EP-4736853-A2 - DEGRADANT COMPOUND IN A MEDICAMENT

Abstract

The present disclosure is directed to ophthalmic formulations comprising carbachol, brimonidine, and less than 5% of one or more impurities, processes for preparing ophthalmic formulations comprising carbachol, brimonidine, and less than 5% of one or more impurities, and methods of treating presbyopia and other ophthalmic conditions by administering ophthalmic formulations comprising carbachol, brimonidine, and less than 5% of one or more impurities.

Inventors

• SCHIFFMAN, Rhett Mead
• FIRESTONE, Bruce Alan

Assignees

• Visus Therapeutics, Inc.

Dates

Publication Date

20260506

Application Date

20211102

Claims (15)

1. An ophthalmic formulation comprising 2.75 wt % carbachol, or a pharmaceutically acceptable salt thereof, 0.1 wt % brimonidine, or a pharmaceutically acceptable salt thereof, and 0.2 wt % hydroxypropylmethyl cellulose (HPMC), wherein the formulation does not contain a preservative, and wherein the formulation comprises less than 5 wt % of one or more impurities.
2. The ophthalmic formulation of claim 1, wherein the formulation further comprises a buffer.
3. The ophthalmic formulation of claim 2, wherein the buffer is a phosphate buffer.
4. The ophthalmic formulation of claim 3, wherein the phosphate buffer comprises sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.
5. The ophthalmic formulation of any one of claims 1-4, wherein the pH of the formulation is from about 7.2 to about 7.6.
6. The ophthalmic formulation of any one of claims 1-5, wherein the pH of the formulation is about 7.4.
7. The ophthalmic formulation of any one of claims 1-6, wherein the brimonidine is brimonidine tartrate.
8. The ophthalmic formulation of any one of claims 1-7, for use in a method of ameliorating or reducing presbyopia in a subject in need thereof, the method comprising administering to at least one eye of the subject the ophthalmic formulation.
9. The ophthalmic formulation for use according to claim 8, wherein the formulation further comprises a buffer.
10. The ophthalmic formulation for use according to claim 9, wherein the buffer is a phosphate buffer.
11. The ophthalmic formulation for use according to claim 10, wherein the phosphate buffer comprises sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.
12. The ophthalmic formulation for use according to any one of claims 8-11, wherein the pH of the ophthalmic formulation is from about 7.2 to about 7.6.
13. The ophthalmic formulation for use according to any one of claims 8-12, wherein the pH of the ophthalmic formulation is about 7.4.
14. The ophthalmic formulation for use according to any one of claims 8-13, wherein the brimonidine is brimonidine tartrate.
15. The ophthalmic formulation for use according to any one of claims 8-14, wherein the amelioration or reduction of presbyopia is effective for at least 9 hours.

Description

FIELD AND BACKGROUND OF THE INVENTION The present disclosure relates to ophthalmic formulations comprising carbachol, brimonidine, and less than 5 wt % of one or more impurities. The formulations disclosed may be useful in treating ophthalmic conditions such as presbyopia. Presbyopia is typically age-related eye deterioration. Young, properly functioning, eyes are able to see at near distances, an ability that deteriorates as one ages. Presbyopia normally develops as a person ages, and is associated with a natural progressive loss of accommodation. A presbyopic eye loses the ability to rapidly and easily focus on objects at near distances. Presbyopia progresses over the lifetime of an individual, usually becoming noticeable after the age of 45 years. By the age of 65 years, the crystalline lens has often lost almost all elastic properties and has only limited ability to change shape. Use of over the counter reading glasses is a very common way of addressing the vision problems associated with presbyopia. Reading glasses allow the eye to focus on near objects and maintain a clear image. This approach is similar to that of treating hyperopia, or farsightedness. Many presbyopes are also prescribed bi-focal eyeglasses, where one portion of the lens is corrected for distance vision and another portion of the lens is corrected for near vision. When peering down through the bifocals, the individual looks through the portion of the lens corrected for near vision. When viewing distant objects, the individual looks higher, through the portion of the bi-focals corrected for distance vision. Contact lenses and intra-ocular lenses (IOLs) have also been used to treat presbyopia, for example, by relying on monovision (where one eye is corrected for distance-vision, while the other eye is corrected for near-vision) or bilateral correction with either bi-focal or multi-focal lenses. Laser ablation has also been used to treat presbyopia. All these procedures seek to correct the problem for long term purposes using drastic steps (surgery, laser ablation, etc) or require wearing corrective lenses. There remains a need for new ways of ameliorating or reducing presbyopia for patients that do not wish to undergo surgery (IOLs, laser ablation, etc.) or use corrective glasses. For people who use corrective lenses, there remains a need to temporarily treat presbyopia without the use of corrective lenses. As with any formulation designed for treatment of a subject in need thereof, it is important to identify and quantify the presence of any impurities in the formulation. In particular, formulations comprising two or more active agents may result in unexpected reactivity between said agents, resulting in the formation of impurity species. Thus, there is a need to identify and quantify the presence of any impurity species in ophthalmic formulations comprising carbachol and brimonidine. BRIEF SUMMARY OF THE INVENTION The present disclosure provides ophthalmic formulations comprising carbachol, brimonidine, and less than 5 wt % of one or more impurities. In some aspects, the ophthalmic formulation comprises from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and wherein the formulation comprises less than 5 wt % impurity A after storage for about 5 months, wherein impurity A has the structure: or a tautomer thereof, wherein the concentration of impurity A is measured by high-performance liquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine. In some aspects, the ophthalmic formulation is stored at 40 °C and not more than (NMT) 25% relative humidity for about 5 months. In some aspects, the ophthalmic formulation comprises less than 3 wt % impurity A after storage at 40 °C and NMT 25% relative humidity for about 3 months. In some aspects, the ophthalmic formulation comprises less than 0.25 wt % impurity A. In some aspects, the ophthalmic formulation comprises less than 1 wt % impurity A after storage at 25 °C and 40% relative humidity for about 5 months. In some aspects, the ophthalmic formulation comprises about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.2 wt % HPMC, and from about 0.05 wt % to about 1 wt % of one or more buffers, wherein the pH is about 7.4, and wherein the formulation comprises less than about 5 wt % impurity A after storage for about 5 months, wherein the concentration of impurity A is measured by high-performance liquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v) and impurity A has a relative rete