Lipid-based formulation that increases the penetration of antibiotics for topical ophthalmic use into the eyeball

Abstract

The present invention relates to a lipid-based formulation for topical ophthalmic use to increase the bioavailability of antibiotics in intraocular tissues, wherein said formulation comprises: Moxifloxacin (M), polyethylene glycol (PEG)-12 glyceryl dimyristate and ethyl alcohol, polyethylene glycol (15)-hydroxystearate (Kolliphor® HS15), anhydrous citric acid and sodium citrate dihydrate. The compositions of the invention contain an effective amount of moxifloxacin (M), 0.001 to 1 mg, in other words, 0.0001 to 0.1% (w / v), polyethylene glycol (PEG)-12 glyceryl dimyristate which is used as a structural component of liposomes in a concentration of 5-15% (w / v) and ethyl alcohol which is used as an organic solvent in a concentration of 0.7 to 2.1% (v / v). Furthermore, the formulation contains 2.5 to 7.5% (w / v) of polyethylene glycol (15)-hydroxystearate (Kolliphor® HS15) as a non-ionic solubiliser and emulsifying agent. Likewise, the aqueous compositions of the present invention optionally comprise more excipients selected from the group consisting of buffering agents, pH-adjusting agents and preservatives. Anhydrous citric acid (0.04 to 0.16%) and sodium citrate dihydrate (0.23 to 0.69%) are used as buffers.

Description

[0001]LIPID-BASED FORMULATION THAT INCREASES PENETRATION OF TOPICAL OPHTHALMIC ANTIBIOTICS INTO THE EYEBALL. FIELD OF THE INVENTION The present invention generally falls within the field of ophthalmic therapies, particularly the use of a lipid base for the application of a fluid pharmaceutical formulation to ocular tissues for the local delivery of antibiotics. BACKGROUND OF THE INVENTION The prevalence of postoperative intraocular infections (infectious endophthalmitis) varies depending on several factors, including the population studied, healthcare practices, and local health conditions.Infectious endophthalmitis is a severe inflammation of the interior of the eye, usually caused by a bacterial or fungal infection. It can be a serious complication after eye surgeries such as cataract surgery or corneal transplants, as well as invasive procedures such as intravitreal injections. In cataract surgery, the incidence of endophthalmitis ranges from 0.1% to 0.3%, in corneal transplants the incidence is 0.1% to 0.5%, and in intravitreal injections it is 0.02% to 0.07%. It is important to note that postoperative eye infections (infectious endophthalmitis) are a serious complication that permanently affects visual function and jeopardizes the preservation of the organ. Therefore, preventive measures such as proper asepsis and the use of prophylactic antibiotics before and after eye surgery are essential.However, the poor penetration of antibiotics into the ocular globe (less than 3%) severely limits such prevention. Likewise, their use in the treatment of these infections is severely affected and limited by this poor penetration. Ocular infections that occur after a surgical procedure, especially eye surgery, can be a worrisome and severe complication that can lead to various symptoms and potential complications, including loss of function and / or the visual organ. These infections are commonly referred to as postoperative ocular infections or endophthalmitis. They can range in severity from mild cases that can be treated with antibiotics to more severe cases that may require aggressive medical intervention with a very guarded visual and anatomical prognosis. The key points related to ocular infections after a surgical procedure are: 1. Causes.Postoperative ocular infections can be caused by a variety of microorganisms, including bacteria, viruses, fungi, and even parasites. The most common causative agents are bacteria, especially Staphylococcus aureus and Streptococcus species, and in more severe cases, Pseudomonas species. The source of the infection may be the patient's own skin flora, surgical instruments, the surgical environment, or other external factors. 2. Risk Factors. Several factors may increase the risk of developing postoperative ocular infections. These include: a. Patient-related factors: Poor ocular hygiene, a compromised immune system, preexisting ocular conditions, and systemic diseases may increase susceptibility to infections. b.Surgical Technique: Improper sterilization of instruments, improper wound closure, and poor surgical technique can introduce pathogens into the surgical site. c. Surgical Environment: An unclean surgical environment or contaminated surgical equipment can contribute to infection. 3. Symptoms. Symptoms of postoperative ocular infections may vary depending on the type and severity of the infection. Common symptoms include redness, pain, swelling, discharge, decreased visual function, photophobia, hypopyon, vitreous clouding, and / or retinal detachment. 4. Diagnosis and Treatment. Diagnosis of postoperative ocular infections involves a thorough ocular examination, including evaluation of visual acuity, slit-lamp biomicroscopy, and possibly culture of ocular specimens to identify the causative microorganisms. Treatment may include: a.Topical Antibiotics: Antibiotic drops or ointments are prescribed to treat bacterial infections. Their application is the primary treatment in cases of postoperative eye infection. However, less than 3% of them penetrate the eyeball due to the presence of anatomical and functional barriers of the eyeball and its adnexa, so this type of treatment is not very effective. b. Topical Anti-inflammatory Medications: These can help control inflammation and general discomfort (eye pain). However, their topical use has the same problem mentioned above, since less than 3% of the concentration penetrates the eyeball. c. Systemic Antibiotics: For this type of infections, oral antibiotics may be necessary, however, it is well described that antibiotics that are administered systemically have an even lower penetration than when they are administered topically (less than 1%). d.Intraocular antibiotics: Intraocular (intravitreal) administration of antibiotics via intraocular injections is a commonly used route for these types of infections. However, there are potentially severe complications with this route of administration, including the development and / or progression of cataracts, vitreous hemorrhage, retinal detachment, and infection (endophthalmitis). Therefore, this route is not used for infection prevention and is limited to the treatment of very severe cases. e. Frequent follow-up: Patients with postoperative ocular infections require close follow-up to ensure that the infection is responding to treatment and to address potential complications, which is why the use of topical antibiotics is often extended over many weeks. f.Surgical intervention: In very severe cases, if the infection does not respond to drug treatment or if the severity of the infection warrants it due to severe visual impairment, surgery may be necessary to drain abscesses or remove infected tissue (vitrectomy). 5. Prevention. Prevention is crucial to minimize the risk of postoperative eye infections. Strict adherence to sterile techniques during surgery, proper wound closure, and appropriate preoperative and postoperative care can significantly reduce the likelihood of infection. There are different groups of antibiotics in ophthalmology. Quinolones and fluoroquinolones are synthetic antibiotics used to prevent and treat various eye infections caused by bacteria.These antibiotics act as bactericides by inhibiting bacterial DNA synthesis, preventing bacteria from reproducing and ultimately killing them. They are indicated for treating a variety of bacterial ocular infections, including conjunctivitis (red eye), keratitis (inflammation of the cornea), and bacterial corneal ulcers. However, their use for the prevention and treatment of intraocular infections (endophthalmitis) has little proven efficacy, as less than 3% of these infections have the potential to penetrate the eyeball when administered topically. This is due to the presence of eyeball barriers, as well as the disadvantages of their pharmaceutical formulations and mode of use, which include: 1. Anatomical Barriers: The eye has several anatomical barriers that protect its tissues and maintain a stable ocular environment. The outermost barrier is the cornea and the sclera, which is a layer that protects the outside of the eye.Likewise, the conjunctiva is an important and relevant ocular appendage. These barriers can hinder the penetration of drugs, especially those that are large or hydrophobic. 2. Tears and Drainage System: Tears play an essential role in maintaining ocular health and can dilute topical drugs, reducing their concentration in the eye. Furthermore, excess tears and the tear drainage system can rapidly eliminate drugs before they have time to exert their action. Likewise, blinking decreases the presence and quantity of drugs administered topically in the eye. 3. Blood Flow: The vascularization of the eye is relatively limited compared to other tissues. This can hinder the delivery of drugs to the site of action and limit their effectiveness in the treatment of ocular diseases that require a high local concentration of medication. 4.Epithelial Barrier: The epithelium of the cornea and conjunctiva can act as an additional barrier to drug penetration. The permeability of this barrier can vary depending on the size and chemical properties of the drugs. 5. Immune Response: The eye has a local immune system that can limit the effectiveness of some topical medications. The immune response may include elimination of drugs before they take effect or the generation of local inflammation. 6. Drug Formulation: The formulation of a topical drug is critical to its effectiveness. Factors such as drug solubility, solution pH, and viscosity can influence bioavailability and drug penetration into ocular tissues. 7. Frequency and Compliance: For some ophthalmic treatments, frequent application of topical medications is required.This can be a challenge in terms of patient compliance and proper medication administration. 8. Eye sensitivity: Some topical medications can cause eye irritation, burning, or allergic reactions. This can limit patient tolerability and acceptance of treatment. Moxifloxacin is a fourth-generation fluoroquinolone with a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria, anaerobes, and atypical organisms. Intravitreal (intraocular) moxifloxacin injection has been used successfully in the treatment of post-traumatic endophthalmitis due to the multidrug-resistant Gram-negative bacillus Ochrobactrum intermedium (MDR-Ochrobactrum intermedium) caused by a metallic intraocular foreign body. In addition, intravitreal moxifloxacin has also been shown to be effective in the treatment of post-traumatic endophthalmitis following penetrating injury with a metallic wire.In order to generate greater penetration of topical ophthalmic antibiotics, to increase their bioavailability in intraocular tissues in an efficient and safe manner, and thus avoid the risks associated with the administration of antibiotics by intravitreal injections and / or surgical procedures, the presented invention is created, a lipid-based formulation containing topical ophthalmic antibiotics (moxifloxacin) that favors the intraocular penetration of the active ingredient. Within the framework of the work developed with moxifloxacin, it has however been surprisingly found that the conventional isotonization method by adding 5% glucose or other sugars or sugar alcohols, such as 2.5% glycerol, is not possible in the case of moxifloxacin, since in all cases the solutions result in unstable.This instability is manifested by the appearance of subvisual particles in the solution, the number of which is above the permissible range of pharmacopoeias (USP XXIII, BP93). During storage, brown amorphous particles are formed, which often appear after 4-8 weeks of storage at 40°C and continue to increase in number over the course of storage. At room temperature or during refrigeration, the formation of these particles slows down. C. Ballow et al., Clinical Therapeutics, vol. 21 (3), 513-522 (1999) discloses an isotonic solution for intravenous administration containing 2 mg / ml of moxifloxacin and 5% dextrose. The iron content of the solution or the adjuvants is not mentioned at all. WO 00 / 18386 represents prior art according to Article 54.3 and 54.4 of the EPC.This application discloses in Example 1 a solution for ophthalmic, optical and / or nasal administration containing 0.35% by weight of moxifloxacin and 4.6% mannitol. Invention MX2012007928A describes methods and materials useful for applying moxifloxacin to the ear. The methods involve delivering a composition containing at least one viscogenic agent and moxifloxacin or a salt thereof to the epidermal surface of the tympanic membrane via the ear canal. The composition is delivered to the tympanic membrane in a fluid form and, after delivery to the tympanic membrane, becomes sufficiently viscous such that the moxifloxacin is localized against the tympanic membrane. These compositions can be used to prophylactically and / or therapeutically treat conditions of the middle and inner ear, including otitis media.In one aspect, a method is provided for administering moxifloxacin to a mammal (e.g., a rodent or a human). The method includes applying a formulation to the epidermal surface of a tympanic membrane of the mammal, wherein the formulation includes a viscogenic agent and moxifloxacin, wherein the formulation has a viscosity of less than 100,000 cps, and wherein the formulation, after application to the tympanic membrane, has an effluence tension sufficient to hold the formulation against the tympanic membrane. The viscogenic agent may be gellan, N-isopropylacrylamide with sodium acrylate and nN-alkylacrylamide, polyacrylic acid with polyethylene glycol, polymethacrylic acid with polyethylene glycol, CARBOPOL® (polyacrylic acid) with hydroxypropylmethylcellulose, cellulose acetate acid phthalate latex, sodium alginate, or a reverse thermosetting gel such as poloxamer or a poloxamine.Moxifloxacin can be transferred across the tympanic membrane into the middle ear space. At least one pharmacological agent may include an antibiotic, and the formulation may further include an anti-inflammatory agent, an anesthetic, an adhesion promoter, a permeability or penetration enhancer, a bioadhesive, a hygroscopic agent, an earwax softener, or a preservative. The present invention relates to a formulation for increasing the penetration of topical ophthalmic antibiotics into the eyeball, and has the potential to serve as a functional alternative for the prevention and / or treatment of intraocular infections, given that its lipid component increases the penetration and bioavailability of antibiotics, in this case a quinolone, in the target ocular tissues.This invention aims to promote the creation of functional therapeutic alternatives to significantly increase the percentage of penetration of the eyeball barriers to achieve therapeutic concentrations in the target tissues (intraocular tissues) of topical ophthalmic antibiotics, in this case, a fluoroquinolone (moxifloxacin). Therefore, it impacts the pharmaceutical industry in ophthalmology, an active and highly productive sector locally, nationally and internationally. OBJECT OF THE INVENTION One object of the present invention is to propose a lipid-based formulation for topical ophthalmic use to increase the bioavailability of antibiotics in intraocular tissues. Another object of the invention is to propose a lipid-based formulation that increases the penetration of topical ophthalmic antibiotics into the eyeball, particularly moxifloxacin, with improved diffusion and bioavailability properties.DESCRIPTION OF THE INVENTION Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It is to be understood that the following detailed description is exemplary and explanatory only and does not limit the invention as claimed. In order that the present invention may be more readily understood, certain terms are defined. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in practicing the invention, suitable methods and materials are described below.All publications, patent publications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, shall prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. The present invention relates to a lipid-based formulation for topical ophthalmic use to increase the bioavailability of antibiotics in intraocular tissues. The formulation comprises an effective amount of an antibiotic agent, a medium-chain fatty acid, an organic solvent, and excipients selected from the group consisting of buffering agents. Wherein said effective amount of an antibiotic agent refers to an aqueous solution of a pharmaceutically acceptable salt of a quinolone, particularly moxifloxacin.The present invention relates to a lipid-based formulation that increases the penetration of topical ophthalmic antibiotics into the eyeball, said formulation comprising: Moxifloxacin (M), polyethylene glycol (PEG-12) glyceryl myristate and ethyl alcohol, polyethylene glycol (15) hydroxystearate (Kolliphor® HS15), anhydrous citric acid and sodium citrate dihydrate. The compositions of the present invention contain an effective amount of moxifloxacin (M), 0.001 to 10 mg, i.e. 0.0001 to 1% (w / v), polyethylene glycol (PEG)-12 glyceryl dimyristate, which is used as a structural component of the liposomes at a concentration of 5-15% (w / v) and ethyl alcohol which is used as an organic solvent at a concentration of 0.7 to 2.1% (v / v). Moxifloxacin is a third-generation synthetic fluoroquinolone that has the chemical formula C21H24 FN3O4.Moxifloxacin binds to and inhibits the bacterial enzymes DNA gyrase (topoisomerase II) and topoisomerase IV, resulting in the inhibition of DNA replication and repair and ultimately cell death in susceptible bacterial species. The amount of moxifloxacin or a salt thereof in a composition as described herein may range from about 0.0001% to about 1% (w / v). In addition to moxifloxacin, the formulation as described herein may include one or a plurality of pharmacological agents. For example, to combat a bacterial infection, reduce tissue inflammation, and relieve irritation, a composition may contain moxifloxacin, an anti-inflammatory, and an anesthetic or analgesic. Those skilled in the art can identify pharmacological agents and combine them as needed to achieve a desired effect.The authors have proposed other inventions such as anti-inflammatory agents, and anesthetics or analgesics. In addition, the formulation contains 2.5 to 7.5% (w / v) of polyethylene glycol (15) hydroxystearate (Kolliphor® HS15) as a non-ionic solubilizer and emulsifying agent. This compound is characterized by its low toxicity and also acts as a permeability enhancer, because it promotes the transport of molecules across cell membranes; increasing the rate of endocytosis and stimulating drug translocation through the paracellular route. Likewise, the aqueous compositions of the present invention optionally comprise further excipients selected from the group consisting of buffering agents, pH adjusting agents and preservatives. Anhydrous citric acid (0.04 to 0.16%) and sodium citrate dihydrate (0.23 to 0.69%) are used as buffers.The lipid-based compositions of the present invention can be prepared by conventional methods for preparing suspension pharmaceutical compositions. Method of preparation. According to the preferred method, moxifloxacin (M) (at a concentration of 0.001 to 10 mg) is first added to a lipid mixture containing polyethylene glycol (PEG)-12 glyceryl dimyristate (5-15%), polyethylene glycol (15) hydroxystearate (Kolliphor® HS15) 2.5 to 7.5% and ethyl alcohol (0.7 to 2.1%), the components being combined by stirring for 10 minutes ^1 minute at 25 ° C^ 1 ° C. On the other hand, an aqueous base mixture composed of grade 2 purified water (QS), anhydrous citric acid (0.04 to 0.16%) and sodium citrate dihydrate (0.23 to 0.69%) is prepared by combining the components by stirring for 10 minutes ^1 minute at 25 ºC^1 ºC. The aqueous mixture is added to the lipid mixture at room temperature and stirred for 5 min ^1 minute to obtain the final formulation.Resulting formulation. The resulting lipid-based formulation object of this invention is formed as follows: Reagent Volume / Amount Moxifloxacin 0.001 to 10 mg (w / v) Polyethylene glycol (15) -hydroxystearate 2.5 to 7.5% (w / v) Polyethylene glycol (PEG)-12 glyceryl dimyristate 0.01 to 15% (w / v) Ethyl alcohol 0.7 to 2.1% (v / v) Anhydrous citric acid 0.04 to 0.16% Sodium citrate dihydrate 0.23 to 0.69% Benzalkonium chloride 0.1 mg Purified water grade 2 QS1.0 ml These and other embodiments of the invention can be further illustrated in the following non-limiting examples. EXAMPLE. The following example is intended to illustrate, but not to limit, the present invention [ingredient concentrations are presented in units of % weight / volume (% w / v) or % volume / volume (% v / v)]. The final concentration of moxifloxacin in the resulting nano suspension in the example is 0.15 mg / ml (0.015%).The composition of the lipid emulsion (LE) containing moxifloxacin (M), hereinafter EL-M, is described below. Reagent Volume / Amount Moxifloxacin 0.15mg Polyethylene glycol (15) hydroxystearate 75mg Polyethylene glycol (PEG)-12 glyceryl dimyristate 100mg Ethyl alcohol 14µl Anhydrous citric acid 0.8mg Sodium citrate dihydrate 4.675mg Benzalkonium chloride 0.1mg Purified water grade 2 QS1.0ml Analysis of the resulting formulation The pH of the LE-M was analyzed by a potentiometer in triplicate at room temperature. The osmolarity was measured by a vapor pressure osmometer in triplicate at 33°C (the ocular surface temperature). The viscosity was also measured in triplicate at 33°C. Viscosity was measured using a thermostatically controlled rheometer when steady state was reached with shear rates increasing from 0 to 1000 s-1.The particle size of the moxifloxacin-containing lipid nanoparticles in EL-M was analyzed by dynamic light scattering, and the zeta potential (ζ) was calculated by measuring the particle velocity using a laser Doppler velocimeter at 25°C (Zetasizer Nano ZS, Malvern Instruments, Malvern, UK). The particle size distribution (Z) and the polydispersity index (PDI) were calculated. The pH of EL-EJ was 6.8. The physiological pH range of tears is between 6.5 and 7.6. The viscosity of EL-M was 35.5 cP (high), which could favor its permanence on the ocular surface. The osmolarity was 398 mOsmol / L, within the isotonic range. The average particle diameter (z-average) was 109.55 nm, while its PDI was 10.8 and its zeta potential was 12.550. The physicochemical characteristics of EL-EJ are summarized below.Physicochemical characteristics of EL-M. Formulation Physicochemical parameters pH Viscosity Osmolarity Z PDI (cP) (mOsm / l) (nm) (nm) EFL-EL 6.8 35.5 398 109.55 10.8 pH= Hydrogen ion potential, cP= centipoise, PDI= Polydispersity index Additionally, diffusion chambers and New Zealand white rabbit corneas were used to perform in vitro diffusion experiments (BW200S Chemotaxis Chambers, NeuroProbe, Gaithersburg, MD, USA) in order to test the formulation’s ability to increase the bioavailability of the antibiotic. Briefly, the central section of the cornea (6 mm in diameter) was placed between the upper and lower compartments of the diffusion chambers to act as a diffusion barrier for EL-M or for a control solution of moxifloxacin in aqueous solution (AM), composed of the active ingredient (0.15 mg) in water for injection.The upper compartment (acceptor chamber) was filled with 180 μL of balanced salt solution (BSS), while the lower compartment (donor chamber) was filled with 200 μL of either EL-M or AM. To prevent evaporation, the diffusion chambers were placed inside a humidified chamber at 37 °C. For EL-M diffusion analysis, the concentration of moxifloxacin (M) in the upper compartment was determined by high-performance liquid chromatography (HPLC) at 2, 4, 6, and 8 hours after the start of the diffusion assay. The determination of M concentration by HPLC was carried out using a Varian 920 LC (Aligent Technologies, Santa Clara, CA, USA) with a Zorbax Eclipse Plus C18, 4.6 x 100 mm, 3.5 μm column (Agilent, Santa Clara, CA, USA) at 30°C. Samples (20 μl) were eluted from the column in a mobile phase composed of water:methanol (30:70) at a flow rate of 1 ml / min.Detection was performed at 296 nm. The retention time and detection limit were 10 min and 0.008 mg / ml, respectively. Regarding the in vitro diffusion analysis, it was observed that EL-M achieved higher concentrations of Men compared to AM. The results of the in vitro diffusion study are presented below. Moxifloxacin (M) concentration in the upper compartment of the diffusion chamber (µg / mL). The values ​​represent the average of three measurements. M concentrations in the acceptor chamber were higher with EL-M, reflecting the ability of the invention to significantly increase the deposition of the anesthetic in the intraocular compartments and tissues. In order to further define the invention, the following terms and definitions are provided herein: DEFINITIONS As used herein, a “composition” refers to a material suitable for administration to an eye of a subject.The compositions may include a drug delivery system if desired. The compositions may comprise a liquid carrier. The term may also be used to refer to materials such as solutions, suspensions, emulsions, and the like. The term “therapeutically effective amount,” as used herein, refers to the level or amount of agent necessary to treat an ocular condition without causing significant adverse or negative side effects to the eye or a region of the eye. The term “pharmaceutically acceptable,” as used herein, means suitable for use in contact with tissues without undue toxicity, irritation, incompatibility, instability, allergic response, and the like. The term “% (w / v)” used herein means parts by weight (expressed in grams) per 100 parts by volume (expressed in milliliters).Therefore, an aqueous solution containing, for example, 0.1% w / v moxifloxacin means that 100 ml of aqueous solution contains 100 mg of moxifloxacin. MOXIFLOXACIN Moxifloxacin or moxifloxicin is an antibiotic drug that belongs to the fourth generation quinolone family, it is widely used to treat various types of bacterial infections including those of the urinary tract and lower respiratory tract. This antibiotic with recognized efficacy and low antimicrobial resistance, which acts against Gram-negative bacteria like most antibiotics belonging to this family and also against Gram-positive bacteria, this is due to its mechanism of action that acts on various topoisomerases, making it a broad-spectrum antibiotic.Quinolones such as moxifloxacin and levofloxacin have a dual mechanism of action involving the inhibition of bacterial topoisomerase IV and DNA gyrase. Consequently, they are less likely to produce resistant organisms because two simultaneous mutations are required to establish resistance. Topoisomerases are enzymes that control the coiling and uncoiling of bacterial DNA. Coiling allows the DNA molecule to package itself within the bacterial cell. This tightly packed structure must then be unwound to allow DNA replication, transcription, and repair. Cessation of the activity of these enzymes prevents the bacterial cell from producing the proteins necessary for repair, growth, and reproduction. Prolonged inhibition will lead to cell death. This antibiotic binds to topoisomerase II and topoisomerase IV, blocking them.Topoisomerase II is the target of choice in Gram-negative microorganisms, while in Gram-positive microorganisms, moxifloxacin inhibits both topoisomerases; it also acts on anaerobic bacteria. Moxifloxacin ophthalmic solution is used to treat bacterial conjunctivitis (infection of the membrane that lines the eyeball on the inside of the eyelid). The authorization report from the German Medicines Agency states that three randomized, double-blind clinical trials were conducted that demonstrated the superiority of moxifloxacin 0.5% ophthalmic solution over placebo, and three randomized, double-blind clinical trials that demonstrated therapeutic equivalence with ofloxacin 0.3% ophthalmic solution, ciprofloxacin 0.3% ophthalmic solution, and levofloxacin 0.5% ophthalmic solution for the indication of bacterial conjunctivitis. The results of these studies have not been published.After 48 hours of treatment, the percentage of eyes that had achieved clinical cure, defined as complete resolution of all ocular symptoms and signs, was analyzed. A significantly higher percentage was obtained in the group of eyes treated with moxifloxacin compared to those treated with polymyxin B / trimethoprim, regardless of whether the unit of analysis had been the eyes with positive culture (81% vs 44%, respectively; p=0.001) or all treated eyes (84% vs 44%, respectively; p=0.0001).

Claims

CLAIMS Having sufficiently described my invention, I consider as a novelty and therefore claim as my exclusive property, the contents of the following clauses: 1.- A lipid-based formulation for topical ophthalmic use to increase the bioavailability of antibiotics in intraocular tissues, characterized in that it comprises a combination of Moxifloxacin (M), polyethylene glycol (PEG)-12 glyceryl dimyristate and ethyl alcohol, polyethylene glycol (15) - hydroxystearate (Kolliphor® HS15), anhydrous citric acid and sodium citrate dihydrate. 2.- The lipid-based formulation for topical ophthalmic use according to claim 1, characterized in that it comprises the following percentages of its components: Moxifloxacin ----------------------------------------------------------- 0.001 to 1 mg (w / v); Polyethylene glycol (15) hydroxystearate ------------------------------ 2.5 to 7.5% (w / v); Polyethylene Glycol (PEG)-12 glyceryl dimyristate -------- 0.01 to 15% (w / v); Ethyl alcohol ------------------------------------------------------------ 0.7 to 2.1% (v / v); Anhydrous citric acid -------------------------------------------------- 0.04 to 0.16%; Sodium citrate dihydrate -------------------------------------------------- 0.23 to 0.69%; Benzalkonium chloride -------------------------------------------------------- 0.1 mg.