SUSTAINED DRUG RELEASE-ENABLED METFORMIN-BASED OCULAR INSERT COMPOSITION AND METHOD OF PREPARATION THEREOF

Abstract

A sustained drug release-enabled metformin-based ocular insert composition, comprising: i) 0.001-0.010% w/w metformin, ii) 0.1-0.9% w/w tamarind seed polysaccharide, iii) 0.2-1.0% w/w xanthan gum, iv) 1.0-2.0% w/v cross-linker, v) 1.5-2.5% w/v propylene glycol, and vi) 90.95-99.95% w/v double distilled water. A method for preparation of composition includes following steps: a) transferring xanthum gum in a beaker containing double distilled water and stirring to obtain a clear solution, b) adding cross-linker and tamarind seed polysaccharide in solution to form a mixture, c) adding metformin and propylene glycol to obtain a liquid mixture which is deaerated and casted in a petri-plate, d) drying casted petri-plate in a hot air oven to form a film on surface of petri-plate, followed by washing with double distilled water, and e) checking pH of washed film to prevent unreacted cross-linker on the film, and storing film in a glass vial of a desiccator.

Specification

Description:CROSS REFERENCE APPLICATION

[0001] This application being a patent of addition, claiming priority from the original patent application 202331050590, titled as PRESERVATIVE-FREE METFORMIN BASED OCULAR INSERT AND METHOD FOR PREPARATION THEREOF filed on 27/07/2023

FIELD OF THE INVENTION

[0002] The present invention relates to a sustained drug release-enabled metformin-based ocular insert composition and method of preparation thereof that provides a controlled release of higher levels of metformin in the vitreous fluid of the eye for treating ocular allergy and enhanced efficacy against diabetes induced retinopathy.

BACKGROUND OF THE INVENTION

[0003] Metformin is primarily used for diabetes as this shows promising effects in treating ocular conditions, but its effectiveness is hindered by rapid elimination when administered topically. There is requirement for a treatment method to provide sustained release with enhanced bioavailability and patient adherence while minimizing systemic side effects. Diabetic retinopathy is treated with invasive administration of steroids or anti-VEGFs (anti-vascular endothelial growth factor) which compromise patient compatibility.

[0004] While steroids aggravate the ocular damage, anti-VEGFs are biologics which have stability and short half-life issues. An ocular insert provides a controlled and sustained release of the drug for improving efficacy and patient compliance. However, there are certain challenges including ensuring the insert's biocompatibility, achieving optimal drug release profiles, and maintaining patient comfort during use.

[0005] Traditionally, there are treatments for ocular conditions including conventional eye drops, gels, and injections. Eye drops are widely used but often require frequent dosing due to rapid drainage and limited bioavailability, which can lead to inconsistent therapeutic levels. Gels provide a longer-lasting effect but can be uncomfortable and may blur vision. Injectable therapies, while effective, are invasive and carry risks of infection and discomfort. Additionally, many existing treatments do not specifically target the underlying conditions like diabetic retinopathy associated with diabetes, limiting their effectiveness.

[0006] US20240042713A1 discloses a method of preparing a sustained release biodegradable ocular insert or implant comprising melt extruding or injection molding a polymer composition and an active agent to form an insert or implant suitable for administration to the body. e.g., ocular administration. The method comprises feeding the polymer composition and the active into an extruder; mixing the components in the extruder; extruding a strand; and cutting the strand into unit dose inserts or implants. Although US'713 discloses a method of preparing a sustained release biodegradable ocular insert. However, the cited art lacks in providing a controlled release of higher levels of metformin in the vitreous fluid of the eye for treating ocular allergy and enhanced efficacy against diabetes induced retinopathy.

[0007] TW201828933A discloses a method for treating an ocular disease, particularly a diabetes related ocular disease, comprising administering to a subject in need thereof an effective amount of a group of compounds having a structure of Formula A1, wherein the ocular disease is selected from the group consisting of proliferative vitreoretinopathy (PVR), uveitis, glaucoma and age related macular degeneration (AMD), and the diabetes related ocular disease is selected from the group consisting of diabetic retinopathy (DR) and diabetic macular edema (DME). Although TW'933 discloses a method for treating diabetes related ocular disease. However, the cited art lacks in providing metformin in the vitreous fluid of the eye for treating ocular allergy and diabetes retinopathy that is biocompatible and preservative-free.

[0008] Conventionally, many treatments are available for ocular conditions. However, the cited art requires frequent dosing due to rapid drainage and limited bioavailability, and may temporarily blur vision. These methods are also invasive and carry risks of infection and discomfort for the patient and do not specifically target the underlying conditions like diabetic retinopathy associated with diabetes, hence, limiting their effectiveness.

[0009] In order to overcome the aforementioned drawbacks, there exists a need in the art to develop an ocular insert for providing metformin in the vitreous fluid of the eye for treating ocular allergy and diabetes retinopathy that is biocompatible and preservative-free.

OBJECTS OF THE INVENTION

[0010] The principal object of the present invention is to overcome the disadvantages of the prior art.

[0011] An object of the present invention is to develop a metformin-based ocular insert that have a higher drug loading capacity in order to provide enhanced efficacy against ocular allergy.

[0012] Another object of the present invention is to develop a metformin-based ocular insert that provides an adequate availability of the metformin in the vitreous fluid of the eye leading to efficacy against diabetes induced retinopathy.

[0013] Another object of the present invention is to develop a metformin-based ocular insert that provide a non-invasive therapeutic strategy for the management of diabetic retinopathy.

[0014] Yet another object of the present invention is to develop a metformin-based ocular insert that does not contain any preservatives and highly stable for upto 6 months.

[0015] The foregoing and other objects, features, and advantages of the present invention will become readily apparent upon further review of the following detailed description of the preferred embodiment as illustrated in the accompanying drawings.

SUMMARY OF THE INVENTION

[0016] The present invention relates to a sustained drug release-enabled metformin-based ocular insert composition and method of preparation thereof that provides a non-invasive ocular insert for transferring higher levels of metformin into the eyes that is effective against acute ocular inflammation, and ocular allergy. The prepared ocular insert is biocompatible and remain aseptic and highly stable without the presence of preservative.

[0017] According to an embodiment of the present invention, a sustained drug release-enabled metformin-based ocular insert composition, comprises of: i) metformin in range of 0.001-0.010% w/w, ii) tamarind seed polysaccharide in range of 0.1-0.9% w/w, iii) xanthum gum in range of 0.2-1.0% w/w, iv) cross-linker in range of 1.0-2.0% w/v, v) propylene glycol in range of 1.5-2.5% w/v, and vi) double distilled water in range of 90.95-99.95% w/v.

[0018] According to another embodiment of the present invention, a method for preparation of the composition includes following steps: a) transferring xanthum gum in a beaker containing double distilled water with continuous stirring at 600 rpm for dissolving the xanthum gum in the water to obtain a clear solution, b) adding cross-linker to the solution along with stirring, followed by adding of tamarind seed polysaccharide in the solution to form a mixture, c) adding metformin in the mixture and stirred, followed by addition of propylene glycol to form obtain a liquid mixture which is deaerated and casted in a petri-plate, d) drying the casted petri-plate in a hot air oven at a temperature in range of 30-60o C which results in development of a film on surface of the petri-plate, followed by washing the film with double distilled water, and e) checking pH of washed film to prevent any trace of unreacted cross-linker on the film, followed by storing of the film corresponding to the composition, in a glass vial of a desiccator.

[0019] While the invention has been described and shown with particular reference to the preferred embodiment, it will be apparent that variations might be possible that would fall within the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings where:
Figure 1 illustrates a flowchart depicting a method of preparation of a sustained drug release-enabled metformin-based ocular insert composition.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The following description includes the preferred best mode of one embodiment of the present invention. It will be clear from this description of the invention that the invention is not limited to these illustrated embodiments but that the invention also includes a variety of modifications and embodiments thereto. Therefore, the present description should be seen as illustrative and not limiting. While the invention is susceptible to various modifications and alternative constructions, it should be understood, that there is no intention to limit the invention to the specific form disclosed, but, on the contrary, the invention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the invention as defined in the claims.

[0022] In any embodiment described herein, the open-ended terms "comprising," "comprises," and the like (which are synonymous with "including," "having" and "characterized by") may be replaced by the respective partially closed phrases "consisting essentially of," consists essentially of," and the like or the respective closed phrases "consisting of," "consists of, the like.

[0023] As used herein, the singular forms "a," "an," and "the" designate both the singular and the plural, unless expressly stated to designate the singular only.

[0024] The present invention relates to a sustained drug release-enabled metformin-based ocular insert composition and method of preparation thereof to treat corneal ulcers and ocular allergy by delivering high metformin in the patient's eye for an extended length of time. The prepared ocular insert is a non-invasive therapeutic strategy that provides an alternate to the available invasive treatments like steroids and anti-VEGFs (anti-vascular endothelial growth factor) which compromise patient compatibility.

[0025] According to an embodiment of the present invention, a sustained drug release-enabled metformin-based ocular insert composition, comprising: i) metformin in range of 0.001-0.010% w/w, ii) tamarind seed polysaccharide in range of 0.1-0.9% w/w, iii) xanthum gum in range of 0.2-1.0% w/w, iv) cross-linker in range of 1.0-2.0% w/v, v) propylene glycol in range of 1.5-2.5% w/v, and vi) double distilled water in range of 90.95-99.95% w/v.

[0026] The preferable value of i) metformin is 0.005% w/w, ii) tamarind seed polysaccharide is 0.5% w/w, iii) xanthum gum is 0.5% w/w, iv) cross-linker is 1.6% w/v, v) propylene glycol is 2% w/v, and vi) double distilled water is 95.95% w/v.

[0027] The cross-linker includes but not limited to citric acid, glutaraldehyde, formaldehyde, borax, genipin, ethylene glycol dimethacrylate, and trimethylopropane trimethacrylate, wherein the cross-linker is preferably citric acid.

[0028] According to another embodiment of the present invention, a method for preparation of the composition includes following steps: a) transferring xanthum gum in a beaker containing double distilled water with continuous stirring at 600 rpm for dissolving the xanthum gum in the water to obtain a clear solution, b) adding cross-linker to the solution along with stirring, followed by adding of tamarind seed polysaccharide in the solution to form a mixture, c) adding metformin in the mixture and stirred, followed by addition of propylene glycol to form obtain a liquid mixture which is deaerated and casted in a petri-plate, d) drying the casted petri-plate in a hot air oven at a temperature in range of 30-60o C which results in development of a film on surface of the petri-plate, followed by washing the film with double distilled water, and e) checking pH of washed film to prevent any trace of unreacted cross-linker on the film, followed by storing of the film corresponding to the composition, in a glass vial of a desiccator as illustrated in Figure 1.

[0029] The method implemented basically involves a solvent casting method. The prepared composition is preservative free with good stability upto 6 months. The composition provides adequate mucoadhesion and compatibility effective in managing diabetes induced retinopathy. The composition includes higher amount of metformin in matrix of TSP-xanthan gum-citric acid.

[0030] The prepared composition has a high drug loading capacity, i.e. 5mg/6mm to ensure adequate availability of metformin in vitreous fluid for managing retinopathy.

EXAMPLE

[0031] The method for preparation of the composition includes following steps: a) transferring 0.5g xanthum gum in a beaker containing double distilled water with continuous stirring at 600 rpm for dissolving the xanthum gum in the water to obtain a clear solution, b) adding 1g citric acid to the solution along with stirring, followed by adding of 0.5g tamarind seed polysaccharide in the solution to form a mixture, c) adding 5mg/6mm metformin in the mixture and stirred, followed by addition of 2g propylene glycol to form obtain a liquid mixture which is deaerated and casted in a petri-plate, d) drying the casted petri-plate in a hot air oven at 50°C which results in development of a film on surface of the petri-plate (7cm diameter), followed by washing the film with double distilled water, and e) checking pH of washed film to prevent any trace of unreacted cross-linker on the film, followed by storing of the film corresponding to the composition, in a glass vial of a desiccator.

CHARACTERIZATION

ALLERGIC CONJUNCTIVITIS SCORES

Table 1 shows Allergic conjunctivitis scores of different groups.
Days Blank Untreated Metformin insert(Current) Standard (Prednisolone /steroid) MET solution Metformin-TSP insert (SB295) Plain
Day 0 0.33 ±0.51 0.33±0.51 0.33± 0.51 0.33±0.51 0.16 ±0.4 0.16±0.408 0.33±0.51
Day 9 0.66±0.51 7.0±0.89 2.33± 0.51* 2.83±0.75* 6.16±1.47 5.66±0.51 6.66±0.81
Day 18 0.66±0.81 11.0±0.63 2.5± 0.55* 2.16±1.16* 10±0.63 9.83±0.98 9.83±1.16


[0032] The prepared Metformin insert and standard groups showed significantly (P<0.05) better reduction in allergic conjunctivitis when compared to untreated.

Blank Untreated Metformin insert (Current) MET solution
14.05 ±1.21 73.20 ±5.48 25.62 ±4.51* 52.08 ±1.95
[0033] Referring to table 2 mentioned below, the prepared Metformin insert (Current) showed significantly (P<0.001) better reduction in vitreous VEGF levels compared to untreated.

Table 2 shows Anti-VEGF levels of different groups of diabetic rat vitreous


[0034] Although the field of the invention has been described herein with limited reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. , C , Claims:1) A sustained drug release-enabled metformin-based ocular insert composition, comprising:

i) metformin in range of 0.001-0.010% w/w;
ii) tamarind seed polysaccharide in range of 0.1-0.9% w/w;
iii) xanthum gum in range of 0.2-1.0% w/w;
iv) cross-linker in range of 1.0-2.0% w/v;
v) propylene glycol in range of 1.5-2.5% w/v; and
vi) double distilled water in range of 90.95-99.95% w/v.

2) The composition as claimed in claim 1, wherein said cross-linker includes but not limited to citric acid, glutaraldehyde, formaldehyde, borax, genipin, ethylene glycol dimethacrylate, and trimethylopropane trimethacrylate.

3) A method for preparation of said composition as claimed in claim 1, includes steps of:

a) transferring xanthum gum in a beaker containing double distilled water with continuous stirring at 600 rpm for dissolving said xanthum gum in said water to obtain a clear solution;
b) adding cross-linker to said solution along with stirring, followed by adding of tamarind seed polysaccharide in said solution to form a mixture;
c) adding metformin in said mixture and stirred to homogenize said mixture;
d) adding propylene glycol to said homogenized mixture to obtain a liquid mixture which is deaerated and casted in a petri-plate;
e) drying said casted petri-plate in a hot air oven at a temperature in range of 30-60o C which results in development of a film on surface of said petri-plate;
f) washing said film with double distilled water to remove any debris of reagents indulged in reactions; and
g) checking pH of washed film to prevent accumulation any trace of unreacted cross-linker on said film, followed by storing of said film corresponding to said composition, in a glass vial of a desiccator.

4) The method as claimed in claim 3, wherein said composition is preservative free.

5) The method as claimed in claim 3, wherein a solvent casting principle is implemented in said method.

6) The method as claimed in claim 3, wherein said composition provides adequate mucoadhesion and compatibility.

7) The method as claimed in claim 3, wherein said composition is effective in managing diabetes induced retinopathy and pollution (particle 2.5) induced conjunctivitis.

8) The method as claimed in claim 3, wherein said composition includes higher amount of metformin in matrix of TSP-xanthan gum-citric acid.

9) The method as claimed in claim 3, wherein said composition has a high drug loading capacity in range of 4-6 mg/6mm.

Documents