WO2004112750A2 - Ophthalmic compositions containing a synergistic combination of three polymers - Google Patents
Ophthalmic compositions containing a synergistic combination of three polymers Download PDFInfo
- Publication number
- WO2004112750A2 WO2004112750A2 PCT/US2004/018067 US2004018067W WO2004112750A2 WO 2004112750 A2 WO2004112750 A2 WO 2004112750A2 US 2004018067 W US2004018067 W US 2004018067W WO 2004112750 A2 WO2004112750 A2 WO 2004112750A2
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- WIPO (PCT)
- Prior art keywords
- composition
- agents
- carboxyvinyl polymer
- polymeric ingredients
- guar gum
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
Definitions
- the present invention relates to pharmaceutical compositions.
- this invention relates to topically administrable ophthalmic compositions that contain three polymeric components.
- polymeric ingredients in topically administrable ophthalmic compositions are well known. Polymeric ingredients are typically used in suspension compositions as physical stability aids, helping to keep the insoluble ingredients suspended or easily redispersible. In solution compositions, polymeric ingredients are typically used to increase the composition's viscosity.
- polymers have been used in topically administrable ophthalmic compositions. Included among these are cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, and ethyl hydroxyethyl cellulose. Also included are synthetic polymers, such as carboxyvinyl polymers and polyvinyl alcohol. Still others include polysaccharides such as xanthan gum, guar gum, and dextran.
- cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, and ethyl hydroxyethyl cellulose.
- synthetic polymers such as carboxyvinyl polymers and polyvinyl alcohol. Still others include polysaccharides such as xanthan gum, guar gum, and dextran.
- Combinations of polymers have also been used in ophthalmic compositions. Certain combinations of polymers are known to provide synergistic effects on viscosity and, in some cases, even a phase transition from a liquid to a gel.
- U.S. Patent No. 4,136,173 discloses ophthalmic compositions containing a combination of xanthan gum and locust bean gum.
- One approach to achieving a target viscosity in a topically administrable ophthalmic composition might involve simply adding a sufficient amount of one polymeric ingredient. Often, however, it is desirable to minimize the total amount of polymeric additives in topically administrable ophthalmic compositions.
- a mixed polymer system containing more than one polymer can significantly enhance the viscosity and lubrication property of a composition while minimizing total polymer concentration and cost of materials.
- the present invention is directed toward ophthalmic compositions that contain three polymeric components.
- the compositions contain hydroxypropyl methylcellulose and a combination of two polymers selected from the group of combinations consisting of guar gum and a carboxyvinyl polymer; guar gum and hydroxyethyl cellulose; guar gum and dextran; hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and a carboxyvinyl polymer.
- the compositions are useful as artificial tear products, but can also serve as vehicles for delivering ophthalmic drugs.
- the present invention is based upon the finding that the specified combinations of three polymers have a synergistic effect on viscosity.
- Fig. 1 shows the viscosity for each of Compositions 1 - 8 (Example 2), demonstrating the remarkable synergy among the three polymer system: hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer.
- Fig. 2 shows the effect of total polymer concentration on viscosity for the three polymer system of hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer for a concentration ratio of 3:1 :1 (hydroxypropyl methylcellulose:guar gum:carboxyvinyl polymer) at pH 7.0.
- the ophthalmic compositions of the present invention are aqueous compositions that include a combination of three polymeric ingredients: hydroxypropyl methylcellulose ("HPMC") and a combination of two polymers selected from the group of combinations consisting of guar gum ("Guar”) and a carboxyvinyl polymer (“carbomer”); Guar and hydroxyethyl cellulose (“HEC”); Guar and dextran; HEC and carbomer; and dextran and carbomer. All of these types of polymers are known and have been used in ophthalmic compositions. All of these types of polymers are also commercially available.
- HPMC hydroxypropyl methylcellulose
- CAB carboxyvinyl polymer
- HEC hydroxyethyl cellulose
- HEC hydroxyethyl cellulose
- dextran and carbomer dextran and carbomer
- HPMC is commercially available from the Dow Chemical Company under the brand name Methocel ® .
- HPMC is available in a variety of grades. Most preferred for use in the compositions of the present invention is Methocel E4M, (HPMC 2910), which has a number average molecular weight of approximately 86,000 dalton.
- the concentration of HPMC in the compositions of the present invention will generally range from 0.05 - 0.5 %, and will preferably be 0.3 %.
- Guar includes guar gum and guar gum derivatives, such as the hydroxypropyl or hydroxypropyltrimonium chloride derivatives of guar gum. Guar and its derivatives are described in U.S. Patent No. 6,316,506, the entire contents of which are hereby incorporated by reference. For purposes of the present application, guar includes unsubstituted guar gum and its substituted derivatives. Guar gum and many of its derivatives are commercially available from Rhone-Poulenc (Cranbury, New Jersey), Hercules, Inc. (Wilmington, Delaware) and TIC Gum, Inc. (Belcamp, Maryland). A preferred derivative for use in the compositions of the present invention is hydroxypropyl guar ("HP- Guar").
- the concentration of guar in the compositions of the present invention will generally range from 0.01 - 0.2 %, and will preferably be 0.1 %.
- Carboxyvinyl polymers suitable for use in the present invention are also known as "carbomers” or carboxypolymethylene. They are commercially available from sources such as Noveon, Inc. (Cleveland, Ohio), which distributes them under the trade name Carbopol ® .
- Carbopol polymers are crosslinked, acrylic acid-based polymers. They are cross-linked with allyl sucrose or allylpentaerythritol.
- Carbopol copolymers are polymers of acrylic acid, modified by C- 10 -30 alkyl acrylates, and crosslinked with allylpentaerythritol.
- a preferred carbomer for use in the compositions of the present invention is a polymer of acrylic acid cross-linked with allyl sucrose or allylpentaerythritol, which is commercially available as Carbopol ® 974P.
- the concentration of carbomer in the compositions of the present invention will generally range from 0.01 - 0.2 %, and will preferably be 0.1 %.
- HEC is commercially available from Hercules Inc. (Aqualon Division) in a variety of grades, including Natrasol 250 LR, Natrasol 250 MR and
- a preferred HEC for use in the compositions of the present invention is the NF grade material, which is commercially available as Natrasol 250HR.
- the concentration of HEC in the compositions of the present invention will generally range from 0.05 - 0.5 %, and will preferably range from 0.1 - 0.2 %.
- Dextran is commercially available from Amresco in a variety of grades, including Dextran 5, 10, 20, 40, 70, 110, 500, and 2000.
- a preferred dextran for use in the compositions of the present invention is Dextran 70 (NOC grade; dry powder).
- the concentration of dextran in the compositions of the present invention will generally range from 0.01 - 0.2 %, and will preferably be 0.1 %.
- the aqueous compositions of the present invention contain the three specified polymeric ingredients in a ratio ranging from 1 :1 :1 to 3:3:3, with a ratio of 3:1 :1 being most preferred, where the amount of HPMC is listed first and the amounts of the other two polymers are listed second and third, respectively.
- the total concentration of the three polymeric ingredients should range from 0.1 - 1 %, preferably 0.3 - 0.9%, and most preferably, 0.4 - 0.7%.
- the aqueous compositions of the present invention may contain other ingredients as excipients.
- the compositions may include one or more pharmaceutically acceptable buffering agents, preservatives (including preservative adjuncts), non-ionic tonicity-adjusting agents, surfactants, solubilizing agents, stabilizing agents, comfort-enhancing agents, emollients, pH-adjusting agents and/or lubricants.
- preservatives including preservative adjuncts
- non-ionic tonicity-adjusting agents surfactants
- solubilizing agents stabilizing agents
- comfort-enhancing agents emollients
- pH-adjusting agents and/or lubricants e.g., glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, g
- compositions contain a carbomer as one of the three polymers, then the compositions of the present invention do not contain any ionic tonicity-adjusting agents, such as sodium chloride, or other ionic excipients, such as boric acid, as these ingredients have a significant, detrimental effect on the composition's viscosity.
- ionic tonicity-adjusting agents such as sodium chloride, or other ionic excipients, such as boric acid
- compositions of the invention have a pH in the range of 5 - 9, preferably 6.5 - 7.5, and most preferably 6.9 - 7.4. If the compositions contain a carbomer as one of the three polymers, it is critical that the compositions are formulated so that the target pH is not exceeded. Once a target pH has been exceeded in compositions containing a carbomer, adding an acid such as hydrochloric acid to adjust the pH downward can compromise the synergistic viscosity. Even relatively small amounts of acid or salts, on the order of 0.005%, can have a significant effect on the viscosity of compositions containing a carbomer.
- compositions of the present invention generally have an osmolality in the range of 220 - 320 mOsm/kg, and preferably have an osmolality in the range of 235 - 260 mOsm/kg.
- aqueous compositions of the present invention are suitable for use as artificial tear products to relieve symptoms of dry eye.
- the compositions of the present invention may act as a vehicle for an ophthalmic drug.
- Ophthalmic drugs suitable for use in the compositions of the present invention include, but are not limited to: anti-glaucoma agents, such as beta- blockers including timolol, betaxolol, levobetaxolol, carteolol, miotics including pilocarpine, carbonic anhydrase inhibitors, prostaglandins, seretonergics, muscarinics, dopaminergic agonists, adrenergic agonists including apraclonidine and brimonidine; anti-angiogenesis agents; anti-infective agents including quinolones such as ciprofloxacin, and aminoglycosides such as tobramycin and gentamicin; non-steroidal and steroidal anti-inflammatory agents, such as suprofen,
- compositions of the present invention may also include combinations of ophthalmic drugs, such as combinations of (i) a beta-blocker selected from the group consisting of betaxolol and timolol, and (ii) a prostaglandin selected from the group consisting of latanoprost; 15-keto latanoprost; travoprost; and unoprostone isopropyl.
- a beta-blocker selected from the group consisting of betaxolol and timolol
- a prostaglandin selected from the group consisting of latanoprost; 15-keto latanoprost; travoprost; and unoprostone isopropyl.
- the amount of drug and/or the amount of carboxyvinyl polymer and/or the identity and amount of other formulation ingredients may need to be adjusted to minimize or eliminate interactions between the carboxyvinyl polymer and the cationic drug.
- the ophthalmic drug is a neutral or negatively-charged drug.
- the amount of drug included in the compositions of the present invention will be whatever amount is therapeutically effective and will depend upon a number of factors, including the identity and potency of the chosen drug, the total concentration of drug will generally be about 5% or less.
- compositions of the present invention are preferably not formulated as solutions that undergo a phase transition to a gel upon administration to the eye.
- compositions illustrated in the Examples below do not gel upon administration to the eye.
- the following examples are presented to illustrate further various aspects of the present invention, but are not intended to limit the scope of the invention in any respect.
- the composition shown in Table 1 can be prepared by at least two methods.
- One method involves adding the following ingredients slowly and in the following order to heated purified water (70 - 80 °C) (approximately 80% of the desired batch volume) with mixing: mannitol, HPMC 2910, Carbopol 974P, and HP-Guar (waiting until each ingredient is mixed well before adding the next). pH is then adjusted with 1 N NaOH, and the remaining amount of purified water is added.
- the composition is then autoclaved at 121 ° C for thirty minutes and subsequently cooled to room temperature with constant stirring.
- An alternative method of preparing the composition shown in Table 1 is as follows. In a first container, add heated purified water (70 - 80 °C) (approximately 60% of the desired batch volume), then mix in mannitol, then HPMC 2910, and then Carbopol 974P, waiting until each ingredient is mixed well before adding the next. Autoclave the resulting composition at 121 ° C for thirty minutes, then allow the composition to cool to room temperature with constant stirring ("the HPMC/Carbopol composition"). In a separate container, add purified water (approximately 30% of the desired batch volume), then mix in HP-Guar. Adjust the pH of the HP-Guar composition with 1 N NaOH to pH 9.
- the HP-Guar composition Autoclave the HP-Guar composition at 121 ° C for thirty minutes, then allow it to cool to room temperature with constant stirring ("the HP-Guar composition"), then aseptically combine the HP-Guar composition with the HPMC/Carbopol composition, and aseptically adjust the final pH to 7.0, if necessary, with 1N NaOH and/or 1 N HCI.
- compositions shown in Table 4 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25 °C) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25 °C) for more viscous samples (viscosity more than 20 cps).
- Airvol 523S is a commercially available polyvinyl alcohol polymer. Chondroitin sulfate is a commercially available polymer.
- K90 is a commercially available polyvinylpyrrolidone polymer.
- Example 5 Lack of Synergistic Effect on Viscosity (Polyvinyl Alcohol + Chondroitin Sulfate + Carbomer; Polyvinyl Alcohol + Polyvinylpyrrolidone + Carbomer; Chondroitin Sulfate + Polyvinylpyrrolidone + Carbomer)
- compositions shown in Table 5 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25 °C) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25 °C) for more viscous samples (viscosity more than 20 cps).
- Airvol 523S is a commercially available polyvinyl alcohol polymer. Chondroitin sulfate is a commercially available polymer.
- K90 is a commercially available polyvinylpyrrolidone polymer.
- the viscosities of the single polymer solutions for polyvinyl alcohol, chondroitin sulfate and polyvinylpyrrolidone can be found in Table 4 - Examples 20 - 22.
- the compositions are shown in Table 5.
- Example 8 Effect of Salt on Viscosity for a Polymer Combination that Contains Carbomer
- compositions shown below in Table 9 were prepared to determine the effect of the addition of boric acid on viscosity.
- the viscosity of each sample was determined using a Brookfield cone/plate viscometer (52 cone, 3 rpm). The results are shown in Table 9.
- compositions containing a combination of HPMC 2910, HP-Guar and Carbopol 974P were evaluated using 5 compositions containing only the three designated polymers, mannitol and purified water.
- the composition contained 4.0 %(w/w) of mannitol and had an adjusted pH of 7.0.
- the total polymer concentrations ranged from 0.1 to 1.0, with the ratio of polymers held constant at 3:1:1 (HPMC:HP-Guar:Carbopol).
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Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0411367A BRPI0411367B1 (en) | 2003-06-13 | 2004-06-08 | ophthalmic compositions containing a synergistic combination of three polymers |
MXPA05013293A MXPA05013293A (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers. |
KR1020057023407A KR101082345B1 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
DK04754623T DK1633324T3 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
AU2004249136A AU2004249136B2 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
EP04754623A EP1633324B1 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
PL04754623T PL1633324T3 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
DE602004003812T DE602004003812T2 (en) | 2003-06-13 | 2004-06-08 | OPHTHALMIC COMPOSITIONS WITH A SYNERGISTIC COMBINATION OF THREE POLYMERS |
CA2527417A CA2527417C (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
SI200430172T SI1633324T1 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
JP2006533589A JP4657213B2 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic composition comprising a synergistic combination of three polymers |
CY20061101843T CY1105877T1 (en) | 2003-06-13 | 2006-12-21 | OPHTHALMIC COMPOSITIONS THREE-POLYME ADHESIVE COMPOSITIONS |
Applications Claiming Priority (2)
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US47871303P | 2003-06-13 | 2003-06-13 | |
US60/478,713 | 2003-06-13 |
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WO2004112750A2 true WO2004112750A2 (en) | 2004-12-29 |
WO2004112750A3 WO2004112750A3 (en) | 2005-08-18 |
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PCT/US2004/018067 WO2004112750A2 (en) | 2003-06-13 | 2004-06-08 | Ophthalmic compositions containing a synergistic combination of three polymers |
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US (4) | US7244440B2 (en) |
EP (1) | EP1633324B1 (en) |
JP (2) | JP4657213B2 (en) |
KR (1) | KR101082345B1 (en) |
CN (1) | CN100340233C (en) |
AR (1) | AR047205A1 (en) |
AT (1) | ATE348600T1 (en) |
AU (1) | AU2004249136B2 (en) |
BR (1) | BRPI0411367B1 (en) |
CA (1) | CA2527417C (en) |
CY (1) | CY1105877T1 (en) |
DE (1) | DE602004003812T2 (en) |
DK (1) | DK1633324T3 (en) |
ES (1) | ES2274476T3 (en) |
MX (1) | MXPA05013293A (en) |
PL (1) | PL1633324T3 (en) |
PT (1) | PT1633324E (en) |
TW (1) | TWI336257B (en) |
WO (1) | WO2004112750A2 (en) |
ZA (1) | ZA200509441B (en) |
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WO2005014046A2 (en) | 2003-08-07 | 2005-02-17 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using the same |
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US7914803B2 (en) | 2003-06-13 | 2011-03-29 | Alcon, Inc. | Ophthalmic compositions containing a synergistic combination of three polymers |
-
2004
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- 2007-06-04 US US11/757,494 patent/US7329411B2/en not_active Expired - Fee Related
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Cited By (10)
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WO2005014046A2 (en) | 2003-08-07 | 2005-02-17 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using the same |
US8512717B2 (en) | 2003-08-07 | 2013-08-20 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using same |
EP1654002B2 (en) † | 2003-08-07 | 2014-01-29 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes |
US8992952B2 (en) | 2003-08-07 | 2015-03-31 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using same |
FR2896152A1 (en) * | 2006-01-17 | 2007-07-20 | Cetem Sarl Lab | Hydrating and regenerating cosmetic compositions, useful for perianal mucous membrane, comprises gelling agents such as (meth)acrylic polymers, cellulose alkylated and guar gum chemical derivatives in a neutralized aqueous excipient |
JP2010502634A (en) * | 2006-08-30 | 2010-01-28 | ボーシュ アンド ローム インコーポレイティド | Ophthalmic pharmaceutical composition and use thereof |
US9192571B2 (en) | 2008-03-03 | 2015-11-24 | Allergan, Inc. | Ketorolac tromethamine compositions for treating or preventing ocular pain |
WO2011140203A3 (en) * | 2010-05-05 | 2012-04-19 | Alcon Research, Ltd. | Stabilized ophthalmic galactomannan formulations |
US8846641B2 (en) | 2010-05-05 | 2014-09-30 | Alcon Research, Ltd. | Stabilized ophthalmic galactomannan formulations |
AU2011248129B2 (en) * | 2010-05-05 | 2014-10-09 | Alcon Inc. | Stabilized ophthalmic galactomannan formulations |
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