WO2015105458A1 - Stable liposomal formulations for ocular drug delivery - Google Patents

Stable liposomal formulations for ocular drug delivery Download PDF

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Publication number
WO2015105458A1
WO2015105458A1 PCT/SG2015/000001 SG2015000001W WO2015105458A1 WO 2015105458 A1 WO2015105458 A1 WO 2015105458A1 SG 2015000001 W SG2015000001 W SG 2015000001W WO 2015105458 A1 WO2015105458 A1 WO 2015105458A1
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formulation
latanoprost
ocular
liposome
stable liposomal
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French (fr)
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Subramanian Venkatraman
Jayagenesh V. NATARAJAN
Tina HOWDEN
Freddy Boey
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Nanyang Technological University
Singapore Health Services Pte Ltd
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Nanyang Technological University
Singapore Health Services Pte Ltd
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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Intraocular pressure (IOP) in the eye is maintained by a continuous flow of aqueous humor produced by the ciliary body. Excess fluid flows out of the eye through the trabecular meshwork. If the outflow is blocked, aqueous humor builds up inside the eye leading to increased IOP and ocular hypertension. The ocular hypertension can damage the optic nerve, resulting in an optic neuropathy and irreversibly impaired vision. This condition, known as glaucoma, affects more than 60 million people worldwide and is the second leading cause of blindness. Increased IOP is the key modifiable risk factor for glaucoma.
  • Topical eye drops contain drugs for controlling IOP which typically act by reducing fluid production by the eye, increasing fluid outflow, or by both
  • Prostaglandin analogues e.g., latanoprost
  • subconjunctival injection of a sustained release IOP-reducing drug can be used to deliver drugs directly to the site of action.
  • a sustained release IOP-reducing drug can be used to deliver drugs directly to the site of action.
  • the formulation includes a liposome containing at least one lipid bilayer that includes a
  • the formulation also contains a prostaglandin F 2a encapsulated in the liposome. Additionally, the liposome has a diameter of less than 2 ⁇ .
  • Fig. 1 is a plot of cumulative release of latanoprost from a palmitoyl oleoyl phosphatidyl choline (POPC) liposome versus time;
  • POPC palmitoyl oleoyl phosphatidyl choline
  • Fig. 2a is a plot of the percentage of the starting amount of latanoprost remaining in liposomes versus time for egg phosphatidyl choline (PC)-containing liposomes and POPC-containing liposomes;
  • PC egg phosphatidyl choline
  • Fig. 2b is a plot of liposome size versus time of storage at 4 °C.
  • Fig. 3 is a plot of intraocular pressure versus days after a single
  • a stable liposomal formulation for ocular delivery includes a liposome containing at least one lipid bilayer that includes a phosphatidylcholine.
  • the liposome is a unilamellar vesicle.
  • the phosphatidyl choline is palmitoyl oleoyl phosphatidyl choline (POPC).
  • the formulation also contains a prostaglandin F 2a encapsulated in the liposome.
  • the prostaglandin F 2a can be latanoprost, bimatoprost, travoprost, or carboprost. In a preferred embodiment, the prostaglandin F 2a is latanoprost.
  • the mole ratio of prostaglandin F 2ot to POPC can be 0.01 : 1 to 0.5: 1. In an embodiment, the mole ratio is 0.01 : 1 to 0.35: 1. In a preferred embodiment, the stable liposomal formulation includes latanoprost and POPC at a mole ratio of 0.01 : 1 to 0.175: 1. Additionally, the liposome can be formulated to include between 2 and 25 wt % of the prostaglandin F 2a .
  • the liposome can have a diameter of less than 2 ⁇ .
  • the diameter of the liposome is 100 nm to 300 nm, e.g., 100 nm, 150 nm, 200 nm, 250 nm, and 300 run. In a preferred embodiment, the diameter is 100 nm.
  • the liposomal formulation described above can be a pre- constituted, ready-to-inject aqueous formulation for sub-conjunctival injection.
  • the ocular disorder can be ocular hypertension or glaucoma.
  • the disorder is glaucoma.
  • the liposomal formulation is administered by subconjunctival injection.
  • Administering the liposomal formulation described above can significantly reduce IOP at one hour post injection. More specifically, administering the liposomal formulation results in a reduction in IOP of at least 30 % (e.g., 30%, 40%, and 50%) compared to the pretreatment IOP. Advantageously, the IOP remains reduced for as long as 4-6 months following a single injection.
  • the injected liposomal formulation can slowly release the prostaglandin F 2a , e.g., latanoprost, over several months.
  • the prostaglandin F 2a e.g., latanoprost
  • 50 % of the initial amount of drug in the liposomes can be released within 10 days after injection of the formulation into the eye.
  • 65 % of the drug is released within 28 days of injection.
  • Chronic topical application of anti- glaucoma drugs often induces ocular surface disease.
  • the slow-release feature of the liposomal formulation obviates the need for daily applications of these drugs, thereby reducing or eliminating the concomitant side effects.
  • drugs which are not stable are lyophilized or frozen at a
  • the liposomal formulation is stable for extended periods of time.
  • the formulation can be stored at 4 °C for up to 6 months (e.g., 1, 2, 3, 4, 5, and 6 months) without aggregation of the liposomes or loss of drug from them.
  • the liposomal formulation can be stored in a vial at 4 °C for extended periods and then can be directly injected straight from the vial.
  • EXAMPLE 1 Preparation of large unilamellar vesicles (LUVs) for drug release studies
  • a thin film hydration technique was used to formulate latanoprost-loaded POPC liposomes for drug release studies. Briefly, POPC was weighed and dissolved in a chloroform:methanol (2: 1 v/v) solvent mixture. Latanoprost (2 mg/ml stock solution in acetonitrile) was added to the lipid solvent mixture at a drug: lipid mole ratio of 0.175:1 and maintained at 40 °C. The solvent mixture was added to a round bottomed flask in a rotary evaporator connected to a water bath maintained at 40 °C. The flask was rotated at 100 rpm under low pressure for 1 h to remove the solvent, thereby forming a thin drug-loaded lipid film.
  • MLVs multilamellar vesicles
  • Drug-loaded LUVs were also prepared for stability studies.
  • POPC was dissolved in PBS at a pH of 6.7 with constant stirring at room temperature for 2 h to form ML Vs.
  • the MLVs were extruded 3-5 times using three 80 nm sized polycarbonate membranes stacked together on a bench top extruder to form POPC LUVs.
  • Latanoprost was dissolved in ethanol and the resulting solution, maintained in a round bottomed flask at 50 °C in a water bath, was dried under a stream of nitrogen gas to form a thin drug film.
  • the drug film was hydrated with the POPC LUVs at room temperature for 2-3 h until no oil droplets were observed on the flask walls.
  • a latanoprost:POPC mole ratio of 0.175:1 was used to prepare the drug-loaded LUVs.
  • Latanoprost-loaded POPC LUVs were sterile filtered at room temperature using a 0.2 ⁇ syringe filter and stored at 4 °C until analyzed.
  • a similar method was used to prepare latanoprost-loaded egg PC liposomes.
  • the macaques were anesthetized by intramuscular injection of a mixture containing ketamine (5-10 mg/kg body weight) and acepromazine maleate (0.25 mg/kg body weight), together with a subcutaneous injection of atropine sulfate (0.125 mg/kg body weight). Their airway, respiration, and pulse were monitored during all procedures. One to two drops of 1% xylocaine was used as a topical anesthesia to reduce possible discomfort to the animals during subconjunctival injection. The animals' pupils were dilated with 2.5% phenylephrine hydrochloride and 1% tropicamide drops (Alcon Laboratories, French's Forest, NSW, Australia).
  • Latanoprost-loaded POPC liposomes were prepared by the technique described in EXAMPLE 2 above.
  • a latanoprost liposomal formulation (100 ⁇ ) having an initial drug/lipid mole ratio of 0.175: 1 was introduced by subconjunctival injection into both eyes of three animals. IOP was measured prior to injection and at daily and weekly intervals post-injection.
  • the monkeys were slightly anesthetized with ketamine (5 mg/kg body weight) before measurement of IOP. Again, 1 -2 drops of 1% xylocaine was used as topical anesthesia to reduce possible discomfort to the animals involved during the measurement procedure. IOP was measured using a calibrated tonometer (Tono- Pen® XL, Reichert Technologies, Depew, NY). IOP was monitored for three days pre-injection and for 120 days post-injection. The results are shown in FIG. 3. A single subconjunctival injection led to an initial rapid drop in intraocular pressure during the first day following the injection. The reduced IOP remained stable for at least 120 days post-injection.

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Abstract

A stable liposomal formulation for ocular delivery. The formulation contains a liposome that includes at least one lipid bilayer containing a phosphatidylcholine, and a prostaglandin F2a encapsulated in the liposome. Also provided is a method for treating an ocular disorder with the formulation.

Description

STABLE LIPOSOMAL FORMULATIONS FOR OCULAR DRUG
DELIVERY
BACKGROUND
Intraocular pressure (IOP) in the eye is maintained by a continuous flow of aqueous humor produced by the ciliary body. Excess fluid flows out of the eye through the trabecular meshwork. If the outflow is blocked, aqueous humor builds up inside the eye leading to increased IOP and ocular hypertension. The ocular hypertension can damage the optic nerve, resulting in an optic neuropathy and irreversibly impaired vision. This condition, known as glaucoma, affects more than 60 million people worldwide and is the second leading cause of blindness. Increased IOP is the key modifiable risk factor for glaucoma.
Conventional treatments for ocular hypertensive and glaucoma patients include ocular surgery and topical eye drop instillation. These treatment modalities have drawbacks. For example, not all patients are candidates for ocular surgery. Additionally, although topical eye drops are generally considered to be effective, patients' long-term compliance with instillation schedules is a major issue. Ocular hypertension and glaucoma cannot be well controlled if patients do not adhere to the proper topical eye drop instillation schedule.
Topical eye drops contain drugs for controlling IOP which typically act by reducing fluid production by the eye, increasing fluid outflow, or by both
mechanisms. Prostaglandin analogues, e.g., latanoprost, are potent drugs which can reduce IOP by increasing aqueous outflow through the uveoscleral pathway.
Typically, only 5% of free drug applied to the corneal epithelium via eye drops successfully penetrates through the cornea. As a result, the amount of drug reaching the aqueous humor often falls below the therapeutically effective concentration. This necessitates repeated administration. Additionally, a substantial portion of the drug can enter the circulation via the conjunctival sac, causing undesirable systemic side effects.
As an alternative to topical eye drops, subconjunctival injection of a sustained release IOP-reducing drug can be used to deliver drugs directly to the site of action. Such a delivery modality solves the problems of patient non-compliance with instillation schedules and inefficient drug transport across the cornea.
The need exists for a stable drug formulation for subconjunctival injection requiring a minimal frequency of administration for long-term stable control of IOP.
SUMMARY
To address the need for an improved treatment for intraocular pressure (IOP), a stable liposomal formulation for ocular delivery is provided. The formulation includes a liposome containing at least one lipid bilayer that includes a
phosphatidylcholine. The formulation also contains a prostaglandin F2a encapsulated in the liposome. Additionally, the liposome has a diameter of less than 2 μιη.
Also provided is a method for treating an ocular disorder by administering the formulation described above.
The details of one or more embodiments of the invention are set forth in the drawings and description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. All references cited herein are hereby incorporated by reference in their entirety.
BRIEF DESCRIPTION OF THE DRAWINGS
The description below refers to the accompanying drawings, of which:
Fig. 1 is a plot of cumulative release of latanoprost from a palmitoyl oleoyl phosphatidyl choline (POPC) liposome versus time;
Fig. 2a is a plot of the percentage of the starting amount of latanoprost remaining in liposomes versus time for egg phosphatidyl choline (PC)-containing liposomes and POPC-containing liposomes;
Fig. 2b is a plot of liposome size versus time of storage at 4 °C; and
Fig. 3 is a plot of intraocular pressure versus days after a single
subconjunctival injection of latanoprost encapsulated in a POPC-containing liposome
DETAILED DESCRIPTION
As mentioned above, a stable liposomal formulation for ocular delivery is provided. The formulation includes a liposome containing at least one lipid bilayer that includes a phosphatidylcholine. In an embodiment, the liposome is a unilamellar vesicle. In a preferred embodiment, the phosphatidyl choline is palmitoyl oleoyl phosphatidyl choline (POPC).
The formulation also contains a prostaglandin F2a encapsulated in the liposome. The prostaglandin F2acan be latanoprost, bimatoprost, travoprost, or carboprost. In a preferred embodiment, the prostaglandin F2a is latanoprost.
The mole ratio of prostaglandin F2ot to POPC can be 0.01 : 1 to 0.5: 1. In an embodiment, the mole ratio is 0.01 : 1 to 0.35: 1. In a preferred embodiment, the stable liposomal formulation includes latanoprost and POPC at a mole ratio of 0.01 : 1 to 0.175: 1. Additionally, the liposome can be formulated to include between 2 and 25 wt % of the prostaglandin F2a.
The liposome can have a diameter of less than 2 μιη. In an embodiment, the diameter of the liposome is 100 nm to 300 nm, e.g., 100 nm, 150 nm, 200 nm, 250 nm, and 300 run. In a preferred embodiment, the diameter is 100 nm. These nano- sized drug-loaded liposomes can release the prostaglandin F2a slowly over time.
In an embodiment, the liposomal formulation described above can be a pre- constituted, ready-to-inject aqueous formulation for sub-conjunctival injection.
Also within the scope of the invention is a method for treating an ocular disorder that relies on administering the liposomal formulation described above. The ocular disorder can be ocular hypertension or glaucoma. Preferably, the disorder is glaucoma. In an embodiment, the liposomal formulation is administered by subconjunctival injection.
Administering the liposomal formulation described above can significantly reduce IOP at one hour post injection. More specifically, administering the liposomal formulation results in a reduction in IOP of at least 30 % (e.g., 30%, 40%, and 50%) compared to the pretreatment IOP. Advantageously, the IOP remains reduced for as long as 4-6 months following a single injection.
As mentioned above, the injected liposomal formulation can slowly release the prostaglandin F2a, e.g., latanoprost, over several months. For example, 50 % of the initial amount of drug in the liposomes can be released within 10 days after injection of the formulation into the eye. Preferably, 65 % of the drug is released within 28 days of injection. Chronic topical application of anti- glaucoma drugs often induces ocular surface disease. The slow-release feature of the liposomal formulation obviates the need for daily applications of these drugs, thereby reducing or eliminating the concomitant side effects.
Typically, drugs which are not stable are lyophilized or frozen at a
temperature of -20 °C or lower to prevent loss of activity over time. Notably, lyophilizing or freezing sustained release formulations of drug-loaded liposomes can adversely affect the drug release profile, resulting in an unpredictable variability in the drug effectiveness.
Advantageously, the liposomal formulation is stable for extended periods of time. For example, the formulation can be stored at 4 °C for up to 6 months (e.g., 1, 2, 3, 4, 5, and 6 months) without aggregation of the liposomes or loss of drug from them. Thus, the liposomal formulation can be stored in a vial at 4 °C for extended periods and then can be directly injected straight from the vial.
Without further elaboration, it is believed that one skilled in the art can, based on the description above, utilize the present invention to its fullest extent. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
EXAMPLE 1 : Preparation of large unilamellar vesicles (LUVs) for drug release studies
A thin film hydration technique was used to formulate latanoprost-loaded POPC liposomes for drug release studies. Briefly, POPC was weighed and dissolved in a chloroform:methanol (2: 1 v/v) solvent mixture. Latanoprost (2 mg/ml stock solution in acetonitrile) was added to the lipid solvent mixture at a drug: lipid mole ratio of 0.175:1 and maintained at 40 °C. The solvent mixture was added to a round bottomed flask in a rotary evaporator connected to a water bath maintained at 40 °C. The flask was rotated at 100 rpm under low pressure for 1 h to remove the solvent, thereby forming a thin drug-loaded lipid film. Isotonic phosphate buffered saline (PBS; 150mM, pH 5.5) was added to this film to form multilamellar vesicles (MLVs). The MLVs were extruded ten times through a polycarbonate filter (0.2 μηι -0.08 μιη). The extrusions resulted in the formation of LUVs having a size distribution of 0.09- 0.12 μπι in diameter. EXAMPLE 2: Preparation of LUVs for drug stability studies
Drug-loaded LUVs were also prepared for stability studies. POPC was dissolved in PBS at a pH of 6.7 with constant stirring at room temperature for 2 h to form ML Vs. The MLVs were extruded 3-5 times using three 80 nm sized polycarbonate membranes stacked together on a bench top extruder to form POPC LUVs. Latanoprost was dissolved in ethanol and the resulting solution, maintained in a round bottomed flask at 50 °C in a water bath, was dried under a stream of nitrogen gas to form a thin drug film. The drug film was hydrated with the POPC LUVs at room temperature for 2-3 h until no oil droplets were observed on the flask walls. A latanoprost:POPC mole ratio of 0.175:1 was used to prepare the drug-loaded LUVs. Latanoprost-loaded POPC LUVs were sterile filtered at room temperature using a 0.2 μηι syringe filter and stored at 4 °C until analyzed. A similar method was used to prepare latanoprost-loaded egg PC liposomes.
EXAMPLE 3: Characterization of drug loaded POPC liposomes
Drug Release studies were performed by dialysing latanoprost-loaded POPC liposomes prepared as described in EXAMPLE 1 above against PBS at a pH of 7.4 and measuring by HPLC the amount of latanoprost released. The results are shown in FIG. 1. Over a 28 day period, approximately 65% of the latanoprost was released from the latanoprost-loaded POPC liposomes in a time-dependent manner.
The physical characteristics of the latanoprost-loaded POPC liposomes were determined essentially as described in Venkatraman et al.. International Application Publication No. 2012/021 107, the content of which is incorporated herein by reference in its entirety.
The stability of latanoprost-loaded POPC liposomes prepared as described in EXAMPLE 2 above was measured and compared to similar latanoprost-loaded egg PC liposomes. Stability of the liposomes stored at 4 °C was assessed for a period of 6-9 months. Stability was assessed by measuring the average size of the liposomes as well as measuring by HPLC the concentration of latanoprost in the liposomes. The results are depicted in FIG. 2A and FIG. 2B. As shown in FIG. 2A, a significant amount of latanoprost was lost from egg PC liposomes over time, demonstrating a 45 % reduction of the starting amount of latanoprost after 3 months of storage at 4 °C. Unexpectedly, no measureable amount of latanoprost was lost from POPC liposomes even after 6 months of storage at 4 °C. Turning to particle size, the results depicted in FIG. 2B reveal that the average size of latanoprost-loaded egg PC liposomes got progressively smaller over a 9 month period of storage at 4 °C. Again unexpectedly, latanoprost-loaded POPC liposomes did not change measurably even after 6 months at 4 °C. Notably, a change in size of a drug-loaded liposome will significantly alter the drug release kinetics.
EXAMPLE 4: In vivo activity of latanoprost liposomal formulation
The efficacy of the latanoprost liposomal formulation described above was tested in an animal model of glaucoma, namely, long tailed macaques (Macaca fascicularis) having ocular hypertension, defined as an IOP > 18 mm Hg. Animal studies were performed in accordance with the statement for the use of animals in ophthalmic and vision research approved by the Association for Research in Vision and Ophthalmology. Additionally, the guidelines of the Animal Ethics Committee of the Singhealth Singapore Association for Assessment and Accreditation of Laboratory Animal Care were also followed.
The macaques were anesthetized by intramuscular injection of a mixture containing ketamine (5-10 mg/kg body weight) and acepromazine maleate (0.25 mg/kg body weight), together with a subcutaneous injection of atropine sulfate (0.125 mg/kg body weight). Their airway, respiration, and pulse were monitored during all procedures. One to two drops of 1% xylocaine was used as a topical anesthesia to reduce possible discomfort to the animals during subconjunctival injection. The animals' pupils were dilated with 2.5% phenylephrine hydrochloride and 1% tropicamide drops (Alcon Laboratories, French's Forest, NSW, Australia).
Latanoprost-loaded POPC liposomes were prepared by the technique described in EXAMPLE 2 above. A latanoprost liposomal formulation (100 μΐ) having an initial drug/lipid mole ratio of 0.175: 1 was introduced by subconjunctival injection into both eyes of three animals. IOP was measured prior to injection and at daily and weekly intervals post-injection.
The monkeys were slightly anesthetized with ketamine (5 mg/kg body weight) before measurement of IOP. Again, 1 -2 drops of 1% xylocaine was used as topical anesthesia to reduce possible discomfort to the animals involved during the measurement procedure. IOP was measured using a calibrated tonometer (Tono- Pen® XL, Reichert Technologies, Depew, NY). IOP was monitored for three days pre-injection and for 120 days post-injection. The results are shown in FIG. 3. A single subconjunctival injection led to an initial rapid drop in intraocular pressure during the first day following the injection. The reduced IOP remained stable for at least 120 days post-injection.
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A stable liposomal formulation for ocular delivery, the formulation comprising a liposome including at least one lipid bilayer that contains a
phosphatidylcholine, and a prostaglandin F2a encapsulated in the liposome, wherein the liposome has a diameter of less than 2 μηι.
2. The stable liposomal formulation of claim 1 , wherein the
phosphatidylcholine is palmitoyl oleoyl phosphatidyl choline (POPC).
3. The stable liposomal formulation of claim 2, wherein the prostaglandin F2a is latanoprost, bimatoprost, travoprost, or carboprost.
4. The stable liposomal formulation of claim 3, wherein the prostaglandin F2a is latanoprost.
5. The stable liposomal formulation of claim 4, wherein the formulation has a mole ratio of latanoprost to POPC of 0.01 : 1 to 0.5: 1.
6. The stable liposomal formulation of claim 5, wherein the mole ratio of latanoprost to POPC is 0.01 : 1 to 0.175: 1.
7. The stable liposomal formulation of claim 5, wherein the liposome has a diameter of 100 nm to 300 nm.
8. The stable liposomal formulation of claim 6, wherein the liposome has a diameter of 100 nm to 300 nm.
9. A method for treating an ocular disorder, comprising administering to an eye of a subject in need thereof the formulation of claim 1.
10. The method of claim 9, wherein the ocular disorder is ocular hypertension or glaucoma.
235
1 1. The method of claim 10, wherein the formulation is administered via subconjunctival injection.
12. A method for treating an ocular disorder, comprising administering to an 240 eye of a subject in need thereof the formulation of claim 7.
13. The method of claim 12, wherein the ocular disorder is ocular hypertension or glaucoma. 45
14. The method of claim 13, wherein the formulation is administered via subconjunctival injection.
15. A method for treating an ocular disorder, comprising administering to an eye of a subject in need thereof the formulation of claim 8.
50
16. The method of claim 15, wherein the ocular disorder is ocular hypertension or glaucoma.
17. The method of claim 16, wherein the formulation is administered via55 subconjunctival injection.
60
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SG10201701773UA (en) * 2012-09-06 2017-04-27 Univ Nanyang Tech Hyaluronic Acid-Based Drug Delivery Systems
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US11452703B2 (en) * 2020-05-21 2022-09-27 Peregrine Ophthalmic PTE LTD. Methods and compositions for reducing adipocyte numbers
AU2024287943A1 (en) 2023-07-10 2026-01-22 Eden Ophthalmic Pte Ltd. Liposomal formulations of corticosteroids and uses thereof
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010006648A1 (en) * 1996-02-26 2001-07-05 Hitoshi Yamauchi Liposomes and liposomal dispersion
US20110070294A1 (en) * 2009-09-23 2011-03-24 Javeri Indu Methods for the Administration of Drugs Using Liposomes
WO2011098578A2 (en) * 2010-02-12 2011-08-18 Bioneer A/S Liposome system for ocular administration
US20130216606A1 (en) * 2010-08-12 2013-08-22 Singapore Health Services Pte Ltd Liposomal formulation for ocular drug delivery

Family Cites Families (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925375A (en) 1987-05-22 1999-07-20 The Liposome Company, Inc. Therapeutic use of multilamellar liposomal prostaglandin formulations
US5082664A (en) 1987-05-22 1992-01-21 The Liposome Company, Inc. Prostaglandin-lipid formulations
US4938965A (en) 1987-07-22 1990-07-03 Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of National Defence Of Her Majesty's Canadian Government Ocular delivery of prophylactic agents
SE8703854D0 (en) 1987-10-07 1987-10-07 Pharmacia Ab PROSTAGLAND INGREDIENTS FOR TREATMENT OF GLAUCOME OR OCULAR HYPERTENSION
JP2602964B2 (en) 1989-10-16 1997-04-23 裕 水島 Prostaglandin analogs and their fat emulsions
US5478819A (en) 1993-06-23 1995-12-26 Simo Tarpila Phospholipid composition and use thereof
US6773719B2 (en) 1994-03-04 2004-08-10 Esperion Luv Development, Inc. Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias
US6015716A (en) * 1996-07-12 2000-01-18 The Liposome Company, Inc. Detection of endotoxin levels in liposomes, lipid bilayers and lipid complexes
US5997899A (en) 1996-10-01 1999-12-07 Skyepharma Inc. Method for producing liposomes with increased percent of compound encapsulated
AU6793598A (en) 1997-03-31 1998-10-22 University Of Iowa Research Foundation, The Glycosylceramide-containing liposomes
JP2003517441A (en) 1998-09-25 2003-05-27 アルコン ラボラトリーズ， インコーポレイテッド Sustained-release and comfortable composition for eye disease and method for treating eye disease
AU2002337815A1 (en) 2001-10-05 2003-04-22 Suwalee Chandrkrachang Active agents using liposome beads
WO2003080659A1 (en) 2002-03-27 2003-10-02 Theratechnologies Inc. Methods and compounds for prevention and treatment of elevated intraocular pressure and related conditions
EP1532981B1 (en) 2002-08-23 2007-09-26 Santen Pharmaceutical Co., Ltd. Stable eye drops containing latanoprost as the active ingredient
US20040224010A1 (en) * 2002-11-15 2004-11-11 Optime Therapeutics, Inc. Ophthalmic liposome compositions and uses thereof
JP2006516027A (en) 2002-12-02 2006-06-15 ジェンベク、インコーポレイティッド Materials and methods for treatment of eye related disorders
NZ540885A (en) 2002-12-20 2009-02-28 Chakshu Res Inc Ophthalmic formulation for the prevention and treatment of ocular conditions
EP1643971A2 (en) 2003-05-22 2006-04-12 Neopharm, Inc. Liposomal formulations comprising a combination of two or more active agents
CA2467410A1 (en) 2003-05-27 2004-11-27 Synphora Ab Method for treatment of glaucoma and ocular hypertension with prostaglandin analgoues without melanogenic side-effect
EP1667705A1 (en) 2003-10-03 2006-06-14 Allergan, Inc. Compositions and methods comprising prostaglandin-related compounds and trefoil factor family peptides for the treatment of glaucoma with reduced hyperemia
US20070224255A1 (en) 2004-04-02 2007-09-27 Italfarmaco, S.A. Liposomal Formulations
US8722097B2 (en) * 2004-04-30 2014-05-13 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
SI1759702T1 (en) 2004-05-26 2009-06-30 Bayardo Arturo Jimenez Method of preparing a latanoprost ophthalmic solution and solution thus produced
US8236292B2 (en) 2004-06-04 2012-08-07 Camurus Ab Liquid depot formulations
HUE033977T2 (en) 2004-08-23 2018-02-28 Sylentis Sau Treatment of eye disorders characterized by an elevated intraocular pressure by sirnas
JP5622351B2 (en) * 2004-09-03 2014-11-12 クレアビリス・セラピューティクス・エスピーエー Protease resistant human and non-human HMGB1Box-A variants and their use in therapy / diagnosis
HRP20160455T1 (en) 2004-09-09 2016-07-15 Yeda Research And Development Co., Ltd. Mixtures of polypeptides, their compositions and methods for their preparation, and their uses
ES2314354T3 (en) 2004-11-09 2009-03-16 Novagali Pharma S.A. EMULSION OF WATER OIL TYPE WITH LOW CONCENTRATION OF CATIONIC AGENT AND POTENTIAL POSITIVE ZETA.
US20060188481A1 (en) 2005-02-22 2006-08-24 Saitama Medical School Methods for prophylactically or therapeutically treating an animal for an ocular-related disorder
US7851504B2 (en) 2005-03-16 2010-12-14 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
KR101396731B1 (en) 2005-03-31 2014-05-19 산텐 세이야꾸 가부시키가이샤 PROTECTIVE AGENT FOR RETINAL NEURONAL CELL CONTAINING PROSTAGLANDIN F2α DERIVATIVE AS ACTIVE INGREDIENT
US20070026061A1 (en) 2005-05-25 2007-02-01 Nahid Ali Liposomal formulation and use thereof
US9539202B2 (en) 2006-04-28 2017-01-10 Universidad Complutense De Madrid Formulation of liposomal vesicles in aqueous solutions with lachrymal film characteristics
WO2008120249A1 (en) 2007-03-30 2008-10-09 Sifi S.P.A. Pharmaceutical formulations based on apolar and polar lipids for ophthalmic use
CN101049504B (en) * 2007-04-05 2010-05-19 广州立恩生物科技有限公司 A kind of liposome drug carrier and preparation method thereof
EP1985298A1 (en) 2007-04-24 2008-10-29 Azad Pharma AG Ophtalmic oil-in-water emulsions containing prostaglandins
EP2187900B1 (en) 2007-08-16 2016-11-09 The Schepens Eye Research Institute, Inc. Therapeutic compositions for treatment of inflammation of ocular and adnexal tissues
IL186598A0 (en) * 2007-10-11 2008-11-03 Mohammad Abdulrazik Composition and method for the treatment or prevention of glaucoma and ocular hypertension
JP5421272B2 (en) 2007-10-12 2014-02-19 リゾルヴィクス・ファーマシューティカルズ・インコーポレイテッド Compositions and methods for the treatment of eye diseases
WO2009107753A1 (en) 2008-02-29 2009-09-03 財団法人 名古屋産業科学研究所 Liposome for delivery to posterior segment of eye and pharmaceutical composition for disease in posterior segment of eye
ITRM20080182A1 (en) 2008-04-07 2009-10-08 Medivis S R L OPHTHALMIC PREPARATION BASED ON DORZOLAMIDE AND LATANOPROST FOR THE TOP TREATMENT OF GLAUCOMA.
CA2722971C (en) 2008-05-09 2019-05-07 Qlt Plug Delivery, Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
EP2127638A1 (en) 2008-05-30 2009-12-02 Santen Pharmaceutical Co., Ltd Method and composition for treating ocular hypertension and glaucoma
EP2303184A4 (en) 2008-06-24 2013-06-19 Quadra Logic Tech Inc GLAUCOMA ASSOCIATION TREATMENT
US20100104654A1 (en) 2008-10-27 2010-04-29 Allergan, Inc. Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof
EP2389221B1 (en) 2009-01-23 2023-08-16 Mati Therapeutics Inc. Sustained released delivery of one or more agents
JP5890182B2 (en) 2009-02-12 2016-03-22 インセプト エルエルシー Drug delivery with hydrogel plugs
US20100247606A1 (en) 2009-03-25 2010-09-30 Allergan, Inc. Intraocular sustained release drug delivery systems and methods for treating ocular conditions
ES2964555T3 (en) 2009-08-24 2024-04-08 Stealth Biotherapeutics Inc Peptide for use in the prevention or treatment of macular degeneration
WO2011034192A1 (en) 2009-09-17 2011-03-24 千寿製薬株式会社 Latanoprost-containing aqueous eye drops and method for inhibiting adsorption of latanoprost to resin
US9034830B2 (en) 2009-10-30 2015-05-19 Intratus, Inc. Methods and compositions for sustained delivery of drugs
WO2011106702A2 (en) 2010-02-25 2011-09-01 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
US20110294730A1 (en) 2010-05-31 2011-12-01 Shantha Totada R Method of treating glaucoma and intraocular hypertension
AU2011327785A1 (en) 2010-11-08 2013-03-07 Healor Ltd. Buffered ophthalmic compositions and methods of use thereof
WO2012100347A1 (en) 2011-01-24 2012-08-02 Inceptum Research & Therapeutics, Inc. Compositions comprising a prostaglandin for treating neuropsychiatric conditions
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
EP3290024B1 (en) 2011-08-29 2019-04-17 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
US9248135B2 (en) 2012-04-24 2016-02-02 Allergan, Inc. Prostaglandin and vasoconstrictor pharmaceutical compositions and methods of use
HK1222810A1 (en) 2012-05-03 2017-07-14 麦提疗法有限公司 Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
SG10201701773UA (en) 2012-09-06 2017-04-27 Univ Nanyang Tech Hyaluronic Acid-Based Drug Delivery Systems
RU2652063C2 (en) 2012-10-26 2018-04-24 Форсайт Вижн5, Инк. Ophthalmic system for sustained release of drug to eye
EP2950782B1 (en) 2013-01-31 2017-12-27 Icon Bioscience, Inc. Sustained release formulations for the treatment of intraocular pressure or glaucoma
HK1216146A1 (en) 2013-03-27 2016-10-21 Comprehensive Drug Enterprises, Ltd. Ophthalmic composition, method for preparing the same, and use of the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010006648A1 (en) * 1996-02-26 2001-07-05 Hitoshi Yamauchi Liposomes and liposomal dispersion
US20110070294A1 (en) * 2009-09-23 2011-03-24 Javeri Indu Methods for the Administration of Drugs Using Liposomes
WO2011098578A2 (en) * 2010-02-12 2011-08-18 Bioneer A/S Liposome system for ocular administration
US20130216606A1 (en) * 2010-08-12 2013-08-22 Singapore Health Services Pte Ltd Liposomal formulation for ocular drug delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POLOZOVA, A. ET AL.: "Formation of homogeneous unilamellar liposomes from an interdigitated matrix", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1668, no. 1, 2005, pages 117 - 125 *

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