WO1989004714A1

WO1989004714A1 - Process for microencapsulation of low-melting solid substances

Info

Publication number: WO1989004714A1
Application number: PCT/EP1988/001010
Authority: WO
Inventors: Massimo Calanchi; Leonardo Gentilini; Luigi Mapelli; Marco Marconi
Original assignee: Eurand International S.P.A.
Priority date: 1987-11-26
Filing date: 1988-11-07
Publication date: 1989-06-01
Also published as: AU2790389A; IT1224642B; PT89021B; PT89021A; IT8722754A0; KR900700183A; ZA888387B; NZ226943A

Abstract

A process of microencapsulation of substances which are solid at ambient temperature but have a low melting point is described. The substances are first melted and microencapsulated in the form of droplets in order to obtain a finished product whose characteristics are better than those which are obtained when the substance is microencapsulated in the solid state and, in particular, with a high concentration of the active principle.

Description

"PROCESS OF MICROENCAPSULATION OF LOW-MELTING SOLID SUBSTANCES"

This invention relates to a process of microencapsulation of low-melting solid substances which presents considerable practical and technical advantages.

Microencapsulation consists of the covering of single particles of a substance with a polymeric membrane. A variety of microencapsulation techniques can be used and are well-known to experts in this field.

Among the preferred techniques are those described in U.S. patents no. 2,800,457 and no. 3,341,466; U.K. patent 1,117,178 and Canadian patents no. 882632 and no. 885949 which are based on coacervation and separation into phases and lead to the microencapsulation of liquids in the form of droplets, or solids in the form of crystals or granules.

The most favourable conditions from the technical point of view are those in which the particles to be covered have homogeneous shapes, ideally spherical, in other words when the total surface to be covered is as small as possible. These conditions obtain, for example, when the substance to be microencapsulated is a liquid which can be divided into uniform droplets.

Thus this invention consists of the melting and transformation into liquids of all those substances which are solid or semisolid at ambient temperature and which have a melting point which is lower than the boiling temperature of water.

The technological approach which is currently adopted to reduce the total surface of the substances to be microencapsulated and to reduce the granulo metric range is that of mechanical selection of the particles by sieving.

Obviously, the fractions with the smallest granulometry and those with the largest one are discarded.

This sieving operation is not always feasible, requiring special equipment and the right type of rooms, particularly because of the risk of explosion in the case of fine powders. In addition, it is also difficult to find a use for the part of the product which is not suitable for microencapsulation, which requires reprocessing and, as an obvious consequence, leads to losses of the product and increased costs.

The alternative process of wet and dry granulation by compaction also does not eliminate the need for a final selection of the granules in order to obtain the most suitable granulometric fraction and the unsuitable fractions, which are sometimes the most numerous, have to be reprocessed and this creates very high costs.

The grinding and granulation operations take a long time, special equipment is required and large fractions of crystals or granules which are too fine or too big have to be recycled. The advantage of this invention is that the laborious and expensive operations described above can be avoided because the total surface of the particles is reduced by melting the product to be microencapsulated into spherical droplets. In addition a smaller quantity of membrane is used and the microcapsules are much more homogeneous.

The desired granulometric range can easily be obtained by varying the speed of agitation and the geometry of the agitators during the process of microencapsulation.

Finally, any problems of aggregation, which are common in the microencapsulation of fine particles, and of non-uniform coverage, which are frequent in the microencapsulation of acicular crystals, are minimized.

This invention also permits the microencapsulation of substances which have a uniform solid or semisolid mass at ambient temperature such as, for example, numerous animal and/or vegetable fats or waxes and which, as a consequence, cannot be encapsulated with the traditional technologies. In fact, these fats have to be reduced to small solid particles, which is difficult and often impossible. These limitations imposed by the known technologies of the day can be overcome by recourse to a rapid and simple melting process.

The process which is the subject of this invention, takes place in a reactor equipped with a heating jacket and consists of the following operations: - the polymer which will lead to the formation of the membrane is dissolved in the reactor in de-ionized or distilled water, agitated and heated to a temperature of between 35° and 65°C.

As a non-limiting example, the following polymers are used as a membrane: gelatin, succinic gelatin, gum arabic, albumin, polyvinyl alcohol hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate, hydroxypropylcellulose phthalate, ethylenevinylacetate, copolymers of maleic anhydride and ethylene or methylvinyl ether, shellac.

The membrane can also be constituted by mixtures of two or more of these polymers.

- The substance to be microencapsulated is melted in another reactor, equipped with a heating jacket. When it has liquified, it is poured into the reactor which contains the membrane solution. All substances which are solid or semisolid at ambient temperature, which do not mix with water and which have a melting point or sintering point which is lower than the boiling temperature of water are suitable. The latter condition is not necessarily required since, in fact, the melting point of the substance to be microencapsulated can be higher than 100 °C as long as the quantity of melted material is not large enough to bring to the boil the water to which, it is added.

As non-limiting examples we cite: dimenhydrinate, ibuprophen, ibuprophen guaiacolester, gemfibrozil, ethofibrate, cocoa butter, glycerϊl palmirate stearate, hydrotropic benzoil acid, bee's wax, hydrogenated castor oil and hydrogenated vegetable oils and fats in general, fatty alcohols with high molecular weights (for example C1 -C22)_. fatty acids with high molecular weights (for example Cio*-C26. and esters of fatty acids with high molecular weights.

The speed of the agitator and/or the viscosity of the solution are then adjusted to produce droplets of the size required. The size can vary between 1 and 4,000 microns but normally falls within the range of 40 to 1,000 microns. - Then the membrane is deposited around the droplets causing the phase separation or coacervation of the polymer by means of: variations to the temperature (normally by decreasing it); the addition of a salt, of a non-solvent of the polymer which constitutes the membrane, of another polymer incompatible with the polymer in solution; a polymer-polymer interaction, normally obtained by varying the pH of the solution.

Obviously, the polymer or polymers constituting the membrane and the substance or substances which are added to cause separation of the phases must be compatible with the substance to be microencapsulated and, therefore, must not react with it.

The membrane is deposited in liquid form around the droplets of the substance to be microencapsulated when the polymer is adsorbed on the droplets.

Adsorption is an essential requisite if continuous and effective coverage is to be obtained.

- The membrane solidifies and hardens for example, by a further reduction in the temperature, by de-solvation or dehydration, by cross-linking.

- Generally, the microcapsules are finally separated from the vehicle in which microencapsulation has taken place, for example by centrifugation or filtration, and are dried for example in a cabinet under vacuum, or with a flow of air or in a fluidized bed.

The invention is now illustrated by some non-limiting examples of substances which have been encapsulated by melting them.

Example 1

200 g of gemfibrozil (5-(2.5 dimethyl phenoxy)-2.2- dimethyl pentanoic acid m.p. 61-63°C) are melted in an appropriate container on a heating plate. They are then brought up to a temperature of 70 °C in order to obtain low viscosity.

20 g of gelatin heated to 55°C is dissolved in 480 ml of deionised or distilled water in another recipient provided with washplates.

30 ml of an aqueous solution of 596 of sodium polyphosphate is added and the pH is corrected to between 3 and 5 by means of acetic acid or diluted sodium hydrate.

The solution is agitated to produce a turbulent movement. The temperature must be maintained constant at a level of 55° C.

The melted substance is added rapidly and the agitation is varied in such a way as to obtain droplets of a diameter of less than 200 microns.

Maintaining the agitation, the contents are slowly cooled down to a temperature of 15°C. This is the stage in which eoacervation takes place i.e. the gelatin is deposited around the droplets of the melted substance.

The temperature is then increased to around 25 °C, 16 ml of aqueous solution of 25% glutaraldehyde is added and agitation is maintained for 18 hours to allow the membrane which covers the particles of gemfibrozil to harden permanently.

16 g of sϊlϊce gel are then added and agitation 'continues for 15 min to ensure that there is no aggregation of the microcapsules during the drying out stage.

The microcapsules are filtered and dried in a cabinet under a flow of air or in a fluidized bed until the humidity is less than 3% and are then sieved using a 420 micron mesh.

Example 2

280 of ibuprophen guaiacol ester (m.p. 36.5-37°C) are gradually melted in a suitable recipient on a heating plate and then brought up to 55 °C to obtain low viscosity.

180 g of aqueous solution of 11% gelatin, 180 g of aqueous solution of 11% of gum arabic and 800 g of de-ionised or distilled water, heated to a temperature of 50°C, are placed in another recipient provided with one or two washplates. The pH value is corrected to between 3 and 5 by acetic acid or diluted sodium hydrate.

The solution is then agitated in such a way as to obtain a turbulent movement. The temperature is maintained constant at around 50°C.

The melted substance is rapidly added and the agitation is varied to obtain droplets of a diameter of less than 400 microns.

Maintaining the agitation, the solution is cooled down slowly to a temperature of 15°C, so that a deposit of gelatin and gum arabic forms around the droplets of melted substance.

The agitation is stopped and the microcapsules are allowed to decant for about 10 minutes. The liquid fraction is removed and they are washed tw.ice with water.

The microcapsules are suspended once again in de-ionised water, 56 g of silica gel are added and the suspension is agitated for 15 minutes to avoid aggregation of the microcapsules during drying out.

The microcapsules are filtered and dried in a cabinet under a flow of air or in a fluidized bed until humidity is less than 3%. They are then sieved using a 500 micron mesh.

Example 3 200 g of cocoa butter (m.p. 30-35°C) are placed in a suitable recipient and graduεilly melted on a heating plate and then brought up to a temperature of 50°C to obtain low viscosity.

200 g of aqueous solution of 10% succinic gelatin, 30 g of aqueous solution of 5% sodium polyphosphate and 400 g of de-ionised or distilled water, heated to a temperature of 50 °C, are placed in another recipient provided with one or more washplates. The pH value is corrected to between 3 and 5 with acetic acid or diluted sodium hydrate.

The melted substance is added rapidly and the agitation is varied to obtain droplets with a diameter of less than 500 microns.

Maintaining the agitation, the solution is cooled slowly down to a temperature of 15°C so that succynic gelatin is deposited around the droplets of melted substance.

The temperature is increased to about 25 °C and 40 g of anhydrous sodium sulphate are added. The solution is agitated for about 10 minutes until the succynic gelatin deposited on the droplets of the product has become completely dehydrated.

20 g of silica gel are added and the solution is then agitated for 15 minutes.

The microcapsules are then filtered and dried in a cabinet under a flow of air or in a fluidized bed and then sieved using a 600 micron mesh.

Claims

CLAIMS 1. Process of microencapsulation of low melting solid substances, characterized by the fact that it comprises the operations of melting a polymeric substance which forms a membrane and separately melting or synterizing the solid substance to be microencapsulated; when said substance has liquified, pouring it into the solution of the membrane-forming substance; depositing the membrane around the droplets of liquified solid or semisolid substance, causing coacervation or separation into phases of the membrane- forming substance, by means of adsorption of the membrane-forming substance on the droplets of the substance to be microencapsulated; solidifying and hardening of the membrane; separation from the microencapsulation vehicle and drying of the microcapsules obtained in this way.

2. Process according to claim 1, characterized by the fact that the separation into phases or coacervation of the polymeric substance which forms the membrane is obtained by means of variations to the temperature, the addition of a salt, of a non-solvent of the said membrane-forming substance, of another polymer which is incompatible with the polymer in solution, or interaction between polymer and polymer, obtained in addition by varying the pH of the solution, the substances eventually added to cause the separation into phases having to be compatible with the substances to be microencapsulated.

3. Process according to claim 1, characterized by the fact that the solidifying and hardening of the membrane are obtained by lowering the temperature, by de-solvation or dehydration or by cross-linking.

4. Process according to claim 1, characterized by the fact that the separation of the microcapsules from the vehicle is achieved by centrifugation or filtration.

5. Process according to claim 1, characterized by -the fact that the microcapsules are dried in a cabinet under vacuum or under a flow of air or in a fluidized bed.

6. Process according to claim 1, characterized by the fact that the substance which constitutes the membrane is chosen from one or more of the following: gelatin, succynilated gelatin, gum arabic, copolymers of maleic anhydride and ethylene or methylvinyl ether, carboxymethylcellulose, albumin, polyvinylalkol, cellulose acetate, hydroxypropylcellulose phthalate, ethylene vinylacetate, shellac and must always be compatible with the substance to be encapsulated, not reacting with it.

7. Proeess according to claim 1, characterized by the fact that the microcapsules have dimensions of between 1 and 4,000 microns, preferably between 40 and 1,000 microns.

8. Process according to claim 1, characterized by the fact that the microencapsulated substance is gemfibrazil.

9. Proeess according to claim 1, characterized by the fact that the microencapsulated substance isibuprophen guaiaeol ester.

10. Process for the microencapsulation of low melting solid substances, essentially as described above and as described in detail in the examples, for the objectives specified herein above.