MXPA99011140A - The use of angiostatic steroids in photodynamic therapy - Google Patents

Abstract

Methods for treating ocular neovascularization using photodynamic therapy in combination with an angiostatic steroid are disclosed.

Description

THE USE OF ANGIOSTATIC STEROIDS IN PHOTODYNAMIC THERAPY Field of the Invention This invention relates to the use of angiostatic steroids in photodynamic therapy (PDT). Description of the Related Art Steroids that function to inhibit angiogenesis in the presence of heparin or specific heparin fragments are presented in Crum et al., A New Class of Steroids Inhibits Angiogenesis In The Presence of Heparin or Heparin Fragment, (Una- new class of steroids inhibits angiogenesis in the presence of heparin or heparin fragments), Science, 230: 375-378, December 20, 1985. The authors refer to such steroids as "angiostatic" steroids. Included in the new class of angiostatic steroids are cortisol, cortexolone, and various dihydro and tetrahydro derivatives. In the follow-up study focused on testing a hypothesis regarding the mechanism by which steroids inhibit angiogenesis, it was shown that angiostatic heparin / steroid compositions caused the dissolution of the base membrane structure on which the endotheliums are fixed dependent on anchorage which results in a capillary involution; see, Ingber, et al., A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary 'Basement Membrane Dissolution, (A Possible Mechanism for the Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Dissolution of the Capillary Basement Membrane ), Endocrinology 119: 768-775, 1986. A group of tetrahydrosteroids useful for inhibiting angiogenesis is presented in US Patent No. 4,975,537, issued to Aristoff and colleagues. The compounds are presented for use in the treatment of head trauma, spinal cord trauma, septic or traumatic shock, stroke, and oropathic shock. In addition, the patent comments on the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis, and arteriosclerosis. The compounds are not presented for ophthalmic use. Some of the tetrahydrosteroids presented in Aristoff et_colegas, are presented in US Pat. No. 4,771, * 042 in combination with heparin or with a heparin fragment to inhibit angiogenesis in a warm-blooded animal. The patent does not present the combination for ophthalmic use. Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,745G, each in combination with a beta-cyclodextrin, inhibit neovascularization of the cornea. Li, and colleagues, Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, (Angiostatic steroids potentiated by sulfated cyclodextrin inhibit neovascularization of the cornea), Investigative Ophthalmology and Visual Science, 32 (11): 2898-2905, October 1991. Steroids alone reduce neovascularization to some extent but are not alone effective in providing regression of neovascularization. Currently there are no effective therapies for the treatment of ocular neovascular diseases that do not include the destruction of healthy viable tissue. Although panretinal photocoagulation is the current medical practice for the treatment of diabetic retinopathy and is effective in inhibiting diabetic retinal neovascularization, this procedure destroys healthy peripheral retinal tissue. This destruction of healthy tissue decreases the retinal metabolic demand and consequently reduces neovascularization driven by retinal ischemia. A new, recent laser procedure is being tested for the inhibition of ocular neovascularization. A photodynamic therapy (PDT) is a method in which a photoactivatable dye is administered systemically followed by laser activation of the dye in the eye at the site of the formation of the new blood vessel (Asrani &Zeimer, Br J Ophthalmol, 79 (8). ): 776-770, August 1995, Asrani et al., Invest Ophthalmol, Vis. Sci, 38 (13); 2702-2710, December 1997; Husain et al., Ophthalmology, 104 (8): 242-1250, August 1997; Lin et al, Curr Eye Res, 13 (7): 513-522, July, 1994). The photoactivated drug generates free oxygen radicals that seal the newly formed blood vessels. This procedure has been used in patients with the form of exudate of macular degeneration and many patients present a regression of their subretinal neovascular membranes. Unfortunately, it appears that the PDT-induced inhibition of neovascularization is transient and lasts only 6 to 12 weeks (Gragoudas et al., Investigative Ophthalmology &Visual Science, 38 (4): S17, March 15, 1997; Sickenberg et al. al., Investigative Ophthalmology &Visual Science, 38 (4): S92, March 15, 1997, Thomas et al, Investigative Ophthalmology &Visual Science, 39 (4): S242, March 15, 1998.) Matter of the present invention includes the combination of PDT-induced regression of ocular neovascular tissue with agents, such as for example angiostatic steroids that inhibit the formation of new blood vessels. SUMMARY OF THE INVENTION This invention relates to methods for the treatment of ocular neovascular diseases by combining the use of PDT with particular angiostatic steroids. BRIEF DESCRIPTION OF THE DRAWING Figure 1 compares the ability of angiostatic steroids to inhibit neovascularization in the rabbit cornea. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The development of blood vessels for the purpose of supporting a vital tissue is known as angiogenesis or neovascularization. Agents that inhibit neovascularization are known by various terms such as angiostatic, angiolytic, or angiotropic agents. For the purposes of this specification, the term "angiostatic agent" refers to compounds that can be employed to inhibit neovascularization. Ocular neovascularization has not been treated successfully in the past. Neovascularization of tissues in the front of the eye (ie, the cornea, iris, and trabecular structure) and other conditions, including conditions in the back of the eye, for example, neovascularization of the optic nerve and retinal, subretinal, macular it can be avoided and treated by administering the steroids of this invention. Angiostatic agents are useful for preventing and treating ocular neovascularization, providing up to the regression of neovascularization. The angiostatic agents of this invention are steroids available from Steraloids, Inc., Wilton, N.H. and they have the following structures and names: 4, 9 (11) -Pregnadien-17a, 21-diol-3,20-dione-21-acetate 4, 9 (11) -pregnadien-17a, 21-diol-3,20-dione 11-epicortisol 17alpha-hydroxyprogesterone H Tetrahydrocortexolone (THS) Tetrahydrocortisol (THF) The above structures include all pharmaceutically acceptable salts of angiostatic steroids. The preferred angiostatic steroids are 4.9 (11) -pregnadien-17alpha, 21-diol-3,20-dione, and 4,9 (11) -pregnadien-17alpha, 21-diol-3,20-dione-21-acetate (anechortavo acetate). Angiostatic steroids in combination with PDT are useful for preventing and treating ocular neovascularization, including, but not limited to: retinal diseases (diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, age-related macular degeneration (ARMD) due to subretinal neovascularization); rubeosis iritis; inflammatory diseases; chronic uveitis; neoplasms (retinoblastoma, pseudoglioma); Fuchs heterochromic iridocyclitis; neovascularization of the cornea (inflammatory, transplant, hypoplasia of iris development); neovascularization that results after combined vitrectomy and lensectomy; vascular diseases (ischemia of the retina, choroidal vascular insufficiency, choroidal thrombosis, ischemia of the carotid artery); neovascularization of the optic nerve; and neovascularization due to the penetration of ocular injury or contusive ocular injury. In particular, this therapy is useful in the treatment of exudative ARMD and diabetic retinopathy. The start of the formation of new blood vessels can arise quite differently in various tissues or as results of different diseases. Many substances induce neovascularization, see, Folkman, and colleagues, Angiogenic Factors, (angiogenic factors), Science, Volume 235, pages 442-447 (1987). However, it is believed that once initiated, the neovascularization process is similar in all tissues and independently of the associated disease, Furcht, Critical Factor Controlling Angiogenesis: Cell Products, Cell Matrix, and Growth Factors, (Critical factors that control angiogenesis: Cell products, cell matrix and growth factors), Laboratory Investigation, Volume 55, No. 5, pages 505-509 (1986).

There are several theories regarding the mechanism of action of angiostatic steroids. For example, an angiostatic steroid-induced inhibition of neovascularization may occur due to dissolution of the capillary base membrane, Ingber and colleagues, supra; inhibition of vascular endothelial cell proliferation, Cariou, et al., inhibition of Human Endothelial Cell Proliferation by Heparin and Steroids, (Inhibition of the proliferation of human endothelial cells by heparin and steroids), Cell Biology International Reports, Vol. 12, No. 12, pages 1037-1047 (December 1988); Effects on vascular endothelial cell laminin expression, Tokida et al., Production of Two Variant Laminin Forms by Endothelial Cells and Shift of Their Relative Levéis by Angiostatic Steroids, (Production of two variant forms of laminin by endothelial cells and displacement of their relative levels by angiostatic steroids), The Journal of Biological Chemistry, vol. 264, No. 30, pages 18123-18129 (October 25, 1990); inhibition of collagen synthesis of vascular cells, Maragoudakis et al., Antiangiogenic of Heparin Plus Cortisone is Associated with Decreased Collagenous Protein Synthesis in Chick Chorioallantoic Membrane System, (The antiangiogenic action of heparin plus cortisone is related to decreased synthesis of collagenous protein in the chorioallantoic membrane system of chicken), The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2, pages 679-682 (1989); and the inhibition of plasminogen activator activity of vascular endothelial cells, Ashino-Fuse, et al., Medroxyprogesterone Acétate, An Anti-Cancer and Anti-Angiogenic Steroid, Inhibits the Plasminogen Activator in Bovine Endothelial Cells, (The medroxyprogesterone acetate, an anticancer and antiangiogenic steroid inhibits plasminogen activator in endothelial cells bovinas), Int. J. Cancer, 44, pages 859-864 (1989). There are many theories associated by the cause of neovascularization, and there may be different inducers depending on the disease or surgical intervention in question, BenEzra, Neovasculogenic Ability of Prostaglandins, Growth Factors, and Synthetic Chemoattractants, (Neovasculogenic ability of prostaglandins, growth factors, and synthetic chemoattractants), American Journal of Ophthalmology, Volume 86, no. 4, pages 455-461 (October 1978). Regardless of the cause or the disease or associated surgery, it is believed that angiostatic agents work by inhibiting one or several steps in the neovascularization process. Accordingly, the angiostatic steroids of this invention are useful in the treatment and prevention of neovascularization associated with various diseases and surgical complications. The angiostatic steroids of the present invention can be incorporated into various formulations for administration to the eyes. For example, topical formulations may be employed which may include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, regulators, sodium chloride, and water to form sterile aqueous solutions and aqueous suspensions. In order to prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in a suitable vehicle, such as, for example, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopol (a carboxyvinyl polymer available from BF Goodrich Company) in accordance with published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents can also be incorporated into these gel formulations. The ocular injection (intravitreal, subtenons, subconjunctival, periocular, retrobulbar), as well as prolonged-release infra-ocular devices and implants can be used, especially for administration to the back of the eye. Systemic formulations are also contemplated, for example orally ingested tablets and formulations for intraocular injection. The specific type of formulation selected will depend on several. factors, such as the angiostatic steroid or its salt used, the frequency of administration and the location of the neovascularization that is being treated. Topical ophthalmic aqueous solutions, suspensions, ointments and gels are the preferred administration forms for the treatment of neovascularization in the frontal part of the eye (cornea, iris, trabecular structure); or neovascularization of the back of the eye if the angiostatic agent can be formulated in such a way that it can be administered topically and the agent can penetrate the tissue in the front part of the eye. The angiostatic steroid will normally be contained in these formulations or other formulations in an amount of about 0.01 to about 15.0% by weight. Concentration ranges of about 0.01 to about 7.5% by weight are preferred. Thus, for topical administration, these formulations are administered on the surface of the eye one to six times a day, at the discretion of the physician. A systemic administration, for example, in the form of tablets, is useful for the treatment of neovascularization, particularly in the posterior part of the eye, for example, the retina. Tablets containing 10 to 100 mg of angiostatic agent can be taken 2 to 3 times a day at the discretion of the doctor. The compounds, irrespective of their form of administration, can be administered before, during, and / or after PDT. It is preferable to administer the compounds both before and after surgical intervention in order to limit or prevent the reoccurrence of neovascularization. The following examples illustrate formulations of the present invention but are not limiting in any way. Example 1 Topical ocular formulation Ingredient quantity (% by weight) Anecortavo acetate 1.0 Tyloxapol 0.01 to 0.05 HPMC 0.5 Benzalkonium chloride 0.01 Sodium chloride 0.8 Disodium edetate 0.01 NaOH / HCl q. s. pH 7.4 Purified water q. s. 100 mL The formulation is prepared by first placing a portion of the purified water in a precipitation vessel and heating to a temperature of 90 ° C. Hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of a vigorous vortex until all the Hydroxypropylmethylcellulose is dispersed. The resulting mixture is then allowed to cool while being mixed in order to hydrate the hydroxypropylmethylcellulose. The resulting solution is then sterilized by autoclaving in a vessel having a liquid inlet and a sterile, hydrophobic air vent filter. The sodium chloride and disodium edetate are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with NaOH / 0.1 M HCl. The solution is then sterilized through filtration. The 4, 9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione-21-acetate is sterilized either by application of heat or ethylene oxide. If sterilization by ethylene oxide is selected, it is necessary to aerate for at least 72 hours at a temperature of 50 ° C. 4, 9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione-21-acetate Sterilized is aseptically weighed and placed in a pressurized ball mill container. The diloxapol, in the form of a sterilized aqueous solution, is added to the ball mill container. Sterilized glass balls are then added to the container and the contents of the container are ground aseptically at 225 revolutions per minute for 16 hours, or until all the particles are within a range of about 5 microns. Under aseptic conditions, the micronized drug suspension formed by the previous step is poured into the HPMC solution with stirring. The ball mill container and the balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the disodium edetate and the benzalkonium chloride. It is then added aseptically rinse to the HPMC solution. The final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to 7.4 with NaOH / HCl. The formulation will be administered topically, in a therapeutically effective amount. In this case, the expression "therapeutically effective amount" refers to an amount that is sufficient to substantially prevent or reverse any ocular neovascularization. The dosage regimen used will depend on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history. Example 2 Topical ocular formulation Ingredient amount (% in pésol Anecortavo acetate 1.0 Mannitol 2.40 Sodium chloride 0.40 Carbopol 974P 0.50 Polysorbate 80 0.05 Disodium edetate 0.01 Benzalkonium chloride 0.01 + 5% XS Sodium hydroxide adjust pH to 7.2 Purified water qs a 100% Example 3 Tablet: 5-100 mg of anecortavo acetate with inactive ingredients such as starch, lactose and magnesia stearate can be formulated according to procedures well known to those skilled in the art of tablet formulation. Example 4 Formulation for sterile intraocular injection each L contains: 4.9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione 10-100 mg sodium chloride 7.14 mg potassium chloride 0.38 mg calcium chloride dihydrate 0.154 mg magnesium chloride hexahydrate 0.2 mg dry sodium phosphate 0.42 mg sodium bicarbonate 2.1 mg dextrose 0.92 mg hydrochloric acid or sodium hydroxide to adjust the pH to approximately 7.2 water for injection. Example 5 Formulation for sterile injection List of compounds mg / ml Anecortavo acetate 0.1-150 (0.0 for vehicle) Monobasic sodium phosphate, monohydrate 0.1-5 Diaphase sodium phosphate, anhydrous 0.1-5 Tyloxapol 0.0-10 Sodium chloride 0.1-10 Hydrochloric acid and / or sodium hydroxide adjust pH 7.0-7.8 water for injection q. s, Example 6 Sterile formulation for injection List of components mg / ml Anecortavo acetate 60 Monobasic sodium phosphate, monohydrate 0.45 Diaphase sodium phosphate, anhydrous 2.0 Tyloxapol 4.0 Sodium chloride 7.0 Hydrochloric acid and / or sodium hydroxide adjust pH 7.4 ± 0.2 Water for injection qs Example 7 Inhibition of angiogenesis in the rabbit cornea neovascularization model: The BenEzra corneal pocket system (Am. J. Ophthalmol 86: 455-461, 1978) was used to induce neovascularization of the cornea in the cornea. rabbit. A small pellet of Elvax containing 0.5 μg of lipopolysaccharide (LPS) was inserted into the middle part of the corneal stroma and placed 2.5 mm from the limbus. An additional Elvax granule with or without 50 μg of angiostatic steroid was placed next to the LPS implant. The eyes were examined daily and the area of neovascularization was calculated. Figure 1 shows the results 8 days after the implantation of LPS. THF - tetrahydrocortisol; A = 4, 9 (11) -pregnadien-17alpha, 21-diol-3,20-dione-21-acetate; B = 4, 9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione. As can be seen, A & B completely inhibited neovascularization of the cornea, whereas THF partially inhibited the "neovascular response.

Claims (5)

1. CLAIMS 1. A method for preventing and treating ocular neovascularization, comprising the use of PDT in combination with a compound selected from the group consisting of 4, 9711) -pregnadien-17alpha, 21-diol-3,20-dione- 21- acetate, 4.9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione, 11-epitortisol, 17alpha-hydroxyprogesterone, tetrahydrocortexolone (THS), and tetrahydrocortisol (THF).
2. 2. The method according to claim 1 wherein the angiostatic steroid is 4, 9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione-21-acetate,
3. 3. The method of claim 1 wherein the Angiostatic steroid is 4, 9 (11) -pregnadien-17alpha, 21-diol-3, 20-dione.
4. 4. The method of claim 1 wherein the angiostatic steroid is administered in a concentration of about 0.01 to 15.0% by weight.
5. 5. The method according to claim 4 wherein the angiostatic steroid is administered at a concentration of about 0.1 to 7.5% by weight.