SE464743B - PROCEDURE FOR PREPARATION OF MEDICINAL PARTICLES - Google Patents

Description

464 743 control of the size distribution to avoid widely varying particle sizes.

Another object of the invention is to provide a method for such preparation of drug particles, which method is very reproducible and easy to control. Yet another object of the invention is to provide a process by which small drug particles can be produced which meet the usual pharmaceutical requirements.

These and other objects of the invention will become apparent from the following detailed description. Accordingly, the invention relates to a process for the preparation of relatively monodisperse drug particles of submicron size of a drug with low water solubility or of a water-insoluble drug by emulsifying an organic solution of the drug in an aqueous phase and then removing the organic solvent resulting in precipitation of the drug. Such a process comprises the following steps: a) emulsifying the organic solution in the presence of an emulsifying agent and, if necessary, a protective colloid comprising a surfactant capable of being adsorbed on the surface of a precipitated drug particle; b) removing the organic solvent from the suspension; and c) recovering the precipitated drug particles from the aqueous phase or storing them in the original aqueous phase.

Removal of the organic solvent from the suspension can take place in various ways. The following procedures are examples of such removal of organic the organic solvent vapor; the organic solvent while continuously removing the organic solvent washing the same by dialysis aqueous phase; the organic solvent solvent: can be removed by pre-can be removed by washing the aqueous phase; can be removed by contact with a reindeer can be removed by circulating the emulsion in contact with an excess of aqueous phase to dissolve in solution of the organic solvent therein in which precipitation of the drug.

Upon removal of the organic solvent by evaporation, water in the aqueous phase may evaporate at the same time, resulting in reduced water content in the emulsion. Such evaporation of water can be compensated by adding additional quantities of aqueous phase to the emulsion during the evaporation of the organic solvent.

There are various possibilities of controlling the droplet diameter of the emulsion, and the droplet size of the emulsion can be kept within a relatively wide range, such as between about 0.1 and about 20 mm. The size of the droplets in the emulsion can be controlled by varying the supply of mechanical energy, by varying the concentration of surfactant and by varying the ratio between organic solvent and aqueous phase in the emulsion. For practical reasons, the concentration of surfactant may be molar related to the molar concentration of the drug.

The surfactant used is subject to a number of requirements with respect to its function. It must thus function satisfactorily as an emulsifier, ie it must result in the formation of a stable emulsion. It is possible to use a protective colloid in combination with the surfactant to improve the stability of the emulsion. The basic requirement of the invention is to use a surfactant capable of being adsorbed on the surface of a precipitated drug particle. By using such surfactants, controlled and reproducible precipitation of small drug particles can take place and particle size distribution can be kept within fairly narrow limits.

Furthermore, the surfactant should preferably inhibit aggregation and agglomeration of the particles and should advantageously be capable of inhibiting crystal growth. Such crystal growth is partially eliminated due to reduced surface energy when the surfactant is adsorbed on the surface of the crystals.

It is preferred to use a protective colloid to stabilize the suspension. Such colloid may be synthetic, semi-synthetic or may be a polysaccharide or a protein. Parts of the protective colloid must be water soluble to provide colloidal stability. Micellar formation in solution should be avoided, but this is not necessary if its solubilizing capacity on the crystal-forming substance is low. Any incorporation of the surfactant and / or protective colloid into the crystal structure of the particle is permitted.

It is important to note that the method according to the present invention does not involve any reaction in the system and that the method is not based on so-called microemulsions.

It is advantageous in the process according to the invention that no or very little mass transport takes place between the droplets in the emulsion, and this requires a certain minimum concentration of drug in said droplets.

The following are non-limiting examples of drugs, organic solvents and surfactants suitable for use in the process of the invention.

MEDICINES As water-insoluble drugs or drugs with low water solubility, the following are of interest.

Examples of drugs whose bioavailability is enhanced as a duktiøn- A, vitamin Medroxyprogesteroneacetate 4-acetamidophenyl, 2,2,2-tri- Nitrofurantoin -kloretvlkarbonat Phenobarbital Aspirin Phenacetin Bishydroxikumarin Procaine penicillin Chloramphenicol Reserpine Cyheptamid Spironolactone Digoxin Sulfadiazine Fluocinolone acetonide Sulphasoxazole Griseofulvin Sulfur p-hydroxypropiophenone Tolbutamide 10 15 20 25 30 35 40 464 743 Drugs with gotentiella bioekvivalensgroblem, Aretazolamid Ac .yldigitoxin AL = roxy1on Aminophylline 'Aminosalicylic acid Bendroflumethiazide benzthiazide Betamethasone Bishydroxikumarin Chlorambucil Chlordiazepoxide chlorothiazide Chlorpromazine cortisone acetate deserpidine dichlorphenamide Dienestrol Dexamethasone Diethylstilbestrol Ethinyl Estradiol Dyphylline Etosuxmid ethotoin ethoxzolamide Fludrocortison Fluphenazine fluprednisolone Hydralazine Hydrochlorothiazide hydroflumethiazide Imipramine Isqproterenol Liotyronine Menadione Mefenytoin Metazolamide Methyclothiazide Methylprednisolone Para-aminosalicylic acid Para-matadione Perphenazine Phenacemide phensuximide Fenylaminosalicylat Phenytoin phytonadione polythiazide Prednisolone Primidone -Probenecid Procainamide Prochlorperazine Promethazine promazine propylthiouracil Pyrimethamine Kinetiazid Quinidine Rauwolfia serpentina rescinnamine reserpine Salicylazosulfapyridine Natriumsulfcxon Spironolactone Sulfadiazine Sulfadimethoxine Sulfamerazine sulfaphenazole Sulfasomidin Sulphasoxazole Theophylline thioridazine Tolbutamide Triamcinolone Trichlormethiazide Trietylmelamin 10 15 20 25 30 35 464 743 6 fgrts, Methyltestosterone Trifluoperazine Nitrofurantoin Triflupromazine Oxtrifylline Trimeprazine Trimethadione Uracil mustand Warfarin ORGANIC SOLVENTS Suitable organic solvents for use in the emulsion include the following; Any organic solvent that is a liquid and has little solubility in water. One requirement is that the solvent must be removed to concentrations that are acceptable from a toxicological point of view.

Examples: - linear, branched or cyclic alkanes having 5 or more carbon atoms; for example n-pentane, n-heptane and higher linear alkanes; 2,2-dimethylbutane or 2,2,4-trimethylpentane; cyclopentane, cyclohexane, methylcyclohexane, etc. - linear, branched or cyclic alkenes having 5 or more carbon atoms; for example 2-pentene, cyclohexene, 1,3-cyclopentadiene or 2,3-dimethyl-1-pentene. linear, branched or cyclic alkynes having 5 or more carbon atoms; for example 2-pentyne or 4-methyl-2-pentyne. - aromatic hydrocarbons; for example toluene, ethylbenzene. fully or partially halogenated hydrocarbons; for example dichloromethane, chloroform, chlorobenzene, chlorobenzoic acid, etc. - ethers; for example diethyl ether etc. - esters; for example ethyl acetate, 9-octadecenoic acid, ethyl ester, ethyl oleate, tetradecanoic acid 1-methylethyl ester, etc. - ketones; for example cyclohexanone, 2-pentanone etc. - mono-, di- or triglycerides; for example, synthetic glycerol triacetate, glycerol monolinolein, etc., and natural oils: almond oil, cottonseed oil, corn oil, olive oil, peanut oil, sesame oil, soybean oil, etc. 10 15 20 25 30 35 40 7 A 464 743; - alcohols; for example benzenemethanolpentanol, hexanol etc. - aldehydes; for example hexanol, - acids, for example hexanoic acid, - amines; for example 1-aminoheptane, nitriles; for example amyl cyanide, silicones, linear or cyclic; for example octamethyltetrasiloxane or hexamethyldisiloxane, - or a combination of these derivatives; for example 1-chloro-3-ethylhexane, - or any combination of these solvents.

SURFACE ACTIVE SUBSTANCE Surfactants or groups of surfactants that meet the above requirements are, for example: Glyceryl monoalkylate; diacetyltartaric acid esters of mono- and diglycerides of edible fats or oils or edible fatty-forming fatty acids; mono- and diglycerides of edible fats or oils or edible fatty acids; monosodium phosphate derivatives of mono- and diglycerides of edible fats or oils or edible fatty acid fatty acids; glycerol ester of wood resin; acyl monoglyceridyl citrate; succistearin (stearoylpropylene glycol hydrogen succinate); dioctyl sodium sulfosuccinate; lecithins (pure and technical qualities); hydroxylated lecithins; methyl glucoside coconut oil ester; sodium alkyl sulfate; potassium alkyl sulphate; sodium or potassium mono- and dimethylnaphthalene sulfonates; sodium or potassium alcyl fumarate; acetylated monoglycerides; succinylated monoglycerides; monoglyceride citrate; ethoxylated mono- and diglycerides; ethoxylated sorbitan esters; sorbitan monostearate; sorbitan esters of fatty acids; calcium alkyloyl 2-lactylate; sodium alcyloyl 2-lactylate; potassium alcyloyl 2-lactylate; lactyl esters of fatty acids; lactylated fatty acid esters of glycerol and propylene glycol; glyceryl lactoesters of fatty acids; ethoxylated alkylphenols and alcohols; polyglycerol esters of fatty acids; propylene glycol mono- and diesters of fats and fatty acids; sucrose fatty acid esters; fatty acids; salts of fatty acids; synthetic fatty alcohols; poloxamers; meroxapol; poloxamine; Pluradotf, or any combination of these. 10 15 20 25 30 35 464 743 PROTECTIVE COLOID The following are also examples of preferred protective colloids: Gums: for example acacia, agar, carrageenan, guar, karaya, locust bean, pectin, propylene glycol alginate, sodium alginate, tragacanth, xanthan, gum arabic.

Celluloses: for example carboxymethylcellulose, sodium microcrystalline cellulose and carboxymethylcellulose, sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, methylcellulose, stylhydroxyethylethylcellulose, metocel. (attapulgite), magnesium silicate (sepiolite).

Various: for example Carbomer NF, gelatin, polyethylene glycols, polypropylene glycols and copolymers thereof, lecithins, Carbopol 934, Veegum, polyacrylic acid, polymethacrylic acid, polyacrylic acid-CO-acrylamide, polyvinylpyrrolidone, polyvinyl alcohol with varying degrees of hydrolysis.

Proteins: for example albumin, gelatin, casein or any combination of these.

The invention will be described in the following by non-limiting examples. In these examples, cholesterol acetate was used as the drug model, which substance is useful to illustrate the problem solved by the present invention.

In these examples reference is made to the accompanying drawings, in which: Fig. 1 illustrates the effect of the emulsification process on the particle size; Fig. 2 illustrates a graph of the size of the emulsion droplets and the size of the cholesterol acetate particles as a function of the concentration of cholesterol acetate in toluene; and Fig. 3 illustrates the size of the emulsion droplets and cholesterol acetate particles as a function of the surfactant concentration.

EXAMPLE 1 An emulsion of cholesterol acetate dissolved in toluene and an aqueous phase containing ethoxylated nonylphenol ether as surfactant is prepared as follows. The model substance for drugs, cholesterol acetate, is dissolved in toluene. The solution is emulsified with an aqueous phase containing ethoxylated nonylphenol ether as a surfactant to form an oil-in-water emulsion.

The organic solvent, toluene, is evaporated from the emulsion, whereby the model substance of the drug precipitates and the crystals are stabilized by the surfactant, which is adsorbed on the surface of the precipitated particles.

Using the above emulsion ingredients, a series of tests are performed to determine the effect of the emulsification method on particle size, the effect of the concentration of the drug substance in toluene on the particle size and the effect of surfactant concentration in the emulsion on the size of the emulsion droplets and so on. the size of the particles of the model substance.

This illustration of different effects is made in relation to the attached drawings numbered 1 to 3 and related to the respective effects stated above. In Fig. Emulsions, which are prepared by vibration, and the particle sizes are measured by an electrozone sensing method. In Fig. 2, the emulsions are prepared by homogenization with a microfluidizer, and the particle sizes are measured by quasi-elastic light scattering. With respect to Fig. 3, the emulsions are prepared by homogenization with a microfluidizer. Another alternative for regulating the emulsion droplet size is to vary the oil / water phase ratio.

EXAMPLE 2 This example illustrates the use of a surfactant capable of stabilizing the emulsion and the suspension of cholesterol acetate and cyclohexane, respectively. The emulsion is homogenized in a microfluidizer. The oil / water phase ratio is 1, the particles were obtained from 10 15 20 25 30 35 40 464 743 1 ”10/90 and the amount of surfactant is 5% by weight based on the weight of the oil phase. The surfactant used is a mixture of Tween 80 and Span 80 in a weight ratio of 1: 9. Span 80 is the trade name for sorbitan monooleate and Tween 80 is the trade name for POE (20) sorbitan monooleate.

The particle size of the suspension is in the range between about 80 nm and about 400 nm. The particle size is measured Q after 10 days and is found to be approximately constant.

EXAMPLE 3 Example 2 is repeated but using a mixture of Tween 20 and Span 80 (weight ratio 15: 1) as surfactant.

Similar results are obtained.

EXAMPLE 4 Example 2 is repeated but using Tween 80 as the surfactant.

EXAMPLE 5 Example 2 is repeated but using DK ESTER F-160 (a sucrose ester) as the surfactant.

EXAMPLE 6 Example 2 is repeated but using Ovothin 170 (egg phospholipid) as the surfactant.

EXAMPLE 7 Example 2 is repeated but using Epicuran 145 (soybean lecithin) as the surfactant.

EXAMPLE 8 Example 2 is repeated but using Epicuran 200 SH (soybean lecithin) and the sodium salt of glycolic acid (4: 1) as the surfactant.

EXAMPLE Q Example 2 is repeated but using Epikuran 200 SH and the sodium salt of taurocolic acid (4: 1) as the surfactant. l:

Claims (10)

EXAMPLE 10 Example 2 is repeated but using Ovothin 170 and the sodium salt of glycolic acid (4: 1) as the surfactant. EXAMPLE 11 Example 2 is repeated but using Ovothin 170 and the sodium salt of taurolic acid (4: 1) as the surfactant. EXAMPLE 12 Example 2 is repeated but using Triodane 55, polyglycerol esters of fatty acids as surfactant. EXAMPLE 13 Example 2 is repeated but using Acid N-12, citric acid esters of monoglycerides as surfactant. EXAMPLE 14 Example 2 is repeated but using Epikuran 200 SH as the surfactant and polyvinylpyrrolidone as the protective colloid. In Examples 4-14 above, results corresponding to the results in Example 2 are obtained Process for the preparation of relatively monodisperse drug particles with submicron size of a drug with low water solubility by emulsifying an organic solution of the drug in an aqueous phase and then removing the organic solvent resulting in precipitation of the drug, characterized by the steps of: a) emulsifying the organic solution in the presence of an emulsifier and, if necessary, a protective colloid comprising a surfactant capable of being adsorbed on the surface of a precipitated drug particle b) 40) separating the organic solvent from the suspension; and c) recovering the precipitated drug particles from the aqueous phase or storing them in the original aqueous phase. Process according to Claim 1, characterized in that the organic solvent is removed by evaporation. Process according to Claim 1, characterized in that the organic solvent is removed by washing while continuously removing the aqueous phase. Process according to Claim 1, characterized in that the organic solvent is removed by washing it by dialysis under contact with a pure aqueous phase. 5. A process according to claim 1, characterized in that the organic solvent is removed by contacting the emulsion with an excess of aqueous phase to dissolve the organic solvent therein which results in precipitation of the drug. A method according to claim 2, wherein aqueous phase is added during the evaporation to compensate for co-evaporation of water from the aqueous phase. A method according to any one of the preceding claims, wherein the droplet diameter of the emulsion is controlled by the concentration of surfactant. The method of claim 7, wherein said concentration is related to the molar concentration of the drug. A method according to any one of the preceding claims, wherein the surfactant is pharmaceutically acceptable. Drug particles prepared by the process according to any one of the preceding claims.