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WO1991001714A1 - Composition a usage ophtalmique - Google Patents

Composition a usage ophtalmique Download PDF

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Publication number
WO1991001714A1
WO1991001714A1 PCT/GB1990/001144 GB9001144W WO9101714A1 WO 1991001714 A1 WO1991001714 A1 WO 1991001714A1 GB 9001144 W GB9001144 W GB 9001144W WO 9101714 A1 WO9101714 A1 WO 9101714A1
Authority
WO
WIPO (PCT)
Prior art keywords
water soluble
cephalosporin
ophthalmic composition
composition according
soluble film
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB1990/001144
Other languages
English (en)
Inventor
Peter Hubert Bentley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith and Nephew PLC
Original Assignee
Smith and Nephew PLC
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 Smith and Nephew PLC filed Critical Smith and Nephew PLC
Publication of WO1991001714A1 publication Critical patent/WO1991001714A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0051—Ocular inserts, ocular implants
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine

Definitions

  • the present invention relates to a solid
  • ophthalmic composition containing a cephalosporin useful for treating bacterial infections of the eye.
  • Cephalosporins which term herein include
  • cephamycins are widely used for the treatment of systemic infections.
  • their use for treatment of infections in the eye by topical administration has been limited because of chemical instability in aqueous solutions (see for example European Patent No. 091313) and also because of their poor solubility in lipid which makes the lipophilic corneal epithelium an effective barrier impeding their absorption.
  • the present invention provides a solid
  • ophthalmic composition which comprises a water soluble film which contains therein a cephalosporin.
  • composition is a unit dose
  • compositions dissolve when placed on the eye and release the cephalosporin which is present for sufficient time to exert its
  • unit dose forms may contain from 0.5 to 5mg of cephalosporin. Aptly the unit dose form will contain at least 0.75mg of
  • cephalosporin and preferably at least 1mg of
  • cephalosporin Most aptly the unit dose will contain not more than 2.5mg of cephalosporin and preferably not more than 2mg of cephalosporin.
  • Suitable cephalosporins for use in this invention include (but are not limited to) Cefotaxime,
  • Cefodizime Cefpirome, Cefazolin, Cefixime,
  • Cephalosporins for example Cefetamet pivoxyl
  • Cef-Axetil and cefomycins for example cefoxitin.
  • compositions of this invention are most suitably provided in the format described in United Kingdom Patent No. 2097680B which is incorporated herein by cross-reference.
  • the composition of this invention is contained in the soluble matrix element.
  • the weight of the soluble matrix element will generally be not more than 550 ⁇ g, suitably not more than 500 ⁇ g and preferably not more than 475 ⁇ g.
  • the weight of the soluble matrix element will be at least 350 ⁇ g, suitably at least 400 ⁇ g and preferably at least 450 ⁇ g, for example 455 ⁇ g, 460 ⁇ g or 465 ⁇ g.
  • the unit does of cephalosporin contained in the format described in UK Patent No 2097680B will generally be not more than 400 ⁇ g or 85% w / w of the water soluble matrix, suitably not more than 350 ⁇ g or 75% w / w and preferably not more than 300 ⁇ g or 64% w / w .
  • the unit dose of cephalosporin will be at least 10 ⁇ g or 2.15% w / w , suitably at least 50 ⁇ g or 10.7% w / w and preferably at least 100 ⁇ g or 21.5%.
  • Most of cephalosporin contained in the format described in UK Patent No 2097680B will generally be not more than 400 ⁇ g or 85% w / w of the water soluble matrix, suitably not more than 350 ⁇ g or 75% w / w and preferably not more than 300 ⁇ g or 64% w / w .
  • the unit dose of cephalosporin will be at least 10 ⁇ g or 2.15% w
  • the unit dose of cephalosporin will be at least 150 ⁇ g or 32.2% w / w and not more than 275 ⁇ g or 59% w/w for example 200 ⁇ g or 43%, 225 ⁇ g or 48% or 250 ⁇ g or 53.6% w / w .
  • the film containing the cephalosporin is most aptly cast from aqueous solution and at ambient temperature.
  • the film may be made from any non-toxic water soluble polymer. Suitable polymers include cellulose derivatives, polyacrylates, polyacrylamides, polyvinyl alcohol and polyvinyl pyrrolidone. Preferred water soluble polymers are polyvinyl alcohols.
  • cephalosporins contained in water soluble films as described above has been found to be considerably greater than the stability of aqueous solutions of cephalosporins.
  • percentage loss of 100 ⁇ g cefotaxime from a PVA film has been found to be approximately 7% in 3 months at 20°C and approximately 6% in 9 months at 5°C.
  • compositions according to this invention are most aptly provided sterile sealed within an openable pouch or package.
  • the compositions may be rendered sterile by gamma irradiation.
  • Solutions of polyvinyl alcohol are prepared by dispersing the granules of the prepolymer in cold distilled water with stirring. This dispersion is heated to a temperature of 65 to 70°C on a steam bath until all the granules have dissolved. The other components are added and finally the weight of the solution is adjusted to 100g by addition of distilled water. The solutions are then allowed to stand
  • Casting solution A is cast onto a silicone coated release paper using a conventional stainless steel spreading box with a gap of 100 ⁇ m. The film is dried in a hot air over at 65 to 70°C, for 4 to 5 minutes.
  • Casting solution A is spread simultaneously on top of the film cast from Solutions B and C.
  • the spreading box used is as before except that the gap width is 200 ⁇ m and the box is split into two channels using an aluminium divider 1mm thick which thereby
  • the membrane which allows the soluble film portion formed by layers of casting solutions A and B to separate from the handle portion of the device.
  • the spread films are dried in a hot air oven as before.
  • a piece of adhesive card may be attached to cast film C to provide stiffness to the handle of the device.
  • the multilaminate sheet is then cut to the appropriate size to provide soluble film portions containing the cephalosporin which are for example 6, 8 or 10mm long and 6mm wide.
  • the applicators are dried overnight before being packed individually into aluminium foil moisture proof pouches.
  • the packaged applicators may be sterilised by exposure to ⁇ -irradiation at 2.5 Mrad.
  • a sterile applicator In use a sterile applicator is removed from its package, and the soluble film portion placed against the moist surface of the eye. The thin membrane portion dissolves separating the soluble film portion from the
  • the soluble film portion readily dissolves in contact with the moisture in the eye to release the cephalosporin.
  • Distilled water to 100% w/w was prepared by making and casting the casting solution B described in Example 1 onto a silicone release paper and drying either in the air or in a hot air oven. The film was cut into appropriate size pieces and packaged.
  • the resultant films were aged at 5°C and 20°C. Content of drug was determined by HPLC. The following results were obtained over 9 months.
  • the sterile film is removed from its package and applied to the moist surface of the eye.
  • the film dissolves so releasing the cephalosporin.
  • Example 1 was repeated but Casting Solution A contained polyvinyl alcohol @ 8% w / w and Casting
  • Solution C contained polyvinyl alcohol @ 20% w / w .
  • the multilaminate sheet was cut to provide soluble film portions containing the cophalosporin which were 4.5mm long and 5mm wide.
  • Example 3 was repeated but Casting Solution B contained 11.28% w / w cefamandol in 15% PVA made up to 100% in distilled water. This is equivalent to a unit dose of 200 ⁇ g or 43% w / w .
  • Example 3 was repeated but Casting Solution B contained 2.88% w / w cefamandol in 15% PVA made up to 100% in distilled water. This is equivalent to a unit dose of 75 ⁇ g or 16.1% w / w .

Landscapes

  • Health & Medical Sciences (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)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

On décrit une composition solide à usage ophtalmique, comprenant un film soluble dans l'eau qui contient de la clonidine ou un sel d'addition acide acceptable en pharmacologie de celle-ci, utile à la réduction de la pression intra-oculaire associée au glaucome et à d'autres pathologies ophtalmiques. Les compositions décrites n'ont pas l'effet secondaire général indésirable de faire baisser la pression sanguine, lequel effet caractérise normalement les solutions aqueuses des mêmes agents à usage ophtalmique. On décrit également un procédé d'utilisation de tels compositions solides à usage ophtalmique.
PCT/GB1990/001144 1989-07-27 1990-07-25 Composition a usage ophtalmique Ceased WO1991001714A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8917216.7 1989-07-27
GB898917216A GB8917216D0 (en) 1989-07-27 1989-07-27 Ophthalmic composition

Publications (1)

Publication Number Publication Date
WO1991001714A1 true WO1991001714A1 (fr) 1991-02-21

Family

ID=10660733

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1990/001144 Ceased WO1991001714A1 (fr) 1989-07-27 1990-07-25 Composition a usage ophtalmique

Country Status (3)

Country Link
AU (1) AU6069890A (fr)
GB (1) GB8917216D0 (fr)
WO (1) WO1991001714A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008085913A1 (fr) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Procédés pour traiter, prévenir, ou réduire le risque d'infections ophtalmiques, otiques, et nasales

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2905033A1 (de) * 1979-02-09 1980-08-28 Thilo & Co Gmbh Dr Wasserloeslicher fester medikamententraeger
US4343787A (en) * 1975-07-29 1982-08-10 Merck & Co., Inc. Shaped ophthalmic inserts for treating dry eye syndrome
GB2097680A (en) * 1981-04-30 1982-11-10 Smith & Nephew Associated Cie Medicament applicator
FR2566270A1 (fr) * 1984-06-25 1985-12-27 Ausonia Farma Srl Formes pharmaceutiques sous forme de gel, pour l'application topique de principes actifs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4343787A (en) * 1975-07-29 1982-08-10 Merck & Co., Inc. Shaped ophthalmic inserts for treating dry eye syndrome
DE2905033A1 (de) * 1979-02-09 1980-08-28 Thilo & Co Gmbh Dr Wasserloeslicher fester medikamententraeger
GB2097680A (en) * 1981-04-30 1982-11-10 Smith & Nephew Associated Cie Medicament applicator
FR2566270A1 (fr) * 1984-06-25 1985-12-27 Ausonia Farma Srl Formes pharmaceutiques sous forme de gel, pour l'application topique de principes actifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STN File Server & File Biosis, (Karlsruhe), AN No. 76:235130, G.L. KHROMOV et al.: "Experimental Study of Polymeric Medicinal *Eye*, *Films* with Kanamycin part 3", & DN No. BA62 : 65130 see the Abstract *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008085913A1 (fr) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Procédés pour traiter, prévenir, ou réduire le risque d'infections ophtalmiques, otiques, et nasales

Also Published As

Publication number Publication date
GB8917216D0 (en) 1989-09-13
AU6069890A (en) 1991-03-11

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