FI80608C - Process for making equal particles of water-insoluble organic compounds - Google Patents

Description

1 80608

A method for producing uniformly sized particles from water-insoluble organic compounds

Particles of sparingly water-soluble compounds are commonly used in a wide variety of applications, including ceramics, paints, inks, dyes, lubricants, pesticides, insecticides, fungicides, fertilizers, chromatography columns, cosmetics, hair lotions, hair lotions. Aqueous dispersions of Par-10 particles are used in many cases to avoid the hazards associated with organic solvents such as flammability and toxicity. Such dispersions typically have a wide range of particle sizes.

In many cases, the performance of the product is improved by controlling the particle size distribution. In general, smaller particles of a compound dissolve faster than larger particles of the same compounds. Particle size control is therefore important in controlling the dissolution rate.

Many drugs have been formulated into particles to provide controlled release after oral administration or implantation. Particle size is one important factor that affects the release rate of these drugs. Those skilled in the art may notice other examples of using particle size to control the operation of the product in addition to those mentioned above.

Drugs that are insoluble in water can have significant advantages when formulated into a stable suspension of particles less than three micrometers in diameter. In this particulate form, the drug can be injected intravenously, circulating and preferably accumulating, for example, in the reticuloendothelial system, where it can promote normal reticuloendothelial functions such as detoxification.

2 80608

Alternatively, the drug may be in the reticuloendothelial cells in which it is stored until it dissolves or is metabolized to an active form that circulates in the blood to other tissues to act there. This "slow" release of ak-5 active drug can result in more constant plasma drug concentrations over hours, days, weeks, or months and result in improved therapeutic efficacy. Biodegradable particles that are X-ray opaque or radiolabeled are useful in diagnosing organs with high concentrations of attached radiculoendothelial activity, such as the liver and spleen.

Many advantages have already been found with insoluble particulate, X-ray opaque shadow media as described, for example, in "Improvement in Radiographic Contrast Media Through the Development of Colloidal or Particulate Media: An Analysis", Harry, W. Fischer, Journal of Theoretical 20 Biology , 67: 653-670 (1977). Recent publications on this topic include: Violante, M.R., Fischer, H.W. and Mahoney, J.A., "Particulate Contrast Media", Invest. Radioi., 15: S329, November-December 1980; and Violante, M.R., Dean, P.B., Fischer, H.W. and Mahoney, J.A., "Part-25 culate Contrast Media for Computer Tomographic Scanning of the Liver," Invest. Radiol., 15: 171 November-December 1980.

Very significant medical results are obtained by intravenous administration of drugs formulated as a suspension of particles three micrometers or smaller in diameter, which particles can accumulate in phagocytic cells and slowly dissolve, thereby delayed release into plasma where they circulate to other organs and tissues. Obvious classes of drugs 35 suitable for formulation into particulate suspensions include 3,80608 pigs. antineoplastic drugs, antimicrobials, antiviral drugs, anticoagulants, antihypertensive drugs, antihistamines, antimalarial drugs, male and female contraceptives, antiepileptic drugs, hormonal antipsychotics, antidepressants and antidepressants, adrenocorticals, adrenocorticals , immunosuppressive drugs, beta-blockers, water-insoluble vitamins, sympathomimetics, hypoglycemic agents, hyperglycemic agents, analgesics, sedatives, mood swings and others. The treatment of deficiency diseases, alcohol abuse, drug abuse, and many others could be improved by administering an intraperitoneal dose of a suitable drug particle-15 pension. Other medical applications for particle suspensions of drugs will be apparent to those skilled in the art.

Accurate particle size control is essential for the safe and effective use of these formulations. The particles must be less than three to 20 micrometers in diameter to pass safely through the capillaries without causing embolism. This is critical for intravenous dosing because the particles must pass through the lung capillaries before they reach the reticuloendothelial cells of the liver and spleen. Limiting the particle diameters of 0.01 to 0.1 micrometers would result in the selective accumulation of these particles in certain tissues, e.g., neoplastic tissue, where the capillaries are somewhat more porous than the capillaries of normal tissues. Particle suspensions with particle diameters greater than 10 micrometers could be useful for selective intravenous dosing to occlude blood vessels that feed abnormal tissue, such as the neoplasm. Accurate and precise control of particle sizes is essential for efficacy 35 while minimizing or avoiding adverse effects in each of these applications.

Conventional methods for preparing water-insoluble compounds produce particles of many different sizes, many of which are unsuitable for the present purpose. Mechanical sorting or separation of the desired particle size from a mixture of different sizes is difficult and unsatisfactory. Centrifugation and filtration do not give high yields of particles that are all exactly the same desired size. 10 Studies with water-insoluble, X-ray opaque contrast agents required uniform particles of certain sizes, which were very difficult to obtain by conventional methods. Accompaniment was then studied as a way to directly form particles with a predetermined size. Partial success was achieved with a single material and method, as reported in "Particulate Contrast Media", Investigative Radiology, 15: S329 November-December 1980; but this method would not work with other materials and would not allow precise variation and control of the particle size produced.

Further studies led to the invention which is the subject of this application, which is effective in the case of any drug or compound having a solubility in water of preferably less than 1: 10,000 to obtain a predetermined particle size for water-insoluble drugs or other compounds used as an aqueous dispersion.

The invention relates to a process for preparing uniformly sized particles from a solid, water-insoluble organic compound by first preparing a solution of the solid organic compound in a water-miscible solvent of the organic compound, and the compound has a substantially low solubility in water; second, injecting an aqueous precipitating liquid into the solution at a temperature of about -10 ° C and 100 ° C and at an injection rate of about 5,80608 0.01 to about 1000 ml per unit volume per 50 ml to form a suspension of the precipitated organic solid, wherein the compound is in substantially non-agglomerated particles having a substantially uniform average particle diameter of less than about 10 micrometers such that the particle size is directly proportional to the solution temperature and inversely proportional to the spray rate, and then separated from the organic liquids and washed with aqueous wash. It is preferable to mix the solution into which the precipitating liquid is injected. This can be done by mixing, shaking, combining the two fluid streams, by infusion itself, or by other techniques familiar to those skilled in the art.

In preferred embodiments of the invention, an additional aqueous precipitation liquid is added to the suspension before the particles are separated from the organic solvents. The separation can be performed, for example, by centrifugation, membrane filtration, reverse osmosis, or other methods.

The aqueous washing liquid may be the same as the aqueous precipitating liquid, and may be pharmaceutically acceptable for injection into a patient.

The aqueous precipitating liquid may be water, a mineral salt solution or a surfactant solution. Suitable aqueous solutions of surfactants include e.g. 5% polyvinylpyrrolidone C-30, 0.1% polyvinylpyrrolidone C-15, 0.1% human serum albumin, 0.1% Pluronic-F-68 (poloxamer 188) and 0.33-30% gelatin alone or with the addition of 0.6% Heta starch, 0.02% propylene glycol or 2% sucrose. The aqueous precipitating liquid can be injected through a needle of normal size.

The average diameter of the particles may be up to about 10 micrometers, preferably from 0.01 to about 5 micrometers.

The particles made in accordance with this invention typically have a particle size distribution such that the maximum relative standard deviation is 95%, with, for example, 95% of the particles having an average size of 1.0 micrometers in the size range of 0.5 to 1.5 micrometers.

The water solubility of the solid organic compound is preferably less than one part per ten thousand, and the compound may be organometallic. In general, any compound of the invention that satisfies the other requirements of the invention is suitable, including many drugs. When using heparin complexes, a surfactant is not necessary.

The organic solvent may be dimethyl sulfoxide, dimethylformamide. N, N'-dimethylacetamide, phenol, iso-propanol or other solvent.

In a preferred embodiment, the method comprises the additional step of diluting the organic solvent with a non-solvent liquid such that the ratio of non-solvent to solvent is between about 100: 1 and about 1: 100, after preparation of the organic solution and before the injection step, thus, that the particle size is directly proportional to the ratio of non-solvent to solvent.

In further preferred embodiments, the non-solvent is one in which the organic compound is slightly more soluble than in water. The non-solvent may be a lower aliphatic alcohol.

In particularly preferred embodiments, the iodopamide ethyl ester, triiodobenzoic acid derivative ethyl ester is dissolved in dimethyl sulfoxide and diluted with ethanol-30 Ia; if the ratio of ethanol to dimethyl sulfoxide is greater than about 2, the average particle diameter is greater than about 1 micrometer, and if the ratio of ethanol to dimethyl sulfoxide is less than about two, the average particle diameter is less than about 1 micrometer.

Figure 1 is a graph showing the free energy of the various phases of the compounds used in the invention.

Figure 2 is a graph showing the relationship between particle size distribution and the time period from initiation of precipitation to complete precipitation.

Fig. 3 is a graph showing the injection rate (ml / min) of the (aqueous precipitation liquid) as a function of the product of the mixing speed (rpm) of the organic solution and the total volume (liters) at constant temperature: ratio: injection rate of the aqueous solution (ml / min) * 23 + 0 , 14 [stirring speed 10 (rpm) x volume of organic solution (1)] determines the parameters for the preparation of iodopamide ethyl ester particles with a diameter of one micrometer at a constant temperature (4 ° C) and in a dimethyl sulfoxide / ethanol mixture; Fig. 4 is a graph showing the particle size of iodopamide ethyl-15 ester as a function of temperature when the ratio of the injection rate of the aqueous precipitation liquid to the expression [mixing speed (rpm) x volume of organic solution] is constant; Fig. 5 is a graph illustrating the effect of liquid precipitation-20 liquid spray rate variation on particle size at a constant temperature and a constant mixing rate of iodopamide ethyl ester solution; and Figure 6 is a schematic diagram of the preferred steps of the method according to the invention.

This invention relates to the preparation of water-insoluble compounds in the form of uniform particles of a predetermined size. The particles are formed by precisely controlled precipitation of the compound into the aqueous phase from an organic solvent in which the compound is soluble.

The physicochemical principles which are intended to form part of the present invention are shown in Figures 1 and 2. Figure 1 shows that the free energy of the system is higher when the compound is dissolved in an organic solvent than when the compound is in particulate or crystalline state. During precipitation, the compound naturally converts to a crystalline form — the lowest free energy state — unless trapped in a metastable particle state, a state where its free energy is between the solution and the free energy of the crystalline state. Properly implemented, this invention allows the compound to be trapped in a metastable particle state by preventing it from converting to a crystalline state.

The size distribution of the particles formed during precipitation can be correlated with the time between the onset of precipitation and complete precipitation. As seen in Figure 2, a very short period of time results in the formation of uniformly sized particles (A), while a very long period of time results in a wide particle size distribution (B). Intermediate ratios produce intermediate particle size distributions. An important parameter for the use of this invention is the water solubility of the compound. The invention requires the use of solid organic compounds having substantially low solubility in water. We have found that compounds with a water solubility of less than one part in ten to 20 swabs are ideally suited for this technology. Compounds that are more water soluble may be used in the process of the invention; but the higher the solubility, the greater the chance that some of the compound will dissolve in the aqueous phase and convert to a more stable crystalline state. Redissolution in the aqueous phase can also lead to a widening of the particle size distribution. For these reasons, we prefer compounds with a water solubility of less than one part in ten thousand.

In order to make particles having a uniform and predetermined size and a solubility of less than one part in ten thousand, a solution of a solid organic compound in a suitable organic solvent is prepared. The solution can be diluted with a non-solvent that does not precipitate the drug or other compound. An aqueous precipitating liquid is also prepared, preferably using 9,80,608 with a surfactant, in an amount sufficient to both precipitate the drug or other compound and to stabilize the particulate suspension of the resulting compound against accumulation. Water can be used alone as a precipitating liquid when compounds that do not accumulate are not used. The aqueous solution is carefully injected into the organic solution, carefully controlling the process parameters, which are: the mixing rate of the organic solution, the injection rate of the aqueous solution, the volume of the organic solution, and the temperature of the solutions and suspension.

In studies that varied parameters for adjusting particle size, three useful ratios were found: 1) dilution of the solution with additional non-solvent-15 produces larger particles and dilution with less non-solvent produces smaller particles; 2) higher temperatures during solution precipitation produce larger particles, and lower solution temperatures during precipitation produce smaller particles; and 3) at a given mixing rate of the organic solution, higher injection rates of the aqueous solution produce smaller particles, while lower injection rates produce larger particles.

When the precipitation is complete, the uniformly sized particles are separated from the liquid and washed to remove the organic solvent. In most cases, the particles should be separated from the liquid rapidly to prevent conversion to the crystalline form.

The compounds used in the process of the invention are solid organic materials, including organometallic compounds, which preferably have a solubility in water of less than one part to ten thousand. Otherwise, the specific compound and its purpose are less important to the mode of operation of the invention.

As a first step, a solution of the compound of interest in an organic solvent suitable for that compound is prepared. This can occur when the compound is synthesized as a dissolved solid, or it can be done simply by dissolving the compound in a selected solvent.

The solvent is selected to suit the compound. For example, dimethylformamide (DMF) is a solvent for iotalamate ethyl ester (IEE) and josefamate ethyl ester (IFE), and dimethyl sulfoxide (DMSO) is a solvent for iodopamide ester (IDE) and IEE. Any satisfactory water-miscible solvent of the compound can be used.

In the next step, the solution is diluted with a non-solvent which does not cause precipitation of the compound. The non-solvent causes a greater dispersion of the dissolved molecules of the compound in the liquid phase. Higher dilution of the solution with a non-solvent produces larger particles, and lower dilution of the solution with a non-solvent produces smaller particles.

A non-solvent should not precipitate the compound when added to the solution. Preferred are non-solvents in which the compound is slightly more soluble than in water. Lower aliphatic alcohols, such as ethanol, are effective non-solvents for IDE and IEE solutions in DMSO. For triiodobenzoic acid ethyl esters, a ratio of at least 2 non-solvent to solvent can produce particles 1-3 microns in size (depending on other parameters), and ratios below 2 can produce particles smaller than micrometers, at least when using ethanol-diluted DMSQ solutions of.

To precipitate a compound from a solution of the desired particle size, an aqueous solution of the surfactant is prepared sufficient to provide complete precipitation of the compound 80608 and to stabilize the particulate suspension of the resulting compound against agglomeration. The surfactant provides stability against agglomeration and water is precipitated. The presence of additional surfactant is desirable to ensure stabilization so that the doped particles suspended in the liquid do not accumulate to form particles of inappropriate size. Although surfactants are used in most cases, some compounds appear to form stable, substantially non-caking particles without surfactants. Examples of such non-caking compounds are certain heparin complexes.

It is thought that particles with a relatively high surface charge will be less likely to require a surfactant in the aqueous precipitation solution. The surface charge of a particle is sometimes called its zeta potential, this is a measure of the charge that decreases with increasing distance. There may be a threshold zeta potential above which no surfactant is required, but below which a surfactant is required to prevent the accumulation of precipitated particles. The zeta potential is directly proportional to the polarity or net charge of the organic compound. Thus, the need for a surfactant in an aqueous doping solution can be estimated in advance from the amount of charge or polarity of the organic compound used in the process of the invention. For example, heparin complexes have very high charges and form stable, non-agglomerated particles when mixed with water.

In general, despite such a theory, empirical methods are sufficient; i.e. precipitation can first be performed with water, and if agglomeration occurs, precipitation is performed in the presence of a surfactant. Surfactants are selected based on their compatibility with the 12,80,608 compound and their ability to stabilize the particle suspension of the compound. When working with IEE and IDE drugs, a solution of 5% polyvinylpyrrolidone (C-30), 0.1% polyvinylpyrrolidone (C-15) or 0.1% human serum albumin is preferred. 0.1% Pluronic F-68 [Poloxamer 188, poly (oxyethylene-oxypropylene) polymer] 0.33% gelatin, 0.33% gelatin and 0.6% Heta starch, 0.33% gelatin can also be used and 0.002% propylene glycol, or 0.33% gelatin-10 and 2% sucrose, or other surfactants known to those skilled in the art.

In order to precipitate the particles of the compound to the desired size, the aqueous solution and the organic solution are combined at a controlled temperature, at a spray rate relative to the stirring rate, and relative to the non-solvent in the dispersed solution.

Precipitation of the compound takes place exothermically by heating the organic solution and the resulting suspension. The temperature of the solution and the resulting suspension is controlled to obtain the desired particle size for the precipitate. Higher solution temperatures during precipitation produce larger particles and lower solution temperatures during precipitation produce smaller particles.

Also, higher injection rates at its constant mixing rate of organic solution-25 produce smaller particles, and lower infusion rates produce larger particles.

Figures 3-5 show the effect of parameter variation on particle size when compounded from an IDE DMSO solution diluted with 2 parts ethanol per part solution using a 5% aqueous solution of polyvinylpyrrolidone at different injection rates and temperatures.

Figure 3 shows that when the mixing rate of the organic compound iodide diethyl ester and the dimethyl sulfoxide / ethanol 35 solution is increased, the injection rate of the aqueous surface solution must be increased in a ratio determined by the expression: infusion rate (ml / min) = 23 + 0 .14 [volume (liters) x mixing speed (rpm) to produce particles 5 micrometers in diameter at 4 ° C.

Figure 4 shows that when the ratio of infusion rate to expression (mixing rate x volume) is constant then the increased precipitation temperature produces larger particles.

Fig. 5 shows three points on the 20 ° C temperature line of Fig. 3 as a function of the precipitation liquid injection rate to estimate the curve that larger particles larger particles are formed at lower injection rates, indicating that when the temperature to expression ratio (mixing rate) x volume) is constant, the particle size is inversely proportional to the spray rate of the precipitation liquid.

Taken together, Figures 3-5 clearly show that higher temperatures and lower mixing rates produce larger particles, and lower temperatures and higher mixing speeds produce smaller particles. Another parameter that can be varied to affect the particle size is the dilution ratio of the solution before precipitation occurs.

When the precipitation is complete, the aqueous surfactant solution can be further added to stabilize the suspended particles against agglomeration. Excess solution can be added at a high rate because substantially all of the compound has now precipitated into uniformly sized particles. The precipitated particles are then rapidly separated from the organic solvents to prevent redistribution and reprecipitation of the particles to undesired sizes. Centrifugation is the preferred way to perform the separation. Other methods, such as membrane filtration, reverse osmosis, etc., known to those skilled in the art, may also be used to remove unwanted substances. As soon as the particles have been separated from the organic liquid, they are washed or rinsed with normal saline to remove solvent and excess surfactant.

The process of the present invention is illustrated by the following examples, which, however, do not limit the invention described above and set out in the claims.

Examples 1-19 are shown in Table I. The solid organic compound was dissolved in an organic solvent and then diluted (unless otherwise indicated) as a non-solvent. The aqueous precipitating liquid was then injected into the solution through the needle at a given rate, at a given temperature and with stirring at a given stirring rate. The size of the particles obtained is shown in each example.

15 80608

Table Ia

Example Example 5 1. solid organic compound 10 mg 2,2'-4,4'-tetra 1> 4 mg RS-nitrocellucroxybenzophenone lozenge compound (1/4 sec) 2. organic solvent 0.2 ml dimethyl sulphonate .2 ml dimethylphoxide sulfoxide 10 3. non-solvent 0.2 ml ethanol 0.2 ml ethanol (99%) (99%) 4. aqueous precipitation 5 ml human serum 5 ml human serum albumin (0, 1%) min albumin (0.1%) 5. spray liquid syringe 2.5 2 15 dosing speed (ml / min) 6. solution stirring speed 200,400 (rpm)

7. solution temperature 20 ° C 20 ° C

8. particle diameter 0.5 μm 0.5 μm 16 80 608

Table Ib

Example Example 3 4 5 _ 1. Solid organic 7 mg RS nitrocellu- 10 mg progesterone compound loose (1/4 sec.) 2. organic solvent 0/4 ml dimethyl sulfoxide 0.2 ml dimethyl sulfoxide phoxide 10 3. no solvent 0.01 ml isopropanol 0.2 ml ethanol (99%) 4. aqueous precipitate- 5 ml human serum 5 ml human serum broth albumin albumin 5. precipitation liquid spray 2.5 2.5 spawning rate (ml / min) 15 6. solution stirring speed (rpm) 200 200

7. solution temperature 20 ° C 20 ° C

8. particle diameter 0.5 μm 1 μm 20 Table Ie

Example Example _5_6_ 1. solid organic 5240 mg josfamate- 10 g jotalamate-2 compound ethyl ester ethyl ester 2. organic solvent 60 ml dimethyl sulfide 32 ml dimethyl sulfoxide phoxide 3. non-solvent 20 ml ethanol (99%) 4. aqueous precipitation - 400 ml polyvinylpyrrh 800 ml polyvinylpyrrolid 30 rolidone C-15 (5%) rolidone C-15 (5%) 5. spray liquid spray rate 3,300 (ml / min) 6. solution mixing speed 200,300 (rpm) min) 35 7. solution temperature 20 ° C 0-2 ° C at the beginning 40 ° C at the end 8. particle diameter 1.0 μm 1.0 μm 17 80608

Table Id

Example Example 5 1.7_8_____ 1. Solid organic 100 mg / 3-2,3,6-triiodo-100 mg /> '- 2,3,6-compound 3-Dimethylformamidinofetriiodo-3-dimethynyl-propionic acid ethyl-formamidinophenyl ester ethyl propionic acid ester 2. organic solvent 2.0 ml dimethyl sulfoxide 2.0 ml dimethyl sulfoxide 3. non-solvent 2.5 ml ethanol (99%) 2.5 ml ethanol (99%) 4. aqueous precipitate ml Poloxamer 188, po- 25 ml human serum liquid 15 (oxyethene coxiprom albumin (0.1%) pen) polymer (Pluronic F-68 (0.1%) 5. precipitation liquid spray 750 750 shaking rate 20 (ml / min) 6. solution mixing- 650 650 speed (rpm)

7. solution temperature 10 ° C 10 ° C

8. particle diameter 0.1 μm 0.1 μm i 18 80608

Table Ie

Example Example 5 _9_10_ 1. solid organic 100 mg β-2,4,6-triiodo-120 mg iodopamide compound 3-dimethylthiformamidinoethyl ester phenylpropionic acid ethyl 10 ester 2. organic solvent 2.0 ml dimethyl sulfoxide 2.0 ml dimethyl sulfoxide 3. non-solvent 2.5 ml ethanol (99%) 2.5 ml ethanol (99%) 4. aqueous precipitate 2.5 ml polyvinylpyrrole 5 ml polyvinylpyrride lidone C-15 (0, 1%) rolidone C-15 (0.1%) 5. precipitation liquid injection 750 300 boiling rate (ml / min) 6. solution mixing- 650 80 20 speed (rpm)

7. solution temperature 10 ° C to 4 ° C

8. particle diameter 0.1 μm 0.1 μm table If 19 80 608

Example Example _11_12_ 5 1. solid organic 1200 mg iodipamide- 120 mg iodopamide compound ethyl ester ethyl ester 2. organic solvent 20 ml dimethyl sulfide 2.0 ml dimethyl sulfoxide phoxide 3. non-solvent 25 ml ethanol 2.5 ml ethanol 10 ( 99%) (99%) 4. aqueous precipitate - 50 ml polyvinyl - 5.0 ml polyvinylation liquid pyrrolidone pyrrolidone C-15 (0.1%) C-15 (0.1%) 5. precipitation liquid spray 19 2 15 boiling speed (ml / min) 6. solution stirring speed 190,200 rpm (rpm)

7. solution temperature 10 ° C 10 ° C

8. particle diameter 1.5 μm 1.0 μm

Table Ig 20 80608

Example Example 5 _13_14_ 1. solid organic 120 mg iodopamide- 10 mg isopropyl compound ethyl ester pyrrolizine derivative female (NSC-278214) 2. organic solvent 2.0 ml dimethyl 0.4 ml dimethyl sulfoxide f oxide 3. no- solvent 2.5 ml ethanol (99%) 4. aqueous precipitation 25 ml poly (axethylene 5 ml human serum Niko-oxypropylene) boom albumin polymer Poloxamer 188 (Pluronic F-65) (0.1%) 5. precipitation liquid injection speed 750 20 (ml / min) 6. solution mixing speed 700 300 20 speed (rpm)

7. solution temperature 0 ° C 17 ° C

8. particle diameter 0.1 μm 0.5 μm 2i 80 608

Table Ih

Example Example 5 - 15_16 _ 1. solid compound 10 mg of isopropyl- 10 mg of isopropylpyrrolizine derivative pyrrolizine] derivative (NSC-278214) (NSC-278214) 10 2. organic solvent 0.4 ml dimethyl 0.4 ml dimethylacetamide sulfoxide 3. non-solvent - 0.2 ml ethanol (99%) 4. aqueous precipitation - 20 ml human sediment 20 ml human sediment rum albumin rum albumin (0.1%) (0.1 %) 5. spray rate of precipitation liquid (ml / min) 38 100 6. mixing speed of solution 20 (rpm) 50 200

7. solution temperature 0 ° C 0 ° C

8. particle diameter 0.5 μm 0.1 μm 22 80608

Table li

Example Example 5_17_18_ 1. solid organic 1.5 mg 1,2-diaminocyclo 10 mg N- (trifluoroacetate hexane malinate platinum) adriomycin na (II) 14-valerate 2. organic solvent 0.05 ml phenol 0.2 ml dimethyl sulphoxide 3. non-solvent 0.45 ml m-aminophenol 0.2 ml ethanol (99%) and 0.25 ethanol (99%) 4. aqueous precipitate- 5 ml human serum- 5 ml human serum ink albumin (0.1%) albumin (0.1%) 15 5. precipitation liquid spray 2.5 boiling rate (ml / min) 6. solution mixing speed 200,200 rpm

7. solution temperature 20 ° C 20 ° C

20 8. particle diameter 0.1 μm 1.0 μm 23 80608

Table Ij

Example Example 5 _19_20_ 1. solid organic 200 mg heparin-benz- 10 mg organic co * * alkonium chloride complex dist (see list) 2. organic solvent 10 ml isopropanol 0.2 ml dimethyl sulfoxide 10 3. non-solvent - 0, 2 ml ethanol (99%) 4. aqueous precipitation 200 ml water 5 ml human serum liquid albumin (0.1%) 5. precipitation liquid injection 3.7 2.5 boiling rate (ml / min) 15 6. solution mixing solution 300,250 pe (rpm)

7. solution temperature 20 ° C 20 ° C

8. particle diameter 0.5 [mu] m 1.0 [mu] m * 20 [mu] m * 20 Norethisterone, acetylsalicylic acid, wafarin, heparin-tridecyloxyl-methyl-anhydrochloride-carplex, sulfamethoxazazole, 2 5 cefalexin, prednisolne acetate, diazepam, clonazepam, methidone, methidone naloxcal, disulfiram, mercaptopurine digitoxin, primaquine, 3 5 mefloquine, atropine, 24 80 608 scopolamine, triazide, furosemide, propanelol, 5 methyl methacrylate, polymethyl methacrylate, 5-fluorideoxyuridine, cyphosin arabinoside, acyclocin arabinoside, acyclocinab

Examples 1-19 show how the method can be used to produce aqueous dispersions of a wide variety of compounds with low water solubility and whose particle size can be controlled substantially accurately and predictably. Conditions were varied for each compound individually in accordance with the invention to optimize the results. This may in some cases involve chemical modification of the compound to achieve the desired solubility.

Due to the wide range of scope covered by the above examples, it will be apparent to one skilled in the art that numerous other compounds can be expected to behave in the same manner.

Example 20 is also shown in Table I. This example would be performed in the same manner as Examples 1-19, and the compounds listed would yield particles within the scope of the invention.

Examples 21-28 are shown in Tables II. In each example, a given amount of iodopamide ethyl ester was dissolved in a given volume of dimethyl sulfoxide and then diluted with a given volume of ethanol. The aqueous precipitation liquid was prepared from polyvinylpyrrolidone and then injected at a given injection rate through a needle having a given size into the solution, and the solution was stirred simultaneously at a given stirring rate.

25 8 0 608

Precipitation was performed in a given vessel at a given temperature. After precipitation, the administered amount of saline was added to further stabilize the dispersion. In each example, the average particle diameter was about 1.0 micrometer and substantially uniform.

Table Ha

Iodipamide ethyl ester particle precipitation parameters 10 Example 21 Example 22 Example 23 material 0.5 g 1 g 2 g iodopamide ethyl ester 15 (60 mg / ml) 10 ml 20 ml 40 ml ethanol (99%) 12.5 ml 25 ml 50 ml polyvinylpyrrolidone 25 ml 50 ml 100 ml 20 0.9% salt 15 ml 30 ml 60 ml solution mixing 125 rpm 190 rpm 300 rpm speed

temperature 4 ° C 4 ° C 4 ° C

25 injection rate 11 ml / min 19 ml / min 30 ml / min injection needle size 19 g 19 g 19 g 30 S.B. - length 3,8 cm 3,8 cm 3,8 cm diameter of the container 6 cm 6 cm 6 cm container 250 ml 250 ml 250 ml 35 polypropylene polypropylene polypropylene bottle bottle pen beaker 26 80 608

Table IIb

Jodlpamldletyyllester1 particle precipitation parameters

Example 24 Example 25 Example 26 5 material 3.5 g 5 g 10 g iodopamide ethyl ester (60 mg / ml) 70 ml 100 ml 200 ml ethanol 10 (99%) 87.5 ml 125 ml 250 ml polyvinylpyrrolidone 175 ml 250 ml 500 ml 0.9 saline 105 ml 150 ml 300 ml stirring speed 330 rpm 200 rpm 300 rpm temperature injection rate 45 ml / min 60 ml / min 85 ml / min injection-20 needles size 19 g 18 g 18 g SB length 4.8 cm 7 cm 7 cm container diameter 8.6 cm 12.5 cm 12.5 cm 25 container 1000 ml 2000 ml 2000 ml glass container glass container glass 30 35 27 80608

Table Ile

Iodipamide ethyl ester particle precipitation parameters 5 Example 27 Example 28 material 20 g 40 g of odipamide ethyl ester (60 mg / ml) 400 ml 800 ml ethanol (99%) 500 ml 1000 ml 10 polyvinylpyrrolidone 1000 ml 2000 ml 0.9% saline 600 ml 1200 ml mixing speed 15 rpm 210 rpm temperature injection speed 120 ml / min 175 ml / min injection needle size 16 g 16 g 20 SB length 8.3 cm 8.3 cm container diameter 22 cm 22 cm container 91 91

Bellco dish Bellco dish 25

Example 29

Preparation of iodopamide ethyl ester particles for dosing in patients

Dipamide diethyl ester particles (IDEs) having a size of about 1 micrometer can be prepared for administration to a patient. IDE is a water-insoluble ethyl ester of iodopamide; iodopamide is a water-soluble X-ray opaque compound used clinically for gallbladder X-ray examination. The synthesis of iodopamide ethyl ester 35 is known in the art (e.g., esterification with alcohol and acid or Schotten-Bauman reaction).

28 8 0 608 IDE is only minimally water soluble (10 * 5M) and can be easily precipitated from a solvent mixture of dimethyl sulfoxide (DMSO) and ethanol. However, the simple addition of water to this solution results in IDE-par-5 particles with a very rough surface; these particles range in size from less than one micrometer to more than 300 micrometers (diameter). Because a rough surface could damage vascular endothelial cells and promote aggregation, and because large particles could cause pulmonary embolism, the method of this invention is a preferred way to control particle size and shape.

Partikkelisaostusmenetelmä. Physical methods for modifying particle size, such as ball mill grinding, grinding, or sonication, result in formulations with a very wide particle diameter distribution. These methods are commonly used to eliminate large particles (greater than 4-5 micrometers that could cause blockages in the capillary vasculature of the lungs, but some particles smaller than micrometers are usually formed; these very small particles have been shown to be more toxic than 1-2 micrometers), possibly due to the increased binding of the small particles to the protein due to the much larger surface area or the excess of the particles entering the bone marrow cells.

A chemical precipitation method to produce particles of a given size was developed to avoid these problems. By adding an aqueous solution of polyvinylpyrrolidone at controlled rates and temperatures to IDE dissolved in dimethyl sulfoxide / ethanol, apparently spherical amorphous particles with a very narrow particle size distribution can be produced. To produce a par-35 particle with an average diameter of one micrometer, the size range of the particle diameters is 0.4 to 2.0 micrometers and 90 percent of the particles are between 0.5 and 1.5 micrometers in size, as determined microscopically.

By carefully controlling the precipitation parameters 5, particle preparations with different average diameters but similarly a narrow range of diameters can be produced.

The IDE particles produced using this methodology are stable in whole blood and have a low tendency to accumulate. When one micrometer IDE particles are suspended in whole blood, they have essentially no tendency to accumulate with each other or with blood elements. IDE particles have smooth outer surfaces.

Claims (30)

30 80 608 A process for preparing uniformly sized particles from a solid, water-insoluble organic compound, comprising the steps of: (a) preparing a solution of the solid organic compound in a water-miscible organic compound solvent, wherein the solid organic compound has 10 essential low solubility in water; (b) injecting an aqueous precipitating liquid into the organic solution at a temperature between about -10 ° C and about 100 ° C and at a spray rate of about 0.01 ml / min to about 1000 ml / min of 50 ml unit volume of the solution to produce a suspension of the precipitated solid organic compound in the form of substantially agglomerating towers of substantially uniform size particles having a particle diameter of up to about 10 micrometers, the particle size being directly proportional to the temperature of the solution during precipitation and inversely proportional to the spray rate; (c) separating the particles from the organic liquids and washing with an aqueous washing liquid. A method according to claim 1, characterized in that the aqueous precipitation solution is further added to the suspension before the particles are separated. Process according to Claim 1, characterized in that the particles are separated by centrifugation, membrane filtration or reverse osmosis. Method according to Claim 1, characterized in that the aqueous washing liquid is the same as the aqueous precipitating liquid. 5 From a group consisting of water and an aqueous solution of a mineral salt. The method of claim 1, characterized in that the aqueous wash is pharmaceutically acceptable for injection into a patient. A method according to claim 1, characterized in that the aqueous precipitating liquid Process according to Claim 1, characterized in that the aqueous precipitating liquid is a solution of a surfactant. A method according to claim 1, characterized in that the precipitating liquid is a solution of a surfactant selected from the group consisting of 5% polyvinylpyrrolidone in water; 0.1% polyvinylpyrrolidone in water, 0.1% human serum albumin in water; 0.1% Pluronic F-68 in water; 0.33% gelatin in water; 0.33% gelatin and 0.6% Heta starch in water, 0.33% gelatin and 0.02% propylene glycol in water, and 0.33% gelatin and 2% sucrose in water. A method according to claim 1, characterized in that the aqueous precipitating liquid is injected by means of a standard-sized needle. The method of claim 1, characterized in that the average particle diameter is selected from the range of about 0.01 micrometers to about 0.1 micrometers. The method of claim 1, characterized in that the average particle diameter is selected from the range of about 1 micrometer to about 4 micrometers. The method of claim 1, characterized in that the average particle diameter is between about 1 micrometer and about 10 micrometers. The method of claim 1, characterized in that the water solubility of the solid organic compound 32 80608 is less than about one part to ten thousand parts at ambient temperature. Process according to Claim 1, characterized in that the solid organic compound is an organometallic compound. A method according to claim 1, characterized in that the solid organic compound is an antineoplastic, antimicrobial or antiviral agent, anticoagulant, antihypertensive agent, antihistamine, antimalarial, infertility, antiepileptic, depressant or antidepressant, adrenocortical, steroid hormone antagonist, cardiac glycoside, anti-rejection agent, β-blocker, water-insoluble vitamin, sympathomimetic-15, hypoglycemic, hyperglycaemic, analgesic or sedative, or mood-altering drug. Process according to Claim 1, characterized in that the solid organic compound is an ethyl ester of a triiodobenzoic acid derivative. A process according to claim 1, characterized in that the solid organic compound is selected from the group consisting of iodopamide ethyl ester, jotalamate ethyl ester, josefamate ethyl ester, 2,2 ', 4,4'-tetrahydroxybenzophenone, RS nitrocellulose, progesterone, β-2,4, 6-Triiodo-3-dimethylformamidinophenyl-propionic acid ethyl ester, isopropylpyrrolizine derivative (NSC-278214), N- (trifluoroacetyl) adriamycin-14-valerate and 1,2-diaminocyclohexane malinate as platinum (II). The method of claim 1, wherein the solid organic compound is selected from the group consisting of Norethisterone, acetylsalicylic acid, wafarin, heparin-tridodecylmethylammonium chloride complex, sulfamethoxazole, cefalexin, prednisolone acetate, diazepam, 80 clonazepam, clonazepam. , naloxone, disulfiram, mercaptopurine, digoxin, primaguin, mefloquine, atropine, scopolamine, thiazide, furosemide, propanelol, methyl methacrylate, polymethyl methacrylate, 5-fluorideoxyuridine, cy-5-tosine arabinoside, acylcosin arabinoside, acylcosin arabinoside, Process according to Claim 1, characterized in that the organic solvent is selected from the group consisting of dimethylsulfoxide, dimethylformamide, N, N'-dimethylacetamide, phenol and isopropanol. Process according to Claim 1, characterized in that the solid organic compound is a heparin complex, the organic solvent is isopropanol and the aqueous precipitating liquid is water or an aqueous mineral salt solution. The method of claim 1, further comprising the step of diluting the organic solution with a non-solvent liquid such that the ratio of non-solvent to solvent is between about 100: 1 20 and about 1: 100 when the solution is prepared and before injection step, and the particle size is directly proportional to the ratio of non-solvent to solvent. Process according to Claim 21, characterized in that the non-solvent liquid is a liquid in which the solid organic compound is slightly more soluble than in water. Process according to Claim 21, characterized in that the non-solvent liquid is a lower aliphatic alcohol. A process according to claim 21, characterized in that the solid organic compound is selected from the group consisting of iodopamide ethyl ester and josefamate ethyl ester, the organic solvent is dimethyl sulfoxide, the non-solvent liquid is ethanol, the ratio of ethanol to organic solution is greater than about 2.0 and the average particle diameter is greater than 1 micrometer. A process according to claim 21, characterized in that the organic solid compound 5 is selected from the group consisting of iodopamide ethyl ester and josefamate ethyl ester, the organic solvent is dimethyl sulfoxide, the non-solvent liquid is ethanol, the ratio of ethanol to organic solution is less than about 2.0 and the average the particle diameter is less than about 1 10 micrometers. Process according to Claim 21, characterized in that the solid organic compound is iodopamide ethyl ester, the organic solvent is dimethyl sulphoxide, the non-solvent is ethanol, the aqueous precipitating liquid is 5% polyvinylpyrrolidone in water, the temperature is 4 ° C and the injection rate (ml / min) corresponds to the expression 23 + 0.14 x [mixing speed (rpm)] x [(volume of organic solvent (liters)], and the average particle diameter is about 1 micrometer. The method of claim 1, characterized in that the average particle diameter is selected from about 0.01 micrometers to about 10 micrometers. The method of claim 1, characterized in that the average particle diameter is selected from about 0.01 micrometers to about 5 micrometers. A method according to claim 1, characterized in that the maximum relative standard deviation of the particle size distribution is 50%. A method according to claim 1, characterized in that the organic solution is stirred while the precipitating liquid is sprayed. 35 80 608