US20050085758A1 - Growth factor delivery system for the healing of wounds and the prevention of inflammation and disease - Google Patents

Growth factor delivery system for the healing of wounds and the prevention of inflammation and disease Download PDF

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US20050085758A1
US20050085758A1 US10/971,820 US97182004A US2005085758A1 US 20050085758 A1 US20050085758 A1 US 20050085758A1 US 97182004 A US97182004 A US 97182004A US 2005085758 A1 US2005085758 A1 US 2005085758A1
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growth factor
contact lens
hydrogel
wound
egf
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Clyde Schultz
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RAPIDHEAL LLC
DirectContact LLC
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Schultz Clyde L.
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Priority claimed from US10/132,843 external-priority patent/US20030203032A1/en
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Priority to US10/971,820 priority Critical patent/US20050085758A1/en
Priority to US11/096,736 priority patent/US7618643B2/en
Publication of US20050085758A1 publication Critical patent/US20050085758A1/en
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    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the fields of hydrogels, drug delivery systems, wound healing, and reduction of pain and inflammation.
  • Corneal wounds caused by injury, disease, or surgery represent a serious medical condition that may lead to loss of sight.
  • persistent epithelial defects can lead to stromal melting, which causes serious visual dysfunction.
  • Wound healing of corneal mucosal tissue has taken on increased importance with the advent of laser corrective surgery to re-establish normal vision for people who do not wish to wear contact lenses or spectacles.
  • laser surgical methods are used to correct vision for nearsightedness (myopia), farsightedness (hyperopia), and astigmatism.
  • the methods include laser in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK), and photo-refractive keratectomy (PRK).
  • LASIK refers to the use of a laser to reshape the cornea without invading the adjacent cell layers.
  • a microkeratome is used to separate the surface layers of the cornea and create a corneal flap (160-180 microns deep). This flap stays attached to the rest of the cornea and is folded back on one side to expose the stroma of the cornea.
  • the laser delivers pulses of ultraviolet light onto the inner cornea (stroma). Each pulse removes a microscopic layer of the inner cornea to reshape the surface of the cornea.
  • the procedure flattens the cornea.
  • the procedure increases the curvature of the cornea.
  • corneal flap is replaced where it bonds without the need for stitches.
  • the anterior layers of the cornea epidermal, Bowman's Layer
  • eye drops which are used to prevent infection & swelling, with varying degrees of success.
  • patients are able to see clearly without depending on glasses or contacts.
  • the surgeon removes the epithelium (the anterior layer of the cornea or Bowman's Layer), which is a thin layer of protective skin that covers the cornea.
  • This layer can be removed with an excimer laser or a brush.
  • the patient stares at a fixation light. In less than a minute, the laser removes the proper amount of tissue while it reshapes the surface of the cornea.
  • the excimer laser delivers pulses of ultraviolet light into the cornea. This exposure to laser radiation reduces or eliminates nearsightedness by flattening the central cornea and relocating the focal point of the lens onto the retina rather than in front of it, which produces sharper vision.
  • a bandage contact lens is placed on the eye for 2-3 days.
  • the purpose of the contact lens given to PRK patients post-surgically is to protect the leading edge of the corneal epithelium that is regenerating along the surface of the eye, post-surgery. As patients blink, the newer leading edge of the epithelium may be removed. As a result, recovery takes longer and there is an increased risk of infection.
  • LASEK is similar to PRK but the epithelium is detached by using an alcohol solution that weakens the epithelium and allows it to fold back into a flap. A laser is then used to re-shape the cornea and correct vision acuity.
  • the present invention features hydrogel drug delivery systems and methods of producing and using such systems for the treatment of wounds.
  • the systems are based on a hydrogel into which a growth factor, e.g., epidermal growth factor (EGF), is passively transferred from a dilute aqueous solution. When placed in contact with a wounded tissue, the growth factor passively transfers out of the hydrogel to provide accelerated healing and a concomitant reduction in pain.
  • a growth factor e.g., epidermal growth factor (EGF)
  • EGF epidermal growth factor
  • the amount of growth factor absorbed into the hydrogel may be ⁇ 350 ppb, but this amount surprisingly is effective in producing a therapeutic effect likely because the delivery system is localized and provides a sustained release of the factor. Higher concentrations of growth factor may also be employed.
  • the systems are applicable to ocular wounds, especially after vision correcting surgery, as well as other wound treatments.
  • the invention features a polymeric hydrogel that contains a substantially pure growth factor.
  • growth factors include epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof.
  • concentration of the growth factor is, for example, between 0.005 and 350 ppb. Other exemplary concentrations include at most 1, 10, 25, 50, or 100 ppm.
  • the hydrogel has a water content of, for example, between 37.5% and 75% by weight.
  • Exemplary hydrogel materials include a tetrapolymer of hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, and methacrylic acid.
  • hydrogels include etafilcon A, vifilcon A, lidofilcon A, vasurfilcon A, and polymacon B.
  • these polymers formed by the use of different packing solutions (e.g., phosphate-buffered saline and boric acid) in the manufacturing process are also included.
  • the hydrogel may be ionic or non-ionic.
  • the growth factor is capable of being passively released into an environment, e.g., an ocular environment, under ambient or existing conditions.
  • the hydrogel may be shaped as a contact lens, e.g., one capable of correcting vision.
  • Such a contact lens may be capable of correcting vision in the range of +8.0 to ⁇ 8.0 diopters, including plano, and may have a base curve between 8.0 and 9.0.
  • Hydrogels of the invention may further include other therapeutic compounds as described herein, e.g., an anti-inflammatory compound, such as dexamethasone, fluorometholone, rimexolone, or prednisolone.
  • the invention features a polymeric hydrogel including an anti-inflammatory compound.
  • exemplary polymers and anti-inflammatory compounds are as described above.
  • the concentration of the anti-inflammatory compounds is, for example, between 0.001 and 100 ppm, e.g., at most 0.01, 0.1, 1, 10, 15, 20, 30, or 50 ppm.
  • the invention further features a method for making a hydrogel drug delivery system by placing the hydrogel, e.g., a contact lens, in an aqueous solution containing a substantially pure growth factor as described herein, which is passively transferred to the hydrogel.
  • This method may further include the steps of washing the hydrogel in an isotonic saline solution and partially desiccating the hydrogel prior to placement in the solution.
  • the aqueous solution has, e.g., a pH between 6.9 and 7.4 and between 0.01 and 10 ng growth factor per ⁇ L.
  • the concentration of growth factor in the hydrogel after soaking is, for example, between 5 and 350 ppb.
  • the hydrogel is placed in the solution of growth factor for at least 30 minutes.
  • the aqueous solution may further include another therapeutic compound as described herein, e.g., an anti-inflammatory compound, such as dexamethasone, fluorometholone, rimexolone, or prednisolone.
  • an anti-inflammatory compound such as dexamethasone, fluorometholone, rimexolone, or prednisolone.
  • Hydrogels containing these other therapeutic compounds may also be obtained by omitting the growth factor in the soaking solution.
  • the invention features a method for treating a wound.
  • the method includes placing a hydrogel, as described herein, in contact with the wound, wherein the growth factor or anti-inflammatory compound or both are passively released from the hydrogel to treat the wound.
  • the hydrogel further acts as a protective shield against mechanical abuse.
  • the wound is in endothelial tissue, epithelial tissue, the lung, the skin, or the digestive tract.
  • the hydrogel may be placed in a body cavity.
  • the method causes a reduction in pain compared to a wound not contacted with the medicated hydrogel.
  • the hydrogel may passively release, for example, at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, or 20 ⁇ g of a growth factor, and the hydrogel may be placed in contact with the wound for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours.
  • the hydrogel may also passively release at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, 20, 50, 100, or 1000 ⁇ g of other compounds, as described herein.
  • the invention also features a method of delivering a growth factor including the steps of placing a polymeric hydrogel of the invention in contact with a wound that is in contact with a replenishable bodily fluid; and allowing the growth factor to release passively from the hydrogel into the replenishable bodily fluid.
  • the release of the growth factor from the hydrogel into the replenishable bodily fluid is accelerated compared to the release of the growth factor from the hydrogel into a non-replenishable bodily fluid.
  • An exemplary wound is an ocular wound, and an exemplary replenishable bodily fluid is tear fluid. This method may also be used to deliver anti-inflammatory or other compounds as described herein.
  • ambient conditions room temperature and pressure
  • substantially pure is meant having a purity of greater than 75% by weight.
  • a growth factor of the invention is, for example, greater than 85%, 90%, 95%, or even 99% pure.
  • Use of the term is intended to define purity from other biological compounds, e.g., proteins, carbohydrates, and lipids that are commonly associated with the growth factor in vivo.
  • treating is meant the medical management of a patient with the intent that a prevention, cure, stabilization, or amelioration of the symptoms will result.
  • This term includes active treatment, that is, treatment directed specifically toward improvement of the disorder; palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disorder; preventive treatment, that is, treatment directed to prevention of the disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disorder.
  • treatment also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disorder. The term further includes the promotion of wound closure or healing.
  • terapéuticaally effective amount is meant an amount of a compound sufficient to produce a preventative, healing, curative, stabilizing, or ameliorative effect in the treatment of a condition, e.g., an eye wound.
  • wound is meant an injury to any tissue. Examples of wounds include burns, lacerations, abrasions, bites, surgical wounds, puncture wounds, and ulcers.
  • ocular environment is meant the tissues of and surrounding the eye, including, for example, the sclera, cornea, and other tissues of the ocular cavity.
  • replenishable bodily fluid is meant a fluid produced by a mammal that is periodically replaced with new fluid.
  • replenishable bodily fluids include tears, saliva, mucous, gastric fluids, and urine.
  • FIGS. 1A and 1B are groups of the uptake (A) and release (B) of EGF from vasurfilcon A contact lenses.
  • This invention provides a polymeric drug delivery system including a hydrogel containing a growth factor, e.g., EGF. Allowing passive transference of the growth factor from a dilute aqueous solution into the hydrogel produces the delivery system.
  • the hydrogel when placed in contact with a wound, delivers a low concentration of the growth factor.
  • the delivery of the growth factor is sustained over an extended period of time, which is of particular utility in environments, e.g., the eye, that are periodically flushed with bodily fluids, e.g., tears. This sustained delivery accelerates the wound healing process while avoiding potential damaging effects of localized delivery of high concentrations of compounds, e.g., from eye drops.
  • Hydrogels may employ different polymer compositions that are useful in the treatment of a variety of tissues.
  • conventional soft contact lenses can be used and can be either ionic or non-ionic hydrogels containing between 37.5%-75% water by weight and can have any base curve, e.g., from 8.0 to 9.0.
  • the contact lenses may also have the ability to correct vision, for example, over a range of diopters of +8.0 to ⁇ 8.0, including plano.
  • Exemplary hydrogel contact lens materials include etafilcon A, vifilcon A, lidofilcon A, polymacon B, vasurfilcon A, and a tetrapolymer of hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, and methacrylic acid. These materials may also be employed, in other physical forms, in treating wounds in other tissues. Other suitable hydrogel materials are known to those skilled in the art.
  • the hydrogels may be insoluble or may dissolve over time in vivo, e.g., over one day or one week.
  • the growth factor is passively delivered, for example, by diffusion out of the hydrogel, by desorption from the hydrogel, or by release as the hydrogel dissolves.
  • the drug delivery system may be produced from a partially desiccated hydrogel (or equivalently a partially hydrated hydrogel).
  • the desiccation step removes, for example, approximately 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or 75% of the water in a hydrogel. Desiccation can occur, for example, by exposure of the hydrogel to ambient or humidity controlled air, by heating the hydrogel for a specific period of time, or by blowing dried gas, such as N 2 , over the hydrogel.
  • the hydrogel is saturated with physiological (isotonic) saline prior to desiccation.
  • the partially desiccated hydrogel is then soaked, e.g., for at least 30 minutes, in a dilute aqueous solution of growth factor, e.g., at a pH between 6.9 to 7.4.
  • the hydrogels may also be soaked for at least 1 hour, 6 hours, 12 hours, or 24 hours.
  • the concentration of growth factor into which the hydrogel is placed is typically 10 ng/ ⁇ L or less, e.g., at most 5 ng/ ⁇ L, 1 ng/ ⁇ L, 0.1 ng/ ⁇ L, or 0.01 ng/ ⁇ L. Higher concentrations may also be used, for example, to reduce the soaking time.
  • the growth factor is passively transferred into the hydrogel. This transfer may occur at least in part by rehydrating the hydrogel. Diffusion of the growth factor into the water in the hydrogel may also occur.
  • a fully hydrated or fully desiccated hydrogel is placed in the soaking solution to produce the medicated hydrogel.
  • the concentration of growth factor transferred to the hydrogel is substantially lower than the solution in which the hydrogel is soaked.
  • the concentration of growth factor in the hydrogel is at least 2 ⁇ , 5 ⁇ , or 10 ⁇ less than that of the soaking solution.
  • Some growth factors may have a higher affinity for a hydrogel than aqueous solution, and such a hydrogel will have a higher concentration of growth factor than the solution in which it was soaked.
  • the water content and type of hydrogel, time and conditions, e.g., temperature of soaking, composition of the soaking solution (e.g., ionic strength and pH), and type of growth factor employed also may influence the concentration of growth factor in the drug delivery system.
  • hydrogel Since the water content of the hydrogel also helps to determine the total amount of growth factor present in a hydrogel, it represents a variable by which to control the amount of growth factor delivered to a tissue.
  • the production of a hydrogel containing a specified amount of growth factor can be accomplished by routine experimentation by one skilled in the art.
  • Exemplary hydrogels include between 5 and 350 ppb of growth factor, for example, between 5 and 250 ppb, 5 and 100 ppb, 5 and 50 ppb, or 5 and 10 ppb.
  • the concentration of growth factor in the hydrogel may, however, be higher, e.g., at most 100, 75, 50, 25, 10, or 1 ppm.
  • Growth factors are a heterogeneous group of proteins capable of stimulating growth and the multiplication of cells.
  • Exemplary growth factors include epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof. These growth factors may be natural, synthetic, or recombinant growth factors or growth factor derivatives from any animal, for example, humans, or any domesticated animal or pet species. Such growth factors also include biologically active growth factors and analogs.
  • Peptide growth factors play important biological roles by regulating many of the processes involved in normal wound healing including migration, mitosis, and differentiation of cells. Growth factors are commercially available or may be isolated using methods known in the art.
  • the hydrogels of the invention may also contain medicaments other than growth factors.
  • additional compounds include, without limitation, analgesics, anti-inflammatory drugs (e.g., dexamethasone, fluorometholone, rimexolone and prednisolone), antibodies, meganins, self-proteins, pharmaceutical drugs, and antibiotic compounds.
  • anti-inflammatory drugs e.g., dexamethasone, fluorometholone, rimexolone and prednisolone
  • antibodies e.g., meganins, self-proteins, pharmaceutical drugs, and antibiotic compounds.
  • antibiotic compounds e.g., antibiotic compounds.
  • these other compounds may also be used at reduced concentrations from their typically prescribed dosages.
  • these chemicals may be delivered in concentrations of less than 100, 50, 25, 10, 1, 0.1, 0.01, or 0.001 ppm at various sites (e.g., the eye) and under different conditions (e.g. ambient or existing).
  • preservatives are non-ideal as they may transfer to a hydrogel at a disproportionately high concentration and cause cytotoxicity.
  • a drug delivery system of the invention may be placed in contact with a damaged tissue.
  • the lens may simply be placed in the eye normally in order to deliver the growth factor.
  • the hydrogel may be part of a bandage or may be adhered (e.g., by adhesives or sutures) to the wounded tissue. If the hydrogel is placed internally in a patient, the hydrogel is advantageously biodegradable.
  • Hydrogels may be considered to be disposable and may be replaced after a specified period of time, e.g., at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours.
  • a hydrogel that has a depleted amount of growth factor may be recycled by desiccating and soaking the hydrogel again.
  • the invention may be used in conjunction with healing many types of wounds, including, without limitation, ocular, oral, lung, digestive tract, skin, large intestine, small intestine, colon, and other wounds to endothelial, mucosal, or epithelial tissues.
  • the invention provides accelerated healing by delivering a growth factor to an injured tissue.
  • a growth factor to an injured tissue.
  • at least 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, or 20 ⁇ g of the growth factor is released from the hydrogel. This delivery occurs by passive transfer and allows medications to be released into fluids of the body, e.g., ocular fluid.
  • the growth factor stimulates proliferation of cells surrounding a wound to close the wound and replace damaged cells.
  • the hydrogel may also act as a physical barrier to provide protection from mechanical abuse and to prevent adherence of the healing tissue to adjacent tissues.
  • the use of hydrogels of the invention may also allow patients to be treated using fewer applications than with traditional methods. For example, a patient treated using the hydrogels of the invention may be able to be treated only once in a period of at least 48 hours.
  • a hydrogel of the invention is used to treat a wound that is in contact with a replenishable bodily fluid, e.g., tears.
  • a replenishable bodily fluid e.g., tears.
  • the growth factor is released from the hydrogel at a more rapid rate than the release of the growth factor into a fixed volume of fluid because as the bodily fluid is replenished, the growth factor released is flushed away from the site of application causing an increase in the relative rate of diffusion of the growth factor out of the hydrogel.
  • the replenishing action of fluids such as tears may also effectively increase the rate of diffusion of the growth factor into the fluid and lead to earlier onset of therapeutic activity.
  • a non-replenishable bodily fluid i.e., one where replacement is very slow or nonexistent on the time-scale of drug release
  • lower concentrations of a drug may be used since the drug is not flushed from the site as quickly as in a replenishable fluid.
  • the wound is an ocular wound, e.g., in corneal epithelial, endothelial, or retinal tissue.
  • the invention is of particular utility after vision correcting surgery, such as LASIK, PRK, or LASEK.
  • Soft and collagen contact lenses may be utilized to minimize post-surgical epithelial trauma and provide a stable healing environment.
  • PRK typically requires a therapeutic contact lens for 3-4 days, and post-operative therapeutic drops are often prescribed.
  • the hydrogel may be shaped as a contact lens that acts as a reservoir for the growth factor and can serve to protect the leading edge of wound healing from normal mechanical abuse.
  • the growth factor gradually delivered in a low concentration from the hydrogel obviates the need for therapeutic drops.
  • Therapeutic drops often include high concentrations of drugs because the majority of the drop is excreted from the eye in a short period of time. These high concentrations can cause additional damage to a wound, which is avoided by the use of the present, localized time-release drug delivery system.
  • a further understanding of the invention may be obtained from the following non-limiting examples.
  • An exemplary drug delivery system was prepared as follows. Contact lenses were removed from their package and rinsed with saline to remove contact lens packing solution. The hydrogel lens materials were allowed to desiccate for 10-30 seconds. The hydrogel lens materials were placed into physiological saline that contained epidermal growth factor (EGF) at concentrations of 10 ng/ ⁇ l or 5.0 ng/ ⁇ l for at least 30 minutes. Lower concentrations may also be used. Longer passive transference times may also be used. Untreated or control lenses were placed in physiological saline without EGF.
  • EGF epidermal growth factor
  • Ocular cells were placed into a sterile plastic dish. This dish contained a 5-mm disk. The purpose of the disk was to prevent cells from growing in the covered area. When the disk was removed, a 5-mm “wound” or “hole” was present.
  • Contact lenses were then added to these cell sheets with the wounds. The lenses were left in contact with the cell sheets for a minimum of 30 minutes. Minimal medium was used to maintain the cell cultures. Cells were incubated at 35° C. ⁇ 2° C. in 5% CO 2 . Contact lenses with or without EGF were produced as in Example 1. The contact lenses used were polymacon B, vifilcon A, and lidofilcon A hydrogel polymers.
  • the cell sheets were then viewed over time, and the diameter of the hole was measured.
  • the results are expressed in terms of closure of the in vitro wound over time.
  • Epithelial Cells and Tissue Epithelial Cells and Tissue.
  • Epithelial (rabbit corneal epithelial cells) cells were seeded on a dish and contacted with control and EGF-containing contact lenses. At 48 hours there was a 25% difference in the closure rate between the EGF-treated cells and the non-EGF treated cells. At 72 hours, there was a 43% difference in the closure rate between the EGF-treated epithelial tissue and the controls.
  • the hydrogel material that was used was vifilcon A, an ionic polymer with a water content of 55%. The polymer had been incubated with 10 ng/ ⁇ L EGF for one hour at 4° C. prior to use in the experiments.
  • Closure rates were calculated by direct measurement of the diameter of the wound. Measurements were taken daily.
  • a vifilcon A lens was incubated under the same conditions as above with 5.0 ng/ ⁇ L of EGF and then contacted with an epithelial “wound” as above. At 48 hours, there was a 21% closure rate difference between controls and EGF treated hydrogel materials. At 72 hours, there was also a 21% difference in the closure rate. These results indicated that over a 72-hour period, the relative healing rates remained essentially the same for the treated and non-treated epithelial tissue, with the epithelial tissue treated with EGF always having an accelerated rate of healing.
  • the rate of wound healing increased with increased exposure of the hydrogel material to the wound. Further, compared to a wound not contacted with any lens, at 48 hours there was a 31% difference in the healing rates.
  • Healing for tissue exposed to a lens soaked in 10 ng/ ⁇ L of EGF increased from 14% at 48 hours to 25% at 72 hours.
  • Endothelial Cells and Tissue Wounds caused in endothelial tissue (bovine corneal endothelial cells) were also healed by release of EGF from a vifilcon A lens.
  • the lens soaked in 10 ng/ ⁇ L of EGF as above, showed a 73% difference in healing rates at 48 hours compared to a control. At 72 hours, the EGF-treated tissue had completely healed. In the control group, less than half (43%) of the tissue had healed.
  • the same lens material exposed to 5 ng/ ⁇ L of EGF showed a 31% difference in closure rate at 48 hours between the EGF treated group and the controls. At 72 hours, 53% of the tissue had healed in the EGF treated group, compared to 43% in the control.
  • the concentration of EGF used in the soaking solution was 10 ng/ ⁇ L.
  • the EGF treated tissue showed a 54% increase in the healing rate (wound closure rate) as compared to controls.
  • the lenses were prepared using a soaking solution of 10 ng/ ⁇ L of EGF.
  • the wound was 60% closed in the treated group and 27% closed in the non-treated group.
  • the difference in closure between the treated and untreated groups was 62%.
  • the wound had closed by 80%, while in the untreated group, the wound had closed by 46.8%.
  • the amount of uptake and release of EGF from a contact lens depends on the water content or composition of the lens or both. Data were collected on the uptake and release of EGF from two types of lenses, lotrafilcon A (24% water) and vasurfilcon A (74% water). Both of these lenses are non-ionic. For uptake studies, thirty lenses of each type were placed in 25 mL of a solution containing 40 ppm of EGF. For release studies, the lenses produced by the uptake study were placed in 25 mL of solution not containing EGF after desiccation for 10-30 seconds. For both types of study, the amount of EGF in the solution was then measured at defined time intervals.
  • vasurfilcon A For vasurfilcon A, about 75% of the EGF in solution was taken up by the lenses after 6 hours ( FIG. 1A ), at which point the lenses appeared to be in equilibrium with the solution, and about 37% of the EGF taken up was released after 7 hours ( FIG. 1B ), at which point the lenses appeared to be at or near equilibrium.
  • the release data indicate that contact lenses can deliver a sustained dosage of EGF over a period of time.
  • no measurable amount of EGF was taken up or released by the lenses. Based on a purely diffusional theory of uptake, at least some growth factor would have been expected to be taken up in the water in the lotrafilcon A contact lens.
  • EGF EGF
  • dexamethasone an anti-inflammatory steroid
  • HGH human growth hormone
  • Medicated contact lenses were prepared by briefly drying the lens and then soaking it in 400 ppb, 4 ppm, or 10 ppm EGF or 400 ppb HGH in PBS for 24 hours. In another experiment, lenses were soaked in 200 ppb EGF and 12.5 ppm dexamethasone for 25 hours. No toxicity was observed in the rabbits at any concentration of EGF tested. Rabbits were visually scored on a 0-4 scale (0 being the best and 4 being the worst) for corneal edema (which is a measure of wound healing), inflammation, and exudate production.
  • EGF (lenses soaked in 400 ppb EGF) released from hydrogel contact lenses (right eye) healed wounds at an accelerated rate when compared to control eyes (left eye) for the first two hours after treatment. Data from four rabbits are shown in Table 1.
  • the rabbits eyes were treated with a solution of lipopolysaccharide from E. coli O111:B4 (1 mg/mL) to induce inflammation.
  • Lenses soaked in 200 ppb EGF and 12.5 ppm dexamethasone controlled inflammation and caused increased wound healing (right eye) compared to control eyes (left eye). EGF controlled healing of wounds even if there was an increase in inflammation.
  • a polymacon B lens having 38% water content was soaked in 400 ppb EGF for 24 hours.
  • This lens was placed in a human patient suffering from a recurring epithelial defect that was not responsive to traditional medical treatments.
  • Clinical efficacy i.e., wound healing
  • treatment lasts for at least one hour.
  • This type of injury is normally treated by the repeated introduction of eye drops, sometimes as often as every 4-5 minutes.
  • a contact lens of the present invention was able to produce a positive result with only one administration.

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US20050275799A1 (en) * 2004-03-10 2005-12-15 Marmo J C Contact lenses, package systems, and method for promoting a healthy epithelium of an eye
US20060155477A1 (en) * 2005-01-13 2006-07-13 Matson Kenneth H Method of multiple attenuation
US8623400B2 (en) 2011-07-08 2014-01-07 National Chiao Tung University Drug-carrying contact lens and method for fabricating the same
EP2838511A4 (fr) * 2012-04-16 2015-12-09 Jade Therapeutics Llc Système d'administration de médicament oculaire

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US20050255144A1 (en) * 2003-04-09 2005-11-17 Directcontact Llc Methods and articles for the delivery of medicaments to the eye for the treatment of posterior segment diseases
US20050074497A1 (en) * 2003-04-09 2005-04-07 Schultz Clyde L. Hydrogels used to deliver medicaments to the eye for the treatment of posterior segment diseases
US9216106B2 (en) 2003-04-09 2015-12-22 Directcontact Llc Device and method for the delivery of drugs for the treatment of posterior segment disease
CN101541303A (zh) 2006-09-29 2009-09-23 庄臣及庄臣视力保护公司 用于治疗眼变态反应性的方法和眼科装置
WO2008118938A1 (fr) * 2007-03-26 2008-10-02 Theta Research Consultants, Llc Procédé et appareil permettant la distribution de médicament ophtalmique et la guérison de blessure oculaire
EP2370054B1 (fr) * 2008-12-11 2015-10-07 Massachusetts Institute of Technology Dispositif d administration de médicament par lentille de contact
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050275799A1 (en) * 2004-03-10 2005-12-15 Marmo J C Contact lenses, package systems, and method for promoting a healthy epithelium of an eye
US20060155477A1 (en) * 2005-01-13 2006-07-13 Matson Kenneth H Method of multiple attenuation
US8623400B2 (en) 2011-07-08 2014-01-07 National Chiao Tung University Drug-carrying contact lens and method for fabricating the same
EP2838511A4 (fr) * 2012-04-16 2015-12-09 Jade Therapeutics Llc Système d'administration de médicament oculaire

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IL164822A0 (en) 2005-12-18
EP1503730A2 (fr) 2005-02-09
CA2483265A1 (fr) 2003-11-06
US7618643B2 (en) 2009-11-17
US20050196428A1 (en) 2005-09-08
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Effective date: 20060705

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION