrier dissolves very rapidly in the lachrymal fluid and is only as effective as using a liquid dosage form.

In other words, this type of plate-like material is not suitable for maintaining continuous drug release for a long period of time.

In view of the above-mentioned drawbacks of conventional dosage forms, ocular inserts for drug administration have recently been devised that, when placed around the eye, gradually release the drug into the eye over a long period of time.

For example, US Pat. No. 3,416,530 (Ness;
Registered on December 17, 1968, name: "Tablet for ocular medication"), US Patent No. 3,618,604 (Ness;
Registered on November 9, 1971, name: "Eye Insert").

All of the ocular inserts disclosed in this patent are inserted around the eye and are molded from materials that are insoluble in lacrimal fluid.

This type of insert has been inserted into the upper or lower cul-de-sac of the eye.

It is sandwiched between the surface of the bulbar sclera and the palpebral conjunctiva, maintains its position and shape, and acts as a reservoir that constantly releases drugs into the eye at a constant rate.

Devices of this type enable controlled and continuous release of drugs and offer multiple benefits.

However, the problem with this insert is that it is insoluble in the intraocular environment and must be removed at the end of treatment, which is often difficult and undesirable for the patient.

Occasionally, the insert may migrate unexpectedly into the upper fornix, making removal difficult and causing it to remain in place long after all of the drug has been released into the eye.

Furthermore, in ophthalmology, there is insufficient contact between doctors and patients, and there is no guarantee that medication instructions will be accurately carried out by patients.

That is, if an insoluble insert is used, the likelihood that the patient will remove the insert on a schedule is very slim.

It is true, especially in elderly patients, that they often forget or are unable to remove the insert due to memory or vision loss.

Accordingly, a primary object of the present invention is an insert for the controlled and continuous administration of drug to the eye over a long period of time, which does not require removal from the eye after completion of treatment with Progera. It is an object of the present invention to provide a method of manufacturing an improved drug delivery ophthalmic insert.

Briefly, the present invention provides a biodegradable ophthalmic device for continuously administering a predetermined dose of a drug to the eye, said device comprising one or more reservoirs, said device comprising one or more reservoirs; Each reservoir encapsulates the prescribed drug within a biodegradable drug release rate controlling material that continuously regulates the flow of a therapeutically effective amount of drug from the reservoir to the eye at a controlled rate over an extended period of time. The device is biodegradable simultaneously with or at an appropriate time after delivery of the therapeutically desired amount of drug, is of a manipulable size, and is capable of disintegrating into the bulbous conjunctival surface of the cul-de-sac of the eye, i.e., the bulbar sclera. It has an initial shape suitable for insertion and retention in the pouch surrounded by the palpebral conjunctiva.

One embodiment of the device according to the present invention comprises a body encapsulating a drug made of a biodegradable drug release rate modulating substance, the body having a size and size suitable for insertion and retention in the cul-de-sac of the eye. having an initial shape and constantly regulating the flow of a therapeutically effective amount of drug to the eye at a controlled rate over an extended period of time, simultaneously with delivery of a predetermined dose of drug, or at an appropriate time after delivery has ended. There are ocular inserts for the controlled and continuous administration of a predetermined dose of drug to the eye over an extended period of time which biodegrades in the periphery of the eye at certain times.

Another embodiment comprises a plurality of reservoirs, each reservoir comprising a drug encapsulated in a biodegradable microcapsule of a release rate controlling material, the microcapsules comprising a biodegradable matrix. The rate of drug permeation through the matrix material is greater than the rate of permeation through the microcapsules comprising the rate regulating material, and the rate regulating material that makes up the microcapsules can be administered to the eye at a controlled rate over an extended period of time. The body of the matrix material has an initial shape suitable for insertion and retention within the cul-de-sac of the eye, and the microcapsules and matrix deliver the therapeutically desired amount of the drug. There are ocular inserts that biodegrade in the intraocular environment either simultaneously or at some appropriate time after the supply has ended.

Such devices disperse a predetermined amount of the drug to be administered to the eye throughout a body of hydrophobic, biodegradable, drug release rate controlling material, and transfer this dispersion to the surface of the bulbar conjunctiva of the sclera of the eyeball and the eyelid. It is manufactured by molding it into a shape suitable for insertion into the cul-de-sac of the eye, which is surrounded by the surface of the conjunctiva, and keeping it there for at least 8 hours.

The features and advantages of the invention will become more precise from the following detailed description of the invention and the drawings.

As used herein, the term "biodegradable" means
Depending on the unit structure or essence, over a long period of time, depending on the peripheral area of the eye, one or more physical or chemical degradation processes, such as enzymatic action, oxidation or reduction, hydrolysis (proteolysis), Disintegrate or disrupt harmlessly by displacement, e.g. by ion exchange, or by solubilization, emulsification or micelle formation, and then be absorbed by the eye and its surrounding tissues or otherwise washed away from the orbit with lacrimal fluid. It can be defined as the properties of substances that form such products.

As used herein, the term "long term" means
Both mean a time interval of 8 hours to approximately 30 days or more, with 1 to 8 days being preferred.

This period is used for the period of drug release as well as for the period of biodegradation of the insert in the intraocular environment, but it is not necessary that the rain periods always begin and end at the same time.

Particularly referring to FIGS. 1 and 2, the human eye is composed of an eyeball 1 and upper and lower eyelids 2 and 3, respectively. is covered by the cornea 5.

The eyelids 2 and 3 are bordered by an epithelial membrane or palpebral conjunctiva.

The sclera 4 is also bordered by an epithelial membrane or bulbar conjunctiva;
The bulbous conjunctiva covers the exposed part of the eyelid, including the cornea 5, and is transparent in the part covering the cornea.

The area between the palpebral conjunctiva that borders the upper eyelid 2 and the bulbar conjunctiva below it is defined as the upper cul-de-sac 7, and the space between the palpebral conjunctiva that borders the lower eyelid 3 and the bulbar conjunctiva below it is defined as the lower cul-de-sac 11. do.

Upper and lower hairs are marked 8 and 9, respectively.

Other parts of the eyeball 1 are omitted because they are not directly related to the structure of the present invention.

The ocular insert 12 is shown in its used position in the lower cul-de-sac 11 of the eye.

The ocular insert of the present invention may be placed in either the upper cul-de-sac 7 or the lower cul-de-sac 11, but it may be preferable to place it in the lower cul-de-sac.

This is because the eyes tend to move upward during sleep, known as the Be1l phenomenon, and some patients complain of discomfort when the insert is placed in the upper cul-de-sac 7.

Insertion of the ocular insert continuously releases a controlled amount of drug into the eye and surrounding tissues over an extended period of time.

After release from the ocular insert, the drug moves into the eye and surrounding tissues, including the corneal epithelium, by tear flow and by blinking of the eyelids.

The release of this drug is primarily carried out by the following transport mechanism.

(1) effusion-controlled release: i.e., the rate of release of the drug from the insert is regulated by the rate of diffusion of the drug determined by the rate-modulating substance of the insert, and/or (
2) Disintegration controlled release: ie, the rate of drug release from the insert is regulated by the rate at which the modulating substance disintegrates in response to the effects of the intraocular environment, liberating the drug contained therein.

Regarding the mechanism (1) mentioned above, namely exudation-controlled release,
The rate modulating material may be non-permeable or microporous.

That is, the outflow of the drug is carried out by molecular dispersion in the case of a rate regulating substance without seepage pores, and by viscous diffusion flow in the case of a microporous rate regulating substance according to permeation of the intraocular secretion fluid.

Both forms of drug transfer are contemplated by the present invention.

Furthermore, hydrophilic substances that initially have no exudation pores but swell in the intraocular environment and assume a microporous structure are also included in microporous substances.

Any substance that has the ability to modulate the release rate of a drug over an extended period of time by either of the above mechanisms or by a combination of both of the above mechanisms is a "drug release rate modulating substance."

The ocular drug delivery device of the present invention has significant advantages over previously known methods for administering drugs to the eye.

One of the important advantages of the device of the present invention is that it provides continuous drug delivery over an extended period of time, and because the device is biodegradable, it can be removed from the patient's eye after the treatment program is completed. There is no need to remove it.

Thus, with the device of the invention, continuous administration can be achieved without the disadvantage of having to remove the ocular insert from the eye after use.

Furthermore, the risk of the patient not following medication instructions regarding removal of the ocular insert is also avoided.

Another important advantage of the device of the invention is the ability to achieve zero-order (constant) drug release rates.

That is, the rate of drug release is constant throughout most of the drug administration period, substantially independent of time.

The fact that the drug is always used at a substantially constant dosage rate greatly increases the therapeutic benefits.

The ocular insert must be constructed in a configuration that allows it to be held comfortably within the cul-de-sac of the eye.

That is, the outline of the eye insert can be oval, donut-shaped, summer-shaped, banana-shaped, circular, etc.

Shapes with sharp corners should be avoided.

The cross section of the ocular insert can be biconvex, one side concave and one side convex, rectangular, etc.

The initial cross-sectional shape of the device is not a critical issue since the ocular insert may be flexible and deform to conform to the anatomy of the eye during use.

The device must be large enough to be handled by hand.

That is, it must be large enough to be inserted manually into the cul-de-sac of the eye.

The lower limit of device size is governed by the amount of specific drug delivered to the eye and surrounding tissues to achieve the desired pharmacological effect, and the upper limit of device size is to hold the ocular insert without discomfort. Therefore, it is governed by the limits of the geometric space inside the eye.

The ophthalmic device inserted into the cul-de-sac of the eye has a length of 4 to 20 mm.
Satisfactory results can be obtained with a width of 1 mm to 12 mtn and a thickness of 0.1 to 2 mm.

Best results are 4 to 10 mm long and 2 to 8 m wide.
m and a thickness of 0.1 to 1.5 mm.

Embodiments of this insert are illustrated in FIGS. 3 and 4.

One embodiment of the invention is an ocular insert comprising: (1) an internal reservoir containing a drug; and (2) an adventitia comprised of a drug release rate-modulating disintegrating material surrounding the internal reservoir.

Although this membrane is permeable to the drug, its rate of permeation is lower than that of the internal reservoir, and the initial size and shape of the insert is suitable for insertion and retention within the cul-de-sac of the eye; The insert continuously regulates the flow of a therapeutically effective amount of drug from the reservoir into the eye at a controlled rate over an extended period of time; It biodecays at the same time or at an appropriate time after supply.

In this insert, the internal reservoir can be a drug, a drug formulation, or a drug encapsulated in a biodegradable internal matrix.

Surrounding the internal reservoir is a biodegradable drug release rate controlling outer membrane.

This type of insert can be applied to release the drug in a zero-order manner, ie at a constant rate over an extended period of time.

By designing and selecting appropriate materials, drug release from the device is preferably achieved first by an "exudation-controlled release mechanism", with controlled drug release through the adventitia, followed by dissolution of the drug by lachrymal fluid and eyelid release. A continuous process combined with the action of blinking results in the transport of drug from the outer adventitial surface to the eye and surrounding tissues.

Another embodiment of the present invention includes a main body composed of a biodegradable drug release rate controlling substance encapsulating a drug, the initial size and shape of the main body being inserted and retained within the cul-de-sac of the eye. The body continuously regulates the flow of a therapeutically effective amount of drug into the eye at a controlled rate over an extended period of time, and the body continuously regulates the delivery of the therapeutically desired amount of drug in the intraocular environment. There are ocular inserts for continuously administering a predetermined dose of drug to the eye at a controlled rate over an extended period of time, which biodisintegrates at the same time or at an appropriate time after the end of delivery.

FIG. 3 illustrates one embodiment of this type of ocular insert, in which the device 50 is a microporous solid or gel-like biodegradable,
It is constructed with a body consisting of a drug release rate adjusting matrix material 51 through which the drug 21 is dispersed.

The matrix material 51 simultaneously functions as a drug reservoir and continuously delivers a controlled amount of drug to the eye and surrounding tissues over an extended period of time using the mechanisms described above, i.e. (1) an exudation controlled release mechanism and/or (2) It functions to release by a decay-controlled release mechanism.

The actual regulation mechanism depends on the design of the insert, particularly the choice of drug and release rate modifier.

The following are general considerations for proper design of ocular inserts, particularly for the administration of water-soluble drugs.

The term "water-soluble" as used herein refers to a substance that dissolves in water at a rate of about 50 ppm or more.

The best results are obtained when the drug to be released is not water soluble and when the drug is water soluble and the drug release rate modulating substance is substantially water valve permeable (hydrophobic).

A satisfactory device is one in which drug release from the device to the eye is achieved by the delivery mechanisms described in (1) or (2) above, or a combination of both.

The actual mode of drug delivery will depend on factors such as whether the drug is soluble or insoluble in the rate-controlling matrix material, and the type of disruption of the matrix material, such as surface disruption.

On the other hand, it is not preferred to use highly water-permeable release rate controlling matrix materials, such as hydrophilic materials, to provide water-soluble drugs.

The rate of drug release in this combination is governed by the simple rate of dissolution of the drug into lachrymal fluid, with neither rate control nor sustained release possible.

Therefore, in such cases, it is preferable to convert the drug into an insoluble form.

Insolubilization of drugs can be achieved in many ways. For example, a drug can be made into a water-insoluble, pharmaceutically acceptable derivative.

Derivatives of this type can be prepared by known techniques, which can also be applied in the practice of the present invention.

Of course, such drug derivatives must be capable of being converted into active drugs in the body by the action of endogenous enzymes, auxiliary conversion, pH 1 specific organ activity, etc.

Alternatively, insolubilization of the drug can be achieved by coating the drug, such as by microencapsulating it with an insoluble material.

That is, in the type of device shown in FIG. 3, if the drug is water-soluble and the rate-adjusting matrix material is water-permeable, it is also preferable to insolubilize the drug by microencapsulation.

A method of microencapsulating a drug to reduce its solubility and the materials used therein will be described below in connection with the reservoir in FIG.

Although the microencapsulation methods, structures, and materials described therein are suitable for encapsulating drugs in embodiments of the type illustrated in FIG. 3, the microencapsulation materials in the device of FIG. It does not provide a process for controlling the rate of release from the device as in .

Another embodiment of the invention is illustrated in FIG.

This embodiment of the ocular insert comprises a plurality of reservoirs, each reservoir comprising a drug encapsulated in microcapsules of biodegradable drug release rate modulating material.

The reservoir is dispersed in a biodegradable matrix that allows the drug to pass through the drug release rate modifier at a higher rate than through the drug release rate modifier, so that the release rate modifier only provides a controlled rate over an extended period of time. regulating the delivery of a therapeutically effective amount of the drug from the reservoir to the eye.

The initial shape of the insert is suitable for insertion and retention within the cul-de-sac of the eye.

The reservoir and matrix are biodisintegrated in the intraocular environment and removed from the orbit through the blind spot.

This removal process occurs simultaneously with or at some appropriate time after the therapeutically desired amount of drug is delivered.

FIG. 4 illustrates an insert 60 of the present invention, particularly an insert suitable for administering a water-soluble drug 64. As shown in FIG.

The drug delivery device 60 consists of a biodegradable matrix 62 with a plurality of reservoirs 61 dispersed therein.

Reservoir 61 is a microcapsule in which the drug is encapsulated in a drug release rate modulating material, either as a solid, liquid, or as a mixture with a carrier.

Drug molecules are released from reservoir 61 into matrix 62 and then travel through matrix 62 to administer the drug to the eye.

The release of the drug from the reservoir becomes a rate regulating process for the release of the drug from the device.

Structurally, the device can be considered a single unit device consisting of two structures that work together to deliver the active agent to the eye.

One structure is a storage part 61, that is, a microcapsule made of fine particles that is a drug release rate adjusting substance that encapsulates a drug 64, and the other structure has a storage part built in and is made of a substance permeable to the drug. A biodegradable matrix 62 is formed.

The storage section 61 is formed as a hollow container in which a medicine is sealed.

This may be a solid particle with the drug distributed therein, or it may have a porous structure.

Tuning the structure of the reservoir of this embodiment allows for controlled release, including zero-order release.

Suitable materials for forming the reservoir 61, whether hollow, solid, porous or semi-porous, are natural or synthetic materials, non-toxic and have low solubility in water. Those with high or low dispersibility are preferred.

This property is generally possessed by hydrophobic substances.

The rate controlling material used to form reservoir 61 must be biodegradable.

In some cases, microcapsules of suitable size (eg, 100 microns or less) can be flushed out of the eye socket through the blind spot, but this method of removal is less preferred than the biodisintegration method.

Suitable materials for making microcapsules large enough to pass through the blind spot include hydrophobic polymers such as polyvinyl chloride and silicone rubber, C1o to C20 fatty acids, and certain hydrophilic polymers.

Biodegradable materials suitable for preparing microcapsules are discussed below.

In practice, substances are used that reduce the rate of release of water-soluble drugs to the desired level.

Hydrophobic substances are preferred.

Other factors that must be considered in determining the rate of drug release from microcapsules include microcapsule size, wall thickness, and drug concentration.

As a qualitative guideline in this regard, it can be said that as the values of each of the above parameters increase, the rate of drug release decreases.

A typical drug and coating combination includes coating 100 micron chloramphenicol particles with polyacetic acid to a thickness of 3 microns.

Microcapsules of this type are suitably dispersed in a cross-linked gelatin matrix.

If desired, drug carrier particles such as starch, gum acacia, charcoal, gum tragacanth, calcium carbonate, polyvinyl chloride, etc. can be used in combination with the drug in the microcapsules.

Any standard encapsulation or impregnation method known in the art can be used to prepare the microcapsules 61 to be encapsulated in the matrix 62 according to the present invention.

The drug can be added to the encapsulating agent as particles or liquid, and when the drug is in liquid or particulate form, the mixture is made into minute microcapsules by a method such as crushing.

Alternatively, small particles or solutions of the drug may be prepared, such as by suspending dry drug particles in an air stream and contacting this fluidized bed with a flow of encapsulating material to coat the drug with a permeable membrane. A drug coating can also be applied.

Other suitable microencapsulation methods include coacervation techniques.

Coacervation techniques primarily employ a composition of three immiscible layers: a liquid production phase, a vegetative phase, and a liquid coating phase.

A liquid polymer coating is deposited onto the core material and cured to form microcapsules, usually by heat, crosslinking or decervation methods.

Other typical microcapsule manufacturing methods include, for example, the Bungenberg, de Jong and Kaas methods, and details can be found in Biochem, Z.
232.338-34.5 (1931), J, Ph.
arm, Sci.

1 above, #1.0 (1970) 1367-1376 (West German patent DT-1939-066) and Remingto
n6 pharmaceutical 5cien
ce Volume XIV (Mack Publishing
Company Easton.

Pal, 1970), pages 1676-1677.

Suitable materials for matrix 62 should be biodegradable and have a drug permeability that is higher than the drug permeation rate of the reservoir material.

Matrix material 62 does not need to have the ability to adjust the rate of drug release.

The rate of biodegradation of the matrix material 62 must be such that it biodegrades simultaneously with or after the supply of the drug from the reservoir 61.

Although not essential to embodying the present invention, m) prior to release of the reservoir from the IJ sock 2 and biodegradation or passage of the blind spot, the release of the drug from the reservoir is substantially complete; It is preferable.

The matrix material may be water permeable or water valve permeable.

If the drug is water-soluble, it is preferably a non-permeable material.

Although the device illustrated in FIG. 4 is suitable for administering water-soluble drugs, it can be applied to administering water-insoluble drugs as well.

Devices of the type shown in Figures 3 and 4 must first be designed by selecting the drug to be used, its dose and duration of treatment.

This determines the required drug release rate and the amount of drug to be encapsulated in the device.

Materials with appropriate drug release rate characteristics and disintegration rates can then be determined in conjunction with the effective surface release area that forms the device, thereby adjusting the desired amount of drug to the eye.

The ocular inserts of the present invention can include any drug used to treat the eye and surrounding tissues.

It also uses the eye or surrounding tissues as a point of introduction for systemic drugs or antigens, with the drug or antigen ultimately entering the bloodstream or into the nasopharynx, esophagus, or gastrointestinal region, away from the site of application of the ocular insert. It is also possible to generate a pharmacological response at the site.

There are no particular limitations on the drugs suitable for use in the treatment of the eye using the ocular inserts of the present invention according to known dosages and regimens.

Antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,
Gramicidin, oxytetracycline, chloramphenicol, gentamicin and erythromycin, antibacterial agents such as sulfonamides, sulfacetamide,
sulfamethizole and sulfisoxazole, antiviral agents such as idoxuridine, and other antibacterial agents such as nitrofurazone and sodium propionate, antiallergic agents such as antazoline, metapyriline, chlorpheniramine, pyrilamine and profuenpyridamine, anti-inflammatory agents For example, hydrocortiscin, hydrocortiscin acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, metricin, prednisolone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromesalone, betamethasone and triamcinolone, decongestants such as phenylephrine, naphazoline and Tetrahydrazolines, miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iosite and demecarium bromide, mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide , oicatropine and hydroxyamphetamine and sympathomimetic agents such as epinephrine.

The drug may be present in various forms, such as uncharged molecules, molecular complexes or non-irritating pharmacologically acceptable salts, such as hydrochloride salts.
It can be used as hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc.

Acidic agents can be used as salts of metals, amines or organic cations (eg quaternary ammonium).

Furthermore, simple derivatives of drugs such as ethers, esters,
Derivatives that have the desired retention, release or solubility properties, such as amides, but are easily hydrolyzed by pH 1 enzymes in the body, can also be used.

The amount of drug added to the ocular insert will vary depending on the length of time the ocular insert is used.

Non-toxic pharmaceutical carriers can also be included in the medicament.

Suitable carriers include, for example, sterile water, common salt, dextrose, castor oil ethylene oxide condensation products bound with about 30 to about 35 moles of ethylene oxide per mole of castor oil, liquid glyceryl triesters of low molecular weight fatty acids, lower alkanols, oils and fats. For example, cereal oils and the like and emulsifiers such as mono- or di-fatty acids.
Glycerides, or phosphates such as lecithin, glycols, polyalkylene glycols, suspending agents such as sodium carboxymethyl cellulose, sodium alginate, poly(vinylpyrrolidone), alone or in aqueous media in the presence of suitable dispersants, such as There are combinations with lecithin, polyoxyethylene stearate, etc.

The carrier may also contain adjuvants such as preservatives, stabilizers, wetting agents,
It may also contain an emulsifier and the like.

The surface of the eye-contacting ocular insert may be coated with a thin layer, e.g., on the order of 1 to 2 microns in thickness, of a biodegradable hydrophilic material such as those described in U.S. Pat. No. 3,576,760 to impart compatibility with the eye and surrounding tissue. water-soluble hydrophilic polymers of non-crosslinked hydroxyalkyl acrylates, such as
For example, Hydron-8, gelatin, polysaccharide, etc. can also be coated.

Ocular inserts provide complete dosage control over an extended period of time.

Thus, enough drug is loaded into the device to maintain the desired dosage level during the treatment period.

For example, the daily dose of pilocarpine in the treatment of glaucoma in adults is 25 μV to 1000 μg.

Therefore, a device for a 7 day maintenance period must contain ~3.5 pilocarpine to release 500 μg of pilocarpine per day.

It is of course possible to prepare devices with different drug contents that are used for different periods of time and release drug at higher or lower rates.

Examples of doses used in the devices of the invention include antibiotics such as poly:25o/insert/.

Examples of mixin sulfonamides include sulfacetamide: 500 μm/insert/day Doudoxuridine: 5□7/insert/day Antibacterial agents and anti-inflammatory agents such as bi1゛":'-f7":/7- ? ? °500 μg/insert/day - 7 inserts.

Ron etc. can be shown.

Typically, the devices of the present invention will have between 1 μg and 0.1 μg.
7 drugs.

Materials suitable for use as biodegradable drug release rate-modulating microcapsules, membranes and matrices and non-rate-modulating biodegradable internal reservoirs and septa in the ocular inserts of the invention include: Materials must be specifically selected that are non-toxic, compatible with the drug used, and that meet the foregoing with regard to desired biodisintegration and release rates.

Examples of materials that can be used in this structure include:

(1) Polyester general formula %formula% Polyesters represented by and mixtures thereof.

where W is a group of formula -CH2- or
It is a number that becomes oooooo.

Polymers of this type are polycondensation products of monobasic hydroxy acids of the formula %, where n is a number of 1 or 2, in particular lactic acid and glycolic acid.

Copolymers obtained from mixtures of these acids may also be used.

The preparation of polymers of formula I is not itself within the scope of the present invention and several methods are known;
hione et al.: Industrial and Eng.
ineering Chemistry 36, #32
23-228 (1964), T 5uruta et al.: Ma
cromo1. Chem, 75. 211-214(
1964) and U.S. Pat. No. 2,703,316, 266
No. 8162, No. 3297033 and No. 2676945.

(2) Cross-linked Gelatin Gelatin, as is well known, is obtained by selective hydrolysis of collagen and consists of a complex mixture of high molecular weight water-soluble proteins.

As used herein, the term cross-linked gelatin refers to gelatin or a gelatin derivative that reacts with a cross-linking agent, i.e., with any of the functional groups of the gelatin molecule, but does not substantially react with the peptide bonds of the gelatin molecule. Refers to the product of reaction with a reagent.

The crosslinking reaction product has an average molecular weight of 20 to 50 during crosslinking.
000 is preferred, but higher values can also be used.

This reaction product biodegrades over time in the intraocular environment.

Crosslinked gelatin and methods of making it are well known.

The degree of gelatin crosslinking is determined by the process conditions used, which significantly affects the biodisintegration potential of the gelatin.

The crosslinking rate (i.e. degree of crosslinking) of gelatin is determined by (
1) effective concentration of reactive groups present, (2) reaction time, (
3) determined by the temperature at which the reaction was carried out and (4) the pH of the reaction medium.

Examples of crosslinking agents include monoaldehydes such as C1-C4 aldehydes such as propanal,
Acetaldehyde, formaldehyde, acrolein,
Crotonaldehyde, 2-hydroxy-adipaldehyde, dialdehydes such as geltaraldehyde, glyoxal, other aldehydes such as starch dialdehyde, paraldehyde, furfural, and aldehyde sulfite adducts such as formaldehyde sulfite adducts, aldehyde sugars Examples include glucose, lactose, maltose, etc., ketones such as acetone, methylolated compounds such as dimethylolurea, trimethylolmelamine, substituted methylolated compounds such as tetra(methoxy-methyl)urea, melamine, and other reagents such as C1-C4 disubstituted Carbodiimide, epichlorohydrin, ebonite 100
Epoxides such as (Eponitel 00.5 hell), parabenzenequinone, dicarboxylic acids such as oxalic acid, disulfonic acids such as m-benzenedisulfonic acid, ions of polyvalent metals such as chromium, iron, aluminum, zinc, copper, amines such as hexamethylenetetramine. and aqueous peroxydisulfates (H,L, Needles, J, Pol
ymer 5science, Part A-1, 5
(1) 1 (1967)].

Aldehydes and ketones, especially those having 1 to 4 carbon atoms, are preferred as crosslinking agents, especially formaldehyde.

Other suitable methods of crosslinking gelatin include irradiation [eg Y, Tomoda and M.

Tsuda, J., Poly, Sci., 54,321 (1
961)].

Reactive hydroxyl, carboxyl and amine groups are present in gelatin 1005' in proportions of approximately 100.75 and 50 meq, respectively.

This amount provides a general guideline for determining the amount of crosslinker to use.

However, it is preferable to determine the actual biodegradation rate experimentally as shown in the Examples.

For example, when formaldehyde is used as a crosslinking agent, it is 0.01% to 60% by weight based on the weight of gelatin.
using a crosslinking agent, reaction time is 0.1 hour to 5 days,
The reaction temperature is 4.0°C to 35°C.

The exact formulation concentration, temperature and time will depend on the desired rate of dissolution.

General knowledge about cross-linked gelatin can be found in the Advance
s in Protein Chemistry V
ol, VI, Academic Press
.

John Bjorksten in 1951: [Cr
ossLinkages in Protein
Chemistry j.

The above substances are merely examples.

Any biodegradable material that is drug compatible, non-toxic, and has the desired biodegradation and release rate can be used for this purpose.

However, the above-mentioned polyesters and crosslinked gelatins are particularly preferred as disintegrable release rate modifiers.

Suitable materials for forming the inner core and matrix that are not for controlling the release rate are those that are compatible with the drug used, are highly permeable, and biodegrade relatively quickly. Good.

Examples include glycerinated gelatin, collagen, gum acacia, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid and metal salts of alginic acid, starch phosphates, starch and gelatin, linear polyacrylamide and polymethacrylamide.

Furthermore, the substances mentioned above as suitable release rate regulating substances can also be used as substances for the above-mentioned purpose other than release rate regulating substances, as long as they have higher drug permeability than the actually used release rate regulating substance.

Many methods can be used to encapsulate drugs into ocular inserts.

For example, if the ocular insert is in the form of a container, any encapsulation, bonding and coating techniques or combinations thereof commonly used in the art may be used.

If the ocular insert is a matrix in which the drug is dispersed, the drug may be added to the monomer prior to polymerization, the drug may be added to a liquid polymer, cast or molded and then cross-linked; It is manufactured by dipping the polymeric material in the drug either before or after shaping the shape of the ocular insert.

Inserts can also be manufactured using lamination methods.

That is, a device is obtained in which a sheet of nuclear material is sandwiched between two sheets of external material.

The inner core can also be perforated or textured to increase the adhesion of each layer.

If the matrix material consists of a plurality of microcapsule reservoirs, it can be mixed with the matrix-forming material, which can be solid, semi-solid or liquid during mixing.

If the reservoir is generally compatible with the monomers or prepolymers used to form the matrix, the reservoir can also be added at an early stage of its formation to form the matrix in situ.

The IJ lax material with the reservoirs dispersed therein can be shaped by molding, rolling, pressing or other similar manufacturing methods depending on the given drug design.

Highly reproducible matrices with constant compositional properties can be easily obtained.

Plasticizers, preservatives and other additives commonly used in dosage forms can be added to the biodegradable release rate modifying material.

Plasticizers suitable for use for the purpose of the present invention are commonly used pharmaceutically acceptable plasticizers, such as diethyl adipate, diisobutyl adipate, di-n-hexyl adipate, diisooctyl adipate, azelain. Di-n-hexyl acid, di-2-ethylhexyl azelate, ethylene glycol shihenzoate, acetyltri-n-butyl citrate, epoxidized soybean oil, glycerol monoacetate, diethylene glycol dipelargonate, propylene glycol dilaurate, isooctyl palmitate , triphenyl phosphate, etc.

In addition, examples of substances that may also be used to adjust or assist the biodegradability of the device include glycerin, dextrose, sorbitol, mannitol, sucrose, poly(ethylene glycol), Examples include monoglyceryl esters of fatty acids and methylcellulose starch.

The proportions of such additives used will vary widely depending on the desired rate of disintegration and the nature of the drug involved.

Generally, it is about 0 depending on the type of additive per 1 part by weight of the drug.
．． 01 to about 10 parts by weight.

If desired, enzymes such as pepsin, trypsin, etc. can be added to the release rate modifier to further control the rate of biodegradation of the membrane or matrix material of the device.

As already mentioned, the device of the present invention is designed to deliver a controlled amount of drug from a reservoir to the eye over an extended period of time, primarily through a leaching or disintegration control mechanism. .

The rate of permeation of a drug through a material or selected combination of polymeric materials can be easily measured.

Standard method for measuring the rate at which drugs pass through drug-permeable materials L Encyl, Polymer 5science
andTechnology 1Vol. 5 and pp. 9.65-85 and 795-807 (1968
), and the documents cited therein, U.S. Pat. No. 3,279.
No. 996, Folkman and Edmonds:
C1rculation Research 10. '
632 (1962), Folkman and Long
: J, Surg, Res, Sat 1.139 (1
964), powers: J.

Parasitology 51.53 (April 1965), 2.5ection 2.

The disintegration rate of a substance can be measured by the method exemplified in the Examples, or it can also be measured using an apparatus similar to the tablet disintegration rate measuring apparatus described in US Pharmacopoeia X■ using artificial lachrymal fluid. can.

The device of the invention disintegrates continuously over an extended period of time, i.e. from 8 hours to 30 days or more;
It also delivers a controlled amount of drug to the eye.

The device releases the drug and simultaneously disintegrates itself.

In general, the following material decay rates are satisfactory:

The exact speed selection is designed based on the above considerations.

Example of disintegration rate My 1 day Not for adjusting release rate 0.5-20 Matrix material Membrane for adjusting release rate or 0.1-15 is matrix material To insert the insert of the present invention into the cul-de-sac of the eye, insert the device into the cul-de-sac of the eye. This can be satisfactorily achieved by placing the holder on the holder or pinching it with the fingertips, or by using a suitable holder among the several types commonly used for inserting or removing corneal contact lenses, artificial eyes, etc.

The present invention also encompasses the use of an indicator stain in the insert to allow visual confirmation of the delivery of drug in the device or the device itself within the eye.

Methylene blue or any other suitable dye material can be used.

The ophthalmic insert is suitably packaged using a drug- and moisture-impermeable packaging material, such as a foil-polylaminate, such as an aluminum foil-polyethylene laminate.

The insert may be wet-packed or dry-packaged, although dry packaging is essential if the biodisintegration process is carried out by dissolution or hydrolysis.

In such cases, dry packaging, such as vacuum packaging, is required.

Preferably, the ophthalmic device is sterilized before insertion into the eye.

Irradiation or ethylene oxide treatment can advantageously be used.

Details of this and other methods can be found in Remingt
on&Pharmaceutical 5cienc
es, Vol, XIV (1970) 1501-15
It is described on page 18.

For a more complete understanding of the nature of the invention, reference is made to the following examples.

However, the following examples merely illustrate the present invention in detail and are not intended to limit the invention.

All parts are by weight unless otherwise specified.

Example 1 A biodegradable ocular insert containing chloramphenicol is manufactured by the following method.

(1) From cyclic lactide, R, K, Kulkarni
et al.: J, of BiomedlMater, Res.
, 5.169-191 (1971).

(2) Polymer 1 (l is methylene chloride 100rI)
Dissolve in 1 ml.

(3) Add 2.01 ml of chloramphenicol while stirring.

(4) Spread the polymer and drug composition on a glass plate.

The coated board is then dried at room temperature and then at 40°C.

(5) Punch out the resulting film into circular inserts with a diameter of 6 mm and a thickness of 0.5 mm.

Each insert contains 2.31 ng chloramphenicol per crA.

When inserted into a monkey's eye, the drug is continuously released at a controlled rate over a long period of time, after which it completely biodegrades within the eye.

Example 2 A biodegradable ocular insert containing pilocarpine is manufactured by the following method.

(1) From hydroxyacetic acid, N, A, Higgi
ns: U.S. Patent No. 2,676,945 (195'44
Poly(glycolic acid) was prepared according to the method described in 2010 (27th April) and was heated at 240°C and 140°C using a Carver press.
0.0 at 6kg/cry (20000psi)
Compression mold to 762 mm (3 mil) film.

(2) The drug-containing core film is manufactured as follows.

(a) Poly(vinyl/1/near/1/) 1
0? (dupontE1vano152-22)
Dissolve 10 fl in 90 m7 of distilled water at 70°C. b) Cool this solution and add 20 g of pilocarpine free base while stirring. (c) Spread the solution on a glass plate to a thickness of 0.152 cm.
d) Cut the pilocarpine-containing film into 4.5 mm discs. Dry the film at room temperature for 24 hours.

(3) Poly(glycolic acid) from which this circular nucleus was previously produced
Place between two sheets of
Heat seal at 50°C for 1 second.

When this insert is inserted into a monkey's eye, it releases medicinal properties over a long period of time, after which it completely biodegrades within the eye.

The basic novelty and preferred embodiments of the present invention have been described above.

It will be appreciated that those skilled in the art may make various modifications to the ocular insert of the present invention without departing from the spirit of the invention.

However, all such modifications are intended to be encompassed by the present invention.

[Brief explanation of the drawing]

Figure 1 shows the eyeball and the upper and lower eyelids, partly from the front, partly diagrammatically, and shows the eye insert of the present invention in the insertion position immediately after being inserted into the eye, and Figure 2 shows the eyeball and its contacts. The upper and lower eyelids are partially cross-sectionally and partially schematically shown, showing the eye insert of the present invention in the insertion position, and FIGS. 3 and 4 each show one embodiment of the eye insert of the present invention. FIG.

Claims (1)

[Scope of Claims] 1 A polyester represented by the general formula (wherein W is a group of the formula -CH2- or such, and Y is a number such that the molecular weight of the polymer is about 4,000 to 100,000), A predetermined amount of the drug to be administered to the eye is dispersed throughout the body of a hydrophobic, biodegradable drug release rate controlling material, and this dispersion is then applied to the surface of the bulbar conjunctiva of the sclera of the eyeball and the palpal conjunctiva of the eyelid. a therapeutically effective amount of medicament, characterized in that it is shaped into a shape suitable for insertion into an eye blind surrounded by the surface of the eye and retained within said eye blind for at least 8 hours. biodegradable device that continuously administers the drug to the eye at a controlled rate for at least 8 hours, the device biodegrading in the intraocular environment simultaneously with administration of the drug or at some time after the end of administration. Method of manufacturing a sex dosing device.