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WO1993017664A1 - Combinaisons de polymeres cellulosiques et de polymeres de vinyle carboxy et leur utilisation dans des compositions pharmaceutiques - Google Patents

Combinaisons de polymeres cellulosiques et de polymeres de vinyle carboxy et leur utilisation dans des compositions pharmaceutiques Download PDF

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Publication number
WO1993017664A1
WO1993017664A1 PCT/US1993/001565 US9301565W WO9317664A1 WO 1993017664 A1 WO1993017664 A1 WO 1993017664A1 US 9301565 W US9301565 W US 9301565W WO 9317664 A1 WO9317664 A1 WO 9317664A1
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WO
WIPO (PCT)
Prior art keywords
composition
weight
percent
carboxy vinyl
concentration
Prior art date
Application number
PCT/US1993/001565
Other languages
English (en)
Inventor
Yusuf Ali
Haresh G. Bhagat
Original Assignee
Alcon Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU37287/93A priority Critical patent/AU3728793A/en
Publication of WO1993017664A1 publication Critical patent/WO1993017664A1/fr

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Classifications

    • 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 invention relates generally to viscosity building agents (viscosity enhancers). More specifically, the present invention relates to combinations of viscosity enhancers which are useful in pharmaceutical compositions, especially in ophthalmic pharmaceuticals and artificial tear formulations.
  • the compositions of the present invention are also useful as lubricating and cushioning agents for the eye after traumatic injury or surgery.
  • Carboxy vinyl polymers have been used since the 1950's as viscosity enhancers in a number of fields, including cosmetics and pharmaceuticals. See, for example, Chemical & Engineering News. September 29, 1958, pages 64-65. Cellulosic polymers are also known in the pharmaceutical arts to be viscosity building agents.
  • Viscosity is generally dependent upon molecular weight and concentration.
  • the present invention is based on the unexpected finding that compositions comprising certain combinations of at least one cellulosic polymer and at least one carboxy vinyl polymer are much more viscous than similar compositions containing only one type of polymer. That is, a lower polymer concentration is required to achieve a higher viscosity when polymer combinations of the present invention are utilized than when only one of the polymers is utilized. This is particularly beneficial in the ophthalmic field, since a reduction in the overall polymer concentration in an ophthalmic composition generally results in patient greater comfort.
  • using the polymer combinations of the present invention higher viscosity can be achieved without increasing the overall polymer concentration. This aids in retention of the composition in the eye and permits the maintenance of a longer moisturizing effect, of particular importance with respect to artificial tear formulations.
  • Figure 1 is a graph comparing the viscosities of Formulations B (0.5% HPMC), F (0.175% Carbomer 934P) and L (0.5% HPMC + 0.175% Carbomer 934P) of Example 1.
  • compositions of the present invention comprise such polymer combinations and have many potential applications, particularly in the field of pharmaceutics.
  • the compositions of the present invention are especially useful for the treatment of dry eye syndrome and related ailments.
  • the cellulosic polymers useful in the pharmaceutical compositions of the present invention include all cellulose derivatives which exhibit viscoelastic properties. In general, such cellulosic polymers have an average molecular weight between about 10,000 and 13 million. Preferred cellulosic polymers include: hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and methyl cellulose (MC). In general, these cellulosic polymers are present in the compositions of the present invention at a concentration between about 0.05 and about 5.0 percent by weight (wt%), preferably between about 0.25 and about 1.0 wt%. It is especially preferred to use the cellulosic polymers at a concentration of about 0.5 wt%.
  • the carboxy vinyl polymers useful in the pharmaceutical compositions of the present invention have an average molecular weight between about 500,000 and 6 million.
  • the polymers are characterized as having carboxylic acid functional groups and preferably contain between 2 and 7 carbon atoms per functional group.
  • Suitable carboxy vinyl polymers include those called carbomers, e.g., Carbopol * (B.F. Goodrich Co., Cleveland, Ohio). Specifically preferred are: carbomer 910, carbomer 940, carbomer 934P and carbomer 1342. (Carbomer 934P is the most preferred.)
  • Such polymers will typically be employed in an amount between about 0.05 and about 3.0 wt%, depending on the desired viscosity of the composition. It is preferred to use the carboxy vinyl polymers at a concentration between about 0.1 and about 0.5 wt%, most preferably at a concentration of about 0.175 wt%.
  • compositions of the present invention may also contain one or more pharmaceutically active agents ("actives").
  • Such actives include, but are not limited to: glaucoma agents, such as miotics (e.g., pilocarpine, carbachol and acetylcholinesterase inhibitors), sympathomimetics (e.g., epinephrine, dipivalylepinephrine and para-amino clonidine), beta-blockers (e.g., betaxolol, levobunolol and timolol) and carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide); dopaminergic antagonists; antihypertensive agents, such as para-amino clonidine (also known as apraclonidine); anti-infectives, such as ciprofloxacin; non-steroidal and steroidal anti-inflammatories, such as suprofen, ketorolac, tetrahydrocortisol, dexamet
  • compositions of the present invention which are suitable for the treatment of dry eye syndrome and other related ailments may also include the following actives: zinc sulfate, Dextran 70, gelatin, glycerin, polyethylene glycols, polysorbates, polyvinyl alcohols and polyvinylpyrrolidone (Povidone). These actives, when present, are generally utilized in the compositions of the present invention at a concentration between about 0.005 to about 2.5 wt%.
  • compositions of the present invention may additionally contain various formulatory ingredients, such as antimicrobial preservatives and tonicity agents.
  • the final composition pH may also be adjusted so that it is in the physiological range
  • antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1 (Polyquad®) and other agents equally well-known to those skilled in the art. Such preservatives, if utilized, will typically be employed in an amount between about 0.0001 to 1.0 wt%.
  • agents which may be utilized to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, sucrose, glycerin and propylene glycol. Such agents, if utilized, will typically be employed in an amount between about 0.5 to 6 wt% and the osmolality will typically be between about 200 and 360 milliOsmoles/kilogram (mOsm/kg), preferably between about 250 and 340 mOsm/kg.
  • mOsm/kg milliOsmoles/kilogram
  • compositions of the present invention generally have a viscosity between about 50 and about 15,000 cps, preferably between about 2,000 and about 10,000 cps, and most preferably between about 3,000 and about 6,000 cps.
  • the viscosity of such compositions will vary, depending on the particular polymer combinations used and the relative concentrations of each polymer.
  • compositions of the present invention are typically formulated by dissolving the tonicity agent in purified water, followed by addition of an antimicrobial preservative agent if desirable.
  • the polymers, previously dissolved in purified water, are then added and the final volume obtained by the addition of purified water.
  • the batch is adjusted for a desirable pH by using sodium hydroxide and/or hydrochloric acid.
  • the bulk product is then subjected to steam sterilization and packaged in either single dose or multiple dose containers according to methods known in the art. If such compositions contain one or more actives, the active is generally incorporated into the compositions prior to addition of the polymers.
  • Table I illustrates some samples which were prepared for the purpose of comparing viscosity.
  • the samples were prepared by dissolving the cellulosic polymer and/or carboxy vinyl polymer in purified water followed by adjustment of pH using sodium hydroxide and/or hydrochloric acid. Sample size was adjusted to final volume and subjected to steam sterilization.
  • Example B As best seen in Figure 1, 0.5% hydroxypropyl methyl cellulose (Sample B) generates a viscosity of only 4 cps. Likewise, 0.175% carbomer 934P alone (Sample F) has a viscosity between 1330 - 1460 cps. On the other hand, when these components are combined (Sample L) the viscosity is 4860 cps. This clearly indicates the potentiation of viscosity.
  • Table III represents some preferred embodiments of compositions of the present invention.
  • Formulations 1 and 2 are the most preferred and their preparation procedures are detailed below. Preparation of the other formulations are analogous to the procedures of Formulation 1 (with preservative) or Formulation 2 (preservative-free).
  • Mannitol was mixed with 60% of the total water volume until dissolved (about 2 minutes), then Carbomer 934P was slowly added and the mixture stirred until the slurry was uniform and had no visible lumps.
  • the pH was adjusted to 7.3-7.5.
  • a second mixture was made by dispersing the HPMC into hot (65-90°C) purified water (approximately 25% of the total water volume). The two mixtures were combined, mixed for about 15 minutes (min) and the pH adjusted if necessary. Purified water was then added to bring the total volume to 100% and the mixture stirred to obtain homogeneity (a minimum of 10 min). Sterilization and packaging were accomplished by methods known to those skilled in the art.
  • Formulation 2 was prepared according to the procedure of Formulation 1, except that benzalkonium chloride (10% solution in water) was added before the first pH adjustment (after the addition of mannitol and carbomer 934P, but before the addition of HPMC).

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  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Des combinaisons d'au moins un polymère cellulosique et d'au moins un polymère de vinyle carboxy présentent une viscosité élevée surprenante. Des compositions contenant ces combinaisons polymères ont une quantité d'applications, telles que dans les produits pharmaceutiques, et notamment dans le domaine de l'ophtalmie. Des compositions ophtalmiques à usage local contenant ces combinaisons polymères sont proposées en vue de faire disparaître les symptômes du syndrome de l'÷il sec.
PCT/US1993/001565 1992-03-02 1993-02-22 Combinaisons de polymeres cellulosiques et de polymeres de vinyle carboxy et leur utilisation dans des compositions pharmaceutiques WO1993017664A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37287/93A AU3728793A (en) 1992-03-02 1993-02-22 Combinations of cellulosic polymers and carboxy vinyl polymers and their use in pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84426992A 1992-03-02 1992-03-02
US07/844,269 1992-03-02

Publications (1)

Publication Number Publication Date
WO1993017664A1 true WO1993017664A1 (fr) 1993-09-16

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Application Number Title Priority Date Filing Date
PCT/US1993/001565 WO1993017664A1 (fr) 1992-03-02 1993-02-22 Combinaisons de polymeres cellulosiques et de polymeres de vinyle carboxy et leur utilisation dans des compositions pharmaceutiques

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WO (1) WO1993017664A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4225489A1 (de) * 1992-07-30 1994-02-03 Michael Prof Dr Rer Na Dittgen Verfahren zur Herstellung bioadhäsiver Augentropfen
WO1995000143A1 (fr) * 1993-06-24 1995-01-05 Leiras Oy Composition a usage ophtalmique
WO1997005880A1 (fr) * 1995-08-03 1997-02-20 Bayvit, S.A. Compositions aqueuses contenant du ciprofloxacine et utilisation et procede correspondants
DE19744113A1 (de) * 1997-10-06 1999-04-15 Mann Gerhard Chem Pharm Fab Dexamethason-Gel
WO1999022713A1 (fr) * 1997-11-04 1999-05-14 Insite Vision Incorporated Compositions ophtalmiques a liberation prolongee contenant des medicaments solubles dans l'eau
WO2000025765A3 (fr) * 1998-10-30 2000-08-03 Bayer Ag Formulation aqueuse d'un medicament d'administration orale
US6379692B1 (en) 1997-09-03 2002-04-30 Chauvin Pharmaceuticals Limited Pharmaceutical composition comprising a suspension for the active ingredient
WO2003072081A1 (fr) * 2002-02-22 2003-09-04 Pharmacia Corporation Formulation ophtalmique contenant un systeme de gomme
WO2004058273A1 (fr) * 2002-12-24 2004-07-15 Alcon, Inc. Utilisation du rimexolone dans le traitement de l'oeil sec
WO2004112750A3 (fr) * 2003-06-13 2005-08-18 Alcon Inc Compositions ophtalmologiques contenant une association synergique de trois polymeres
WO2005014046A3 (fr) * 2003-08-07 2006-06-01 Allergan Inc Compositions d'administration d'agents therapeutiques dans les yeux et leurs methodes d'elaboration et d'utilisation
JP2007500244A (ja) * 2003-06-13 2007-01-11 アルコン，インコーポレイテッド ２種のポリマーの相乗作用的組み合わせを含む眼科用組成物
CN100360132C (zh) * 2003-08-25 2008-01-09 成都三明药物研究所 一种用于眼部的抗病毒药物组合物及其制备方法
US7842714B2 (en) 2008-03-03 2010-11-30 Allergan, Inc. Ketorolac tromethamine compositions for treating ocular pain
US7914803B2 (en) 2003-06-13 2011-03-29 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
US7947295B2 (en) 2003-06-13 2011-05-24 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of two polymers
US9192571B2 (en) 2008-03-03 2015-11-24 Allergan, Inc. Ketorolac tromethamine compositions for treating or preventing ocular pain
US20220160674A1 (en) * 2020-05-18 2022-05-26 Vyluma Inc. Low-Dose Carbachol Compositions And Methods For Treatment Of Night Vision Disturbance

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920810A (en) * 1974-04-23 1975-11-18 Burton Parsons And Company Inc Polyacrylamide containing ophthalmic solutions
FR2333500A1 (fr) * 1975-12-04 1977-07-01 Alcon Lab Inc Solution ophtalmique a base de polysaccharide, de chlorure de benzalkonium et d'eau
DE3440352A1 (de) * 1984-11-05 1986-05-07 Dr. Thilo & Co GmbH, 8029 Sauerlach Dry-eye-packung
EP0286791A1 (fr) * 1987-03-02 1988-10-19 American Cyanamid Company Gel d'acétazolamide
WO1991019481A1 (fr) * 1990-06-15 1991-12-26 Allergan, Inc. Compositions de gelification reversible et modes d'emploi

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920810A (en) * 1974-04-23 1975-11-18 Burton Parsons And Company Inc Polyacrylamide containing ophthalmic solutions
FR2333500A1 (fr) * 1975-12-04 1977-07-01 Alcon Lab Inc Solution ophtalmique a base de polysaccharide, de chlorure de benzalkonium et d'eau
DE3440352A1 (de) * 1984-11-05 1986-05-07 Dr. Thilo & Co GmbH, 8029 Sauerlach Dry-eye-packung
EP0286791A1 (fr) * 1987-03-02 1988-10-19 American Cyanamid Company Gel d'acétazolamide
WO1991019481A1 (fr) * 1990-06-15 1991-12-26 Allergan, Inc. Compositions de gelification reversible et modes d'emploi

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4225489A1 (de) * 1992-07-30 1994-02-03 Michael Prof Dr Rer Na Dittgen Verfahren zur Herstellung bioadhäsiver Augentropfen
WO1995000143A1 (fr) * 1993-06-24 1995-01-05 Leiras Oy Composition a usage ophtalmique
WO1997005880A1 (fr) * 1995-08-03 1997-02-20 Bayvit, S.A. Compositions aqueuses contenant du ciprofloxacine et utilisation et procede correspondants
ES2106680A1 (es) * 1995-08-03 1997-11-01 Vita Invest Sa Composiciones acuosas conteniendo ciprofloxacino y utilizacion y procedimiento correspondiente.
US5786363A (en) * 1995-08-03 1998-07-28 Bayvit, S.A. Aqueous compositions containing ciprofloxacine, and related use
US6379692B1 (en) 1997-09-03 2002-04-30 Chauvin Pharmaceuticals Limited Pharmaceutical composition comprising a suspension for the active ingredient
DE19744113A1 (de) * 1997-10-06 1999-04-15 Mann Gerhard Chem Pharm Fab Dexamethason-Gel
WO1999017780A1 (fr) * 1997-10-06 1999-04-15 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Gel de dexamethasone
WO1999022713A1 (fr) * 1997-11-04 1999-05-14 Insite Vision Incorporated Compositions ophtalmiques a liberation prolongee contenant des medicaments solubles dans l'eau
US6159458A (en) * 1997-11-04 2000-12-12 Insite Vision Sustained release ophthalmic compositions containing water soluble medicaments
AU745339B2 (en) * 1997-11-04 2002-03-21 Insite Vision Incorporated Sustained release ophthalmic compositions containing water soluble medicaments
WO2000025765A3 (fr) * 1998-10-30 2000-08-03 Bayer Ag Formulation aqueuse d'un medicament d'administration orale
WO2003072081A1 (fr) * 2002-02-22 2003-09-04 Pharmacia Corporation Formulation ophtalmique contenant un systeme de gomme
US7128928B2 (en) 2002-02-22 2006-10-31 Pharmacia Corporation Ophthalmic formulation with novel gum composition
WO2004058273A1 (fr) * 2002-12-24 2004-07-15 Alcon, Inc. Utilisation du rimexolone dans le traitement de l'oeil sec
AU2003299696B2 (en) * 2002-12-24 2009-08-13 Alcon, Inc. Use of rimexolone in the treatment of dry eye
JP2006513213A (ja) * 2002-12-24 2006-04-20 アルコン、インコーポレイテッド ドライアイの治療におけるリメキソロンの使用
US7244440B2 (en) 2003-06-13 2007-07-17 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
JP4860475B2 (ja) * 2003-06-13 2012-01-25 アルコン，インコーポレイテッド ２種のポリマーの相乗作用的組み合わせを含む眼科用組成物
JP2007500244A (ja) * 2003-06-13 2007-01-11 アルコン，インコーポレイテッド ２種のポリマーの相乗作用的組み合わせを含む眼科用組成物
US20130039879A1 (en) * 2003-06-13 2013-02-14 Novartis Ag Ophthalmic Compositions Containing A Synergistic Combination Of Two Polymers
US7306802B2 (en) 2003-06-13 2007-12-11 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
US8313754B2 (en) * 2003-06-13 2012-11-20 Novartis Ag Ophthalmic compositions containing a synergistic combination of two polymers
US7329411B2 (en) 2003-06-13 2008-02-12 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
WO2004112750A3 (fr) * 2003-06-13 2005-08-18 Alcon Inc Compositions ophtalmologiques contenant une association synergique de trois polymeres
AU2004249136B2 (en) * 2003-06-13 2009-09-03 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
JP2006528990A (ja) * 2003-06-13 2006-12-28 アルコン，インコーポレイテッド ３種のポリマーの相乗作用的組み合わせを含む眼科用組成物
US7618620B2 (en) 2003-06-13 2009-11-17 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
AU2004249137B2 (en) * 2003-06-13 2010-03-11 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of two polymers
US7709012B2 (en) 2003-06-13 2010-05-04 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of two polymers
US7947295B2 (en) 2003-06-13 2011-05-24 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of two polymers
US7914803B2 (en) 2003-06-13 2011-03-29 Alcon, Inc. Ophthalmic compositions containing a synergistic combination of three polymers
JP2011026355A (ja) * 2003-06-13 2011-02-10 Alcon Inc ３種のポリマーの相乗作用的組み合わせを含む眼科用組成物
JP4657213B2 (ja) * 2003-06-13 2011-03-23 アルコン，インコーポレイテッド ３種のポリマーの相乗作用的組み合わせを含む眼科用組成物
AU2004263149B2 (en) * 2003-08-07 2010-08-19 Allergan, Inc. Compositions for delivery of therapeutics into the eyes and methods for making and using same
EP2113246A1 (fr) * 2003-08-07 2009-11-04 Allergan, Inc. Compositions d'administration d'agents therapeutiques dans les yeux et leurs methodes d'elaboration et d'utilisation
WO2005014046A3 (fr) * 2003-08-07 2006-06-01 Allergan Inc Compositions d'administration d'agents therapeutiques dans les yeux et leurs methodes d'elaboration et d'utilisation
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
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
CN100360132C (zh) * 2003-08-25 2008-01-09 成都三明药物研究所 一种用于眼部的抗病毒药物组合物及其制备方法
US7842714B2 (en) 2008-03-03 2010-11-30 Allergan, Inc. Ketorolac tromethamine compositions for treating ocular pain
US9192571B2 (en) 2008-03-03 2015-11-24 Allergan, Inc. Ketorolac tromethamine compositions for treating or preventing ocular pain
US20220160674A1 (en) * 2020-05-18 2022-05-26 Vyluma Inc. Low-Dose Carbachol Compositions And Methods For Treatment Of Night Vision Disturbance

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