EP3968949A1 - Formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin - Google Patents

Formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin

Info

Publication number
EP3968949A1
EP3968949A1 EP20727542.1A EP20727542A EP3968949A1 EP 3968949 A1 EP3968949 A1 EP 3968949A1 EP 20727542 A EP20727542 A EP 20727542A EP 3968949 A1 EP3968949 A1 EP 3968949A1
Authority
EP
European Patent Office
Prior art keywords
cataract
lens
triamcinolone acetonide
formulation
surgery
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20727542.1A
Other languages
German (de)
English (en)
Inventor
Arturo SANTOS
Jane H. Hsiao
Jose Navarro
Juan C. ALTAMIRANO
Alejandro Gonzalez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
OPKO Pharmaceuticals LLC
Original Assignee
OPKO Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/426,712 external-priority patent/US11458199B2/en
Application filed by OPKO Pharmaceuticals LLC filed Critical OPKO Pharmaceuticals LLC
Publication of EP3968949A1 publication Critical patent/EP3968949A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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

Definitions

  • the invention relates to triamcinolone acetonide-loaded liposomes topical ophthalmic formulations for prevention of macular thickening and its associated visual outcomes after lens surgery.
  • Phacoemulsification is the current preferred method wherein the lens material is softened using ultrasonic energy (emulsify) followed by extraction from the eye through irrigation and suction.
  • Specific steps in conventional lens surgery through phacoemulsification include creating comeal incisions using a blade or keratome, manually opening the anterior capsule (capsutotomy) using a forceps or bent needle, fragmenting the lens with ultrasonic energy and chopper instruments, suction of lens material, implantation of an infraocular lens (10L) and finally aspiration and cleanup of viscoelastic and retained lens cortical fragments.
  • the femtosecond laser has been utilized to perform the vital steps of corneal incision, anterior capsulotomy and lens fragmentation.
  • a femtosecond laser is an infrared laser ( 1053 nm) that works by photodisruption wherein laser energy absorbed by the tissue induces rapid expansion, creating microcavitation bubbles and acoustic shock waves that cause morphological changes ( 1).
  • FLAGS Femtosecond laser-assisted cataract and lens surgery
  • PCME pseudophakic cystoid macular edema
  • CVA central visual acuity
  • OCT optical coherence tomography
  • CME postoperative cystoid macular edema
  • PCME cardiovascular disease
  • TA-LF topical triamcinolone acetonide-loaded liposomes formulation
  • compositions of the present invention comprise a combination of triamcinolone acetonide as the active pharmaceutical ingredient, polyethylene glycol (PEG- 12) glyceryl dhnyristate as structural constituent of liposomes, ethyl alcohol as organic solvent for liposomes generation, kolliphor HS 15 as penetration enhancer, citric acid anhydrous and sodium citrate dehydrate as buffers, benzalkonium chloride as preservative, and grade 2 purified water as inorganic solvent.
  • PEG- 12 polyethylene glycol
  • glyceryl dhnyristate as structural constituent of liposomes
  • ethyl alcohol as organic solvent for liposomes generation
  • kolliphor HS 15 as penetration enhancer
  • citric acid anhydrous and sodium citrate dehydrate as buffers
  • benzalkonium chloride as preservative
  • grade 2 purified water as inorganic solvent.
  • the formulations of the present invention are useful for prevention of macular thickening and its associated visual outcomes after lens surgery, such as; visual acuity and contrast sensitivity.
  • FIG. 1 shows a flow diagram representing the number of eyes randomized and analyzed, and shows TA-LF treatment provided significant results in preventing CSME (clinically significant macular edema).
  • CSME was present in 6/27 cases of treatment with a non-liposomal commercial triamcinolone product versus 0/27 cases in the treatment arm with TA-LF (formulation 2).
  • FIG. 2 shows Baseline and post-operative images of fluorescein eye surface staining and OCT images in the TA and TA-LF groups.
  • the tomographic images in the TA Group correspond to one of the six cases of CSME whereas the tomographic images in the TA-LF group showed only one case of CSME.
  • FIG. 3 shows corneal endothelial cell density analysis in healthy subjects treated with triamcinolone acetonide loaded liposomes formulation.
  • the present invention relates to topical ophthalmic formulations suitable for the treatment of conditions which occur in association with lens surgeries.
  • the inventors have discovered a use of a topical ophthalmic liposomal formulation developed for the treatment of posterior segment diseases of the eye.
  • the present invention relates to the further discovery that this formulation is particularly useful for the treatment of patients that have undergone cataract surgeries.
  • compositions of the present invention contain a pharmaceutically effective amount of triamcinolone acetonide (TA).
  • concentration of TA in liposomes formulations ranges from 0.01 to 2.00% (w/v).
  • TA is a known synthetic corticosteroid with an empirical formula of C24H31FO6 and a molecular weight of 434.50 Da.
  • TA has a powerful antiinflammatory activity (7.5 times more potent than cortisoneX32).
  • Polyethylene glycol (PEG- 12) glyceryl dimyristate is used as structural constituent of liposomes in a concentration of 5-15% (w/v) and ethyl alcohol is used as organic solvent for liposomes generation in a concentration of 0.7 to 2.1% (v/v).
  • the liposomes formulation contain polyethylene glycol (15)-hydroxystearate or KolliphorHS 15 from 2.5 - 7.5% (w/v), as a potent non-ionic solubilizer and emulsifying agent, with low toxicity proposed to act as a permeability enhancer.
  • KolliphorHS 15 promotes drug transport across cell membranes (increasing the endocytosis rate) and stimulates drug translocation through the paracellular route (affects actin organization on the cell cytoskeleton with the subsequent tight junction opening)(33).
  • the aqueous compositions of the present invention optionally comprise more excipients selected from the group consisting of buffering agents, pH-adjusting agents, and preservatives.
  • Citric acid anhydrous (0.04 - 0.16%) and sodium citrate dehydrate (0.23 - 0.69%) are used as buffers, whereas benzalkonium chloride (0.001 - 0.015%) as preservative. All of these compounds in units of % w/v.
  • the pH can range from about 5 to about 7.5.
  • compositions of the present invention may be prepared by conventional methods of preparing pharmaceutical suspension compositions.
  • the drug triamcinolone acetonide
  • a lipid mixture containing polyethylene glycol (PEG-12) glyceryl dimyristate and ethyl alcohol.
  • An aqueous mixture having grade 2 purified water, polyethylene glycol (15)-hydroxystearate (KolliphorHS 15), citric acid anhydrous, sodium citrate dehydrate and benzalkonium chloride was commingled in a flask and set aside for compounding. The water mixture is gently added to the lipid mixture to obtain the final formulation.
  • Triamcinolone acetonide-loaded liposomes topical ophthalmic formulation (TA-LF)
  • Particle size of the TA-LFs was analyzed by means of Dynamic Light Scattering and zeta potential (z) was calculated by measuring the velocity of the particles using l aser Doppler Velocimetry at 25°C (Zetasizer Nano ZS, Malvern Instruments, Malvern, UK). The Z-average (mean particle diameter) and polydispersity index (PDI) were calculated from the particle size distribution.
  • TA-LF from example 1 was evaluated in an in vitro diffusion assay. Diffusion chambers and rabbit corneas were used to conduct diffusion experiments (Chemotaxis Chambers BW200S, NeuroProbe, Gaithersburg, MD, USA). Rabbit corneas from New Zealand white rabbits were used for this experiment. The central corneal tissue was located between the top and bottom compartments of the diffusion chambers to act as a TA diffusion barrier. The top compartment was filled with 180 ml of balanced salt solution (BSS) while the bottom compartment was filled with 200 ml of TA-LFs (TA-LF 1 to TA- LF4). To avoid evaporation, the diffusion chambers were located into a 37°C humidity camera.
  • BSS balanced salt solution
  • HPLC high performance liquid chromatography
  • an eye examination was performed under anesthesia (intramuscular injection of ketamine hydrochloride 30 rag/kg and chlorpromazine hydrochloride 15 mg/kg). This evaluation included slit-lamp biomicroscopy, fluorescein staining, funduscopy with direct ophthalmoscope, and intraocular pressure (IOP) measurement (iCare Tonometer i350, Vantaa, Finland). Additionally, ocular irritability test was evaluated according to pharmacopeia of Estados Unidos Mexicanos.
  • a positive irritant reaction is considered when more than one rabbit presented: cornel ulceration revealed by fluorescein staining, corneal opacity, iris or conjunctival inflammation and dilatation of conjunctival vessels especially around the cornea.
  • conjunctiva, cornea, retina, 150 ml of aqueous humor and 200 ml of vitreous were collected.
  • the solid tissues were washed in PBS.
  • tissues were homogenized with 0.3 ml of acetonitrile (Sigma- Aldrich, Mexico). Posteriorly, each sample was centrifuged at 15,294x g for 5 min. The supernatants were evaporated to add 100 ml of methanol. Another centrifugation was performed and 20 ml of the resultant supernatants were used for analysis of TA concentration by HPLC, performed as previously described.
  • C max was 2156.07 ⁇ 1055.41 ng/g in cornea, 1886.33 ⁇ 398.95 ng/g in conjunctiva, 9.9 ⁇ 1.95 ng/g in aqueous humor, 83.3 ⁇ 30.49 ng/g in lens, 32.6 ⁇ 10.27 ng/g in vitreous and 252.10 ⁇ 90.00 ng/g in retina.
  • TA-LF topical triamcinolone acetonide-loaded liposomes formulation
  • PCME refractory pseudophakic cystoid macular edema
  • IOP Intraocular pressure
  • CFT central foveal thickness
  • This study was performed to report tolerability, safety and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) in healthy subjects, with no ocular nor systemic disease. They received the TA-LF and were instructed to apply one drop every two hours in the right eye, while awake (six times), for 2 weeks. Demographic and baseline clinical exams were collected on day 14 to 1 before starting the administration of TA-LF. Retinal optical coherence tomography (OCT) was performed at baseline (to confirm no CME by OCT) and every week until the end of the follow-up.
  • OCT Retinal optical coherence tomography
  • BCVA using the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart at 4 m, slit lamp evaluation of the eye surface with fluorescein 2% staining and posterior segment findings were recorded on every visit. Subjects were withdrawn from the study if they presented any evidence of poor tolerability (any adverse event related to the use of the topical formulation). Tolerability was assessed through collection and summary of ocular and non-ocular adverse events (AEs), serious AEs (SAEs), ocular assessments and vital signs, whether volunteered by the patient, discovered by study site personnel during questioning, or other means.
  • EDRS Diabetic Retinopathy Study
  • AEs were assigned standard codes terms for the event based upon the MedDRA Coding dictionary version 18.1.
  • CS contrast sensitivity
  • IOP intraocular pressure
  • cECD comeal endothelial cell density
  • TA-LF was well tolerated in healthy subjects. Twenty right eyes of 20 healthy subjects (38.45 ⁇ 9.06 years old, female; 45%, male; 55%) without evidence of systemic or eye disease were enrolled to evaluate tolerability of the TA-LF. These subjects were instructed to apply one drop of TA-LF every two hours in the right eye, while they were awake (six times), during 2 weeks. Demographic and baseline clinical characteristics of these subjects are summarized in Table 7. In data analysis, no AEs were reported. OCT showed no significant change in CFT as compared with baseline (CFT change of 0.85 ⁇ 0.29 mm). BCVA did not have a significant change in all 20 patients (average change of -0.01 ⁇ 0.16 ETDRS letters).
  • Table 7 Demographics and Clinical Characteristics of healthy subjects treated with TA-LF.
  • FIG. 3 A and B show corneal endothelial cell density analysis in healthy subjects treated with triamcinolone acetonide loaded liposomes formulation.
  • A. Images of specular microscopy of a representative case at baseline and after 14 days of TALF instillation are presented.
  • B. Column bar graph from cECD analysis is presented. Non-significant difference on cECD values was stablished between baseline and after 14 days of TALF instillation.
  • cECD comeal endothelial cell density, TALF; triamcinolone acetonide loaded liposomes formulation.
  • the aim of this assay is to explore tolerability, safety and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) to prevent Clinical significant pseudophakic cystoid macular edema (CSME) after femtosecond laser-assisted cataract surgery (FLAGS).
  • TA-LF topical triamcinolone acetonide-loaded liposomes formulation
  • CSME clinical significant pseudophakic cystoid macular edema
  • FLAGS femtosecond laser-assisted cataract surgery
  • TA group eyes were exposed to a conventional topical formulation of triamcinolone acetonide 0,1% for 21 days postoperatively whereas patients in the TA-LF group received a liposomal formulation containing 2 mg/ml of TA (0.2%).
  • a follow up consisting of slit lamp examination, visual acuity, contrast sensitivity, central fovea l thickness (CFT) and total macular volume (TMV) (both measured by retinal optical coherence tomography) was performed. Study visits were scheduled at 1 day, 6 and 12 weeks after surgery.
  • CFT central fovea l thickness
  • TMV total macular volume
  • CFT and TMV correlate significantly with contrast sensitivity only in TA-LF group.
  • TA-LF shown the best preventive action for CSME.
  • CME cystoid macular edema
  • CSME clinical significant CME
  • TA -loaded liposomal formulation is effective for the prevention of CSME associated with FLACS and it seems that its therapeutic activity could be superior to the activity of conventional topical steroids formulation.
  • the use of TA-LF was related to better visual outcomes like visual acuity and contrast sensitivity.
  • FIG. 1 represents the number of eyes randomized and analyzed.
  • TA-LF showed excellen t resul ts preventing CSME (clinically significant macular edema).
  • CSME clinically significant macular edema
  • triamcinolone commercial product
  • TA-LF TA-LF
  • FIG. 2 represents Baseline and post-operative images of fluorescein eye surface staining and OCT images in the TA and TA-LF groups are presented.
  • the tomographic images in TA group correspond to one of the six cases of CSME, whereas the tomographic images in the TA-LF group correspond to the only case of CME.
  • non-ocular surface adverse events were revealed by fluorescein stain at 6 weeks of follow-up in any group.
  • Panteleontidis V Detorakis ET, Pallikaris IG, Tsilimbaris MK.. Latanoprost- Dependent Cystoid Macular Edema Following Uncomplicated Cataract Surgery in Pseudoexfoliative Eyes. Ophthalmic Surg Lasers Imaging. 2010:1-5.

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Abstract

L'invention concerne des formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin. La formulation liposomale comprend des liposomes à formation autonome par voie thermodynamique qui sont utiles sous forme topique pour traiter des maladies du segment postérieur de l'oeil.
EP20727542.1A 2019-05-16 2020-05-05 Formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin Pending EP3968949A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201962848907P 2019-05-16 2019-05-16
US16/426,712 US11458199B2 (en) 2012-08-21 2019-05-30 Liposome formulations
PCT/US2020/031417 WO2020231670A1 (fr) 2019-05-16 2020-05-05 Formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin

Publications (1)

Publication Number Publication Date
EP3968949A1 true EP3968949A1 (fr) 2022-03-23

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EP20727542.1A Pending EP3968949A1 (fr) 2019-05-16 2020-05-05 Formulations ophtalmiques topiques contenant des liposomes chargés d'acétonide de triamcinolone pour la prévention de l'épaississement maculaire et de ses résultats visuels associés après une chirurgie du cristallin

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EP (1) EP3968949A1 (fr)
MX (1) MX2021014000A (fr)
WO (1) WO2020231670A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2022015656A (es) * 2020-06-15 2023-03-22 Opko Pharmaceuticals Llc Formulaciones oftalmaticas topicas de liposomas cargados con acetonido de triamcinolona como terapia primaria para el edema macular secundario a la oclusion de la vena retiniana de rama.
US11793789B2 (en) 2021-07-23 2023-10-24 Somerset Therapeutics, Llc Treatment of ophthalmological conditions using buffer-free ophthalmological compositions of ketorolac and phenylephrine

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* Cited by examiner, † Cited by third party
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RU2680096C2 (ru) * 2012-08-21 2019-02-15 ОПКО ФАРМАСЬЮТИКАЛС, Эл Эл Си Липосомальные препараты
CN105997872B (zh) * 2016-07-08 2019-02-19 河南省立眼科医院 一种含有泊沙康唑的眼用纳米胶束抗真菌溶液

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MX2021014000A (es) 2021-12-10
WO2020231670A1 (fr) 2020-11-19

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