FI64899B - FREQUENCY REQUIREMENT FOR MICROSULAR BESTAOENDE AV EN POLYMER OCH ETT KAERNMATERIAL - Google Patents

Description

RSSF * 1 M (11) ANNOUNCEMENT / i «gg

Mjfi lJ '' UTLÄGGNINGSSKRIFT θ4 0? 7 • «S® c (45) rater. Ui uy.V.r. ‘.’Y n 32 1934 ^ ^ (51) Kv.ik.3 / i« .a. 3 B 01 J 13/02, A 61 K 9 / 5Ο FINLAND — FINLAND (*) Patent application - PatentaiuBknlng 7 82 5 01 (22) Hekemlspllvi —AnsBknlnjKlag l6.O8.78 '* (23) AlkupUvi - Giltighetsdif l6.O8. 78 (41) Tullut | ulklMksl - Blivit offentllg 26.02.79

Patent and registry held ..... . . ,,, _ ^ *. (44) Date of issue and date of issue. -

Patent and registration authorities Anatkan utiagd och uti.skriften pubiicerad 3i.lO.83 (32) (33) (31) Claim priority - Begird prlorltet 25.08.77 USA (UC) 827 710 (71) Sandoz A.G. , CH-1 * 002 Basel, Switzerland-Switzerland (CH) (72) Jones Wing Fong, Parsippany, NJ, USA (7 ^) Oy Kolster Ab (5¼) Method for the production of microspheres consisting of polymer and core material - Förfarande för framställning the microsphere is best equipped with a polymer and a handheld material

The invention relates to a process for the preparation of microspheres consisting of a polymer and a solid core material by a phase separation process.

The term "microspheres" refers to both microcapsules formed from a body of core material and the surrounding layer of polymeric material and microspheres formed from homogeneous mixtures of core material and polymer. The term "microspheres" also refers to individual microcapsules or microspheres as well as nearly spherical aggregates consisting of several microcapsules or microspheres. The diameters of the microspheres are 1 to 500 microns, usually 20 to 200 microns.

It is known to obtain microcapsules by phase separation methods in which a core material of a desired particle size is dispersed in a continuous phase of a solution of a polymeric coating material and the polymeric material is deposited on the core material by gradually precipitating Often, such methods result in uncontrolled aggregation of the encapsulated particles and thus are not satisfactory for obtaining separate round microspheres of polymer and core material by phase separation.

It has now been found that these problems can be overcome by performing phase separation at low temperatures.

The invention relates to a process for the preparation of microspheres consisting of a polymer and a core material by adding a phase separating agent to a medium consisting of a polymer solution and a dispersion or solution of the core material and curing at a temperature below -40 ° C. The process is characterized in that the phase separation also takes place at a low temperature between -40 ° C and -100 ° C.

To prepare the microcapsules, the polymer is dissolved in a solvent that does not dissolve the core material, the core material microparticles are dispersed in the polymer solution, and a phase separator is added to the system at -40 ° C and -100 ° C to precipitate the polymer and coat the core material particles.

To prepare the microspheres, the polymer and the core material are dissolved in a common solvent, and a phase separation agent is added to the solution at a temperature between -40 ° C and -100 ° C to precipitate particles formed from a homogeneous mixture of the polymer and the core material.

It should be noted that the process step of lowering the temperature of the system to a temperature between -40 ° C and -100 ° C is not critical as long as the phase separation occurs in this temperature range.

The core materials of the microspheres prepared by the method of the invention may be agricultural agents such as insecticides, fungicides, herbicides, rodenticides, pesticides, fertilizers, virus particles to protect the crop, etc., cosmetics such as deodorants and perfumes, pharmaceuticals and oils, flavorings, food additives such as flavorings. . Microspheres that contain drugs as the core material can act as long-acting forms of administration when administered orally or parenterally. Pharmaceuticals such as medicaments are particularly preferred cardiac materials and the invention is illustrated below using medicaments as cardiac material.

The term "phase separator" means both non-solvents for the polymer and the core material, as well as polymeric materials that are incompatible with the coating polymer and the core material. When the phase separator is incompatible with the polymer, a non-solvent must also be added simultaneously or later to harden the surface of the microspheres and to prevent undesired agglomeration. The addition of the non-solvent used as hardener also takes place at a temperature between -40 ° C and -100 ° C. As used in the following description, the term "non-solvent" refers to both non-solvents used as phase separators and non-solvents used as hardeners when the phase separator is an incompatible polymer.

In a preferred embodiment of the process according to the invention, the phase separation agent is a non-solvent and no incompatible polymer is used.

The formation of microcapsules is based on the phase separation phenomena of the polymer. When the phase separating agent is initially added to a polymer solution containing dispersed solid particles of the drug, the separating polymer is initially in the form of a liquid phase which precipitates as a coating on the dispersed drug particles. By then adding the non-solvent, the coating hardens to completely encapsulate the drug particle. By varying process conditions, the coated drug particles can remain as individual capsules or agglomerate in a controlled manner to larger agglomerates of microcapsules. Unwanted, strong agglomeration occurs as the encapsulated particles adher and grow together in uncontrolled precipitation. The low temperature method according to the invention makes the microspheres sufficiently hard, thus preventing undesired agglomeration.

Homogeneous microbeads are also formed by phase separation. When a polymer and drug phase separation agent is added to a homogeneous solution of polymer and drug, both the polymer and drug precipitate together to form homogeneous microbeads. Depending on the process conditions, they may remain as single beads or may be administered in a controlled manner to larger, homogeneous microbeads that agglomerate.

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Depending on the end use of the product, it may be desirable to produce microsphere aggregates larger than individual microspheres. For example, for controlled release of a drug suitable for parenteral administration, the size of the microspheres must be large enough to provide a suitable duration of release, but still small enough to pass through the standard injection needles used. Then, for about 20 needles, a suitable size is about 150 microns.

For other uses, it may be desirable to allow controlled agglomeration into microspheres larger or smaller than 150 microns in size.

The temperature range used in the process of the invention is about -40 ° C and -100 ° C, preferably -40 ° C and -75 ° C, more preferably -50 ° C and -70 ° C. between. Preventing strong agglomeration sets the upper temperature limit. Operating at a lower temperature generally provides a wider margin for unwanted agglomeration. The freezing point of the solvent, non-solvent or mixture of two used forms the upper temperature limit.

Natural and synthetic polymers can be used in the process of the invention for the preparation of microspheres. These include, for example, cellulose polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, natural and synthetic rubbers, polyacrylates and polystyrene. When using the microspheres of this invention in pharmaceutical injections, biodegradable polymers such as polylactic acid, polyglycolic acid and polyhydroxybutyric acid and copolymers thereof can be used. The polymer must, of course, be compatible with the core material used.

Multiple encapsulated microcapsules can be prepared by the low temperature phase separation process of the invention using preformed microcapsules or microbeads dispersed in a polymer solution as the core material. In some cases, it may be necessary to lower the polymer solution to a temperature between -40 ° C and -100 ° C before adding the preformed microspheres to prevent them from dissolving in the polymer solution. This method is particularly useful in reducing the initial release rate and thus increasing the release time, whereby an additional layer of polymer is deposited on the preformed microspheres for protection. This technique can be used to make multilayer microspheres.

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Multiple encapsulation can also be used to prepare novel microcapsules obtained by phase separation of a polymer solution containing one or more preformed microspheres dispersed and one or more drugs in particulate form or without these drugs. For example, two or more drugs can be microencapsulated separately, either because of incompatibility or because there is no common microencapsulation method for all drug components. These preformed microcapsules can then be mixed together and dispersed in a polymer solution for a second microencapsulation to obtain new microcapsules containing previously encapsulated drug particles. Compared to the physical mixture, such compartmentalized microcapsules have the advantage of continuous homogeneity because the components cannot settle unevenly during storage.

Another use of partitioned microcapsules could be to separate one or more reactants for a subsequent reaction. Release for the reaction can occur by pressure violation, exposure to water, air, light, or heat, or other release mechanism.

The solvent chosen to make the microcapsules must dissolve the polymer but not the dispersed core material, e.g., drug particles. This requirement is more easily met at low temperatures because these usually reduce the solubility of the drug. To produce homogeneous microbeads, the solvent must dissolve both the polymer and the drug at a very low temperature. In the manufacture of both microcapsules and microspheres, the solvent must be relatively volatile, unreactive to both the polymer and the drug. Its freezing point must be sufficiently below the required operating temperature and it must also be miscible with the non-solvent in question. at low temperature.

If necessary, solvent mixtures can be used, e.g. to lower the freezing point of the preferred solvent to allow operation below its normal freezing point. If the drug to be encapsulated is to some extent soluble in the selected polymer solvent, a sufficient amount of the second solvent can be added to reduce the solubility of the drug without significantly affecting the solubility of the polymer. If it is desired to prepare microbeads and not find a common solvent for the drug and the polymer, the solvent system, on the other hand, can act as a suitable common solvent for the 64899.

When the polymer is e.g. naturally degradable such as polylactic acid, polyglycolic acid or a copolymer thereof, a suitable solvent is e.g. toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol and mixtures thereof.

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

In addition, the non-solvent must be relatively volatile or easily removed by washing with another non-solvent, chemically inert to both the polymer and the drug. Its freezing point must be sufficiently below the required operating temperature and it must also be miscible with the solvent in question. at low temperature.

Although both polar and non-polar non-solvents can be used, polar non-solvents are preferred. Examples of non-polar non-solvents are alkane hydrocarbons (e.g. hexane, heptane and cyclohexane). Examples of polar non-solvents are water, alcohols (e.g. isopropanol and isobutyl alcohol), ethers, polyhydric alcohols (e.g. 1,2-glycols such as propylene glycol; 1,3-glycols such as trimethylene glycol and polyhydric alcohols such as glycerol) and polyhydric alcohols. ethers and esters. Polyhydric alcohols are particularly preferred for the preparation of non-solvents larger diameter microsphere aggregates. Other useful non-solvents include hydrofluorocarbons (e.g., Freon-11 and Freon-113, manufactured by DuPont).

The non-solvent need not be limited to a one-component system, and mixed non-solvent systems may be used, e.g., to lower the freezing point of the non-solvent to allow for a very low operating temperature. Another example is the case where the drug is to some extent soluble in the preferred non-solvent of the polymer, whereby a sufficient amount of the second non-solvent can be added to reduce the solubility of the drug. For example, a non-polar non-solvent such as heptane may be added to reduce the solubility of the drug in isopropanol. A common non-solvent can also be used to mix the preferred non-solvent and the preferred solvent.

When the phase separator is incompatible with the polymer, the polymeric phase separator must be incompatible with both the coating polymer and the core material and must be miscible with the solvent. The polymeric phase separator should preferably be mixed with the non-solvent used in the curing step, whereby the non-solvent removes residues of the polymeric phase separator from the microspheres.

Useful polymeric phase separators include poly-butadiene, polydimethylsiloxane and the like.

The following examples 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 25 ° C) in 50 ml of toluene was cooled to about -65 ° C on a dry ice. isopropanol bath. The polymer solution was dispersed with stirring at 160 rpm. 0.5 g of micronized Mellaril pamoate (thioridazine, Sandoz, Inc.). 150 ml of isopropanol were added dropwise to the dispersion, the first 50 ml being added in one hour and the remaining 100 ml in half an hour. The dry ice bath was removed and the microcapsules were allowed to settle before decanting the supernatant. The product was washed twice with heptane, dried to give 1.15 g (77% yield). Microscopic examination (210x) showed that the product was in the form of round microcapsules, about 25-30 microns in diameter.

Example 2

The procedure of Example 1 was followed except that 150 ml of isobutyl alcohol (2-methyl-1-propanol) was used instead of isopropanol as the non-solvent. 50 ml of heptane was then added over ten minutes to promote hardening of the capsule wall. The yield was 1.37 g (91%) of round microcapsules with a diameter of 20-30 microns.

Example 3

The procedure of Example 1 was followed except that 150 ml of 50:50 (w / v) n-propanol isopropanol was added instead of isopropanol at the rate of the first 50 ml over 40 minutes and the remaining 100 ml over 35 minutes. Then 50 ml of heptane was added. The yield was 1.42 g (95%) of round microcapsules with a diameter of 20-40 microns.

Example 4

The procedure of Example 1 was followed except that 150 ml of heptane was used instead of isopropanol and the dispersion was allowed to warm to room temperature over four hours with constant stirring.

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The weight of the product was 1.22 g (yield 81%). Aggregated microspheres, 50-200 microns in diameter, were obtained.

Example 5

The procedure of Example 1 was followed except that 150 ml of 15:85 (v / v) heptane-isopropanol was used instead of isopropanol. The yield was 1.1 g (73 S) of round microcapsules, 25-35 microns in diameter.

Example 6

Slightly larger microcapsules were prepared using propylene glycol isopropanol as a non-solvent. A solution of 1.0 g of poly (D, L-lactic acid) polymer (intrinsic viscosity 2.32 in hexafluoroisopropanol at 25 ° C) in 50 ml of toluene was cooled to -50 ° C (slightly higher temperature to prevent freezing of propylene glycol, freezing point -59 ° C) in a dry ice-iso-propanol bath. 0.5 g of micronized Mellaril pamoate was dispersed in the polymer solution with stirring at 160 rpm. To the dispersion was added dropwise 100 ml of 33:67 (v / v) propylene glycol isopropanol at a rate of the first 50 ml over one hour and the remaining 50 ml over 20 minutes. Then 50 ml of heptane was added over 10 minutes. The dry ice bath was removed and the microcapsules were allowed to settle before decanting the supernatant. The product was washed once with 1: 1 (v / v) heptane-isopropanol, twice with isopropanol and twice with heptane. After a short air drying, microscopic examination showed the product to consist of well-shaped, round microcapsules, 50-150 in diameter, mostly 100-125 microns. But after drying for four hours in a vacuum oven at 50 ° -60 ° C, the diameter of the capsules decreased to 50-75 microns and became serrated. The dried product weighed 1.16 g (77% yield) and contained 14.4% Mellaril pamoate.

Example 7

A homogeneous solution of 1.0 g of poly (D, L-lactic acid) polymer and 0.5 g of Mellaril pamoate in 50 ml of 1: 1 (v / v) toluene-chloroform was cooled to -65 ° C with stirring at 160 ° C. rpm. The addition of toluene allowed working at -65 ° C without freezing the chloroform (freezing point -63 ° C).

Was added dropwise to 150 mL of isopropanol at a rate of 64 899 a first set of 100 ml over 1.5 hours and the remainder over 50 ml of a half-hour. The product was washed twice with heptane, dried to give 1.4 g (93% yield). Microscopic examination showed the microbeads of the homogenes formed to be 20-50 microns in diameter.

Example 8

Larger microbeads were prepared using propylene glycol isopropanol as a non-solvent. A homogeneous solution of 1.0 g of poly (D, L-lactic acid) polymer and 0.5 g of Mellaril pamoate in 50 ml of chloroform was cooled to -50 ° C. to stirring at 160 rpm. To the above solution was added dropwise 100 mL of 35:65 (v / v) propylene glycol isopropanol at a rate of the first 50 mL over 70 minutes and the remaining 50 mL over 20 minutes. Then 50 ml of heptane was added over 15 minutes.

After decanting the supernatant, the product was washed once with 1: 1 (v / v) heptane-isopropanol, twice with isopropanol and twice with heptane. After drying, the weight was 1.44 g (yield 96%). Microscopic examination showed that the microbeads of the homogenes formed ranged in diameter from 100 to 125 microns. The product was found to contain 15.1% Mellaril 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 -65 ° C in a dry ice-isopropanol bath. 0.75 g of microcapsules (about 35 microns in diameter, previously prepared according to Example 1 to contain 33% Mellaril pamoate) were dispersed in the polymer solution with stirring at 160 rpm. 150 ml of isopropanol was added dropwise to the dispersion, and the procedure of Example 1 was followed. The yield was 0.73 g (75%). Careful examination under a microscope (210x) revealed that each microcapsule was surrounded by a thin, transparent poly- (D, L-lactic acid) polymer wall.

Example 10 The values in this example showed that the microencapsulated drug Mellaril pamoate released the drug more slowly than the unencapsulated Mellaril pamoate. In addition, the release rate of double-encapsulated Mellaril pamoate microcapsules (25-40 microns) was initially significantly lower than that of once-encapsulated microcapsules (50-200 microns).

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The shorter release time of the double encapsulated material is due to its smaller size.

Release%

Hours Unencapsulated Once encapsulated Double encapsulated drug drug drug Example 4 example 9 1 48 42 23 4 - 42 37 6 - 44 46 24 100 65 78 30 - 75 100 48 - 77 72 - 100

Method A sample corresponding to 4.0 mg of Mellaril pamoate was placed in a dissolution flask containing 1000 ml of 0.2 M phosphate buffer, pH 7.4. The mixture was kept at 37 ° C and stirred at 500 rpm. Samples were taken at various time intervals and the absorbance was measured at 224 nm with a UV epectrophotometer. The percentage of drug released was based on the measured maximum absorbance of 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 dry ice-isopropanol bath. Microbeads containing 16% Mellaril pamoate prepared according to Example 8 were dispersed in the polymer solution with stirring at 160 rpm. The procedure of Example 1 was followed except that 100 ml of 20:80 (w / v) heptane isopropanol and 50 ml of heptane were used instead of isopropanol. The yield was 0.89 g (89%) of double-encapsulated microbeads, 100-150 microns in diameter and containing 10.8% Mellaril pamoate.

Example 12

A dispersion of 0.6 g of bromocriptine (Sandoz, Inc.) in a solution of 1.4 g of poly- (D, L-lactic acid) polymer in 55 ml of toluene was stirred at 140 rpm. cooling to -70 ° C in a dry ice-isopropanol bath. The procedure of Example 1 was followed with the difference of 11,64899 using 100 ml of 25:75 (v / v) heptane-isopropanol and 50 ml of heptane instead of isopropanol. The yield was 1.71 g (86%) of round microcapsules, 15-40 microns in diameter, microscopic examination of the oil-immersed microcapsules under polarized light showed that the microcapsules contained drug particles with radiation visible through the capsule wall.

Example 13

A dispersion of 1.0 g of pindolol (Sandoz, Inc.) (carefully ground with a mortar and pestle) in a solution of 1.0 g of poly (D, L-lactic acid) polymer in 100 ml of toluene was stirred for 150 rpm. ./min while cooling to -70 ° C in a dry ice-isopropanol bath. The procedure of Example 1 was followed except that 50 ml of 5:95 (v / v) heptane-isopropanol and 50 ml of heptane were used instead of isopropanol. The yield was 1.82 g (91%) of round microcapsules, 50-75 microns in diameter, microscopic examination of the oil-immersed microcapsules under polarized light showed that the microcapsules contained drug particles with radiation visible through the capsule wall.

Example 14

A dispersion of 1.0 g of dihydroergotamine mesylate (Sandoz, Inc.) (carefully ground with a mortar and pestle) in a solution of 1.0 g of poly (D, L-lactic acid) polymer in 100 ml of toluene was stirred for 140 rpm. ./min while cooling to -70 ° C in a dry ice-isopropanol bath. The procedure of Example 1 was followed except that 100 ml of isopropanol and 100 ml of heptane were used instead of isopropanol alone. The yield was 1.98 g (99%) of round microcapsules, 75-150 microns in diameter, microscopic examination of the oil-immersed microcapsules in polarized light showed that the microcapsules contained drug particles with radiation visible through the capsule wall.

Claims (13)

A process for preparing microspheres consisting of a polymer and a core material by adding a phase separating agent to a medium consisting of a solution of the polymer and a dispersion or solution of the core material and by curing at a temperature below -40 ° C. characterized in that the phase separation also occurs at a low temperature between -40 ° C and -100 ° C. Process according to claim 1, characterized in that microcapsules comprising a polymer coating are formed which surround a solid core material body, by adding a phase separation agent to a medium consisting of a dispersion of the core material microparticles in a solution of the polymer. 3. A process according to claim 1, characterized in that microbeads are formed consisting of a homogeneous mixture of a polymer and a core material by adding a phase separating agent to a common solution of the polymer and the core material. Method according to any of the preceding claims, characterized in that the core material is a medicament. Process according to any of the preceding claims, characterized in that the core material comprises preformed microspheres. Process according to claim 4, characterized in that the polymer is a biodegradable polymer. Process according to claim 6, characterized in that the polymer is a polylactic acid, polyglycolic acid, polyhydroxybutyric acid or their copolymers.