WO2013110152A1 - Compositions pharmaceutiques contenant des activateurs de l'axe enzyme de conversion de l'angiotensine 2/angiotensine-(1-7)/récepteur mas pour le traitement de pathologies oculaires - Google Patents

Compositions pharmaceutiques contenant des activateurs de l'axe enzyme de conversion de l'angiotensine 2/angiotensine-(1-7)/récepteur mas pour le traitement de pathologies oculaires Download PDF

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WO2013110152A1
WO2013110152A1 PCT/BR2013/000029 BR2013000029W WO2013110152A1 WO 2013110152 A1 WO2013110152 A1 WO 2013110152A1 BR 2013000029 W BR2013000029 W BR 2013000029W WO 2013110152 A1 WO2013110152 A1 WO 2013110152A1
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treatment
pharmaceutical compositions
eca2
activator
glaucoma
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PCT/BR2013/000029
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Portuguese (pt)
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Anderson José FERREIRA
Giselle FOUREAUX DE FARIA
José Carlos NOGUEIRA
Bárbara SILVA NOGUEIRA
Gustavo DE OLIVEIRA FULGÊNCIO
Juçara RIBEIRO FRANCA
André Augusto GOMES FARACO
Robson Augusto Souza Dos Santos
Danielle CARVALHO DE OLIVEIRA COUTINHO
Mohan K RAIZADA
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Universidade Federal De Minas Gerais - Ufmg
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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention describes pharmaceutical compositions containing Angiotensin 2 (ECA2) / Angiotensin- (1-7) [Ang- (1-7)] / Receptor Axis Enzyme Axis Activators and their use in the treatment of related eye conditions. with increased intraocular pressure (IOP) and / or retinal and / or optic nerve degeneration such as glaucoma and retinopathy, preferably diabetic retinopathy.
  • Such pharmaceutical compositions may be administered by any drug administration route, preferably oral, topical, intraocular, periocular, conjunctival or intravenous routes, among others.
  • the pharmaceutical forms used are preferably solution, suspension, emulsion, capsule (hard or gelatinous), tablet, gel, cream, lotion, film, microcapsule, nanocapsule, nanosphere, microsphere, nanoemulsion, microemulsion and / or liposomes.
  • Glaucoma is a neurodegenerative disease characterized by progressive death of retinal ganglion cells and degeneration of the optic nerve. It is estimated that the disease affects more than 67 million people worldwide, being the third leading cause of partial vision loss and the second leading cause of blindness (Johnson TV, Tomarev SI. Rodent models of glaucoma. Brain Res. Buli. , v. 81, pp. 349-58, 2010; Cronemberger S, Lourenco LFS, Silva LC, Calixto, Pires MC Prognosis of glaucoma in relation to blindness at a university hospital Arq. Bras Oftalmol., v.72, n.2, pp. 199-204, 2009; Who. World Health Organization.
  • IOP intraocular pressure
  • glaucoma may be congenital, primary or secondary to other pathologies.
  • the most common manifestation of the disease is primary glaucoma.
  • GPAF angle-closure
  • GPAA angle-closure
  • retinopathies Another group of conditions that can lead to impaired vision through retinal cell degeneration are retinopathies.
  • One of the main retinopathies is diabetic.
  • DM diabetes mellitus
  • Bosco A Lerário AC, Soriano D, Santos RF, Massote P, Galv ⁇ o D, Franco AC, Purisch S, Ferreira AR. Retinopathy Endocrinol Metab., V.49, No. 2, pp. 217-227, 2005.
  • DM is considered one of the major public health problems, being among the top 10 causes of mortality (Malerbi DA, Franco LJ.
  • Diabetic retinopathy is one of the most common complications of DM and can be present in both type 1 and type 2 DM patients, becoming the most frequent cause of acquired blindness (Bosco A, Lerário AC, Soriano D, Santos RF). , Massote P, Galvao D, Franco AC, Purisch S, Ferreira AR Diabetic Retinopathy Arq Bras Endocrinol Metab, v.49, no 2, pp 217-227, 2005; Ferris III FL Diabetic retinopathy Diabetes Care, v. 16, pp.
  • Angiotensin II (Ang II), a well-known blood pressure control molecule, is also present in various retinal layers (ganglion cells, photoreceptor layer, endothelial cells and Muller cells) (Savaskan E, Loffler KU, Meier F, Muller S, Flammer J, Meyer P. Immunohistochemical localization of angiotensin II and AT1 receptor in human ocular tissues. Ophthalmic, v. 36, p. 312-320, 2004). With respect to Muller cells, Ang II appears to be involved in regulating vascular permeability and blood flow, and in forming and maintaining the blood-retinal barrier.
  • the Muller cell is a very specialized cell and is the main retinal glial cell, spanning the full depth of this structure. As a result of this arrangement, these cells intersect between the vessels and neurons, playing an important role in glucose uptake from the circulation and energy transfer to the neurons (Park SH, Park JW, Park SJ, et al. Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina Diabetologia, v. 46, pp. 1 260-1268, 2003; Senanayake P, Drazba J, Shadrach K, Milsted A, Rungger-Brandle E, Nisbiyama K, Miura S, Karnik S, Sears JE, Hollyfield J. Angiotensin II and its receptor subtypes in the human retin Invest Invest Ophthalmol Vis Sci, v. 48, no 7, pp 3301-331, 2007).
  • ECA2 Angiotensin-Converting Enzyme 2
  • ACE Angiotensin-Converting Enzyme 2
  • the main activity of ECA2 is the conversion of Ang II, which has vasoconstrictor and hypertensive activity, to the peptide Angiotensin- (1 - 7) [Ang- (1 -7)], which in turn has vasodilatory and antiproliferative activity (Chappell MC, Ferrario CM Angiotensin (1-7) in hypertension Curr Opin Opin Nephrol Hypertens, v.
  • Drugs used to lower systemic blood pressure have also shown activity in reducing IOP (Hashimoto M, Silva MRBM, Neto, FJT. Effect of drugs used in treatment of systemic arterial hypertension on intraocular pressure: experimental study in dogs. Arq. Bras. Ophthalmol., V.65, p. 229-33, 2002; Mohamed R, Al-Sereiti, Turner, P. Effect of Captopril (an Angiotensin-Converting Enzyme Inhibitor) on Intraocular Pressure in Healthy Human Volunteers. J. Ocul. Pharmacol. Ther., V. 5, no. 1, p. 1-5, 1989).
  • Ang II has been associated with the risk of developing both diabetic retinopathy and glaucoma (Sramek SJ, Wallow IH, Tewksbury DA, Brandt CR, Poulsen GL. An ocular renin-angiotensin system. Immunohistochemistry of angiotensinogen. Invest. Ophthalmol Vis. Sci., V. 33, pp. 1627-1632, 1992; Nadal JA, Scicli GM, Carbini LA, Nussbaum JJ, Scicli AG, Angiontensin II and retinal perieytes migration; Fong DS, Aiello LP, Ferris FL , Klein R. Diabetic retinopathy Diabetes Care, v.
  • drugs capable of modulating the SARS in addition to acting as potent antihypertensive drugs, may also act as hypotensive and antiproliferative drugs.
  • ECA2 / Ang- (1-7) / Receptor axis may play an important role in ocular pathologies involving increased IOP and degeneration of retinal and / or optic nerve cells such as the glaucoma and retinopathies.
  • ECA2 activators have been developed as potential antihypertensive agents and from virtual scanning, xanthenone, 1 - [(2-dimethylamino) ethylamino] -4- (hydroxymethyl) -7 - [(4-methylphenyl) sulfonyloxy] - 9xanthen-9-one (XNT) and resorcinolnaphthalein have been identified as ECA2 activating agents.
  • XNT exhibits in vivo activity in lowering blood pressure (Hernandez Prada JA, AJ Ferreira, Katovich MJ, Shenoy V, Qi Y, Santos RAS, Castellano RK, AJ Lampkins, Gubala V, Ostrov Mida.
  • Diminazene (DIZE) has also recently been identified as an ECA2 activator and potential precursor of new antihypertensive agents (Dasgupta, C, Zhang L. Angiotensin II receptors and drug discovery in cardiovascular disease. Drug Discov. Today, v. 16, n Gjymishka A, Kulemina LV, Shenoy V, Katovich MJ, Ostrov DA, Rooted MK Decreased Aceturate is an ACE2 activator and a novel antihypertensive drug FASEB J., v. 24, p. 1,033, 2010).
  • DIZE is an aromatic diamidine used as a veterinary antiparasitic that has demonstrated significant trypanocidal activity (except for Trypanosoma cruzi) and leishmanicide (Jean-Moreno, Rojas R., Goyeneche D., Coombs GH and Walker J, Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays. Exp. Parasite /. , v. 1112, p.
  • the drug has been used to control trypanosomiasis in animals for over 40 years and, although never approved for human use, has been widely used in Africa to treat diseases caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense (Akpa PO, Ezeokonkwo).
  • RC Eze CA, Anene BM Comparative efficacy assessment of pentamidine isethionate and diminazene aceturate in the chemotherapy of Trypanosoma brucei brucei infection in dogs Parasito Vet., V. 2-4, pp. 39-49, 2008; Combination chemotherapy of CNS trypanosomiasis, Acta Tropica, v.
  • DIZE has also been associated with silver and has high antitumor activity and lipid nanoparticles containing the drug for potential brain release of the drug in the treatment of sleep sickness (Olbrich C, Gessner A, Schroder W, Kayser O, Muller RH, Olbrich C, Gessner A, Schroder W, Kayser O, MUIIer RH Lipid-drug conjugate nanoparticles of the hydrophilic drug diminishing cytotoxicity testing and mouse serum adsorption J. Control, Release, v.96, p.425-35 , 2004).
  • RU20081 50401 describes a formulation containing DIZE for the treatment of babesiosis.
  • WO9428162 describes the use of DIZE in the treatment of chronic trypanosomiasis in humans and other animals.
  • WO2008066770 describes pharmaceutical compositions containing DIZE for treating cardiovascular and cardiopulmonary diseases, preferably hypertension and pulmonary injuries.
  • controlled release systems for drug delivery is an important alternative among known treatment strategies.
  • Demand for controlled release systems for drug delivery has been widely reported in the literature. These systems have the advantage of allowing continuous, constant and prolonged release of the drug, maintaining a stable level of the drug in the patient's body and avoiding adverse effects that could occur compared to conventional administration.
  • new solid, semi-solid and liquid dosage forms have been developed to meet this need. Examples include liposomes, micro and nanospheres, micro and nanocapsules, coated tablets, transdermal patches and implants, among others.
  • the use of these systems in the treatment of chronic diseases, such as glaucoma and diabetic retinopathy is even more interesting given that prolonged treatment and the need for frequent use of the drug limit the patient's adherence to treatment. can culminate in the blindness of the individual.
  • the present technology describes controlled or uncontrolled release pharmaceutical compositions containing ECA2 / Ang- (1-7) / Receptor axis activators and their use for the treatment of eye diseases involving increased IOP and / or degeneration of retinal cells and / or optic nerve.
  • compositions were administered by different routes, evaluating them for the treatment of diseases such as glaucoma and retinopathy, preferably diabetic retinopathy.
  • the results show the potent activity of ECA2 / Ang- (1 -7) / Receptor Mas axis activators in reducing IOP and protecting retinal and optic nerve cells.
  • angiotensin II and ACE antagonists in the treatment of retinopathy and glaucoma (CN 1 01690816, CN 1 01658675, CY2567, US7906501, PI001 0084-6, BRPI0409293), but no document found reports the use of activators. of ECA2.
  • Figure 1 Hydration potential of white implants and implants containing the ACE2 activator (DIZE).
  • FIG. 2 Infrared absorption spectrum of a model of ECA2 activator (DIZE) (A), white implants (B) and implants containing ECA2 activator (DIZE) (C).
  • DIZE ECA2 activator
  • FIG. 3 Differential exploratory calorimetry curves for a model of ECA2 activator (DIZE), white implants and implants containing ECA2 activator (DIZE) (a, first run; b, second run).
  • DIZE ECA2 activator
  • DIZE white implants and implants containing ECA2 activator
  • FIG. 4 Side scan electron micrographs of white implants (a) and implants containing ACE2 activator (DIZE) (b).
  • FIG. 5 In vitro release profile for implants containing ECA2 activator (DIZE).
  • Figure 6 Comparison of IOP values between control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated and ECA2 activator-treated (DIZE) treated animals as oral solution (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks. * p ⁇ 0.05 vs. Untreated control. #p ⁇ 0.05 vs. Untreated Glaucoma
  • Figure 7 Comparison of mean blood pressure values between control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated animals and ECA2 activator-treated (DIZE) treated animals. oral (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.
  • FIG 8 Comparison between retinal ganglion cell (Cg) morphometric data of control group (normal animals) and glaucoma group (animals with induced glaucoma), both subdivided into untreated animals and animals activated with ECA2 (SAYS) in the form of oral solution (gavage). Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.
  • Cg retinal ganglion cell
  • Figure 9 IOP of normal animals (control group) and with induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) in the form of eye drops (instillation), compared with normal animals (control group) and with induced glaucoma ( glaucoma group) untreated.
  • Study period 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks * p ⁇ 0.001 vs. Untreated control. #p ⁇ 0.001 vs. untreated glaucoma.
  • Figure 10 Systemic blood pressure of normal animals (control group) and induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) as eye drops (instillation) compared to normal animals (control group) and glaucoma. induced (glaucoma group) untreated. Study period: 4 weeks. Initiation of treatment: after first induction. End of treatment: after 4 weeks.
  • Figure 11 IOP of normal (control group) and induced glaucoma (glaucoma group) animals when treated with the eye receptor activator But in the form of eye drops (instillation), compared to animals with untreated induced glaucoma (glaucoma group).
  • Study period 1 week. Beginning of treatment: after first induction. End of treatment: 1 week. * p ⁇ 0.05 vs. Control. #p ⁇ 0.05 vs. Untreated glaucoma.
  • Figure 12 IOP of normal animals (control group) and induced glaucoma (glaucoma group) when treated with ECA2 activator (DIZE) in the form of eye drops (instillation), compared to normal animals (control group) and induced glaucoma ( glaucoma group) untreated. Study period: 5 weeks. Beginning of treatment (first arrow on graph): after second induction. End of treatment (second arrow on graph): before fourth induction. * p ⁇ 0.001 vs. untreated control. #p ⁇ 0.001 vs. untreated glaucoma.
  • DIZE ECA2 activator
  • Figure 13 Systemic blood pressure of normal (control group) and induced glaucoma (glaucoma group) animals when treated with eye drop activator (DIZE) in the form of eye drops (instillation) compared to normal animals (control group) and glaucoma induced (glaucoma group) untreated. Study period: 5 weeks. Beginning of treatment: after the second induction. End of treatment: before the fourth induction.
  • DIZE eye drop activator
  • FIG 14 IOP of normal (C) and induced glaucoma (G) animals when treated with ECA2 activator (DIZE) in the form of eye drops (instillation) with or without Mas A-779 receptor blocker compared to normal animals (control group) and with induced glaucoma (glaucoma group) not treated or treated with Mas receptor only.
  • Study period 3 weeks.
  • FIG 15 IOP of normal animals (control group) and with induced glaucoma (glaucoma group) when treated with implant-activated ECA2 activator (DIZE) compared to normal animals (control group) and induced glaucoma (glaucoma group) not treated. Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction. * p ⁇ 0.001 vs. untreated control. #p ⁇ 0.001 vs. untreated glaucoma.
  • DIZE implant-activated ECA2 activator
  • Figure 16 Systemic arterial blood pressure of normal animals (control group) and induced glaucoma (glaucoma group) when treated with an ACE2 activator (DIZE) as an implant compared to normal animals (control group) and induced glaucoma (group untreated glaucoma). Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction.
  • DIZE ACE2 activator
  • FIG 17 IOP of normal animals (graph B) and animals with induced glaucoma (graph A) when treated with the ECA2 activator (DIZE) in the form of eye drops (instillation) and in the implant form, compared to untreated and non-treated animals. with animals treated with white implants. Study period: 5 weeks. Initiation of treatment: after the second induction. End of treatment: before the fourth induction.
  • DIZE ECA2 activator
  • FIG. 18 Retinal ganglion cell (Cg) morphometry in diabetic animals treated with ECA2 activator (XNT) as oral solution (gavage) compared to untreated diabetic animals. Study period: 7 weeks. Initiation of treatment: after the second week. End of treatment: seventh week.
  • the present invention describes different pharmaceutical compositions containing ECA2 / Ang- (1-7) / Mas receptor activators, preferably ECA2 activators, for example DIZE and XNT, and Mas receptor activators such as HP CD / Ang. - (1-7). It also describes their use in the treatment of eye disorders related to increased IOP and / or retinal and / or optic nerve degeneration, such as glaucoma and retinopathies, preferably diabetic retinopathy.
  • the mentioned ECA2 / Ang- (1-7) / Receptor axis activators have been administered in conventional and extended release pharmaceutical compositions in the treatment of experimental hyauronic acid-induced glaucoma in rats and in the treatment of diabetic retinopathy. These activators caused potent IOP reduction in animals with induced glaucoma. In addition, activation of this axis reduced retinal cell degeneration in rats with retinopathy due to induced DM.
  • compositions which may be used for the delivery of ECA2 / Ang- (1-7) / Receptor Shaft Activators include, but are not limited to, conventional pharmaceutical compositions such as solutions, suspensions, tablets, gels, creams, capsules ( hard or gelatinous), emulsions, lotions, among others, and unconventional pharmaceutical compositions such as implants, micro or nanocapsules, micro or nanospheres, micro or nanoemulsions, liposomes, among others, whether they consist of any raw materials (for example, (lipid or mixed), with or without controlled release of ECA2 / Ang- (1-7) /
  • Such pharmaceutical compositions may be administered orally, topically, intraocularly, intraocularly, periocularly, conjunctivally or intravenously, among others.
  • the invention may be better understood without limitation from the following examples.
  • XNT and DIZE were used as the ECA2 activator model
  • HPpCD / Ang- (1-7) was used as the Mas Receiver activator model
  • the A-779 was used as the Mas Receiver blocker model.
  • Example 1 Obtaining and Characterization of Pharmaceutical Compositions Containing ECA2 Activators and Mas Receptor Activators
  • formulations for delivery of ECA2 activators conventional pharmaceutical forms have been developed. (oral solutions and eye drops) and implants for controlled drug release.
  • Oral solutions were obtained by diluting the ECA2 activators and the Receptor Mas activator in distilled water or another pharmacologically acceptable excipient.
  • Adjuvants such as preservatives, antioxidants, solubilizers, colorants, flavors, flavorings, sugars, viscous, sweeteners, chelators, pH correctors, among others, may be used.
  • Other oral dosage forms such as tablets, capsules, suspensions and syrups may also be used.
  • the oral solutions were clear and had a pH between 5.0 and 10.0, preferably between 6.0 and 9.0.
  • the eye drops were prepared by diluting the ECA2 activator or Mas receptor activator in pharmacologically acceptable excipient.
  • Isotonizers eg NaCl, Glycerol, Glucose
  • buffering agents eg phosphorus and sulfate salts
  • pH correctors eg HCl, NaOH
  • viscous antioxidant, chelating and preservative, among others.
  • Eye drops were sterilized and isotonia and pH were adjusted before use. The pH was between 5.0 and 10, preferably between 6.0 and 9.0.
  • Other pharmaceutical forms such as suspensions, ophthalmic ointments, gels, hydrogels and emulsions may also be used for topical drug delivery.
  • polymeric implants were developed. To obtain the implants, the polymer was dispersed in an aqueous solution containing ECA2 activator (when necessary, acid was used to promote polymer dispersion). The obtained dispersion was stirred to obtain a gel. This gel was spread on a smooth metallic, polymeric, glassy or ceramic surface, preferably polymeric, such as silicone plates, and allowed to dry to obtain the implants. Drying can be performed at room temperature or under heating. Multilayer implants can also be obtained by repeating the same procedure. After drying the first layer, solutions previously prepared as described for the first layer are spread over it and dried. This process can be repeated several times (between one and ten times, on average 3 times) to obtain the multilayer implants.
  • ECA2 activator-containing layers of the multilayer devices may or may not be layered without layers (white).
  • the number of white layers in the device ranges from 0 to n-1, where n is the number of device layers.
  • the order of distribution of layers is variable. Any distribution combination can be accepted. Distributions that allow ECA2 activator layers to be in the center and layers without ECA2 activator to be at the ends of implants are preferred.
  • inorganic acid preferably HCl, H3PO4, H2SO4, or organic acid, preferably acetic acid
  • the polymer concentration may range from 0.5 to 20% of the gel, preferably from 1 to 5%.
  • the final concentration of the ECA2 activator may range from 0.01 to 99% of the dry device weight, preferably from 0.1 to 30%.
  • the acid concentration may range from 0.5 to 50%.
  • the agitation time of the gel may vary from seconds to one week, preferably one or two days.
  • the stirrer used may be of any type. Drying can be done up to 40 ° C.
  • the polymer employed to obtain the implants may be natural, preferably selected from the group comprising celluloses, gums, exudates, gelatin, keratin, alginates, galactomannans, chitosans or their derivatives methyl, hydroxypropyl, acetophthalate, acetate, methoxy, hydropropoxy, acetophthalyl, carboxy carboxymethyl, thio, whether or not hydrolyzed, or their salts of Li, Na, K, Ca, Mg, Al, Zn, Fe, Cu, Ni, alone, or in combination or in the form of copolymers; or synthetic, preferably selected from the group comprising acrylic acid derivatives, preferably polyacrylate, polymethyl methacrylate, polyethylacrylate or polyethyl methacrylate, acid derivatives glycolic acid derivatives, hydrophilic or hydrophobic caprolactone derivatives, biodegradable or non-biodegradable.
  • Table 1 shows an example of gel formulation used to obtain the implants.
  • Table 1 Gel Composition for Obtaining ECA2 Activator Implants
  • Table 2 shows an example of gel composition for implants without ECA2 activator.
  • the implants obtained after drying of the formulations were further characterized.
  • the in vitro release profile of the implant was evaluated by dipping the devices in PBS buffer. After predetermined stirring times at a controlled temperature, all medium was removed and a new volume of medium was added to the implants.
  • the ECA2 activator present in the removed medium was dosed by a validated quantitation method (ultraviolet or visible absorption spectrophotometry, detector-coupled high performance liquid chromatography or mass spectrometer, gas-coupled gas chromatography). mass spectrometer, titration, or other suitable method, defined in accordance with ECA2 activator used). About 70% release of the implant ECA2 activator can be observed within the first two hours of the experiment. The remainder was not released even after 8 hours of study, suggesting an implant potential for controlled drug release (Figure 5).
  • micro and nanospheres such as micro and nanospheres, micro and nanocapsules, micro and nano emulsions and liposomes may be developed.
  • ECA2 activators and Mas receptor activators for the treatment of eye disorders has yet to be performed by other routes such as intravenous, intravitreal, periocular, intraocular, subconjunctival, intramuscular and subcutaneous.
  • routes such as intravenous, intravitreal, periocular, intraocular, subconjunctival, intramuscular and subcutaneous.
  • other controlled or uncontrolled release formulations such as injectable solutions, suspensions and emulsions may be produced, provided that pharmaceutically acceptable excipients are used.
  • Unilateral glaucoma was induced in the right eye of rats by injecting 30 ⁇ _ of hyaluronic acid (10mg / ml_) in the anterior chamber near the horny scleral limb once a week for 1 to 6 weeks, preferably 3 to 5 weeks. , always on the same day and time, following the protocol of Moreno et al., 2005 (Moreno MC, Marcos BHJA, Croxatto CJO, Sandea PH, Campanellia J, Jaliffaa CO, Benozzia J, Rosensteina RE. A new experimental model of glaucoma in rats through intracameral injections of hyaluronic acid (Experimental Eye Research, v. 81, pp.
  • the animals were anesthetized with general anesthetic (eg ketamine (70 mg / kg) exilazine 10 mg / kg) intraperitoneally and local anesthetic (eg 0.4% benoxinate in the cornea. No procedure was performed in left eye, which was used as a control group.
  • general anesthetic eg ketamine (70 mg / kg) exilazine 10 mg / kg
  • local anesthetic eg 0.4% benoxinate in the cornea.
  • IOP insulin-phosphate-semiconductor Activator
  • a tonometer eg TonoPen XL (Mentor, Norwell, MA)
  • TonoPen XL TonoPen XL (Mentor, Norwell, MA)
  • the measurement was performed on non-sedated animals contained gently with a small towel.
  • three IOP readings were obtained in each eye, and the mean of these three measurements was considered to be the corresponding IOP value for that day.
  • Example 3 Activity of the pharmaceutical composition containing orally administered ECA2 activators.
  • the IOP of the treated glaucoma (GT) group was significantly lower than that of the untreated glaucoma (GNT) group during the four weeks of ECA2 activator administration (Figure 6).
  • GT group was not statistically different from the untreated control group (CNT) at all 4 weeks.
  • CNT untreated control group
  • MAP mean arterial pressure
  • Example 5 Activity of conventional pharmaceutical composition containing topical ECA2 activators applied after the second induction of glaucoma.
  • the evaluation of the activity of conventional formulations containing ACE2 activators in the treatment of glaucoma was performed by induction of unilateral glaucoma once a week for 5 weeks. IOP measurements were also performed weekly for 5 weeks on the day before next induction. The location and daily treatment with eye drops containing ACE2 activator started after the second induction, that is, after confirming the elevated IOP. The treatment lasted for 15 days. After this period, the animals continued to undergo weekly induction for a further 2 weeks, but did not receive treatment.
  • Example 6 Blocking the activity of the conventional formulation containing ECA2 activators in reducing IOP by inhibiting the Mas receptor.
  • Example 7 Activity of controlled release pharmaceutical composition containing topical ECA2 activators in reducing IOP.
  • the activity of the extended release pharmaceutical compositions containing ECA2 activator described in Example 1 was evaluated by induction of unilateral glaucoma once a week for 5 weeks. IOP measurement was also performed weekly for 5 weeks on the day before the next induction.
  • the animals received a polymeric implant for controlled release of ACE2 activator, which was implanted into the conjunctival sac of animals after the confirmation of elevated IOP (2 after induction). The animals remained with the implant until the end of treatment.
  • the white implants also implanted immediately after the second induction
  • treatment by instillation of a solution containing ACE2 activator was considered. Treatment with the solution was also started immediately after the second induction and maintained daily for fifteen days.
  • ECA2 is expressed in the following retinal layers: pigmented epithelium (Ep), photoreceptors, external and internal plexiform cells and ganglion cells (Cg). ECA2 activator treatment increased ECA2 expression in these layers in both normal and diabetic rats.
  • Ep pigmented epithelium
  • Cg ganglion cells

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Abstract

La présente invention concerne des compositions pharmaceutiques contenant des activateurs de l'axe enzyme de conversion de l'angiotensine 2 (ECA2) / angiotensine-(1-7) [Ang-(1-7)] /récepteur Mas ainsi que l'utilisation de celles-ci dans le traitement de pathologies oculaires asosciées à une augmentation de la pression intraoculaire (PIO) et/ou à la dégénérescence de la rétine et/ou du nerf optique, telles que, par exemple, le glaucome et la rétinopathie, de préférence la rétinopathie diabétique. Ces compositions pharmaceutiques peuvent être administrées par n'importe quelle voie d'administration de médicaments, de préférence les voies orale, oculaire topique, intraoculaire, périoculaire, conjonctivale ou endoveineuse, entre autres. Les formes pharmaceutiques utilisées sont, de préférence, la solution, la suspension, l'émulsion, la capsule (dure ou gélatineuse), le comprimé, le gel, la crème, la lotion, le film, la microcapsule, la nanocapsule, la nanosphère, la microsphère, la nanoémulsion, la microémulsion et/ou les liposomes.
PCT/BR2013/000029 2012-01-27 2013-01-25 Compositions pharmaceutiques contenant des activateurs de l'axe enzyme de conversion de l'angiotensine 2/angiotensine-(1-7)/récepteur mas pour le traitement de pathologies oculaires WO2013110152A1 (fr)

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BR102012001875-6A BR102012001875A2 (pt) 2012-01-27 2012-01-27 composiÇço farmacÊuticas contendo ativadores do eixo enzima conversora de angiotensina 2/angiotensina-(1-7)/receptor mas para tratamento de patologias oculares
BRBR1020120018756 2012-01-27

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Cited By (1)

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US20190328828A1 (en) * 2017-01-06 2019-10-31 Uniao Quimica Farmaceutica Nacional S/A Pharmaceutical composition, process for producing the same, use of a peptide, use of a pharmaceutical composition and method for treating diseases associated with intraocular hypertension or glaucoma

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WO2008066770A2 (fr) * 2006-11-22 2008-06-05 University Of Florida Research Foundation, Inc. Composés activateurs de l'ace2 et procédés d'utilisation de ceux-ci
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WO2007041593A2 (fr) * 2005-10-03 2007-04-12 Combinatorx, Incorporated Associations de medicaments empechant la formation de cicatrices et leur utilisation
WO2007126857A1 (fr) * 2006-03-27 2007-11-08 Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs diamidine de tdp1
WO2008066770A2 (fr) * 2006-11-22 2008-06-05 University Of Florida Research Foundation, Inc. Composés activateurs de l'ace2 et procédés d'utilisation de ceux-ci
WO2008112659A2 (fr) * 2007-03-09 2008-09-18 Pathologica Llc Régulation de l'ostéopontine
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190328828A1 (en) * 2017-01-06 2019-10-31 Uniao Quimica Farmaceutica Nacional S/A Pharmaceutical composition, process for producing the same, use of a peptide, use of a pharmaceutical composition and method for treating diseases associated with intraocular hypertension or glaucoma

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