WO2017151651A1 - Compositions pharmaceutiques se gélifiant in situ - Google Patents

Compositions pharmaceutiques se gélifiant in situ Download PDF

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WO2017151651A1
WO2017151651A1 PCT/US2017/019997 US2017019997W WO2017151651A1 WO 2017151651 A1 WO2017151651 A1 WO 2017151651A1 US 2017019997 W US2017019997 W US 2017019997W WO 2017151651 A1 WO2017151651 A1 WO 2017151651A1
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composition
gellan
weight
ion exchange
eye
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PCT/US2017/019997
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English (en)
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Kenneth W. Reed
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Belmont University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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

Definitions

  • the present disclose generally relates to pharmaceutical in situ gelling compositions comprising an aqueous mixture of an anionic polysaccharide, a source of a polyvalent cation and a polymer.
  • the in situ gelling compositions advantageously form gels upon contact with the tear fluid in the eye.
  • the present disclosure also relates to in situ gelling compositions comprising a mixture of high acyl or low acyl gellan and a source of a polyvalent cation, or high acyl gellan, low acyl gellan and a source of a polyvalent cation.
  • the tear film of the eye fulfils several functions, including hydration, lubrication, anti-bacterial, tra nsportation of oxygen and carbon dioxide and clearing of harmful substances.
  • the flow of tears provides an effective defense against environmental pathogens.
  • the eye lids can be thought of as the wiper blades of a car, with a resultant high shear rate that helps clear debris from the surface of the eye.
  • Hea lthy human tears generally contain a n aqueous mixture of mucin, lipids, lysozyme, lactoferrin, lipoca lin, lacitin, immunoglobulins, glucose, urea, sodium, ca lcium and potassium.
  • Tears further have a pH ra nging from 5.2 to 8.5, with mean values being about 7.4. Changes in the pH of tears can occur due to the opening time of the eyelids, when bicarbonate present in the lachrymal filmquilibrates with carbon dioxide in the air, resulting an alkalization of the film. Tear secretion and blinking lead to a decrease in pH of tears. (Chemical and physical parameters of tears relevant for the design of ocular drug delivery formulations by Vincent Baeyens and Robert Gurny, Pharmaceutica Acta Heivetiae, 72:191 -202 (1997)).
  • the defense mechanisms of the eye include rapid tear flow which enables the removal of foreign material from the tear fluid bathing the eye.
  • This effective defense mechanism is an obstacle to the delivery of drugs to the anterior portion of the eye when the drug is administered as a commonly used eye drop.
  • a proven approach to slow drug removal is to increase the viscosity of the medication. However, large increases in viscosity are often needed in order to observe any improvement in clinical effect.
  • Hydrogels are three-dimensional, cross-linked networks of water-soluble polymers. Drugs can be loaded into the gel matrix due to porosity of the gel, and subsequent drug release occurs at a rate dependent on the diffusion coefficient of the small molecule or macromolecule through the gel network.
  • a depot formulation is created from which drugs slowly elute, maintaining a high local concentration of drug in the surrounding tissues over an extended period. Biocompatibility is promoted by the high water content of hydrogels.
  • Cross-links between the different polymer provide networks that have visco- elastic and sometimes pure elastic behavior.
  • Polymers can be cross linked physically in addition to chemically.
  • Alginate for example, can be cross linked by ionic interactions, such as through calcium ions.
  • hydrogels can also be obtained by complexation of polyanions with polycations. lonically crosslinked chitosan hydrogels are formed by complex formation between chitosan and polyanions, such as dextran sulfate or polyphosphoric acid.” (Novel Crosslinking methods to design hydrogels by W.E. Hennink and C.R. van Nostrum, Advanced Drug Delivery Reviews 64:223-236 (2012) .)
  • Ophthalmic in situ gelling vehicles undergo a solution to gel (sol-to-gel) phase transition upon exposure to the physiological conditions present in the eye.
  • the latter are highly advantageous over preformed gels, which do not allow for accurate and reproducible administration of a desired dosage of a drug and, after administration, often produce blurred vision, crusting of the eyelids and lacrimation.
  • In situ gelling systems furthermore have the potential to be easily and accurately applied to the eye in liquid form while prolonging the formulation 's residence time on the surface of the eye due to gelling.” (Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1 :Physicochenmical characterization and in vitro release by llva D.
  • Timop ⁇ ic-XE® is an example of an in situ gel that is administered as a drop from an ophthalmic bottle and then forms a high viscosity gel upon instillation onto the eye.
  • the increased Timolol bioavailability possible with Timop ⁇ ic-XE results in effective dosing occurring once a day rather than twice a day as needed with simple Timolol solution.
  • Timoptic XE® contains low acyl (LA) Gellan. Gellan is a high molecular weight polysaccharide produced by the micro-organism Pseudomonas elodea.
  • HA gellan high acyl (HA) gellan.
  • Timop ⁇ ic-XE makes use of a chemically modified gellan known as low acyl (LA) gellan.
  • LA gellan A low viscosity solution, dispensable from a bottle, of LA gellan is known to significantly increase in viscosity in the presence of cations that are present in tear fluid.
  • Gellan has been used in various formulations to increase pre-corneal residence times with human contact times up to 20 hr being reported.
  • other polymers have also been investigated for their abilities to gel due to ocular environmental changes in pH and temperature. Products based upon these concepts are often referred to a gel forming solutions (GFS) .
  • GFS gel forming solutions
  • Thermo reversible hydro gels are in the liquid state at ambient temperature (20°- 25°C) and then transition into semisolid gels when held at body temperature (35°-37°C) .
  • Pluronic F-127 is the most commonly used polymer for this purpose.
  • Gelation induced by pH includes using the polymer Carbopol® to form a solution with a low viscosity at acidic pH (e.g., pH of 3) that transforms into a still gel when neutralized by tears (pH of 7.4) .
  • acidic pH e.g., pH of 3
  • Such acidic compositions are disadvantageous for ophthalmic use.
  • compositions that can applied to the surface of the eye that are non-irritating and provide reliable release of a desired dose of a drug.
  • Such compositions may be easier to apply because they may dropped into the eye as a liquid and then transition into a gel in the presence of tear fluids.
  • Such gels are expected to have longer retention time and reduced loss from being washed out by the action of tears.
  • such compositions are expected to improve dosing of pharmaceuticals due to the prolonged contact with the surface of the eye and improved drug retention in the gel.
  • Compositions that provide a controlled, sta ble release of a drug would a lso improve accuracy of dosing and reduce the freq uency of dosing.
  • compositions that can be applied topically to the eye that are non-irritating a nd non-blurring would improve patient complia nce.
  • the present disclosure addresses these needs by providing an in situ gelling composition having surprising thixotropic properties and an advantageous drug release profile.
  • the present disclosure provides an in situ gelling pharmaceutica l composition
  • a n in situ gelling pharmaceutical composition comprises a n aqueous mixture of a high acyl gellan, a low acyl gella n, and a source of polyva lent cations.
  • an in situ gelling pharmaceutica l composition comprises an aqueous mixture of a high acyl gellan a nd a low acyl gellan.
  • the present disclosure further provides a method of administering the aforementioned in situ gelling pharmaceutical composition to the surface of the eye of a patient in need thereof.
  • Figure 1 depicts a stepwise viscosity sweep of 1 to 1000 s- 1 for an in situ gelling composition of 0.75% low-acyl gellan with 0.0625% calcium gluconate a nd 0.375% povidone, with a pH of 7.2.
  • Figure 2 depicts viscosity v. shear rate of an in situ gelling composition of 0.6% low-acyl gellan and 0.4% high-acyl gellan .
  • Figure 3 is a Gra ph depicting k va lues of a preparation of 0.9% low-acyl gella n with 0.06% gluconate alone, in a 5: 1 ratio with ATS, or in a 5: 1 ratio of D l .
  • Figure 4 is a gra ph depicting the Ta u va lues of a preparation of 0.9% low-acyl gellan with 0.06% gluconate alone, in a 5: 1 ratio with ATS, or in a 5: 1 ratio of D l .
  • Figure 5 is a graph of timolol release rates as a function of time for various in situ gelling preparations.
  • Figure 6 depicts the primary and secondary viscosity of a mixed LA a nd HA gellan composition in artificial tears.
  • Figure 7 depicts the Tau values for a composition having 1 % sodium alginate as the polysaccharide based on percent of calcium gluconate.
  • Figure 8 depicts the va lues for a 1 .5 % sodium alginate preparation based on percent of calcium gluconate in PATS and Dl water.
  • the present application is, in some embodiments, generally directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an anionic polysaccharide, a source of a polyvalent cation, and a polymer.
  • the anion polysaccharide is present in an amount ranging from about 0.05 to about 2% by weight of the composition, or about 0.1 to about 2.0%, about 0.2 to about 2.0%, about 0.3 to about 1 .2%, about 0.3 to about 1 .0%, or about 0.5 to about 0.9% by weight of the composition.
  • the anionic polysaccharide is, in some embodiments, selected from the group consisting of gellan, alginate, pectin, xanthan gum, chondroitin sulfate, gum Arabic, gum kaya, gum tragacanth, and combinations thereof.
  • the anionic polysaccharide is gellan, and more particularly low-acyl gellan.
  • Low-acyl gellan is available commercially, for example from CP elco as Gelzan® or kelcogel®.
  • Gellan gum is a wafer-soluble anionic polysaccharide produced by the bacterium Sphingomonas elodea (formerly Pseudomonas elodea). It was initially identified as a substitute gelling agent at significantly lower use level to replace agar in solid culture media for the growth of various microorganisms.
  • the repeating unit of the polymer is a tetrasaccharide, which consists of two residues of D-glucose and one of each residues of L-rhamnose D-glucoronic acid.
  • the tetrasaccharide repeat has the following structure:
  • Gellan gum is extremely effective at low use levels in forming gels, and is available in two types: high and low acyl content. Low-acyl gellan gums form firm, non-elastic, brittle gels, whereas high acyl gellan gum forms soft, very elastic, non-brittle gels. Varying the ratios of the two forms of gellan produces a wide variety of textures.
  • gellan gum is the ability to suspend while contributing minimal viscosity via the formation of a uniquely functioning fluid gel solution with a weak gel structure.
  • Fluid gels exhibit an apparent yield stress, i.e., a finite stress which must be exceeded before the system will flow. These systems are very good at suspending particulate matter since, provided the stress exerted by the action of gravity on the particles is less than the yield stress, the suspension will remain stable.
  • gellan gum fluid gels are the setting temperature, degree of structure and thermal stability. All of these properties are, as with normal unsheared gels, dependent upon the concentration of gellan gum and the type and concentration of gelling ions.
  • LA low-acyl
  • HA high-acyl
  • the gellan e.g., low-acyl gellan
  • the gellan is present in an amount ranging from about 0.05 to 2% by weight of the composition, or about 0.1 to about 2.0%, about 0.2 to 2.0%, about 0.3 to 1 .2%, about 0.3 to about 1 .0%, or about 0.5 to about 0.9% by weight of the composition.
  • the gellan is present in about 0.15%, 0.3%, 0.6%, 0.9%, 1 .2% or 1 .8% by weight of the composition.
  • Gellan may advantageously be purified prior to incorporation into the present compositions.
  • Commercially available gellans contain small amounts of cations, such as calcium.
  • the gellan may be purified by dialysis to remove these cations, particularly divalent cations, along with other low molecular weight impurities, thereby improving its ability to form the in situ gelling vehicle when combined with the polyvalent cation source.
  • the gellan is a dialyzed or purified low-acyl gellan.
  • the term purified low-acyl gellan refers to low-acyl gellan that is free of or substantially free of low molecular weight impurities, such as calcium.
  • the source of polyvalent cation can be a molecular cation exchange agent or cation exchange resin, and may comprise
  • the source of the polyvalent cation can comprise any polyvalent cation, but in particular, Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+ , or combinations thereof.
  • the amount used may be in a range of about 0.01 to about 0.1 %, about 0.02 to about 0.1 %, about 0.03 to about 0.08, about 0.03 to about 0.07% by weight of the composition.
  • the amount of the molecular cation exchange agent is in a range of about 0.232 to about 2.32 mMole divalent cation per kg of the composition, 0.465 to about 2.32 mMole divalent cation per kg of the composition, about 0.698 to about 1 .68 mMole divalent cation per kg of the composition, or about 0.698 to about 1 .626 mMole divalent cation per kg of the composition.
  • the source of the polyvalent cation can be a cation exchange resin, such as a dextran cross-linked with epichlorohydrin, which is commercially available as Sephadex® (e.g. SP Sephadex C-25, available from GE Healthcare Life Sciences.
  • a polyvalent cation especially useful with the cation exchange resin is Zn 2+ .
  • the ion exchange agent may be present in the compositions in an amount ranging from about 0.2 to about 5 % by weight, about 0.3 to about 5 % by weight, about 0.3 to about 3% by weight, about 0.5 to about 3 % by weight, or about 0.5 to about 2% by weight, or about 0.6 to about 1 .5% by weight of the composition.
  • ion exchange agents loaded with divalent cations may be present in the compositions in amounts such that 0.232 mMole divalent cation are available per kg of GFS to about 2.32 mMole divalent cation per kg of GFS, about 0.465 mMole divalent cation available per kg of gel forming solution to about 2.32 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .86 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .626 mMole divalent cation available per kg of GFS.
  • 0.232 mMole divalent cation are available per kg of GFS to about 2.32 mMole divalent cation per kg of GFS, about 0.465 mMole divalent cation available per kg of GFS to about 2.32 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .86 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .626 mMole divalent cation available per kg of GFS.
  • the divalent cat ion exchange may be present in the compositions in amounts such that about 1 .1 62 mMole to about 1 1 .62 mMole of divalent cation are available per kg of GFS.
  • the ion exchange agent whether molecular or cation exchange resin, makes polyvalent cations (e.g., Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+ ) available to an ion-sensitive, viscosity increasing polysaccharide, such as gellan, after initial contact with the tear fluid in the eye at an optimized amount that is not feasible with the polysaccharide alone
  • polyvalent cations e.g., Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+
  • combining the anionic polysaccharide with a polyvalent cation source advantageously exchanges the sodium and potassium present in tear fluid with the polyvalent cation. This exchange improves the in situ gelling properties of the composition once it is instilled in the eye.
  • gellan contains carboxylic and hydroxyl functional groups which may interact with other polymers through electrostatic attractions and/or hydrogen bonding. Accordingly, a polymer that interacts through electrostatic attractions with gellan is advantageously incorporated into the present compositions to improve the gelling and rheological properties of the in situ vehicles.
  • Polymers useful in the present compositions include polyvinylpyrolidone (PVP, also referred to as povidone and available commercially, for example, as PlasdoneTM -12 from Ashland, Inc.), copolymers of vinylpyrrolidone/acrylic acid/lauryl methacrylate (commercially available, for example, as Styleze® 2000), and combinations thereof.
  • the polymer comprises a mixture of povidone and Styleze® 2000.
  • the polymer is present in an amount ranging from about 0.05 to about 1 % by weight of the composition. In other embodiments, the polymer is present in an amount ranging from about 0.05 to about 0.5%, about 0.1 % to about 0.5% by weight of the composition.
  • compositions comprising low and high acyl gellan. Both high- and low-acyl gellans form hydrogels in the presence of cations in a temperature-dependent manner.
  • a mixture of high acyl and low acyl gellan in combination with a polyvalent cation source surprisingly provides an in situ gelling vehicle that increases in viscosity upon exposure to tear fluid.
  • the high-acyl gellan and low-acyl gellan in some embodiments have a weight ratio ranging from about 0.5:1 to about 1 :0.5. In other embodiments the weight ratio of high and low acyl gellan is about 1 :1 .
  • the low-acyl gellan is, in some embodiments, present in the composition in an amount ranging from about 0.1 to about 1 .0% by weight. In other embodiments the low acyl gellan is present in an amount of about 0.1 , 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9% by weight.
  • the high-acyl gellan is, in some embodiments, present in the composition in an amount ranging from about 0.1 to about 1 .0% by weight. In other embodiments the high acyl gellan is present in an amount of about 0.1 , 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9% by weight.
  • the gellan used in a mixed high- and low-acyl in situ gelling composition described herein may be purified, for example by dialysis, to remove these cations. Accordingly, in some embodiments, the low- and high-acyl gellans are dialyzed and purified low- and high-acyl gellans.
  • the term purified low-acyl gellan and purified high acyl gellan refers to gellan that is free of or substantially free of calcium.
  • the source of polyvalent cation can be a molecular cation exchange agent or cation exchange resin, and may comprise
  • the source of the polyvalent cation can comprise any polyvalent cation, but in particular, Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+ , or combinations thereof.
  • the amount used may be in a range of about 0.01 to about 0.1 %, about 0.02 to about 0.1 %, about 0.03 to about 0.08, about 0.03 to about 0.07% by weight of the composition.
  • the amount of the molecular cation exchange agent is in a range of about 0.232 to about 2.32 mMole divalent cation per kg of the composition, 0.465 to about 2.32 mMole divalent cation per kg of the composition, about 0.698 to about 1 .68 mMole divalent cation per kg of the composition, or about 0.698 to about 1 .626 mMole divalent cation per kg of the composition.
  • the source of the polyvalent cation can be a cation exchange resin, such as a dextran cross-linked with epichlorohydrin, which is commercially available as Sephadex® (e.g. SP Sephadex C-25, available from GE Healthcare Life Sciences.
  • a polyvalent cation especially useful with the cation exchange resin is Zn 2+ .
  • the ion exchange agent may be present in the compositions in an amount ranging from about 0.2 to about 5 % by weight, about 0.3 to about 5 % by weight, about 0.3 to about 3% by weight, about 0.5 to about 3 % by weight, or about 0.5 to about 2% by weight, or about 0.6 to about 1 .5% by weight of the composition.
  • ion exchange agents loaded with divalent cations may be present in the compositions in amounts such that 0.232 mMole divalent cation are available per kg of GFS to about 2.32 mMole divalent cation per kg of GFS, about 0.465 mMole divalent cation available per kg of GFS to about 2.32 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .86 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .626 mMole divalent cation available per kg of GFS.
  • 0.232 mMole divalent cation are available per kg of GFS to about 2.32 mMole divalent cation per kg of GFS, about 0.465 mMole divalent cation available per kg of GFS to about 2.32 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .86 mMole divalent cation available per kg of GFS, about 0.698 mMole divalent cation available per kg of GFS to about 1 .626 mMole divalent cation available per kg of GFS.
  • the ion exchange agent whether molecular or resin, makes polyvalent cations (e.g., Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+ ) available to the mixed high- and low-acyl gellan after initial contact with the tear fluid in the eye.
  • polyvalent cations e.g., Ca 2+ , Al 3+ , Mn 2+ , Sr 2+ , Zn 2+ , Fe 2+
  • a polyvalent cation source such as an ion exchange agent
  • a polyvalent cation source such as an ion exchange agent
  • the in situ gelling compositions disclosed herein may advantageously be used as ophthalmic drug delivery vehicles to administer drugs directly to the surface of the eye. It is believed that the compositions provide an increased exposure time to the drug by slowing the ability for natural tears to wash away the compositions.
  • the in situ gelling vehicles described above also help prolong the release of the drug and reduce systemic exposure to the drug.
  • the present compositions may be used independent of additional pharmaceutical ingredients in order to provide relief to dry eye or injury to the surface of the eye.
  • the size of drops from ophthalmic containers may vary from about 30 to 50 ⁇ . and the resident tear volume differs from 7 to 10 ⁇ .. The eye is thought to be able to hold about 30 ⁇ . without spillage. Therefore, the ratio of eye medication to resident tear volume after administration of a drop could reasonably range from as much as 50:7 (7.1 to 1 .0) to as little as 30:10 (3.0 to 1 .0).
  • compositions in some embodiments, have a pH ranging from about 5 to about 8, about 5.5 to about 7.5, about 6 to about 7.5, or about 6 to about 7.2.
  • the pH of the compositions can be adjusted by conventional means known in the art, for example by adding appropriate acid or base solutions until the desired pH is achieved.
  • the pH may be adjusted by the addition of NaOH or HCI as needed.
  • the present compositions may further comprise a buffer, such as sodium lauryl sulfate, docusate sodium, polyethylene glycol 400, and TR 1 .
  • the present compositions may in some embodiments further comprise a preservative.
  • a preservative Any preservative or combination of preservatives routinely used in the art may be employed.
  • suitable preservatives include, without limitation, sorbic acid, chlorobutanol, phenylethanol, edetate and its salts, benzalkonium chloride, methyl and ethyl parabens, hexetidine, phenyl mercuric salts and the like and mixtures thereof.
  • the amounts of preservative components included in the present compositions are such to be effective in preserving the compositions and can vary based on the specific preservative component employed, the specific composition involved, the specific application involved, and the like factors. Preservative concentrations often are in the range of about 0.00001 % to about 0.05% or about 0.1 % (w/v) of the composition, although other concentrations of certain preservatives may be employed.
  • preservative components in the present compositions also include, but are not limited to, chlorite components.
  • Other useful preservatives include antimicrobial peptides.
  • antimicrobial peptides include, without limitation, defensins, peptides related to defensins, cecropins, peptides related to cecropins, magainins and peptides related to magainins and other amino acid polymers with antibacterial, antifungal and/or antiviral activities.
  • Mixtures of antimicrobial peptides or mixtures of antimicrobial peptides with other preservatives are also included within the scope of the present invention.
  • the above-described compositions exhibit thixotropic behavior.
  • Thixotropy is a time-dependent shear thinning property of certain fluids. Specifically, certain gels or fluids that are viscous under static conditions will flow, becoming less viscous or even liquid over time when shaken, agitated, or applied with a shear force. Such fluids or gels will then return to a more viscous state after being static for a period of time. Thus, the compositions, upon forming a gel in the eye, will thin under the shear stress of an eyelid. Accordingly, the present compositions are believed ⁇ o advantageously prevent discomfort and blurring that is often associated with the application of gels and ointments to the eye.
  • LA form of gellan more easily transforms from a solution to a gel due to the increased ease in which cations can form bridges between the LA gellan polymer chains as compared to HA gellan (Morris et.al., 1 996, 1999) .
  • High acyl gellan solutions form gels at much higher temperatures than low acyl gellan solutions.
  • An additional purpose of this investigation was to determine if mixtures of LA and HA gellan form stronger gels than LA-Gellan alone.
  • Povidone 12 and StylezeTM 2000 (vinyl pyrrolidone and acrylate backbone with a hydrophobic pendant C-12 chain) were both provided by Ashland Inc. Both LA gellan gum sourced from Spectrum Chemical and from CP elco were used in this study. HA gellan was provided from CP Kelco.
  • LA gellan polymer solutions were dialyzed at 23° C, whereas HA gellan or LA/HA gellan mixtures were dialyzed at 90° C.
  • the conductivity of the deionized wash water was measured regularly using a Venier conductivity probe. Once the conductivity readings had stabilized, the deionized water was discarded and replaced with fresh deionized water. The wash cycles were continued until the measured conductivity approached that measured with deionized water. Dialyzed gellan solutions were harvested by carefully squeezing the gellan solutions out of the tubing.
  • Concentrated solutions or slurries of polymers were prepared and allowed to hydrate for at least 12 hours. Ingredients were measured according to target weights and thoroughly mixed together. Deionized water was added to give a final batch weight of 80 to 90% of final target. If a target pH was desired for the candidate formulation, then Sodium hydroxide or hydrochloric acid was used to adjust the pH to target values of 6.0, 6.5, or 7.2. Sufficient deionized water was added to the preparations to give a final batch weight of 100 or 200 g.
  • ATS Artificial tear solution
  • a citric acid buffer is used in ATS rather than the carbonic acid buffer that is present in tears.
  • the pH of water buffered at physiological pH, such as tear fluid changes with time because of an exchange of carbonic acid with air that results in an increased pH.
  • the calculated p a of carbonic acid is given as 6.05.
  • the calculated p a values for citric acid are given as 3.05, 4.67, and 5.39. At the pH of 7.4, 95.6% of carbonic acid would be in the ionized form and 99% of the citric acid would be in the fully ionized form.
  • PATS physiological artificial tear solution
  • the components of the STF were added with mixing to water at about 80% of the final batch weight.
  • the resulting solution was titrated to a target pH of 7.4 ⁇ 0.4 using sodium hydroxide or hydrochloric acid.
  • Deionized water was added in quantities sufficient to achieve the final target batch weight.
  • Viscosities were measured from 1 to 1 ,000 sec-1 at 23° C for GFS preparations using a Haake Viscotester 550. Experimental preparations were mixed thoroughly with simulated tear fluid (STF) at a 5:1 ratio. That is, 10 g of ATS (screening studies) or PATS (confirmatory studies) was added to 50 g of the gellan sample GFS preparation. For initial screening studies; the gellan and STF mixtures were set aside for at least 15 minutes, gently transferred to the water jacketed cup, and then viscosities were measured from 1 to 1 ,000 sec-1 at 34° ⁇ 1 C.
  • STF simulated tear fluid
  • k the viscosity related constant
  • n the flow behavior index
  • Fluids are considered to be Newtonian if n is equal to 1 .
  • Fluids are considered to be pseudoplastic (shear thinning) if n is less than 1 and considered more shear thinning as the value for n decreases.
  • the Bingham model allowed for the calculation of the yield value for each gel preparation.
  • Timolol solution was prepared by dissolving the appropriate amount of Timolol maleate in Dulbecco's Phosphate Buffered Saline (DPBS).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • a 1 .36% solution of Timolol in deionized water was combined with concentrated solutions of polymers at target concentrations given in Table 3.
  • Deionized water was added to give a weight of 80 to 90% of final target.
  • Sodium hydroxide was used to adjust the pH to target values.
  • Sufficient deionized water was added to the preparations to give a final batch weight of 10 g.
  • the preparations were tested for Timolol transmembrane diffusion characteristics within 3 days after manufacture.
  • a UV-Visible Spectrophotometer was used to measure the amount of UV absorbance at 295 nm of Timolol maleate standard solutions at nine different concentrations.
  • a calibration curve was generated between Timolol maleate absorbance at 295 nm and concentration. The equation was not forced to a Y- intercept of zero and had a r2 value of 0.995. Concentrations of Timolol in experimental samples were determined using the standard curve.
  • the dialysis tubing was removed from the soaking CBS, closed at one end, filled with approximately 1 g of preparation, and the top end was clamped.
  • Each filled dialysis membrane bag was placed in a beaker filled with 100 mL of fresh CBS to elicit sink conditions.
  • a stir bar was placed in the beaker that was then covered with parafilm.
  • Each sample set up was placed on a multi-station stir plate at ambient temperature and stirred at 1000 rpm. Total weight was documented for each experimental set up and deionized water was added, if needed ⁇ >] % deviation), to compensate for water loss due to evaporation.
  • the data was initially fit using the sigmoidal equation with M2 held constant and the other three variables being allowed to vary.
  • the fitted value for Ml was considered the total possible Timolol that can be released.
  • the theoretical value for Ml is 0.067 mg/mL and the average of the variable values for Ml was 0.069 ⁇ 0.007.
  • the values for release were redefined as the % total release which is equal to the measured amount of Timolol (mg/mL) divided by the fitted value for Ml (mg/mL) and times 100.
  • the amount of Timolol that diffused through the dialysis membrane into CBS was expressed as % total release and plotted versus the time at which the sample was pulled from the receiving fluid.
  • the curve fit parameters Ml (100 %) and M2 (0%) were held constant at their theoretical values in order to improve the degrees of freedom for the fitting procedure.
  • the parameters M3 and M4 were left to vary in value during the curve fitting process.
  • the M3 parameter is the time at which the midpoint (50% theory) or point of inflection is reached between the lowest (0.0%) and highest amounts (100%) of Timolol release.
  • the parameter M4 is considered a shape parameter and has no direct physical significance. It gives much less information as to how rapidly Timolol is being diffused as compared to M3.
  • the and ⁇ values for the same GFS were measured at 0, 5, 10, 1 5, and 65 min after the primary viscosity curve was performed.
  • the linear fits indicate that rest times of 4.5 and 10.5 hr are needed for gels to return to their initial gel strength following high sear. If the secondary viscosity curve is taken 5 min after the primary viscosity curve is complete, then a n error of about 0.1 units for both the and ⁇ values will occur.
  • Figure 2 depicts viscosity v. shear rate of a n in situ gelling composition of 0.6% low-acyl gellan and 0.4% high-acyl gellan .
  • Screening results indicated that the viscosities of gellan GFS increased as the added calcium gluconate was increased in concentration, with particularly good results achieved at a concentration of 0.6% by weight. It appears that calcium ions were in equilibrium between being in association with gluconate or gellan molecules. As calcium gluconate concentrations were increased, equilibrium favored a greater association with gellan and hence a larger viscosity for the GFS before it was mixed with STF. Screening results indicated that Gellan (0.9%) in solution with 0.06% calcium gluconate resulted in an efficient GFS.
  • Tables 3-4 indicate that the simple addition of 0.06% calcium gluconate to 0.9% LA-gellan results in a large increase in both the viscosity (K) and yield value ( ⁇ ) when this GFS is mixed with ATS. It also results in a stronger gel when subjected to an initial tear contact environment than 0.6% LA-gellan.
  • Table 6 Primary and secondary viscosity data (K values) for gellan and 0.06% calcium gluconate from two different sources.
  • Table 7 Tau values for gellan and 0.06% calcium gluconate from two different sources.
  • Table 9 Tau values of low-acyl gellan with an insoluble ion exchange resin and alternate polyvalent cations
  • Figure 5 further depicts the release rates of timolol from various in situ gelling preparations as a function of time.
  • Table 1 1 values of preparations of 0.75% low-acyl gellan, calcium gluconate and povidone.
  • Table 12 Tau values of preparations of 0.75 % low-acyl gellan, calcium gluconate and povidone.
  • Table 13 K values of preparations of 0.9% low-acyl gellan, calcium gluconate and povidone.
  • Table 14 Tau values of preparations of 0.9% low-acyl gellan, calcium gluconate and povidone.
  • Table 15 values of preparations of 0.9% low-acyl gellan, calcium gluconate a Styleze®.
  • Table 16 Tau values of preparations of 0.9% low-acyl gellan, calcium gluconate and Styleze®.
  • Table 17 K values of high and low acyl gellan compositions.
  • Table 18 Tau values of high and low acyl gellan compositions.
  • Table 19 values of high and low acyl gellan compositions with calcium gluconate.
  • Table 20 Tau values of high and low acyl gellan compositions with calcium gluconate.
  • Figure 6 depicts the primary and secondary viscosity of a mixed LA and HA gellan composition in artificial tears.
  • FIG. 7 depicts the Tau values for a composition having 1 % sodium alginate as the polysaccharide based on percent of calcium gluconate in PATS
  • Figure 8 depicts the values for a 1 .% sodium alginate preparation based on percent of calcium gluconate in PATS and Dl water.

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Abstract

La présente invention concerne d'une manière générale des compositions pharmaceutiques se gélifiant in situ comprenant un mélange aqueux d'un polysaccharide anionique, une source de cation polyvalent et un polymère. Les compositions se gélifiant in situ présentent l'avantage de former des gels transparents quand elles sont mises au contact du fluide lacrymal dans l'œil, et sont utilisables en tant que vecteurs d'administration de médicaments. La présente invention concerne également des compositions se gélifiant in situ comprenant un mélange de gellane à forte teneur en acyle, de gellane à faible teneur en acyle, et d'une source de cation polyvalent. Enfin, l'invention concerne également des méthodes permettant d'administrer un médicament au niveau ophtalmique.
PCT/US2017/019997 2016-02-29 2017-02-28 Compositions pharmaceutiques se gélifiant in situ WO2017151651A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126141A (en) * 1988-11-16 1992-06-30 Mediventures Incorporated Composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides
US5935604A (en) * 1993-05-20 1999-08-10 Danbiosyst Uk Limited Nasal drug delivery composition containing nicotine
US20030143274A1 (en) * 1991-10-30 2003-07-31 Viegas Tacey X. Medical uses of in situ formed gels
US20050084534A1 (en) * 2001-02-28 2005-04-21 Yawei Ni Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
US20050197614A1 (en) * 2004-03-04 2005-09-08 Wilson Pritchard Occlusive biomedical devices, punctum plugs, and methods of use thereof
US20070264206A1 (en) * 2006-05-11 2007-11-15 Kimberly-Clark Worldwide, Inc. Mucosal formulation
US20090143529A1 (en) * 2004-06-14 2009-06-04 Milton Thomas William Hearn Peptide purification by means of hard metal ion affinity chromatography

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126141A (en) * 1988-11-16 1992-06-30 Mediventures Incorporated Composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides
US20030143274A1 (en) * 1991-10-30 2003-07-31 Viegas Tacey X. Medical uses of in situ formed gels
US5935604A (en) * 1993-05-20 1999-08-10 Danbiosyst Uk Limited Nasal drug delivery composition containing nicotine
US20050084534A1 (en) * 2001-02-28 2005-04-21 Yawei Ni Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
US20050197614A1 (en) * 2004-03-04 2005-09-08 Wilson Pritchard Occlusive biomedical devices, punctum plugs, and methods of use thereof
US20090143529A1 (en) * 2004-06-14 2009-06-04 Milton Thomas William Hearn Peptide purification by means of hard metal ion affinity chromatography
US20070264206A1 (en) * 2006-05-11 2007-11-15 Kimberly-Clark Worldwide, Inc. Mucosal formulation

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