TREATMENT OF DRY EYE DISEASE WITH PARASYMPATHETIC & ANTI-SYMPATHETIC AGENTS

Abstract

Provided are methods and combinations for treating and/or preventing dry eye disease (DED) by treating a subject in need thereof with a combination of at least one parasympathetic agent at least one anti-sympathetic effective to treat said dry eye disease.

Claims

1. A method for treating and/or preventing dry eye disease in a subject in need thereof comprising administering an amount of at least one parasympathomimetic agent and at least one anti-sympathetic agent effective to treat said dry eye disease.

2. The method according to claim 1, wherein said agents are administered topically.

3. The method according to claim 1, wherein said subject is administered said parasympathomimetic agent and/or anti-sympathetic agent in an amount at least 10% below known effective dosage to treat glaucoma or other eye diseases.

4. The method according to claim 1, wherein said anti-sympathetic agent is a beta-blocker.

5. The method according to claim 1, wherein said parasympathomimetic agent is selected from the group consisting of pilocarpine and carbachol.

6. The method according to claim 4, wherein said beta-blocker is selected from the group consisting of niprodilol, nebivolol, propranolol.

7. The method according to claim 1 wherein said method acts by mimicking a physiological homeostatic parasympathetic shift.

8. The method according to claim 1, wherein said parasympathomimetic agent and anti-sympathetic agent are administered in the form of a composition.

9. A composition or combination for treating and/or preventing dry eye disease to a subject in need thereof comprising an amount of at least one parasympathomimetic agent and at least one anti-sympathetic agent effective to treat said dry eye disease.

10. The method according to claim 1, wherein said DED is contact lens induced DED.

11. The method according to claim 1, wherein said agents are applied to contact lenses.

12. The method according to claim 8, wherein said composition is in the form of drops or in the form of contact lenses comprising at least one parasympathomimetic agent and at least one anti-sympathetic agent.

13. A method for preventing and/or treating contact lens induced DED in a subject in need thereof comprising inserting a contact lens comprising an amount of at least one parasympathomimetic agent and optionally at least one anti-sympathetic agent effective to treat said contact lens induced DED.

14. A contact lens comprising an amount of at least one parasympathomimetic agent and at least one anti-sympathetic agent effective to treat and/or prevent DED.

15. The contact lens according to claim 14, wherein said DED is contact lens induced DED.

16. A method for producing the contact lens of claim 14, comprising applying amounts of at least one parasympathomimetic agent and optionally at least one anti-sympathetic agent effective to treat and/or prevent DED.

17. The method according to claim 1 wherein said parasympathetic and/or anti-sympathetic agent is an angiotensin blocker.

18. The method according to claim 13 wherein said parasympathetic and/or anti-sympathetic agent is an angiotensin blocker.

19. The composition or combination according to claim 9 wherein said parasympathetic and/or anti-sympathetic agent is an angiotensin blocker.

20. The contact lens according to claim 14 wherein said parasympathetic and/or anti-sympathetic agent is an angiotensin blocker.

Description

DETAILED DESCRIPTION

[0025] As set forth above, provided are methods for administering and compositions for preventing and/or treating dry eye disease comprising one or more parasympathomimetic agents and at least one anti-sympathetic agent in amounts effective to prevent and/or treat said dry eye disease. Also provided is the use of at least one parasympathomimetic and at least one anti-sympathetic agent in amounts effective to prevent and/or treat dry eye disease and/or formulate a medicament for the prevention and/or treatment of dry eye disease.

Parasympathomimetic Agents

[0026] There are multiple parasympathomimetic agents, and several are formulated for topical use. These include but are not limited to pilocarpine, carbachol, ecothiopate, demecarium bromide and diisopropyl fluorophosphate mentioned. In a specific embodiment, the parasympathomimetic agent may be carbachol, echothiophate iodide, physostigmine and/or demecarium bromide. More than one parasympathomimetic agent may be used to secure a wider spectrum of results.

Sympathetic Blockers/Anti-Sympathetic Agents

[0027] Sympathetic blockers are either alpha or beta selective. Alpha blockers probably are not helpful. As an example, the alpha blocker tamsulosin can cause the floppy iris syndrome during eye surgery (Chang D F, Campbell J R, Colin J, Schweitzer C. Prospective masked comparison of intraoperative floppy iris syndrome severity with tamsulosin versus alfuzosin. Ophthalmology 2014; 121:829-34) and also can cause retrograde ejaculation (Agrawal M, Gupta M, Gupta A et al. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ereteral stones. Urology 2009; 73:706-9). However, to ensure a more physiological blocking of sympathetic activation, an alpha blocker, probably at rather low doses, might be used.

[0028] In another specific embodiment, the sympathetic blocker or anti-sympathetic agent may be a beta-blocker. The beta-blocker may be a beta-selective or non-selective agent and may include but is not limited to propanolol (nonselective) timolol (nonselective), betaxolol (beta 1 selective antagonist), levobunolol (nonselective beta 1 and 2 blocking agent), carteolol (nonselective beta-blocker), metipranolol (nonselective beta-blocker) levobetaxolol (beta 1 inhibitor) as well as nitric oxide (NO) donors such as nipradilol (nonselectable beta-blocker) and nebivolol (betal selective blocker) and additionally, substances having ISA or intrinsic sympathetic action such as oxyprenolol and pindolol.

Dose Levels

[0029] As noted above in more detail, in one embodiment, at least one of the agents set forth above is administered at a lower dose than of any known therapeutic dose level for glaucoma or other eye disease. In a particular embodiment, at least one of the agents is administered at a dose at least about 10% lower than that used to treat glaucoma or other eye diseases. In an even more particular embodiment, at least one of said agents are administered at a dose of at least about 50% to about 80% lower than the known effective dose used to treat glaucoma or other eye diseases and in even yet a more particular embodiment, said agents are administered at a dose of at least about 40% to about 25% lower than the known effective dose used to treat glaucoma or other eye diseases.

[0030] The agents set forth above may be administered once, twice or three times a day. In one embodiment, the two agents would be administered in one formulation or together. In a particular embodiment, the two agents are administered in one formulation.

[0031] In a specific embodiment, carbachol, a parasympathomimetic agent, which stimulates both muscarinic and nicotinic receptors, may be administered at around 0.25% w/v to about 0.5% w/v and nipradilol, a beta-blocker with nitroglycerin-like vasodilative activities may be administered at a dose of about 0.05% to about 0.1% w/v. Alternately, the beta blocker, carteolol, which has some intrinsic sympathomimetic activity may be used. It may be administered at a dose of between about 0.25% w/v to about 0.35% w/v.

Angiotensin Blockers

[0032] Also provided are angiotensin blockers which include but are not limited to ACE inhibitors and angiotensin II receptor blockers. Angiotensin blockers may, as noted above, may act as anti-sympathetic agents as well as parasympathomimetic agents. Examples of ACE inhibitors include but are not limited to benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. Examples of angiotensin ll receptor antagonists include but are not limited to Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan, Eprosartan.

Compositions/Formulation

[0033] In certain embodiments, the composition comprises at least one parasympathomimetic and at least one anti-sympathetic agent. Preferably, the compositions will be formulated as solutions, suspensions and other dosage forms for topical ophthalmic administration in a pharmaceutically acceptable carrier, adjuvant, or vehicle. Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions.

[0034] Any of a variety of carriers may be used in the topical formulations including water, mixtures of water and water-miscible solvents, such as C1- to C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, such as neutral Carpool, or mixtures of those polymers. The concentration of the carrier is, typically, from 1 to 100,000 times the concentration of the active ingredient.

[0035] Additional ingredients that may be included in the formulations include tonicity enhancers, preservatives, solubilizers, non-toxic excipients, demulcents, sequestering agents, pH adjusting agents, co-solvents and viscosity building agents.

[0036] For the adjustment of the pH, preferably to a physiological pH, buffers may especially be useful. The pH of the present solutions should be maintained within the range of 4.0 to 8.0, more preferably about 4.0 to 6.0, more preferably about 6.5 to 7.8. Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na.sub.2HPO.sub.4, NaH.sub.2PO.sub.4 and KH.sub.2PO.sub.4) and mixtures thereof. Borate buffers are preferred. Generally, buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent.

[0037] Tonicity is adjusted, if needed, typically by tonicity enhancing agents. Such agents may, for example, be of ionic and/or non-ionic type. Examples of ionic tonicity enhancers are alkali metal or earth metal halides, such as, for example, CaCl.sub.2, KBr, KCl, LiCl, NaI, NaBr or NaCl, Na.sub.2SO.sub.4 or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. The aqueous solutions of the present invention are typically adjusted with tonicity agents to approximate the osmotic pressure of normal lachrymal fluids which is equivalent to a 0.9% solution of sodium chloride or a 2.5% solution of glycerol. An osmolality of about 225 to 400 mOsm/kg is preferred, more preferably 280 to 320 mOsm.

[0038] In certain embodiments, the topical formulations additionally comprise a preservative. A preservative may typically be selected from a quaternary ammonium compound such as benzalkonium chloride, benzoxonium chloride or the like. Benzalkonium chloride is better described as: N-benzyl-N-(C8-C18 alkyl)-N,N-dimethylammonium chloride. Examples of preservatives different from quaternary ammonium salts are alkyl-mercury salts of thiosalicylic acid, such as, for example, thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, sodium perborate, sodium chlorite, parabens, such as, for example, methylparaben or propylparaben, alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives, such as, for example, chlorohexidine or polyhexamethylene biguanide, sodium perborate, Germal® or sorbic acid. Preferred preservatives are quaternary ammonium compounds, in particular, benzalkonium chloride or its derivative such as Polyquad (see U.S. Pat. No. 4,407,791), alkyl-mercury salts and parabens. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by bacteria and fungi.

[0039] In another embodiment, the topical formulations do not include a preservative. Such formulations would be useful for patients who wear contact lenses, or those who use several topical ophthalmic drops and/or those with an already compromised ocular surface wherein limiting exposure to a preservative may be more desirable.

[0040] In a particular embodiment, said parasympathetic agent(s) and sympathetic agent(s) may be incorporated, attached or carried on a contact lens using procedures known in the art. In a particular embodiment for preventing and/or treating DED, in particular, contact lens-induced DED, the invention includes loading parasympathomimetic and anti-sympathetic agents into or onto drug-eluting contact lenses, as hydrogel contact lenses, at doses appropriate for preventing and treating DED, in particular, contact lens induced DED. As an example of drug loading of drug-eluting contact lenses, as hydrogel contact lenses, a preliminary study for the treatment of glaucoma uses the beta-blocker timolol loaded into drug-eluting contact lenses, such as

silicone-hydrogel contact lenses (see, for example, Jung H J, Abou-Jaoude M, Carbia B E, Plummer C, Chauhan A. Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. J Controlled Release 2013; 165:82-9). Of interest, in another preliminary study of drug-eluting contact lenses, two agents were used for the purpose of treating glaucoma. (Hsu K H, Carbia B E, Plummer C, Chauhan A. Dual drug delivery from vitamin E loaded contact lenses for glaucoma therapy. Eur J Pharmaceut Biopharmaceut 2015; 94:312-21).

[0041] The topical formulation may additionally require the presence of a solubilizer, in particular if the active or the inactive ingredients tends to form a suspension or an emulsion. A solubilizer suitable for an above concerned composition, is for example, selected from the group consisting of tyloxapol, fatty acid glycerol polyethylene glycol esters, fatty acid polyethylene glycol esters, polyethylene glycols, glycerol ethers, a cyclodextrin (for example alpha-, beta- or gamma-cyclodextrin, e.g. alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono- or diglycosyl-alpha-, beta- or gamma-cyclodextrin, mono- or dimaltosyl-alpha-, beta- or gamma-cyclodextrin or panosyl-cyclodextrin), polysorbate 20, polysorbate 80 or mixtures of those compounds. A specific example of a solubilizer is a reaction product of castor oil and ethylene oxide, for example the commercial products Cremophor EL® or Cremophor RH40®. Reaction products of castor oil and ethylene oxide have proved to be particularly good solubilizers that are tolerated extremely well by the eye. Another solubilizer is selected from tyloxapol and from a cyclodextrin. The concentration used depends especially on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is from 0.1 to 5000 times the concentration of the active ingredient.

[0042] The formulations may comprise further non-toxic excipients, such as, for example, emulsifiers, wetting agents or fillers, such as, for example, the polyethylene glycols designated 200, 300, 400 and 600, or Carbowax designated 1000, 1500, 4000, 6000 and 10000. The amount and type of excipient added is in accordance with the particular requirements and is generally in the range of from approximately 0.0001 to approximately 90% by weight.

[0043] Other compounds may also be added to the formulations of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family and vinyl polymers. In other embodiments, the pharmaceutical compositions according to the present invention will be formulated for other types of administration, such as oral, parenteral, inhalation spray, nasal, buccal, or via an implanted reservoir. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. Methods of formulating pharmaceutical compositions for such forms of administration are well-known to one of skill in the art.

[0044] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a molecule thereof as an active ingredient. Compositions of the present invention may also be administered as a bolus, electuary, or paste.

[0045] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the particle is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium molecules; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0046] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the supplement or components thereof moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0047] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in p articular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0048] Suspensions, in addition to compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0049] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.