WO1997021441A1

WO1997021441A1 - Ophthalmic composition comprising polyoxyethylene-polyoxypropylene polymers

Info

Publication number: WO1997021441A1
Application number: PCT/US1996/019830
Authority: WO
Inventors: Larry R. Brown
Original assignee: Mdv Technologies, Inc.
Priority date: 1995-12-11
Filing date: 1996-12-11
Publication date: 1997-06-19
Also published as: AU1332997A

Abstract

A long lasting treatment for dry eye syndrome which imparts superior water retention and comfort to the eye for time periods greater than one hour has been developed based on polyoxyethylene-polyoxypropylene block copolymers (referred to herein as poloxamers). The compositions can be used for drug delivery. The preferred composition is isotomic. The polymer is added to an isotomic aqueous solution to form a concentration between 1 % and 35 %, most preferably 16 % to 25 %. The preferred polyoxyethylene-polyoxypropylene block copolymers have a sol-gel transition dependent on the concentration of the polymer and transform to a solid, clear gel having excellent optical properties at a temperature of 25 °C, and significantly increase in viscosity at the temperature of the eye.

Description

OPHTHALMIC COMPOSITION COMPRISING POLYOXYETHYLENE-POLYOXYPROPYLENE POLYMERS

Background of the Invention

The present invention is generally directed to ophthalmic compositions as wetting agents and to reduce irritation, and more 5 particularly is osmotically balanced polyoxyethylene -polypropylene block copolymer solutions and their use in alleviating eye irritation and dryness.

Eyes are irritated by many environmental factors, including dust, allergens, strain, sunlight, and wind. The use of contact lens, whether "soft" or "rigid", causes drying of the eye, oxygen deprivation, especially

10 at the edge of the contact lens, and irritation. "Dry eye" is a condition caused by lack of production of adequate tears, which can be due to an autoimmune disorder referred to as Sjogrens syndrome, disease or other disorder of the lacrimal glands, long term use of contact lens or association with other eye irritants, or as a result of some unknown

15 etiology.

Currently, the most common treatment is the use of artificial "tears", osmotically balanced, hydrophilic solutions having physiological pH, which are instilled into the eyes on a frequent basis, sometimes as often as every fifteen to thirty minutes. Although most drugs are

20 ineffective in treatment of dry eye, it has been discovered that cyclosporin, administered in a vegetable oil base, in a concentration of between 0.2 and 2% cyclosporin, induces tearing for an extended period of time. Cyclosporin is a strong immunosuppressant, however, and may have long term side effects.

25 Many compositions have been tried in an effort to prolong or increase the amount of relief provided by these solutions. For example, U.S. Patent No. 5, 185,152 to Peyman describes the use of drugs incorporated into biodegradable polymeric microspheres which are suspended in a hydrophilic polymer solution, such as collagen or

30 polysaccharides. U.S. Patent Nos. 4,100,271 and 4,188,373 to

Krezanoski describe the use of polyoxyethylene -polyoxypropylene block copolymers having gel transition temperatures between 25 and 40 °C to deliver drugs to the eye. The gels include salts to adjust osmotic pressure, preservatives to prevent bacterial growth, and buffering agents.

U.S. Patent No. 5,300,295 to Viegas, et al. , also describes the use of polyoxyethylene-polyoxypropylene block copolymers for controlled drug delivery to the eye. Viegas, et al., control the osmolarity of their compositions based on their discovery that the polymers do not contribute to the osmolarity of the compositions.

It is desirable to have compositions for use as wetting agents which are available over-the-counter and therefore cannot include prescription drugs, for use in alleviating the symptoms of dry eye, as well as in decreasing irritation of contact lens and other ophthalmic devices.

Since many people plagued with dry eye or long term contact lens use are highly sensitive to preservatives, especially chlorohexidine and thimerosol, it is also very desirable to have solutions which do not require the use of preservatives.

It is therefore an object of the present invention to provide ophthalmic compositions useful as wetting agents and to sooth irritation of the corneal surface. It is a further object of the present invention to provide a wetting solution which can be used for drug delivery and which provides relief over an extended period of time.

It is a still further object of the present invention to provide a wetting solution which does not require a preservative.

Summary of the Invention

A long lasting treatment for dry eye syndrome which imparts superior water retention and comfort to the eye for time periods greater than one hour has been developed based on polyoxyethylene- polyoxypropylene block copolymers (referred to herein as poloxamers). The compositions can be used for drug delivery. The preferred composition is isotonic. The polymer is added to an isotonic aqueous solution to form a concentration between 1 % and 35%, most preferably 16% to 25% . The preferred polyoxyethylene-polyoxypropylene block copolymers have a sol-gel transition dependent on the concentration of the polymer and transform to a solid, clear gel having excellent optical properties at a temperature of 25 °C, and significantly increase in viscosity at the temperature of the eye.

Brief Description of the Drawings

Figure 1 is a graph of the presence of sodium fluorescein over time for eyes treated with phosphate buffered saline, 16% poloxamer, and 25% poloxamer.

Detailed Description of the Invention Polymer Solutions

U.S. Patent No. 4,810,503 describes polyoxyalkylene polymers, especially polyoxyethylene-polyoxypropylene block copolymers, which form gels at low concentrations in water. The copolymers are prepared by capping conventional polyether polyols with an alpha-olefin epoxide having an average of about 20 to about 45 carbon atoms, or mixtures. Aqueous solutions of these copolymers gel in combination with surfactants, which can be ionic or non-ionic. The combination of the capped polyether polyols and the surfactants provide aqueous solutions of these copolymers gel in combination with surfactants, which can be ionic or nonionic. The combination of the capped polyether polyols and the surfactants provide aqueous gels at low concentrations of the capped polyol and surfactant, which generally do not exceed 10% by weight total.

A typical copolymer polyether polyol is prepared by preparing block or heteric intermediate polymers of ethylene oxide and at least one lower alkylene oxide having three to four carbon atoms as intermediates. These are then capped with the alpha-olefin epoxide to prepare the polymers. Ethylene oxide homopolymers capped with the alpha-olefin oxides are also useful as intermediate. The heteric copolymer intermediate is prepared by mixing ethylene oxide and at least one lower alkylene oxide having three to four carbon atoms with a low molecular weight active hydrogen-containing compound initiator having at least two active hydrogens and preferably 2 to 6 active hydrogen atoms such as a polyhedric alcohol, containing from 2 to 10 carbon atoms and from 2 to 6 hydroxyl groups, heating the mixture to a temperature in the range of from about 50°C to 150°C, preferably from 80°C to 130°C, under an inert gas pressure preferably from about 30 psig to 90 psig. A block copolymer intermediate is prepared by reacting either the ethylene oxide or said alkylene oxide having 3 to 4 carbon atoms with said active hydrogen-containing compound followed by reaction with the other alkylene oxide.

The ethylene oxide and the alkylene oxides having from 3 to 4 carbon atoms are used in said intermediates in amounts so that the resulting polyether product will contain at least 10 percent by weight, preferably about 70 percent to about 90 percent by weight, ethylene oxide residue. The ethylene oxide homopolymer intermediate is prepared by reacting ethylene oxide with said active hydrogen-containing compound. The reaction conditions for preparing the block copolymer and ethylene oxide homopolymer intermediates are similar to those for the heteric copolymer intermediate. The temperature and pressure are maintained in the above ranges for a period of about one hour to ten hours, preferably one to three hours. The alpha-olefin oxides which are utilized to modify the conventional polyether intermediate of the prior art are those oxides and the commercially available mixtures thereof generally containing an average of about 20 to 45, preferably about 20 to 30, carbon atoms. The amount of alpha-olefin required to obtain the more efficient capped polyethers is generally about 0.3 to 10 percent, preferably about 4 to 8 percent, of the total weight of the polyethers. Since the preparation of heteric and block copolymers of alkylene oxides and ethylene oxide homopolymers are well known in the art, further description of the preparation of said copolymers is unnecessary. Further details of the preparation of heteric copolymers of lower alkylene oxide can be obtained in U.S. Pat. No. 3,829,506. Further information on the preparation of block copolymers of lower alkylene oxides can be obtained in U.S. Pat. Nos. 3,535,307; 3,036, 118; 2,979,578; 2,677,700; and 2,675,619.

The surfactants may be ionic or non-ionic and many surfactants and types of surfactants may be employed. While all surfactants may not be effective in the preparation of the isotonic gels of the instant invention, the fact that many are effective makes it a simple matter for one skilled in the art to select such surfactant with a minimum of trial and error.

The amounts of capped polyether copolymer and surfactant may be as little as 1.0 percent by weight or less of each depending on the type and amount of the other component. There appears to be no maximum amount of either component than that dictated by economic considerations. However, the total amount of capped copolymer and surfactant would generally not exceed 10 percent by weight. Poloxamers are commercially available from BASF and from

Wyandotte Chemical Corporation as "PLURONICS". A particularly preferred PLURONIC is Pluronic F-127 or Poloxamer 407. These are closely related block copolymers that may be generically classified as polyoxypropylene-polyoxyethylene condensates terminating in primary hydroxyl groups. They are formed by the condensation of propylene oxide into a propylene glycol nucleus followed by the condensation of ethylene oxide onto both ends of the polyoxypropylene base. The polyoxyethylene hydrophilic groups on the ends of the molecule are controlled in length to constitute anywhere from 10% to 80% by weight of the final molecule. The "Pluronic" series of products may be represented empirically by the formula:

HO(CH₂CH₂O)_a(CHCH₂O)_b(CH₂CH₂O)_cH CH₃

where a and c are statistically equal. They have been available in average molecular weights of from about 1100 to about 15,500.

A preferred polyoxyethylene-polyoxypropylene block copolymer for use in the pharmaceutical vehicle of this invention is one in which the number of polyoxyethylene units is about 70% of the total number of monomeric units in the molecule and where the copolymer has an average molecular weight of about 11,500. "Pluronic F-127" is such a material, and it has a solubility greater than 10 gmsJIOO ml. water as well as a cloud point in 1 % aqueous solution higher than 100° C. The concentration of the poly oxyethylene-poly oxypropylene condensate is an important parameter. Significantly, by ready adjustment of the concentration of the copolymer to accommodate other solutes present in the vehicle, any desired gel transition temperature in the critical range of above ambient temperature and below body temperature can be achieved. Thus, the principal consideration is the selection of a concentration which, in conjunction with all of the constituents of the vehicle composition, will provide a sol-gel transition temperature in the required range.

It has been found that a useful block copolymer concentration is from about 10% to about 33% by weight, particularly from about 17% to about 26 % . Excellent results have been obtained using aqueous solutions of from about 17% to about 26% by weight of "Pluronic F-127" ( - hydro-ω-hydroxypoly(oxyethylene)_a poly(oxypropylene)_b- poly(oxyethylene)_a block copolymer), preferably at a concentration of between 14 and 33% weight by volume, most preferably at 16% weight by volume. The water content is generally from about 67% to about 90% by weight of the vehicle composition. The water used in forming the aqueous solution is preferably purified, as by distillation, filtration, ion- exchange or the like.

Other Poloxamer copolymers may also be appropriate, including Poloxamer 188. Critical characteristics of the polymer solutions are that they be isotonic when suspended in an isotonic solution and that they have the same optical properties as the fluid normally present on the surface of the eye. This is not achieved using other materials such as collagen. Type I collagen "gels" at elevated temperatures by a fibril interaction or sort of crosslinking mechanism. However, it is fundamentally different from poloxamer as a pharmaceutical excipient for the following reasons. Collagen fibrils are opaque when they gel, rendering such a formulation less useful than poloxamer which is a clear gel possessing excellent optical clarity whether in the liquid or gelled state. Second, collagen in its liquid state must be acidified. Therefore it cannot be instilled into the eye as it will cause great discomfort and possibly damage to the eye's tissues and epithelial cells. Next, in order to gel the collagen, not only must it be heated, but one must adjust the pH with NaOH. Furthermore, the collagen is a protein which must be purified and is consequently very expensive compared to poloxamer. Poloxamer and other similar synthetic polymers are inexpensive and readily available as a pharmaceutical excipient. Proteins such as collagen should also be avoided due to the potential for eliciting an immunological response. Carriers The polymer is dissolved in an aqueous solution having physiologically acceptable salts added to yield an isotonic solution. PH is adjusted to between 6.5 and 8.0, most preferably between 7.2 and 7.4. Aqueous solutions of Poloxamer 407, at concentrations between 1 and 35% (wt/vol), undergo a phase change where they transform from a liquid to a solid at temperatures greater than 15 to 20°C. The exact temperature of this phase transition is dependent on the concentration of the poloxamer. Therefore, a 25% Poloxamer solution is a liquid below 10 to 15°C and transforms to a clear, solid gel at 25 °C or greater. Formulations of poloxamer for ophthalmic applications can be made which are liquids at room temperature (16% Poloxamer) and which increase their viscosity significantly at the temperature of the eye (approximately 33°C) so that they remain in the eye for extended time periods. The viscosity of 28% poloxamer in aqueous solution is greater than 250,000 cps as measured by a Brookfield viscometer. The pH of the poloxamer is easily controlled and adjusted to physiological values (pH 7.4), preferably with tromethamine and maleic acid. The osmolarity of the poloxamer is adjusted with NaCl to 290 to 300 mOs to make it physiologic.

In preferred embodiments, a 25% formulation for ophthalmic use was prepared as follows. 350 g poloxamer 407 was melted in a 65°C water bath. Potassium phosphate, monobasic (0.045 % w/w, 0.45 g) sodium phosphate, dibasic (0.270 %w/w, 2.70 g), sodium chloride (0.320 %w/w, 3.20 g), sodium acetate (0.230 %w/w, 2.30 g), sodium citrate, dihydrate (0.170 %w/w, 1.70 g), dextrose (d-glucose) (0.90 %w/w, 0.90), water (73.88 %w/w, 738.75 g). Osmolarity was 291 mOs/kg. Pour molten Poloxamer into water.

Other excipients can be added to the formulation including viscosity enhancing agents such as polyethylene glycol, polyvinyl alcohol, dextran and other polysaccharides. NaCl or other physiological salts can be used to adjust tonicity. Tromethamine base and maleic acid are preferred to adjust the pH of the formulation. Preservatives which are acceptable for ophthalmic use include sorbic acid, benzalkonium chloride, chlorobutanol, methyl and propyl parabens, thimerosal and EDTA. The preferred pH range is between 7 and 7.6. Applications

The polymer solutions are topically applied using a dropper or other conventional means for applying a solution to the surface of the eye. Aqueous poloxamer solutions, particularly Poloxamer 407 in concentrations ranging from 1 % to 35 % , are retained in the eye for time periods exceeding several hours. This imparts superior comfort to the eye, either through its ability to deliver water, retain water or through its surfactant properties. A 1 % to 35 % aqueous solution of an osmotically, buffered solution of Poloxamer 407 is preferred for the treatment of dry eye or use as a contact lens solution. The sustained release of pharmaceutical products to treat eye diseases, such as antibiotics like erythromycin for eye infections, steroids to treat inflammatory eye conditions, immunomodulators such as cyclosporin for corneal transplant applications, or diagnostic agents such as sodium fluorescein may also be advantageous in the poloxamer delivery system. These agents are incorporated into aqueous poloxamer solutions at concentrations up to the point of their maximum solubility, and then placed on the eye.

The present invention will be further understood by reference to the following non-limiting examples. Example 1: Treatment of dry eye.

Formulations of poloxamer 407 at concentrations of 20, 25 and 28% in a buffer with an osmolarity of between 290 and 300 mOs have been administered topically to normal and dry eyes of humans. Approximately one to two drops were administered to each eye. Lubrication was achieved for periods ranging from one to three hours in normal eyes and relief from symptoms of dry eye was achieved for thirty to sixty minutes. Example 2: Extended lubrication by poloxamer solutions.

In order to quantify the retention of the Poloxamer 407 and compare it to products which claim "longer lasting relief" (package insert Aquasite lubricant drops, Ciba Vision, Atlanta, GA.), sodium fluorescein at 0.25% wt/vol concentration was incorporated into Phosphate Buffered Saline, AquaSite™ with Durasite™ for long lasting delivery, and into 16% aqueous Poloxamer 407 solution and 25 % aqueous Poloxamer 407 solution. The formulation was prepared by adding 72 g water to 28 g 28% w/w Poloxamer 407 in sterile maleic acid buffer (50 mis: 0.0547 g tromethamine base, 0.05275 g maleic acid, 0.0215 g sodium hydroxide, water to 50 g).

One drop (approximately 50 mg) of each of these formulations was placed on the eyes of C57 mice. The eyes were visualized through Zeiss slit lamp ophthalmic microscope to determine the presence or absence of the fluorescein dye. If the fluorescein was present, the eye was scored with a 1, if there was no fluorescein observed, the eye was scored with a 0. Each formulation was placed on three (3) eyes. The maximum score each formulation could obtain was a 3 and the minimum was a 0. The results for the four formulations containing the fluorescein dye are shown in Figure 1. The results clearly show that the Poloxamer formulations retained the fluorescein on the eye for 2 to 3 times as long as phosphate buffer saline and Aquasite™ formulations.

The same formulations were also administered to humans, one with normal eyes and one with dry eyes. The gel remained visible on the surface of the eye for thirty minutes. Fluorescein normally remains visible on the surface of the eye for approximately five to ten minutes, an increase of more than 300% .

Claims

We claim:

1. A composition for relieving dry eye and irritation of the eye comprising an isotonic aqueous solution of a polyoxyethylene-polypropylene oxide at concentrations between 1 and 35% (wt/vol), which undergoes a phase change from a liquid to a solid at temperatures greater than 15 to 20 C.

2. The composition of claim 1 wherein the polymer solution is a liquid at room temperature which increases in viscosity significantly at the temperature of the eye.

3. The composition of claim 2 wherein the polymer is α-hydro-ω- hydroxypoly(oxyethylene)_a poly(oxypropylene)_b-poly(oxyethylene)_J block copolymer at a concentration of between 14 and 33% weight by volume.

4. The composition of claim 1 in a pharmaceutically acceptable carrier for use as a contact lens wetting solution.

5. The composition of claim 1 in a pharmaceutically acceptable carrier for use as a dry eye treatment.

6. A method for lubricating the dry eye comprising administering to the surface of the eye an effective amount of any of the compositions of claims 1 to 5.

7. A method of use of the composition of any of claims 1 to 5 for use in lubricating the eye.

8. The method of use of the composition of claim 7 wherein the polymer solution is used as a contact lens wetting solution.

9. The method of use of the composition of claim 7 wherein the polymer solution is used as a dry eye treatment.

10. The method of use of the composition of claim 7 wherein the polymer solution is administered when the eye is irritated by abrasion.

11. A method of manufacturing a composition useful as an ophthalmic lubricant comprising preparing the composition of any of claims 1 to 5.