CA2073096C

CA2073096C - Phospholipid composition

Info

Publication number: CA2073096C
Application number: CA002073096A
Authority: CA
Inventors: Rainer Losch; Bernd-Rainer Gunther; Jorg Hager
Original assignee: Rhone Poulenc Rorer GmbH
Current assignee: PHOSPHOLIPID GmbH
Priority date: 1991-07-05
Filing date: 1992-07-03
Publication date: 1999-01-19
Anticipated expiration: 2012-07-03
Also published as: ATE172600T1; EP0521398B1; EP0521398A2; IE922176A1; DE59209542D1; JP3213391B2; JP2002037794A; EP0521398A3; DK0521398T3; ES2122975T3; CA2073096A1; JP3500130B2; JPH05252875A

Abstract

A phospholipid composition exhibiting a phosphatidylcholine content of at least 80% by weight is described. Whereby this pulverized or granulated composition is free from additives.

In order to prepare such a phospholipid composition the phospholipid starting material is comminuted after cooling to a temperature below - 50 °C.

Description

Phospholipid Composition This invention relates to a phospholipid composition having a phosphatidylcholine content of at least 80% by weight with the composition being free of additives, and to a process for the manufacture of such a phospholipid composition.

Phospholipids occur in both animal and vegetable matter and have to be isolated from these. The main source are eggs, soybean, oil seeds and oil fruit, such as coconut copra, palm kernel, groundnuts, rape, sunflower seeds, oil palms and olives.

Phospholipids are isolated from vegetable products by de-gumming the corresponding vegetable oil with, for example, a small quantity of steam or water. The phospholipid composition produced, as known as lecithin sludge, generally contains ca. 8 to 59% by weight phospholipids and is dried by various methods to yield crude lecithin on drying.

2~7~Q96 Depending on the initial lecithin sludge used in each case this crude lecithin will have a different chemical composi-tion. Thus according to Weber E.J.; J.A. O.C.S. 58 898 (1981) the most important crude lecithin, soy (soybean) lecithin, is composed, after drying, of ca.:

Triglycerides 34.2% phosphatidylcholine 19.1%
Diglycerides 0.4% lysophosphatidylcholine 0.7%
Free fatty acids 0.4% phosphatidylethanolamine 8.6%
Other neutral lipids 0.8% phosphatidylinositol 8.8%
Glycolipids 6.5% phosphatidic acid 4.2%
Carbohydrate 6.7% N-acylphosphatidyl-ethanolamine 1.0%
others 8.6%

Neutral lipids, such as, for example, triglycerides, digly-cerides and the like, can be removed from the crude lecithin by deoiling with acetone. The deoiled crude lecithin, also referred to as pure lecithin, is a solid powder capable of being poured, which is available commercially as lecithin granules. The phosphatidylcholine content of pure lecithin lies between ca. 25% by weight and 30% by weight.

The phosphatidylcholine in crude lecithin or pure lecithin can be enriched by known processes. Preferably according to the processes described in European Patents 00 54 770 or 00 54 769. Hereby the crude lecithin is extracted with alcohol.
The alcohol-soluble extraction phase is then chromatographed on silicon dioxide at elevated temperatures. On account of its high phosphatidylcholine content the phospholipid com-position resulting from the aforesaid process is used for pharmaceutical, cosmetic and dietetic applications. However it exhibits the disadvantage that it is paste-like or waxy depending on its chemical composition. The further processing of this product is often accompanied by considerable problems on account of its consistency which makes it difficult to dose and cause it to stick to the inside walls of vessels, so that the residues remaining in the vessels make frequent and expensive cleaning of the vessels necessary.

In order to eliminate the aforesaid disadvantages in the handling of phospholipid compositions containing large proportions of phosphatidylcholine attempts have already been made to process these products in such a manner that powdered or granule-like high purity lecithins or specific high purity phospholipids are formed.

Thus German Patent 973 741 proposed deoiling crude lecithin with a suitable solvent, for example acetone, separating the deoiled lecithin from the oil extract, then loosening the separated lecithin and drying it as a thin layer.
Thereafter the deoiled lecithin can be separated from the layer support used in the form of flocks or leaflets.
However it is unlikely that such a process could be carried out nowadays at an economically acceptable cost.
Furthermore the phosphatidylcholine content of 30% is too low for the applications described above.

Processes involving the use of additives are also known (US
patents 20 57 695 and 30 12 888).

A similar process has been proposed in German patent 38 26 946. Here a special sugar mixture marketed under the trade-mark PALATINIT is employed as an additive during the manufacture of the high purity phospholipid composition in order to yield powdered of granulated high purity specific phospholipids or phospholipid compositions.

4 ~ ~ 7 ~

However the aforesaid known methods possess the disadvantage that additional effort is involved, namely that it is necessary to add and work in an additive. Furthermore the phospholipid compositions prepared by the known methods are only of very restricted application on account of their relatively low phosphatidylcholine concentrations.

The present invention is intended to make available a phospholipid composition and a process for manufacturing such a phospholipid composition, that is particularly simple to carry out and leads to products which are stable on storage.

A phospholipidic powder or granulate according to the invention has a phosphatidylcholine content of at least 80% by weight, the phospholipidic powder or granulate being free of additives, and the phospholipidic powder or granulate being isolated from soybean lecithin and the powder or granulate having a particle size or a crystallite size between 18 mm and 0.07 mm.

The powdered or granulated phospholipid composition according to the invention exhibits a range of advantages. Thus it is particularly easy to handle on account of its granule-like or powdered consistency, so that the disadvantages described for the state of the art do not occur. Unexpectedly it was also found that the powdered or granule-like consistency is also maintained when the processing temperature of the powdered or granule-like composition rises to a temperature of about 30~C.
The phospholipid composition also possesses long storage stability of up to several years without any changes occurring in the chemical or physical structure. This is particularly the case if the phospholipid composition is stored at a temperature below 10~C,.......................................

7 ? Q96 preferably at a temperature between 1 ~C and 6 ~C, prefer-ably under an inert gas.

The aforesaid advantages of the phospholipid composition according to the invention mean that this composition is very readily applied to the manufacture of appropriate fin-ished products, such as, for example, cosmetics, dietetic preparations or pharmaceutical preparations. This is on account of the fact that such powdered or granule-like compositions are particularly simply dosed and can be weigh-ed out with great accuracy and reproducibility, which is not possible in the case of highly viscous or paste-like products. On account of the absence of additives (solidi-fiers) the composition according to the invention can also be applied where the known phospholipid compositions cannot be used on account of the additives they contain and/or their low phosphatidylcholine content, that is, in particu-lar, for pharmaceutical products.

A particularly suitable embodiment of the composition accor-ding to the invention involves the composition according to the invention that, as has already been described, contains at least 80% by weight phosphatidylcholine, being predomin-antly crystalline. Especially when the composition according to the invention contains more than 80% by weight, and preferably more than 90%, crystalline phosphatidylcholine components, it is found that sllch a composition particularly possesses the aforesaid advantages that have been described in detail above. In other words such a composition according to the invention contains at least 6g% by weight and prefer-ably 72% by weight crystalline phosphatidylcholine compon-ents on an absolute basis. Unexpectedly it could be demon-strated that such a composition according to the invention, that preferably was composed primarily of crystalline components, is excellently dispersible in water, which, for example, considerably eases the manufacture of appropriate aqueous suspensions of cosmetic dietetic or pharmaceutical preparations. The aforesaid ready dispersibility is unknown for phospholipid compositions according to the state of the art which is attributable to the fact that such known compositions are predominantly amorphous in nature.

A further embodiment of the composition according to the invention proposes that this possesses a concentration of at least 90~ by weight phosphatidylcholine.

Another embodiment of the aforesaid composition contains the composition according to the invention 93% by wt. + 3% by wt. phosphatidylcholine and 3% by wt. + 3% by wt. lysophosphatidylcholine, whereby the aforesaid values have been checked by a known quantitative thin-layer chromatographic analysis method. Such a composition preferably does not contain any phosphatidyle-thanolamine and/or any phosphatidylinositol.

With respect to the particle size of the phospholipid composition according to the invention it may be said that this is adjusted according to the particular field of application. As stated above, the phospholipid composition is comminuted to a particle or crystallite size between 18 mm and 0.07 mm, and preferably between 6mm to 0.5mm.

The present invention also applies to a process for the preparation of the aforesaid phospholipid compositions.

The process according to the invention for the preparation -7 ~ ~ 7~ 9~

of a phospholipidic powder or granulate comprises so comminuting a highly pure phospholipidic substance have a phosphatidylcholine content of at least 80% by weight after cooling to a temperature below -50~C that after the comminution a phospholipidic powder or granulate results, having a particle size or crystallite size between 18 mm and 0.07 mm.

Unexpectedly it could be established that phospholipid compositions could be comminuted without problems under these temperatures without the need for admixture of the solidifying agents required in the known methods. In addition, compositions that have been comminuted in this manner and that contain at least 80% by weight phosphatidylcholine are stable up to a temperature of 30~C for several months and years so that chemical and physical changes do not occur.

A further specifically favoured embodiment of the process according to the invention provides for the storage of the phospholipid composition at temperatures between +5~C and -60~C, particularly at temperatures between -10~C and -30~C
before comminution. Whereby the storage time varies between one day and 150 days, preferably between 30 days and 70 days depending on the storage temperature chosen. A phospholipid composition stored in the aforesaid manner can be comminuted to the initially mentioned particle size of 18 mm or 0.07 mm, preferably of 6 mm to 0.5 mm within a very short time.

Depending on the particular phospholipid composition employed a further method of execution of the process according to the invention involves the comminution and/or storage of the particular phospholipid composition at the aforesaid temperatures and for the aforesaid storage time under inert ~r '- 2~7~Q~6 gas. In particular the inert gas can be liquid nitrogen, carbon dioxide, a noble gas or a mixture of the aforesaid gases. This method of operation under inert gas prevents an undesired oxidative modification of the phospholipid compos-ition.

As already described above various highly purified phospho-lipid compositions isolated from natural products can be employed as starting materials for the process according to the invention, provided that they contain at least 80% by weight phosphatidylcholine. Such a composition can be iso-lated preferably from eggs, oil seeds and oil fruit and particularly soybean by the known procedures. However, it is particularly suitable when a soy (soybean) lecithin whose phosphatidylcholine content is at least 90% by weight and preferably 93 + 3% by weight is employed in the process according to the invention. Such a high purity soy lecithin can, for example, be isolated by the methods as they are described in the European patents 0 054 770 and 0 054 769.
In order to be able to store the powdered or granulated product prepared by the process according to the invention over a long period of time without chemical or physical change a further embodiment of the process according to the invention envisages storage at a temperature below 10 ~C and preferably between 1 ~C and 6 ~C.

A further improvement in the storage stability is achieved if the phospholipid composition is sealed into airtight sachets, for example of appropriate aluminium foil, and stored at the aforesaid temperatures.

A further embodiment of the aforesaid process envisages displacing the air contained in the sachets after they have ~ Z(:~7~Q96 been filled with an inert gas, for example, nitrogen, a noble gas, carbon dioxide or a mixture of the aforesaid gases.

As already described above the powdered or granulated phos-pholipid composition according to the invention is very easy to handle and can be employed for various purposes. Thus, for example, such a powdered or granulated phospholipid composition can be used as solution promoter, natural sur-factant and/or liposome former in cosmetic products andespecially in pharmaceutical products, since the phospho-lipid composition according to the invention is free from solidifying agents.

Advantageous further embodiments of the phospholipid com-position according to the invention and the process accord-ing to the invention are set out in the subsidiary claims.

The process according to the invention is further illus-trated by the examples that follow.

Example 1 300 kg of a phospholipid composition containing 93% + 3% by weight phosphatidylcholine that, for example, had been isolated from soybeans according to the processes described in European patents 00 54 770 or 00 54 769 was stored at - 20 ~C for 2 months. Immediatley before the phospholipid composition was comminuted it was brought to room tempera-ture (17 ~C to 21 ~C). Then the composition was comminutedin a conventional cold milling plant with liquid nitrogen cooling and sealed portionwise in aluminium sachets under inert gase (nitrogen). The product that had been so packed was stored at + 4 ~C.

2~7q~6 Stability tests revealed that the product retained its pow-dered or granulated form at temperatures up to + 30 ~C.

Immediately before such a product is processed it is warmed to room temperature to avoid the condensation of water onto the comminuted product.

Example 2 As described above 100 kg of the aforesaid composition were comminuted in the cold. However in contrast to example 1 the storage time before comminution was one month at -17 ~C.

Stability tests revealed that there was no change in consis-tency even after storage for 12 weeks at room temperature (20 ~C + 2 ~C) after comminution and packing.

The powdered or granulated phospholipid composition so iso-lated had the following chemical composition:
Phosphatidylcholine 94.2% by wt.
Phophatidylethanolamine not detectable Phosphatidylinositol not detectable Lysophosphatidylcholine 3.7% by wt.
Water 1.3% by wt.
Triglycerides (oils) 0.8% by wt.

Example 3 As previously described in example 1, 300 kg phospholipid composition were comminuted together with 150 kg carbon dioxide granules. Whereby the other conditions corresponded to those described in example 1.

2C~7~Q~6 Stability tests revealed that the composition prepared according to example 3, which contained the aforesaid high phosphatidylcholine content, also remained unchanged in consistency even on storage for six months after comminu-tion.

Claims

1. A phospholipidic powder or granulate having a phosphatidylcholine content of at least 80% by weight, wherein the phospholipidic powder or granulate is free of additives, and wherein the phospholipidic powder or granulate is isolated from soybean lecithin and the powder or granulate has a particle size or a crystallite size between 18 mm and 0.07 mm.

2. A powder or granulate according to claim 1, having a particle size between 6 mm and 0.5 mm.

3. A powder or granulate according to claim 1, which is predominantly crystalline.

4. A powder or granulate according to claim 3, which comprises more than 80% by weight of crystalline phosphatidylcholine components.

5. A powder of granulate according to claim 3, wherein more than 90% by weight of the phosphatidylcholine content is crystalline.

6. A powder or granulate according to claim 1, 2, 3, 4 or 5, which comprises a phosphatidylcholine content of at least 90% by weight.

7. A powder or granulate according to claim 1, 2, 3, 4, 5 or 6, which contains 93 ~ 3% by weight of phosphatidylcholine and 3 ~ 3% by weight of lysophosphatidylcholine.

8. A process for the manufacture of a phospholipidic powder or granulate according to claim 1, 4, 5, 6 or 7, wherein a highly pure phospholipidic substance having a phosphatidylcholine content of at least 80% by weight is comminuted after cooling to a temperature below -50°C so that after the comminution a phospholipidic powder or granulate results, having a particle size or crystallite size between 18 mm and 0.07 mm.

9. A process according to claim 8, wherein the phospholipidic powder or granulate has a particle size or crystallite size between 6 mm and 0.5 mm.

10. A process according to claim 8 or 9, wherein the phospholipidic substance is stored at a temperature between +5°C and -60°C before being comminuted.

11. A process according to claim 8 or 9, wherein the phospholipidic substance is stored at a temperature between -10°C and -30°C before being comminuted.

12. A process according to claim 10 or 11, wherein the phospholipidic powder or granulate is stored for 1 day to 150 days.

13. A process according to claim 10 or 11, wherein the phospholipidic substance is stored for 30 days to 70 days.

14. A process according to any one of the claims 8, 9, 10, 11, 12 and 13, wherein the comminution of the phospholipidic substance is carried out under inert gas.

15. A process according to any one of claims 10, 11, 12 and 13, wherein the storage of the phospholipidic substance before being comminuted is carried out under inert gas.

16. A process according to any one of claims 10, 11, 12 and 13, wherein the comminutive and storage of the phospholipidic substance before being comminuted is carried out under inert gas.

17. A process according to claim 14, 15 or 16, wherein the inert gas is selected from the group consisting of nitrogen, carbon dioxide, a noble gas, and a mixture of these gases.

18. A process according to claim 10, 11, 12 or 13, wherein the temperature of the phospholipidic substance is returned to room temperature after the storage and before the comminution.

19. A process according to any one of the claims 8 to 18, inclusive, wherein after comminution the phospholipidic powder or granulate is stored at a temperature lower than 10°C.

20. A process according to any one of claims 8 to 18, inclusive, wherein after comminution the phospholipidic powder or granulate is stored at a temperature between 1°C and 6°C.

21. The process according to claim 19 or 20, wherein after comminution the phospholipidic powder or granulate is stored under inert gas.