SE431942B - PROCEDURE FOR MANUFACTURING MICROSPHERES CONSISTING OF A POLYMERIC MATERIAL AND A SOLID CORE MATERIAL - Google Patents

Description

10 H0 7808759-o 2 aggregation of encapsulated particles and does not constitute a satisfactory procedure for the production of delimited, spherical microspheres of polymer and core material by phase separation which would be suitable for use in a wide range.

It has now been shown that these problems can be eliminated by that the phase separation is carried out at low temperatures, ie from -no to -1oo ° c.

Accordingly, the present invention relates to a method for the production of microspheres consisting of a polymer and core material, which process is characterized by a step for the addition of a phase separator to a medium consisting of those of a solution of the polymer and a dispersion or solution of the core material at a temperature of -40 to -10000.

For the production of microcapsules, the polymer is dissolved in one solvent in which the core material is insoluble, the micro- particles of the core material are dispersed in the solution of and a phase separator is added to the system at a temperature of -M0 to -100 ° C for precipitation of the polymer and coating of the nuclear material particles.

For the production of microbubbles, the polymer and core the material in a common solvent and a phase separation agent is added to the solution at a temperature from -U0 to -10% for precipitating particles consisting of a homogeneous mixture of polymer and core materials.

It should be noted that it is not critical at which stage of the process to which the system temperature is lowered to -40 -10000, provided that the phase separation takes place within this temperature area.

The core material in the microspheres produced by the process of the present invention may be products for agriculture such as insecticides, fungicides, herbicides, denticides, pesticides, fertilizers, virus particles for plant protection and the like cosmetics such as deodorants, fragrances ser o.dyl .; food additives such as flavorings, oils, fats o.dyl .; and drugs, e.g. drugs. Microspheres consisting of drugs as core materials may be suitable as retard forms with long-term effect for oral or parenteral administration.

Drugs, e.g. drugs, are especially preferred core materials and the invention will hereinafter comprise core materials in the form of drugs. 1; STAY HO Z »7808759-0 The term "phase separator" includes both non-solvent polymer and core material and polymeric materials which are incompatible with the coating polymer and core material. let. When the phase separator is an incompatible polymer, so must the non-solvent is also added simultaneously or later for providing hardening of the surface of the microspheres and for preventing inappropriate agglomeration. The addition of a non-solvent agents, used as a curing agent, should also be used in the temperature from -H0 to -10000. The term "non-solvent" agents "in the following description are used both for non- solvents used as phase separators and for non-solvents used as harder when the phase separator is one incompatible polymer.

In a preferred embodiment of the invention, the phase a non-solvent and any incompatible polymer was not used. ' The formation of microcapsules according to the present invention is based on a polymeric phase separation phenomenon. When a phase separating agent at the start of the process is added to a lymer solution in which particles of a drug in solid form are dispersed, there is the polymer which is initially separated in liquid form and precipitates as a coating on the dispersed the drug particles. Subsequent addition of non-solvent means causes the coating to cure to a capsule wall which completely encloses the drug particle. By changing procedures the conditions are obtained the coated drug particles as special capsules or agglomerates designed in a controllable manner for larger units of microcapsules. Undesirable massive agg- lomeration is obtained when adhesion and coalescence of the encapsulants laid particles suddenly develop out of control. Compatible low temperature procedure makes the microspheres sufficient stable to prevent undesired agglomeration.

The homogeneous microclumps of the present invention has also been formed by the phase separation phenomenon. When a phase ration agent for both the polymer and the drug is added to one homogeneous solution of polymer and drug, so both differ polymer and drug to form homogeneous microclumps.

Depending on the conditions during the process, they remain individual spheres or they may agglomerate in an adjustable manner during formation of larger homogeneous microclumps. 50 HO ïsnsvse-o, Depending on the end use of the product, it may it may be desirable to aggregate the microspheres into larger formations than individual microspheres. For example, for regulated release should of drugs suitable for parenteral administration, microspheres be large enough to obtain a pass. true duration of release but still small enough in order not to restrict the passage through the standardized needles used. Thus, the preferred size should be about 150 '/ um for a needle caliber no. 20.

For other uses it may be appropriate to allow one controlled agglomeration to form microspheres larger or less than 150 / um.

The temperature range of the process of the present invention finding is about -ho to -100 ° C, preferably -ho to -75 ° c, especially -50 to -70 ° C. The upper temperature limit is dictated of the need to avoid large agglomeration. Generally operation at a lower temperature leads to a larger margin against this undesirable agglomeration. The lower temperatures are bounded by the freezing point of the solution, non-solvent or mixed of two used.

Natural and synthetic polymers are useful in processes according to the present invention for the production of micro- spheres. The polymers may, for example, comprise those in the form of lulose polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, natural and synthetic rubber, polyacrylate and poly- styrene. When microspheres of the present invention are intended for injectable pharmaceutical application, biodegradable polymers, such as polylactic acid, polyglycolic acid, polyhydric oxybutyric acid and the like and copolymers thereof are used. Poly- should of course be compatible with the core material smnanwà fi es.

Multiple encapsulated microcapsules can be produced by the low temperature phase separation process of the present invention by using preformed microcapsules or microcapsules roe lumps, dispersed in a polymeric solution, as core material.

In some cases, it may be necessary to lower the polymer the temperature of the solution to -Ä0 to -10000 before the introduction of the preformed microspheres to avoid dissolution of the preforms formed the microspheres in the polymer solution. This approach method is particularly suitable for reducing the first release phase, and therefore the release phase is increased by application 55 HO 7808759-o of an extra layer of polymer as a partition on the preforms the microspheres. This technique can be extended to form multiple layer microspheres.

Multiple encapsulation can also be used for production of new microcapsules formed by phase separation in a polymer solution containing a dispersion of one to several kinds of preform made microspheres with or without one to several free drugs in separated form. For example, two or more drugs may be separate microencapsulated, either due to incompatibility or lack of of a standard microencapsulation procedure suitable for constituent medicinal products. These preformed microcapsules can then mixed with each other and dispersed in a polymeric solution for subsequent microencapsulation to form new microcapsules containing the previously encapsulated drug particles. Such partition-separated microcapsules offer an advantage over one physical mixing by maintaining uniformity through avoiding any non-uniform deposition of the components at storage.

Another use of partition-separated microcapsules is to separate one to several reactants for subsequent they reaction when needed. Release for reaction can be achieved by decomposition by pressing, time passage, water, air, light, heat exposure or any other trigger mechanism nism. In the manufacture of microcapsules, the selected solution must be dissolve the polymer but not the dispersed core material. material, such as the drug particles. This claim is easy- to meet at low temperatures because the solution of the drug usually decreases at lower temperatures. For the presentation of homogeneous microclumps, the solvent must dissolve both polymer and drug substance at very low temperature. For both micro- capsules and lumps, the solvent should be relatively volatile. , inert to both polymer and drug, have a freezing point sufficiently below the required process temperature and also be miscible with the non-solvent at this low temperature. ratur.

Mixtures of solvents may be used as appropriate, for example to lower the freezing point of a preferred solution means for enabling the procedure to be carried out in a temperature below the normal freezing point of the solvent. Another H0 7808759--0 6 example is when the drug to be encapsulated has a certain solubility. heat in the selected solvent for the polymer; here a duck- Raw solvents are added in an amount sufficient to reduce of the solubility of the drug without significantly affecting the polymer solubility. In contrast, when the intention is to form micro- beet lumps, and a single common solvent for the drug and for the polymer can not be found, in which case a mixture in the form of a solvent system be suitable as common solvent.

When, for example, the polymer is a biodegradable polymer. more such as polylactic acid, polyglycolic acid and copolymers thereof, suitable solvents are toluene, xylene, chloroform, methylene chloride chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoro propanol and mixtures thereof.

The non-solvent used must, either in phase separation step or in a subsequent curing step, be one non-solvent for both the polymer and the drug, at least at the process temperature.

In addition, the non-solvent must be relatively volatile or easy to remove by washing with another volatile non-solvent, chemically inert to both the polymer and the drug have a freezing point sufficiently below the required process temperature and also be miscible with the solvent the agent at this low temperature.

Although both non-polar and polar non-solvents can be used reversed, polar non-solvents are preferred. Examples of non-polar non-solvents are alkane hydrocarbons (eg hexane, heptane, cyclohexane). Examples of polar non-solvents include water, alcohols (eg isopropanol, isobutyl alcohol), polyhydric alcohols (eg 1,2-glycols such as propylene glyc coal; 1,3-glycols such as trimethylene glycol; trivalent alcohols such as glycerol) and ethers and esters of polyhydric alcohols.

Polyhydric alcohols are especially preferred as non-solvent means for producing aggregated microspheres with larger diameter. Other useful non-solvents are fluorocarbons (eg "Freon-11", "Freon-113" from du Pont).

The non-solvent need not be limited to a single one component systems and mixed non-solvent systems can e.g. be used to lower the freezing point of a non-solvent to enable the process at very low temperature.

HO 7 7808759-0 Another example is when the drug substance has a certain solubility. similarity in the preferred non-solvent for the polymer. To- sufficient amount of another non-solvent can then be added for necessary reduction of the solubility of the drug, e.g. to- batch of a non-polar non-solvent such as heptane to reduce the solubility of a drug in isopropanol. A co- -non solvent can also be used to maintain the miscibility between the preferred non-solvent and that preferred solventl When the phase separator is an incompatible polymer, so must the polymeric phase separator may be incompatible with both the tensile polymer and with the core material, and miscible with means. Preferably, the polymeric phase separation agent must be be miscible with the non-solvent used in curing step, so that the non-solvent removes traces of it polymeric phase separator from the microspheres.

Of useful polymeric phase separators can be cited polybutadiene, polymethylsiloxane and the like.

The following examples further illustrate the invention.

Example 1. A solution of 1.0 g of poly (D, L-lactic acid) polymer (intrinsic viscosity 2.32 in hexafluoroisopropanol at 2500) in 50 ml toluene was cooled to about -6500 in a dry ice-isopropanol bath. 0.5 g micronized thioridazine pamoate ("Mallorol", Sandoz AG) was dispersed in the polymeric solution with stirring at 160 ° C laps'per min. 150 ml of isopropanol was added dropwise to the dispersion. the first 50 ml were added over 1 hour and the remaining the 100 ml for 0.5 h. The dry ice bath was removed and the microcapsule were allowed to settle until the above solution was decanted. rades. The product was washed twice with heptane, dried and weighed 1.15 å (77% yield). Microscopic under- search (210X) showed that the product consisted of spherical micro- capsules with a diameter of about 25-50 jum- 3 Example 2. The procedure of Example 1 was followed except that 150 ml of isobutyl alcohol (2-methyl-1-propanol) were used instead for isopropanol as non-solvent. This was followed by addition of 50 ml of heptane in the course of 10 minutes to promote the curing process of the canister walls The yield was 1.37 g (91%) spherical microcapsules with a diameter of 20-30 μm.

Example 3. The procedure of Example 1 was followed except that 150 ml of 50:50 (v / v) n-propanol / isopropanol were added in H0 Example Ä. 7808759-0 s instead of isopropanol, the first 50 ml being added below . HO min and the remaining 100 ml for 35 min. Thereafter, batch of 50 ml of heptane. The yield was 1.1 U2 å (95%) spherical micro capsules with a diameter of 20-Ä0 / um.

The procedure of Example 1 was followed except that 150 ml of heptane were used instead of isopropanol, and the dispersion The temperature of the medium was then allowed to rise to room temperature under the course of H h with constant stirring. The product weighed 1.22 g (yield 81%), which consisted of aggregated microspheres with a size of 50-200 / Pm-Ü _ Example 5. The procedure of Example 1 was followed except that 150 ml of 15:85 (v / v) heptane / isopropanol was used in place let for.isopropanol. The yield was 1.1 g (73%) of spherical microcapsules. leaves with a diameter of 25-35 μm- I Example 6. Slightly larger microcapsules were obtained when propylene glycol / isopropanol was used as the non-solvent. Thereby a solution was cooled. 1.0 g of poly (D, L-lactic acid) polymer (intrinsic viscosity 2.32 i hexafluoroisopropanol at 2500) in 50 ml of toluene to -50 ° C (slightly higher temperature was used to prevent freezing of the propylene englycol, freezing point -5900) in a bath of dry ice-isopropanol. 0.5 g of micronized thioridazine pamoate was dispersed in polymer solution. while stirring at 160 rpm. 100 ml solution of 33:67 (v / v) propylene glycol / isopropanol was added dropwise to the dispersion, the first 50 ml being added over 1 hour and the remaining 50 ml for 20 minutes. Then 50 ml was added heptane over the course of 10 min. The dry ice bath was removed and the microcapsules were allowed to settle until the supernatant was decanted. The product was washed once with 1: 1 (v / v) heptane / isopropanol, twice with isopropanol and then twice times with heptane. After a short air drying, one showed microscopic examination that the product consisted of well-designed made spherical microcapsules with a diameter of 50-150, however, mostly 100-125 / Um- After drying in a vacuum oven at 50-60 ° C for at least kades the capsules to about 50-75, zum 5 The product weighed 1.16 g (yield 77%) and contained 1H, H% thioridazine pamoate.

Example 7. A homogeneous solution of 1.0 g of poly (D, L-lactic acid) poly- more and 0.5 g thioridazine pamoate in 50 ml 1: 1 (v / v) toluene / chloroform was cooled to -65 ° C with stirring at 160 rpm.

The addition of toluene made it possible to carry out the operation at and were nibbled. The tor- H0 9 7808759-o -6500 without freezing the chloroform (freezing point -6300). 150 ml of isopropanol were added dropwise, the first being 100 ml was added over 1.5 hours and the remaining 50 ml during 0.5 h. The product was washed twice with heptane, dried and weighed 1, H g (yield 95%). Microscopic examination showed that the resulting homogeneous microclumps had a diameter of 20-50 / um.

Example 8. propanol was used as the non-solvent. Thereby, a homo- solution of 1.0 g of poly (D, L-lactic acid) polymer and 0.5 g of thio- ridazine pamoate in 50 ml of chloroform to -5000 with stirring at 160 rpm. 100 ml solution of 35:65 (v / v) propylene- glycol / isopropanol was added dropwise to the above solution, the first 50 ml being added during 70 n fi xx and the remaining 50 ml for 20 minutes. Then 50 ml of heptane were added during the process of 15 min. ' After the supernatant was decanted off, it was washed (vol./vol.) heptanliso- Larger microclumps were obtained when propylene glycol / iso- the remaining product once with 1: 1 propanol, twice with isopropanol and then twice with heptane. After drying, the product weighed 1, hü g (yield 96%). Mik- Roscopic examination showed that the resulting homogeneous microclumps the pairs had a diameter of 100-125 hold 15.1% by weight of thioridazine pamoate.

Example 9. A solution of 0.22 g of poly (D, L-lactic acid) polymer in 50 ml of toluene was cooled to about -6500 in a dry ice-isopropane bath. nol. 0.75 g microcapsules (approx. 35 / Um pile 1 containing 53% thioridazine pamoate) was dispersed in The product was found in prepared according to the additional solution by stirring at 160 rpm. 150 ml iso- propanol was added dropwise to the dispersion and then followed the procedure of Example 1. Thereby a yield of 0.73 g was obtained (75%). Careful microscopic examination showed that one thin transparent coating of poly (D, L-lactic acid) polymer enclosed each microcapsule.

Example 10. added the drug thioridazine-pamoate had a slower release than non-encapsulated thioridazine pamoate. Furthermore, double-in- encapsulated microcapsules with thioridazine pamoate (25-40 microns) a significantly reduced initial release compared to those once -encapsulated microcapsules (50-200 / um). The reason for the the duration of the release of a double-encapsulated The data in this example showed that the microencapsulation 7308759-0 10 the material depends on its smaller size.

Release in% h non-encapsulated once encapsulated double-encapsulated 0 drugs drugs, drugs, ___ example U example 9 1 H8 42 23 H - H2 37 6 - HH 46 to 1oo "ss vs - 75 _ 100 H8 - 77 - 72 - 100 - Procedure: A sample containing an equivalent of H, 0 mg thioridazine pamoate was introduced for reconstitution in a vial containing the 1000 ml 0.2 M phosphate buffer pH 7, Ä. The mixture was kept at 3700 with stirring at 500 rpm. Aliquot quantities were taken at at different times, the absorbance was measured at 224 nm with an ultra- violet spectrophotometer. The percentage of drugs that released was based on the maximum absorption measured for each sample.

Example 11. A solution of 0.25 g of poly (D, L-lactic acid) polymer in 50 ml of toluene was cooled to -65 ° C in a bath of dry ice-isopropanol.

Micro lumps prepared according to Example 8 containing 16% thio- ridagin pamoate was dispersed in the polymer solution with stirring at 160 rpm. The procedure of Example 1 was followed except to 100 ml 20:80 (v / v) heptane / isopropanol and then 50 ml heptane was used instead of isopropanol. The yield was 0.89 g (89%) double-encapsulated micro-lumps with a diameter of 100- 150 microns and containing 10.8% thioridazine pamoate.

Example 12.

Sandoz AG) in a solution of 1, u g poly (D, L-lactic acid) polymer in 55 ml of toluene were stirred at 100 rpm with cooling to A dispersion of 0.6 g of bromocriptine ("Pravidel", -70 ° C in a dry ice-isopropanol bath. The procedure according to pile 1 was followed except that 100 ml of 25:75 (v / v) heptane / iso- propanol and then 50 ml of heptane were used instead of iso- propanol. The yield was 1.71 g (86%) of spherical microcapsules with diameter 15-H0 / Um-j fl light of microcapsules immersed in oil showed that microcapsules Microscopic examination under polar The cells contained drug particles whose iridescence was visible through the capsule wall. 11 7808759-0 Example 13. A dispersion of 1.0 pindolol ("Visken", Sandoz AG) (well powdered row with mortar and pestle) in a solution of 1.0 g poly (D, L-lactic acid) polymer in 100 ml of toluene was stirred at 150 rpm per minute while cooling to -7000 in a bath with dry ice isoprop- nol. The procedure of Example 1 was followed except that 50 ml : 95 (v / v) heptane / isopropanol and then 50 ml of heptane was used instead of isopropanol. The yield was 1.82 g (91%) spherical microcapsules with 50-75 / Um in diameter. Microscopic examination of the microcapsules under polarized light immersed in oil showed that these contained drug particles whose irritants sering was visible through the capsule wall.

Example lü. A dispersion of 1.0 g of dihydroergotamine mesylate ("0rstanorm", Sandoz AG) (well powdered with mortar and pestle) in a solution of 1.0 g of poly (D, L-lactic acid) polymer in 100 ml of toluene was stirred at 140 rpm while cooling to -7000 in a bath with dry ice-isopropanol. The procedure of Example 1 was followed except that 100 ml of isopropanol and then 100 ml of heptane are used instead of isopropanol alone. The yield was 1.98 g (99%) spherical microcapsules with 75-150 / um gi diameter. Microscopic examination of the microcapsules under polarized light immersed in oil showed that these contained drug particles whose irritants sering was visible through the capsule wall.

Claims (9)

7808759-0 12 PATENT REQUIREMENTS 1; Process for producing microspheres consisting of a polymer and a core material, characterized by a step of adding a phase separating agent to a medium consisting of a solution of the polymer and a dispersion or solution of the core material at a temperature of -40 to -100 ° c. A method according to claim 1 for the production of microspheres in the form of microcapsules consisting of a coating of polymer around a solid particle of a core material, characterized by a step for adding a phase separating agent to a medium consisting of a dispersion of microparticles of the core material in a solution of the polymer at a temperature of -40 to -100 ° C. A process according to claim 1 for the preparation of microspheres in the form of microclumps consisting of a homogeneous mixture of a polymer and a core material, characterized by a step of adding a phase separating agent to a common solution of the polymer and the core material at a temperature. temperature of -40 to -100 ° C. A method according to any one of the preceding claims, characterized in that the core material contains a medicament. 5. A method according to any one of the preceding claims, characterized in that the core material contains preformed microspheres. in Process according to Claim 4, characterized in that the polymer is a biodegradable polymer. 7. Process according to claim 6, characterized in that the polymer consists of polylactic acid, polyglycolic acid, polyhydroxybutyric acid or copolymers thereof. Process according to any one of the preceding claims, characterized in that the phase separation agent is a non-solvent for the polymer and the core material. ' 9. A process according to any one of the preceding claims, characterized in that aggregates of microspheres are prepared by using a polyhydric alcohol as a non-solvent. lO. Process according to any one of the preceding claims, characterized in that the phase separating agent is added at a temperature from -50 to -70 ° C. The present invention relates to a process for producing microspheres consisting of a polymer and a core material, preferably drug, while adding a phase separating agent to a medium consisting of a solution of the polymer and a dispersion or solution of the core material at a temperature. of -no to -1oo ° c. l