A method to enhance the systemic hypoglycemic effect of topically applied insulin by using prostaglandin analogs: Novel fixed combination eye drops of insulin and prostaglandin analogs to lower blood glucose levels

Abstract

Pharmaceutical compositions for the treatment of diabetes via application to the eyes, including the following: A composition comprising insulin, a set of excipients, and a penetration enhancer, wherein the penetration enhancer is a prostaglandin analog. A method for lowering blood glucose levels, comprising the step of administering an effective amount of insulin and a penetration enhancer to the eye. A method for increasing insulin absorption when applied topically to the eye by using a prostaglandin analog as a penetration enhancer.

Description

Technical Field

[0001] The present invention relates to a method of increasing the systemic hypoglycemic effect of insulin when topically applied to the eye via the use of prostaglandin analogs as penetration enhancers, and more specifically, to an ophthalmic composition of insulin and a prostaglandin analog for reducing blood glucose levels.

Background Art

[0002] True diabetes is a chronic metabolic disorder characterized by hyperglycemia or elevated blood glucose levels, affecting millions of individuals worldwide (International Diabetes Federation, 2019). According to the International Diabetes Federation (IDF), as of 2021, an estimated 537 million adults worldwide are living with diabetes, corresponding to approximately 1 in 11 adults. Due to factors such as the aging of the population, urbanization, and lifestyle variations including unhealthy diets and reduced physical activity, the prevalence of diabetes is increasing globally. Diabetes is a major cause of morbidity and mortality, associated with complications such as cardiovascular disease, kidney disease, nerve damage, and blindness.

[0003] The IDF estimates that diabetes was the cause of 4.2 million deaths in 2019, making it one of the leading causes of death worldwide. Insulin therapy is the basis for the treatment of type 1 diabetes and is often required for advanced type 2 diabetes. Insulin is a hormone used to lower blood glucose levels to normal levels. It achieves its hypoglycemic effect by promoting the uptake and storage of glucose in the body's tissues.

[0004] There are several types of insulin products available, which can be classified based on the onset, peak, and duration of their action.

[0005] Due to these differences in action profiles, healthcare providers can adjust insulin therapy to meet the individual needs of diabetic patients. The main types of insulin are as follows. Rapid-acting insulin: Rapid-acting insulin begins to act within 15 minutes of administration, peaks in about an hour, and lasts for 2 to 4 hours. It is typically taken immediately before or with meals to help control postprandial blood glucose spikes. Examples include insulin lispro (Humalog), insulin aspart (NovoLog), and insulin glulysin (Apidra).

[0006] Short-acting insulin: Short-acting insulin, also known as regular or soluble insulin, begins to act within 30 minutes to 1 hour, peaks in 2 to 4 hours, and lasts for 5 to 8 hours. It is usually taken 30 minutes before a meal. Examples include Humulin® and Novolin®.

[0007] Intermediate-acting insulin: Intermediate-acting insulin has a later onset and longer duration of action compared to short-acting insulin. They begin acting within 1-2 hours, peak at 4-12 hours, and last for 12-18 hours. They are typically used to provide basal insulin action throughout the day. Examples include NPH insulin (neutral protamine Hagedorn), such as Humulin N and Novolin N.

[0008] Long-acting insulin: Long-acting insulin provides a slow, steady release of insulin without a pronounced peak, and its effects last for 15 to 24 hours or more. They are used to provide basal insulin action and are often combined with rapid or short-acting insulin to prevent mealtime blood glucose spikes. Examples include insulin glargine (Lantus, Tujeo), insulin detemir (Levemir), and insulin degludec (Tresiba). The chemical properties of different insulin types, including their amino acid sequences and molecular structures, play a crucial role in determining their absorption rates.

[0009] Insulin molecules can exist as monomers or assemble into dimers or hexamers. These assembly states affect insulin absorption. Insulin monomers are more soluble and absorbed more rapidly than dimers or hexamers. The following is a general overview of the chemical properties of various insulin types and how they affect absorption rates.

[0010] Rapid-acting insulin analogs: Rapid-acting insulin is engineered to have slight mutations in its amino acid sequence compared to human insulin. These mutations result in mutated insulin molecules that do not readily self-assemble into hexamers like normal insulin, thus promoting faster absorption into the bloodstream. For example, insulin lispro (Humalog) has a reversal of proline and lysine at positions B28 and B29. This mutation inhibits hexamerization, enhances its solubility, and leads to faster absorption. Insulin aspart (NovoLog) has proline at position B28 substituted with aspartic acid, which also reduces hexamerization and increases the absorption rate. Insulin glutarylsin (Apidra) has asparagine at position B3 substituted with lysine and lysine at position B29 substituted with glutamic acid, which leads to faster dissociation into monomers and faster absorption.

[0011] Short-acting insulin (regular insulin): Conventional insulin, which is structurally identical to human insulin, forms hexamers in the presence of zinc ions. These hexamers must dissociate into dimers and then monomers before being absorbed into the bloodstream. This dissociation process slows the absorption of conventional insulin compared to its rapidly acting analogues.

[0012] Intermediate-acting insulin (NPH): NPH insulin is a suspension of human insulin combined with protamine, a protein that forms a complex with insulin. The protamine-insulin complex has reduced solubility, slowing the absorption of insulin from the injection site into the bloodstream and resulting in an intermediate duration of action.

[0013] Long-acting insulin analogs: Long-acting insulin analogs have modifications or additional components in their amino acid sequences that slow their absorption and prolong their effects. For example, insulin glargine (Lantus, Toujeo) has a glycine substitution with asparagine at position A21 and two arginine units added to the B chain. These mutations reduce the solubility of insulin glargine at physiological pH and cause it to precipitate at the injection site. The precipitate dissolves slowly over time, providing a slow and stable release of insulin. Insulin detemir (Levemir) has a myristic acid fatty acid chain bound to lysine at position B29. This modification increases the binding of insulin detemir to albumin in the bloodstream and at the injection site, slowing its absorption and prolonging its duration of action. Insulin degludec (Tresiba) has a hexadecanoic acid side chain at position B29, facilitating the formation of a multihexamer. These multi-hexamers slowly release monomers, resulting in a sustained and stable action profile.

[0014] Insulin is primarily administered by subcutaneous injection. Administration of insulin via the ocular route has been challenging due to ocular barriers. While these barriers are essential for ocular protection and homeostasis, they present significant challenges for delivering insulin via eye drops. Overcoming these barriers is crucial for the development of a viable intraocular insulin delivery system.

[0015] Insulin is a large molecule consisting of 51 amino acids. It has a molecular weight of approximately 5.8 kDa. Its relatively large size results in inadequate passive diffusion across the ocular barrier, corneal epithelium, intercellular tight junctions, and active efflux transporters, significantly reducing its absorption and bioavailability when delivered via eye drops.

[0016] In addition, the lipophilic nature of the corneal epithelium creates a significant barrier to the absorption of hydrophilic molecules. Insulin is hydrophilic, which further hinders its passive diffusion. Besides the corneal barrier, the conjunctiva and sclera also contribute to limiting drug absorption in the eye. While these tissues are more permeable to hydrophilic molecules than the cornea, their ability to allow the passage of larger molecules like insulin remains limited. Absorption from the eye is also affected by precorneal factors. Eye drops have a short residence time due to rapid drainage by tear fluid. Furthermore, tears contain peptidases and proteases that can potentially break down insulin, reducing its bioavailability.

[0017] Currently, there are no insulin eye drops available to lower blood glucose levels. Insulin is typically administered by injection or via an insulin pump, as it needs to be delivered directly into the bloodstream to be effective. This invention leverages the previously undescribed effects of prostaglandins and prostaglandin analogs on the corneal and conjunctival permeability to macromolecules for use as insulin permeability enhancers.

[0018] Prostaglandins and prostaglandin analogs have been used clinically as intraocular pressure lowering agents since 1998. The first prostaglandin analog approved by the FDA for clinical ophthalmology was latanoprost. Subsequent drugs include unoprostone, travoprost, bimatoprost, tafluprost, and latanoprostone.

[0019] Prostaglandin analogs are prodrugs that undergo hydrolysis in the cornea to become active, selectively stimulating prostaglandin F2α receptors, leading to the upregulation of matrix metalloproteinases and remodeling of the extracellular matrix within the ocular structures adjacent to Schlemm's canal, through which aqueous humor drains. These actions result in increased tissue permeability of these structures, thereby reducing their resistance to outflow into aqueous solutions, and consequently lowering intraocular pressure. Aqueous solutions contain cells and large proteins.

[0020] Although studies showing similar effects on the cornea have not been conducted, variations in the biomechanical properties of the cornea after topical prostaglandin analog treatment suggest that similar variations occur in the cornea.

[0021] The application of latanoprost has been shown to increase corneal hysteresis and is not correlated with the drug-induced reduction in intraocular pressure. This suggests a direct effect of latanoprost on viscoelastic corneal properties (References 1, 2, 3). Other prostaglandin analogs (travoprost, latanoprost, and bimatoprost) have also been shown to be associated with varying degrees of reduction in tissue stiffness and variations in corneal microstructure (Reference 4).

[0022] The biomechanical effects of prostaglandin analogs on the cornea suggest that variations in corneal tissue permeability may also occur, but there are no reports of studies conducted to confirm this. The present invention utilizes this effect to increase the ocular absorption of topical insulin.

Prior Art Documents

Patent Documents

[0023]

Patent Document 1

Chemical Formula

[0024] [Patent Document 2] International (WIPO) Patent Publication No. WO2010097800 ('800): Reference '800 teaches a non-hypoglycemic or euglycemic combination of insulin and a prostaglandin analogue via invasive methods such as injection, implantation, and / or insertion into the Schlemm's canal or other eye tissues and sites associated with or surrounding the Schlemm's canal for the purpose of reducing intraocular pressure. This reference does not teach the use of a prostaglandin analogue as a penetration enhancer to enhance the ocular absorption of topically applied insulin. Nor can it teach a combination of insulin and a prostaglandin analogue for topical ocular application to lower blood glucose levels. The present disclosure specifically excludes hypoglycemic compositions by specifically limiting itself to euglycemic insulin. [Summary of the Invention] [Problems to be Solved by the Invention]

[0025] This invention provides a method for increasing insulin penetration when applied topically to the eye. The invention utilizes the penetration-enhancing properties of prostaglandin analogs to facilitate insulin transport across the corneal and conjunctival barriers, resulting in improved bioavailability and therapeutic efficacy. The invention provides an ocular topical formulation for managing diabetes, comprising insulin and prostaglandin analogs that induces a significant systemic hypoglycemic effect. The invention offers a comfortable and patient-friendly alternative to subcutaneous insulin injection, reducing the burden of frequent injections, improving patient compliance, and providing a versatile platform for drug delivery to the eye, which can be further adapted and optimized for the administration of other therapeutic agents with limited ocular penetration.

[0026] This invention relates to a novel insulin delivery system that utilizes the application of insulin to the eye.

[0027] The present invention relates to a novel insulin delivery system for topical administration to the eye, providing at least one rapid or short-acting form of insulin and at least one prostaglandin analog.

[0028] The present invention relates to a novel insulin formulation comprising at least one insulin in a rapid or short-acting form and at least one prostaglandin analog. The present invention also relates to an insulin formulation having a prostaglandin analog further comprising an excipient used for ocular application.

[0029] This invention relates to a method for producing an ophthalmic solution using insulin and prostaglandin analogs. This invention has the potential to revolutionize diabetes management by providing a convenient method of insulin administration while avoiding the complications and problems associated with conventional subcutaneous injections. [Modes for carrying out the invention]

[0030] The present invention is further disclosed in the following paragraphs. Terms used in this disclosure are considered to be those used in the art of the present invention. No new usages of these words are introduced in the further disclosure.

[0031] As already presented in the previous section, the present invention relates to a novel ocular insulin delivery system that utilizes prostaglandin analogs as penetration enhancers. The present invention utilizes insulin identified as rapid-acting or short-acting insulin.

[0032] This invention utilizes, but is not limited to, rapid-acting insulins such as insulin lispro and insulin aspart. While not limited to these, this invention also utilizes short-acting insulins such as regular insulin (insulin R).

[0033] This invention utilizes prostaglandin analogs as penetration enhancers. This invention utilizes, but is not limited to, prostaglandin analogs such as latanoprost, bimatoprost, travoprost, or tafluprost. By leveraging the corneal penetration-enhancing properties of prostaglandin analogs, this invention promotes insulin transport across the corneal and conjunctival barriers, resulting in a significant systemic hypoglycemic effect.

[0034] The present invention is not limited to the use of excipients and other components commonly used in the preparation of ophthalmic drugs, such as: Preservative: Benzalkonium chloride (final concentration range may be 0.005% to 0.08%); Surfactants: Polysorbate 80, Polyoxyl 40 hydrogenated castor oil, Metacresol; Chelating agents: Disodium edetate, tromethamine; Buffering agents: Sodium dihydrogen phosphate, sodium monobasic phosphate, citrate monohydrate, sodium hydrogen phosphate dihydrate, hydrochloric acid, sodium hydroxide, boric acid, sodium borate; Viscosity enhancers: HPMC 4000 cps, PVA, carbomer, PEG, sodium hyaluronate, glycerin; Isotonic agents: sodium chloride, glycerol, zinc chloride, zinc oxide pH adjusters: HCl / NaOH qs at pH 6.4-7.4; and Solvent: Water for injection.

[0035] The insulin concentration in this invention is in the range of 1.735 mg / mL to 69.4 mg / mL or 0.1735% to 6.94%. The concentration of the prostaglandin analog within the scope of this invention varies depending on which analog is used. In the case of latanaprost, the final concentration range is 0.000625% to 0.2%. In the case of unoprostone, the final concentration range is 0.015% to 0.6%. In the case of travoprost, the final concentration range can be 0.002% to 0.16%. In the case of bimatoprost, the final concentration range can be 0.00125% to 0.12%. In the case of tafluprost, the final concentration range can be 0.00018775% to 0.06%. Prostaglandin analogs are relatively insoluble and typically must be dissolved with a surfactant at a high temperature of 80°C and then cooled before mixing with insulin, because insulin denatures above 40°C. Insulin itself is relatively insoluble at pH 6.4–7.4 and must be dissolved in water at pH 2–3. Then, the pH is adjusted by buffering until the desired pH of 6.4–7.4 is achieved.

[0036] The present invention is prepared by dissolving a selected aqueous solution of insulin at an appropriate concentration and adjusting its pH to 6.4-7.4, and mixing it with a selected solution of a selected prostaglandin analog together with a selected surfactant at an appropriate concentration and similarly adjusted pH in water. A selected excipient is added to the combination while maintaining the pH by buffering. The mixture is gently stirred until the components are completely combined to obtain a homogeneous insulin eye drop solution.

[0037] The present invention is administered topically to the eye in amounts recommended by the user's healthcare professional. As established in the background of the present invention, there are various factors that hinder the application of insulin via the ocular administration route. The most prominent factors are biological factors and how insulin interacts with them. As a relatively large molecule, insulin poses significant challenges to absorption in the eye. Insulin also has 18 hydrophilic residues on its surface, which makes it difficult to be absorbed through the lipophilic barrier of the eye. Tear turnover (metabolic turnover) due to nasolacrimal drainage also shortens the drug contact time with the cornea and limits absorption.

[0038] The technical solutions presented by this invention, which are not disclosed in the prior art, are the use of prostaglandin analogs as osmotic enhancers for insulin, and the combination of prostaglandin analogs and insulin to lower blood glucose levels. It was previously unknown that this drug combination could lower blood glucose levels through topical application to the eye.

[0039] As found in prior art, prostaglandin analogs are hydrolyzed to an active form in the cornea, selectively stimulating prostaglandin F2α receptors, leading to the upregulation of matrix metalloproteinases and the remodeling of the extracellular matrix in ocular structures adjacent to Schlemm's canal, through which aqueous humor is drained.

[0040] These effects result in increased tissue permeability of these structures, thereby reducing efflux resistance to aqueous solutions and consequently lowering intraocular pressure. This mechanism also allows for increased uptake of insulin applied locally to the eye, thus solving the problems of prior art.

[0041] To further increase insulin uptake, excipients such as polysorbate 80 and benzalkonium chloride are used in this invention. These excipients affect the corneal epithelial barrier, enabling increased paracellular transport. This novel method of administering insulin also eliminates the fear of needles, which is a highly invasive method of introducing insulin into the bloodstream, thus enabling increased compliance by the user.

[0042] The present invention is not intended to limit its scope, but rather will be further discussed in the following specific examples, which give embodiments in which the invention has been used and tested. [Examples]

[0043] Example 1 Preparations of insulin eye drops using regular insulin (insulin R) and latanoprost. Regular insulin: 0.1735% Latanoprost: 0.0025% Benzalkonium chloride: 0.01% Polysorbate 80: 0.1% Buffer: qs buffering capacity nmt 0.5% Isotonic agent: A sufficient amount of 0.5-2% NaCl to achieve an osmotic pressure of approximately 308 mOsMol / Kg. Solvent: qs2.5mL

[0044] Example 2 Preparations of insulin eye drops using insulin lispro and tafluprost Insulin lispro: 0.1735% Tafluprost: 0.0025% Polysorbate 80: 0.5% Buffer: qs buffering capacity nmt 0.5% Isotonic agent: A sufficient amount of 0.5-2% NaCl to achieve an osmotic pressure of approximately 308 mOsMol / Kg. Solvent: qs2.5mL

[0045] Example 3 Preparations of insulin eye drops using insulin aspart and bimatoprost Insulin aspart: 6.94% Bimatoprost: 0.12% Benzalkonium chloride: 0.01% Polysorbate 80: 0.5% Buffer: qs buffering capacity nmt 0.5% Isotonic agent: A sufficient amount of 0.5-2% NaCl to achieve an osmotic pressure of approximately 308 mOsMol / Kg. Solvent: qs2.5mL

[0046] Example 4 Preparations of insulin eye drops using regular insulin (insulin R) and travoprost. Regular insulin: 0.1735% Travoprost: 0.002% Polysorbate 80: 0.5% Buffer: qs buffering capacity nmt 0.5% Isotonic agent: A sufficient amount of 0.5-2% NaCl to achieve an osmotic pressure of approximately 308 mOsMol / Kg. Solvent: qs2.5mL

[0047] Example 5 Preparations of insulin eye drops using regular insulin (insulin R) and unoprostone. Regular insulin: 0.1735% UnoProstone: 0.015% Benzalkonium chloride: 0.01% Polysorbate 80: 0.5% Buffer: qs buffering capacity nmt 0.5% Isotonic agent: A sufficient amount of 0.5-2% NaCl to achieve an osmotic pressure of approximately 308 mOsMol / Kg. Solvent: qs2.5mL

[0048] Example 6 Dose response of latanoprost and regular insulin (insulin R) Fasting fluid glucose was measured (using an Abbott Freestyle Libre Continuous Glucose Monitor). Then, the test drug (0.1735% insulin r versus 0.1735% insulin r + 0.0025% latanoprost) was instilled into both eyes. Tissue glucose was then measured continuously for 8 hours. We compared fasting levels (mg / dL), trough levels (mg / dL), the difference between fasting levels (mg / dL) and trough levels (mg / dL), and the time to trough (hrs.). [Table 1]

[0049] Example 7 Insulin lispro (without BAK) with taflupros Fasting fluid glucose levels were measured (using an Abbott Freestyle Libre Continuous Glucose Monitor). Then, the test drug (insulin lispro 0.1735% vs. insulin lispro 0.1735% + latanoprost 0.0025%) was instilled into both eyes. Tissue glucose levels were then continuously measured for 3 hours. The levels after 3 hours were compared to fasting levels. [Table 2]

[0050] References 1. G Bolivar, et al. Effect of topical prostaglandinanalogues on corneal hysteresis. Acta Ophth. 29 February 2015. Volume 93, Issue6. P. e495 toe4985 2. N Wu, et al. Changes in Corneal BiomechanicalProperties after Long-Term Topical Prostaglandin Therapy. PLOS ONE. 17 May2016. 3. P Tsikripis, et al. The effect of prostaglandinanalogs on the biomechanical properties and central thickness of the cornea ofpatients with open-angle glaucoma: a 3-year study on 108 eyes. Drug Design,Development and Therapy. 3 October 2022. Volume 7, 2013 pages 1149- 1156 4. J Wang, et al. Effect of travoprost, latanoprost andbimatoprost PGF2a treatments on the biomechanical properties of in-vivo rabbitcornea. Exp Eye Res. Volume 215 February 2022, 108920

Claims

1. Pharmaceutical compositions for the treatment of diabetes via application to the eyes, including the following: Insulin and, A set of excipients, Contains a penetration enhancer, Herein, the composition is characterized in that the penetration enhancer is a prostaglandin analog.

2. The pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 1, wherein the insulin is selected from rapid-acting or short-acting insulin.

3. The pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 2, wherein the rapid-acting insulin is selected from insulin lispro and insulin aspart.

4. A pharmaceutical composition for the treatment of diabetes via application to the eye, according to claim 2, wherein the short-acting insulin is regular insulin (insulin R).

5. A pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 1, wherein the prostaglandin analog is selected from latanoprost, unoprostone, bimatoprost, travoprost, tafluprost, and latanoprostene.

6. The pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 1, wherein the set of excipients further comprises a surfactant, a buffer, a thickener, an isotonic agent, a preservative, and a solvent.

7. A pharmaceutical composition for the treatment of diabetes via application to the eye, according to claim 6, wherein the surfactant is selected from polysorbate 80, polyoxyl 40 hydrogenated castor oil, and metacresol.

8. A pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 6, wherein the buffering agent is selected from sodium dihydrogen phosphate, sodium monobasic phosphate, citrate monohydrate, boric acid, sodium hydrogen phosphate dihydrate, hydrochloric acid, sodium hydroxide, sodium citrate dihydrate, and sodium borate.

9. The pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 6, wherein the thickening agent is selected from hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), or carboxymethylcellulose (CMC), and sodium hyaluronate.

10. The pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 6, wherein the isotonic agent is selected from sodium chloride, glycerol, zinc chloride, and zinc oxide.

11. A pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 6, wherein the preservative is selected from benzalkonium chloride, phenol, and sorbic acid.

12. A pharmaceutical composition for the treatment of diabetes by application to the eye, according to claim 6, wherein the solvent is water.

13. The pharmaceutical composition for the treatment of diabetes via application to the eye according to claim 6, wherein the set of excipients further comprises a chelating agent.

14. A pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 13, wherein the chelating agent is selected from disodium edetate and tromethamine.

15. A pharmaceutical composition for the treatment of diabetes by application to the eye, according to claim 1 or 2, wherein the insulin concentration is in the range of 1.735 mg / mL to 34.7 mg / mL.

16. A pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 1 or 3, wherein the concentration of latanoprost is in the range of 0.000625% to 0.2%.

17. A pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 1 or 3, wherein the concentration of unoprostone is in the range of 0.015% to 6%.

18. A pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 1 or 3, wherein the concentration of travoprost is in the range of 0.002% to 0.16%.

19. A pharmaceutical composition for the treatment of diabetes by application to the eye according to claim 1 or 3, wherein the concentration of bimatoprost is in the range of 0.00125% to 0.12%.

20. A pharmaceutical composition for the treatment of diabetes via application to the eye according to claims 1 and 3, wherein the concentration of tafluprost is in the range of 0.0001875% to 0.06%.

21. A method for lowering blood glucose levels, comprising the step of administering an effective amount of insulin and an osmosis enhancer to the eye.

22. The method for lowering blood glucose levels according to claim 21, wherein the insulin is selected from rapid-acting or short-acting insulin.

23. The method for lowering blood glucose levels according to claim 21, wherein the rapid-acting insulin is selected from insulin lispro and insulin aspart.

24. The method for lowering blood glucose levels according to claim 21, wherein the short-acting insulin is regular insulin (insulin R).

25. The method for lowering blood glucose levels according to claim 21, wherein the insulin is selected from insulin lispro, insulin aspart, and regular insulin (insulin R).

26. The method for lowering blood glucose levels according to claim 21, wherein the penetration enhancer is a prostaglandin analog.

27. The method for lowering blood glucose levels according to claim 21 or 25, wherein the penetration enhancer is selected from latanoprost, unoprostone, bimatoprost, travoprost, tafluprost, and latanoprosten.

28. A method for increasing insulin absorption when applied topically to the eye by using a prostaglandin analog as a penetration enhancer.

29. A method for increasing the absorption of insulin when applied topically to the eye, according to claim 28, wherein the insulin is selected from insulin lispro, insulin aspart, and regular insulin (insulin R).

30. The method for increasing insulin absorption when applied topically to the eye, according to claim 28, wherein the prostaglandin analog is selected from latanoprost, unoprostone, bimatoprost, travoprost, tafluprost, and latanoprosten.

Images