IE910761A1 - Method for coating active principles with zein - Google Patents

Abstract

New process for coating medicinal and/or alimentary active principles which consists in spraying onto the latter an emulsion or aqueous dispersion of zein.

Description

The present invention relates to coating active principles with formulations containing zein.

It has been known for a long time to coat active principles with zein, which may be mixed with a hydrophobic substance such as stearic acid and/or a water-insoluble polymer such as ethylcellulose. These coatings are described in particular in relation to animal feeds in the European patent applications published under the numbers EP 321 337 and EP 188 953.

According to these applications, particles of methionine and/or lysine are coated by the fluidised bed technique using a solution of zein dissolved in a mixture of dichloromethane and ethanol (50/50). This technique permits easy spraying of the zein but has the disadvantage of introducing a significant amount of halogenated solvents, approximately 20 to 50 g of dichloromethane per 1 g of zein. Zein is a natural product, which has a considerable advantage from the standpoint of ecotoxicity. It is regrettable to have to introduce concomitantly, in the course of the process, a significant amount of halogenated solvents for which the ecotoxicity is less satisfactory.

The present invention makes it possible to coat active principles such as amino acids or vitamins with zein while avoiding to the maximum extent the use of organic solvents which are incompatible with biological media.

The present invention provides a method for coating medicament or foodstuff active principles with zein which comprises spraying onto said active principles an aqueous emulsion or dispersion of zein. The medicament or foodstuff active principle to be coated is preferably in the form of granules having a diameter of between 0.3 and 3 mm.

The use of an aqueous emulsion permits a significant economy in the implementation of the method because it avoids the use of installations for recovery of solvents which are expensive from the standpoint of safety and investment. It also permits a productivity which is distinctly improved compared with the methods of the prior art using solvents.

The medicament active principle may be, in particular, a vitamin, antibiotic, antiparasitic compound or hormone. The foodstuff active principle may be, in particular, assumed limiting essential amino acids such as methionine and/or lysine or its derivatives and/or tryptophan.

Fillers, which may be lamellar and which facilitate the disintegration of the granule in the digestive tract, may be added to the active principles. These fillers, which may or may not be pH-sensitive, can be one or more of, for example: talc, silica, a carbonate, or a complex polyphosphate, e.g. based on Na20, CaO, P2O5 and A12O3. A binder e.g. a fatty acid or -i - 4 fatty ester, cellulose (for example that marketed under the name Avicel) or a derivative thereof, especially ethylcellulose or carboxymethylcellulose, or a basic copolymer, may also be added to the active principle. The combination of active principle or principles and additives (if any) forms the core of the granule, which is coated with zein sprayed in the form of an aqueous dispersion or emulsion.

The medicament or foodstuff active 10 principle, optionally containing one or more of the abovementioned additives, and coated with zein in accordance with the invention is particularly valuable for feeding to ruminants because it is not degraded during passage through the rumen and is liberated in the abomasum and/or the intestine.

The coating is carried out by spraying an aqueous emulsion or dispersion of zein. The coating emulsion may also contain additives, such as those mentioned above for the core, antistatic agents, plasticisers, colorants or appetite stimulants.

It is preferred to use an aqueous dispersion containing zein and a hydrophobic substance and optionally containing a water-insoluble polymer. The hydrophobic substance is preferably a fatty acid containing 12 to 22 carbon atoms, such as, for example, stearic acid or behenic acid. The emulsifier may be a fatty acid ester or fatty acid salt. In the latter case, the emulsifier may be produced in situ by converting the fatty acid into a salt with an alkali metal hydroxide or ammonium hydroxide.

The water-insoluble polymer (when used) is 5 advantageously a water-insoluble cellulose ether or ester, such as ethylcellulose, cellulose acetate, cellulose propionate or cellulose acetobutyrate.

The emulsion or dispersion is produced by mixing a solution of zein in a small amount of organic solvent and an aqueous solution containing an emulsifier. The emulsion contains a major proportion of aqueous phase and a minor proportion of organic phase, and preferably the aqueous phase represents 95 to 50 % by volume and the organic phase represents 5 to 50 % by volume.

The aqueous phase contains the emulsifier and/or a precursor allowing formation of the emulsifier in situ. More particularly it may contain 0 to 10 % by weight of an emulsifier, chosen, as mentioned above, from fatty acid esters or salts, and/or 0 to 1 % by weight of an alkali metal hydroxide or ammonium hydroxide. For the emulsion to form, at least one of the two groups of constituents, either the emulsifier or the combination of alkali metal hydroxide or ammonium hydroxide and the fatty acid, must be present. The minimum amount of emulsifier added or formed in situ, calculated on the basis of sodium hydroxide, is 0.2 % by weight.

The organic phase is obtained by dispersing or dissolving a solid mixture, preferably having the following composition by weight: - 10 to 100 % of zein, - 0 to 90 % of one or more hydrophobic substances, and - 0 to 90 % of one or more water-insoluble polymers, in a liquid composition consisting of, by volume: - 100 to 40 % of organic solvent or mixture of organic solvents, and - 0 to 60 % of water.

The organic solvent, or mixture of organic solvents, used to form the organic phase may be a straight-chain or branched alcohol containing at least four carbon atoms, or a mixed solvent comprising alcohol and a halogenated solvent such as, for example, tetrachloroethane, trichloroethane, dichloroethane, chloroform or dichloromethane.

The percentages by weight of the solid mixture and the liquid composition are preferably within the following limits: - solid mixture, 85 to 20 %, and - liquid composition, 15 to 80 %.

The organic phase, obtained after dispersing or dissolving the solid mixture in the liquid composition, is mixed with the aqueous phase prepared previously. If the organic phase does not contain a fatty 2acid, the aqueous phase must contain an emulsifier; on the other hand, if the organic phase contains at least one fatty acid, the aqueous phase may contain an alkali metal hydroxide or ammonium hydroxide and/or an emulsifier.

The emulsion may be produced by introducing the organic phase into the aqueous phase or vice versa.

Before the emulsion is sprayed, it is kept liquid at a temperature between ambient temperature and 90°C and preferably between 50 and 70°C. It may be sprayed onto a bed of granules to be coated using the fluidised bed technique, for example of the WURSTER type. This technique is described, for example, in the United States Patent No. 2 799 241 and European Specification No. 188 953.

The granules obtained after coating can be used, depending on the nature of the active principle, in feeding ruminants or in treating them with a medicament.

The following Examples illustrate the method 20 of the invention.

EXAMPLE 1 „ Stearic acid (88 g; m.p. = 66.9°C, acid number 199) (PRIFRAC® acid, marketed by UNICHEMA) and zein F 4000 (marketed by BENZIAN) (14 g) are dissolved with ethylcellulose N 22 (marketed by HERCULES) (8 g) in a mixture (60 g) containing n-butanol and water (100:20 by volume). - 8 This solution is heated to 72 *C and added in the course of 7.5 minutes to a mixture, which ie stirred using a Polytron-type turbine, of water (495 cc) and 10 % (w/v) aqueous sodium hydroxide solution (4.2 ml). An emulsion is thus obtained which is fluid and homogeneous at tanperatures above about 65°C, i.e. above the melting point of stearic acid.

Using the fluidised bed technique with a tank fitted with a WURSTER system, methionine (350 g), previously granulated in the form of spherical particles assaying 98 % by weight of methionine and having an average diameter of between 0.63 and 0.88 mm, is coated with the emulsion obtained previously by spraying the emulsion, kept at 70°C, over the course of 48 minutes. Coated granules (437 g) assaying 77.5 % by weight of methionine are thus obtained.

In vitro test The liberation of the methionine contained in the granules obtained is examined, under set conditions, by stirring a known amount of the granules in a buffered medium kept at constant pH at a temperature of 40°C. The rates of liberation from samples subjected to various pHs are compared.

Granules (8 g) containing 77.5 % by weight of methionine, prepared using the above method, are placed in a medium (1000 ml) kept at pH 6. After hours the granules have liberated 3.3 % by weight of methionine.

In vivo test The resistance of the granules to residence in the rumen is determined, in sheep, by measuring the total amount of nitrogen which has disappeared from sachets containing the granules.

Nylon sachets (mesh 46 microns square) each containing coated granules weighed exactly (about 3 g) are incubated for 17 hours in the rumen of two sheep using two sachets per product and per sheep.

After incubation in the rumen, the sachets are washed with cold water and then lyophilised for 48 hours. The sachets are weighed and the amount of granules which has disappeared is determined. The residues are then removed from the sachets and sampled in duplicate for determination of total nitrogen.

After 17 hours the amount of amino acid liberated in the rumen is 2 % by weight.

£XAMPL£_2 Example 1 is repeated replacing the stearic acid/zein/ethylcellulose mixture (110 g) by zein alone (110 g). If 10 % of sodium oleate with respect to the dry matter is added as an aqueous solution, the formation of a homogeneous emulsion is observed. This emulsion may be used in the same way as that of Example 1.

EXAMPLES Stearic acid (PRIFAC& acid marketed by UNICHEMA) (156 g) and zein F 4000 (marketed by ΒΕΝΖΙΆΝ) (24.8 g) are dissolved at elevated temperature (75-80°C) with ethylcellulose N 22 (marketed by HERCULES) (14.2 g) in a mixture (106 g) containing n-butanol and water (100:20 by volume).

Distilled water (877 cc), to which 10 % sodium hydroxide solution (7.5 cc) had been added, is charged into a 2 litre reactor placed in a water bath and fitted with a Polytron turbine stirrer. The contents of the reactor are heated to 65*C. The zein solution is run into the diluted sodium hydroxide solution in the course of 2 minutes 30 seconds, with stirring (Polytron 11,000 revolutions per minute). After the solution has been run in, the mixture is stirred for about 1 minute 30 seconds.

Lysine hydrochloride (350 g), previously granulated in the form of spherical particles assaying 90.4 % by weight of lysine and having an average diameter of 0.8 mm, is coated using the fluidised bed technique with a tank fitted with a WURSTER system by spraying the particles with the emulsion obtained as described above, kept at 75°C, over the course of one hour 36 minutes.

Coated granules assaying 61 % by weight of lysine hydrochloride are thus obtained. The coating constitutes 32.5% by weight of the coated granules.

These granules are tested in vitro using the same technique as in Example 1. The rate of liberation of the lysine hydrochloride at pH 6 at 40°C is: - in 6 hours: 3 % by weight - in 24 hours: 21 % by weight.

Claims (19)

1. A method for coating a medicament or foodstuff active principle with zein, which comprises spraying onto the active principle an aqueous emulsion or dispersion of 5 zein.

2. Method according to claim 1, wherein the aqueous emulsion or dispersion of zein comprises an organic phase, containing zein and optionally a hydrophobic substance and/or a water-insoluble polymer, and an 10 aqueous phase containing an emulsifier or a precursor permitting in situ formation of the emulsifier.

3. Method according to claim 2, wherein the emulsifier is a fatty acid salt or ester.

4. Method according to claim 2 or 3, wherein the 15 organic phase contains a hydrophobic substance which is a fatty acid containing 12 to 22 carbon atoms.

5. Method according to claim 4, wherein the hydrophobic substance is stearic acid.

6. Method according to claim 4 or 5, wherein the 20 precursor permitting in situ formation of the emulsifier is an alkali metal hydroxide or ammonium hydroxide.

7. Method according to any one of claims 2 to 6, wherein the organic phase contains a water-insoluble polymer which is a water-insoluble cellulose ether or 25 ester. Method according to any one of claims 1 to 7, wherein the active principle is mixed with a filler which may or may not be pH-sensitive.

8. 9. Method according to claim 8, wherein the filler is talc, silica, a carbonate, and/or a complex 5 polyphosphate, based on Na 2 O, CaO, P 2 O 5 and A1 2 O 3 .

9. 10. Method according to any one of claims 1 to 9, wherein the emulsion or dispersion of zein also contains one or more fillers as defined in claim 8 or 9, antistatic agents, plasticisers, dyes and/or appetite 10 stimulants.

10. 11. Method according to any one of the preceding claims, wherein an aqueous emulsion of zein is used comprising 95 to 50 % by volume of aqueous phase and 5 to 50 % by volume of organic phase. 15

11. 12. Method according to claim 11, wherein the aqueous phase contains 0 to 10 % by weight of a fatty acid salt or ester emulsifier and/or 0 to 1 % by weight of an alkali metal hydroxide or ammonium hydroxide, the sum of the two being at least 0.2 % by weight of sodium 20 hydroxide equivalent.

12. 13. Method according to claim 11, wherein the organic phase is obtained by dispersing or dissolving a solid mixture comprising, by weight: - 10 to 100 % of zein, - 0 to 90 % of one or more hydrophobic substances, and - 0 to 90 % of one or more water-insoluble polymers - 13 in a liquid composition comprising, by volume: - 100 to 40 % of one or more organic solvents, and - 0 to 60 % of water.

13. 14. Method according to claim 13, wherein the 5 percentages by weight of the solid mixture and the liquid composition are: - 85 to 20 % solid mixture, and - 15 to 80 % liquid composition.

14. 15. Method according to claim 13 or 14, wherein 10 the organic solvent is a straight-chain or branched alcohol containing at least four carbon atoms or a mixed solvent comprising alcohol and halogenated solvents.

15. 16. Method according to any one of claims 1 to 15, wherein the active principle is methionine, lysine, 15 or a derivative thereof.

16. 17. Method according to claim 16, wherein an emulsion consisting of a mixture of zein, ethylcellulose, stearic acid, sodium stearate and water is sprayed onto granules of methionine and/or lysine. 20

17. 18. Method according to claim 1 substantially as described in any one of Examples 1 to 3.

18.

19. An active principle when coated with zein by the method of any of the preceding claims.