Multi-dose preservative-free (MDPF) ophthalmic dose delivery with added pharmaceutical surfactant.

Abstract

This disclosure relates, in general, to ophthalmic compositions and multi-dose systems for topically applying the compositions to a surface, for example, the ocular surface. The multi-dose systems of this disclosure may include a multi-dose preservative-free (MDPF) eye drop bottle system and an ophthalmic composition having a therapeutic agent, a viscosity modifier having a concentration of about 0.01% w / v to about 5% w / v, and a surfactant having a concentration of about 0.005% w / v to about 7% w / v, wherein the composition is preservative-free.

Description

Technical Field

[0001] Aspects of the present disclosure generally relate to ophthalmic compositions.

Background Art

[0002] Aqueous multi-dose pharmaceutical compositions have been prepared to have sufficient antibacterial activity to meet the preservation effectiveness requirements of the United States Pharmacopeia ("USP") and similar guidelines in other countries without the need for conventional antibacterial preservatives such as benzalkonium chloride, polyquaternium-1, sodium perborate, or chlorine-containing agents.

[0003] Many pharmaceutical compositions are sterile for use. Examples of such compositions include various types of compositions that are applied directly to the eye, such as artificial tears, irrigation solutions, and drug products, or are applied to devices that contact the eye, such as contact lenses.

[0004] The aforementioned types of compositions can be manufactured under sterile conditions by procedures well known to those skilled in the art. However, if the product packaging is opened and the composition contained therein is exposed to the air and other potential sources of microbial contamination, the sterility of the composition may be compromised. Because multi-dose products are frequently and repeatedly exposed to the risk of microbial contamination, multi-dose preservative-free (MDPF) eye drop bottle systems can be used to prevent or reduce the risk of microorganisms reaching the pharmaceutical composition in the container. Examples of commercially available MDPF systems include Novelia® preservative-free multi-dose eye drop bottles by Nemera and Ophthalmic Squeeze Dispenser preservative-free multi-dose eye drop bottles available from Aptar Pharma. Novelia, Aptar, and other MDPF systems are outlined in Campolo et al., "A Review of the Containers Available for Multi-Dose Preservative-Free Eye Drops," Biomed J Sci & Tech Res 45(1)-2022.

[0005] Unfortunately, due to the functionality of MDPF systems, excess pharmaceutical composition is often administered at each delivery, and when certain viscosity modifiers are used to enhance bioavailability, residues form on the MDPF system nozzle. These residues cause increased inconsistent dosing, known as spreading upwards on the MDPF nozzle. This has been observed in a wide range of MDPF systems. Furthermore, these residues can act as a source of contamination at the nozzle tip.

[0006] Therefore, in this field, there is a need for improved multi-dose pharmaceutical compositions that can be administered by a wider range of MDPF eye drop bottle systems while maintaining sufficient viscosity to reduce or prevent droplet spreading, without requiring antimicrobial preservatives. [Overview of the Initiative] [Means for solving the problem]

[0007] This disclosure relates, in general, to ophthalmic compositions and multi-dose eye drop bottle systems for applying the compositions to a surface, for example, the ocular surface. The multi-dose systems of this disclosure may include multi-dose preservative-free (MDPF) eye drop bottles and ophthalmic compositions having a therapeutic agent, a viscosity modifier having a concentration of 0.01% w / v to 5% w / v, and a surfactant having a concentration of 0.005% w / v to 7% w / v, wherein the ophthalmic compositions are preservative-free.

[0008] Aspects of the present disclosure also relate to ophthalmic compositions comprising a therapeutic agent having a concentration of 0.01% w / v to 1% w / v, a viscosity modifier having a concentration of 0.01% w / v to 0.8% w / v, and a surfactant having a concentration of 0.01% w / v to 1% w / v, wherein the multi-dose preservative-free system substantially does not contain benzalkonium chloride or other conventional antimicrobial preservatives.

[0009] To allow for a more detailed understanding of the above-mentioned features of this disclosure, a more specific description of this disclosure, which has been briefly summarized above, can be obtained by referring to embodiments, some of which are shown in the accompanying drawings. However, it should be noted that the accompanying drawings are merely illustrative embodiments and should not be considered to limit the scope of the invention. [Brief explanation of the drawing]

[0010] [Figure 1] The end tip of the MDPF system according to the embodiment of this disclosure is shown. [Figure 2A-2D] Alternative embodiments of the air-permeable membrane according to embodiments of the present disclosure are shown. Figure 2A shows a first air-permeable membrane. Figure 2B shows a second air-permeable membrane. Figure 2C shows a third air-permeable membrane. Figure 2D shows a fourth air-permeable membrane. [Figure 3] This figure shows a graph of droplet size over the number of dispensed droplets of ophthalmic composition A3 and ophthalmic composition A5 according to embodiments of the present disclosure. [Figure 4]The graph shows the surface tension of ophthalmic composition A or ophthalmic composition B over a range of surfactant concentrations added to ophthalmic composition A or ophthalmic composition B according to embodiments of the present disclosure. [Figure 5] The graph shows the surface tension of ophthalmic composition A or ophthalmic composition B over a range of surfactant concentrations added to ophthalmic composition A or ophthalmic composition B according to embodiments of the present disclosure. [Figure 6] The graph shows the size of dispensed droplets of ophthalmic composition A or ophthalmic composition B across the surface tension of the embodiments of the present disclosure. [Figure 7] This diagram shows the droplet size over the number of dispensed droplets of ophthalmic composition B according to an embodiment of the present disclosure. [Figure 8] This graph shows the droplet size over the number of dispensed droplets of ophthalmic composition B containing the surfactant tyroxapole, according to embodiments of the present disclosure. [Figure 9] This graph shows the droplet size over the number of dispensed droplets of ophthalmic composition B containing the surfactant polysorbate 80 according to an embodiment of the present disclosure. [Figure 10] This graph shows the droplet size over the number of dispensed droplets of ophthalmic composition B containing the surfactant polyoxyl stearate 40 according to embodiments of the present disclosure. [Figure 11] This diagram shows the droplet size over the number of dispensed droplets of ophthalmic composition A containing a preservative, according to the embodiments of this disclosure. [Figures 12A-12B] This graph shows the droplet size over the number of dispensed droplets of ophthalmic composition A with or without flickering, according to embodiments of the present disclosure. [Figure 13A-13C]Figure 13A shows a graph of the average droplet size of ophthalmic composition A dispensed against the concentration of surfactant according to embodiments of the present disclosure. Figure 13B shows a graph of the average droplet size of ophthalmic composition A dispensed against the concentration of tyroxapole. Figure 13C shows a graph of the average droplet size of ophthalmic composition A dispensed against the concentration of polysorbate 80. [Modes for carrying out the invention]

[0011] For ease of understanding, the same reference numerals are used to refer to the same elements common to the figures where possible. Elements and features of one embodiment are considered to be usefully incorporated into other embodiments without further detail.

[0012] As used herein, “ophthalmic composition lacking preservatives” means that the composition substantially does not contain conventional antimicrobial preservatives (i.e., has about 0.001% w / v or less). “Conventional antimicrobial preservatives” means preservative components that have a primary function of providing preservative efficacy in topically administered ophthalmic compositions, such as benzalkonium chloride, polyquaternium-1, sodium perborate, chlorobutanol, methylparaben, and thimerosal. Preservative enhancers are not considered preservative components that have a primary function of providing preservative efficacy, and examples of preservative enhancers include sodium borate, boric acid, citrate, tartaric acid, disodium EDTA, BHA, BHT, sodium metabisulfite, tocopherol, ascorbic acid, and sorbic acid.

[0013] Aspects of this disclosure generally relate to ophthalmic compositions and multi-dose eye drop bottle systems for topically applying the compositions to a surface, such as the ocular surface. The multi-dose systems of this disclosure may include multi-dose preservative-free (MDPF) eye drop bottle or container systems and ophthalmic compositions having a therapeutic agent, a viscosity modifier having a concentration of 0.01% w / v to 5% w / v, and a surfactant having a concentration of 0.005% w / v to 7% w / v, wherein the ophthalmic composition is preservative-free. It has been shown that surfactants present in ophthalmic compositions simultaneously reduce spreading at the tip of the eye drop bottle while maintaining the benefits of the bioavailability of the viscosity modifier. When using MDPF containers, the surfactant ensures that the ophthalmic composition is delivered at a constant dose / droplet size, reducing the amount of droplet spreading. In addition, the enhanced control of administration when using surfactants reduces the overall amount of ophthalmic composition that can be used to provide a sufficient dose of the therapeutic agent, resulting in lower costs for consumers of ophthalmic compositions.

[0014] Aspects of the present disclosure also relate to an ophthalmic composition comprising a therapeutic agent having a concentration of 0.01% w / v to 1% w / v, a viscosity modifier having a concentration of 0.01% w / v to 0.8% w / v, and a surfactant having a concentration of 0.01% w / v to 1% w / v, more preferably 0.01% to 0.5% w / v, wherein the ophthalmic composition lacks a preservative.

[0015] Aspects of the present disclosure also relate to a method for forming a multi-dose system for ophthalmic topical medication, comprising dispensing an ophthalmic composition having a therapeutic agent, a viscosity modifier having a concentration of 0.01% w / v to 5% w / v, and a surfactant having a concentration of 0.005% w / v to 7% w / v, but lacking a preservative, into an MDPF dropper bottle system, in order to provide enhanced control of administration.

[0016] Ophthalmic composition The ophthalmic pharmaceutical composition of the present disclosure may contain various types of therapeutic agents. Examples of possible therapeutic agents include beta blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, and propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), alpha-1 antagonists (e.g., nipradolol), alpha-2 agonists (e.g., apraclonidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travoprost, and unoprostone), hypotensive lipids (e.g., bimatoprost), neuroprotective agents (e.g., memantine), serotonin agonists, e.g., serotonin (5-hydroxytryptamine) agonists, e.g., S-(+)-1-(2-aminopropyl)-indazole-6-ol), anti-angiogenic agents (e.g., anecortave acetate), anti-infective agents (e.g., quinolones such as moxifloxacin and gatifloxacin and aminoglycosides such as tobramycin and gentamicin), non-steroidal and steroidal anti-inflammatory agents (e.g., prednisolone, dexamethasone, loteprednol, suprofen, diclofenac, and ketorolac), growth factors (e.g., EGF), immunosuppressive agents (e.g., cyclosporine), and anti-allergic agents (e.g., olopatadine). For example, without limitation, the therapeutic agent can be apraclonidine or apraclonidine hydrochloride. As a further non-limiting example, the therapeutic agent can be olopatadine or olopatadine hydrochloride.

[0017] The ophthalmic drug may exist in the form of a pharmaceutically acceptable free base, such as apraclonidine free base or olopatadine free base, or a pharmaceutically acceptable free salt, such as apraclonidine hydrochloride or olopatadine hydrochloride. The therapeutic agent can be anionic, cationic, or neutral. If the selected therapeutic agent is anionic at an ophthalmically acceptable pH level in an aqueous solution, the buffers described herein are included.

[0018] The therapeutic agent has a concentration of 0.01% w / v to 1% w / v. For example, the therapeutic agent has a concentration of about 0.06% w / v to about 0.8% w / v, such as about 0.06% w / v, about 0.12 to about 0.13% w / v, or about 0.77% w / v to about 0.78% w / v. As a further non-limiting example, the therapeutic agent can be apraclonidine having a concentration of 0.06% w / v to 0.125% w / v, such as 0.06% w / v or 0.125% w / v. As a further non-limiting example, the therapeutic agent can be olopatadine, and its concentration is 0.6% w / v to 0.8% w / v, such as 0.7% w / v.

[0019] The present disclosure particularly relates to ophthalmic compositions for the treatment of conditions where frequent application of the composition is required, such as in the presence of inflammation in the cornea or adjacent eye tissues, or in the treatment of dry eye patients, patients with congested eyes, or patients with eye allergies. Thus, the ophthalmic compositions of the present disclosure are particularly useful in the fields of artificial tears, ocular lubricants, and other compositions used to treat dry eye conditions and other conditions associated with eye inflammation or discomfort.

[0020] The ophthalmic compositions of this disclosure include one or more viscosity modifiers to enhance the bioavailability of the therapeutic agent in the ophthalmic composition. In addition, the viscosity modifiers can provide eye comfort and / or retention of the composition on the eye after topical application. Types of viscosity modifiers that may be used include water-soluble cellulose derivatives, e.g., cellulose ethers, e.g., hydroxypropyl guar, hydroxypropyl methylcellulose ("HPMC"), hereafter referred to as "hp-guar"; dextran 70, hydroxymethylcellulose ("HMC"), hydroxyethylcellulose ("HEC"), or hydroxypropylcellulose ("HPC"); polyethylene glycol; polyethylene oxide polymers; polyvinylpyrrolidone polymers, e.g., N-vinyl-2-pyrrolidone; propylene glycol; carboxyvinyl polymers; water-soluble polyvinyl alcohol polymers or copolymers; copolymers having at least one vinyl lactam and one or more hydrophilic monomers; and polysaccharides. For example, but not limited to, a viscosity modifier may be hydroxypropyl methylcellulose, which provides enhanced bioavailability of the therapeutic agent compared to other viscosity modifiers.

[0021] The viscosity modifier may comprise one or more copolymers of vinylpyrrolidone having one or more hydrophilic monomer units. The viscosity modifier may also comprise a polyvinylpyrrolidone copolymer having a copolymer of vinylpyrrolidone and at least one amino-containing vinyl monomer. Examples of amino-containing vinyl monomers include alkylaminoalkyl methacrylates having 8 to 15 carbon atoms, alkylaminoalkyl acrylates having 7 to 15 carbon atoms, dialkylaminoalkyl methacrylates having 8 to 20 carbon atoms, dialkylaminoalkyl acrylates having 7 to 20 carbon atoms, and N-vinylalkylamides having 3 to 10 carbon atoms. The vinylpyrrolidone copolymer may be an N-vinylalkylamide, such as N-vinylformamide, N-vinylacetamide, N-vinylisopropylamide, or N-vinyl-N-methylacetamide. For example, but not limited to, the viscosity modifier is N-vinyl-2-pyrrolidone.

[0022] The viscosity modifier is present in the composition in an amount of 0.01% w / v to 5% w / v, for example, 0.01% w / v to 3% w / v, preferably 0.1% to 0.8% w / v.

[0023] The ophthalmic compositions of this disclosure may include buffers. The buffers maintain the pH within a physiologically acceptable range of about 6 to about 8. Examples of buffers include citric acid, citrates, boric acid, borates, e.g., sodium borate, bicarbonates, e.g., sodium bicarbonate, sodium hydroxide, hydrochloric acid, TRIS (2-amino-2-hydroxymethyl-1,3-propanediol), Bis-Tris (bis-(2-hydroxyethyl)-imino-tris-(hydroxymethyl)methane), bis-aminopolyols, triethanolamine, ACES (N-(2-hydroxyethyl)-2-aminoethanesulfonic acid), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), HEPES (4-2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), M Examples of buffers include OPS (3-[N-morpholino]-propanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid), TES (N-[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid), phosphate buffers such as NaHPO4, NaH2PO4, NaH2PO4, and KH2PO4, or their hydrates or mixtures, or combinations of one or more buffers. For example, but not limited to, an ophthalmic composition may include a mixture of buffers containing boric acid, sodium hydroxide, and hydrochloric acid. In further non-limiting examples, the buffer may include a mixture of buffers containing sodium chloride, sodium citrate dehydrate, sodium hydroxide, and hydrochloric acid.

[0024] The buffering agents in the ophthalmic composition may have concentrations sufficient to maintain the composition's pH between approximately 6.0 and approximately 8.5. The concentration of each buffering agent may range from 0.001% w / v to 2% w / v. For example, but not limited to, each buffering agent may have concentrations of 0.01% w / v to 1% w / v, e.g., 0.05% w / v to 0.30% w / v.

[0025] The ophthalmic compositions of this disclosure may be isotonic with tears. A solution isotonic with tears is generally understood to be a solution whose concentration corresponds to 0.7% w / v to 1.5% w / v (308 mOsm / kg) of a sodium chloride solution, for example, about 0.9% w / v. The tonicity of an ophthalmic composition can be adjusted by adding one or more isotonic agents, such as organic or inorganic substances, that affect the tonicity. Examples of isotonic agents include sodium chloride, potassium chloride, glycerol, propylene glycol, polyol, mannitol, sorbitol, xylitol, and mixtures thereof. The tonicity of the solution is typically adjusted to a range of 200 to 450 milliosmoles per kilogram (mOsm / kg), preferably 210 to 350 mOsm / kg.

[0026] The ophthalmic compositions of this disclosure include a surfactant, which may be a nonionic, anionic, or amphoteric surfactant. In one embodiment, the surfactant is a nonionic, anionic, or amphoteric surfactant having at least one polyether alcohol moiety. Suitable surfactants include alkylallyl polyether alcohols, e.g., tyroxapol; poloxamers, e.g., Pluronic® F108, F88, F68, F68LF, F127, F87, F77, P85, P75, P104, and P84; poloxamines, e.g., Tetronic 707, 1107, and 1307; polyethylene glycol esters of fatty acids, e.g., Tween® 20 or Tween® 80; polyoxyethylene or polyoxypropylene ethers of C12-C18 alkanes, e.g., polyethylene glycol 400 or Brij® 35; polyoxyethylene stearate, e.g., Myrj® 52 or polyoxyl stearate 40; sorbitol; sorbitan esters, e.g., sorbitan monostearate, sorbitan tristearate, or sorbitan monolaurate; polyoxyethylene propylene glycol stearate, e.g., Atlas Examples include amphoteric surfactants such as G2612, Mirataine®, and Miranol®. The surfactant may consist of a combination of one or more surfactants. Preferred surfactants are tyloxapol, polysorbate 80, and polyoxyl stearate 40.

[0027] Surfactants may be present in ophthalmic compositions at concentrations of 7% w / v or less, for example, 0.005% w / v to 7% w / v, or 0.01% w / v to 2% w / v, or 0.01% w / v to 1% w / v, or 0.01% to 0.5% w / v. As a non-limiting example, surfactants containing tyroxapole may have concentrations of 0.05% w / v to 0.3% w / v. As a further non-limiting example, surfactants containing polysorbate 80 may have concentrations of 0.1% w / v to 0.2% w / v. As a further non-limiting example, surfactants containing polyoxyl stearate 40 may have concentrations of 0.1% w / v to 7% w / v. Surfactants in ophthalmic compositions allow for enhanced dose control and promote stable droplet size after each continuous dose. In addition, surfactants allow for a smaller overall ophthalmic composition to be required to provide a sufficient dose of the therapeutic agent. In addition, or, although we do not wish to be bound by theory, surfactants containing a polyether alcohol moiety can reduce droplet size through interaction between the alcohol moiety and the surrounding diluent, thereby lowering the surface tension of the composition.

[0028] The surface tension of the ophthalmic composition may decrease as the concentration of the surfactant increases. The surface tension of the ophthalmic composition may be about 30 mN / m to about 45 mN / m, for example, about 30 mN / m to about 40 mN / m, about 35 mN / m to about 40 mN / m, about 37 mN / m to about 39 mN / m, etc. While we do not wish to be bound by theory, a lower surface tension may reduce the droplet size of the ophthalmic composition, and tyroxapol, polyoxyl stearate 40, and polysorbate 80 each reduce the surface tension of the ophthalmic composition described herein. For example, as the surfactant concentration increases from a first surfactant concentration to a second surfactant concentration (where the second surfactant concentration is higher than the first surfactant concentration), the surface tension of the ophthalmic composition may decrease from the first surface tension to the second surface tension (where the second surface tension is lower than the first surface tension).

[0029] The ophthalmic compositions of this disclosure are generally prepared as sterile solutions having one or more diluents, such as water, to form sterile aqueous solutions. The diluents may include any suitable diluent that can function as an ophthalmic composition, and the suitable aqueous solvent is compatible with the eye and / or other tissues treated with the ophthalmic composition. For example, but not limited to, the diluent of the ophthalmic compositions described herein may be water.

[0030] The compositions of this disclosure are prepared to be compatible with the eye and / or other tissues treated with the ophthalmic compositions. Ophthalmic compositions intended for direct application to the eye are prepared to have a pH and tonicity compatible with the eye. Importantly, the ophthalmic compositions of this disclosure are free of preservatives that may cause irritation to the eye and / or other tissues treated with the ophthalmic compositions described herein.

[0031] Multi-dose preservative-free (MDPF) system Figure 1 shows an end portion 10 of a multi-dose, preservative-free eye drop bottle system for dispensing liquid in droplet form, which is screw-on onto the neck of a reservoir 12. The reservoir 12 is a storage reservoir for liquid, such as the ophthalmic compositions described herein. The reservoir 12 contains capacities ranging from about 1 mL to about 15 mL, for example, about 5 mL, about 7 mL, about 8 mL, about 11 mL, about 15 mL, etc. The reservoir 12 can be deformed to dispense liquid by pressing the reservoir. The liquid is dispensed by pressure that can be applied by the user to the body of the reservoir 12. The reservoir has elasticity that allows it to return to its initial shape after the pressure applied by the user is released, creating a recess inside the reservoir 12.

[0032] In this example, the end portion 10 includes a support 14, a dispensing valve 16 with a dispensing opening 18, a spring 20, an outer envelope 22, a channel 24 for passing liquid from the reservoir 12 to the dispensing opening 18, and a channel 26 for passing air to the reservoir 12, the channel 26 being closed by an air permeable member 28.

[0033] In this example, the support 14 includes a fastening portion 32 located at the proximal end of the support 14 for fastening to the reservoir 12. The fastening portion 32 includes an external skirt 34 with threads that allow it to be screwed onto the neck of the reservoir 12. The fastening portion 32 also includes a tubular internal skirt 36 that ensures a seal between the reservoir 12 and the dispensing end portion 10.

[0034] Furthermore, the support 14 has a cylindrical shape and includes a central sealing portion 38 extending distally on the side opposite to the internal skirt 36. The central sealing portion 38 includes a support surface 40 at its distal end for a valve 16 to block the flow of liquid in the blocking configuration. In this example, the support surface 40 has an annular bead shape.

[0035] In this example, the support 14 also includes a channel 26 for passing air to the reservoir 12, and the channel 26 opens into a proximal cylindrical cavity 42. This cavity 42 opens into a member 28 at its proximal end.

[0036] In this example, the support 14 also includes a housing 44 that forms a cylindrical cavity, which opens to a reservoir 12 at its proximal end and to a channel 24 at its distal end for the passage of liquid. The channel 24 is formed in the support 14 and extends in the longitudinal direction of the device, corresponding to the direction of liquid discharge indicated by arrow 46. The channel 24 opens to an intermediate cavity 48, which itself opens to a second channel 50 for the passage of liquid.

[0037] The housing 44 is adjacent to the cavity 42, separated by an annular wall 52 that extends in the opposite direction to the sealing portion 38.

[0038] The air-permeable member 28 is made of an air-permeable polymer material, such as polypropylene, which is non-porous and blocks the passage of particles such as bacteria with a diameter of about 0.1 micrometers, but allows the passage of molecules such as air molecules with a diameter of about 0.299 nm to about 0.363 nm. Air passes through the air-permeable member 28 by diffusion across the member 28. The polymer material includes elastomer materials, such as silicone. The member 28 has a substantially cylindrical or conical shape. Its central axis is collinear with the central axis of the end portion 10, and this axis corresponds to the liquid dispensing direction, and therefore arrow 46. For example, the member 28 includes an air passage wall that facilitates gas exchange, has a cylindrical or conical shape, has an upper part closed by a disk-shaped surface, and a base including an annular collar 30 for fastening to the end portion 10, the collar 30 being thicker than the thickness of the air passage wall.

[0039] The member 28 is housed within a defined cylindrical cavity 54, whose boundary is defined by the internal skirt 36 of the support 14, and is fastened to the annular wall 52, for example, by mechanical clamping or by the cooperation of the collar 30. The inner diameter of the collar 30 is smaller than the outer diameter of the wall 52 so that the collar is held against the wall 52 by elastic force. Snap fastening means may include an internal annular bead formed on the collar 30 that snaps into an annular groove formed on the outer surface of the wall 52. In addition, mechanical means may be used to fasten the collar 30 to the wall 52. The disclosure also envisions mechanical mounting means that traverse the portion 14 and reach the cavity 48, or means for mounting on the inner wall of the cylinder.

[0040] In addition, the support 14 includes a portion 56 for fastening the valve 16 to the support 14. This portion 56 also functions as a portion used to fasten the outer envelope 22 to the support 14. The portion 56 includes an annular groove 58 whose periphery is defined by an annular wall 60. The annular groove 58 is also defined at its inner periphery by annular ribs created in the wall, forming a disk which is traversed by the channel 24 and defines the boundary of the cavity 48.

[0041] The valve 16 may include an elastomer material, and in cooperation with the support 14, the valve 16 can be configured to block liquid and to dispense liquid. Alternatively, only a portion of the valve 16 may be made from the elastomer material, and the other portion may be made from a more rigid material that can function as a seat for the spring 20. The valve 16 includes a fastening portion 62 for fastening to the support 14, which forms a tubular skirt. This fastening portion 62 is connected to a disc-shaped web 64 from which a cylindrical central portion 66 protrudes. The web 64 also includes a seat 68 for the spring 20. The portion 66 forms a cylindrical internal cavity complementary to the portion 38. The portion 38 and the cylindrical portion 66 are coaxial and jointly define the boundary of a channel 50 for liquid passage. This channel 50 for liquid passage opens to a dispensing opening 18 formed at the distal end of the valve 16, which itself opens to a shaped portion for forming droplets.

[0042] The outer envelope 22 includes an annular portion 70 for fastening to the support 14 and an annular portion 72 coaxial with the annular portion 70, forming a groove 74 for accommodating the annular wall 60. The outer envelope 22 also includes a seat 76 for the spring 20, which extends along its inner periphery by the annular wall 78, traverses portion 66, and is designed to centrally position portion 66 of the valve 16.

[0043] The air-permeable member 28 includes at least one channel 80 for the passage of liquid. The channel 80 for the passage of liquid functions as a liquid flow limiter and opens into the channel 24 for the passage of liquid. The collar 30 of member 28 includes a plurality of grooves 80 and boundary delimiting channels 82 for reducing liquid flow on its outer annular surface, as shown in Figures 2A to 2D. These boundary delimiting channels 82 have a relatively small diameter to reduce the liquid pressure when the user presses the reservoir. The grooves 80 can have a change of direction or a helical shape. Depending on the number and size of the grooves 80 positioned opposite the housing 44, the outflow of liquid is reduced by more or less.

[0044] For example, member 28 can take one of the shapes shown in Figures 2A to 2D. A reduction shape 80 is created on the outer peripheral edge of its collar 30, forming a recess on the peripheral edge.

[0045] Member 28 includes a thin air passage wall in a cylindrical or conical shape. To increase the rigidity of the thin air passage wall, the wall also includes reinforcing ribs 84 that correspond to localized increases in the wall thickness, as shown in Figure 2A.

[0046] The members 28 in Figures 2B to 2D show another type of member 28 in which the air passage wall includes multiple reliefs that increase the air exchange area between the inside and outside of the reservoir 12 without increasing the size of member 28. These reliefs are formed in the wall so as to remain relatively thin to allow air to pass through. In addition, these reliefs can be used to increase the rigidity of member 28, and the need for reinforcing members 84 is avoided, as is particularly shown in Figure 2C, which shows a corrugated air passage wall having a clover-shaped cross-section.

[0047] Referring again to Figure 1, when stationary, for example when the user is not pressing the reservoir 12, the valve 16 is permanently fastened to the support 14 that exerts an elastic force on the valve, and is configured to shut off the liquid due to the pressure acted by the spring 20, and is pressed against, for example, the surface 40.

[0048] A force is applied to the reservoir 12, pressurizing the fluid, which flows into a single channel, allowing it to flow through, for example, channel 82 for the liquid to pass through. Although not bound by theory, a multi-dose pharmaceutical composition containing a surfactant can reduce the amount of operating force or pressure required to dispense the dose. As it passes through channel 82, the fluid flow rate decreases due to the pressure drop. The fluid flows through channel 24 to cavity 48 and then to channel 50. Under the influence of pressure, the fluid lifts valve 16, which then switches to a configuration for dispensing liquid, and thus flows between valve 16 and the bearing surface 40, passing through the channels and cavities, and thus taking the form of droplets.

[0049] When a droplet is dispensed, the user releases pressure on the deformable reservoir 12, which tends to return to its initial shape, creating a depression inside the reservoir 12. This depression is compensated for by the intake of outside air through the channel 26 to allow air to pass through the air-permeable member 28, which may take from about 1 second to about 24 hours due to the non-porous nature of the material forming the member 28. Although not bound by theory, the deformable reservoir 12 may be deformed by rapid dispensing of the drug composition, and rapid dispensing may include dispensing more than one drop per second.

[0050] Method for forming a multi-dose system This disclosure provides a method for forming a multi-dose system. The method includes receiving an ophthalmic composition having a therapeutic agent, a viscosity modifier having a concentration of 0.01% w / v to 0.5% w / v, and a surfactant having a concentration of 0.005% w / v to 7% w / v, but lacking a preservative. The method includes dispensing a certain amount of the ophthalmic composition into a reservoir of an MDPF dispensing bottle system. The ophthalmic composition is heat-sterilized and / or sterile-filtered. The method may include placing an ophthalmic composition of about 1 mL to about 15 mL, about 11 mL, etc., into a reservoir of, for example, about 5 mL, in a Class A clean area (room, filling line) under laminar flow. The end portion of the MDPF dispensing bottle system is fastened to the reservoir, for example, by mechanical tightening through the cooperation of the collar 30 and the annular wall 52. [Examples]

[0051] Example 1: Droplet size of ophthalmic composition A that does not contain surfactants The compositions shown in Table 1 below were prepared as follows.

[0052] [Table 1]

[0053] Compositions A1, A2, A3, A4, and A5 had densities of 1.0063 g / mL, 1.0065 g / mL, 1.0065 g / mL, 1.0066 g / mL, and 1.0058 g / mL, respectively.

[0054] Example 2: Droplet size of ophthalmic composition A containing tyroxapol, polysorbate 80, or polyoxyl stearate 40 As shown in Table 3 and Figure 3, spreading and droplet size increase occurred in both samples of composition A3 and composition A5. Surfactants containing tyroxapole, polysorbate 80, or polyoxyl stearate 40 having compositions of 0.100% w / v, 0.025% w / v, or 0.010% w / v were added to compositions A3 and A5 shown in Tables 4-6 above. The droplet sizes of the compositions with tyroxapole at 0.10% w / v, 0.025% w / v, and 0.010% w / v remained stable over time, and no increase in droplet size occurred. Furthermore, as shown in Table 4, higher concentrations of tyroxapole resulted in smaller droplet sizes. While not theoretically bound, preventing droplet size increase not only enables consistent administration of ophthalmic compositions but also provides enhanced control over the delivery site, as larger droplets may be too large to be retained in the orbit.

[0055] [Table 2]

[0056] The droplet sizes of compositions containing tyroxapole at concentrations of 0.10% w / v, 0.025% w / v, and 0.010% w / v were stable over time, and as shown in Table 4, higher concentrations of tyroxapole resulted in smaller droplet sizes.

[0057] [Table 3]

[0058] The droplet sizes of compositions containing 0.10% w / v, 0.025% w / v, and 0.010% w / v polysorbate 80 remained stable over time, and as shown in Table 5, higher concentrations of polysorbate resulted in smaller droplet sizes.

[0059] [Table 4]

[0060] The droplet sizes of compositions containing polyoxyl stearate 40 at concentrations of 0.10% w / v, 0.025% w / v, and 0.010% w / v were stable over time, and as shown in Table 6, higher concentrations of polyoxyl stearate 40 resulted in smaller droplet sizes.

[0061] [Table 5]

[0062] As shown in Figures 4 and 5, for each surfactant, a concentration of 0.10% w / v resulted in a corresponding decrease in surface tension. As shown in Figures 4 and 5, the surface tension decreased most significantly with tyroxapole compared to polyoxyl stearate 40 or polysorbate 80. Furthermore, as shown in Figure 6, for each surfactant, a concentration of 0.10% w / v resulted in smaller droplet sizes of the samples, expressed as the minimum droplet size by weight. The intermediate droplet size by weight for each sample was with the 0.025% w / v surfactant, and the maximum droplet size by weight for each sample was with the 0.010% w / v surfactant. While we do not wish to be bound by theory, surfactants with higher surface activity may reduce the droplet size of ophthalmic compositions, and tyroxapole has stronger surface activity compared to both polyoxyl stearate 40 and polysorbate 80 due to the aromatic behavior of its structure. While we do not wish to be bound by theory, droplet sizes of less than 40 μL can be achieved using at least 0.05% w / v tyroxapole, 0.10% w / v polysorbate 80, or 0.10% w / v polyoxyl stearate 40.

[0063] Example 3: Droplet size of ophthalmic composition A containing sorbitol and / or PEG400. Surfactants containing sorbitol and / or PEG400 of various compositions were added to composition A1. As shown in Table 7, spreading occurred in all samples, including those containing sorbitol and / or PEG400. With 0.4% PEG400 in composition A1, the average droplet size decreased from 85.7 mg to 79.3 mg. As shown in Table 7, with 1.4% sorbitol, the droplet size increased from 85.7 mg to 87.4 mg.

[0064] [Table 6]

[0065] Example 4: Droplet size of ophthalmic composition B containing tyroxapol, polysorbate 80, or polyoxyl stearate 40 The compositions shown in Table 8 below were prepared as follows.

[0066] The first mixture was prepared by adding approximately 800 mL of purified water to a beaker and heating it to approximately 80°C to 90°C. Hydroxypropyl-γ-cyclodextrin was added to the solution and stirred, and 25 mL of 1N NaOH per 100 g of providedone raw material was added. This solution was stirred for 85 to 140 minutes. Polyethylene glycol (400) and providedone K29 / 32 were added, followed by boric acid. Mixing was continued, and mannitol was added to the mixture. The mixture was then cooled to approximately 27°C to 40°C. Olopatadine and HCl were then added until dissolved. The pH was then adjusted to 7 / 0+ / -0.1 using 1N NaOH. The mixture was then sterilized by sterile filtration using a 0.22 μm hydrophilic filter.

[0067] The second mixture was prepared by adding 8 g of HPMC to 150 mL of solvent in a separate beaker and heating to approximately 60°C with gentle stirring. 350 mL of cold water (approximately 1°C to 24°C) was added and mixed for approximately 30 minutes. The solution was then autoclaved and cooled to room temperature with stirring. The solution was filtered using a 10 μm microfiltration system.

[0068] Next, the first and second mixtures were slowly mixed, and the volume was adjusted according to density-weight. The mixture had an osmolality of 297 mOsm, was yellow by visual inspection, and had a viscosity of 15.4.

[0069] [Table 7]

[0070] Although B1 and B1' contained the same formulation, they were manufactured at different time points, with B1 being the first to be manufactured and B1' the second to be prepared. Tyroxapol was added to the first sample set of ophthalmic composition B1 and the first sample set of ophthalmic composition B1', where tyroxapol was present at concentrations of 0.100% w / v, 0.025% w / v, and 0.010% w / v, as shown in Table 9.

[0071] [Table 8]

[0072] Polysorbate 80 was added to the second sample set of ophthalmic composition B1 and the second sample set of ophthalmic composition B1', where the polysorbate 80 had concentrations of 0.100% w / v, 0.025% w / v, and 0.010% w / v, as shown in Table 10.

[0073] [Table 9]

[0074] Polyoxyl stearate 40 was added to the third sample set of ophthalmic composition B1 and the third sample set of ophthalmic composition B1', where the concentrations of polyoxyl stearate 40 were 0.100% w / v, 0.025% w / v, and 0.010% w / v, as shown in Table 11.

[0075] [Table 10]

[0076] In composition B1, as shown in Figure 7, spreading and an increase in droplet size occurred, with the droplet size increasing from 40 mg to over 100 mg after approximately 10 drops. As shown in Figure 8, the droplet size of compositions containing 0.100% w / v, 0.050% w / v, or 0.025% w / v tyroxapole remained stable over time, staying stable between approximately 40 mg and approximately 20 mg after more than 50 drops had been dispensed. Furthermore, the addition of 0.1% w / v tyroxapole reduced the surface tension, as measured by the Biolin Sigma 700 / 701 tensile meter described below. The results are shown in Figures 4 and 6.

[0077] As shown in Figure 9, the droplet size of the compositions containing 0.250% w / v and 0.200% w / v polysorbate 80 remained stable after more than 50 drops were dispensed. As shown in Figure 9, the droplet size of the composition containing 0.100% w / v polysorbate 80 showed a short-term spreading after approximately 50 drops were dispensed, and the droplet size decreased again to less than 40 mg after approximately 52 drops. Furthermore, as shown in Figures 4 and 6, the surface tension decreased with the addition of 0.1% w / v polysorbate 80.

[0078] As shown in Figure 10, the droplet size of compositions containing 0.500% w / v and 0.300% w / v polyoxyl stearate 40 remained stable after more than 50 drops were dispensed. Furthermore, as shown in Figure 5, the surface tension decreased upon the addition of 0.1% w / v polyoxyl stearate 40.

[0079] Example 5: Droplet size of ophthalmic composition A containing and without a preservative Compositions A6 to A12 were prepared by adding therapeutic agents, viscosity modifiers, and preservatives of various concentrations. The variations are shown in Table 12 below.

[0080] [Table 11]

[0081] As shown in Figure 11, the droplet size of compositions A6-A8, A10, and A12 remained stable at approximately 26 mg per drop. As shown in Figure 11, the droplet size of composition A9, which does not contain BAK and HPMC, was larger than that of compositions A6-A8, A10, and A12, at approximately 38 mg. As shown in Figure 11, the droplet size of composition A11, which does not contain BAK but contains HPMC, increased from approximately 45 mg to approximately 100 mg over 5 days (approximately 20 drops).

[0082] Example 6: Droplet size of ophthalmic composition B with and without flickering. The compositions shown in Table 13 below were prepared as follows.

[0083] [Table 12]

[0084] As shown in Figure 12A, the droplet size of compositions B2-B4 was approximately 40 mg, with smaller droplet sizes observed. Flicking was induced by making sudden, abrupt movements against the end portion of the multi-dose system described herein. Flicking did not contribute to the change in droplet size for compositions B2-B4. As shown in Figure 12B, the droplet size of composition B5 with flicking increased from approximately 25 mg to approximately 41 mg in 9 days, while the droplet size of composition B5 increased from 25 mg to approximately 72 mg in 7 days.

[0085] Example 7: Droplet size of ophthalmic composition A containing a surfactant and / or preservative A surfactant containing tyroxapole, polysorbate 80, or polyoxyl stearate 40 having a composition of 0.100% w / v, 0.050% w / v, or 0.010% w / v, or a preservative containing BAK, was added to composition A3 shown in Table 1 above. As shown in Table 1 and Figure 13, composition A3 showed spreading and an increase in droplet size. As shown in Table 14, the droplet size of the composition having 0.050% w / v tyroxapole, 0.100% w / v polysorbate 80, 0.100% polyoxyl stearate 40, and 0.010% w / v BAK did not result in spreading or an increase in droplet size.

[0086] [Table 13]

[0087] It was found that droplet size was inversely proportional to the surfactant concentration, and as shown in Figures 13A, 13B, and 13C, surfactant concentrations that yielded droplet sizes of less than 40 mg included 0.05% w / v tyroxapole, 0.1% w / v polyoxyl stearate 40, or 0.1% w / v polysorbate 80.

[0088] Further Embodiments This disclosure provides, in particular, the following embodiments, each of which may optionally include any alternative embodiments. E1. A multi-dose system for topically administering a composition to the eye, A dropper bottle system for multiple doses without preservatives, An ophthalmic composition, Treatment drugs, Viscosity modifiers containing concentrations of approximately 0.01% w / v to approximately 5% w / v, Surfactants containing concentrations of approximately 0.005% w / v to approximately 7% w / v, Includes, The composition lacks preservatives. Ophthalmic compositions and A multi-dose system including... E2. A multi-dose system of Embodiment E1, wherein the therapeutic agent is apraclonidine or olopatadine. E3. The therapeutic agent is apraclonidine, in the multi-dose system of Embodiment E2. E4. The therapeutic agent is olopatadine, in the multi-dose system of Embodiment E2. E5. A multi-dose system according to any one of Embodiments E1 to E4, wherein the therapeutic agent is present in the composition at a concentration of approximately 0.01% w / v to approximately 1% w / v. E6. The multi-dose system of Embodiment E5, wherein the therapeutic agent is present at a concentration of approximately 0.01% w / v to approximately 0.7% w / v. E7. The therapeutic agent is present at a concentration of approximately 0.125% w / v in the multi-dose system of Embodiment E6. E8. The therapeutic agent is present at a concentration of approximately 0.70% w / v in the multi-dose system of Embodiment E5. E9. A multi-dose system according to any one of Embodiments E1 to E8, wherein the viscosity modifier is present at a concentration of approximately 0.1% w / v to approximately 0.8% w / v. E10. The viscosity modifier is present at a concentration of approximately 0.3% w / v in the multi-dose system of Embodiment E9. E11. The viscosity modifier is present at a concentration of approximately 0.4% w / v in the multi-dose system of Embodiment E9. E12. The viscosity modifier is hydroxypropyl methylcellulose (HPMC) in the multi-dose system of Embodiment E9. E13. A multi-dose system according to any one of Embodiments E1 to E12, wherein the surfactant is selected from the group consisting of tyroxapol, polysorbate 80, and polyoxyl stearate 40. E14. The surfactant is tyroxapol, in the multi-dose system of Embodiment E12. E15. The surfactant is polysorbate 80 in the multi-dose system of Embodiment E12. E16. The surfactant is polyoxyl stearate 40 in the multi-dose system of Embodiment E12. E17. A multi-dose system according to any one of embodiments E1 to E16, wherein the surfactant is present at a concentration of approximately 0.01% w / v to approximately 1% w / v. E18. The ophthalmic composition is a multi-dose system according to any one of embodiments E1 to E17, having a pH of approximately 6.0 to approximately 8.5. E19. An ophthalmic composition comprising any one of embodiments E1 to E17, comprising a buffering agent, in a multi-dose system. E20. The buffer is present at a concentration of approximately 0.001% w / v to approximately 2% w / v in the multi-dose system of Embodiment E19. E21. Ophthalmic composition, Treatment drugs, Viscosity modifiers with concentrations of approximately 0.01% w / v to approximately 5% w / v, Alkyl allyl polyether alcohol surfactants at concentrations of approximately 0.005% w / v to approximately 7% w / v, The composition contains, and lacks preservatives. Ophthalmic composition. E22. An ophthalmic composition of Embodiment E21, wherein the therapeutic agent is apraclonidine or olopatadine. E23. An ophthalmic composition of Embodiment E22, wherein the therapeutic agent is apraclonidine. E24. The ophthalmic composition of Embodiment E22, wherein the therapeutic agent is olopatadine. E25. The therapeutic agent is an ophthalmic composition according to any one of embodiments E21 to E24, present at a concentration of approximately 0.01% w / v to approximately 1% w / v. E26. An ophthalmic composition of Embodiment E25, wherein the therapeutic agent is present at a concentration of approximately 0.01% w / v to approximately 0.25% w / v. E27. The ophthalmic composition of Embodiment E26, wherein the therapeutic agent is present at a concentration of approximately 0.125% w / v. E28. The therapeutic agent is present at a concentration of approximately 0.7% w / v in the ophthalmic composition of Embodiment E25. E29. An ophthalmic composition according to any one of Embodiments E21 to E28, wherein the viscosity modifier is present at a concentration of approximately 0.01% w / v to approximately 0.8% w / v. E30. The ophthalmic composition of Embodiment E29, wherein the viscosity modifier is present at a concentration of approximately 0.3% w / v. E31. The ophthalmic composition of Embodiment E29, wherein the viscosity modifier is present at a concentration of approximately 0.4% w / v. E32. The ophthalmic composition of Embodiment E29, wherein the viscosity modifier is hydroxypropyl methylcellulose (HPMC). E33. An ophthalmic composition according to any one of embodiments E21 to E32, wherein the surfactant is tyroxapol. E34. An ophthalmic composition according to any one of Embodiments E21 to E33, wherein the surfactant is present at a concentration of approximately 0.01% w / v to approximately 1% w / v. E35. An ophthalmic composition having a pH of approximately 6.0 to approximately 8.5, one of the ophthalmic compositions of embodiments E21 to E34. E36. An ophthalmic composition further comprising a buffering agent, any one of the ophthalmic compositions of embodiments E21 to E35. E37. The ophthalmic composition of Embodiment E39, wherein the buffering agent is present at a concentration of approximately 0.001% w / v to approximately 2% w / v. E38. A method for forming a multi-dose system, To receive an ophthalmic composition comprising a therapeutic agent, a viscosity modifier in a concentration of approximately 0.01% w / v to approximately 0.5% w / v, and a surfactant in a concentration of approximately 0.01% w / v to approximately 7% w / v, Dispensing a certain volume of ophthalmic composition into the reservoir of the MDPF system, The end portion is fastened to the reservoir of the MDPF system, Sterilizing the MDPF system, Methods that include... E39. The method of Embodiment E38, wherein the volume is approximately 1 mL to approximately 15 mL. E40. The method of Embodiment E39, the volume is approximately 5 mL.

[0089] Overall, the ophthalmic compositions and multi-dose systems of the present invention can provide the benefit of maintaining bioavailability while simultaneously reducing droplet spread. When using MDPF dropper bottles or containers, the surfactants of the present disclosure ensure that the ophthalmic composition is delivered in a consistent dose / droplet size, reducing the amount of droplet spread. In addition, the enhanced control of administration when using surfactants reduces the overall amount of ophthalmic composition that can be used to provide a sufficient dose of the therapeutic agent, resulting in lower costs for consumers of ophthalmic compositions.

[0090] The foregoing relates to embodiments of the present disclosure, but other and further embodiments of the present disclosure may be devised without departing from the basic scope thereof, the scope of which will be determined by the following claims.

Claims

1. A multi-dose system for topically administering a composition to the eye, A bottle system for eye drops without preservatives for multiple doses, An ophthalmic composition, Treatment drugs, Viscosity modifiers with concentrations of 0.01% w / v to 5% w / v, Surfactants at concentrations of 0.005% w / v to 7% w / v, Includes, The aforementioned composition lacks a preservative. Ophthalmic compositions and A multi-dose system including...

2. The multi-dose system according to claim 1, wherein the therapeutic agent is apraclonidine or olopatadine.

3. The multi-dose system according to claim 1, wherein the therapeutic agent is present at a concentration of 0.01% w / v to 1.0% w / v.

4. The multi-dose system according to claim 1, wherein the viscosity modifier is present at a concentration of 0.01% w / v to 0.8% w / v.

5. The multi-dose system according to claim 1, wherein the viscosity modifier is hydroxypropyl methylcellulose (HPMC).

6. The multi-dose system according to claim 1, wherein the surfactant is selected from the group consisting of tyroxapol, polysorbate 80, and polyoxyl stearate 40.

7. The multi-dose system according to claim 1, wherein the surfactant is present at a concentration of 0.01% w / v to 1% w / v.

8. The ophthalmic composition has a pH of 6.0 to 8.5, as described in claim 1, for the multi-dose system.

9. The multi-dose system according to claim 1, wherein the ophthalmic composition further comprises a buffering agent.

10. The aforementioned ophthalmic composition is The multi-dose system according to claim 1, comprising an alkylallyl polyether alcohol surfactant in a concentration of 0.01% w / v to 7% w / v.

11. The multi-dose system according to claim 10, wherein the therapeutic agent is apraclonidine or olopatadine.

12. The multi-dose system according to claim 10, wherein the therapeutic agent is present at a concentration of 0.01% w / v to 1% w / v.

13. The multi-dose system according to claim 10, wherein the viscosity modifier is present at a concentration of 0.01% w / v to 0.8% w / v.

14. The multi-dose system according to claim 10, wherein the viscosity modifier is hydroxypropyl methylcellulose (HPMC).

15. The multi-dose system according to claim 10, wherein the alkylallyl polyether alcohol surfactant is tyroxapol.

16. The multi-dose system according to claim 10, wherein the alkylallyl polyether alcohol surfactant is present at a concentration of 0.01% w / v to 1% w / v.

17. The ophthalmic composition has a pH of 6.0 to 8.5, as described in claim 10, for the multi-dose system.

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