[go: up one dir, main page]

WO1992017162A1 - Emulsion lyophilisee - Google Patents

Emulsion lyophilisee Download PDF

Info

Publication number
WO1992017162A1
WO1992017162A1 PCT/US1991/002353 US9102353W WO9217162A1 WO 1992017162 A1 WO1992017162 A1 WO 1992017162A1 US 9102353 W US9102353 W US 9102353W WO 9217162 A1 WO9217162 A1 WO 9217162A1
Authority
WO
WIPO (PCT)
Prior art keywords
emulsion
agent
oil
water
surfactant
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1991/002353
Other languages
English (en)
Inventor
Pravin Chaturvedi
Shahid Lodhi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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 Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Priority to PCT/US1991/002353 priority Critical patent/WO1992017162A1/fr
Priority to PT9743691A priority patent/PT97436A/pt
Publication of WO1992017162A1 publication Critical patent/WO1992017162A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a process for lyophilizing an oil-in-water emulsion and the emulsion resulting from said process.
  • European Application 86109369.8 (Publication Number 211,257) describes a lyophilized dry composition which can be reconstituted with water to form an oil-in-water emulsion suitable for parenteral administration.
  • the freeze-dried composition contains 5% to 60% of a pharmaceutically acceptable lipid, 0.1% to 10% of an e ulsifier, and 40% to 90% of a solid carbohydrate.
  • the freeze-drying step is accomplished by spraying the emulsion as fine droplets into a bath of boiling fluid having a boiling point below -20°C, e.g., a fluorocarbon, collecting the dried particles, then sterilizing and packaging them.
  • the freeze-dried composition is similar to the composition of the present invention, the lyophilization process is markedly different.
  • the composition also differs from the present invention, e.g., in the quantity of carbohydrate employed. Also, the description of the "manufacture" of the composition indicates that the carbohydrate is added to the emulsion just prior to
  • U.S. Patent 4,616,047 describes a lyophilized oil-in-water emulsion suitable for oral administration. Although many of the components of this composition are the same as or similar to those employed in the present invention, other of the components are not suitable for parenteral administration. For example, the polysorbates and sorbitan esters useful as nonionic surfactants are not suitable for parenteral use.
  • the emulsion is placed in alveolar packets and freeze-dried. The amount of oil or lipid used in this formulation (60%-100%) is much higher than the amount employed in the present invention (5%-30%) .
  • Japan Application Number 50-96910 (Disclosure Number 60-239417) describes a freeze-dried oil-in—water emulsion which can be reconstituted and used for parenteral administration. No details of the freeze-drying step are described. The disclosure states that the emulsion is portioned into containers and freeze-dried by an ordinary freeze-drying program.
  • the composition differs from the composition of the present invention in that the prior art composition contains a water soluble polymer in the aqueous phase.
  • European Application 87111680.2 (Publication Number 257,454) describes an oil-in-water emulsion containing 1-[2,4-dichlorophenyl) -3-methyl-l- pentenyl]—lH-imidazole as the active ingredient.
  • the emulsion can be freeze-dried but no details of the method are given.
  • the disclosure specifically excludes the use of egg phosphatides as emulsifiers, stating that it has a low phosphatidylcholine content and does not show sufficient emulsifying effect.
  • the present invention provides a novel method for preparing lyophilized oil-in-water emulsions which comprises freezing and lyophilizing the emulsion in a single cycle.
  • the emulsion is maintained at the following temperatures for the times indicated:
  • the condenser is cooled to approximately -60°C.
  • the goal is to begin with a temperature differential of about 20°C between the shelf temperature and the condenser temperature.
  • a vacuum is applied to obtain a pressure of less than about 60 millitorr.
  • the chamber is pressurized with nitrogen.
  • the present invention also provides an oil-in-water emulsion composition which comprises a lipid or an oil suitable for injection; a surfactant; an agent to improve the isotonicity; a carbohydrate; and water.
  • the oil-in-water emulsion contains from 5% to 30% of a lipid or an oil suitable for injection; from 0.5% to 5.5% of a surfactant; from 5% to 15% of a carbohydrate; and from 2% to 4% of an agent which provides isotonicity to the emulsion; the active ingredient; and water for the balance of the composition.
  • the composition is lyophilized and suitable for injection upon reconstituting the lyophilized compositions with sterile water.
  • the composition of the present invention contains a pharmaceutically active compound in the lipid phase of the emulsion.
  • Active ingredients which may be incorporated into the lipid phase of the emulsion of the present invention are any lipophilic compound and includes, for example, anticancer compounds such as adriamycin, trimetrexate, carmustine, semustine, lomustine, streptozotocin, methotrexate, cyclophosphamide, bleomycin; barbiturates such as hexobarbital, thiopental, pentobarbital, secobarbital, cyclobarbital; antiinflammatories such as phenyl butazone; cognition activators such as physostigmine salicylate; steroids such as prednisone, progestin, tamoxifen, androgens, dexamethasone palmitate; tranquilizers such as diazepam; antiepileptics such as phenytoin; antivirals such as acyclovir, vidarabine, idoxuridine; anti-AIDS drugs such as zidovudin
  • Oils suitable for use in the oil-in-water emulsion include medium chain triglycerides, linoleic acid, and vegetable oils such as soybean, safflower, sesame, sunflower, olive, rapeseed, and bran oils. Mixtures of the oils may be used also.
  • the emulsifier or surfactant used in the present invention is, for example, egg yolk phospholipids, i.e., egg lecithin, and the quantity employed varies from 1% to 2%. Additionally, non-ionic surfactants can be employed and the amount of such surfactant used varies from 0.5% to 2%.
  • non-ionic surfactants include Pluronic F68, non-ionic esters of glycerol stearate, glycerol distearate, propylene glycol monostearate, glyceryl monostearate, tetraglyceryl monooleate, sorbitan mono-, di-, and tri-acylates, sucrose mono-, di-, and tri-acylates, polysorbate 40, polyoxyethylene, and sorbitan monopal itate.
  • Combinations of egg lecithin and non-ionic surfactant or egg lecithin and acetylated monoglycerides are useful in forming suitable compositions of the present invention.
  • Agents used to improve the isotonicity of the present composition include dextrose, glucose, glycerin, sorbitol, and xylitol or lower alcohols such as ethanol.
  • agents such as preservatives or anti-oxidants may find use in the invention.
  • a carbohydrate is employed to provide some bulk to the composition.
  • the preferred carbohydrate is lactose although others such as dextrose, xylose, mannitol, dextran, maltose, and sucrose may be used. It has been found that certain oils and carbohydrates are not particularly compatible. For example, dextran and lactose are more compatible with soybean and safflower oils than are some of the other oils.
  • the oil-in-water composition comprises about 5% to 30% of a lipid or oil; about 5% to 15% of a carbohydrate; from about 0.5% to 5% of emulsifier; from about 2% to 4% of glycerin or equivalent agent thereof; and from 60% to 70% of water. All percentages as used herein are on a weight per volume basis.
  • the concentration of active ingredient employed in the present invention would be an amount equivalent to provide the quantity known to be suitable for an injectable unit dose.
  • the emulsion is placed in a container, preferably a sterile vial, prior to lyophilization.
  • the vial can be any of the known types available in the market including the type into which sterile water is injected to achieve reconstitution of the lyophilized emulsion cake as well as the two-chamber type vials wherein the lyophilized emulsion cake is contained in one chamber and the sterile water for reconstitution is contained in the other chamber.
  • the lyophilization process comprises subjecting the oil-in—water emulsion to a series of temperature gradients whereby the emulsion is frozen then gradually warmed to about 30°C.
  • the entire process requires about 72 hours and provides the product in final packaged form ready for use.
  • the major advantage of this process is the ease of manufacture of the finished product formulation and a stable formulation for compounds known to be unstable in the presence of water and insoluble in water but soluble in oil.
  • Another major advantage is the fact that the entire process is carried out in a sterile environment so opportunity for contamination of the composition is virtually nonexistent.
  • the oil-in-water emulsion is prepared at about
  • composition is placed in vials containing 10 mL each and lyophilized as follows:
  • Vacuum is applied between steps (a) and (b) to approximately less than 60 millitorr and the chamber is repressurized with nitrogen after step (d) . Also at the beginning of the freeze-drying process, the chamber is cooled to about —60°C. The pH of the emulsion is approximately 8.0 and the particle size is about 280 nm. After the lyophilization cycle is completed, the product is obtained in a dry, lyophilized form. The reconstitution of the product was achieved instantaneously with a mean particle size of approximately 340 nm.
  • compositions were lyophilized.
  • Phenylbutazone (Antiinflammatory) 2. 00
  • Acetylated monoglycerides 5. 00
  • Lactose USP Spray Dried 10. 0
  • Lactose USP Spray Dried 10 0
  • Rhizoxin cytotoxic and antifungal

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à un nouveau procédé pour lyophiliser une émulsion d'huile dans l'eau.
PCT/US1991/002353 1991-04-05 1991-04-05 Emulsion lyophilisee Ceased WO1992017162A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1991/002353 WO1992017162A1 (fr) 1991-04-05 1991-04-05 Emulsion lyophilisee
PT9743691A PT97436A (pt) 1991-04-05 1991-04-22 Processo para a liofilizacao de uma emulsao de oleo em agua

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1991/002353 WO1992017162A1 (fr) 1991-04-05 1991-04-05 Emulsion lyophilisee

Publications (1)

Publication Number Publication Date
WO1992017162A1 true WO1992017162A1 (fr) 1992-10-15

Family

ID=22225440

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/002353 Ceased WO1992017162A1 (fr) 1991-04-05 1991-04-05 Emulsion lyophilisee

Country Status (2)

Country Link
PT (1) PT97436A (fr)
WO (1) WO1992017162A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014418A1 (fr) * 1992-12-24 1994-07-07 Schwarz Pharma Ag Emulsion lyophilisee contenant une substance active
US5851510A (en) * 1994-05-16 1998-12-22 The Board Of Regents Of The University Of Michigan Hepatocyte-selective oil-in-water emulsion
EP1165048A4 (fr) * 1999-04-06 2007-12-05 Lipocine Inc Compositions et procedes d'administration amelioree d'agents therapeutiques hydrophobes ionisables
WO2016178158A1 (fr) * 2015-05-07 2016-11-10 Csir Procédé d'encapsulation de principes actifs pharmaceutiques
WO2019081435A1 (fr) * 2017-10-25 2019-05-02 Fresenius Kabi Deutschland Gmbh Émulsion multi-vitamine lyophilisée tout-en-un pour application parentérale

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0159237A1 (fr) * 1984-03-30 1985-10-23 LABORATOIRE L. LAFON Société anonyme dite: Forme galénique pour administration orale et son procédé de préparation par lyophilisation d'une émulsion huile-dans-eau
EP0211257A2 (fr) * 1985-07-29 1987-02-25 Abbott Laboratories Emulsions lyophilisées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0159237A1 (fr) * 1984-03-30 1985-10-23 LABORATOIRE L. LAFON Société anonyme dite: Forme galénique pour administration orale et son procédé de préparation par lyophilisation d'une émulsion huile-dans-eau
EP0211257A2 (fr) * 1985-07-29 1987-02-25 Abbott Laboratories Emulsions lyophilisées

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1056746C (zh) * 1992-12-24 2000-09-27 施瓦茨制药有限公司 含有效成分的冻干乳液
US5882684A (en) * 1992-12-24 1999-03-16 Schwarz Pharma Ag Lyophilized emulsion containing an active substance
JP2944756B2 (ja) 1992-12-24 1999-09-06 シュバルツ ファルマ アクチエンゲゼルシャフト 凍結乾燥された、作用物質含有エマルジョン
WO1994014418A1 (fr) * 1992-12-24 1994-07-07 Schwarz Pharma Ag Emulsion lyophilisee contenant une substance active
US5612058A (en) * 1992-12-24 1997-03-18 Schwarz Pharma Ag Lyophilized emulsion containing an active substance
US6126946A (en) * 1994-05-16 2000-10-03 University Of Michigan, The Board Of Regents Hepatocyte-selective oil-in-water emulsion
US5851510A (en) * 1994-05-16 1998-12-22 The Board Of Regents Of The University Of Michigan Hepatocyte-selective oil-in-water emulsion
US5985941A (en) * 1994-05-16 1999-11-16 University Of Michigan Method of making hepatocyte-selective oil-in-water emulsion
EP1165048A4 (fr) * 1999-04-06 2007-12-05 Lipocine Inc Compositions et procedes d'administration amelioree d'agents therapeutiques hydrophobes ionisables
WO2016178158A1 (fr) * 2015-05-07 2016-11-10 Csir Procédé d'encapsulation de principes actifs pharmaceutiques
CN110573142B (zh) * 2017-10-25 2024-01-16 费森尤斯卡比德国有限公司 用于胃肠外应用的多合一冻干复合维生素乳剂
CN110573142A (zh) * 2017-10-25 2019-12-13 费森尤斯卡比德国有限公司 用于胃肠外应用的多合一冻干复合维生素乳剂
WO2019081435A1 (fr) * 2017-10-25 2019-05-02 Fresenius Kabi Deutschland Gmbh Émulsion multi-vitamine lyophilisée tout-en-un pour application parentérale
AU2018356481B2 (en) * 2017-10-25 2024-02-29 Fresenius Kabi Deutschland Gmbh All-in-one lyophilized multivitamin emulsion for parenteral application

Also Published As

Publication number Publication date
PT97436A (pt) 1992-01-31

Similar Documents

Publication Publication Date Title
US5750142A (en) Dry compositions for preparing submicron emulsions
AU2009226618B2 (en) Lyophilized nanoemulsion
AU675930B2 (en) Dry compositions for preparing submicron emulsions
EP0556394B1 (fr) Preparation lyophilisee et sa production
CA2030029A1 (fr) Composition emulsionnee
KR20110036075A (ko) 안정한 주입 가능 수중유형 도세타셀 나노에멀젼
FR2561916A1 (fr) Forme galenique pour administration orale et son procede de preparation par lyophilisation d'une emission huile dans eau
HU180792B (en) Process for producing water-containing compositions
CZ221596A3 (en) Oil-in-water emulsion, its use and pharmaceutical composition containing thereof
PT99113B (pt) Processo para a preparacao de matrizes que originam particulas de lipidos
WO1992017162A1 (fr) Emulsion lyophilisee
CN1056746C (zh) 含有效成分的冻干乳液
JP2009062386A (ja) インスタントベシクル製品
EP1204417B1 (fr) Emulsion de cisplatine pour administration par voie parenterale
IE911169A1 (en) Lyophilized emulsion
KR19990029589A (ko) 사이클로스포린을 함유한 신규 조성물
JPH08506081A (ja) サブミクロン・エマルジョンの調製のための乾燥組成物
EP0451103B1 (fr) Formulation pour application parentérale de liposomes à base de lipides synthétiques
JPH08508016A (ja) キットの形の薬剤学的組成物
JPH0570793A (ja) 脂質の粒状組成物
RU2839882C1 (ru) Микроэмульсионная лекарственная форма для перорального введения
WO2024235489A1 (fr) Composition de cannabinoïdes solide à usage parentéral
KR20260009833A (ko) 비경구용 고체 칸나비노이드 조성물
KR19980031601A (ko) 난용성 약물의 가용화 방법
CN109984995A (zh) 一种伊维菌素纳米乳注射液及其制备方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA