WO1991001714A1 - Ophthalmic composition - Google Patents
Ophthalmic composition Download PDFInfo
- 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
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 .
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- 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)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A solid ophthalmic composition is described comprising a water soluble film containing clonidine or a pharmacologically acceptable acid addition salt thereof useful in controlling intraocular pressure associated with glaucoma and other ophthalmic conditions. The compositions described do not have the undesirable systemic side effect of lowering blood pressure usually associated with aqueous solutions of the same ophthalmic agents. A method of use of such solid ophthalmic compositions is also described.
Description
OPHTHALMIC COMPOSITION
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. However, 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. However, it has now been discovered that it is possible to provide an effective ophthalmic composition of a cephalosporin for treating bacterial infections in the eye.
The present invention provides a solid
ophthalmic composition which comprises a water soluble film which contains therein a cephalosporin.
Most aptly the composition is a unit dose
composition. Such unit dose compositions dissolve when placed on the eye and release the cephalosporin which is present for sufficient time to exert its
antibacterial effect. Generally such 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,
Ceftazidime, Cefamandole, Cefotiam, Ceftriaxone,
Cefodizime, Cefpirome, Cefazolin, Cefixime,
Ceftizoxime, 1-carba-1 dethia Cephalosporins,
pharmaceutically acceptable salts and prodrugs of
Cephalosporins (for example Cefetamet pivoxyl,
Cef-Axetil) and cefomycins for example cefoxitin.
The 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. in the format described in UK Patent No 2097680B 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 550μg, suitably not more than 500μg and preferably not more than 475μg. Aptly the weight of the soluble matrix element will be at least 350μg, suitably at least 400μg and preferably at least 450μg, for example 455μg, 460μg or 465μg.
Suitably the unit does of cephalosporin contained in the format described in UK Patent No 2097680B will generally be not more than 400μg or 85% w/w of the water soluble matrix, suitably not more than 350μg or 75% w/w and preferably not more than 300μg or 64% w/w. Aptly the unit dose of cephalosporin will be at least 10μg or 2.15% w/w, suitably at least 50μg or 10.7% w/w and preferably at least 100μg or 21.5%. Most
preferably the unit dose of cephalosporin will be at least 150μg or 32.2% w/w and not more than 275μg or 59% w/w for example 200μg or 43%, 225μg or 48% or 250μg 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.
The stability of cephalosporins contained in water soluble films as described above has been found to be considerably greater than the stability of aqueous solutions of cephalosporins. For example the percentage loss of 100μg 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. The
degradation of an aqueous solution of cephalosporin at pH7.5 at 37°C is 55% in 60 hours (J. Pharm. Sci. 1984, 73, 611). The present invention therefore offers considerable commercial advantages compared to
solutions of the same ophthalmic agent.
The 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.
The invention will now be illustrated by the following examples.
Example 1
To prepare a composition of this invention in the format described in United Kingdom Patent No. 2097680B the following casting solutions were prepared.
Casting Solution A.
Polyvinyl alcohol 10.0% w/w
Distilled water to 100.0% w/w
Casting Solution B.
Cefotaxime 4% w/w
Polyvinyl alcohol 15% w/w
Distilled water to 100% w/w
Casting Solution C.
Polyvinyl alcohol 35% w/w
Distilled water to 100% w/w
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
overnight for de-aeration to take place.
Casting solution A is cast onto a silicone coated release paper using a conventional stainless steel spreading box with a gap of 100μm. 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 200μm and the box is split into two channels using an aluminium divider 1mm thick which thereby
provides 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 γ-irradiation at 2.5 Mrad.
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
handle. The soluble film portion readily dissolves in contact with the moisture in the eye to release the cephalosporin.
Example 2.
A film containing the following components:
Cefotaxime 4% w/w
Polyvinyl alcohol 15% w/w
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.
% w/w Cefotaxime ( % loss )
Time
5°C 20°C
Initial 21.3 21.3
1 month 20.5 (3.8) 20.0 (6.1)
3 months 20.4 (4.2) 19.9 (6.6)
9 months 20.0 (6.1) -
In use 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 3
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 4
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 200μg or 43% w/w.
Example 5
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 75μg or 16.1% w/w.
Claims
1. A solid ophthalmic composition which comprises a water soluble film which contains a cephalosporin.
2. An ophthalmic composition according to Claim 1 in which the cephalosporin is present in a unit dose from 0.5 to 2.5mg.
3. An ophthalmic composition according to Claims 1 or 2 in which the water soluble film is attached to a disposable applicator in the form of an elongate strip by a water soluble membrane such that in use the water soluble film will be detached from the applicator and will dissolve thereby delivering the cephalosporin to the eye.
4. An ophthalmic composition according to Claim 3 in which the water soluble film comprises a non-toxic water soluble polymer.
5. An ophthalmic composition according to Claim 4 in which the non-toxic water soluble polymer is polyvinyl alcohol.
6. An ophthalmic composition according to any of the preceeding claims in which the cephalosporin is present in the water soluble film at a weight of at least 10μg .
7. An ophthalmic composition according to any of the preceeding claims in which the cephalosporin is present in the water soluble film at a weight of not more than 400μg.
8. An ophthalmic composition according to any of the preceeding claims in which the cephalosporin is present in the water soluble film at a weight of at least 2.15% w/w.
9. An ophthalmic composition according to any of the preceeding claims in which the cephalosporin is present in the water soluble film at a weight of not more than 85% w/w.
10. A sterilised ophthalmic composition according to any of the preceeding claims.
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 (en) | 1991-02-21 |
Family
ID=10660733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1990/001144 Ceased WO1991001714A1 (en) | 1989-07-27 | 1990-07-25 | Ophthalmic composition |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6069890A (en) |
| GB (1) | GB8917216D0 (en) |
| WO (1) | WO1991001714A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008085913A1 (en) * | 2007-01-04 | 2008-07-17 | Rib-X Pharmaceuticals, Inc. | Methods for treating, preventing, or reducing the risk of opthalmic, otic, and nasal infections |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2905033A1 (en) * | 1979-02-09 | 1980-08-28 | Thilo & Co Gmbh Dr | Prolonged release medicament carrier esp. for ocular use - contg. physico-chemically modified polyvinyl alcohol, water, softening agents, and agents for isotonic regulation |
| 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 (en) * | 1984-06-25 | 1985-12-27 | Ausonia Farma Srl | Pharmaceutical dosage forms in gel form, for the topical application of active principles |
-
1989
- 1989-07-27 GB GB898917216A patent/GB8917216D0/en active Pending
-
1990
- 1990-07-25 WO PCT/GB1990/001144 patent/WO1991001714A1/en not_active Ceased
- 1990-07-25 AU AU60698/90A patent/AU6069890A/en not_active Abandoned
Patent Citations (4)
| 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 (en) * | 1979-02-09 | 1980-08-28 | Thilo & Co Gmbh Dr | Prolonged release medicament carrier esp. for ocular use - contg. physico-chemically modified polyvinyl alcohol, water, softening agents, and agents for isotonic regulation |
| GB2097680A (en) * | 1981-04-30 | 1982-11-10 | Smith & Nephew Associated Cie | Medicament applicator |
| FR2566270A1 (en) * | 1984-06-25 | 1985-12-27 | Ausonia Farma Srl | Pharmaceutical dosage forms in gel form, for the topical application of active principles |
Non-Patent Citations (1)
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008085913A1 (en) * | 2007-01-04 | 2008-07-17 | Rib-X Pharmaceuticals, Inc. | Methods for treating, preventing, or reducing the risk of opthalmic, otic, and nasal infections |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8917216D0 (en) | 1989-09-13 |
| AU6069890A (en) | 1991-03-11 |
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