Use of melphalan in the preparation of an intravitreal medicament for the prevention of vitreoretinal proliferation

Abstract

The present application for a patent of invention relates to the use of melphalan in the preparation of an intravitreal medicament for the prevention of vitreoretinal proliferation. It belongs to the technical field of pharmaceuticals, particularly ophthalmic medicines, and comprises melphalan at a concentration of 5 μg / 0.1 mL, intended for intravitreal injectable administration during pars plana vitrectomy.

Description

[0001] "USE OF MELPHALAN IN THE PREPARATION OF AN INTRAVITREAL MEDICATION FOR THE PREVENTION OF VITREORETINAL PROLIFERATION"

[0002] INTRODUCTION

[0003] [1] This descriptive report refers to a patent application for the Use of Melphalan in the Preparation of an Intravitreal Medication for the Prevention of Vitreoretinal Proliferation, belonging to the technical sector of medicines, particularly ophthalmic medicines.

[0004] STATE OF THE ART

[0005] [2] Melphalan is an alkylating agent known for its ability to cause cellular damage through alkylation of DNA bases, resulting in breaks and cross-linking of the DNA molecule. This mechanism makes melphalan an effective agent in the treatment of several neoplastic diseases, including multiple myeloma, ovarian carcinoma, choroidal melanoma, and lymphomas. However, its systemic toxicity, particularly dose-dependent myelosuppression, has limited its systemic use. Recently, the intravitreal use of melphalan has been explored due to its potential to reduce cell proliferation, especially in ocular diseases such as retinoblastoma.

[0006] [3] Proliferative Vitreoretinal Proliferation (PVR): This is a serious complication of rhegmatogenous retinal detachment (RRD), where abnormal proliferation of cells in the retina leads to the formation of preretinal membranes, resulting in re-detachment and significant visual loss. Current therapeutic options for PVR include pars plana vitrectomy (PPV) and scleral buckling, many

[0007] Replacement sheets (rule 26) are sometimes not effective in preventing recurrence.

[0008] [4] Rationale for the use of Melphalan in PVR: Given the ineffectiveness of available therapeutic options for the treatment of PVR and considering that Melphalan is effective in inhibiting nucleic acid biosynthesis and cell proliferation, it was chosen for investigation, study, as a possible therapeutic intervention to prevent PVR recurrence after DRR surgery.

[0009] OBJECTIVE OF THE INVENTION

[0010] [5] The objective of the present invention is the use of Melphalan in the Preparation of an Intravitreal Medication for the Prevention of Vitreoretinal Proliferation.

[0011] [6] DRAWINGS

[0012] [7] The attached figures refer to Melphalan's usual kit, in which:

[0013] - Fig. 1 shows a diagram for preparing a standard intravitreal kit containing Melphalan 30mcg / 0.05ml, intended to be sent to the operating room in a double dose, in a 1 ml syringe with a 13x3 needle; in a sterile surgical-grade package with external identification on the packaging; and

[0014] - Fig. 2 shows a diagram for preparing a standard intravitreal kit containing Melphalan 20mcg / 0.05ml, intended to be sent to the operating room in a double dose, in a 1 ml syringe with a 13x3 needle; in a sterile surgical-grade package with external identification.

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] - STUDIES

[0017] [8] Studies have been carried out on the use of intravi- Melphalan

[0018] REPLACEMENT LEAF (RULE 26) during pars plana vitrectomy as a possible therapy to prevent recurrence of vitreoretinal proliferation after rhegmatogenous retinal detachment, which included a prospective safety pilot procedure of 3 months, as follows:

[0019] [9] - Regarding adverse effects of intravitreal melphalan already described in the literature for its established indication.

[0020]

[0010] Intravitreal melphalan is marketed under the name "Alkeran" by Aspen Pharmacare. It is primarily used in the treatment of retinoblastoma. The side effects observed with its use are:

[0021] - Local Retinal Toxicity: Pigmentary changes in the retina at the injection site.

[0022] - Cataract

[0023] - Uveitis: Inflammation of the uvea

[0024] - Vitreous Hemorrhage: Occurrence of bleeding in the vitreous humor.

[0025] Retinal Detachment

[0026] - Optic Atrophy: Degeneration of the optic nerve.

[0027] Endophthalmitis: Infection inside the eye.

[0028]

[0011] - Comparative Study of the Use of Intravitreal Melphalan: Current Treatment vs. Proposed Use for PVR and Retinal Detachment, Subject of the Present Invention

[0029]

[0012] About Current Treatment (Intraocular Retinoblastoma)

[0030] Preparation Instructions - Melphalan 30 mcg / 0.05 mL

[0031] Concentration and Dose:

[0032] - Concentration: 5 mg / mL - Initial Volume: 1.2 mL (6 mg) of Melphalan + 8.8 mL of 0.9% saline solution - Final Concentration: 600 mcg / mL - Dose: 30 mcg in each 0.05 mL - Preparation and Administration: - Dilution: A so-

[0033] REPLACEMENT SHEET (RULE 26) Melphalan solution is diluted in normal saline solution (0.9% NaCl). - Administration: Direct intravitreal injection through the pars plana using a fine needle (usually 30 gauge). Objective: - Effective and safe elimination of intraocular tumor cells, preserving visual function as much as possible and reducing the risk of metastatic complications.

[0034] - See attached figure 1 regarding: Preparation scheme for Intravitreal Chemotherapy - Melfano 30mgc / 0.05ml; and Instructions for sending to the operating room: Send in duplicate dose, in a 1 ml syringe, with a 13x3 needle; in a sterile surgical grade package, with external identification on the package.

[0035] Preparation instructions - Melphalan 20 mcg / 0.05 ml

[0036] Concentration and Dose:

[0037] - Concentration: 5 mg / mL - Initial Volume: 0.8 mL (4 mg) of Melphalan + 9.2 mL of 0.9% saline solution - Final Concentration: 400 mcg / mL - Dose: 20 mcg in each 0.05 mL Preparation and Administration: - Dilution: The Melphalan solution is diluted in normal saline solution (0.9% NaCl). - Administration: Direct intravitreal injection through the pars plana using a fine needle (usually 30 gauge). Objective: - Effective and safe elimination of intraocular tumor cells, maximizing visual function preservation and reducing the risk of metastatic complications.

[0038] - See attached figure 2 regarding: Preparation scheme for Intravitreal Chemotherapy - Melfano 20mgc / 0.05ml; and Instructions for sending to the operating room: Send in duplicate dose, in a 1 ml syringe, with a 13x3 needle; in sterile surgical grade packaging, with external identification on the packaging -.

[0039] REPLACEMENT SHEET (RULE 26)

[0013] - Regarding the new Proposed Use (Retinal Detachment and P-VR), subject of the present invention

[0040] Concentration and Dose:

[0041] - Proposed Concentration: 5 micrograms per 0.1 ml. - Injection Volume: 0.1 ml.

[0042] - Proposed Osmolarity: 270 to 290 mOsm / L.

[0043] Preparation Method

[0044] Step 1: Solution A Preparation

[0045] - Vial of Melphalan (Alkeran): 50 mg / 10 ml. - Initial Dilution: - Divide the 50 mg vial into 10 vials of 5 mg. - Inject 1 ml of diluent into the 5 mg Alkeran vial to obtain a concentration of 5000 pg / ml (micrograms per ml).

[0046] Step 2: Preparation of Solution B

[0047] -Solution A: 5000 pg / ml. -Dilution of Solution B: -Take 1 ml of Solution A. -Add 9 ml of BSS (balanced saline solution). -Total of 10 ml of solution resulting in 500 pg / ml (5000 pg / 10 ml = 500 pg / ml).

[0048] Step 3: Preparation of Solution C

[0049] -Solution B: 500 pg / ml. -Final Dilution for Solution C: -Take 1 ml of Solution B. -Add 9 ml of BSS. -Total of 10 ml of solution resulting in 50 pg / ml (500 pg / 10 ml = 50 pg / ml).

[0050] - Final Concentration

[0051] -To obtain a concentration of 5 pg / 0.1 ml:

[0052] -50 pg / ml is equal to 5 pg / 0.1 ml.

[0053]

[0014] Additional information regarding studies related to the present invention:

[0054]

[0015] About Differences between BSS (Balanced Salt Solution) and SF

[0055] Replacement sheet (rule 26) (physiological saline solution) in eye surgery:

[0056]

[0016] Compositions:

[0057]

[0017] BSS (Balanced Salt Solution): BSS is a balanced saline solution specifically formulated for use in ophthalmic surgery. In addition to sodium chloride (NaCl), it contains additional ions such as potassium, calcium, magnesium, and bicarbonate. These components help maintain ionic homeostasis and pH balance during surgery, which is essential for preserving the normal functions of eye cells.

[0058]

[0018] Physiological Saline (PS) (0.9% NaCl): Physiological saline is a simple solution composed of 0.9% sodium chloride dissolved in water. It does not contain the additional ions found in BSS and therefore does not offer the same support for cellular function.

[0059]

[0019] Osmolarity:

[0060]

[0020] BSS: The osmolarity of the BSS is adjusted to more closely approximate the osmolarity of the eye's natural fluids, which helps prevent osmotic disturbances that could cause edema or cellular dehydration during surgery.

[0061]

[0021] Physiological Saline Solution: The osmolarity of physiological saline solution is fixed at around 308 mOsm / L, which, although isotonic with respect to blood, may not be ideal for ocular tissues, especially during prolonged procedures.

[0062]

[0022] £H:

[0063]

[0023] BSS: BSS is buffered to maintain a stable pH, typically around 7.4, which is crucial to avoid changes in the ocular environment that could affect cellular function and metabolism during surgery.

[0064] REPLACEMENT SHEET (RULE 26)

[0024] Physiological Saline: Physiological saline is not buffered, which means that there may be pH fluctuations that can negatively affect eye tissues during delicate procedures.

[0065]

[0025] Benefit of Using BSS:

[0066]

[0026] The use of BSS, instead of saline solution, during vitrectomy in the intravitreal Melphalan study provides a more suitable solution for maintaining the health and function of ocular tissues. This is particularly important when considering the fragility of retinal tissue and the need to minimize any additional risk of cell damage or inflammation during surgery. BSS helps avoid complications that could arise from the use of a less balanced solution such as saline solution.

[0067]

[0027] This adjustment may be crucial to ensure the safety and efficacy of Melphalan in the treatment of Vitreoretinal Proliferation (VR-P), resulting in better surgical outcomes and a lower risk of adverse effects.

[0068]

[0028] About Objective:

[0069]

[0029] Treatment of PVR and Retinal Detachment: Aims to reduce cell proliferation and fibrosis associated with PVR, improving the success rate in the treatment of retinal detachment and reducing the need for repeated surgical interventions for retinal re-detachment.

[0070]

[0030] About Comparison

[0071]

[0031] Drug Concentration: The proposed concentration (5 micrograms / 0.1 ml) is significantly lower than that used in the treatment of retinoblastoma (20-30 micrograms per injection). This may be beneficial in minimizing potential toxic effects on the retina.

[0072] REPLACEMENT LEAF (RULE 26) and other sensitive ocular structures, considering the different pathologies and physiology involved. Therapeutic Objective: While current treatment focuses on eliminating tumor cells in retinoblastoma, the proposed use focuses on modulating the cellular response and fibrosis in PVR and retinal detachment, requiring adjustments in dosage and osmolarity to optimize therapeutic results and minimize adverse effects.

[0073]

[0032] About Methodology

[0074]

[0033] About Study Design:

[0075]

[0034] -Type:

[0076] - Prospective, interventional, and cross-sectional study.

[0077] Participants:

[0078] Six patients with primary DRR and PVR were included, aged between 18 and 85 years. All signed an informed consent form for the off-label use of domelphalan.

[0079] - Surgical Procedures: - All patients underwent VVPP, PVR removal, scleral buckle, and intravitreal injection of Melphalan (5 pg / 0.1 ml) in the posterior pole over the macula and optic disc before silicone oil implantation.

[0080] - Safety and Monitoring: - Patients were followed up for 90 days post-operatively with corrected visual acuity (BCVA) tests, wide-angle retinography, wide-angle autofluoresceinography, wide-angle fluorescein angiography, and optical coherence tomography (OCT).

[0081]

[0035] - Results

[0082] - Visual Acuity:

[0083] Significant improvement in visual acuity was observed in all

[0084] REPLACEMENT SHEET (RULE 26) patients. The mean BCVA (LogMAR) improved from 2.11 ± 0.22 preoperatively to 0.84 ± 0.42 at 90 days postoperatively (p<0.01).

[0085] - PVR recurrence:

[0086] Neither eye showed signs of PVR recurrence during the 90-day follow-up.

[0087] - Toxicity:

[0088] No signs of intraocular toxicity attributable to the use of Melphalan were observed.

[0089]

[0036] Discussion:

[0090]

[0037] The study demonstrated that intravitreal administration of Melphalan (5 pg / 0.1 ml) during WPP is safe and not associated with signs of intraocular toxicity or recurrence of PVR in a short-term follow-up of 3 months. The absence of systemic complications and the improvement in visual acuity suggest that Melphalan may be a promising agent for preventing PVR after DRR surgery. Innovative Advantage of the Study: This study is the first to explore the use of intravitreal Melphalan in association with WPP and Scleral Buckling to treat PVR secondary to DRR. The technique shows promise in preventing PVR recurrence, which could revolutionize the therapeutic approach to this condition.

[0091]

[0038] Conclusion:

[0092]

[0039] This pilot study demonstrated that intravitreal administration of Melphalan during pars plana vitrectomy (PPV) is a promising therapeutic approach to prevent the recurrence of proliferative vitreoretinal proliferation (PVR) after surgery.

[0093] Replacement sheet (rule 26) rhegmatogenous retinal detachment (RRD).

[0094]

[0040] Furthermore, during the 90-day follow-up period, no patient showed signs of PVR recurrence, suggesting that Melphalan can effectively inhibit the cell proliferation that leads to this complication. Another crucial point is that no signs of intraocular toxicity related to the use of Melphalan were observed, which reinforces the safety of the drug when used at a dosage of 5 pg / 0.1 ml.

[0095]

[0041] These findings are particularly relevant given that current therapeutic options for PVR, such as VVPP and Scleral Buckling, are often insufficient to prevent recurrence of the condition. The introduction of Melphalan as part of the surgical protocol may represent a significant innovation in the management of PVR, potentially improving patients' visual outcomes and reducing recurrence rates.

[0096]

[0042] In conclusion, intravitreal administration of Melphalan during VVPP represents an innovative and potentially effective approach in the treatment of PVR, offering new hope for patients suffering from rhegmatogenous retinal detachment. This study lays the groundwork for future research that may consolidate the role of Melphalan in the treatment of vitreoretinal complications.

[0097] ABOUT THE OBJECT TO BE PROTECTED IN THE PATENT APPLICATION

[0098]

[0043] Based on the studies described above, the subject of this patent application is the use of Melphalan in obtaining an Intravitreal Medication for the Prevention of Vitreoretinal Proliferation.

[0099] REPLACEMENT SHEET (RULE 26)

[0044] The aforementioned medicine comprises: Melphalan in a dilution of 5pg / 0.1 ml; and the diluent comprises Balanced Saline Solution, BSS.

[0100]

[0045] The aforementioned medicine is formulated to have an osmolarity between 270 and 290 mOsm / L.

[0101]

[0046] The aforementioned medication is intended for intravitreal injection during pars plana vitrectomy and is packaged in an ampoule.

[0102]

[0047] This medication is indicated for the prevention of vitreoretinal proliferation.

[0103]

[0048] The above-described medicine is obtained by usual industrial processes, suitably adjusted for the application.

[0104]

[0049] Within the basic solutions described above, it is claimed that the Intravitreal Medication for the Prevention of Vitreoretinal Proliferation, consisting of Melphalan in a dilution of 5pg / 0.1 ml, the subject of this patent application, may undergo modifications relating to ingredients, steps and parameters of production without departing from the scope of the protection sought.

[0105] REPLACEMENT SHEET (RULE 26)

Claims

Claims 1) “USE OF MELPHALAN”, characterized by being in the preparation of an intravitreal medication for the prevention of vitreoretinal proliferation. 2) “INTRAVITREAL MEDICINE FOR PREVENTION OF VITREORRETINAL PROLIFERATION”, characterized by Melphalan at a concentration of 5 pg / 0.1 ml; and by a diluent comprising Balanced Saline Solution, BSS. 3) “INTRAVITREAL MEDICATION FOR PREVENTION OF VITREORRETINAL PROLIFERATION”, according to claim 2, characterized by an osmolarity of 270 to 290 mOsm / L.

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