CO2017012628A2 - Métodos para mejorar la adsorción de conjugados de polisacárido-proteína y una formulación de vacuna multivalente obtenida con los mismos - Google Patents

Métodos para mejorar la adsorción de conjugados de polisacárido-proteína y una formulación de vacuna multivalente obtenida con los mismos

Info

Publication number
CO2017012628A2
CO2017012628A2 CONC2017/0012628A CO2017012628A CO2017012628A2 CO 2017012628 A2 CO2017012628 A2 CO 2017012628A2 CO 2017012628 A CO2017012628 A CO 2017012628A CO 2017012628 A2 CO2017012628 A2 CO 2017012628A2
Authority
CO
Colombia
Prior art keywords
polysaccharide
methods
adsorption
vaccine formulation
protein conjugates
Prior art date
Application number
CONC2017/0012628A
Other languages
English (en)
Inventor
Rajeev Mhalasakant Dhere
Hitesh Kumar Malviya
Swapan Kumar Jana
Sambhaji Shankar Pisal
Asha Dinesh MALLYA
Sunil Mahor
Manish Maheshkumar Gautam
Chetan Vilas Joshi
Venkata Vamsi Krishna Malepati
Prashant Shivaji Jadhav
Original Assignee
Serum Inst Of India Private 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 Serum Inst Of India Private Ltd filed Critical Serum Inst Of India Private Ltd
Publication of CO2017012628A2 publication Critical patent/CO2017012628A2/es

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/62Medicinal 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
    • A61K47/64Drug-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
    • A61K47/646Drug-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 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/09Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092Streptococcus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/085Staphylococcus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/09Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/116Polyvalent bacterial antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/39Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/62Medicinal 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
    • A61K47/64Drug-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
    • A61K47/6415Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505Inorganic adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55516Proteins; Peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/60Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031Proteins
    • A61K2039/6037Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/70Multivalent vaccine

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Toxicology (AREA)
  • Inorganic Chemistry (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Métodos para la preparación de formulaciones estables de vacunas antineumocóccicas conjugadas de polisacárido-proteína multivalentes. Las formulaciones estables de la presente presentan un porcentaje óptimo de adsorción para cada conjugado, en donde se puede prevenir la agregación mediante el uso de i) una adsorción individual o separada de conjugados que de lo contrario presentan un porcentaje de adsorción menor con una adsorción combinada ii) un sistema de solución amortiguadora de histidina-ácido succínico junto con un cambio en el pH de pH neutro a pH ácido iii) una relación de polisacárido a proteína de 0,5 a aproximadamente 1,4 iv) un impulsor de turbina tipo Rushton de seis hojas en los recipientes de formulación.
CONC2017/0012628A 2015-06-08 2017-12-07 Métodos para mejorar la adsorción de conjugados de polisacárido-proteína y una formulación de vacuna multivalente obtenida con los mismos CO2017012628A2 (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2185MU2015 2015-06-08
PCT/IB2016/053265 WO2016199003A1 (en) 2015-06-08 2016-06-03 Methods for improving the adsorption of polysaccharide-protein conjugates and multivalent vaccine formulation obtained thereof

Publications (1)

Publication Number Publication Date
CO2017012628A2 true CO2017012628A2 (es) 2018-03-28

Family

ID=57503115

Family Applications (1)

Application Number Title Priority Date Filing Date
CONC2017/0012628A CO2017012628A2 (es) 2015-06-08 2017-12-07 Métodos para mejorar la adsorción de conjugados de polisacárido-proteína y una formulación de vacuna multivalente obtenida con los mismos

Country Status (18)

Country Link
US (1) US10729780B2 (es)
EP (1) EP3302542A4 (es)
JP (2) JP7258463B2 (es)
KR (2) KR20180030498A (es)
CN (1) CN107847571A (es)
AU (1) AU2016276269B2 (es)
BR (1) BR112017026343A2 (es)
CA (1) CA2988366C (es)
CO (1) CO2017012628A2 (es)
EA (1) EA201792470A1 (es)
IL (1) IL256118B (es)
MX (1) MX2017015985A (es)
MY (1) MY187461A (es)
PE (1) PE20180460A1 (es)
PH (1) PH12017502244A1 (es)
SA (1) SA517390495B1 (es)
WO (1) WO2016199003A1 (es)
ZA (1) ZA201708325B (es)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20180172A1 (es) 2015-05-04 2018-01-22 Pfizer Conjugados proteina-polisacarido de estreptococo grupo b, metodos para producir conjugados, composiciones inmunogenas que comprenden conjugados y sus usos
MY187461A (en) * 2015-06-08 2021-09-23 Serum Inst Of India Private Ltd Methods for improving the adsorption of polysaccharide-protein conjugates and multivalent vaccine formulation obtained thereof
CN106822884B (zh) * 2016-12-28 2021-04-30 北京民海生物科技有限公司 一种多价肺炎球菌荚膜多糖结合疫苗的制备方法
US11951165B2 (en) 2016-12-30 2024-04-09 Vaxcyte, Inc. Conjugated vaccine carrier proteins
KR20190119108A (ko) * 2017-02-24 2019-10-21 머크 샤프 앤드 돔 코포레이션 폐렴구균 접합체 백신 제제
US10729763B2 (en) 2017-06-10 2020-08-04 Inventprise, Llc Mixtures of polysaccharide-protein pegylated compounds
CN111065388A (zh) * 2017-09-07 2020-04-24 默沙东公司 肺炎球菌多糖及其在免疫原性多糖-载体蛋白缀合物中的用途
KR102573200B1 (ko) 2017-12-06 2023-08-31 머크 샤프 앤드 돔 엘엘씨 스트렙토코쿠스 뉴모니아에 폴리사카라이드-단백질접합체를 포함하는 조성물 및 그의 사용 방법
CN108524926B (zh) * 2018-06-29 2021-06-29 康希诺生物股份公司 一种多价肺炎球菌结合疫苗的制剂组合及其应用
PE20211888A1 (es) 2018-12-19 2021-09-22 Merck Sharp & Dohme Composiciones que comprenden conjugados de polisacarido de streptococcus pneumoniae con proteina y sus metodos de uso
WO2020247299A1 (en) * 2019-06-05 2020-12-10 Merck Sharp & Dohme Corp. An immunogenic serotype 35b pneumococcal polysaccharide-protein conjugate and conjugation process for making the same
US20210070890A1 (en) 2019-09-06 2021-03-11 Serum Institute Of India Private Limited Method for obtaining purified bacterial polysaccharides
CN113607939A (zh) * 2021-08-05 2021-11-05 艾美探索者生命科学研发有限公司 肺炎球菌多糖结合疫苗各型结合原液吸附率测定方法

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2059692C (en) * 1991-01-28 2004-11-16 Peter J. Kniskern Pneumoccoccal polysaccharide conjugate vaccine
CN102319427A (zh) * 2003-01-30 2012-01-18 诺华疫苗和诊断有限公司 抗多种脑膜炎球菌血清组的可注射性疫苗
US9173931B2 (en) 2003-08-06 2015-11-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Process for preparing polysaccharide-protein conjugate vaccines
US8119146B2 (en) * 2005-04-18 2012-02-21 Angelica Medina-Selby Expressing hepatitis B virus surface antigen for vaccine preparation
NO345368B1 (no) * 2005-12-22 2021-01-04 Glaxosmithkline Biologicals Sa Streptococcus pneumoniae immunogen sammensetning for anvendelse ved behandling eller forebygging av sykdommer forårsaket av Streptococcus pneumoniae infeksjon ved serotype 19A-stammer.
JP2009520771A (ja) * 2005-12-23 2009-05-28 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム コンジュゲートワクチン
TW200806315A (en) * 2006-04-26 2008-02-01 Wyeth Corp Novel formulations which stabilize and inhibit precipitation of immunogenic compositions
CN101784282B (zh) * 2007-06-26 2015-07-08 葛兰素史密丝克莱恩生物有限公司 包含肺炎链球菌荚膜多糖缀合物的疫苗
TW201136603A (en) * 2010-02-09 2011-11-01 Merck Sharp & Amp Dohme Corp 15-valent pneumococcal polysaccharide-protein conjugate vaccine composition
JP2014502595A (ja) 2010-12-10 2014-02-03 メルク・シャープ・アンド・ドーム・コーポレーション 免疫原性組成物の撹拌誘導凝集を緩和する新規な製剤
SG11201404447WA (en) * 2012-01-30 2014-08-28 Serum Inst India Ltd Immunogenic composition
KR102057217B1 (ko) * 2012-06-20 2020-01-22 에스케이바이오사이언스 주식회사 다가 폐렴구균 다당류-단백질 접합체 조성물
MX363511B (es) * 2012-08-16 2019-03-26 Pfizer Proceso de glucoconjugación y composiciones.
CN103893751B (zh) * 2014-03-26 2016-04-20 天津康希诺生物技术有限公司 一种肺炎球菌多糖蛋白缀合疫苗及其制备方法
MY187461A (en) * 2015-06-08 2021-09-23 Serum Inst Of India Private Ltd Methods for improving the adsorption of polysaccharide-protein conjugates and multivalent vaccine formulation obtained thereof

Also Published As

Publication number Publication date
KR20240007690A (ko) 2024-01-16
ZA201708325B (en) 2019-05-29
CA2988366C (en) 2021-12-07
CA2988366A1 (en) 2016-12-15
SA517390495B1 (ar) 2023-03-23
US10729780B2 (en) 2020-08-04
JP2018516962A (ja) 2018-06-28
NZ738090A (en) 2023-09-29
PE20180460A1 (es) 2018-03-06
IL256118B (en) 2021-12-01
AU2016276269B2 (en) 2021-01-28
JP2021185152A (ja) 2021-12-09
EA201792470A1 (ru) 2018-10-31
EP3302542A4 (en) 2019-04-10
EP3302542A1 (en) 2018-04-11
BR112017026343A2 (pt) 2019-11-19
IL256118A (en) 2018-02-28
KR20180030498A (ko) 2018-03-23
MY187461A (en) 2021-09-23
PH12017502244A1 (en) 2018-06-11
MX2017015985A (es) 2018-08-15
AU2016276269A1 (en) 2018-01-18
CN107847571A (zh) 2018-03-27
US20180161445A1 (en) 2018-06-14
JP7258463B2 (ja) 2023-04-17
WO2016199003A1 (en) 2016-12-15

Similar Documents

Publication Publication Date Title
CO2017012628A2 (es) Métodos para mejorar la adsorción de conjugados de polisacárido-proteína y una formulación de vacuna multivalente obtenida con los mismos
CL2018000320A1 (es) Coadyuvantes basados en aceite (divisional de solicitud 201600650)
CY1125697T1 (el) Σταθερες, υδατικες φαρμακοτεχνικες μορφες αντισωματων
CO7240387A2 (es) Composición conjugada de polisacáridos-proteínas neumocócica polivalente
BR112020004509A8 (pt) Conjugado polissacarídeo-proteína carreadora, composição imunogênica compreendendo o mesmo e uso do referido conjugado
AR092897A1 (es) Composiciones inmunogenicas
AR097791A1 (es) Formulaciones de anticuerpos anti-pdl1
CY1122483T1 (el) Λυοφιλοποιημενες παρασκευες μελφαλανης φλουφεναμιδης
BRPI0800867A2 (pt) concentrado embalado, processo para a preparaÇço de um concentrado embalado e uso de um concentrado
EA201890400A1 (ru) Способы и композиции для иммунной защиты против внекишечной патогенной e. coli
BR112015013560A8 (pt) Composição imunogênica multivalente; e composição farmacêutica para induzir uma resposta imunológica aos conjugados de polissacarídeo capsular de streptococcus pneumoniae
BRPI0801060A2 (pt) concentrado embalado, processo para preparaÇço de um concentrado embalado e uso de um concentrado
AR060565A1 (es) Vacuna para la gripe aviaria y metodos de uso
BR112018075785A2 (pt) formulação de vacina para o hiv
BRPI0800853A2 (pt) concentrado embalado, processo para preparaÇço de um concentrado embalado e uso de um concentrado embalado
NZ630990A (en) Aminoacid lipids
BRPI0918806A2 (pt) composição compreendendo quitosana para administração ocular de vaninas em aves
BR112015008417A2 (pt) composição imunogênica, e, vacina
BR112012030616A2 (pt) concentração de antígenos de vacina com liofilização.
NI201300034A (es) Conjugado de naloxol - peg cristalino
CY1125033T1 (el) Σκευασμα μεθοτρεξατης
BR112015025392A2 (pt) composição de vacina e método de utilização
BR112015032200A2 (pt) conjugado anticorpo-droga com estabilidade melhorada, método de preparação, composição farmacêutica e uso do mesmo
HRP20191053T1 (hr) Nova stabilna formulacija
BR112014026407A2 (pt) formulação de vacina líquida