阅读说明：本技术 减少组合在一起用于眼科用途的抗生素-抗炎药组合物中的抗生素剂量 (Reducing antibiotic dose in antibiotic-anti-inflammatory compositions combined for ophthalmic use ) 是由 M·卡尔诺瓦里 L·马尔切洛尼 F·贝尔托基 于 2020-03-10 设计创作，主要内容包括：本发明涉及一种眼用组合物,其包括：混合物,所述混合物包括抗生素和皮质类固醇,或由其组成；以及可选的一种或多种药用级添加剂和赋形剂；所述组合物用于在先前接受眼部手术(优选白内障手术)的患者中预防术后感染并治疗炎症事件的方法。本发明涉及减少组合在一起用于眼科用途的抗生素/抗炎药组合物中的抗生素剂量的方法。(The present invention relates to an ophthalmic composition comprising: a mixture comprising or consisting of an antibiotic and a corticosteroid; and optionally one or more pharmaceutically acceptable additives and excipients; the compositions are useful in methods of preventing post-operative infection and treating inflammatory events in patients who have previously undergone eye surgery, preferably cataract surgery. The present invention relates to a method of reducing the amount of antibiotic doses in an antibiotic/anti-inflammatory composition combined for ophthalmic use.)

1. An ophthalmic composition in the form of a solution comprising: a mixture comprising or consisting of the antibiotic levofloxacin or a salt thereof or a hydrate thereof or a hemihydrate thereof, and the corticosteroid dexamethasone or a salt thereof or a hydrate thereof or a hemihydrate thereof; and optionally one or more pharmaceutically acceptable additives and excipients and water; the composition is applied to a method for treating postoperative infection of a patient who has previously undergone eye surgery;

wherein the composition is administered to the eye of the patient daily by a non-intravitreal route over a period of 1 to 7 days post-ocular surgery.

2. The composition for use of claim 1, wherein the ocular surgery is cataract surgery.

3. The composition for use of claim 1 or 2, wherein the method for treating post-operative infections in patients previously subjected to ocular surgery provides for administration of the composition by an ocular topical route.

4. The composition for use according to any one of the preceding claims, wherein the levofloxacin or a salt thereof or a hemihydrate or hydrate thereof is present in the composition in solution form at a concentration of 1mg/ml to 10mg/ml of liquid composition, preferably it is 3mg/ml to 7mg/ml of liquid composition, even more preferably it is 4mg/ml to 6mg/ml of liquid composition, such as 4.5mg/ml, or 5mg/ml, or 5.5 mg/ml.

5. The composition for use according to any one of the preceding claims, wherein the dexamethasone or salt thereof or hemihydrate thereof or hydrate thereof is present in the composition in solution form at a concentration of 0.25 to 2.5mg/ml of liquid composition, preferably it is 0.5 to 2mg/ml of liquid composition, even more preferably it is 1 to 1.5mg/ml of liquid composition, such as 1.2mg/ml, or 1.3mg/ml, or 1.4 mg/ml.

6. The composition for use of any one of the preceding claims, wherein the ophthalmic composition further comprises one or more pharmaceutical grade additives and excipients selected from the group comprising or consisting of: sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dodecahydrate, sodium citrate, sodium chloride, boric acid and/or borate, benzalkonium chloride, sodium hyaluronate or hyaluronic acid, NaOH1N for calibrating pH to 6.5 to 7.5, preferably 7 or 7.2, and distilled water.

7. The composition for use of any one of the preceding claims, wherein the composition is administered to the eye of the patient several times per day over a period of 7 days after ocular surgery, comprising 1 or 2 drops of the composition administered 1 to 4 times per day, preferably 1 drop of the composition administered 4 times per day.

8. The composition for use according to any one of the preceding claims, wherein the method for prophylactically or therapeutically treating post-operative infection in a patient who has previously undergone eye surgery does not provide for the subsequent administration of the antibiotic levofloxacin alone, but rather provides for the subsequent administration of the anti-inflammatory dexamethasone alone.

Technical Field

Ocular diseases often have a combination of inflammation and infection that are concomitant to each other.

From the innermost zone to the outermost zone of the eye, we find the following distinct physical zones: retina, vitreous, cornea, lens, extraocular muscles, conjunctiva, lacrimal duct.

Some diseases are associated with the first ocular region of the above-mentioned diseases, which are mainly treated by surgery (except glaucoma, which is a disease caused by elevated intraocular pressure, can also be treated with appropriate drugs).

However, eye surgery usually requires treatment to prevent infection at the pre-and post-operative stages, with eye drops treated with antibiotics and anti-inflammatory drugs that also control pain.

Conjunctival disorders of the lacrimal passage can be conveniently cured using drugs carried in eye drops and ointments for most of the time, sometimes even with ocular inserts. The disease with specific indications most commonly treated with eye drops is selected from the group consisting of: (i) glaucoma, (ii) conjunctivitis, (iii) allergic conjunctivitis, (iv) bacterial-derived external eye infection, (v) viral conjunctivitis, (vi) dry eye, and (vii) eye tearing.

The form of administration using eye drops is generally the only form of treatment and cure for certain diseases. Unfortunately, however, the administration of drugs by instillation through eye drops is very variable. In fact, most of the applied drops are discharged from the application area and lost, since the defense mechanisms of the eye (blinking and tearing) aim to continuously discharge foreign substances such as dust and fibers. It is estimated that the drained and lost portions can be quantified on average as around 70% of the dispensed amount (in drops). It can sometimes be up to 90% of the amount applied. Typically, the amount that can be administered by eye drops is 20 to 50 microliters per drop.

More typically, eye drops have a volume of 30 to 35 microliters, and they are administered in multiple administrations throughout the day. The most common dose for each single administration is 1 or 2 drops per eye, but in some cases, multiple drops per single administration are required several times per day. Multiple administrations throughout the day are usually provided, even in amounts of 8-10 administrations per day, to compensate for tear washout.

Another key is the location of dispensing of the drops (the application area), and if more or longer residence time is required, the cornea or conjunctival sac of the eye can simply be selected.

Bacterial infections can be superficial (conjunctivitis) or deep (keratitis), sometimes requiring the use of antibiotics, anti-inflammatory agents and even analgesics.

As mentioned previously, eye surgery usually requires treatment to prevent infection at the pre-and post-operative stages, with eye drops being treated by antibiotics and anti-inflammatory drugs.

In addition to treatments aimed at limiting and reducing infections, anti-infectives are also used in the treatment of postoperative infections (postoperative phase) during the preoperative phase, one of the most common treatments today being cataract surgery.

It is common practice to prescribe the use of 2 drugs simultaneously in the postoperative treatment of cataract surgery, one to reduce the inciting events due to the formation of tissue healing and the other to act as antibiotics, aimed at preventing bacterial infections.

In the context of the present invention, the term "prevention" is used to denote any medical procedure whose purpose is to avoid or prevent the spread of infections and diseases (prophylactic treatment).

Document EP3216451a1 describes an aqueous ophthalmic composition comprising levofloxacin (or a salt or solvate thereof), dexamethasone (or an ester or salt thereof) and one or more isotonicity agents for use in the treatment of inflammatory diseases of the outer ocular region, such as post-operative inflammation. The composition is not directed against post-operative infection and the document states that over time, administration is not particularly limited until the desired efficacy is achieved.

Disclosure of Invention

One of the existing products is named asThe medicament of (1), which combines the anti-inflammatory steroid dexamethasone with the antibiotic tobramycin in a single eye drop.Are recommended for the treatment of the pre-and post-operative stages of cataract surgery.

Having a volume of 1mlEye drop-suspension contains: 3mg tobramycin and 1mg dexamethasone. Other excipients were: benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfate, tyloxapol, hydroxyethyl cellulose and purified water. The bottle is typically a 5ml bottle. It is recommended to administer the composition 4-5 times a day, 1 or 2 drops each time. Fixed combination (e.g. for) Is a form in which two active ingredients are administered simultaneously in predetermined doses, which, relative to the sum of the two individual active ingredients, produces a therapeutic effect and provides undeniable comfort of use.

However, the administration of a fixed combination (combination/combination of two active pharmaceutical ingredients (a) and (b)) has the disadvantage that the administration of one of the two ingredients (e.g. active ingredient (a)) is prolonged over time, even though it may no longer be useful or necessary, simply to comply with the required recommended dose of the other ingredient (e.g. active ingredient (b)) in order for the latter to complete its dose and thus be effective.

Tobramycin and dexamethasone-basedEye drops are prescribed for 14 days, so that the antibiotic tobramycin is administered for 14 days. All these antibiotic treatment days are unnecessary. Furthermore, in addition to over-stimulation of the tissue, such prolonged antibiotic treatment can create potential antibiotic resistance and have a highly demanding environmental dispersion.

Preferred embodiments of the present invention will be outlined in the following detailed description by way of example, and thus, not limiting the scope of the invention.

Fig. 1 shows the structural formula of levofloxacin.

Fig. 2 shows the structural formula of dexamethasone disodium phosphate.

Figure 3 shows the study protocol used in the present invention.

Figure 4 shows the indications detected as the primary endpoints of the study: no cells were observed under the slit lamp. No cells were present under the slit lamp.

Figure 5 shows the indications detected as the primary endpoints of the study: no material (aqua FLARE) was observed under the slit lamp.

Figure 6 shows the indications detected as secondary endpoints: percentage of patients with congestion at different stages of the study.

Figure 7 shows the symptoms detected as secondary endpoints: percentage of patients with discomfort/irritation at different stages of the study.

The following are the meanings of the expressions used in figures 3 to 7: levofloxacin/dexamethasone was used to represent the subject of the compositions of the invention, for example the composition of example 1.

The composition subject of the invention is used for prophylactic or preventive treatment or prophylactic treatment of patients (post-operative or post-operative stages) who have undergone eye surgery (e.g. cataract removal).

The treatment and treatment methods of the present invention provide for the administration of a composition, preferably an ophthalmic composition. The compositions of the present invention are pharmaceutical compositions. The compositions of the invention are in the form of a single or multi-dose packaged eye drop, sterile solution or spray solution or ointment pharmaceutical comprising or consisting of a mixture comprising an antibiotic in combination or association with an anti-inflammatory agent.

Relative to the useSimilar treatment with eye drop administration, although applied in a reduced dose regimen, the compositions, treatments, and methods of treatment provided for application of the compositions of the present invention are effective to prevent, reduce, or eliminate infection and/or inflammation in patients who have undergone eye surgery (e.g., in the case of patients who have undergone cataract surgery).

Advantageously, the treatments and treatment methods provided for applying the compositions of the present invention (e.g., the compositions of examples 1-4, see below) are capable of reducing the antibiotic administered to a patient undergoing ocular surgery (e.g., in the case of intervention in a patient undergoing cataract surgery) by at least about 30%, or 40%, or 50%.

Advantageously, the treatment and treatment methods of the invention (by administering the compositions of the invention) are capable of preventing an infectious state within only 7 days after treatment; immediately after, or preferably not immediately after, the treatment, followed by another 7 days of treatment based on the anti-inflammatory drug dexamethasone alone, this enables treatment of inflammatory events in patients who have undergone eye surgery.

Advantageously, the treatment and treatment methods of the invention (by administering the compositions of the invention) are performed via a non-intravitreal route.

In the present description, the expression "non-intravitreal" is used to indicate that neither injection nor administration implanted in the eye of a patient is provided for the subject composition of the invention. More precisely, such expression is used to denote an administration in which the subject of the composition of the invention should not pass through the cornea, the lens, the sclera or the limbus by mechanical action in order to place it intravitreally.

Advantageously, the treatment and the treatment method of the invention (by administering the composition of the invention) are carried out via the ocular topical route. Preferably, the composition of the invention is in the form of a single or multi-dose packaged eye drop, sterile solution or spray solution or ointment pharmaceutical comprising or consisting of a mixture comprising an antibiotic in combination or association with an anti-inflammatory agent.

In one embodiment, the dosage and dosage regimen are reported below. In the case of postoperative prophylaxis, administration of the present composition based on levofloxacin and dexamethasone to the patient is prescribed for 1 to 7 days, advantageously 7 days, multiple administrations or daily administration, including 1 to 4 administrations per day, advantageously 3 or 4 administrations per day, preferably 4 administrations per day, 1 or 2 drops (preferably 1 drop) each, followed by administration of dexamethasone alone for 7 days (followed by no administration of the antibiotic levofloxacin alone), or wherein, preferably, no subsequent administration of dexamethasone alone, a sole anti-inflammatory agent, is prescribed and no subsequent administration of levofloxacin alone is prescribed. Thus, in the latter embodiment, the dosage and dosage regimen does not contemplate further administration of levofloxacin or dexamethasone alone, after administration to the patient of a levofloxacin and dexamethasone-based composition of the invention for 1 to 7 days, preferably 7 days.

Objects forming the present invention are (i) ophthalmic compositions in the form of solutions comprising (ii) a mixture and optionally (iii) one or more pharmaceutical grade additives and/or excipients. Mixture (ii) comprises or consists of (iia) a combination or association of an antibiotic with reduced bacterial resistance and an anti-inflammatory agent (iib) selected from corticosteroids. Composition (i) is used in a method for the pre-or post-operative treatment of a bacterial infection in a patient undergoing an ocular surgery. Ocular surgery may be used to remove cataracts. Composition (i) is administered in the eye of the patient before and/or after surgery. If composition (i) is administered post-operatively, the method of treatment prescribes a daily pattern over a period of 1 to 7 days post-ocular surgery.

Furthermore, it is an object of the present invention to form (i) an ophthalmic composition in the form of a solution comprising (ii) a mixture and optionally (iii) one or more pharmaceutical grade additives and/or excipients. Mixture (ii) comprises or consists of (iia) a combination or association of an antibiotic with reduced bacterial resistance and an anti-inflammatory agent (iib) selected from corticosteroids. Composition (i) is used in a method for the pre-or post-operative treatment of a bacterial infection in a patient undergoing an ocular surgery. Ocular surgery may be used to remove cataracts. Composition (i) is administered in the eye of the patient before and/or after surgery. If composition (i) is administered post-operatively, the method of treatment provides for the composition to be administered to the eye of the patient via a non-intravitreal route.

The antibiotic (iia) with reduced antibacterial properties is selected from the group of antibiotics belonging to the family of quinolones, in particular fluoroquinolones, such as levofloxacin.

The anti-inflammatory agent (iib) is selected from compounds belonging to the family of corticosteroids. The family includes compounds belonging to the dexamethasone class of compounds.

The applicant has found that it is useful to develop a composition in the form of eye drops combining the two active ingredients in the field of treatments for preventing, reducing or eliminating pre-and/or post-operative bacterial infections. In the mixture contained in the composition, one of the two active ingredients is an antibiotic, such as levofloxacin, which has a low environmental dispersion over the last years (reduced induction of bacterial resistance).

Table 1 below shows, as bacterial susceptibility, the changes in bacterial resistance recorded over the past 20 years for the predominant antibiotic (the greater the value, the lower the resistance of the antibiotic; journal of the industry, entitled "L' Oculista italino", Special edition of Netilmicin, 9 months from XLVII to 2016).

TABLE 1

Sensitivity to antibiotics: for 20 years

According to the data published in table 1, levofloxacin should be considered as one of the antibiotics with lower bacterial resistance. The levofloxacin molecule showed a minimal level of antibiotic resistance.

Levofloxacin (CAS No:100986-85-4) is a third generation synthetic fluoroquinolone antibacterial agent, which inhibits the supercoiled activity of DNA bacterial gyrase and blocks DNA replication. This is the isomer of ofloxacin (L). Levofloxacin appears as a pale-yellowish-yellow-white crystal or crystalline powder. It is poorly soluble in water and has a molecular weight of 361.4 g/mol.

Levofloxacin, of the formula shown in figure 1, is more soluble in water at neutral pH than ofloxacin, norfloxacin or ciprofloxacin (Raizman et al, 2002; Koch et al, 2005). The solubility in water after 13 weeks of mixing was 1.85% (Robertson et al, 2005). Its lipophilicity is sufficient to penetrate into the eye (keting, 2009).

Dexamethasone is a molecule belonging to the class of steroidal anti-inflammatory drugs, which may exist in an insoluble or soluble lipophilic form, such as phosphate, a prodrug of dexamethasone. In current compositions, such as eye drops, dexamethasone is used in the form of a phosphate ester, such as sodium phosphate or disodium phosphate [2- [ (8S,9R,10S,11S,13S,14S,16R,17R) -9-fluoro-11, 17-di-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,11,12,14,15, 16-octahydrocyclopenta [ a ] phenanthren-17-yl ] -2-oxo-ethyl ] phosphate. The structural formula of dexamethasone sodium phosphate is shown in figure 2.

Table 2 illustrates the dose of each product in its usual clinical practice per day of treatment in drops per day of treatment.

TABLE 2

P is product; d is day.

P1 ═ Maxidex (dexamethasone), the composition of which is disclosed below:

dexamethasone 0.1% (1 mg/ml).

Benzalkonium chloride 0.01% (0.2 mg/ml).

Hydroxypropyl methylcellulose, water.

Dosage:

1 drop every 4 hours. In the case of severe inflammation, 1 or 2 drops every 30 or 60 minutes until the symptoms disappear. The dosage should be gradually reduced.

Composition example 1-levofloxacin/dexamethasone 2 ═ P2

The composition is disclosed as follows:

tobramycin 0.3% (3 mg/ml).

Dexamethasone 0.1% (1 mg/ml).

Benzalkonium chloride 0.01% (0.2 mg/ml).

Excipient: tyloxapol, EDTA, sodium chloride, hydroxyethyl cellulose, sodium sulfate, sulfuric acid and/or sodium hydroxide, water.

Dosage: the medicine is administered 4-5 times per day, 1 or 2 drops each time, within the time period prescribed by the doctor.

Levofloxacin was first recommended for use in preventing bacterial infections before and after eye surgery in patients who have undergone surgery, such as cataract surgery. In addition, the dose of levofloxacin was reduced from 8 drops/day on the first two days to 4 drops/day on the first two days, as was the case with the remaining 5 days of treatment. Compared with the utilization of P4For 14 days of treatment, P3 (composition example 1-levofloxacin/dexamethasone) was able to avoid long-term use of antibiotics for more than 7 days.

In addition to levofloxacin and dexamethasone, the compositions of the invention also comprise a preservative selected from the usual classes or uses, in particular quaternary ammonium salts (preferably and most commonly benzalkonium chloride); and a buffering system, such as a phosphate buffer, citrate, borate, or a combination thereof, capable of stabilizing the pH of the composition at a value near neutral pH 7 (including 6 to 8), such as 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, 8.

Dexamethasone in the form of a phosphate ester is a molecule that is soluble at a particular pH. Levofloxacin (shown in figure 1), on the other hand, is in zwitterionic form, i.e. it is an internal salt containing an anionic portion and a cationic portion, and has a pKa 1: 5.6: pKa 2: 7.9, which means that the anionic, cationic, zwitterionic forms of the molecules coexist in solution. The balance between the different forms of levofloxacin depends on the pH of the solution and should preferably be kept between 7 and 8 to stabilize the dissolution of the two active ingredients.

One embodiment relates to treatments and methods of treatment that provide for the administration of an ophthalmic composition comprising a mixture comprising levofloxacin or a salt thereof or a hydrate thereof or a hemihydrate thereof (e.g., levofloxacin hemihydrate), and dexamethasone or a salt thereof (e.g., dexamethasone sodium phosphate or dexamethasone disodium phosphate). The concentration of levofloxacin, for example levofloxacin hemihydrate, is from 1mg/ml to 10mg/ml of the liquid composition, preferably it is from 3mg/ml to 7mg/ml of the liquid composition, even more preferably it is from 4mg/ml to 6mg/ml of the liquid composition, for example 4.5mg/ml, or 5mg/ml, or 5.5 mg/ml.

Dexamethasone or a salt thereof or a hydrate thereof or a hemihydrate thereof (e.g. dexamethasone sodium phosphate) (fig. 2) is in a concentration of 0.25 to 2.5mg/ml of the liquid composition, preferably it is in a concentration of 0.5 to 2mg/ml of the liquid composition, even more preferably it is in a concentration of 1 to 1.5mg/ml of the liquid composition, e.g. 1.2mg/ml, or 1.3mg/ml, or 1.4 mg/ml.

Further, the ophthalmic composition comprises the following: one or more substances selected from the group comprising or consisting of: sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dodecahydrate, sodium citrate, sodium chloride, boric acid and/or borate, benzalkonium chloride, sodium hyaluronate, or hyaluronic acid; NaOH1N for calibrating pH to 6.5 to 7.5, preferably 7, advantageously 7.2; and distilled water

A preferred embodiment relates to a treatment and a method of treatment, which provides for the administration of a composition as reported in example 1, as shown in table 3.

Forming an object of the present invention is a method of administering said composition, which is used with the following dosage regimen:

-administering the composition by a non-intravitreal route to the eye of the patient daily after ocular surgery for a period of 1 to 7 days, advantageously 7 days, multiple administrations or daily administration comprising administration 1 to 4 times daily, advantageously 3 or 4 times daily, preferably 4 times daily, 1 or 2 drops (preferably 1 drop) each time;

preferably, dexamethasone, the only anti-inflammatory drug alone, is administered subsequently for 3 to 7 days, which enables treatment of inflammatory events in patients undergoing ocular surgery, even more preferably levofloxacin, the antibiotic alone, is not administered subsequently.

Preferred embodiments of the invention e (n) are listed below:

E1. an ophthalmic composition in the form of a solution comprising: a mixture comprising or consisting of the antibiotic levofloxacin or a salt thereof or a hydrate thereof or a hemihydrate thereof, and the corticosteroid dexamethasone or a salt thereof or a hydrate thereof or a hemihydrate thereof; and optionally one or more pharmaceutically acceptable additives and excipients and water; the composition is applied to a method for treating postoperative infection of a patient who has previously undergone eye surgery;

wherein the composition is administered to the eye of the patient daily by a non-intravitreal route over a period of 1 to 7 days post-ocular surgery.

E2. The composition for use of E1, wherein the ocular surgery is cataract surgery.

E3. The composition for use of E1 or E2, wherein the method for treating post-operative infection in a patient who has previously undergone ocular surgery provides for administration of the composition by an ocular topical route.

E4. The composition for use of any one of E1-E3, wherein the levofloxacin or salt thereof or hemihydrate or hydrate thereof is present in the composition in solution form at a concentration of 1mg/ml to 10mg/ml of liquid composition, preferably it is 3mg/ml to 7mg/ml of liquid composition, even more preferably it is 4mg/ml to 6mg/ml of liquid composition, for example 4.5mg/ml, or 5mg/ml, or 5.5 mg/ml.

E5. The composition for use of any one of E1-E4, wherein the dexamethasone or salt thereof or hemihydrate thereof or hydrate thereof is present in the composition in solution form at a concentration of 0.25 to 2.5mg/ml of liquid composition, preferably it is 0.5 to 2mg/ml of liquid composition, even more preferably it is 1 to 1.5mg/ml of liquid composition, e.g. 1.2mg/ml, or 1.3mg/ml, or 1.4 mg/ml.

E6. The composition for use of any one of E1-E5, wherein the ophthalmic composition further comprises one or more pharmaceutical grade additives and excipients selected from the group comprising or consisting of: sodium phosphate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate dodecahydrate, sodium citrate, sodium chloride, boric acid and/or borate, benzalkonium chloride, sodium hyaluronate or hyaluronic acid, NaOH1N for calibrating pH to 6.5 to 7.5, preferably 7 or 7.2, and distilled water.

E7. The composition for use of any one of E1-E6, wherein the composition is administered to the eye of the patient several times per day over a period of 7 days after ocular surgery, comprising 1 or 2 drops of the composition administered 1 to 4 times per day, preferably 1 drop of the composition administered 4 times per day.

E8. The composition for use of any one of E1-E7, wherein the method for prophylactically or therapeutically treating a postoperative infection in a patient who has previously undergone ocular surgery does not provide for the subsequent separate administration of the antibiotic levofloxacin, but rather provides for the subsequent separate administration of the anti-inflammatory drug dexamethasone.

Example 1

TABLE 3

The composition of example 1 in table 3 is a clear green solution at pH 7.2, the main chemical and physical specifications of which are given in table 4.

TABLE 4

Appearance of the product	Clear solution
		Color of solution	≤GY3
pH	7.2(±0.2)
		Osmotic concentration	300mOsm/Kg(±30)

Object forming the present invention is a process for the preparation of composition (i), preferably in the form of a medicament as eye drops, by methods, devices and apparatuses known to the person skilled in the art of sterile ophthalmic solutions.

The subject of the ophthalmic composition (i) of the present invention is a sterile composition.

The process for preparing the composition (i) of the invention comprises adding and dissolving the ingredients of example 1 in water for injection in a zone of reduced and controlled contamination.

After the above-mentioned dissolution step, a sterile filtration step is carried out using a sterile filter with a porosity of about 0.2 μm capable of retaining all the microorganisms.

The above-mentioned filtration step is followed by a step of filling/sealing the composition in the form of a sterile solution in a previously sterilized ophthalmic container; the container is provided with a dropper device and a sealing cover device. The filling/sealing step is carried out under conditions of almost no contamination, the so-called class a zone.

The composition in solution form is filtered under sterile conditions and packaged in plastic (primary) containers made of opaque polyethylene, since levofloxacin is photosensitive. The container was equipped with a dropper, dispensing 30 microliters (0.03ml) per drop.

The primary container of the eye drop solution is an opaque plastic bottle, conveniently made of Low Density Polyethylene (LDPE) containing 50 microliters of solution, fitted with an opaque LDPE dropper and a High Density Polyethylene (HDPE) screw cap.

Other embodiments of the compositions of the present invention are described in examples 2 (table 5), 3 (table 6) and 4 (table 7) below.

EXAMPLE 2 preservative-free Multi-dose formulations

5ml (3 to 10ml) of a solution having the following composition.

TABLE 5

Example 3 Single dose formulation without preservatives

A solution having the following composition in a volume of 0.4ml (0.1 to 1 ml).

TABLE 6

Example 4 tackification formulation with better bioadhesive Properties

TABLE 7