Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• This invention relates to a method of reducing clinical signs and symptoms of chronic posterior blepharitis, preferably inflammatory and not associated with infection, in a subject.
• the method involves administering to the subject in need thereof an ophthalmic formulation consisting essentially of azithromycin.
• Blepharitis is a chronic disorder producing inflammation of the anterior and posterior lid margin, with involvement of skin and its related structures (hairs and sebaceous glands), the mucocutaneous junction, and the meibomian glands. It can also affect the conjunctiva, tear film, and the corneal surface in advanced stages and may be associated with dry eye.
• Blepharitis is commonly classified into anterior or posterior blepharitis, with anterior affecting the lash bearing region of the lids, and posterior primarily affecting the meibomian gland orifices (American American Academy of Ophthalmology, Blepharitis. 2003; Thygeson, Arch Ophthalmol, 1946, 36:938-942; Foulks, Ocul Surf.
• Blepharitis is one of the most common ocular disorders seen by ophthalmologists and has no cure to date or FDA-approved treatments for this condition. Blepharitis in its mild form is usually undiagnosed and rarely managed. In one study, the prevalence of blepharitis was estimated at 10% in the general population (Claoue, Eye, 1997, 11(6):865-868) but is probably higher in the elderly. Between 30% and 50% of patients with blepharitis also have keratoconjunctivitis sicca (Wu, In: Lee DA, Higginbotham EJ, eds. Clinical Guide to Comprehensive Ophthalmology, 1st ed. Thieme Medical Pub, 1999:189). Blepharitis, with or without a dry eye component, is associated with a broad spectrum of ocular symptoms ranging from mild transient irritation to persistent irritation, burning, itching, redness, pain, ocular fatigue and vision disturbances.
• Blepharitic changes limited primarily to the posterior lid margin arise predominantly from pathological processes centered around the meibomian glands.
• the meibomian glands are holocrine glands that supply the lipids, which form the external oily layer of the precorneal tear film. It is the alteration in this excretory process and the composition of tear film lipids that cause the clinical manifestations seen with this disease.
• MMD meibomian gland disease/dysfunction
• Meibomian seborrhea is characterized by excessive meibomian secretion in the absence of inflammation (hypersecretory form).
• Primary meibomitis by contrast, is distinguished by stagnant and inspissated meibomian secretions (obstructive form).
• Acne rosacea, seborrheic dermatitis, psoriasis, atopy and hypersensitivity to bacterial products may all contribute to the etiology of blepharitis (Cher, Mod Med Austr., 1997, 52- 62).
• Dry eye disease is a disorder due to an insufficient quantity of tears.
• the signs and symptoms of dry eye disease include ocular surface staining, eyelid swelling and redness, ocular irritation and foreign body sensation (gritty or sandy eyes).
• the quantity of tears can be reduced by either a failure to produce a sufficient amount of tears or by rapid evaporation of the tear film.
• Bron et al. disclose that the tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in the thickness or functional integrity of the tear film may cause evaporative dry eye. Obstructive meibomian gland dysfunction is the most common cause of evaporative dry eye.
• a chronic nongranulomatous inflammatory reaction is observed in most cases of chronic blepharitis and blepharoconjunctivitis (Yanoff, Ocular pathology. 3rd ed. Lippincott Williams & Wilkins Publishers, 1989;171-172).
• the pathophysiology of blepharitis is not well understood, but current consensus is that bacteria, altered meibum lipid composition and inflammation are the major contributors to the process.
• Azithromycin is a macrolide antibiotic.
• AZASITE ® (azithromycin ophthalmic solution) is a 1% sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE ® (polycarbophil, edetate disodium, sodium chloride).
• DURASITE ® polycarbophil, edetate disodium, sodium chloride.
• AZASITE ® is approved by the U.S. Food and Drug Administration (FDA) for treatment of bacterial conjunctivitis, caused by susceptible isolates of CDC coryneform group G, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae (AZASITE ® Package Insert, 2007).
• the recommended dosage regimen for the treatment of bacterial conjunctivitis is as follows: instill 1 drop in the affected eye(s) twice daily, 8 to 12 hours apart for the first 2 days and then instill 1 drop in the affected eye(s) once daily for the next 5 days (AZASITE ® Package Insert, 2007).
• blepharitis is a poorly understood clinical entity.
• the present therapies such as warm compresses, lid cleansing, oral nutritional supplements, and oral tetracycline antibiotics present compliance difficulties and disappointing results. Therefore, there is a need for an effective and safe method to treat the inflammatory aspects of blepharitis.
• the present invention is directed to a method for treating inflammatory chronic posterior blepharitis, preferably non-infectious, inflammatory chronic posterior blepharitis in a subject.
• the method comprises identifying a subject suffering from non-infectious, inflammatory chronic posterior blepharitis, and topically administering a pharmaceutical formulation consisting essentially of an effective amount of azithromycin to the eye of the subject.
• the present invention is also directed to a method for treating chronic posterior blepharitis in a subject.
• the method comprises identifying a subject suffering from chronic posterior blepharitis, and topically administering a pharmaceutical formulation consisting essentially of an effective amount azithromycin to the eye of the subject for a period of more than two weeks.
• the present methods are effective in reducing the symptoms and/or clinical signs of blepharitis in a subject such as lid debris, redness of eyelid margin, eyelid swelling, plugging of the meibomian gland, and obstructed meibomian gland secretion.
• the present invention is further directed to a method for treating dry eye secondary to blepharitis in a subject.
• the method comprises the steps of: identifying a subject suffering from dry eye secondary to blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation comprising an effective amount of azithromycin.
• the present invention is further directed to a method for reducing contact lens intolerance of a subject due to blepharitis or dry eye secondary to blepharitis.
• the method comprises: identifying a subject suffering from contact lens intolerance due to blepharitis or dry eye secondary to blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation comprising an effective amount of azithromycin.
• Figure 1 depicts the mean total sign scores (sum of the five clinical sign severity scores) from subjects treated with topical azithromycin plus warm compresses and subjects treated with warm compresses only (mean ⁇ SEM).
• Figure 2 depicts the mean total symptom scores (sum of the five clinical symptom severity scores) from subjects treated with topical azithromycin plus warm compresses and subjects treated with warm compresses only (mean ⁇ SEM).
• Figure 3 shows the effect of topical azithromycin treatment on the signs of posterior blepharitis. The mean values for the individual signs are presented as pre and post treatment with once daily dosing of AZASITE ® for four weeks (mean ⁇ SEM).
• Figure 4 shows the effect of topical azithromycin treatment on the symptoms of posterior blepharitis. The mean values for the individual symptoms are presented as pre and post treatment with once daily dosing of AZASITE for four weeks (mean ⁇ SEM).
• Figure 5 shows the effect of topical azithromycin treatment for four weeks on the hydrocarbon chain order of meibomian gland lipids.
• the mean values of the lipid analysis of patients with (i) meibomian gland disease (MGD), (ii) MGD patients treated with topical azithromycin, and (iii) normal subjects (control) are presented (mean ⁇ SEM).
• the numbers in parentheses represent the number of samples analyzed.
• Figure 6 shows the effect of topical azithromycin treatment for four weeks on the phase transition temperature of meibomian gland lipids.
• the mean values of the lipid analysis of patients with (i) meibomian gland disease (MGD), (ii) MGD patients treated with topical azithromycin, and (iii) normal subjects (control) are presented (mean ⁇ SEM).
• the numbers in parentheses represent the number of samples analyzed.
• Figure 7 shows the mean dry eye symptom scores before and after treatment with AZASITE ® for 4 weeks (mean ⁇ SEM).
• Figure 8 shows the mean tear break-up time (TBUT) scores before (Pre Rx) and after (Post Rx) treatment with AZASITE ® for 4 weeks (mean ⁇ SEM).
• azithromycin in the eyes has strong anti-inflammatory properties, and azithromycin alone (without additional anti-inflammatory agents such as corticosteroids or anti-allergic agents) is effective as a medicament for topically treating a subject suffering from chronic posterior blepharitis, preferably inflammatory posterior blepharitis that is not associated with bacteria infection.
• treatment with topical azithromycin ophthalmic solution produces high and sustained azithromycin concentrations in various ocular tissues particularly in the eyelids, and thus is effective in treating chronic posterior blepharitis or chronic meibomian gland disease.
• the present invention is directed to a method for treating inflammatory chronic posterior blepharitis in a subject.
• the present invention is preferably directed to a method for treating non-infectious, inflammatory chronic posterior blepharitis in a subject.
• the method comprises identifying a subject suffering from inflammatory chronic posterior blepharitis, or non-infectious, inflammatory chronic posterior blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation consisting essentially of an effective amount of azithromycin.
• Non-infectious blepharitis refers to blepharitis patient that is not suffering from a current infection by an active pathogenic bacterial species or by overgrowth of normal bacterial flora.
• Identifying a non-infectious patient can include means that are well known in the art and can include, but are not limited to: taking a bacterial culture of a patient to assess that the bacterial load is below pathogenic levels for the various species present, or identifying a patient that has gone through a round of antibiotics.
• Blepharitis is associated with a broad spectrum of ocular symptoms ranging from mild transient irritation to persistent irritation, burning, itching, redness, pain, ocular fatigue and vision disturbances.
• Typical clinical signs of blepharitis include Hd debris, redness of eyelid margin, eyelid swelling, plugging of the meibomian gland, and obstructed meibomian gland secretion. Redness of eyelid margin, which is a typical sign of acute inflammation, is improved by the present method.
• an “effective amount” of azithromycin topically administered to the ocular surface of a subject is an amount effective to reduce the clinical signs and/or symptoms of a disease.
• the present invention provides a rapid and effective method to treat inflammatory and non-infectious chronic posterior blepharitis, without the use of a topical steroid.
• patients After one to 2 weeks of topical treatment with azithromycin, patients demonstrate reduced lid margin erythema and improvement in the appearance of the meibomian orifices and/or meibomian gland secretions.
• the rapid and significant improvement is due to the anti-inflammatory activity of azithromycin independent of its antimicrobial effects.
• the efficacy is also due to the sustained high concentrations of azithromycin in cornea, conjunctive, and lid, after topical administration on the ocular surface, and the high affinity of azithromycin for the tissue.
• the present invention is more effective than the anti-inflammatory treatment using a tetracycline drug such as oral doxycycline, which takes 6 weeks or longer, often 3 months or longer to produce clinical improvements (Aronowicz, et al., J Ophthalmol, 2006, 90:856-860)
• the present invention is also directed to a method for treating chronic posterior blepharitis in a subject by treating the subject daily for over two weeks.
• the method comprises identifying a subject suffering from chronic posterior blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation consisting essentially of an effective amount of azithromycin daily for more than two weeks, at least three weeks, or at least four weeks.
• AZASITE ® azithromycin ophthalmic solution, 1%
• it warns against the prolonged use of azithromycin ophthalmic solution because it may result in overgrowth of non-susceptible organisms, including fungi.
• a patient is treated intermittently with a topical azithromycin formulation for a time period of longer than two weeks.
• "Intermittently" as used herein, means that a patient is not treated every day.
• the intermittent dosing can be every other day, every other two days, every other three days, 2-6 days on and 2-6 days off, one week on and one week off, one week on for every month, etc.
• One preferred intermittent dosing is once a day for one week in each month.
• the intermittent dosing is effective because topical azithromycin formulation produces high and prolonged azithromycin concentration in various ocular tissues including eyelids; thus allowing dosing to be skipped.
• the intermittent dosing provides a benefit of using lower total dosage of azithromycin.
• a subject is treated intermittently after the initial daily dosing of two weeks or more than two weeks.
• the present invention also provides a method for treating dry eye symptoms or signs, secondary to blepharitis, such as anterior blepharitis, posterior blepharitis, inflammatory posterior blepharitis, and non-infectious inflammatory posterior blepharitis.
• the method comprises the steps of: identifying a subject suffering from dry eye secondary to blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation comprising an effective amount of azithromycin.
• the inventors have discovered that by treating inflammation of the ocular surface with a topical application of azithromycin to the eye, the meibomian glands, which are primarily responsible for the production of the lipid layers of the tear film, improve their function and produce a better quality of tear film, thus the dry eye symptoms or signs are reduced.
• Symptoms of dry eye disease that can be treated by the present method include foreign body sensation (sandiness or grittiness), ocular dryness and ocular burning or pain. Tear-film break-up time (TBUT) is improved after the treatment, indicating a more stable tear film.
• a subject is administered with the pharmaceutical formulation daily for at least two weeks, more than two weeks, at least three weeks, or at least four weeks.
• a subject is administered with the pharmaceutical formulation intermittently for at least two weeks, more than two weeks, at least three weeks, or at least four weeks.
• a subject is administered with the pharmaceutical formulation intermittently after the initial daily dosing of at least two weeks.
• the present invention is also directed to a method for reducing contact lens intolerance of a subject due to blepharitis or dry eye secondary to blepharitis.
• the subject suffers posterior blepharitis or dry eye secondary to posterior blepharitis.
• the subject suffers inflammatory posterior blepharitis or dry eye secondary to inflammatory posterior blepharitis.
• the method comprises the steps of: identifying a subject suffering from contact lens intolerance due to blepharitis or dry eye secondary to blepharitis, and topically administering to the eye of the subject a pharmaceutical formulation comprising an effective amount of azithromycin.
• a subject is administered with the pharmaceutical formulation daily for at least two weeks, more than two weeks, at least three weeks, or at least four weeks.
• a subject is administered with the pharmaceutical formulation intermittently for at least two weeks, more than two weeks, at least three weeks, or at least four weeks.
• a subject is administered with the pharmaceutical formulation intermittently after the initial daily dosing of at least two weeks.
• Contact lens intolerance limits the time that a subject is able to comfortably wear contact lenses.
• the method of the present invention increases comfortable contact lens wearing time per day in a subject, increases the total contact lens wearing time per day in a subject, or makes wearing contact lens more comfortable to the user.
• the improvement in contact lens intolerance can be evaluated by: comfortable contact lens wearing time, total contact lens wearing time, ocular itch, overall eye comfort, and/or frequency of rewetting drop use.
• the magnitude of the increase of comfortable contact lens use described in this invention depends of the severity of the contact lens intolerance. For example, the present invention enables a subject with a mild contact lens intolerance to comfortably wear contact lenses for an additional 3 to 6 hours, thus allowing the subject to achieve an optimal wearing time of approximately 14 hours per day.
• the present invention also benefits a subject with a severe contact lens intolerance.
• the present method can increase the comfortable contact lens wearing time by at least 2-3 hours per day.
• the present invention is concerned primarily with the treatment of human subjects, but can also be employed for the treatment of other mammalian subjects, such as dogs, cats, sheep, horses, pigs, goats, and rabbits.
• Azithromycin can be administered to the eyes of a patient by any suitable means, but are preferably administered as a liquid or gel suspension in the form of drops, spray or gel.
• azithromycin is in the form of drops, and is dropped onto the ocular surface.
• azithromycin is contained within a swab or sponge which can be applied to the ocular surface.
• azithromycin is contained within a liquid spray or ointment which can be applied to the ocular surface.
• azithromycin is injected directly into the lacrimal tissues or onto the eye surface.
• the azithromycin formulation (e.g., in the form of drops) is first applied on a finger tip or other applicator, then applied or rubbed directly onto the lid margin.
• azithromycin can be applied to the eye via liposomes.
• azithromycin can be infused into the tear film via a pump-catheter system.
• Another embodiment of the present invention involves azithromycin contained within a continuous or selective-release device, for example, membranes such as, but not limited to, those employed in the OCUSERTTM System (polymeric ocular inserts for the administration of drugs, Alza Corp., Palo Alto, CA).
• azithromycin can be contained within, carried by, or attached to contact lenses or other compatible controlled release materials, which are placed on the eye.
• the concentration of azithromycin included in the topical solution is an amount sufficient to reduce the signs and/or symptoms of blepharitis or dry eye.
• the azithromycin concentration is preferably in the range of about 0.01-5%, preferably 0,1% to 2%, more preferably about 0.5 to 1.5%, and most preferably about 1% (w/v).
• "About” as used herein, refers to ⁇ 15% of the recited value.
• the invention described herein is not limited to the free base of azithromycin, but also includes pharmaceutically acceptable salts of azithromycin.
• Pharmaceutically acceptable salts are salts that retain the desired biological activity of azithromycin and do not impart undesired toxicological effects.
• the topical solution containing azithromycin can contain a physiologically compatible vehicle, as those skilled in the ophthalmic art can select using conventional criteria.
• the ophthalmic vehicles include, but are not limited to, saline solution, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl raethylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.
• the preferred ophthalmic formulations of azithromycin suitable for the present method are those disclosed in U.S. Patent Nos. 6,239,113, 6,569,443 and 7,056,893; the formulations of which are incorporated herein by reference.
• the formulation is an aqueous polymeric suspension comprising water, azithromycin, and 0.1 to 10% of a polymeric suspending agent.
• the polymeric suspending agent comprises a water-swellable water-insoluble crosslinked carboxy-vinyl polymer.
• the polymeric suspending agent comprises least 90% acrylic acid monomers and 0.1% to 5% crosslinking agent.
• AZASITE ® (azithromycin ophthalmic solution), which is a 1% sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE ® (polycarbophil, edetate disodium, sodium chloride), is the most preferred ophthalmic formulation.
• the preferred ophthalmic formulations are able to keep prolonged high azithromycin concentration on the ocular surface, thus facilitating its penetration into the eye tissues.
• the formulation optionally includes a preservative, such as benzalkonium chloride and other inactive ingredients such as EDTA.
• a preservative such as benzalkonium chloride and other inactive ingredients such as EDTA.
• benzalkonium chloride has the benefit of increasing the penetration of azithromycin into eye tissues.
• preferred formulations are those without any preservatives due to the potential for damage to the corneal epithelium that may result from long term, frequent exposure to preservatives such as benzalkonium chloride.
• the formulations without preservatives are prepared in a unit dose and stored in a single-use container.
• the pH of the formulation is adjusted by adding any physiologically and ophthamologically acceptable pH adjusting acids, bases or buffers to within the range of about 5 to 7.5; preferably 6 to 7.
• acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
• bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylamino-methane), and the like.
• Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
• the osmotic pressure of the aqueous ophthalmic composition is generally from about 200 to about 400 milliosmolar (mOsM), more preferably from 260 to 340 mOsM.
• the osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthamologically acceptable ionic or non-ionic agents.
• Sodium chloride is a preferred ionic agent, and the amount of sodium chloride ranges from about 0.01% to about 1% (w/v), and preferably from about 0.05% to about 0.45% (w/v).
• Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can be used in addition to or instead of sodium chloride to achieve osmolality within the above-stated range.
• non-ionic agents such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust the osmolality.
• the daily dose to treat chronic blepharitis can be divided among one or several unit dose administrations.
• the daily dose for azithromycin for example, can range from one drop (about 50 ⁇ l), one to four times a day, depending upon the age and condition of the subject.
• a preferred regimen for azithromycin is one drop of 1% (w/v) solution, about 1 to 2 times a day.
• a preferred dosage is one drop in each eye twice a day for two days and then once a day thereafter.
• the present method can be combined with mechanical therapy such as warm compress or lid hygiene (lid cleansing).
• mechanical therapy such as warm compress or lid hygiene (lid cleansing).
• the objective of this study was to compare the efficacy of study drug, AZASITE ® (azithromycin ophthalmic solution) 1%, in conjunction with mechanical therapy (warm compress) versus mechanical therapy alone over a two week treatment period on the signs and symptoms of subjects with posterior blepharitis.
• Subjects were 18 years of age or older, and had a clinical diagnosis of moderate to severe posterior blepharitis. Subjects did not have suspected ocular infection, lid structural abnormalities, or have presence of inflammation and/or active structural change in the iris or anterior chamber. A total of 21 subjects were enrolled in the study.
• Lid debris (collarettes, clumps/strands) (0) Normal: clear eyelid margin
• Moderate between 1/3 and 2/3 of orifices contain turbid or oily secretions
• Severe more than 2/3 of orifices but not all contain turbid or oily secretions
• Total Clinical Outcome Severity Score is defined as the sum of the above five severity scores as described above.
• the Combination group After 14 days of treatment, the Combination group showed significant improvement compared to the Compress treated group in mean Total Clinical Outcome Severity Score (Table 1), meibomian gland plugging, meibomian gland secretions, and redness of the eyelid margin (Table 2). The Combination group also showed improvement as compared to the Compress treated group in the subject-rated global assessment of the efficacy on the signs and symptoms of blepharitis (Table 3). the combination treatment attenuated eyelid redness, a cardinal sign of acute inflammation.
• Table 1 Effects of topical azithromycin in combination with warm compress (Combination) versus warm compress alone (Compress) on total clinical outcome score in blepharitis patients
• the total severity score was the sum total of individual severity scores of all 5 signs for each treatment at each visit as presented in Table 1. Number in the parenthesis indicates the number of eyes evaluated. A negative change from baseline indicates improvement. Mean change from the baseline in the combination group were significantly different (PO.001, ANCOVA) from that in the compress group.
• the objective of this study was to compare the safety and efficacy of AZASITE ® (azithromycin ophthalmic solution, 1% ) in conjunction with mechanical therapy versus mechanical therapy alone without the use of AZASITE over a 4-week treatment period on signs and symptoms in subjects with chronic blepharitis.
• Subjects were 18 years of age or older, and had a clinical diagnosis of moderate to severe chronic blepharitis, with a clinical sign severity score of at least 2 (moderate) on either redness or swelling (or both) of the eyelid margin and on either eyelid debris or plugging of the meibomian gland (or both). Subjects also had a symptom severity score of at least 2 (moderate) on their self-reported "most bothersome" symptom at baseline and a score of at least 2 (moderate) on any other symptom. Subjects did not have suspected ocular infection, lid structural abnormalities, or have presence of inflammation and/or active structural change in the iris or anterior chamber. A total of 76 subjects were enrolled in the study. Methods
• Subjects assigned to the study drug treatment arm continued to administer study drug BID on Day 2 and once daily (QD) for the duration of the study treatment period ending at Visit 5 (approximately 29 days total on study drug treatment). Subjects returned to the clinic on a weekly basis for Visits 2-5 and attended a follow- up visit, Visit 6, 2 weeks following the end of the treatment period. Efficacy assessments performed at every visit included subject-reported symptom scores and investigator-reported scores on the signs of blepharitis.
• Total Symptom Score is defined as the sum of the above five symptoms severity scores as described above.
• the objective of this study was to assess the effects of AZASITE ® (azithromycin ophthalmic solution, 1%) on the physicochemical properties of the meibomian gland secretions in patients with meibomian gland disease (posterior blepharitis).
• FTIR Fourier Transform Infrared
• NMR Nuclear Magnetic Resonance
• MALDI-TOF Matrix Assisted Laser Desorption Ionization-Time of Flight
• Clinical data was analyzed as change from baseline by comparison of mean scores using two tailed Student t-test.
• Example 4 Use of azithromycin for reducing the signs and symptoms of dry eye in patients with posterior blepharitis (meibomian gland disease)
• the objective of this study was to assess the efficacy of study drug, AZASITEP (azithromycin ophthalmic solution, 1%), over a four week treatment period on the signs and symptoms of dry eye disease in subjects with posterior blepharitis.
• AZASITEP azithromycin ophthalmic solution, 1%
• Subjects were 18 years of age or older, and had a clinical diagnosis of moderate to severe posterior blepharitis. A total of 17 subjects were enrolled in the study.
• FBS Foreign body sensation
• Fluorescein dye was applied to the subject's ocular surface to facilitate the assessment of the subject's TBUT. Via examination with a slit lamp, the subjects were instructed to blink after the administration of the fluorescein and the time until the appearance of the first dry spot was recorded as the TBUT.

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