BR112022023618A2 - Formulação líquida de conjugado de ação prolongada de derivado de glucagon - Google Patents

Formulação líquida de conjugado de ação prolongada de derivado de glucagon

Info

Publication number
BR112022023618A2
BR112022023618A2 BR112022023618A BR112022023618A BR112022023618A2 BR 112022023618 A2 BR112022023618 A2 BR 112022023618A2 BR 112022023618 A BR112022023618 A BR 112022023618A BR 112022023618 A BR112022023618 A BR 112022023618A BR 112022023618 A2 BR112022023618 A2 BR 112022023618A2
Authority
BR
Brazil
Prior art keywords
long
liquid formulation
glucagon derivative
derivative conjugate
conjugate liquid
Prior art date
Application number
BR112022023618A
Other languages
English (en)
Inventor
Kyu Lim Hyung
Young Dong Joo
Yun Kim Sang
Min Bae Sung
Original Assignee
Hanmi Pharm Ind Co Ltd
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 Hanmi Pharm Ind Co Ltd filed Critical Hanmi Pharm Ind Co Ltd
Publication of BR112022023618A2 publication Critical patent/BR112022023618A2/pt

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K38/22—Hormones
    • 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
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • 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
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Vascular Medicine (AREA)
  • Toxicology (AREA)
  • Genetics & Genomics (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

FORMULAÇÃO LÍQUIDA DE CONJUGADO DE AÇÃO PROLONGADA DE DERIVADO DE GLUCAGON. A presente invenção refere-se a uma formulação líquida de um conjugado de ação prolongada de um derivado de glucagon e um método para preparar o mesmo.
BR112022023618A 2020-05-22 2021-05-24 Formulação líquida de conjugado de ação prolongada de derivado de glucagon BR112022023618A2 (pt)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20200061877 2020-05-22
PCT/KR2021/006441 WO2021235907A1 (ko) 2020-05-22 2021-05-24 글루카곤 유도체의 지속형 결합체의 액상 제제

Publications (1)

Publication Number Publication Date
BR112022023618A2 true BR112022023618A2 (pt) 2023-02-07

Family

ID=78707973

Family Applications (1)

Application Number Title Priority Date Filing Date
BR112022023618A BR112022023618A2 (pt) 2020-05-22 2021-05-24 Formulação líquida de conjugado de ação prolongada de derivado de glucagon

Country Status (11)

Country Link
US (1) US20230192800A1 (pt)
EP (1) EP4154868A1 (pt)
JP (1) JP2023526551A (pt)
KR (1) KR20210144606A (pt)
CN (1) CN115803015A (pt)
AU (1) AU2021277116A1 (pt)
BR (1) BR112022023618A2 (pt)
CA (1) CA3179603A1 (pt)
IL (1) IL298396A (pt)
MX (1) MX2022014669A (pt)
WO (1) WO2021235907A1 (pt)

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096871A (en) 1995-04-14 2000-08-01 Genentech, Inc. Polypeptides altered to contain an epitope from the Fc region of an IgG molecule for increased half-life
EP0904107B1 (en) 1996-03-18 2004-10-20 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
RU2428430C2 (ru) 2005-08-16 2011-09-10 Ханми Холдингс Ко., Лтд. СПОСОБ МАССОВОГО ПРОИЗВОДСТВА ОБЛАСТИ Fc ИММУНОГЛОБУЛИНА С УДАЛЕННЫМИ НАЧАЛЬНЫМИ МЕТИОНИНОВЫМИ ОСТАТКАМИ
US8703701B2 (en) * 2009-12-18 2014-04-22 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
EP2635296B1 (en) * 2010-11-03 2014-12-24 Arecor Limited Novel composition comprising glucagon
AR092862A1 (es) * 2012-07-25 2015-05-06 Hanmi Pharm Ind Co Ltd Formulacion liquida de insulina de accion prolongada y un peptido insulinotropico y metodo de preparacion
CN105848645A (zh) * 2013-09-27 2016-08-10 韩美药品株式会社 持续型人生长激素制剂
SG11201705376SA (en) 2014-12-30 2017-08-30 Hanmi Pharm Ind Co Ltd Glucagon derivative having improved stability
KR102005456B1 (ko) * 2015-06-30 2019-07-30 한미약품 주식회사 신규 글루카곤 유도체 및 이의 지속형 결합체를 포함하는 조성물

Also Published As

Publication number Publication date
WO2021235907A1 (ko) 2021-11-25
KR20210144606A (ko) 2021-11-30
JP2023526551A (ja) 2023-06-21
IL298396A (en) 2023-01-01
AU2021277116A1 (en) 2023-02-02
MX2022014669A (es) 2023-02-13
CA3179603A1 (en) 2021-11-25
CN115803015A (zh) 2023-03-14
US20230192800A1 (en) 2023-06-22
EP4154868A1 (en) 2023-03-29

Similar Documents

Publication Publication Date Title
CO2018013978A2 (es) Derivados de ácido borónico y usos terapéuticos de los mismos.
ECSP18094790A (es) Piridinas sustituidas con heteroarilo y métodos de uso referencia cruzada a solicitudes relacionadas
CL2016000916A1 (es) Co-cristales que comprenden un compuesto derivado de quinolina-2carboxamida de fórmula (i) y un formador de cristales; composiciones que los comprenden; método de preparación de los co-cristales y uso de estos en la preparación de un medicamento útil para el tratamiento de cáncer
BR112019017417A2 (pt) composições farmacêuticas de um derivado de um ácido biliar e microbioma e usos das mesmas
BR112018005497A2 (pt) compostos heterocíclicos e usos dos mesmos
DOP2017000151A (es) Derivados de quinazolina utilizados para tratar el vih
CR20160212A (es) Composiciones y métodos para modular los receptores x farnesoides
BR112017013661A8 (pt) Conjugado derivado de antraciclina (pnu), conjugado de fármaco-proteína de ligação (bpdc), método para a produção de um conjugado de fármaco-proteína de ligação (bpdc), uso de um conjugado de proteína de ligação-fármaco (bpdc) e composição farmacêutica
UY36077A (es) Derivados de 6-amino-8h-pteridin-7-ona como moduladores de ror gamma y composiciones farmacéuticas que los contienen
CO2017012566A2 (es) Piridinas sustituidas y método de uso
BR112018010389A8 (pt) método para preparação de compostos
BRPI1016132B8 (pt) composição, formulação farmacêutica, processo de obtenção de uma formulação farmacêutica estável
EA201990455A1 (ru) КОНДЕНСИРОВАННОЕ ТРИЦИКЛИЧЕСКОЕ ПРОИЗВОДНОЕ γ-АМИНОКИСЛОТЫ, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ЕГО МЕДИЦИНСКОЕ ПРИМЕНЕНИЕ
BR112021015238A2 (pt) Novos anticorpos de ligação a cd40
CL2017002170A1 (es) Desacetoxitubulisina h y análogos de esta.
BR112016000563A2 (pt) Método de preparar uma formulação farmacêutica, método de usar ácido hexanóico e/ou ácido cítrico ou pelo menos um sal dos mesmos, formulação farmacêutica e método de modular ou determinar respostas imunes relacionadas à administração de uma formulação farmacêutica
MX352386B (es) Nuevos derivados quinona de cannabidiol.
CO2017007325A2 (es) 2,4 diamino-quinolina sustituida como nuevos agentes anti-cancerigenos
CO2019001181A2 (es) Compuestos de heteroarilcarboxamida como inhibidores de ripk2
EA201791600A1 (ru) Производные гидроксиалкилпиперазина в качестве модуляторов cxcr3 рецептора
CL2019001991A1 (es) Moduladores del receptor de estrógeno.
CO2018003473A2 (es) Nuevos derivados de imidazo[4,5-b]piridina, un proceso para su preparación y composiciones farmacéuticas que los contienen
CO2022018636A2 (es) Moduladores de il-17a
BR112017021631A2 (pt) composto, composição farmacêutica, combinação farmacêutica, método de tratamento, uso de um composto e processo para preparação de dito composto
BR112018068414A2 (pt) derivados de ácido a-truxílico e composições farmacêuticas dos mesmos