WO2002064071A1

WO2002064071A1 - Device and method for anterior segment drug delivery

Info

Publication number: WO2002064071A1
Application number: PCT/AU2002/000149
Authority: WO
Inventors: Celia R Hicks; Xia Lou; Traian V Chirila; Ian J Constable
Original assignee: The Lions Eye Institute Of Western Australia
Priority date: 2001-02-13
Filing date: 2002-02-13
Publication date: 2002-08-22
Also published as: AUPR313801A0

Abstract

The invention relates to a device, method and kit for prolonged drug delivery to the eye. Preferably, the invention provides a device comprising a hydrated hydrogel sponge carrying a unit dose of a desired therapeutic agent.

Description

DEVICE AND METHOD FOR ANTERIOR SEGMENT DRUG DELIVERY

This invention relates to a device and method for prolonged drug delivery to the cornea and anterior segment of the eye, suitable for use in human patients and in veterinary ophthalmology. The invention provides a means of achieving therapeutic drug levels at the desired site for prolonged periods by a method which avoids repeated topical application or injection.

BACKGROUND OF THE INVENTION

All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Diseases of the cornea and anterior segment of the eye are often managed by giving therapeutic agents topically, either as ointments or in guttae form (drops) . In many conditions, this provides adequate treatment. The therapeutic agents are formulated so as to maximise uptake through the cornea and the conjunctiva, with factors such as solubility, lipophobicity/lipophilicity and therapeutic half-life (T_M) being particularly important. Most medication given in this manner has to be administered at intervals varying from once daily to hourly. In many conditions multiple therapy, such as a combination of steroids with cycloplegic agents in the management of uveitis, is required. Common problems relating to topical guttae medication include:

1) Frequent dosage. Serious conditions may require administration of drops at hourly or even half- hourly intervals, day and night, for several days. This is difficult and burdensome for patients, and clearly affects compliance. For paediatric and geriatric patients, home treatment may not be practicable. Patients may have to be admitted to hospital for treatment . 2) Frequency of administration may cause epithelial toxicity, largely because of preservatives in the drops. This may necessitate provision of drugs in preservative-free, single-dose form, which is expensive and inconvenient . 3) The exact dose delivered may vary. In general, the volume of a single 'drop' is greater than the capacity of the tear film and conjunctiva-1 fornices to

' catch' and contain it, resulting in spillover and wastage.

4) Many drops cause stinging on application, and are disliked by patients. This affects compliance.

5) The need to administer drops to patients who are unable to use the bottle themselves, such as children, the infirm or elderly, and sufferers from disabling conditions such as rheumatoid arthritis also reduces compliance in many cases, as helpers may not be available as frequently as required.

Similar problems are encountered with ointments, although generally these- need to be administered less frequently than drops. However, ointments are generally unpopular with patients because they are messy, and they disturb clear vision.

In some conditions, such as severe uveitis or infections, topical medication is augmented by a subconjunctival or orbital floor injection. Disadvantages of these routes include: 1) The risk of iatrogenic damage, which can range from subconjunctival haemorrhage to globe perforation.

2) The possibility of spike rises in intraocular pressure.

3) Patient discomfort or outright refusal.

4) Inability to reverse or remove treatment once administered, for example if an allergic reaction occurs . 5) Lack of availability of all of the medications which might be required in an injectable form.

6) The patient cannot self-administer, nor, generally can a nurse or general practitioner, necessitating attendance at a specialist clinic for each treatment.

Others have considered the need for methods of prolonged ocular drug delivery, in particular for the posterior segment (vitreous and retina) , and surgically- implanted devices for drug release are used in diseases such as HIV-related infections (Schoenwald et al , 1997) .

For anterior segment delivery, devices such as drug-loaded vicryl "threads', which are left inside the anterior chamber after cataract extraction, and which gradually dissolve and release the drug, drug-loaded collagen contact lenses which dissolve in si tu (Kuwano et al , 1997) , and in si tu-foi ming gels (Kumar et al , 1994) have all been suggested. A non-invasive method which avoids corneal contact would be preferable to these for any condition not requiring surgery or the bandage effect of a lens. More recently ocular insert devices for slowly releasing drugs to the eye over a long period of time have been described. See for example U.S. Patent No. 3,416,630, No. 3,618,604 and No. 4,014,335 assigned to Alza Corporation. US-4,014,335 describes an insert device which is placed between the sclera and the eyelid, and comprises a reservoir of drug retained in a polymer reservoir ^"By a drug-permeable release rate-controlling barrier. However, such devices are complex, expensive, and of limited acceptability to patients.

The usefulness of hydrogels in drug delivery is being increasingly recognised, and altering the polymer structure of heterogeneous polymers is known to affect loading and release characteristics (Kim et al, 1992) . Experimentally, sustained release of macromolecules from polymers including polyvinyl alcohol, Hydron-S, and ethylene-vinyl acetate copolymer has been achieved, and the rate of release can be retarded by coating the macromolecule-loaded matrix with pure polymer (a "sandwich") (Langer and Folkman, 1976) . A number of different types of drug-impregnated hydrogel contact lenses or ocular inserts have been suggested. However, these still present a number of problems, including difficulty with insertion and the risk of corneal edema.

Hydrogel implants, in which a drug, such as cytarabine, is incorporated into gel which is implanted into the body have been proposed (Blanco et al, 1997; Ichien et al , 1997) for prolonged antineoplastic drug release. However, the use of porous non-degradable hydrogel sponges for drug delivery to the eye via a conjunctival route does not appear to have been considered. It is therefore clear that there is a need in the art for a means of prolonged drug delivery to the eye from a once-daily, or less frequent, application which can be self-administered. We have surprisingly found that a hydrated hydrogel sponge provides a very simple means whereby a desired drug can be administered to the inferior conjunctival fornix. The sponge fits comfortably within the inferior fornix, where it is not felt, and is not visible to others.

Summary of the Invention

According to a first aspect, the invention provides a device for ocular administration of a therapeutic agent, comprising a hydrated hydrogel sponge carrying a unit dose of a desired therapeutic agent.

The hydrated hydrogel may be any suitable material which can provide a soft sponge, is physiologically compatible, and is able to be sterilised, preferably by a means of heat sterilisation such as autoclaving. In a preferred embodiment, the sponge is made of poly (2-hydroxyethyl methacrylate) or PHEMA. We have found that this polymer is particularly useful for ocular applications; see for example our International Patent Application No. PCT/AU97/00512, and Australian Patent No.650156, equivalent to US Patent No. 5,458,819. The person skilled in the art will be aware of other suitable materials, including but not limited to microporous materials. The optimal material for the sponge may vary, depending on the nature of the therapeutic agent to be administered.

Preferably the sponge is formed, then coated with a thin layer of non-porous polymer; more preferably the non-porous polymer is PHEMA.

It will be clearly understood that the sponge may carry more than one individual therapeutic agent, depending on the nature of the condition to be treated.

In an alternative embodiment, the invention provides a kit for treatment of an ocular condition, separately comprising

(a) a hydrated hydrogel sponge, and

(b) a therapeutic agent in liquid form such that a patient or attendant can load the therapeutic agent on to the sponge immediately prior to use.

By "attendant" is meant a person assisting the patient; such a person can be a medical professional such as a doctor, nurse, nursing aide, or may be a non- professional such as a friend or relative of the patient. In a second aspect, the invention provides a method of treatment of an ocular condition, comprising the step of inserting a hydrated hydrogel sponge carrying a desired therapeutic agent, as defined above, into the inferior conjunctival fornix, maintaining the sponge in the fornix for a period adapted to maintain a desired therapeutic level in the tear film, cornea, or anterior segment of the patient's eye, removing and discarding the sponge at the end of this period, and optionally administering a new sponge.

In an alternative embodiment, the invention provides a method of treatment of an ocular condition, comprising the steps of placing a sterile hydrated hydrogel sponge in the inferior conjunctival fornix, and administering a desired dosage of a therapeutic agent in drop form.

According to a third aspect, the invention provides a method of preparation of a hydrated hydrogel sponge for treatment of an ocular condition, comprising the steps of

(a) preparing a suitable polymer sponge,

(b) cutting the sponge to the shape suitable for administration to the inferior conjunctival fornix,

(c) sterilising the sponge,

(d) optionally dehydrating the sponge, and

(e) loading the sponge with a desired therapeutic agent . If sterilisation is performed by autoclaving, steps (c) and (d) are performed in this order; otherwise this is not essential .

The sponge of the invention is suitable for treatment of a variety of ocular conditions, including but not limited to infections, including bacterial, viral and acanthamoebal infections; inflammatory disease such as uveitis; and glaucoma. Suitable therapeutic agents for use with the device and method of the invention include but are not limited to antibiotics and antiviral agents; anti- inflammatory agents including steroids; and cycloplegic agents, including atropine and cyclopentolate . Both hydrophobic and hydrophilic agents are suitable for use with the invention. The invention is suitable for use with combinations of two or more therapeutic agents.

Optionally, particularly where two or more agents are to be delivered at different rates, the hydrogel sponge may comprise further materials adapted to modify the release characteristics of the individual therapeutic agents. A second material, such as^' nano particles (for example chitosan, or gelatin micro/nano particles) , could be incorporated within the porous structure, and being biodegradable, could release additional drugs through different release kinetics.

There are two potential ways of utilising the sponges in clinical practice, which are not mutually exclusive. Pre-loaded, individually packaged sponges may be supplied, eg a patient may be given 7 sponges for a week's treatment course. Alternatively, a patient may simply place a 'blank' sponge in the inferior fornix prior to administration of drops in the normal way; the extra depot, and prevention of spillover wastage, should prolong the effective period of treatment, allowing a longer gap before the next drop being given (eg an iritis patient could avoid having to wake up for a 2 am dose) .

It will be clearly understood that the invention does not provide tear replacement for patients with dry-eye syndromes: on the contrary, it depends upon an adequate tear circulation to carry the drug from the depot to the site of absorption.

For the purposes of this specification it will be clearly understood that the word "comprising" means "including but not limited to", and that the word "comprises" has a corresponding meaning.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the release profile of Al loaded with 1% Prednisolone. _. . -

Figure 2 shows the release profile of Cl loaded with 1% Prednisolone. Figure 3 shows the release profile of C2 loaded with 5% Prednisolone.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment, the sponge is made of poly (2-hydroxyethyl methacrylate) or PHEMA, although other types of hydrogel sponge with different chemistries and morphology may also be used, and are included in the scope of the invention. Furthermore, it may prove beneficial to incorporate additional materials, such as biodegradable nano particles, in order to achieve the required drug release characteristics, especially where two or more therapeutic agents are to be delivered at different rates. The degree of hydration of the sponge may vary, depending on the therapeutic agent to be delivered.

Therapeutic agents will partition into the water in the holes of the sponge, and into the structure of the sponge polymer chains as well, which allows manipulation of the time-course of release of the therapeutic agent. The person skilled in the art will readily be able to determine the appropriate degree of hydration to use with a given therapeutic agent, using knowledge of the materials' physical/chemical properties. The sponge is sterilised. Drug loading may be effected prior to packaging; alternatively sterile sponges may be supplied as a kit together with drops for patients to load a sponge prior to insertion. The preferred method will depend on the particular therapeutic agent and the condition to be treated, either may be appropriate in different circumstances. Both hydrophilic and hydrophobic drugs may be incorporated. Drugs will be released with differing time-courses into the tear film.

The sponge is suitably cut to an approximately semicircular shape, 5 mm long, 2 mm deep and 0.5 mm thick, and is worn with the flat edge upwards within the inferior fornix, parallel with the eyelid margin. Drugs are loaded by soaking the sponge in the required drug solution, the strength of which is determined for each intended therapeutic agent, for a period also determined for each agent . The sponge may be dehydrated prior to drug loading . To administer the sponge, the patient or attendant simply washes his/her hands, removes the sponge from its packet and pulls down the lower eyelid with the fingers of the other hand. The sponge is then placed in the inferior fornix, and disappears from view as the patient blinks and looks up. To remove a sponge, the lower eyelid is pulled down, and the sponge appears; it is then very easily removed with the fingers of the other hand.

Example 1 : Assessment of Comfort, Ease of Use, Cosmesis and Release of a Marker Dye in

Human Volunteers . Two poly (2-hydroxyethyl methacrylate) sponges were made and loaded with fluorescein by pressing both sides of the sponge, which had been soaked in normal saline, against a sodium fluorescein strip (Fluoret-TM) .

One sponge was self-administered in the inferior fornix of the right eye in two volunteers. At the same time, another fluorescein paper was used to administer fluorescein into the other eye. Slit lamp examinations were performed at 15, 30 and 60 minutes and at 2, 4, 6, 8 and 24 hours, with photographs being taken at 2 and 24 hours. The sponges were removed at 24 hours.

Both volunteers found insertion and removal of the sponges easy, and neither experienced any discomfort during wearing or alteration of vision. Neither sponge was lost prior to the planned removal time. The sponges were not cosmetically apparent when worn; they did not protrude above the lower lid margin, nor did they produce a visible bulge in the lower lid. The fellow eye was grossly yellow after fluorescein administration, with the entire ocular surface being affected and with significant spillover; however, no trace of visible fluorescein was present after 30 minutes, either on gross inspection, or on slit lamp examination of the anterior chamber. In contrast, the right eye was not so noticeably yellow immediately after sponge insertion, but on upgaze a localised yellowness was observed in the inferior fornix near the sponge. On slit lamp examination at all time points to 24 hours the tear film was yellow, and an aqueous flare of dye was present, which gradually diminished. Some dye persisted in the sponges at 24 hours on removal . The sponges were easy to use and produced a considerable prolongation of fluorescein dye on the ocular surface and in the anterior chamber when compared with standard administration, despite no attempt having been made to 'load' the sponge with more dye than that applied to the fellow eye. The sponges were comfortable to wear, and were- cosmetically undetectable. Placing and removing a sponge was not painful or uncomfortable, and was no more difficult than applying drops. However, the infirm , poorly-sighted, or children would require assistance.

Example 2 : Device and Method for Anterior Segment Drug Delivery. 2 -Hydroxyethyl methacrylate (HEMA) was dissolved in water (1:4). Ethyleneglycol dimethacrylate (EDMA) , 0.3 wt%, ammonium persulphate (APS), 0.2 wt% and tetramethyl ethylenediamine (TEMED) , 2 wt% were added into the monomer mixture. The mixture was then dispensed into cylindrical plastic moulds of approximately 12mm diameter and cured for 24 hours at 30°C. The formed opaque poly (2-hydroxyethyl methacrylate) (PHEMA) sponge was cut into discs 10mm in diameter and 5mm thick. They were then extracted by continuous water flow for about 20 hours before further processing. Three versions of the sponge (unmodified Al and modified Cl and C2) were prepared and tested as described below for Case I, Case II and Case III respectively. For Case II and Case III, a coating of PHEMA hydrogel was applied on to disc A so as to make reservoir discs. In brief, disc A was dipped into a mixture of HEMA and EDMA (0.5%) and TEMED (5%) and removed from the mixture after 1 minute. The disc was blotted on a tissue to remove excess coating mixture and then gently spun in air for about 5 minutes. The disc was then placed in a conventional oven at 60°C for 20 hours. The residual chemicals were removed from the coated disc by means of 20- hours extraction in water.

Case I .

One disc, Al, was soaked in prednisolone (1 wt% in a buffer solution pH 7.4) over 48 hours to ensure full equilibration. The disc was then removed from the drug solution and gently blotted on a filter paper to remove the surface solution. It was then put into a custom-made diffusion cell (M. W. Tsang. Opthalmic Drug Release from Porous Poly-HEMA Hydrogels. Honours Thesis, University of Western Australia, 2001) .

Fresh phosphate-buffered saline, pH 7.4 (PBS) solution was then pumped from a reservoir into the diffusion cell at a constant rate of 2.91 ml/min. The discharge, containing released drugs from the diffusion cell, was monitored by UV/vis spectroscopy at a wavelength of 247 nm. The fractional release rate, ie. the release rate of a device at a particular time point divided by the total mass of the drug initially loaded into the device, of disc A was calculated according to the monitored data. The normalised fractional release profile of device A is shown in Figure 1. The release rate at 22.5 hours was 0.03 μg/h.

Case II.

Coated disc Cl was soaked in 1% prednisolone in a buffer solution (pH 7.4) for over 72 hours to ensure full equilibration of the device and the solution. The disc was removed from the drug solution and gently blotted on a filter paper to remove the surface solution. The diffusion and monitoring process was applied to disc Cl, in the same way as described for Case I . The release profile of Cl is shown in Figure 2. The release rate at 24 hours was 74.2 μg/h.

Case III.

Coated disc C2 was soaked in 5% prednisolone in a buffer solution (pH 7.4) for over 72 hours to ensure full equilibration of the device and the solution. The disc was removed from the drug solution and gently blotted on a filter paper to remove the surface solution. The diffusion and monitoring process was applied to disc C2 , in the same way as described for Case I . The release profile of C2 is shown in Figure 3. The release rate was 608 μg/h at 24 hours and 206 μg/h at 48 hours.

A comparison of the release profiles for each of the three cases is shown in Table 1.

Table 1. Summary of the major differences between the release profiles of sponges Al (Case I) , Cl (Case II) and C2 (Case III) .

The devices used in Case II and Case III, coated with a thin layer of non-porous polymer, demonstrated a significantly greater release rate at 24 and 48 hours than the unmodified device, indicating that a prolonged release had been achieved in Cases II and III. A less rapid decline in release rate was also evident in Case II and Case III. The demonstrated duration of sustained prednisolone release, at a high and effective therapeutic level (Sustained and Controlled Release Drug Delivery Systems, Ed J. R. Robinson, Marcel Dekker, New York, 1978) in Case III has demonstrated the great potential for such devices to be used as controlled drug delivery systems in ophthalmic or other applications.

Example 3 : Further evaluation and optimisation.

Further evaluation and optimisation includes: 1) Assessing sponges with different chemistry or morphology, so as to select the optimum mechanical and chemical properties.

2) In vi tro assessment of delivery kinetics.

3) Assessment of drug loading methods for both high and low molecular weight drugs, hydrophobic and hydrophilic drug, drugs alone and in combination, eg a steroid with a cycloplegic agent to provide a combined treatment for uveitis.

4) Assessment of kinetic release profiles of single drugs and combinations to determine the optimum loading methods .

5) Assessment of drug levels in the anterior chamber at intervals after sponge placement, in an animal model . These require routine experimentation well within the capacity of those skilled in the art.

It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.

References cited herein are listed on the following page, and are incorporated herein by this reference.

REFERENCES

Blanco, M.D., Trigo, R.M. , 'Garcia, O. and Teijon, J.M. J. Biomater. Sci. Polymer Edn., 1997 8 709-719.

Kuwano, M. , Horibe, Y. and Kawashima, Y. J. Ocular Pharm. Ther. , 1997 13 31-40

Schoenwald, R.D., Deshpande, G.S., Rethwisch, D.G. and Barfknecht , C . F .

J. Ocular Pharm. Ther., 1997 13 41-59

Ichien, K. , Yamamoto, T., Kitazawa, Y. , Oguri, A., Ando, H. , Kondo, Y Br. J. Ophthalmol., 1997 81 72-75

Langer, R. and Folkman, J. Nature, 1976 263 797-799

Kumar, S., Haglund, B.O. and Himmelstein, K.J. J. Ocular Pharm., 1994 10 47-56

Kim, S.W., Bae, Y.H. and Okano, T. Pharm. Res., 1992 9 283-290

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A device for ocular administration of a therapeutic agent, comprising a hydrated hydrogel sponge carrying a unit dosage of a desired therapeutic agent.

2. A device according to claim 1, wherein the hydrogel is PHEMA.

3. A device according to claim 1 or claim 2, wherein said therapeutic agent is a hydrophobic or hydrophilic agent .

4. A device according to claim 1 or claim 2 , wherein said therapeutic agent is an antibiotic, antiviral agent, anti-inflammatory or cycloplegic agent.-

5. A device according to claim 1 or claim 2 , in which the hydrogel carries an additional coating of a non- porous polymer.

6. A device according to claim 5, in which the additional coating is PHEMA.

7. A device according to any one of claims 1 to 6, in which the device carries two or more therapeutic agents.

8. A method of treating an ocular condition, comprising the steps of: a) inserting a device according to any one of claims 1 to 7 into the eye of a patient, b) maintaining the sponge in the eye for a period adapted to maintain a desired therapeutic level in the tear film, cornea or anterior segment, c) removing the sponge at the end of this period, and d) optionally administering a new sponge.

9. A method according to claim 8, wherein the sponge is inserted into the inferior conjunctival fornix of the eye.

10. A method according to claim 8 or claim 9, wherein the hydrated hydrogel sponge is pre-loaded with the therapeutic agent prior to insertion in the eye.

11. A method according to claim 8 or claim 9, wherein the therapeutic agent is administered after insertion of the hydrated hydrogel sponge into the eye .

12. A method according to claim 11, wherein the therapeutic agent is administered in liquid form.

13. A method according to any one of claims 8 to 12, wherein the ocular condition is a bacterial, viral or acanthamoebal infection.

14. A method according to any one of claims 8 to 12 , wherein the ocular condition is an inflammatory disease.

15. A method according to claim 14, wherein said inflammatory disease is uveitis or glaucoma.

16. A method of preparation of a hydrated hydrogel sponge for treatment of an ocular condition, comprising the steps of: (a) preparing a suitable hydrogel sponge,

(b) cutting the sponge to the shape suitable for administration to the eye,

(c) sterilising the sponge,

(d) optionally dehydrating the sponge, and (e) loading the sponge with a desired therapeutic agent.

17. A method according to claim 16, wherein the hydrogel is PHEMA.

18. A method according to claim 16 or claim 17, wherein the hydrogel sponge is coated with a non-porous polymer prior to step (e) .

19. A method according to claim 18, wherein the non- porous polymer is PHEMA.

20. A method according to any one of claims 8 to 18, wherein said therapeutic agent is a hydrophobic or hydrophilie agent .

21. A method according to any one of claims 8 to 20, wherein said therapeutic agent is an antibiotic, antiviral agent, anti-inflammatory or cycloplegic agent.

22. A kit for treatment of an ocular condition, comprising:

(a) a hydrated hydrogel sponge, and

(b) a therapeutic agent.

23. A kit according to claim 22, in which the hydrated hydrogel sponge is coated with a non-porous polymer .

24. A kit according to claim 22 or claim 23, further comprising a means to load the therapeutic agent onto the sponge .