CH649217A5 - BROMOCRIPTIN CONTAINING MICROCAPSULES. - Google Patents

Description

The invention relates to microcapsules containing bromocriptine as the core material and poly-D, L-lactic acid as the outer layer, as well as a process for their production according to claim 2.

To produce the microcapsules, the poly-D, L-lactic acid is dissolved in a solvent in which the bromocriptine core material is insoluble, and the core material is dispersed therein in microparticle form. A phase separation agent is added at temperatures between -40 and -100 ° C, whereby the polymer precipitates and the particles of the core material are coated.

When the temperature of the system is brought up to -40 to -100 ° C is not critical as long as the phase separation takes place within this temperature range.

“Phase release agent” is understood to mean not only a solvent in which the polymer and core material are not soluble, but also a polymeric material that is incompatible with the coating polymer and with the core material. The phase separation agent is preferably the solvent form.

The formation of the microcapsules according to the invention is based on polymer phase separation. When a phase separation agent is added to a polymer solution in which solid bromocriptine particles are dispersed, the polymer separates first as a liquid phase and then precipitates on the dispersed particles of the bromocriptine. If the phase release agent is also the solvent, further addition of the phase release agent will cause the coating to harden as a capsule wall surrounding all of the bromocriptine. In the event that the phase separation agent consists of polymeric material, a solvent must also be added at the same time or subsequently, which hardens the surface of the microcapsules, thereby avoiding agglomeration. By adjusting the process conditions, the coated bromocryptine particles can precipitate out in a controlled manner either as separate capsules or as larger agglomerates. Unwanted massive union occurs when the adhesion and sticking of the capsules are uncontrolled and sudden. The low-temperature process allows the microcapsules to set sufficiently and thereby prevents unwanted agglomeration.

Concentrated microcapsules larger than the separate microcapsules are sometimes preferred in connection with the type of use of the product. The microcapsules should be so large that the release of the bromocriptine is guaranteed for a certain period of time and they can still pass through an injection needle. In such a case, the preferred size is about 150 | i for a No. 20 standard needle.

For other possible uses, the agglomeration can be carried out in a controlled manner so that microcapsules larger or smaller than 150 | i are formed.

The temperature range for the process for the production of the microcapsules is between -40 ° and -100 ° C, preferably between -40 ° and -75 ° C, especially between -50 ° and -70 ° C. The upper limit is determined by the endeavor to avoid massive agglomeration. Generally there is more latitude at lower temperatures without undesirable agglomeration. The lowest temperature is determined by the freezing point of the solvents or the solvent mixture.

Double-encapsulated microcapsules can be produced according to the phase separation method at low temperature if preformed microcapsules, dispersed in a solution of poly-D, L-lactic acid, are used as the core material. In some cases it is necessary to cool the polymer solution to -40 ° to 100 ° C before adding the preformed microcapsules, otherwise the microcapsules are dissolved in the polymer solution. If the initial release rate needs to be throttled and the release time extended, double encapsulation is a useful method because an additional layer of poly-D, L-lactic acid inhibits release. This method can even be used several times and multiple encapsulation can be achieved.

Toluene, xylene, chloroform, methylene dichloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and their mixtures are used as solvents in the above process.

The phase separation agent used in the process is said to be volatile or easily removable by washing with another volatile phase separation solvent, to have a freezing point below the process temperature and to be miscible with the polymer solvent at that temperature.

The phase separation agent in question may be non-polar, but polar ones are preferred. Examples of the non-polar are the alkane hydrocarbons, such as hexane, hep-tan or cyclohexane. Examples of the polar agents are water, alcohols such as isopropanol or isobutyl alcohol, ether, polyalcohols such as 1,2-glycols, e.g. Propylene glycol or 1,3-glycols, such as trimethylene glycol, or triols, such as glycerol, or also ethers and esters of the polyalcohols. Polyalcohols are particularly preferred for the production of aggregates with larger diameters. Fluorocarbons are also suitable.

Solvent mixtures can also be used as the phase separation agent, for example if the freezing point of a solvent has to be lowered in order to work at a very low temperature or if the bromocriptine in the phase separation agent has a certain solubility for the polymer. For example, the non-polar heptane can be added to reduce the solubility of the bromocriptine in isopropanol. A component can be added to the phase separation agent which ensures the miscibility of phase separation agents and polymer solvents.

A phase release agent in the form of a polymer that is incompatible with the coating polymer and core material is said to be miscible with the solvent of these two components. Preferably, the polymeric phase release agent is also miscible with the solvent used for curing, whereby traces of the polymeric phase release agent can be removed from the microcapsules.

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Polymeric phase separation agents that can be used include: a. Polybutadiene and polydimethylsiloxane.

example

1.4 g of poly-D, L-lactic acid, which has an intrinsic viscosity of 2.32 in hexafluoroisopropanol 5 at 25 ° C., is dissolved in 55 ml of toluene and cooled to -70 ° C. in a bath of isopropanol and solid carbonic acid . With stirring (140 rpm), 0.6 g of microform-ground bromocriptine is dispersed in the solution of the polymer. 100 ml of a 10 mixture of heptane and isopropanol (25:75 v / v)

649217

added dropwise to the dispersion, followed by the addition of 50 ml of heptane. The cooling bath is removed. The microcapsules formed precipitate and the supernatant is decanted. The residue is washed twice with heptane and dried. The yield is 1.71 g (86%) of spherical microcapsules with a diameter of 15 to 40 p. Microscopically, when the microcapsules are suspended in oil and irradiated with polarized light, it is perceived that their drug particles shimmer through the capsule wall.

Claims (2)

649 217 PATENT CLAIMS 1. Microcapsules containing bromocriptine as the core material and poly-D, L-lactic acid as the outer layer. 2. Process for the production of microcapsules according to claim 1, characterized in that the poly-D, L-lactic acid is dissolved in a solvent, the core material bromocriptine in microparticle form is dispersed therein and by adding a phase separating agent at a temperature between -40 and -100 ° C achieves precipitation of the polymer to form a coating on the particles of the core material.