WO1992017162A1 - Emulsion lyophilisee - Google Patents
Emulsion lyophilisee Download PDFInfo
- 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
Links
- 239000000839 emulsion Substances 0.000 title claims description 32
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000007764 o/w emulsion Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 29
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
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- 150000001720 carbohydrates Chemical class 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
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- 239000004094 surface-active agent Substances 0.000 claims description 9
- 239000002736 nonionic surfactant Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- DZVPGIORVGSQMC-UHFFFAOYSA-N 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine Chemical compound COC1=NC(C(Cl)(Cl)Cl)=C(Cl)C(OC)=C1Cl DZVPGIORVGSQMC-UHFFFAOYSA-N 0.000 claims description 4
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- 239000000583 progesterone congener Substances 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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.
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 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)
| 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)
| 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 |
-
1991
- 1991-04-05 WO PCT/US1991/002353 patent/WO1992017162A1/fr active Application Filing
- 1991-04-22 PT PT9743691A patent/PT97436A/pt not_active Application Discontinuation
Patent Citations (2)
| 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)
| 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 |
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