WO1992015283A1 - Parenteral emulsion - Google Patents
Parenteral emulsion Download PDFInfo
- Publication number
- WO1992015283A1 WO1992015283A1 PCT/DK1992/000061 DK9200061W WO9215283A1 WO 1992015283 A1 WO1992015283 A1 WO 1992015283A1 DK 9200061 W DK9200061 W DK 9200061W WO 9215283 A1 WO9215283 A1 WO 9215283A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lipid
- fact
- parenteral
- phospholipids
- parenteral emulsion
- Prior art date
Links
- 239000000839 emulsion Substances 0.000 title claims abstract description 56
- 150000002632 lipids Chemical class 0.000 claims abstract description 39
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 31
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008344 egg yolk phospholipid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229940068998 egg yolk phospholipid Drugs 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 239000000470 constituent Substances 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 108010004103 Chylomicrons Proteins 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 235000010469 Glycine max Nutrition 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- PHIQHXFUZVPYII-LURJTMIESA-O (S)-carnitinium Chemical compound C[N+](C)(C)C[C@@H](O)CC(O)=O PHIQHXFUZVPYII-LURJTMIESA-O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000005205 gut mucosa Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
Definitions
- This invention relates to a parenteral emulsion consisting essentially of water, lipids, glycerol and phospholipids.
- soy oil generates an unstable parenteral emulsion, i.e. a parenteral emulsion with larger particles and/or a parenteral emulsion which separates into two phases on standing. Documentation will be presented later in this specification.
- the purpose of the invention is the provision of a stable parenteral emulsion of the above indicated kind, in which the concentration of the phospholipids is reduced considerably below 1.20% w/w.
- the lipid is selected from a specified category of lipids, which does not comprise triglycerides with only long chain fatty acid radicals, e.g. soy bean oil, if the weight ratio between the lipid and the phospholipid falls within certain, specified ranges, and if the concentration of the lipid falls within certain specified ranges.
- the parenteral emulsion according to the invention consisting essentially of water, lipids, glycerol and phospholipids and wherein the concentration of the lipid is between 10 and 30% w/w, and the lipid contains long chain acyl radicals and other acyl radicals, is characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1.
- acyl radicals can be saturated or unsaturated, and branched or with straight chains. Also, as appears from the following, the lipids can be randomized or structured.
- parenteral emulsion according to the invention is considerably cheaper than the prior art parenteral emulsions, because the phospholipid is by far the most expensive constituent of the parenteral emulsion.
- these prior art parenteral emulsions contain conventional lipids i.e. not the lipids used in the parenteral emulsions according to the invention.
- WO 90/03786 describes a parenteral emulsion of the type indicated in the preamble of the main claim.
- the weight ratio between the lipid and the phospholipids is 8.3, i.e. well outside the interval for this ratio according to the invention.
- the particle size should be less than 400 nm and preferably less than 350 nm.
- the emulsions were prepared with the following ingredients: oil egg lecithin glycerol sterile water
- the emulsions were prepared as follows:
- the pH value was measured and adjusted to around 9.5. Osmolality and particle size was determined.
- the emulsion was filled on bottles and autoclaved at 121°C for 25 minutes.
- the emulsions were stored at 4°C.
- the above table shows that experiment no. 3 yielded an emulsion, which did not fulfil the stability requirements, vide an earlier section of this specification; both visually and in regard to particle size it was evident that no stable emulsion was formed.
- the above table illustrates the prior art (experiment 1 ) and the invention (experiment 4).
- an emulsion with 1.2% PL in combination with 20% MLM gives rise to a satisfactory emulsion; this, however, is outside the scope of the invention
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the phospholipids comprise egg yolk phospholipids and/or soy lecithins.
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the weight ratio between the lipid and the phospholipid is 19:1 to 25:1, preferably 19:1 to 21:1. This weight ratio comes very close to the corresponding weight ratio in the genuine chylomicrons, which is approximately 20:1.
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the concentration of the lipid is between 20 and 30% w/w. From a process technical point of view it is difficult to manufacture emulsions with a lipid concentration above 30% w/w, and emulsions with a lipid concentration less than 20% exhibit an unwanted low energy content.
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the total amount of phospholipid is equal to or less than 1% w/w. As previously indicated, a low amount of phospholipids is advantageous from different points of view.
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other acyl radicals in the lipid are short chain radicals. This emulsion provides a better growth of the endothelium cells of the gut mucosa.
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other radicals in the lipid are medium chain radicals. This emulsion provides a better energy substrate.
- R is L
- R 2 is M
- R is L
- R 2 is S
- R 2 is L, R, is M, or 4) R 2 is L, R. is S, where L is a long chain acyl radical,
- M is a medium chain acyl radical
- S is a short chain acyl radical
- a preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the lipid with the composition indicated has a purity of at least 20% w/w, preferably at least 50% w/w, and more preferably at least 80% w/w. The higher the purity, the more pronounced the claimed effect.
- the weight ratio triglyceride:phospholipid (TG:PL) is around 20:1, i.e. a ratio equal to or close to the ratio TG:PL used in the emulsion according to the invention.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The parenteral emulsion, which comprises water, lipids, glycerol and phospholipids as the four main constituents is characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1, that the concentration of the lipid is between 10 and 30 % w/w, and that the lipid contains long chain acyl radicals and other acyl radicals. In this manner the concentration of phospholipids can be reduced considerably below 1.20 % w/w, which is an advantage both from a therapeutic and an economic point of view.
Description
PARENTERAL EMULSION
This invention relates to a parenteral emulsion consisting essentially of water, lipids, glycerol and phospholipids.
To the best of applicant's knowledge no commercial parenteral emulsions of this type are known which contain less than around 1.20% w/w phospholipid, which functions as an emulsifier. A reduction of the phospholipid concentration would be a desideratum. In the first place, the tendency towards generation of phospholipid vesicles containing exclusively or almost exclusively phospholipid would be reduced, if the concentration of phospholipids could be reduced considerably below 1.20% w/w. In the second place infusion of the commercial emulsions generates chylomicrons which are not directly compatible to the genuine chylomicrons in the blood stream, but which could be made more compatible or compatible to those, if the concentration of phospholipids could be reduced considerably below 1.20% w/w. Reference is made to a later part of this specification, in which the composition of chylomicrons are discussed in more detail.
So far efforts to reduce the phospholipid concentration of the commercial parenteral emulsions have been in vain. It has turned out that a reduction of the phospholipid concentration to e.g. 0.9% w/w in parenteral emulsions with around
20% soy oil generates an unstable parenteral emulsion, i.e. a parenteral emulsion with larger particles and/or a parenteral emulsion which separates into two phases on standing. Documentation will be presented later in this specification.
Thus, the purpose of the invention is the provision of a stable parenteral emulsion of the above indicated kind, in which the concentration of the phospholipids is reduced considerably below 1.20% w/w. Now, surprisingly it has been found that the purpose of the invention can be fulfilled, if the lipid is selected from a specified category of lipids, which does not comprise triglycerides with only long chain fatty acid radicals, e.g. soy bean oil, if the weight ratio between the lipid and the phospholipid falls within certain, specified ranges, and if the concentration of the lipid falls within certain specified ranges. Thus, the parenteral emulsion according to the invention consisting essentially of water, lipids, glycerol and phospholipids and wherein the concentration
of the lipid is between 10 and 30% w/w, and the lipid contains long chain acyl radicals and other acyl radicals, is characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1.
In this specification with claims "radicals" is to be understood as the three acyl radicals attached to the structure
CH2-0-
I
CH-O-
I CH2-0-
in the lipid at the three positions indicated. By long chain acyl radicals is understood acyl groups with 14-24 C-atoms. By medium chain acid radicals is understood acyl groups with 6-13 C-atoms, and by short chain acyl radicals is understood acyl groups with 2-5 C-atoms. If not anything to the contrary is indicated, it is to be understood that the acyl radicals can be saturated or unsaturated, and branched or with straight chains. Also, as appears from the following, the lipids can be randomized or structured.
Furthermore, it has been found that the parenteral emulsion according to the invention is considerably cheaper than the prior art parenteral emulsions, because the phospholipid is by far the most expensive constituent of the parenteral emulsion.
The reason why substitution of the soy oil (with exclusively long chain radicals) with lipids containing both long chain radicals and other acyl radicals makes it possible to reduce the concentration of phospholipid and yet maintain a stable parenteral emulsion is not completely understood.
It appears from EP 211 258 and DE 3032300 that it should be possible to produce parenteral emulsions with a concentration of phospholipids below 1.20% w/w, but our experiments have shown that such parenteral emulsions are unstable.
Also, these prior art parenteral emulsions contain conventional lipids i.e. not the lipids used in the parenteral emulsions according to the invention.
DE-A-3032200, EP-A-0233849, and Patent Abstracts of Japan, vol. 13, number 336, Appl. no. 62-266632 describe parenteral emulsions, which besides the
constituents indicated in the preamble of the main claim contain an active component, i.e. carnitin, pregnolone or vitamin K^
WO 90/03786 describes a parenteral emulsion of the type indicated in the preamble of the main claim. However, in the sole example the weight ratio between the lipid and the phospholipids is 8.3, i.e. well outside the interval for this ratio according to the invention.
In order to obtain a stable lipid emulsion the particle size should be less than 400 nm and preferably less than 350 nm. We have prepared the following emulsions, which illustrate the invention in comparison to prior art:
10
The emulsions were prepared with the following ingredients: oil egg lecithin glycerol sterile water
The emulsions were prepared as follows:
The work was performed in an LAF bench, and the microfluidizer was placed in immediate proximity thereof. Argon was bubbled through all liquids constantly. 12 or 9 g of egg lecithin were dispersed in 0.5 I of water by means of an Ultra Turrax mixer. When the foam fell the dispersion was finished.
200 g of oil was added, and dispersion was carried out with an Ultra Turrax mixer.
22.5 g of glycerol was added together with water to a total weight of 1 kg, and dispersion was carried out with an Ultra Turrax mixer.
Homogenization was performed on a microfluidizer (120E, Micro fluidic Corp.). The emulsion was passed through totally 5 times.
The pH value was measured and adjusted to around 9.5. Osmolality and particle size was determined. The emulsion was filled on bottles and autoclaved at 121°C for 25 minutes.
After heat treatment the pH value, the osmolality and the particle size was determined.
The emulsions were stored at 4°C. The above table shows that experiment no. 3 yielded an emulsion, which did not fulfil the stability requirements, vide an earlier section of this specification; both visually and in regard to particle size it was evident that no stable emulsion was formed. Also, the above table illustrates the prior art (experiment 1 ) and the invention (experiment 4). Furthermore, it appears from the above table that an emulsion with 1.2% PL in combination with 20% MLM gives rise to a satisfactory emulsion; this, however, is outside the scope of the invention
A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the phospholipids comprise egg yolk phospholipids and/or soy lecithins. These phospholipids are easily available commercially. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the weight ratio between the lipid and the phospholipid is 19:1 to 25:1, preferably 19:1 to 21:1. This weight ratio comes very close to the corresponding weight ratio in the genuine chylomicrons, which is approximately 20:1. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the concentration of the lipid is between 20 and 30% w/w. From a process technical point of view it is difficult to manufacture emulsions with a lipid concentration above 30% w/w, and emulsions with a lipid concentration less than 20% exhibit an unwanted low energy content. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the total amount of phospholipid is equal to or less than 1% w/w. As previously indicated, a low amount of phospholipids is advantageous from different points of view.
A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other acyl radicals in the lipid are short chain radicals. This emulsion provides a better growth of the endothelium cells of the gut mucosa.
A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other radicals in the lipid are medium chain radicals. This emulsion provides a better energy substrate.
A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the lipid exhibits a structure
1) R, is L, R2 is M,
2) R, is L, R2 is S,
3) R2 is L, R, is M, or 4) R2 is L, R. is S, where L is a long chain acyl radical,
M is a medium chain acyl radical, S is a short chain acyl radical.
These lipids can easily be produced enzymatically. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the lipid with the composition indicated has a purity of at least 20% w/w, preferably at least 50% w/w, and more preferably at least 80% w/w. The higher the purity, the more pronounced the claimed effect.
It appears from Carpentiers, Y.A., Intravascular metabolism of fat emulsions: The Arvid Wretlind Lecture, Espen, 1988. Clin.Nutr. (1989) 8: 115-125, that the chylomicrons, which are the natural gut generated lipid transport agents in the blood, exhibit the following composition
From the above it appears that the weight ratio triglyceride:phospholipid (TG:PL) is around 20:1, i.e. a ratio equal to or close to the ratio TG:PL used in the emulsion according to the invention.
Claims
1. Parenteral emulsion consisting essentially of water, lipids, glycerol and phospholipids and wherein the concentration of the lipid is between 10 and 30% w/w, and the lipid contains long chain acyl radicals and other acyl radicals, characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1.
2. Parenteral emulsion according to Claim 1 , characterized by the fact that the phospholipids comprise egg yolk phospholipids and/or soy lecithins.
3. Parenteral emulsion according to Claims 1 -2, characterized by the fact that the weight ratio between the lipid and the phospholipid is 19:1 to 25:1, preferably 19:1 to 21:1.
4. Parenteral emulsion according to Claims 1 - 3, characterized by the fact that the concentration of the lipid is between 20 and 30% w/w.
5. Parenteral emulsion according to Claims 1 - 4, characterized by the fact that the total amount of phospholipid is equal to or less than 1% w/w.
6. Parenteral emulsion according to Claims 1 - 5, characterized by the fact that the other acyl radicals in the lipid are short chain radicals.
7. Parenteral emulsion according to Claims 1 - 5, characterized by the fact that the other radicals in the lipid are medium chain radicals.
8. Parenteral emulsion according to Claims 1 - 7, characterized by the fact that the lipid exhibits a structure
wherein
1) R, is L, R2 is M, 2) R, is L, R2 is S,
3) R2 is L, R, is M, or
4) R2 is L, R, is S, where L is a long chain acyl radical,
M is a medium chain acyl radical, S is a short chain acyl radical.
9. Parenteral emulsion according to Claims 1 - 8, characterized by the fact that the lipid with the composition indicated has a purity of at least 20% w/w, preferably at least 50% w/w, and more preferably at least 80% w/w.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91610012 | 1991-03-01 | ||
| EP91610012.6 | 1991-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992015283A1 true WO1992015283A1 (en) | 1992-09-17 |
Family
ID=8208764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK1992/000061 WO1992015283A1 (en) | 1991-03-01 | 1992-02-28 | Parenteral emulsion |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1992015283A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5851510A (en) * | 1994-05-16 | 1998-12-22 | The Board Of Regents Of The University Of Michigan | Hepatocyte-selective oil-in-water emulsion |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0211257A2 (en) * | 1985-07-29 | 1987-02-25 | Abbott Laboratories | Lyophilized emulsion compositions |
| EP0257454A1 (en) * | 1986-08-18 | 1988-03-02 | Morishita Pharmaceutical Co. Ltd. | Oil-in-water type fat emulsion of 1-[2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl]-1H-imidazole |
| EP0271909A2 (en) * | 1986-12-17 | 1988-06-22 | Green Cross Corporation | Triglyceride composition |
| WO1990003787A1 (en) * | 1988-10-10 | 1990-04-19 | Novo Nordisk A/S | Emulsion and use of the emulsion as a parenteral preparation |
-
1992
- 1992-02-28 WO PCT/DK1992/000061 patent/WO1992015283A1/en not_active Application Discontinuation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0211257A2 (en) * | 1985-07-29 | 1987-02-25 | Abbott Laboratories | Lyophilized emulsion compositions |
| EP0257454A1 (en) * | 1986-08-18 | 1988-03-02 | Morishita Pharmaceutical Co. Ltd. | Oil-in-water type fat emulsion of 1-[2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl]-1H-imidazole |
| EP0271909A2 (en) * | 1986-12-17 | 1988-06-22 | Green Cross Corporation | Triglyceride composition |
| WO1990003787A1 (en) * | 1988-10-10 | 1990-04-19 | Novo Nordisk A/S | Emulsion and use of the emulsion as a parenteral preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US6126946A (en) * | 1994-05-16 | 2000-10-03 | University Of Michigan, The Board Of Regents | Hepatocyte-selective oil-in-water emulsion |
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