Preservative free pharmaceutical compositions for ophthalmic administration
Inventors
Karavas, Evangelos • Koutris, Efthimios • SAMARA, VASILIKI • Koutri, Ioanna • Kalaskani, Anastasia • KAKOURIS, ANDREAS • GOTZAMANIS, GEORGE
Assignees
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Publication Number
US-10350161-B2
Publication Date
2019-07-16
Expiration Date
Abstract
The present invention relates to a preservative-free, aqueous solution in the form of eye drops packed in a container that ensures stability of the product, ideal eye drop volume and reduced drop volume variability and provides efficient dispensing.
Core Innovation
A multi-use ophthalmic kit is described that includes a container with an integral bacterial protection system and a dispensing tip, together with a preservative-free aqueous ophthalmic composition configured to be dispensed as drops into an eye of a patient. The ophthalmic composition comprises chloramphenicol as an active ingredient and pharmaceutically acceptable excipients, while being free of viscosity increasing agents. The formulation is defined by physical properties measured in accordance with European pharmacopoeia requirements, including viscosity, surface tension, and osmolality.
The dispensing tip orifice geometry is tightly specified by an inner diameter to an outer diameter ratio from 1:1 to 1:6, with the inner diameter more than 0.3 mm and less than 2 mm and the outer diameter more than 1 mm and less than 4 mm. The container is configured to dispense drops having a volume between 22 μL and 31 μL when the dispensing tip is oriented at an angle of 45° relative to a horizontal axis, with variability between each drop dispensed of ±5 μL. The use of lower surface tension and controlled tip geometry is stated to reduce drop volume and variability when dispensing at 45°.
The integral bacterial protection system is described as using mechanical tip-seal technology that prevents bacterial contamination, including a spring loaded valve located directly below the dispensing tip orifice. Additional bacterial protection options are described conceptually for multi-use containers, including venting/air-inlet protection options such as filters, a collapsible bag, and unvented containers. Oligodynamic germ-reducing components using oligodynamically active silver are also described as part of the bacterial protection approach.
Claims Coverage
The document provides one independent claim (clm-00001) directed to a multi-use ophthalmic kit, with dependent refinements in clm-00002 through clm-00005 that further restrict composition and dispensing performance and add an antimicrobial material feature within the dispensing tip orifice.
Multi-use ophthalmic kit with integral bacterial protection and dispensing tip
A container comprising an integral bacterial protection system and a dispensing tip, and an ophthalmic composition contained within the container and configured to be dispensed as drops from an orifice of the dispensing tip into an eye of a patient.
Dispensing tip orifice geometry and drop performance at 45°
The dispensing tip orifice geometry comprises a ratio of an inner diameter to an outer diameter from 1:1 to 1:6, with the inner diameter more than 0.3 mm and less than 2 mm and the outer diameter more than 1 mm and less than 4 mm; the container is configured to dispense drops having a volume of between 22 μL and 31 μL when the dispensing tip is oriented at an angle of 45° relative to a horizontal axis, wherein variability between each drop dispensed is ±1 μL.
Preservative-free chloramphenicol solution engineered to physical-property constraints
The ophthalmic composition comprises a preservative-free aqueous solution of chloramphenicol as an active ingredient and pharmaceutically acceptable excipients selected so as to provide viscosity of less than 200 cP at 25° C, surface tension of less than 22 mN/m and more than 10 mN/m at 25° C, and osmolality value of 250 to 300 mOsm/Kg, wherein the ophthalmic composition is free of viscosity increasing agents.
Mechanical tip-seal technology using a spring loaded valve directly below the orifice
The integral bacterial protection system uses a mechanical tip-seal technology to prevent bacterial contamination and the mechanical tip-seal technology comprises a spring loaded valve located directly below the dispensing tip orifice.
Pharmacopoeia-based pH constraint (dependent feature)
The ophthalmic kit is specified such that the ophthalmic composition has a pH value between 5.5 and 7.5 measured according to European pharmacopoeia requirements.
Narrower osmolality sub-range to meet European pharmacopoeia requirements (dependent feature)
The ophthalmic kit is specified to have an osmolality value from 266 to 296 mOsm/Kg to meet European pharmacopoeia requirements.
Drop-to-drop variability limit (dependent feature)
The ophthalmic kit is configured so that the variability between each dispensed drop is ±1 μL.
Active silver as a bactericide in the dispensing tip orifice (dependent feature)
The integral bacterial protection system uses active silver in the dispensing tip orifice as a bactericide.
Overall, the claim set covers a preservative-free chloramphenicol multi-use ophthalmic kit in which drop dispensing is controlled by the specified dispensing tip orifice geometry and 45° orientation, while contamination is addressed through an integral bacterial protection system that includes mechanical tip-seal technology with a spring loaded valve directly below the orifice and, in a dependent refinement, active silver as a bactericide in the dispensing tip orifice. Composition constraints are enforced through pharmacopoeia-measured physical properties (viscosity, surface tension, and osmolality) and a stated absence of viscosity increasing agents, with additional dependent constraints on pH/osmolality and measured drop variability.
Stated Advantages
Maintains sterility in a multi-use container by using an integral bacterial protection system and mechanical tip-seal technology.
Enables accurate dispensing with controlled drop volume and reduced variability when the dispensing tip is oriented at 45°.
Provides drop volumes and drop-to-drop variability within specified ranges for dispensing performance.
Documented Applications
Preservative-free aqueous ophthalmic eye-drop use in multi-use ophthalmic dispensing into an eye of a patient.
Example ophthalmic drug formulations are described for drugs including travoprost, timolol, dorzolamide, and chloramphenicol in preservative-free aqueous ophthalmic eye-drop compositions.
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