WO2021163776A1 - Implants sous-cutanés pour la libération lente et contrôlée d'agents actifs - Google Patents

Implants sous-cutanés pour la libération lente et contrôlée d'agents actifs Download PDF

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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
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WIPO (PCT)
Prior art keywords
implants
subcutaneous
slow
collagen
active
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Application number
PCT/BR2020/050528
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English (en)
Portuguese (pt)
Inventor
Marco Antonio BITTENCOURT
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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.)
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Publication date
Application filed by Bittencourt Marco Antonio filed Critical Bittencourt Marco Antonio
Publication of WO2021163776A1 publication Critical patent/WO2021163776A1/fr

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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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des implants sous-cutanés constitués par l'association d'agents actifs à l'un des types de collagène connus, ou encore à d'autres substances présentes dans le tissu cellulaire sous-cutané, telles que l'élastine, la graisse saturée, les peptides de collagène, l'acide hyaluronique ou les acides gras, conçus pour assurer une libération plus longue d'un principe actif biochimique, avec des taux de dégradation constants et homogènes, en vue d'une libération dans l'interstice d'animaux domestiques ou d'êtres humains, présentant un faible risque de rejet par l'organisme. La présente invention permet de résoudre les problèmes observés dans l'état actuel de la technique, en lien avec : le temps de dégradation, ; la nécessité de retirer/remplacer les implants ; le taux élevé de rejet et de dégradation irrégulière de l'agent actif.
PCT/BR2020/050528 2020-02-19 2020-12-09 Implants sous-cutanés pour la libération lente et contrôlée d'agents actifs WO2021163776A1 (fr)

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BRBR1020200034839 2020-02-19
BR102020003483-9A BR102020003483A2 (pt) 2020-02-19 2020-02-19 Implantes subcutâneos para liberação lenta e controlada de ativos.

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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 (zh) * 2016-03-30 2016-11-02 圆容生物医药无锡有限公司 一种长效皮下植入物及其制备方法

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 (zh) * 2016-03-30 2016-11-02 圆容生物医药无锡有限公司 一种长效皮下植入物及其制备方法

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