IT202200000821A1 - TOPICAL OPHTHALMIC FORMULATIONS BASED ON XANTHANE WITH REDUCED DOSAGE - Google Patents

Description

Title: "Topical ophthalmic formulations based on xanthan with reduced dosage"

DESCRIPTION

The present invention finds application in the medical field and, in particular, concerns formulations for ophthalmic use characterized by a reduced dosage.

The treatment of eye pathologies through the administration of topical ophthalmic formulations can? be problematic due to the reduced contact time of the formulations, which are quickly washed out due to eye and eyelid movements.

This criticality? can? be only partially remedied by an increase in the frequency of administration of the formulation, as it can? be annoying for the patient, leading to a reduction in adherence to therapy (compliance).

Therefore, research continues into formulations suitable for topical ophthalmic administration which allow a prolonged contact time and greater effectiveness of the active ingredient contained therein.

Summary of the invention

The inventors of the present patent application have surprisingly found that a basic ophthalmic formulation comprising xanthan gum allows for a reduction in dosage and a synergistic increase in the effectiveness of the active ingredient.

Object of the invention

In a first object, the present patent application describes topical ophthalmic formulations comprising xanthan gum for medical use in the treatment of ocular pathologies, characterized by the fact of being administered to a patient according to a reduced dosage.

According to a particular aspect of the invention, xanthan gum is included in a basic formulation.

In another aspect of the invention, xanthan gum-based formulations may comprise one or more active principles.

According to a preferred aspect, these active ingredients are represented by anti-inflammatories, antibiotics, anti-glaucomatous and anti-allergic agents.

Brief description of the figures

Figure 1 shows the results of the cytotoxicity assays. in vitro for A) BME - negative control; B) SDS -positive control; C) Carbopol 980; D) Lutrol F127; E) Xanthan gum.

Figure 2 shows the results of the viability assay? cell on xanthan gum SIRC cells

Figure 3 shows the IQ results determined for single-dose netilmicin eye drops compared to conjunctival ocular isolates (A) MSSA, (B) MRSA, (C) MSCoNS, (D) MRCoNS.

Figure 4 shows the IQ results determined for single-dose netilmicin gel versus conjunctival ocular isolates (A) MSSA, (B) MRSA, (C) MSCoNS, (D) MRCoNS.

Figure 5 shows the IQ results determined for single-dose netilmicin eye drops compared to corneal ocular isolates (A) MSSA, (B) MRSA, (C) MSCoNS, (D) MRCoNS.

Figure 6 shows the QI results determined for single-dose netilmicin gel versus corneal ocular isolates (A) MSSA, (B) MRSA, (C) MSCoNS, (D) MRCoNS.

Detailed Description of the Invention According to a first subject matter, the present invention describes topical ophthalmic formulations comprising xanthan gum in a quantity of approximately 0.7-5.0% (weight/volume) for medical use in the treatment of ocular pathologies, characterized by the fact of being administered to a patient who needs it twice a day.

In a preferred aspect, such formulations are no longer administered? twice a day.

For the purposes of the present invention, within the formulations described xanthan gum (xanthan gum) has a mucomimetic and interaction effect with the tear and the ocular surface, thus contributing to cellular homeostasis.

In particular, the present patent application describes a formulation comprising xanthan gum, as reported above, together with appropriate excipients, such as for example buffers, ionic and non-ionic isotonizing agents, and any preservatives.

In one aspect of the present invention, the described formulations may comprise an additional polymer.

Preferably, this further polymer is unbranched and ? represented by hyaluronic acid or a pharmaceutically acceptable salt thereof.

For the purposes of the present invention, the swab is chosen from the group that includes: acetate buffers, citrate buffers, phosphate buffers, borate buffers or a combination thereof (e.g. citrate/phosphate, etc.) or even tris buffers or other phosphate-free buffers.

As regards the isotonizing agent, this can? understand one or more? of the following ionic salts, such as for example: sodium citrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and non-ionic molecules such as glycerol, mannitol and polyethylene glycol.

According to a particular aspect of the present invention, the described topical formulations may comprise one or more active ingredients chosen from the group which includes: anti-inflammatory, non-steroidal anti-inflammatory, anti-allergic, beta blockers, prostaglandin inhibitors, carbonic anhydrase inhibitors, alpha adrenergic agonists, antivirals, antibiotics, anaesthetics, mydriatics.

According to a preferred aspect of the invention, these active ingredients are characterized by a log P ? 2.5.

Preferably, this active ingredient? represented by an antibiotic.

More? preferably, such an antibiotic? chosen from the group that includes: levofloxacin, ofloxacin, netilmicin, tobramycin and azithromycin and, in an even more important aspect? favorite, ? represented by netilmicin.

In one aspect of the present invention, the described formulations comprise an antibiotic and an anti-inflammatory.

More? preferably, such anti-inflammatory ? represented by dexamethasone, or bromfenac, or nepafenac and their derivative salts.

In a preferred aspect, the described formulations include netilmicin and dexamethasone and their derivative salts.

The formulations of the invention are water-based.

In accordance with a further object of the invention, the formulations are indicated for medical use in the treatment of ocular pathologies and administered with a dosage ranging from two to once a day.

As described above, by way of example, the following topical ophthalmic formulations are reported:

Formulation 1

Formulation 2

Formulation 3

Formulation 4

With the aim of demonstrating the effectiveness in reducing the dosage and the safety of the ophthalmic formulation based on xanthan gum? A clinical study was conducted for the formulation containing netilmicin/dexamethasone in a xanthan gum polymer matrix. In detail of the invention, the dosage reduction involves the administration of netilmicin/dexamethasone in the xanthan gum-based formulation twice a day (BID, bis in day) compared to the eye drops four times a day (QID, quarter in day), in the treatment of inflammatory conditions after cataract surgery, in the presence or risk of microbial infection.

The study, defined as multicenter (n=5) international phase III, double-blind and non-inferiority, involved the enrollment of 168 patients, male and female, aged over 40 years of age, who were randomized to receive the netilmicin/dexamethasone ophthalmic BID in a xanthan gum-based formulation (N = 85) or the QID for eye drops (N = 83) from the day of cataract surgery (Day 0) , until Day 15.

The percentage of complete responders (patients with no cells and flare in the anterior chamber) at 7 days? was evaluated as the primary endpoint. Secondary parameters (microbial measurements, IOP, assessment of clinical signs/symptoms, VA, and safety) were assessed at each visit.

The results obtained demonstrated that the signs of flare and absence of cells (cellularity) resolved at 7? post-operative day in 92.5% of patients and completely by 15? day. In both the ITT (Intent to Treat) and PP (per protocol) populations, the efficacy analysis demonstrated that the netilmicin/dexamethasone combination administered twice daily in a xanthan-based formulation? not less than that in eye drops administered four times a day.

The evidence demonstrated that in the clinical response obtained after 7 days, the xanthan-based formulation made it possible to reduce the dosage (2 times a day), surprisingly demonstrating non-inferiority. compared to the approved dosage for eye drops (4 times a day). Both treatments were very well tolerated and effective.

To the benefit of the invention, the xanthan-based formulation is ? was evaluated in comparison with other compositions of different polymeric nature.

In particular, ? Has the in vitro safety profile and tolerability been evaluated? in vivo for formulations based on xanthan gum, carbopol 980 and lutrol F127.

In the results of the acute (8 administrations per day) and sub-acute (5 administrations for four days) Draize, the xanthan polymer matrix formulation demonstrated excellent performance without cellular toxic effects, as demonstrated by the cellular morphology and the viability test. MTT (figures 1 and 2). In support of the invention, ? an analysis was also conducted to determine the QIs of levofloxacin, ofloxacin, netilmicin, tobramycin and azithromycin. In detail ? The maximum effective concentration (Cmax) and the minimum inhibitory concentration (MIC90) were evaluated on the most bacterial isolates? widespread in corneal and conjunctival ocular infections (MSSA, MRSA, MSCoNS, MRCoNS).

The obtained MIC90 and Cmax data were put into relation to calculate the IQ in both tissues.

In particular, corneal and conjunctival Cmax values for netilmicin, tobramycin, levofloxacin, ofloxacin and azithromycin, in single and multiple doses, were extrapolated from several in vivo pharmacokinetic studies.

The MIC90 values for the five antibiotics under consideration were obtained from two studies that fully correspond to the selection criteria

The Cmax values were compared with the MIC 90 and the IQs obtained were plotted.

The IQ values show that, regarding the single dose, the eye drops containing netilmicin are ? revealed the best in conjunctiva against the bacterial isolates MRSA, MRCoNS and MSCoNS (Fig.3).

? interesting to note that, under the same conditions, the xanthan-based gel formulation of netilmicin allowed a significant general increase in IQs, taking into account the fact that, even against MSSA, it was revealed the most formulation? effective among those studied (Fig.4).

In the cornea, netilmicin eye drops showed higher IQ higher than other formulations in MRSA and MRCoNS strains.

It also outperformed azithromycin and some quinoion formulations in MSCoNS (Fig. 5). Surprisingly also in this case, under the same conditions, the netilmicin gel formulation determined a significant general increase in IQ so that, with the exclusion of a 1.5% levofloxacin solution (not used in commercial ophthalmic products ), netilmicin gel has proven to be the most effective formulation effective against MSCoNS. Against MSSA, netilmicin gel achieved better IQ values in the cornea than azithromycin (Azasite?) and ofloxacin formulations (Fig. 6).

This evidence supports the invention, demonstrating that in the gel formulation of netilmicin, the molecule? capable of interacting with the xanthan-based polymeric matrix, significantly amplifying its power and favoring the increase in IQ within the target tissues.

Claims (12)

CLAIMS: 1. A topical ophthalmic formulation comprising xanthan gum in a quantity of approximately 0.7-5.0% (weight/volume) and dexamethasone for medical use in the treatment of ocular pathologies, characterized by the fact of being administered to a patient who needs it 2 times a day. 2. The topical ophthalmic formulation for use according to the previous claim, wherein the xanthan gum has an effect of enhancing the efficacy of the drug and improving tolerability. eye of the formulation. 3. The topical ophthalmic formulation for use according to the preceding claims which includes one or more active ingredients chosen from the group which includes: steroidal anti-inflammatories, non-steroidal anti-inflammatories, antiallergics, beta blockers, prostaglandin inhibitors, carbonic anhydrase inhibitors, alpha adrenergic agonists, antivirals, antibiotics, anaesthetics, mydriatics. 4. The topical ophthalmic formulation for use according to claim 3, wherein the active ingredients have a log P ? 2.5 5. The topical ophthalmic formulation for use according to any of the preceding claims, wherein the xanthan gum further has a mucomimetic and interacting effect with the tear and the ocular surface, thus contributing to cellular homeostasis. 6. The topical ophthalmic formulation for use according to any of the preceding claims further comprising: a tampon and/or at least one isotonizing agent. 7. The topical ophthalmic formulation for use according to any of the preceding claims, which can? furthermore contain a further unbranched polymer represented by hyaluronic acid or a pharmaceutically acceptable salt thereof. 8. The ophthalmic topical formulation for use according to one of the preceding claims 6 or 7, wherein said swab can? include phosphate buffer, citrate buffer, phosphate/citrate buffer, tris buffer, or any buffer not containing phosphates. 9. The topical ophthalmic formulation for use according to one of claims 6 or 7, wherein said isotonizing agent is chosen from the group that includes ionic salts and non-ionic molecules such as: sodium citrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glycerol, mannitol, polyethyl glycol. 10. The topical ophthalmic formulation for use according to any of the preceding claims comprising an antibiotic represented by netilmicin. 11. The topical ophthalmic formulation for use according to any of claims 1 to 10, comprising: or including: i ? 12. The topical ophthalmic formulation for use according to the previous claim, characterized in that it is administered to a patient who needs it once a day.