WO2021163776A1 - Subcutaneous implants for slow controlled release of active agents - Google Patents

Subcutaneous implants for slow controlled release of active agents Download PDF

Info

Publication number
WO2021163776A1
WO2021163776A1 PCT/BR2020/050528 BR2020050528W WO2021163776A1 WO 2021163776 A1 WO2021163776 A1 WO 2021163776A1 BR 2020050528 W BR2020050528 W BR 2020050528W WO 2021163776 A1 WO2021163776 A1 WO 2021163776A1
Authority
WO
WIPO (PCT)
Prior art keywords
implants
subcutaneous
slow
collagen
active
Prior art date
Application number
PCT/BR2020/050528
Other languages
French (fr)
Portuguese (pt)
Inventor
Marco Antonio BITTENCOURT
Original Assignee
Bittencourt Marco Antonio
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bittencourt Marco Antonio filed Critical Bittencourt Marco Antonio
Publication of WO2021163776A1 publication Critical patent/WO2021163776A1/en

Links

Classifications

    • 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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • DE ACTIVES which refers to subcutaneous implants to be used for the slow and controlled release of active agents both in domesticated animals and in humans, making their degradation rate constant, effective and safe. Therefore, implants are understood by the association of active agents to one of the known types of collagens, or even to other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids.
  • the present invention belongs to the section of human need, to the field of health; more specifically, to preparations for veterinary and medical purposes; for describing subcutaneous implants for human and veterinary use to release the active ingredient of interest, understood by the association of active agents with one of the types of collagen, or with other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, peptides of collagen, hyaluronic acid or fatty acids.
  • Controlled release systems have several advantages over conventional release systems, among them, according to Rodrigues (2012: Study of the Controlled Release of Drugs by Hydrogel of PVA/Atapulgite) we can mention: i. decreased toxicity and longer permanence of the drug in the bloodstream; ii. decreased side effects, due to the higher level of precision and location of the drug in the body; iii. progressive and controlled release of the drug, from matrix degradation, thus increasing therapeutic efficacy; iv. safe administration with no local inflammatory reactions and fewer doses; v. possibility of incorporating hydrophilic and lipophilic substances.
  • the present invention describes subcutaneous implants comprised by the association of active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed in order to provide a slow and controlled release of biochemical active agents (hormones, vasoactive drugs, steroid or non-steroid anti-inflammatory drugs, any class of drugs, as shown in table 1), both in domesticated animals and in humans , making its rate of degradation constant, effective to be released in the interstice, in addition to low risk of rejection by the body.
  • active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed in order to provide a slow and controlled release of biochemical active agents (hormones, vasoactive drugs, steroid or non-steroid anti-inflammatory drugs, any class of drugs,
  • the present invention makes an important contribution to the technical field, by providing implants that consist of the association of an active agent with one of the 29 types of collagen known or other substances already existing in the subcutaneous cellular tissue such as elastin, saturated fats , collagen peptides, hyaluronic acid and fatty acids; which delay the release of active agents, making the rate of degradation constant, and at the end of the process, the entire implant and its active were degraded and by the body, being incorporated or excreted, therefore, it is not necessary to remove the implants after the treatment.
  • the degradation of the proposed implants its contribution is also observed, since it is biochemical and slow, and can take up to 12 months, through it, the active agent is released into the bloodstream.
  • the process has a low risk of rejection, as collagen, fatty acids, collagen peptides and saturated fat are part of the subcutaneous cellular tissue.
  • the degradation time of the implants depends on the action of the active agent, since it is mixed with these substances, being released at constant and safe rates.
  • compositions for slow release of active agents there are some prior art that describe compositions for slow release of active agents.
  • subcutaneous implants comprised by the association of active agents with one of the known types of collagen, or with other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids.
  • Priority ES2290971T3 entitled “Device for local administration of solid or semi-solid formulations", describes solid or semi-solid formulations intended for the slow release of active agents in the site of interest.
  • the formulations described are obtained from a mixture of PVA with or without excipient, water, an organic solvent, oil or any other injectable liquid capable of giving the semi-solid form; such excipients being inorganic salts (calcium, magnesium, bismuth, zinc); lipids; carbohydrates (polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixture); proteins (gelatin, modified collagen, albumin, casein, derivatives and mixtures); natural and synthetic polymers (polyisobutyric acid, polylactic acid, polyglycolic acid, polylactide-polyglycolide copolymer (PLGA), polyester, polycaprolactone, polyethylene glycol, polypropylene glycol, Polyonics ® , polyanhydrides and their mixtures
  • Priority BRPI0210722B1 entitled “Biodegradable injectable implants and related methods of production and use”, describes injectable implants comprising glycolic acid and biocompatible/bioabsorbable polymeric particles containing a lactic acid polymer, in a pre-activated solid form or an activated form (eg suspension or emulsion for injection).
  • the implant particles are small enough to be injected through a needle, but large enough to prevent macrophage involvement.
  • Priority BRPI0620268A2 entitled “Sublimable controlled release delivery system and method of manufacturing the same” refers to compositions suitable for the delivery and/or stabilization of biologically active substances.
  • the compositions comprise a sublimable matrix material and the biologically active agent to be delivered.
  • the compositions can be used as drug delivery systems to treat a wide variety of diseases or as systems for the protection and stabilization of such substances. Methods for preparing compositions of the present invention are also disclosed.
  • Priority BRPI0511807B1 entitled “Pre-formulation, process of formation of a pre-formulation and its use” refers to formulation precursors (pre-formulations) for the in situ generation of controlled release lipid compositions.
  • the invention concerns preformulations in the form of low viscosity mixtures (such as molecular solutions) of amphiphilic components, and at least one bioactive agent that experiences at least one phase transition after exposure to aqueous fluids, such as bodily fluids, thereby forming a controlled release matrix that is optionally bioadhesive.
  • Priority BRPI0721055 entitled “Intraocular drug delivery systems” describes an injectable and biocompatible intraocular drug delivery system characterized by comprising: (a) a plurality of microspheres, and (b) an aqueous vehicle for the microspheres, wherein the microspheres consist essentially of: (1) a therapeutic agent which is an estradiol, and; (2) one or more biodegradable polymers, of which all biodegradable polymers are polylactic acid (PLA) polymers, and; wherein the drug delivery system has a viscosity that allows the drug delivery system to be injected into an intraocular location via a 20 to 30 gauge syringe needle.
  • PHA polylactic acid
  • Previous ES2259665T3 entitled "Neurotoxin implant” describes a controlled botulinum toxin release system, constituted of an association of inert polymeric matrix and botulinum toxin, where the toxin disperses in the matrix for a prolonged period without causing a significant immune response.
  • US20140371189A1 entitled “Testosterone replacement therapy in animals, including dogs” describes a form of testosterone replacement therapy in animals, and such replacement can be done in several ways, such as by intramuscular injection (IM) , with a syringe; transdermal application via a gel, cream or patch applied to the skin; orally by taking pills (this method is uncommon as it has been shown to have negative effects on the liver); sublingual / buccal dissolving a tablet under the tongue or against the gums; or even, by a tablet inserted under the skin, and it was observed that injectable and subcutaneous testosterone tablets remain active in the body for longer.
  • IM intramuscular injection
  • transdermal application via a gel, cream or patch applied to the skin orally by taking pills (this method is uncommon as it has been shown to have negative effects on the liver); sublingual / buccal dissolving a tablet under the tongue or against the gums; or even, by a tablet inserted under the skin, and it was observed that injectable and subcutaneous testosterone tablets remain
  • implants that comprise the association of active agents to one of the known types of collagen, or to other substances existing in the cell tissue subcutaneous, which allows the slow availability of the active with homogeneous degradation, safe and with low rejection rates considering that they are subcutaneous implants, whose structure is fully compatible with the application environment.
  • the invention aims to provide subcutaneous implants for the release of active agents in the interstitium, in a prolonged manner, with constant and homogeneous degradation rates, minimizing the risk of rejection and increasing the effectiveness of treatments that use them.
  • the present invention relates to subcutaneous implants comprised by the association of active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cell tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed for veterinary or human use, to release active agents in the interstitium, in a prolonged manner, with degradation rates constant and homogeneous, minimizing the risk of rejection and increasing the effectiveness of the treatments that use them.
  • active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cell tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed for veterinary or human use, to release active agents in the interstitium, in a prolonged manner, with degradation rates constant and homogeneous, minimizing the risk of rejection and increasing the effectiveness of the treatments that use them.
  • the present invention has as main advantages: Provide subcutaneous implants for the release of active agents in the interstitium in a prolonged manner with constant degradation rates; Provide subcutaneous implants for the release of active agents with low levels of rejection by the body, considering that they are produced from substances existing in the subcutaneous cellular tissue, such as one of the types of collagen, elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids; Provide subcutaneous implants whose active release is delayed, which makes their degradation constant; Provide subcutaneous implants for the release of active agents that, at the end of their release, have been totally degraded by the body, either through incorporated or through its excretion in a natural way.
  • Subcutaneous implants for slow release of actives are understood by the association of active agents, such as: hormones, vasoactive drugs, steroid or non-steroidal anti-inflammatory drugs, or any class of drugs recognized by the FDA (listed in table 1 , previously presented); associated with one of the 29 types of collagen or substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, fatty acids or hyaluronic acid, one of its main characteristics being the miscegenation of the active agent of interest to the vehicle.
  • active agents such as: hormones, vasoactive drugs, steroid or non-steroidal anti-inflammatory drugs, or any class of drugs recognized by the FDA (listed in table 1 , previously presented); associated with one of the 29 types of collagen or substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, fatty acids or hyaluronic acid, one of its main characteristics being the miscegenation of the active agent of interest to the vehicle.
  • the final composition of the implants is defined as a function of the need for each chemical species (type of active agent) and, in the case of animals, the patient species and the pathology to be treated.
  • chemical species type of active agent
  • the idealized proportion can vary between 1% to 99% of active up to 99% to 1% of vehicle, in equivalent mass and/or volumetric proportions.
  • the recommendation for use is diagnosed on a case-by-case basis, but generally it is a formulation with 30% active for 70% vehicle, which is considered the best combination to prolong its release, regardless of its morphology and /or physical state.
  • the degradation of the proposed implants is biochemical and slow, and may take up to 12 months, the same period of action of the active agent, since it is mixed with these substances, being released at constant and safe rates.
  • the active agent is released into the bloodstream, through a process that presents a low risk of rejection, as collagen, hyaluronic acid or fatty acids, collagen peptides and saturated fat are part of the subcutaneous cellular tissue.
  • the proposed implants can be made available in three forms: pellets, gel or liquid, depending on the original state of its components. Nevertheless, all presentation forms are constituted by the association of the active agent (in solid, liquid or gel state) to the vehicle (solid, liquid or gel), making it possible to obtain a multicomponent mixture in different states of matter, and in this case , the proportion between each substance will define the final state of the composite (implant). If the morphology is predominantly solid, then the likely implant configuration will be pellet. On the other hand, if the morphology is predominantly liquid, the implant is likely to be a gel configuration.
  • the components will be combined according to the desired formulation in a solid-solid mixture and properly homogenized to ensure and ensure that all components are well dispersed and physically integrated, which it takes place from the use of a mixer. After the mixing step, the composite will be weighed and compressed into pellets (implant in pellet form) of adequate size and weight for the desired therapeutic purpose. The recommendations for temperature, humidity, luminosity and/or other properties must follow the information and declarations of the raw material suppliers. [030] In order to obtain the implants in the form of gels, the combination of liquid and/or pasty components of the assets and vehicles is foreseen, properly homogenized to ensure and ensure that all components are well dispersed and physically integrated.
  • the gel composite (gel implant) will be weighed and filled in ampoules with adequate weight and/or volume for the desired therapeutic purpose.
  • the recommendations for temperature, humidity, luminosity and/or other properties must follow the information and declarations of the raw material suppliers.
  • each formulation will correspond to a specific and distinct formula. It is important to note that the vehicles used will also be absorbed by the body and play an important role in the controlled release of the active. However, when considering the active as the main element due to the physiological effects generated, then all implant formulations are the same, and only the release time may differ, with the effect of the active being exactly the same, regardless of the release time.

Abstract

The present invention relates to subcutaneous implants comprising associations of active agents in one of the known types of collagen, or in other substances present in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed in order to prolong the release of a biochemical active substance with constant uniform degradation rates in the interstitium of pets or humans, with a low risk of rejection by the organism. The present invention resolves the problems in the prior art related to degradation time, the need to remove/replace implants, high rates of rejection and irregular degradation of the active agent.

Description

IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E CONTROLADASUBCUTANEOUS IMPLANTS FOR SLOW AND CONTROLLED RELEASE
DE ATIVOS ASSET
BREVE DESCRIÇÃO BRIEF DESCRIPTION
[001] Trata a presente solicitação de patente de invenção de inéditos “IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E CONTROLADA[001] Treats this patent application for the invention of unpublished "SUBCUTANEOUS IMPLANTS FOR SLOW AND CONTROLLED RELEASE
DE ATIVOS”, que se refere a implantes subcutâneos a serem empregados para liberação lenta e controlada de agentes ativos tanto em animais domesticados quanto em seres humanos, tornando sua taxa de degradação constante, eficaz e segura. Para tanto, os implantes são compreendidos pela associação de agentes ativos a um dos tipos de colágenos conhecidos, ou ainda a outras substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos. DE ACTIVES”, which refers to subcutaneous implants to be used for the slow and controlled release of active agents both in domesticated animals and in humans, making their degradation rate constant, effective and safe. Therefore, implants are understood by the association of active agents to one of the known types of collagens, or even to other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids.
CAMPO DE APLICAÇÃO APPLICATION FIELD
[002] A presente invenção pertence à seção de necessidade humana, ao campo da saúde; mais especificamente, a preparações para finalidades veterinárias e médicas; por descrever implantes subcutâneos de uso humano e veterinário para liberação do princípio ativo de interesse, compreendidos pela associação de agentes ativos a um dos tipos de colágeno, ou ainda a outras substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos. CONVENCIMENTO [002] The present invention belongs to the section of human need, to the field of health; more specifically, to preparations for veterinary and medical purposes; for describing subcutaneous implants for human and veterinary use to release the active ingredient of interest, understood by the association of active agents with one of the types of collagen, or with other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, peptides of collagen, hyaluronic acid or fatty acids. CONVINENCE
[003] Os sistemas de liberação de agentes ativos que visam controlar sua liberação, a partir do condicionamento da velocidade e do local de liberação, cada vez mais, tem sido objeto de investigação da indústria farmacêutica e veterinária, alguns desses sistemas são: lipossomas, bombas osmóticas, revestimentos entéricos, sistemas transdérmicos, pró-fármacos e os sistemas matriciais poliméricos (Lopes, et. ai, 2005: Formas farmacêuticas de liberação modificada: polímeros hidrofílicos). [003] The release systems of active agents that aim to control their release, from the conditioning of the release rate and location, have increasingly been the object of investigation by the pharmaceutical and veterinary industry, some of these systems are: liposomes, osmotic pumps, enteric coatings, transdermal systems, prodrugs and polymeric matrix systems (Lopes, et. al, 2005: Modified release dosage forms: hydrophilic polymers).
[004] A tecnologia associada à modificação da liberação agentes ativos a partir de preparações farmacêuticas vem se desenvolvendo notoriamente nas últimas décadas, a fim de aproveitar ao máximo as vantagens inerentes às formas farmacêuticas de liberação controlada (Das, Das, 2003: Controlled-release of oral dosage forms). [004] The technology associated with modifying the release of active agents from pharmaceutical preparations has been developing remarkably in recent decades, in order to take full advantage of the inherent advantages of the forms controlled-release pharmaceuticals (Das, Das, 2003: Controlled-release of oral dosage forms).
[005] Sistemas de administração convencionais promovem um aumento na concentração do agente ativo logo após sua administração, atingindo um pico máximo de dosagem no sangue e declinando, conforme o tempo de ação do agente ativo. Com a liberação controlada tem-se uma constância na liberação durante quase todo o tempo de ação do ativo, o qual é administrado em dosagem terapêutica durante a maior faixa de tempo (Lyra, 2007: Sistemas Matriciais Hidrofílicos e Mucoadesivos para Liberação Controlada de Fármacos). [005] Conventional administration systems promote an increase in the concentration of the active agent soon after its administration, reaching a maximum dose peak in the blood and declining, according to the time of action of the active agent. With controlled release there is a constant release during almost the entire time of action of the active, which is administered in therapeutic dosage during the longest period of time (Lyra, 2007: Hydrophilic and Mucoadhesive Matrix Systems for Controlled Drug Release) .
[006] Os sistemas de liberação controlada apresentam diversas vantagens em relação aos sistemas de liberação convencionais, dentre elas, de acordo com Rodrigues (2012: Estudo da Liberação Controlada de Fármacos por Hidrogel de PVA/Atapulgita) pode-se citar: i. diminuição da toxidade e maior tempo de permanência da droga na circulação sanguínea; ii. diminuição dos efeitos colaterais, devido ao maior nível de precisão e localização do fármaco no organismo; iii. liberação progressiva e controlada do fármaco, a partir da degradação da matriz, aumentando assim a eficácia terapêutica; iv. administração segura com ausência de reações inflamatórias locais e um menor número de doses; v. possibilidade de incorporação de substâncias hidrofílicas e lipofílicas. [006] Controlled release systems have several advantages over conventional release systems, among them, according to Rodrigues (2012: Study of the Controlled Release of Drugs by Hydrogel of PVA/Atapulgite) we can mention: i. decreased toxicity and longer permanence of the drug in the bloodstream; ii. decreased side effects, due to the higher level of precision and location of the drug in the body; iii. progressive and controlled release of the drug, from matrix degradation, thus increasing therapeutic efficacy; iv. safe administration with no local inflammatory reactions and fewer doses; v. possibility of incorporating hydrophilic and lipophilic substances.
[007] Neste contexto, a presente invenção descreve implantes subcutâneos compreendidos pela associação de agentes ativos a um dos tipos de colágeno conhecidos, ou ainda a outras substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos, desenvolvidos com o intuito de proporcionar liberação lenta e controlada de agentes ativos bioquímico (hormônios, drogas vasoativa, anti-inflamatórios esteroides ou não esteroides, quaisquer classe de drogas, conforme tabela 1 ), tanto em animais domesticados quanto em seres humanos, tornando sua taxa de degradação constante, eficaz a serem liberadas no interstício, além de baixos riscos de rejeição pelo organismo. [007] In this context, the present invention describes subcutaneous implants comprised by the association of active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed in order to provide a slow and controlled release of biochemical active agents (hormones, vasoactive drugs, steroid or non-steroid anti-inflammatory drugs, any class of drugs, as shown in table 1), both in domesticated animals and in humans , making its rate of degradation constant, effective to be released in the interstice, in addition to low risk of rejection by the body.
Classes de drogas reconhecidas pela FDA
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
FDA Recognized Drug Classes
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Tabela 1 : Classes de drogas reconhecidas pela FDA, retirado e traduzido de https://www.drugs.com/drug-classes.html Table 1: FDA Recognized Drug Classes, removed and translated from https://www.drugs.com/drug-classes.html
[008] Atualmente, são largamente conhecidos implantes subcutâneos hormonais e de drogas como a metformina, esses implantes ressurgiram no mercado farmacêutico brasileiro na década de 2000, como uma forma segura, eficaz e, relativamente, duradoura para tratamentos hormonais diversos (Manica e Nucci, 2017: Sob a pele: implantes subcutâneos, hormônio e gênero). No entanto, tais implantes são disponibilizados em sua forma pura, sem estruturas de apoio, ou em tubos de silicone, quando se deseja retardar a liberação do ativo. [008] Currently, subcutaneous hormonal implants and drugs such as metformin are widely known, these implants reemerged in the Brazilian pharmaceutical market in the 2000s, as a safe, effective and relatively long-lasting way for various hormonal treatments (Manica and Nucci, 2017: Under the skin: subcutaneous implants, hormone and gender). However, such implants are available in their pure form, without support structures, or in silicone tubes, when you want to delay the release of the active.
[009] Os implantes atuais possuem alguns inconvenientes, os implantes com a forma pura do ativo apresentam um tempo de degradação bastante curto, cerca de 3 a 4 meses, em média, o que demanda novos procedimentos para colocação de novos implantes em intervalos menores. Já, a utilização dos implantes com silicone, os quais não apresentam seu uso regulamentado, necessitam ser removidos ao término de sua ação, tendo em vista se tratar de um corpo estranho ao organismo, além de ter uma degradação irregular, sendo necessárias aplicações de um grande número de implantes ( pellets ) sem a garantia de homogeneidade na transferência do agente ativo para o interstício. [010] É importante ressaltar que a implantação e a retirada dos implantes de silicone são procedimentos médicos veterinário e para humanos, portanto, envolvem o emprego de equipamentos técnicos e, portanto, procedimentos específicos a serem realizados por uma equipe médica em consultório/clínica. Esse transtorno é minimizado ao se empregar implantes que ao final do tratamento se degradam completamente no organismos, como os implantes propostos na presente invenção, que, por se constituírem de uma associação entre o agente ativo e substâncias naturalmente presentes no tecido celular subcutâneo, além de ter risco de rejeição baixíssimo, é completamente degradado, seja por sua absorção ou por excreção de maneira natural. [009] Current implants have some drawbacks, implants with the pure form of the active have a very short degradation time, about 3 to 4 months, on average, which requires new procedures for placing new implants at shorter intervals. On the other hand, the use of implants with silicone, which do not have their use regulated, need to be removed at the end of their action, since it is a foreign body to the body, in addition to having an irregular degradation, requiring applications of a large number of implants (pellets) without the guarantee of homogeneity in the transfer of the active agent to the interstitium. [010] It is important to emphasize that the implantation and removal of silicone implants are veterinary medical procedures and for humans, therefore, involve the use of technical equipment and, therefore, specific procedures to be performed by a medical team in the office/clinic. This disorder is minimized by using implants that, at the end of the treatment, completely degrade in the body, such as the implants proposed in the present invention, which, as they are constituted by an association between the active agent and substances naturally present in the subcutaneous cell tissue, in addition to having a very low risk of rejection, it is completely degraded, either by its absorption or excretion in a natural way.
[011] Assim, a presente invenção traz importantes contribuição ao campo técnico, por disponibilizar implantes que se constituem da associação de um agente ativo a um dos 29 tipos de colágeno conhecidos ou outras substâncias já existente no tecido celular subcutâneo como a elastina, gorduras saturas, peptídeos de colágeno, ácido hialurônico e ácidos graxos; as quais retardam a liberação dos agentes ativos, tornando a taxa de degradação constante, sendo que ao final do processo todo o implante e seu ativo foram degradados e pelo organismo, sendo incorporada ou excretada, portanto, não é necessária a retirada dos implantes após o tratamento. [011] Thus, the present invention makes an important contribution to the technical field, by providing implants that consist of the association of an active agent with one of the 29 types of collagen known or other substances already existing in the subcutaneous cellular tissue such as elastin, saturated fats , collagen peptides, hyaluronic acid and fatty acids; which delay the release of active agents, making the rate of degradation constant, and at the end of the process, the entire implant and its active were degraded and by the body, being incorporated or excreted, therefore, it is not necessary to remove the implants after the treatment.
[012] Em relação a degradação dos implantes propostos, também é observada sua contribuição, uma vez que ela é bioquímica e lenta, podendo levar até 12 meses, através dela, o agente ativo é liberado para a corrente sanguínea. O processo apresenta baixos riscos de rejeição, pois o colágeno, ácidos graxos, peptídeos de colágeno e gorduras saturadas fazem parte do tecido celular subcutâneo. Assim, o tempo de degradação dos implantes é mesmo da ação do agente ativo, uma vez que ele se encontra miscigenado a essas substâncias, sendo liberado em taxas constantes e seguras. Assim, a presente invenção resolve, de maneira inovadora, problemas presentes no campo técnico. [012] Regarding the degradation of the proposed implants, its contribution is also observed, since it is biochemical and slow, and can take up to 12 months, through it, the active agent is released into the bloodstream. The process has a low risk of rejection, as collagen, fatty acids, collagen peptides and saturated fat are part of the subcutaneous cellular tissue. Thus, the degradation time of the implants depends on the action of the active agent, since it is mixed with these substances, being released at constant and safe rates. Thus, the present invention solves, in an innovative way, problems present in the technical field.
ANTECEDENTES DA INVENÇÃO BACKGROUND OF THE INVENTION
[013] No atual estado da técnica, estão presentes algumas anterioridades que descrevem composições para liberação lenta de agentes ativos. No entanto, nenhuma delas descreve implantes subcutâneos compreendidos pela associação de agentes ativos a um dos tipos de colágeno conhecidos, ou ainda a outras substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos. [013] In the current state of the art, there are some prior art that describe compositions for slow release of active agents. However, none of them describe subcutaneous implants comprised by the association of active agents with one of the known types of collagen, or with other substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids.
[014] A anterioridade ES2290971T3, intitulada " Dispositivo de administracion local de formulaciones solidas o semi-sólidas" , descreve formulações sólidas ou semi-sólidas destinadas a liberação lenta de agentes ativos no local de interesse. As formulações descritas são obtidas a partir de uma mistura de PVA com ou sem excipiente, água, um solvente orgânico, óleo ou qualquer outro líquido injetável capaz de dar a forma semi-sólida; sendo tais excipientes sais inorgânicos (cálcio, magnésio, bismuto, zinco); lipídios; carboidratos (polissacarídeos, sacarose, glicose, agarose, dextrina, ciclodextrina e mistura); proteínas (gelatina, colágeno modificado, albumina, caseína, derivados e misturas); polímeros naturais e sintéticos (ácido poli-isobutírico, ácido polilático, ácido poliglicólico, copolímero de polilactídeo-poliglicolídeo (PLGA), poliéster, policaprolactona, polietileno glicol, polipropileno glicol, Polyonics®, polianidretos e suas misturas), podendo ainda apresentar quantidades de excipiente injetáveis, tais como: manitol e derivados celulósicos. [014] Priority ES2290971T3, entitled "Device for local administration of solid or semi-solid formulations", describes solid or semi-solid formulations intended for the slow release of active agents in the site of interest. The formulations described are obtained from a mixture of PVA with or without excipient, water, an organic solvent, oil or any other injectable liquid capable of giving the semi-solid form; such excipients being inorganic salts (calcium, magnesium, bismuth, zinc); lipids; carbohydrates (polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixture); proteins (gelatin, modified collagen, albumin, casein, derivatives and mixtures); natural and synthetic polymers (polyisobutyric acid, polylactic acid, polyglycolic acid, polylactide-polyglycolide copolymer (PLGA), polyester, polycaprolactone, polyethylene glycol, polypropylene glycol, Polyonics ® , polyanhydrides and their mixtures), which may also have excipient quantities injectables, such as: mannitol and cellulosic derivatives.
[015] A anterioridade BRPI0210722B1, intitulada "Implantes injetáveis biodegradáveis e métodos relacionados de produção e uso", descreve implantes injetáveis que compreendem ácido glicólico e partículas poliméricas biocompatíveis/bio-absorvíveis contendo um polímero de ácido láctico, em uma forma sólida pré-ativada ou uma forma ativada (por exemplo, suspensão ou emulsão injetável). As partículas dos implantes são pequenas o suficiente para serem injetadas através de uma agulha, mas, largas o suficiente para evitar o envolvimento pelos macrófagos. [015] Priority BRPI0210722B1, entitled "Biodegradable injectable implants and related methods of production and use", describes injectable implants comprising glycolic acid and biocompatible/bioabsorbable polymeric particles containing a lactic acid polymer, in a pre-activated solid form or an activated form (eg suspension or emulsion for injection). The implant particles are small enough to be injected through a needle, but large enough to prevent macrophage involvement.
[016] A anterioridade BRPI0620268A2, intitulada "Sistema de fornecimento com liberação controlada sublimável e método de fabricar o mesmo" refere-se a composições apropriadas para o fornecimento e/ou estabilização de substâncias biologicamente ativas. As composições compreendem um material de matriz sublimável e o agente biologicamente ativo a ser fornecido. As composições podem ser utilizadas como sistemas de fornecimento de droga para tratar uma ampla variedade de doenças ou como sistemas para a proteção e estabilização de tais substâncias. São também revelados métodos para preparar composições da presente invenção. [016] Priority BRPI0620268A2, entitled "Sublimable controlled release delivery system and method of manufacturing the same" refers to compositions suitable for the delivery and/or stabilization of biologically active substances. The compositions comprise a sublimable matrix material and the biologically active agent to be delivered. The compositions can be used as drug delivery systems to treat a wide variety of diseases or as systems for the protection and stabilization of such substances. Methods for preparing compositions of the present invention are also disclosed.
[017] A anterioridade BRPI0511807B1 , intitulada "Pré-formulação, processo de formação de uma pré-formulação e uso da mesma" refere-se a precursores de formulações (pré-formulações) para a geração in situ de composições lipídicas de liberação controlada. Em particular, a invenção diz respeito a pré- formulações na forma de misturas de baixa viscosidade (tais como as soluções moleculares) de componentes anfifílicos, e pelo menos um agente bioativo que experimente pelo menos uma transição de fase após a exposição a fluidos aquosos, tais como os fluidos corporais, desse modo formando uma matriz de liberação controlada que, opcionalmente, seja bioadesiva. [017] Priority BRPI0511807B1 , entitled "Pre-formulation, process of formation of a pre-formulation and its use" refers to formulation precursors (pre-formulations) for the in situ generation of controlled release lipid compositions. In particular, the invention concerns preformulations in the form of low viscosity mixtures (such as molecular solutions) of amphiphilic components, and at least one bioactive agent that experiences at least one phase transition after exposure to aqueous fluids, such as bodily fluids, thereby forming a controlled release matrix that is optionally bioadhesive.
[018] A anterioridade BRPI0721055, intitulada "Sistemas de liberação de fármacos intraoculares" descreve um sistema de liberação de fármaco intraocular injetável e biocompatível caracterizado por compreender: (a) uma pluralidade de microesferas, e (b) um veículo aquoso para as microesferas, em que as microesferas consistem essencialmente em: (1) um agente terapêutico o qual é um estradiol, e; (2) um ou mais polímeros biodegradáveis, dos quais todos os polímeros biodegradáveis são polímeros de ácido poliláctico (PLA), e; em que o sistema de liberação de fármaco tem uma viscosidade que permite que o sistema de liberação de fármaco seja injetado em uma localização intraocular através de uma agulha de seringa de calibre 20 a 30. [018] Priority BRPI0721055, entitled "Intraocular drug delivery systems" describes an injectable and biocompatible intraocular drug delivery system characterized by comprising: (a) a plurality of microspheres, and (b) an aqueous vehicle for the microspheres, wherein the microspheres consist essentially of: (1) a therapeutic agent which is an estradiol, and; (2) one or more biodegradable polymers, of which all biodegradable polymers are polylactic acid (PLA) polymers, and; wherein the drug delivery system has a viscosity that allows the drug delivery system to be injected into an intraocular location via a 20 to 30 gauge syringe needle.
[019] A anterioridade ES2259665T3, intitulada "Implante de neurotoxina" descreve um sistema de liberação controlado de toxina botulínica, constituído de uma associação de matriz polimérica inerte e toxina botulínica, sendo que a toxina se dispersa na matriz durante um período prolongado sem provocar resposta imunológica significativa. [019] Previous ES2259665T3 entitled "Neurotoxin implant" describes a controlled botulinum toxin release system, constituted of an association of inert polymeric matrix and botulinum toxin, where the toxin disperses in the matrix for a prolonged period without causing a significant immune response.
[020] A anterioridade US20140371189A1 , intitulada "Testosterone replacement therapy in animais, including dogs ", descreve uma forma de terapia de reposição de testosterona em animais, sendo que tal reposição pode ser feita de diversas maneiras, tais como por injeção intramuscular (IM), com uma seringa; aplicação transdérmica através de um gel, creme ou adesivo aplicado na pele; por via oral por ingestão de comprimidos (esse método é incomum, pois demonstrou ter efeitos negativos no fígado); sublingual / bucal dissolvendo um comprimido embaixo da língua ou contra as gengivas; ou ainda, por uma pastilha inserida sob a pele, sendo que foi observado que as pastilhas de testosterona injetáveis e subcutâneas permanecem ativas no organismo por mais tempo. [020] The former US20140371189A1 , entitled "Testosterone replacement therapy in animals, including dogs", describes a form of testosterone replacement therapy in animals, and such replacement can be done in several ways, such as by intramuscular injection (IM) , with a syringe; transdermal application via a gel, cream or patch applied to the skin; orally by taking pills (this method is uncommon as it has been shown to have negative effects on the liver); sublingual / buccal dissolving a tablet under the tongue or against the gums; or even, by a tablet inserted under the skin, and it was observed that injectable and subcutaneous testosterone tablets remain active in the body for longer.
[021] Apesar do grande número de anterioridades localizadas e da variedade de composições empregadas em implantes para liberação lenta, nenhuma delas descreve implantes que compreendem a associação de agentes ativos a um dos tipos de colágeno conhecidos, ou ainda a outras substâncias existentes no tecido celular subcutâneo, que possibilita a disponibilização lenta do ativo com degradação homogénea, segura e com baixos índices de rejeição tento em vista se tratar de implantes subcutâneos, cuja estrutura é totalmente compatível com o ambiente da aplicação. [021] Despite the large number of localized anteriorities and the variety of compositions used in implants for slow release, none of them describe implants that comprise the association of active agents to one of the known types of collagen, or to other substances existing in the cell tissue subcutaneous, which allows the slow availability of the active with homogeneous degradation, safe and with low rejection rates considering that they are subcutaneous implants, whose structure is fully compatible with the application environment.
OBJETIVO DA INVENÇÃO PURPOSE OF THE INVENTION
[022] A invenção tem por objetivo disponibilizar implantes subcutâneos para liberação de agentes ativos no interstício, de maneira prolongada, com taxas de degradação constantes e homogéneas, minimizando riscos de rejeição e aumentando a eficácia dos tratamentos que os utilizam. [022] The invention aims to provide subcutaneous implants for the release of active agents in the interstitium, in a prolonged manner, with constant and homogeneous degradation rates, minimizing the risk of rejection and increasing the effectiveness of treatments that use them.
DA INVENÇÃO THE INVENTION
[023] A presente invenção refere-se a implantes subcutâneos compreendidos pela associação de agentes ativos a um dos tipos de colágeno conhecidos, ou ainda a outras substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos, desenvolvidos para uso veterinário ou humano, para liberação de agentes ativos no interstício, de maneira prolongada, com taxas de degradação constantes e homogéneas, minimizando riscos de rejeição e aumentando a eficácia dos tratamentos que os utilizam. [023] The present invention relates to subcutaneous implants comprised by the association of active agents to one of the known types of collagen, or to other substances existing in the subcutaneous cell tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, developed for veterinary or human use, to release active agents in the interstitium, in a prolonged manner, with degradation rates constant and homogeneous, minimizing the risk of rejection and increasing the effectiveness of the treatments that use them.
VANTAGENS DA INVENÇÃO ADVANTAGES OF THE INVENTION
[024] A presente invenção apresenta como principais vantagens: Disponibilizar implantes subcutâneos para liberação de agentes ativos no interstício de maneira prolongada com taxas de degradação constantes; Disponibilizar implantes subcutâneos para liberação de agentes ativos com baixos índices de rejeição pelo organismo, tendo em vista que eles são produzidos a partir de substâncias existentes no tecido celular subcutâneo, tais como um dos tipos de colágenos, elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos; Disponibilizar implantes subcutâneos cuja liberação de ativo é retardada, o que torna sua de degradação constante; Disponibilizar implantes subcutâneos para liberação de agentes ativos que, ao final de sua liberação tenham sido totalmente degradados pelo organismo, seja por meio de incorporada ou por meio de sua excreção de maneira natural. [024] The present invention has as main advantages: Provide subcutaneous implants for the release of active agents in the interstitium in a prolonged manner with constant degradation rates; Provide subcutaneous implants for the release of active agents with low levels of rejection by the body, considering that they are produced from substances existing in the subcutaneous cellular tissue, such as one of the types of collagen, elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids; Provide subcutaneous implants whose active release is delayed, which makes their degradation constant; Provide subcutaneous implants for the release of active agents that, at the end of their release, have been totally degraded by the body, either through incorporated or through its excretion in a natural way.
DESCRIÇÃO DETALHADA DA INVENÇÃO DETAILED DESCRIPTION OF THE INVENTION
[025] Os implantes subcutâneos para liberação lenta de ativos são compreendidos pela associação de agentes ativos, tais como: hormônios, drogas vasoativa, anti-inflamatórios esteroides ou não esteroides, ou ainda, quaisquer classe de drogas reconhecidas pela FDA (dispostas na tabela 1 , anteriormente apresentada); associados a um dos 29 tipos de colágeno ou ainda substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácidos graxos ou ácido hialurônico, sendo, uma de suas principais características, a miscigenação do agente ativo de interesse ao veículo. [025] Subcutaneous implants for slow release of actives are understood by the association of active agents, such as: hormones, vasoactive drugs, steroid or non-steroidal anti-inflammatory drugs, or any class of drugs recognized by the FDA (listed in table 1 , previously presented); associated with one of the 29 types of collagen or substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, fatty acids or hyaluronic acid, one of its main characteristics being the miscegenation of the active agent of interest to the vehicle.
[026] A composição final dos implantes é definida em função da necessidade de cada espécie química (tipo de agente ativo) e, no caso de animais, à espécie paciente e à patologia a ser tratada. Considerando a possibilidade de diferentes e distintos veículos com propriedades também distintas: um dos 29 tipos de colágeno ou ainda substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos; a proporção idealizada pode variar entre 1% a 99% de ativo até 99% a 1% de veículo, em proporções mássicas e/ou volumétricas equivalentes. Assim, a recomendação de uso é diagnosticada caso a caso, porém, geralmente, trata-se de uma formulação com 30% de ativo para 70% de veículo, a qual é considerada a melhor combinação para prolongar sua liberação, independentemente da sua morfologia e/ou estado físico. [026] The final composition of the implants is defined as a function of the need for each chemical species (type of active agent) and, in the case of animals, the patient species and the pathology to be treated. Considering the possibility of different and distinct vehicles with also distinct properties: one of the 29 types of collagen or substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids; the idealized proportion can vary between 1% to 99% of active up to 99% to 1% of vehicle, in equivalent mass and/or volumetric proportions. Thus, the recommendation for use is diagnosed on a case-by-case basis, but generally it is a formulation with 30% active for 70% vehicle, which is considered the best combination to prolong its release, regardless of its morphology and /or physical state.
[027] Vale ressaltar que a degradação dos implantes propostos é bioquímica e lenta, podendo levar até 12 meses, mesmo período da ação do agente ativo, uma vez que ele se encontra miscigenado a essas substâncias, sendo liberado em taxas constantes e seguras. Através dela, o agente ativo é liberado para a corrente sanguínea, por um meio de um processo que apresenta baixo riscos de rejeição, pois o colágeno, ácido hialurônico ou ácidos graxos, peptídeos de colágeno e gorduras saturadas fazem parte do tecido celular subcutâneo. [027] It is noteworthy that the degradation of the proposed implants is biochemical and slow, and may take up to 12 months, the same period of action of the active agent, since it is mixed with these substances, being released at constant and safe rates. Through it, the active agent is released into the bloodstream, through a process that presents a low risk of rejection, as collagen, hyaluronic acid or fatty acids, collagen peptides and saturated fat are part of the subcutaneous cellular tissue.
[028] Os implantes propostos podem ser disponibilizados em três formas: pellets, gel ou líquida, a depender do estado original de seus componentes. Apesar disso, todas as formas apresentações são constituídas pela associação do agente ativo (em estado sólido, líquido ou gel) ao veículo (sólido, líquido ou gel), sendo possível a obtenção de uma mistura multicomponentes em diferentes estados da matéria, e nesse caso, a proporção entre cada sustância definirá o estado final do compósito (implante). Se a morfologia for predominantemente sólida, então a provável configuração do implante será pellet. Por outro lado, se a morfologia for predominantemente líquida, a provável configuração do implante será um gel. [028] The proposed implants can be made available in three forms: pellets, gel or liquid, depending on the original state of its components. Nevertheless, all presentation forms are constituted by the association of the active agent (in solid, liquid or gel state) to the vehicle (solid, liquid or gel), making it possible to obtain a multicomponent mixture in different states of matter, and in this case , the proportion between each substance will define the final state of the composite (implant). If the morphology is predominantly solid, then the likely implant configuration will be pellet. On the other hand, if the morphology is predominantly liquid, the implant is likely to be a gel configuration.
[029] Assim, para a obtenção dos implantes na forma de pellets, os compoentes serão combinados de acordo com a formulação desejada numa mistura sólido-sólido e devidamente homogeneizado para garantir e assegurar que todos os componentes estejam bem dispersos e integrados fisicamente, o que se dá a partir da utilização de um misturador. Após a etapa de mistura, o compósito será pesado e comprimido em pellets (implante em forma de pellet) de calibre e peso adequados para a finalidade terapêutica desejada. As recomendações de temperatura, umidade, luminosidade e/ou outras propriedades devem seguir as informações e declarações dos fornecedores das matérias-primas. [030] Para a obtenção dos implantes na forma de géis, é prevista a combinação de componentes líquidos e/ou pastosos dos ativos e veículos, devidamente homogeneizado para garantir e assegurar que todos os componentes estejam bem dispersos e integrados fisicamente, sendo para tanto, empregado um misturador. Após etapa de mistura, o compósito em gel (implante em forma de gel) será pesado e envasado em ampolas com peso e/ou volume adequados para a finalidade terapêutica desejada. As recomendações de temperatura, umidade, luminosidade e/ou outras propriedades devem seguir as informações e declarações dos fornecedores das matérias primas. [029] Thus, to obtain the implants in the form of pellets, the components will be combined according to the desired formulation in a solid-solid mixture and properly homogenized to ensure and ensure that all components are well dispersed and physically integrated, which it takes place from the use of a mixer. After the mixing step, the composite will be weighed and compressed into pellets (implant in pellet form) of adequate size and weight for the desired therapeutic purpose. The recommendations for temperature, humidity, luminosity and/or other properties must follow the information and declarations of the raw material suppliers. [030] In order to obtain the implants in the form of gels, the combination of liquid and/or pasty components of the assets and vehicles is foreseen, properly homogenized to ensure and ensure that all components are well dispersed and physically integrated. employed a mixer. After the mixing step, the gel composite (gel implant) will be weighed and filled in ampoules with adequate weight and/or volume for the desired therapeutic purpose. The recommendations for temperature, humidity, luminosity and/or other properties must follow the information and declarations of the raw material suppliers.
[031] Em relação à formulação dos implantes, é importante salientar que considerando-se que o ativo e o veículo fazem parte de um mesmo sistema terapêutico, cada formulação corresponderá a uma fórmula específica e distinta. É importante observar que os veículos utilizados, também serão absorvidos pelo organismo e desempenhando importante papel de liberação controlada do ativo. Porém, ao se considerar o ativo como o elemento principal pelos efeitos fisiológicos gerados, então todas as formulações dos implantes são iguais, podendo diferir apenas o tempo de liberação, sendo o efeito do ativo exatamente o mesmo, independentemente, do tempo de liberação. [031] Regarding the formulation of implants, it is important to note that considering that the active and the vehicle are part of the same therapeutic system, each formulation will correspond to a specific and distinct formula. It is important to note that the vehicles used will also be absorbed by the body and play an important role in the controlled release of the active. However, when considering the active as the main element due to the physiological effects generated, then all implant formulations are the same, and only the release time may differ, with the effect of the active being exactly the same, regardless of the release time.
[032] Tendo em vista que a presente invenção não foi antecipada no atual estado da técnica e que ela resolve, de maneira inovadora, problemas do campo técnico relacionados à disponibilização de agentes ativos de maneira lenta e com degradação homogénea de um sistema com baixíssimas chances de rejeição, compreendidos pela associação de agentes ativos, tais como hormônios, drogas vasoativa, anti-inflamatórios esteroides ou não esteroides, ou ainda, quaisquer classe de drogas, associados a um dos 29 tipos de colágeno ou ainda substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos, tanto para uso humano quanto veterinário, nota-se que a presente invenção é merecedora do privilégio de patente. [032] Given that the present invention was not anticipated in the current state of the art and that it solves, in an innovative way, problems in the technical field related to the availability of active agents slowly and with homogeneous degradation of a system with very low chances of rejection, comprised by the association of active agents, such as hormones, vasoactive drugs, steroid or non-steroid anti-inflammatory drugs, or any class of drugs, associated with one of the 29 types of collagen or substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids, for both human and veterinary use, it is noted that the present invention deserves the patent privilege.

Claims

REIVINDICAÇÕES
1. IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E1. SUBCUTANEOUS IMPLANTS FOR SLOW AND SLOW RELEASE
CONTROLADA DE ATIVOS caracterizado por serem compreendidos pela associação de agentes ativos, tais como hormônios, drogas vasoativa, anti-inflamatórios esteroides ou não esteroides, ou ainda, quaisquer classe de drogas reconhecida pela FDA; a um dos 29 tipos de colágeno ou ainda a substâncias existentes no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos. ACTIVE CONTROL characterized by being comprised by the association of active agents, such as hormones, vasoactive drugs, steroid or non-steroid anti-inflammatory drugs, or any drug class recognized by the FDA; to one of the 29 types of collagen or to substances existing in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides, hyaluronic acid or fatty acids.
2. IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E2. SUBCUTANEOUS IMPLANTS FOR SLOW AND SLOW RELEASE
CONTROLADA DE ATIVOS, de acordo com a reivindicação 1 , caracterizados pelo agente ativo estar miscigenado ao veículo, o qual é um dos 29 tipos de colágeno ou a uma das substâncias presente no tecido celular subcutâneo, tais como elastina, gordura saturada, peptídeos de colágeno, ácido hialurônico ou ácidos graxos. ACTIVE CONTROL, according to claim 1, characterized in that the active agent is mixed with the vehicle, which is one of the 29 types of collagen or one of the substances present in the subcutaneous cellular tissue, such as elastin, saturated fat, collagen peptides , hyaluronic acid or fatty acids.
3. IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E3. SUBCUTANEOUS IMPLANTS FOR SLOW AND SLOW RELEASE
CONTROLADA DE ATIVOS, de acordo com qualquer uma das reivindicações 1 ou 2, caracterizados por serem compreendidos pela associação de agentes ativos numa proporção entre 99 e 1% e de veículo numa proporção de 1 a 99%, preferencialmente, numa proporção de 30% de agente ativo para 70% de veículo, em proporções mássicas e/ou volumétricas equivalentes. ACTIVE CONTROL, according to any one of claims 1 or 2, characterized in that they are comprised by the association of active agents in a proportion between 99 and 1% and of vehicle in a proportion of 1 to 99%, preferably in a proportion of 30% of active agent for 70% of vehicle, in equivalent mass and/or volumetric proportions.
4. IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E4. SUBCUTANEOUS IMPLANTS FOR SLOW AND SLOW RELEASE
CONTROLADA DE ATIVOS, de acordo com qualquer uma das reivindicações 1 , 2 ou 3, caracterizados por serem disponibilizados em forma de pellets, gel ou líquida. ASSET CONTROL, according to any one of claims 1, 2 or 3, characterized in that they are available in the form of pellets, gel or liquid.
5. IMPLANTES SUBCUTÂNEOS PARA LIBERAÇÃO LENTA E5. SUBCUTANEOUS IMPLANTS FOR SLOW AND SLOW RELEASE
CONTROLADA DE ATIVOS, de acordo com qualquer uma das reivindicações 1 , 2, 3 ou 4, caracterizados por serem de uso veterinário ou humano. ASSET CONTROL, according to any one of claims 1, 2, 3 or 4, characterized in that they are for veterinary or human use.
PCT/BR2020/050528 2020-02-19 2020-12-09 Subcutaneous implants for slow controlled release of active agents WO2021163776A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR102020003483-9A BR102020003483A2 (en) 2020-02-19 2020-02-19 Subcutaneous implants for slow and controlled release of assets.
BRBR1020200034839 2020-02-19

Publications (1)

Publication Number Publication Date
WO2021163776A1 true WO2021163776A1 (en) 2021-08-26

Family

ID=77390261

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2020/050528 WO2021163776A1 (en) 2020-02-19 2020-12-09 Subcutaneous implants for slow controlled release of active agents

Country Status (2)

Country Link
BR (1) BR102020003483A2 (en)
WO (1) WO2021163776A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200836778A (en) * 2006-12-06 2008-09-16 Fabre Pierre Dermo Cosmetique Hyaluronic acid gel for intradermal injection
CN106063948A (en) * 2016-03-30 2016-11-02 圆容生物医药无锡有限公司 A kind of long-acting hypodermic implant and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200836778A (en) * 2006-12-06 2008-09-16 Fabre Pierre Dermo Cosmetique Hyaluronic acid gel for intradermal injection
CN106063948A (en) * 2016-03-30 2016-11-02 圆容生物医药无锡有限公司 A kind of long-acting hypodermic implant and preparation method thereof

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BRUNK ARIANE; NONN MARION; LANG VICTORIA; HENSCHLER REINHARD; HERR WOLFGANG; HARTWIG UDO F: "Functional Analyses of Human T Cell Extravasation in a Humanized NOD/SCID/ IL 2Rycnull Transplantation Model.", BLOOD, vol. 114, no. 22, 2448, 20 November 2009 (2009-11-20), US, pages 1 - 3, XP086687854, ISSN: 0006-4971, DOI: 10.1182/blood.V114.22.2448.2448 *
CAO DY, YAO C, CHEN DX, BIAN WH, ZHANG XQ, YIN H, GUO MM: "Angiogenesis and scar inhibition after subcutaneous implantation of Shengji Yuhong collagen", CHINESE JOURNAL OF TISSUE ENGINEERING RESEARCH, vol. 17, no. 34, 2013, pages 6144 - 6151, XP055848403, ISSN: 2095-4344, DOI: 10.3969/j.issn. 2095-4344 .2013.34.013. *
CHANTAL DEBLOIS , MARIE-FRANCE COTE , CHARLES J DOILLON: "Heparin-fibroblast growth factor-fibrin complex: in vitro and in vivo applications to collagen-based materials", BIOMATERIALS, vol. 15, no. 9, 1 July 1994 (1994-07-01), pages 665 - 72, XP002460505, ISSN: 0142-9612, DOI: 10.1016/0142-9612(94)90164-3 *
DAAMEN, W.F. ; LOWIK, D. ; VAN KUPPEVELT, T.H.: "Nicked elastin fibres do not calcify after subcutaneous implantation", JOURNAL OF CONTROLLED RELEASE, vol. 132, no. 3, 18 December 2008 (2008-12-18), pages e23 - e24, XP025714848, ISSN: 0168-3659, DOI: 10.1016/j.jconrel.2008.09.013 *
DOS SANTOS BRUNO PAIVA; GARBAY BERTRAND; FENELON MATHILDE; ROSSELIN MARIE; GARANGER ELISABETH; LECOMMANDOUX SÉBASTIEN; OLIVEIRA HU: "Development of a cell -free and growth factor- free hydrogel capable of inducing angiogenesis and innervation after subcutaneous implantation", ACTA BIOMATERIALIA, vol. 99, 16 August 2019 (2019-08-16), pages 154 - 167, XP085897090, ISSN: 1742-7061, DOI: 10.1016/j.actbio.2019.08.028 *
ELIOPOULOS NICOLETTA, GAGNON RAYMONDE F., FRANCOIS MOIRA, GALIPEAU JACQUES: "Erythropoietin delivery by genetically engineered bone marrow stromal cells for correction of anemia in mice with chronic renal failure", JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, vol. 17, no. 6, June 2006 (2006-06-01), US, pages 1576 - 84, XP055848396, ISSN: 1046-6673, DOI: 10.1681/ASN. 20051010 35 *
HELARY CHRISTOPHE, ABED AICHA, MOSSER GERVAISE, LOUEDEC LILIANE, LETOURNEUR DIDIER, CORADIN THIBAUD, GIRAUD-GUILLE MARIE MADELEINE: "Evaluation of dense collagen matrices as medicated wound dressing for the treatment of cutaneous chronic wounds", BIOMATERIALS SCIENCE, vol. 3, no. 2, 1 February 2015 (2015-02-01), GB, pages 373 - 82, XP055848412, ISSN: 2047-4830, DOI: 10.1039/c4bm00370e *
HIRSCHI KAREN K., ROHOVSKY STEPHANIE A., D'AMORE PATRICIA A.: "PDGF, TGF-beta, and heterotypic cell - cell interactions mediate endothelial cell -induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate", THE JOURNAL OF CELL BIOLOGY, vol. 141, no. 3, 4 May 1998 (1998-05-04), US, pages 805 - 14, XP055848395, ISSN: 0021-9525, DOI: 10.1083/jcb.141.3.805. *
LIU GUIHUA; WANG XISHENG; SUN XIANGZHOU; DENG CHUNHUA; ATALA ANTHONY; ZHANG YUANYUAN: "The effect of urine-derived stem cells expressing VEGF loaded in collagen hydrogels on myogenesis and innervation following after subcutaneous implantation in nude mice", BIOMATERIALS, vol. 34, no. 34, 9 August 2013 (2013-08-09), pages 8617 - 29, XP028697264, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2013.07.077 *
PARALKARSQ VISHWAS M, NANDEDKARG ARVIND K N, POINTER& RICHARD H, KLEINMANLL HYNDA K, REDDISII A H: "Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen", J BIOL CHEM., vol. 265, no. 28, 5 October 1990 (1990-10-05), pages 17281 - 17284, XP055848391, DOI: 10.1016/S0021-9258(17)44900-3 *

Also Published As

Publication number Publication date
BR102020003483A2 (en) 2021-08-31

Similar Documents

Publication Publication Date Title
US5540912A (en) Viscous suspensions of controlled-release drug particles
US6488952B1 (en) Semisolid therapeutic delivery system and combination semisolid, multiparticulate, therapeutic delivery system
CN103140226B (en) Preparation for treatment of spinal cord injury
KR100245395B1 (en) Formulations and methods for providing prolonged local anesthesia
JP2000511941A (en) Long-acting anesthesia in the joint space and body space
US9700567B2 (en) Dexamethasone formulations in a biodegradable material
PT99345A (en) PROCESS FOR THE PREPARATION OF APPROPRIATE SYSTEMS FOR THE LIBERATION OF THERAPEUTIC AGENTS
US8956642B2 (en) Bupivacaine formulation in a polyorthoester carrier
US20050287180A1 (en) Phospholipid compositions and methods for their preparation and use
JP2011518167A (en) Compositions and methods for treating postoperative pain using clonidine and bupivacaine
MX2007006833A (en) Compositions and methods for treating conditions of the nail unit.
US8475823B2 (en) Baclofen formulation in a polyorthoester carrier
US8586073B2 (en) Methods and formulations for administration of resolvin anti-inflammatory compounds
WO2021163776A1 (en) Subcutaneous implants for slow controlled release of active agents
WO2009129145A2 (en) Sulfasalazine formulations in a biodegradable polymer carrier
DE202011111037U1 (en) Device for the treatment of gum disease
CN116669717A (en) Long-acting in-situ forming/gelling composition
CN101007171A (en) Skeleton slow releasing implant for deworming from dogs and its preparation method
US9707323B2 (en) Devices and methods for inhibiting adhesion formation
WO2021237322A1 (en) Long-lasting reabsorbable subcutaneous implant with sustained release of pre-concentrated pharmacologically active substance in polymer for the treatment of erectile dysfunction and benign prostatic hyperplasia
PT1484033E (en) Liquid polymeric compositions for controlled release of bioactive substances
WO2021237321A1 (en) Long-lasting reabsorbable subcutaneous implant with sustained release of pre-concentrated pharmacologically active substance in polymer for the treatment of chronic adrenal insufficiency or hypocortisolism
BR102020010933A2 (en) SUBCUTANEOUS REABSORBABBLE IMPLANT FOR LONG TERM WITH PROLONGED RELEASE OF PRECONCENTRATELY PHARMACOLOGICALLY ACTIVE SUBSTANCE IN POLYMER FOR TREATMENT OF ERECTILE DYSFUNCTION AND BENDING PROSTATIC HYPERPLASIA
BR102021010270A2 (en) Long-term resorbable subcutaneous implant with prolonged release of pre-concentrated, polymer-concentrated pharmacologically active substance for the treatment of chronic adrenal insufficiency or hypocortisolism and the process of obtaining
DE102004031014A1 (en) Device for targeted liberation of substances in a cavity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20920061

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20920061

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 20920061

Country of ref document: EP

Kind code of ref document: A1