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US-20260124179-A1 - FORMULATIONS

US20260124179A1US 20260124179 A1US20260124179 A1US 20260124179A1US-20260124179-A1

Abstract

Described herein are formulations including pharmaceutical agents comprising ester and/or lactone ring structures, and methods of using the same. The invention is also directed to a method and ophthalmic pharmaceutical compositions including solution and semisolid dosage forms (i.e. ophthalmic creams, gels, lotions, serums, and/or ointments) of treating a patient with various ocular diseases including presbyopia and dry eyes. The method comprising instructing a patient to apply one strip of the ophthalmic composition to the eyelids that includes pilocarpine or other active pharmaceutical ingredients containing ester and/or lactone ring structures with and without the buffering system.

Inventors

  • Xiaojun Michael Liu
  • James Jane-Guo Shiah
  • Gabriella Szekely

Assignees

  • GLAUKOS CORPORATION

Dates

Publication Date
20260507
Application Date
20251230

Claims (20)

  1. 1 . A semi-solid formulation for ophthalmic therapy, the semi-solid formulation comprising: a pharmaceutical agent having a lactone ring structure and/or an ester structure; a Lewis acid; a buffer selected from the set consisting of citrate buffer, acetic acid/acetate buffer, glycolic acid buffer, and boric acid/borate buffer; and a thickener; wherein the semi-solid formulation has a viscosity at least about 2000 cps.
  2. 2 . The semi-solid formulation of claim 1 , wherein the pharmaceutical agent includes a pK aAPI and the semi-solid formulation includes a pH less than the pK aAPI .
  3. 3 . The semi-solid formulation of claim 1 , wherein the semi-solid formulation includes a pH between about 4 and about 5.
  4. 4 . The semi-solid formulation of claim 1 , wherein the semi-solid formulation has a viscosity of about 2000 cps to about 200000 cps.
  5. 5 . A semi-solid formulation for ophthalmic therapy, the semi-solid formulation comprising: a pharmaceutical agent having a lactone ring structure and/or an ester structure; a Lewis acid; a buffer; a thickener; and a stabilizer selected from the set consisting of lactic acid, ascorbic acid, and azelaic acid; wherein the semi-solid formulation has a viscosity at least about 2000 cps.
  6. 6 . The semi-solid formulation of claim 5 , wherein the stabilizer is configured to form physical conjugates or complexes with the pharmaceutical agent.
  7. 7 . The semi-solid formulation of claim 6 , wherein the stabilizer and the pharmaceutical agent interact by hydrophobic interactions.
  8. 8 . The semi-solid formulation of claim 6 , wherein the stabilizer and the pharmaceutical agent interact by hydrogen bonding.
  9. 9 . The semi-solid formulation of claim 6 , wherein the stabilizer and the pharmaceutical agent interact by hydrophobic interactions and hydrogen bonding.
  10. 10 . The semi-solid formulation of claim 5 , wherein the pharmaceutical agent includes a pK aAPI and the semi-solid formulation includes a pH less than the pK aAPI .
  11. 11 . The semi-solid formulation of claim 5 , wherein the semi-solid formulation includes a pH between about 4 and about 5.
  12. 12 . The semi-solid formulation of claim 5 , wherein the semi-solid formulation has a viscosity of about 2000 cps to about 200000 cps.
  13. 13 . A semi-solid formulation for ophthalmic therapy, the semi-solid formulation comprising: a pharmaceutical agent having a lactone ring structure and/or an ester structure; an API stabilizing agent; a buffer; and one or both of a stabilizer and a thickener; wherein the semi-solid formulation has a viscosity at least about 2000 cps.
  14. 14 . The semi-solid formulation of claim 13 , wherein the stabilizer is configured to form physical conjugates or complexes with the pharmaceutical agent.
  15. 15 . The semi-solid formulation of claim 14 , wherein the stabilizer and the pharmaceutical agent interact by hydrophobic interactions.
  16. 16 . The semi-solid formulation of claim 14 , wherein the stabilizer and the pharmaceutical agent interact by hydrogen bonding.
  17. 17 . The semi-solid formulation of claim 14 , wherein the stabilizer and the pharmaceutical agent interact by hydrophobic interactions and hydrogen bonding.
  18. 18 . The semi-solid formulation of claim 13 , wherein the pharmaceutical agent includes a pK aAPI and the semi-solid formulation includes a pH less than the pK aAPI .
  19. 19 . The semi-solid formulation of claim 13 , wherein the semi-solid formulation includes a pH between about 4 and about 5.
  20. 20 . The semi-solid formulation of claim 13 , wherein the semi-solid formulation has a viscosity of about 2000 cps to about 200000 cps.

Description

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. application Ser. No. 18/529,306, filed Dec. 5, 2023, which is a continuation of U.S. application Ser. No. 17/587,510, filed Jan. 28, 2022, which claims the benefit of U.S. provisional patent application No. 63/142,889, filed Jan. 28, 2021, the entire disclosure of which is incorporated herein by reference. FIELD Described herein are compositions including pharmaceutical agents comprising ester and/or lactone ring structures, in sustained-release solid, semi-solid (gel, lotion, cream or ointment) formulations for topical and ophthalmic applications and methods of using the same. SUMMARY Described herein are compositions/formulations and processes for stabilizing active pharmaceutical ingredients including an ester and/or lactone ring structure in a liquid, semi-solid or solid composition. Methods of using these compositions in ophthalmic applications are also described. In some embodiments, the compositions described herein are considered stable chemically and physically. In some embodiments, that stability is when the compositions are being stored at room temperature. Development of any pharmaceutical drug product must provide a composition that can maintain both physical and chemical stabilities in order to achieve a stable, scalable, safe, efficacious, and robust pharmaceutical product. The compositions and processes described herein can achieve this end. In some embodiments, the physical stability is achieved at lower pH such as 3.5 while maintaining chemical stability when the compositions are being stored at room temperature. In some embodiments, described herein are selections of active pharmaceutical ingredient (API) free based as well as salt forms that can achieve control over chemical hydrolysis and/or oxidation. In some embodiments, described herein are approaches to controlling chemical hydrolysis. These approaches can be applied alone (such as API stabilizer) or in combination (such as API stabilizers plus pH control) to achieve drug products with desirable properties. In some embodiments, selection of pH buffers that can be used alone, as dual buffers, or as triple buffers to maintain high product quality and desirable physical and chemical stability are described. In some embodiments, selection of charged low molecular weight peptides or amino acids (i.e. arginine, lysine, or histidine) or acidic amino acids (i.e. glutamate and aspartate) that can be used alone, or in combination with buffers to maintain high product quality and desirable physical stability and chemical stability are described. In some embodiments, selection of one or more stabilizers can allow use with other active pharmaceutical ingredients that can form physical conjugates or complexes to achieve chemical stability. In some embodiments, the API is added to a composition at a particular time to optimize formulation. In some embodiments, described are drug compositions and compounding processes that occur at a controlled pH without use of any pH adjusters such as NaOH or HCl. In some embodiments, described herein are compositions that are physically stable as semi-solids with conventional thickening agents at pH values favorable for API stability but, would otherwise have sub-optimal viscosity when compounded using common acid/base pH adjusters. The present compositions and processes can be applicable to similar APIs that contain the same or similar chemical functional groups. In some embodiments, described are compositions including: a pharmaceutical agent including an ester, a lactone ring, or an ester and a lactone ring, and a buffer, a stabilizer, or a combination thereof, wherein the composition is at a pH of between about 3.0 and 8.0. The buffer can be a citrate buffer, acetate buffer, a glycolic acid buffer, a borate buffer, or a combination thereof. The stabilizer can be lactic acid, ascorbic acid, azeliac acid, or a combination thereof. In some embodiments, the composition can further include a Lewis acid, such as, MgCl2 or CaCl2). In some embodiments, the pharmaceutical agent is pilocarpine. Pilocarpine can be provided as a free base, as an HCl salt, nitrate salt, or a combination thereof. In some embodiments, the composition can include a thickener or thickeners, such as Sepineo P600 and cellulosic derivatives including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC), hydroxyl ethyl cellulose (HEC), ethyl cellulose (EC), carboxylmethyl cellulose (CMC), and polysaccharides such as hyaluronic acid, carrageenan. In some embodiments, the composition can have a pH of about 3.0 or about 5.5. Other embodiments describe methods of producing a stable composition including a pharmaceutical agent. The methods can comprise mixing the pharmaceutical agent and other excipients in an aqueous medium to form a mixture and neutralizing the mixture to form the stabilized composition. In some embodiments, the o