JPH06501872A - How to create uniformly sized particles from insoluble compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] BACKGROUND OF THE INVENTION Method for making particles of uniform size from insoluble compounds Compound particles with low solubility in dispersion media have a wide range of applications, such as medical products, ceramics, Paints, inks, dyes, lubricants, pesticides, insecticides, fungicides, fertilizers, chromatography Used in ficolumns, cosmetics, lotions, ointments, and detergents. many To avoid hazards such as flammability and toxicity associated with organic solvents, remove particles from water. A dispersion is used. Such dispersions can generally have a wide range of particle sizes. Ru.

Controlling particle size distribution often improves product performance. in general, Relatively small particles of a compound give a more uniform dispersion, while larger particles of the same compound Dissolves faster than larger particles. Therefore, particle size control is important for controlling solubilization rate. It is essential.

After oral, aerosol, subcutaneous, intramuscular, or other routes of administration, A number of drugs have been formulated as particles for sustained release. This is the particle size This is one important factor that affects the rate of drug release. Those skilled in the art should We recognize other examples of using particle size to control product performance of listed substances. Wear.

Water-insoluble drugs are formulated with stable suspensions of particles smaller than 3 μm in diameter (- It can be of great benefit when In this particular form, the drug is given intravenously injected, circulates in the blood, and accumulates preferentially in the reticuloendothelial tissue, where it is detoxified. Promote the functions of reticuloendothelial tissues such as Instead, this drug treats the reticuloendothelial tissue. It resides in cells, is solubilized or metabolized into an active form, circulates in the blood, and is used by other organisms. Go to weaving to reveal its efficacy. The 1' slow J release of this active drug lasts for several hours. Provide relatively constant drug concentrations in plasma over days, weeks, or months Ru. Radiopaque or radioisotope-labeled biodegradable particles are , is useful for diagnostic images of the liver and spleen, which have a high concentration of fixed reticuloendothelial tissue function. It is for use.

As an insoluble particulate radiopaque contrast material, numerous advantages have already been recognized. ing. For example, Journal of Theoretical Biolo gy.

67: 653-670 (1977) to Harry W. Fischer. By “ImprOVement inRadiographic Contr ast Media Through the Development of Co11oida■ or Particulate Media: “an Analysis” It is explained in the article.

For a more recent paper on this issue, see Violante, M.R.

Fischer, H.W., and Mahoney, J.A., Pa. rticulate ContrastMedia,” Invest, Ra diol,, +5: 5329 November-December 19 80; and Violante, M.R., Dean, P.B., Fis. cher, H, W, and Mahoney.

J, A,, “Particulate Contrast Media f or Computer Tomographic Scanning of t he Liver”, Invest, Radiol, +5: 171 No There is venmber-December 1980.

Accumulated by phagocytic cells, slowly solubilized and released continuously into the plasma. Formulated as a suspension of particles with a diameter of 3 μm or less that can be passed on to other organs and tissues. There are enormous medical uses for intravenous administration of drugs. Formulate as a granular suspension Types of drugs that are clearly suitable for use include: Injuries, antibiotics, antivirals, anticoagulants, antihypertensives, antihistamines, antimalarial drugs drugs, male and female contraceptives, antiepileptics, depressants and antidepressants, adrenal skin steroids, hormones and hormone antagonists, cardiac glycosides, betabro Car-1 water-insoluble vitamins, sympathomimetic agents, hypoglycemic agents, hyperglycemic agents, analgesics, Stabilizers, mood-altering drugs, etc. Treatment of deficiency diseases, alcohol abuse, drug abuse, etc. is improved by intravenous administration of a granular suspension of the appropriate drug. Granular drug suspension Other pharmaceutical uses of will be apparent to those skilled in the art.

Accurate control of particle size is essential for the safe and effective use of these formulations. It is. In order to pass through capillaries without causing emboli, particles must have a diameter of 3 Must be less than μm. These particles are the fixed reticuloendothelium of the liver and spleen. intravenous because it must pass through the capillaries of the lungs before reaching the tissue cells. This is important for administration. Set the particle size to 0. O1~0. Limited to 1μm These particles are found in certain tissues, for example, where capillaries are larger than normal tissue capillaries. will also accumulate selectively in the somewhat porous neoplastic tissue. From 10μm Suspensions of large diameter particles are intentionally introduced into blood vessels that feed abnormal tissue, such as neoplasms. Useful for selective intra-arterial administration to form emboli. For each of these uses In order to maximize effectiveness while avoiding or minimizing adverse effects, precise granulation is required. Control of diameter is essential.

Traditional methods of making insoluble compounds result in particles of a large number of different sizes, many of which is inappropriate as something that can be used at any time.

Mechanical sorting or separation of desired particle sizes from mixtures of various sizes is It is difficult and unsatisfactory. Centrifugation and filtration all achieve exactly the same desire. sized particles in high yield.

For the study of water-insoluble and radiopaque contrast materials, uniform Unique particles were required, which was extremely difficult to obtain using conventional methods. There The precipitation method was investigated as a method to directly form particles of a desired size. one thing Partial success was achieved using quality and one method. This is “Particu late Contrast Media", lnvestigative Ra Diology, 15: 5329 November-December1 980 reported. However, this method may not work well for other substances. wax, and the resulting particle size would not be precise and controllable.

Further research led to the present invention. This is preferably 10,000 in a given liquid. Effective for compounds that develop a solubility of less than 1/2 of the solubility of a compound of a predetermined particle size. Give the liquid powder.

Summary of the invention The present invention first involves preparing a solution of the solid compound dissolved in a suitable solvent. and second, a substantially uniform average particle diameter selected from a range of up to about 10 μm. to produce a suspension of precipitated solid compounds in the form of substantially unagglomerated particles. Then, add the precipitate to the solution at a temperature between about -50°C and about 100°C, and add the precipitate to the unit body. Inject at an injection rate of about 0.01 mL/min to about 3000 mL/min per volume, and The compound essentially has little solubility in the precipitation solution, and the solvent is compatible with the precipitation solution. The particle size is positively correlated to the solution temperature, negatively correlated to the injection rate, and then The particles are separated from the solvent with a sterilizer and washed with a suitable washing solution to obtain a homogeneous solid compound. The method includes a method of producing particles with a particle size of

In a preferred embodiment of the invention, additional precipitation liquid is suspended before separating the particles from the solvent. Add to the suspension. For example, by centrifugation, membrane filtration, reverse osmosis, or other methods. Perform separation and vine.

The average particle diameter of the particles is up to about IO μm, preferably from 0.01 μm to about 5 μm. It's possible.

Particles made according to the present invention generally have a particle size distribution with a maximum relative standard deviation of 30%. . For example, the average particle size is 1. 95% of 0 μm particles have a particle size range of 0.5 to 1.5 μm exists in The present invention preferably has essentially little solubility in the precipitating liquid, In other words, it is suitable for compounds with a solubility of less than about 10,000 parts in the precipitation solution. Generally, the present invention Any compound that meets the other requirements of the drug is also suitable, including many drugs. this compound may be an organic compound or an inorganic compound.

The solvent has a solubility of the compound in the solvent greater than about 10 mg/mL. An organic solvent or an inorganic solvent may be used as long as the solvent is suitable. In addition, this solvent Must be compatible with the liquid.

The washing liquid may be the same as the precipitation liquid or may be different. In some cases, the collection To maximize efficiency, this solution should be more of a wash solution than a precipitate solution or a soluble solution for compounds. It is advantageous whether the gender is low or not.

When the solid compound essentially has little solubility in water, the precipitate is Water, mineral acid solutions, surfactant solutions, or organic solvents are poor solvents for this compound. I can do it. Suitable surfactants include 5% polyvinylpyrrolidone C-30,0, 5% polyvinylpyrrolidone C-15, 0.1% human serum albumin, 0.1% Pl uronic F-68 (Moe Ml) and 0.3394 gelatin, alone or 0.3394 gelatin. 6% hetastarch, 0.02% propylene glycol or in combination with 2% sucrose. The organic solvent is dimethyl sulfate. Foxide It can be tylacetamide, phenol, isopropanol, or other solvents.

In one embodiment of the invention, the solid compound has poor solubility in water. That is, The solubility in water is about 1/10,000 to about 100%. This mode is normally Significant yield loss when compounds that are considered water-insoluble are precipitated from aqueous solution This is particularly appropriate when encountering Precipitation solution and washing solution to improve yield The above compounds may be selected to have lower solubility in water. In this aspect, The solvents used include, inter alia, the organic solvents mentioned above. However, the precipitate is at least substantially non-aqueous. Suitable non-aqueous solvents include ethanol, alcohol, 1% (w/v) polyvinylpyrrolidone in ethanol, other low aliphatic alcohols, acids, amides, aldehydes, ketones and glycols Ru.

In one embodiment, the compound is a non-solvent, i.e. the compound is poorly soluble. or a liquid that does not cause precipitation of the compound, with a non-solvent to solvent ratio of about 100: 1 and approximately 1:100, and is positively correlated to particle size or non-solvent to solvent ratio. After preparing the solution, include an additional step of diluting it before the injection step.

In one preferred embodiment, the solid compound is iosibamide ethyl ester. , an ethyl ester of triiodobenzoic acid derivatives, dimethyl sulfur and diluted with ethanol.

This compound is then precipitated with an aqueous surfactant solution. Ethanol vs. dimethyl sulfur When the oxide ratio is greater than about 2, the average particle diameter is greater than about 1 μm; When the ratio of ethanol to dimethyl sulfoxide is less than about 2, the average particle The diameter is less than about 1 μm.

In another preferred embodiment, the solid compound is mitindo mide), molecular formula C. ．． H. 2N1 0. and molecular weight 272.3 dissolved in id. The precipitation solution used was 1% (W/ν) polyvinylpyro in 99% ethanol. It's Lydon.

In yet another preferred embodiment, the solid compound is aluminum chloride hexahydrate. It is. This is dissolved in ethanol (99%) and then diluted with acetone. Next This compound is then precipitated with an aqueous surfactant solution.

Brief description of the drawing FIG. 1 is a graph of the free energies of various phases of the compounds used in the present invention.

Figure 2 is a graph showing the relationship between particle size distribution and the time interval between the beginning and end of precipitation. It is.

Figure 3 shows the relationship between the product of the stirring speed (rpm) and the total volume of organic solvent (L) at a constant temperature. Figure 2 is a graph of injection rate (mL/min) (of water precipitate) as a number. Relational formula: water injection Input rate (mL/min) = 23 + 0.14 C stirring rate (rpm) x organic solvent product (L)] at constant temperature (4°C) and dimethyl sulfoxide/ethyl Particles for the production of yosibamide ethyl ester particles of diameter jum in ethanol determine the parameter.

Figure 4 shows the injection rate of the water precipitate versus the constant ratio of [stirring speed (rpm) x organic solvent volume]. Graph showing the particle size of iosibamide ethyl ester as a function of temperature at be.

Figure 5 shows the water precipitation of the iosibamide ethyl ester solution with constant temperature and stirring speed. It is a graph showing the effect on particle size when changing the injection rate of precipitate.

FIG. 6 is a schematic flowchart of the preferred steps of the method of the invention.

Detailed description of the invention The present invention relates to the preparation of uniform particles of predetermined size. One aspect of the invention is , the concentration of the compound in the vehicle or the solubility of the compound in the vehicle. A method for preparing uniform particles of predetermined size in a large vehicle. combination Careful control of compound precipitation from the solvent in which it is soluble or into an appropriate precipitation solution Particles are formed by the precipitation.

The physicochemical principles believed to be involved in the present invention are illustrated in FIGS. 1 and 2. Figure 1 shows When a compound is dissolved in an organic solvent, the compound is in a granular or crystalline state. This shows that the free energy of the system is higher than when During precipitation, this compound or Captured in a stable particle state whose free energy is intermediate between the solution phase and the crystalline phase. If not captured, it will naturally convert to the crystalline state - the lowest free energy state. Dew. Properly carried out, the present invention allows compounds to be transformed into quasi- Enables capture in a stable particle state.

The particle size distribution of particles formed during precipitation depends on the time interval between the beginning and end of precipitation and Correlate vine. As shown in Figure 2, very short time intervals produce particles of uniform size. (A) On the other hand, very long time intervals lead to a wide particle size distribution (B ). Intermediate conditions result in intermediate particle size distributions.

An important parameter for the use of the present invention is the solubility of the compound in the precipitation solution. It's easy to understand. That is, in order to obtain very good yields, water solubility or essential Compounds with almost no solubility in water, that is, compounds whose solubility in water is less than 1/10,000, are It is best to precipitate it in a solution.

More water-soluble compounds are prepared using an aqueous precipitation solution. However, the solubility of the compound The higher the temperature, the more likely some of the compound will dissolve in the aqueous phase and convert to a more stable crystalline state. Sexuality increases. Also, redissolution into the aqueous phase leads to an expansion of the particle size distribution. These reasons Therefore, the water precipitate can be used for compounds whose solubility in water is less than 1/10,000. It is preferable to be there.

The solubility in aqueous solutions is poor, that is, the solubility is about 1/10,000%/100%. using an acceptable precipitation solution that has a lower solubility than that of the compound in water. It has been found that suspensions of compounds with excellent solubility can be prepared by . The solubility of the compound in water compared to the precipitate is significant in terms of yield. If the difference is large, there is no need to worry.

A solid compound dissolved in a suitable solvent to create particles of uniform and predetermined size Prepare a solution of a substance. This solution should be diluted with a non-solvent that will not precipitate the drug or other compounds. You can interpret it. Precipitating the drug or other compound and the resulting granules of this compound Precipitate with a sufficient amount of surfactant to stabilize the suspension of particles from agglomeration. It is also preferable to let them dine. When using compounds that do not aggregate, it is also possible to use the precipitate alone. good. into a solution in which the compound is dissolved under carefully controlled conditions. Inject the precipitation solution. These conditions include the stirring speed of the organic solution and the injection speed of the aqueous solution. , the volume of the organic solutions and the temperature of these solutions and suspensions. The precipitation liquid is, for example, Can be injected through a standard gauge needle.

We studied various parameters to adjust particle size and found three relationships. . That is, (1) diluting the solution with more non-solvent will produce larger particles; Diluting with less non-solvent will produce smaller particles. (2) of the solution during precipitation Higher temperatures produce larger particles; lower temperature of the solution during precipitation produces smaller particles. occurs.

and (3) for a given agitation rate of the organic solution, the injection rate of the precipitate is The faster the injection speed, the smaller the particles, and the slower the injection speed, the larger the particles.

Once the precipitation is complete, the uniformly sized particles can be washed, e.g. by centrifugation or filtration. Solvent is removed by etc. In most cases, the particles are dissolved to prevent them from converting to the crystalline state. This means that it can be quickly separated from the medium.

Is water precipitation useful for many compounds, including organic and inorganic compounds such as: Organic compounds including, but not limited to, iombamide ethyl ester, iodine Lamic acid ethyl ester, iosefamate ethyl ester Tetra, 2.2’, 4,4”-tetrahydroxybenzophenone, RS Nitro Cellulose, progesterone, β-2,4,6-dryiodo-3-dimethylform Lumamidinophenylpropion (NSC-278214), N-()Lifluoroacetyl)Adrimaine 1 4valerate, 1,2-diaminocyclohexane marinated platinum(II) (dia minocyclohexane malinate platinum (I I)), norethisterone, acetylsalicylic acid, wafarin ), heparin-tridodecylmethylammonium chloride complex, sulfame Toxazole, cephalexin, prednisolone acetate, diazepam, crocodile Nasebum, methidone, naloxone, disulfiram, Mercaptopurine, digitoxin, primaquine, mefloquine (mefloqui ne), atrobin, scopolamine, thiazide, furosem Propanalol, Methyl methacrylate, Polymer Chil methacrylate, 5-fluorodeoxyuridine, cytosine arabinoside , acyclovir, and levonorgestrel (levon) orgestrel); and aluminum chloride hexahydrate as an inorganic compound, Oxides of iron, copper, manganese, and tin.

A compound more suitable for use with non-aqueous precipitation solutions is mitindomide (mit indomide), isopropylpyrrolidine (IPP, or carbamic acid) , (1-methylethiol)-, (5-(3.4-dichlorophenol)-2. 3-dihydro-1,H-pyrrolidine-6.

Organic compounds such as 7-diyl)bis(methylene ester) and iron citrate. , iron iodate, calcium pyrophosphate, calcium salicylate, platinum dichloride and Contains inorganic compounds such as vilorinsan sodium.

The first step is to prepare a solution of the compound in question in a suitable solvent. It is. This can occur when the compound is synthesized as a dissolved solid. , or by dissolving the compound in the solvent of choice.

The solvent is chosen to be suitable for the compound. For example, trimethylforma Mido (DMF) is iothalamic acid ethyl ester (IEE), It is a solvent for iosefamate ethyl ester (IFE) and dimethyl ethyl ester (IFE). Rusulfoxide (D~ISO) is ionpamitoethyl ester (IDE) and a solvent for IEE.

DMS○ is also a suitable solvent for compounds such as mitindomide.

Another suitable solvent for many compounds, especially IPP, is tetrahydrofuran (THF). be.

The second solution is then optionally diluted with a non-solvent that does not cause precipitation of the compound.

This non-solvent provides a greater dispersion of dissolved molecules of the compound in the liquid phase. Ras. Dilution of the solution with a non-solvent produces larger particles; dilution of the solution with a non-solvent However, small particles with small diameters are produced.

The non-solvent does not tend to precipitate the compound when it is added to the solution. low grade fat Aliphatic alcohols, such as ethanol, are added to solutions of IDE and TEE in DMSO. It is an effective non-solvent for For triiodobenzoic acid, at least ethanol When diluted with a solvent, if the ratio of solvent to non-solvent is 2 or more, the particle size is 1 to 3 μm. particles (depending on other parameters). When this ratio is less than 2 can produce submicron particles.

The compound is completely precipitated from the solution to the desired particle size. The resulting suspension of particles of this compound is charged to stabilize it from agglomeration. Prepare sufficient amount of surfactant solution.

Surfactants provide stabilization against agglomeration, while suitable precipitating agents causes precipitation. Suspended sediment particles in a liquid or aggregated to an inappropriately large size Excess surfactant should be removed to ensure stabilization without forming aggregates. It is desirable to have a sex agent present. In most cases, surfactants or chemicals are used. Some compounds contain substantially non-agglomerated particles that are stable even without the use of surfactants. It depends on what you form. Examples of such non-aggregating compounds are certain hepa It is a phosphorus complex.

Particles with relatively high surface charges require less surfactant in the precipitation solution. Seems low. The surface charge of a particle, sometimes called zeta potential, varies with distance. is the measurement of the charge that decreases to . Higher than that, no surfactant is needed; If lower, surfactants are needed to prevent particles from settling or flocculating. There may be a threshold zeta potential. This zeta potential is related to the polarity or effective charge of the compound. directly correlated. Therefore, the need for a surfactant in the precipitation solution is It can be predicted from the charge or polarity of the compound.

For example, heparin complexes are highly charged and form stable, non-agglomerated particles when precipitated in water. do.

Regardless of such theory, empirical methods are generally sufficient.

That is, precipitation is first carried out with water, and if flocculation occurs, precipitation in the presence of a surfactant is This indicates whether precipitation should be performed. The surfactant has compatibility and compatibility with the above compounds. and their ability to stabilize suspensions of compound particles. IEE and II) To test for E drug, 5% polyvinylpyrrolidone (C-30) , 0.1% polyvinylpyrrolidone (C-15), or 0.1% human serum aluminum Bumin is preferable. In addition, 0.1% Pluronic (trademark) F-68, (P o I oxame r I 8 8, poly(oxyethylene-cooxypropylene) Pyrene) Polymer L 0.33% gelatin, 0.33% gelatin plus 0.6% H etastarch, 0.33% gelatin brass 0.002% propylene glyco 0.3396 gelatin plus 2% sucrose, or others known to those skilled in the art. surfactants may be used.

In order to precipitate the compound to the desired size, temperature, injection rate vs. stirring rate must be controlled. precipitation under controlled conditions of ratio and proportion of non-solvent to solvent in the dispersion. Combine the precipitate and the solution.

Preferably, the solution into which the precipitation liquid is injected is stirred. This is done by stirring and shaking. This can be done by injection itself as well as by other techniques known to those skilled in the art. This effect is This can also be achieved by combining a flow of precipitation liquid with a flow of solution.

When precipitation of the compound occurs, an exotherm is generated, heating the solution and resulting suspension. child The temperature of the solution and the resulting suspension is controlled to achieve the desired particle size of the precipitate. to call. The higher the solution temperature during precipitation, the larger the particles will be. The lower the temperature, the smaller the particles. The lower the temperature, the lower the solubility of a large number of compounds. Therefore, it is generally preferable to inject the precipitate at a low temperature to increase the yield. stomach. The lower temperature limit at which precipitation can occur depends, of course, on the solvent, the freezing point of the precipitate, and economic considerations. Dependent.

Also, when the stirring speed of an organic solution is constant, the faster the injection speed, the smaller particles will be produced. However, a slower injection rate will result in larger particles.

Figures 3-5 show various injection rates and temperatures using 5% polyvinylpyrrolidone aqueous solution. Precipitate IDE from a solution of 1 part DMSO solution diluted with 2 parts ethanol. The influence of various parameters on particle size is shown in Fig. 2.

Figure 3 shows the organic compounds iotsubamide ethyl ester and dimethyl sulfoxide. /Increasing the volume and stirring speed of the ethanol solution produced particles with a diameter of 1 μm at 4°C. To calculate this, the injection rate of the surfactant aqueous solution should be calculated as the acid injection rate (lIll/min) = According to 23 + 0.14 (body fi (liter) x stirring speed (r, p, m,)) This indicates that it must be increased proportionately.

Figure 4 shows that when the ratio of injection speed to [stirring speed x volume] is constant, increasing the precipitation temperature This indicates that large particles are generated.

Figure 5 shows the injection rate of the precipitate into the organic solution from the 20°C temperature curve in Figure 3. Three points are plotted and the curve is approximated. According to this, the injection speed is slow If reasonably large particles are obtained and the ratio of temperature to [stirring speed x volume] is constant, the particle size is This shows that it is negatively correlated with the injection rate of the precipitate.

Considering Figures 3 to 5 together, the higher the temperature and the slower the mixing speed, the greater the The lower the temperature and the higher the mixing rate, the faster the mixing rate, the higher the mixing rate, the higher the temperature, the higher the mixing rate, the faster the mixing rate, the faster the It clearly shows that. Other parameters that can be varied to affect grain size ter is the amount of dilution of the solution before precipitation occurs.

When the precipitation is complete, excess surfactant is added to further stabilize the suspended particles from agglomeration. Add sex drugs. Essentially all of the compounds are already precipitated into uniformly sized particles So excess solution is added quickly.

Precipitated particles quickly to prevent re-dissolution and reprecipitation of particles of undesirable size. separated from the solvent. Centrifugation is the preferred method for performing this separation. Tooru Other methods are also desirable, including membrane filtration, reverse osmosis and pond methods known to those skilled in the art. A vine used to remove non-existent substances. Immediately after separating the particles, immerse them in 1N salt. Wash or rinse with water to remove solvent and excess surfactant. Using an aqueous precipitation solution For this purpose, use 1N salt water.

Particles prepared by the method outlined above can be prepared in a suitable solution, which is water or optionally a non-aqueous solution. The suspension may be resuspended in a suitable suspension vehicle. For example, particles formed or for parenteral administration , the particles are eventually resuspended in an aqueous solution such as sterile water. It will be done. In other instances, the particles are suspended in a carrier such as an ointment, gel, etc. . The compound has a similar solubility in the suspension vehicle as in the precipitation solution. I like it.

The invention is illustrated by the following examples, which are set out above and in the claims. It is not intended to limit the invention.

Examples 1 to 19 are shown in Table 3. A solid organic compound is dissolved in an organic solvent and then, in particular, cleaved. Diluted with non-solvent unless otherwise noted. then at a given temperature and at a given speed This precipitate is injected through a needle at a given rate into this solution which is being stirred at Ta. The size of the particle is shown for each example.

[Table 1a] l Solid 10mg2.2', 4.4°-Tetrahy 1.4mgR3-=- Toro organic compound droxybenzophenone cellulose compound 2 residual solvent 0 ．． 2ml dimethyl sulfo 0.2ml dimethyl sulfide 117 year old oxide 3 Nonsolvent 0.2ml ethanol 0.2ml ethanol (9994) (9 9%) 4 Aqueous precipitate 5ml 1 human serum albumin 5ml 1 human serum albumin (0.5%) Min (0,5%) 5 Precipitation liquid injection 2,52 6 Stirring of solution 200 400 Speed (rpm) 7 Solution temperature 20″C20’C [Table Ib) l Solid organic paste 7mg R5 nitrocellulose 10mgm Sugelonose (l/4 minutes) Compound 2 Organic solvent 0.4ml dimethyl sulfide 0.2ml shishmethyl sulfoxide Ruff oxide 3 Non-solvent 0.01ml Isopropano 0.2ml Ethanol (99% ) 4 Aqueous precipitate 5ml 1 human serum albumin 5ml 1 human serum albumin (0.1%) Min (0.1%) 5 Precipitation liquid 2. 5 2. 5 Injection speed (18 gauge needle (ml/min) through) 6 Stirring of solution 200 200 Speed (rpm) 7 Solution temperature 20°C20°C 1. j Phantom-1 [Table 1c) l Solid 5240mg Iosefamate 10g Iotalam organic compound Tyl ester Toethyl ester 2 Organic solvent 60ml dimethyl sulfoki 32ml dimethyl sulfide phoxide 3 Non-solvent 20ml! Tanol (99%) -4 Aqueous Precipitation Solution 400ml 1 Poly Vinylpyrroli 800ml Polyvinylton C-15 (5%) Pyrolidone C-1 5 (5%) 5 Precipitation liquid injection 3 300 6 Stirring of solution 200 300 Speed (rpm) 7 Solution temperature 20°C Initial 0-2°C Final 40°C 8 particle size 1.　oμm　1.　0μm 1 Solid 1100ff1β-2,3,6-) Ryo 100mgβ-2,3,6 -Organic compounds -B-3-dimethylfor triiodo-3-diamicinof Methylfluoropionate ethyl ester Ethyl ropionate luester 2 Organic solvent 2. Oml dimethyl sulfuride 2.0ml dimethyl sulfide 117 year old Kiside 3 Nonsolvent 2.0ml ethanol (99%) 2.0ml ethanol (99% ) 4 Aqueous precipitation solution 25+nl Poloxamer 188 25ml 1 person serum a Rubpoly(oxyethylene-mine (0.1%) cooxypropylene) Poly? -(Pluronic F-68) (0.1%) 5 Precipitation liquid injection 750 750 6 Stirring of solution 650 650 Speed (rpm) 7 Solution temperature 10°C 10°C [Table re] ■ Solid organic loomgβ-2,4,6-tryo 120mg: L Chirni Susivamide-bi-3-dimethylform compound muamidinophenylbro Pionic acid ethyl ester 2 Organic solvent 2. 0ml dimethyl sulfo 2.0ml dimethyl sulfide 117 year old Kiside 3 Non-solvent 2.5ml ethanol 2.5ml ethanol (99%) (99 %) 4 Aqueous precipitate 25ml polyvinyl 25ml polyvinylpyrrolidone pylori Don C-15 (0.1%) C-15 (0.1%) 5 Precipitation liquid injection 750 300 6 Stirring of solution 650 80 Speed (rpm) 7 Solution temperature lOoC 4°C 8 Particle size 0.1μm 0.1μm [Table If] 1 Solid 1200mg Yosibamide 2Qmg Yosibamide organic compound Tyl ester Doethyl ester 2 Organic solvent 20m I dimethyl sulfochloride 2. CI+nt dimethylsuside 117 years old 3 Non-solvent 25ml ethanol (99%) 2.5ml ethanol (99% ) 4 Aqueous precipitate 50 ml polyvinyl pylori 5. Omlml polyvinyl N-15 (0.1%) Pyrrolidone C-15 (0.1%) 5 Precipitation liquid pouring 19 2 6 Stirring of solution 190 200 Speed (rpm) 7 Solution temperature 10'C10'C 8 particle size 1.5μm 1, 0, 1. ! III [Table Ig) 1 Solid 120 + ng Yosibamide 10 mg Isopropyl organic compound Tyl ester pyrrolidine derivative (NSC-278214) 2 Organic solvent 2.0ml dimethylsulfo 0.4ml dimethylsuicide Rufoxide 3 Non-solvent 2.5ml ethanol - (99%) 4 Aqueous precipitate 25ml Poly(oxyethylene) 5ml Human serum Albunco Gicibroviremin (0,1%) Boria-, po1oxamer188 (Pluronic F-65) (0.1%) 5 Precipitation liquid injection 750 20 6 Stirring of solution 700 300 Speed (rpm) 7 Solution temperature 0’C17°C [Table Ih] 1 Solid 10mg isopropylpyrroli 10mg isopropyl organic compound non Derivative Pyrrolidine derivative (NSC-278214) (NSC-278214 )2 Organic solvent 0.4 ml N, N’-Shime 1,000, 4 ml dimethyls Ruacetamide 117 year old Kiside 3 Nonsolvent 0.2ml ethanol (99%) 4 Aqueous precipitation solution 20m 1 person serum albumin 20m 1 person serum albumin (0, 1%) Min (0.1%) 5 Precipitation liquid pouring 38 100 6 Stirring of solution 50 200 Speed (rpm) 7 Solution temperature 0°C0°C 8 particle size 0. 5 μm o, lbm [Table Ti] ■ Solid 1.5mg 1.2-diaminosif 10mgN-(Triff organic Compound Rohexane Marinate White Ruoloacetyl) Gold(II) Adriomysi hmm 14 valerate 2 Organic solvent 0.05ml phenol 0.2ml dimethyl sulfoxide 3 Non-solvent 0.45ml m-aminophenol 0.2ml ethanol and 0.25ml ethanol (99%) ethanol (99%) 4 Aqueous precipitate 5ml 1 person serum albumin 5ml 1 person serum albumin (061%) Min (0,1%) 5 Precipitation liquid pouring 5 2.5 6 Stirring of solution 200 200 Speed (rpm) 7 Solution temperature 20'C20'C [Table N] l Solid 200mg heparin-chloride 10mg organic compound organic compound Ruconium complex (*see list below) 2 Organic solvent 10ml isopropanol 0.2ml dimethyl sulfoxy de 3 Nonsolvent 0.2ml ethanol (99%) 4 Aqueous precipitation solution 200ml 1 water 5ml human serum albumin (0.1%) 5. Note on precipitation solution 3. 7 2. 5 6 Stirring of solution 300 250 Speed (rpm) 7 Solution temperature 20°C20°C acetylsalicylic acid, Waharin (wafari mouth), heparin-tridodecylmethylammonium chloride complex, clonacebam, methidone, mefloquine, thiazide, furosemide, propanelol, methyl methacrylate, polymethyl methacrylate, 5-fluorodeoxyuridine, cytosine arabinoside, acyclovir, levonorgestrel estrel) for which granularity can be controlled with substantial accuracy and predictability. How can this method be used to make aqueous suspensions of a wide range of compounds with low water solubility? Examples 1 to 19 illustrate the use of vines in this manner. For optimal results, According to the present invention, the conditions vary depending on the compound.

In some cases this includes chemical modification to obtain the desired solubility.

Because of the scope of the examples given above, it is likely that many other compounds behave in a similar manner. It is reasonable to predict whether the company will

Example 20 is also shown in Table I. This example is performed similarly to Examples 1-19, with columns It is intended that particles of the listed compounds fall within the scope of the present invention.

Examples 21-28 are shown in Table I+. On each side, a given amount of yosibamide The ester is dissolved in the given amount of dimethyl sulfoxide and then the given diluted with the obtained amount of ethanol. Aqueous precipitation solution prepared with polyvinylpyrrolidone and then while the solution is being stirred at a given stirring speed, injected at the given injection rate using a gauge. given in a given container Precipitation was carried out. After precipitation, a given amount of silica was added to further stabilize the dispersion. added. On each side, the average diameter is approximately 1.0 μm and is substantially uniform. It was.

[Example IIa) Yosibamide ethyl 10ml 20ml 40ml Ester (60mg/ml ) Ethanol (99%) 12.5ml 25ml 50ml Polyvinylpyrrolid 25ml 50ml 100ml 10.9% silane 15ml 30ml 60ml Stirring speed 125rpm 190rpm 300rpm Temperature 4℃ 　4℃　4℃ Injection speed 11m1/min 19m1/min 30m1/min Injection needle size 19g 19g 19g5. B. Length 1.5" 1.5" Container diameter 2. 38” 2.38” 2.38” container 250 ml 250 ml 250 ml polypro polypro polypro [Example rib] Yosibamide ethyl 70ml 100ml 200ml Ester (60mg/ ml) Ethanol (99%) 87.5ml 125ml 250ml Polyvinyl pylori Don 175m1 250m1 500m1O,9O6 Shira:/105m1 150ml 300ml Stirring speed 330rpm 20Orpm 300rpm Temperature --- Injection speed 45m1/min 60m1/min 85m1/min Injection needle size 19g 18g 18g5. B. Length 1.88" 2.75" 2.75" Container diameter 3.38" 5.0" 5.0" container 250 m2 250 ml 250 ml glass glass glass 0 example 1 (b) Material 20gm 40gm Yoyosibamide ethyl 00rtJ1 800ml ester (60mg/ml ) Ethanol (99%) 5001+11 10001111 polyvinylpyrrolid ]0000m1 2000m10.9% silane 600m1 1200m1 Stirring speed 175rl)m 210rpm Temperature -- Injection speed 120 m 17 min 175 ml/l Minute needle size 16 g 16 g 5. B. Length 3.25" 3.25" Container diameter 8.6" 8.6" Container 9L 9L Belco (Bet Belco (Bet) Ico) Container 1co) Container (Example 29) (Preparation of yosibamide ethyl ester particles for administration to patients) Size approximately 1μ Particles of iosibamide ethyl ester (IDE) of m are prepared for administration to a patient. Ru. IDE is a radiolucent, water-resistant material used clinically for gallbladder radiation testing. It is a water-insoluble ethyl ester of the soluble compound Yosibamide. Yosibamide ethyl Synthesis of esters is known in the art (e.g., with alcohols or acids). esterification or esterification by Schotten-Baumann reaction).

IDE dissolves only in a very small amount in water (10-5M), dimethyl sulfoxide (D MSO)/ethanol solvent mixture.

However, simply adding water to this solution produces IDE particles with extremely rough external shapes. The size of these offspring varies from 1 μm to over 300 μm in diameter. be. Rough contours can damage the endothelial cells of blood vessels and promote aggregation, and large particles can cause damage to the lungs. In view of the fact that particles can embolize, the present invention aims to control particle size and shape. Provide a more accurate way to troll.

Particle precipitation process - Physical methods to alter and control particle size, such as ball milling, grinding or Sonic disintegration produces formulations with a very wide range of particle diameters. These methods remove lung hair Generally used to remove large particles (larger than 4-5 μm) that can embolize small blood vessels. Generally, some submicron sized particles are also produced. these very Small particles have been found to be more nurturing than particles of 1-2 μm.

This probably results from the greater surface area inherent in smaller diameter particles. by increased protein binding or perhaps by excessive uptake by bone marrow cells. It would be something like that.

Chemical precipitation methods to produce particles of a given size avoid these problems. A law was developed. An aqueous solution of polyvinylpyrrolidone is added at a controlled rate and IDE dissolved in dimethyl sulfoxide/ethanol solvent at By this method, clearly spherical, amorphous particles can be produced with a very narrow size distribution. Can be manufactured. When preparing particles with an average diameter of 1 μm, use a microscopic examination method. For example, the entire range of particle diameters is between 0.4 and 2.0 μm, with 90% of the particles being 0.5 μm. within the range of

By carefully controlling the precipitation parameters, various diameters of However, particle formulations with a narrow diameter range can be produced as well.

IDE particles produced using this method are stable in whole blood and are clearly free from aggregation. There was almost no trend. When suspended in whole blood, 1 μm IDE particles clot by themselves. Essentially, it does not aggregate or aggregate with any solid components of blood. This IDE The particles have a smooth outer shape.

(Example 30) (Preparation of uniformly sized particles from inorganic compounds) Aluminum chloride hexahydrate (A ICh, 6H20), add 1 g of this compound to 10 ml of 99% ethanol. Prepared by: Substantially all of the AlCl3.614.0 was dissolved in this mixture. Heat to about 50'C until melted. The solution is then cooled to room temperature. followed by 2 2.5ml (7) AICIz in a 5ml beaker, 61 (5ml to 20/solution) of acetone and heat to 4°C.

Stir the solution rapidly using a magnetic stirrer.

Next, 0.5% polyvinylpyrrolidone (PVP) was added at a rate of 114 ml/min at pH 5. ) aqueous solution is injected into this solution. Immediately after injection, AlCl3゜6)120 particles? The solution becomes cloudy as it forms. When examined with a B microscope (400x), it is small. The existence of small particles and monodispersed particles becomes clear. This suspension was then heated to 1100 Centrifuge for 15 minutes in OORP and transform the pellet into 0.1% PVP 10.9% Na. Resuspend in C1 aqueous solution. Laser light scattering analysis of this suspension reveals that the average particle diameter is It becomes clear that it is 285 nm.

(Example 31) (Preparation of uniformly sized particles in non-aqueous media) mitindo This parenteral drug has a water solubility of 70 ug/ml at room temperature. . This substance is generally considered water-insoluble, or we can precipitate it and dissolve it in water. When washing with Anhydrous ethanol of micindomide The solubility in the solution is 4 ug/ml at room temperature. The solubility difference between water and ethanol is Although small, it is significant with respect to large-scale manufacturing yields. Therefore, micindomide We developed a method to prepare particles in ethanol. Prepare the final suspension in aqueous medium. Ru. However, most preparations use non-aqueous solvents.

A 30 mg/ml mitindomide solution in DMSO was prepared and 0.2 μm immediately before use. Filter through a nylon filter. 1% (W/V) in 99% ethanol Prepare a polyvinylpyrrolidone (PVP) solution and apply a 0.2 μm film immediately before use. filter through a filter. 1% PVP/ethanol solution at a rate of 6 L/min. Mixing the Ndomide/DMSO solution at a rate of 250 ml/min at a temperature of 0 °C. Michindomide particles were prepared by After 90 minutes of recirculation at this temperature, the It was determined by laser light dispersion analysis that the particle diameter was approximately 4001 m.

At this stage, you can transfer the suspension to a 500ml bottle and store it for further processing. , you may proceed directly to the steps below.

Before use, this suspension must be washed free of DMSO. This is centrifugal This may be achieved by separation, filtration or any other method known to those skilled in the art. wash The liquid may be water. However, to maximize yield, 99% ethanol It is preferable to wash it with a towel.

After washing, the particles may be resuspended in ethanol and stored at -20°C.

When preparing this suspension in its final form, it is centrifuged to separate Mitintomide particles are suspended in a PVP aqueous solution. The suspension vehicle contains buffering agents, It may contain preservatives or other excipients that may be considered necessary. Then, get The resulting "concentrated" suspension is lyophilized to remove the ethanol and most of the water. this Freeze-dried products are reconstituted into liquid form by adding sterilized water just before use.

The above examples are not meant to be exclusive. Many other variations of this invention will be apparent to those skilled in the art. and is intended to be within the scope of the following claims.

□ - Sori 1F Honcho Injection rate (mI/m1n) Particle size as a function of temperature FIG, 4° Submission of translation of written amendment (Article 184-8 of the Patent Law) February 22, 1993

Claims (17)

[Claims] 1. Uniform size of a solid compound with a solubility in water of about 1/10,000 to about 1/100 A method of making particles of a solid compound comprising: (a) a suitable particle of the solid compound; preparing a solution by dissolving this compound in a suitable solvent; (b) At a temperature between about -50°C and about 100°C, the injection rate was adjusted to a unit volume of 50 ml of solution. from about 0.01 ml/min to about 3000 ml/min. Injecting an aqueous precipitation solution, but with uniform particles selected from a particle size range up to about 10 μm. a precipitated amorphous, non-crystalline solid in the form of substantially unagglomerated particles of uniform size This solid compound has essentially little solubility in the precipitating liquid, so as to produce a and this solvent is compatible with this precipitation solution, and particle size is positively correlated to solution temperature during precipitation. and (c) separating said particles from said solvent and applying a suitable cleaning with a substantially non-aqueous cleaning solution, provided that said particles are essentially non-aqueous in said cleaning solution; Hardly soluble. 2. 2. Adding additional sedimentation liquid to the suspension before separating the particles. Method. 3. Claim 1: The particles are separated by centrifugation, membrane filtration, or reverse osmosis. the method of. 4. 2. The method of claim 1, wherein said washing liquid is the same as said precipitation liquid. 5. 2. The method of claim 1, wherein said cleaning liquid is a surfactant solution. 6. The solution is prepared such that the concentration of the solid compound is close to the solubility limit in the solvent. The method of claim 1 for producing. 7. The solvent may be dimethyl sulfoxide, dimethylformamide, N,N'-dimethyl tylacetamide, phenol, isopropanol, ethanol and tetrahydride The method of claim 1, wherein the organic solvent is selected from the group consisting of Lofuran. 8. The solid compound is mitindomide, and the solid compound is mitindomide. The medium is DMSO and the precipitate is 1% (w/v) in 99% ethanol. The method of claim 1, wherein the polyvinylpyrrolidone is polyvinylpyrrolidone. 9. 2. The method of claim 1, wherein said precipitation liquid is injected into said solution stream. 10. Before step (b), the zeta potential of the solid compound is measured and this zeta potential Select a surfactant using 2. The method of claim 1, further comprising determining the amount of the agent. 11. The particles are placed in a suspension that is pharmaceutically acceptable for injection into a patient. The method of claim 1 of resuspending. 12. of uniform size of solid compounds with organic solubility from about less than 1 in 10,000 A method of making particles comprising: (a) dissolving the solid compound in an aqueous solution; preparing a solution by dissolving the compound in a medium; (b) Temperature uniformity between 50 °C and approximately 100 °C, injection rate per unit volume of solution 50 ml from about 0.01 ml/min to about 3000 ml/min. Injecting an aqueous precipitation solution, but with uniform particles selected from a particle size range up to about 10 μm. a precipitated amorphous, non-crystalline solid in the form of substantially unagglomerated particles of uniform size This solid compound has essentially little solubility in the precipitating liquid, so as to produce a and this solvent is compatible with this precipitation solution, and particle size is positively correlated to solution temperature during precipitation. and (c) separating said particles from said solvent and substantially cleaning with a non-aqueous cleaning solution, provided that the particles are essentially virtually soluble in the cleaning solution. It's not decomposable. 13. 13. The method of claim 12, wherein said precipitation solution comprises a surfactant solution. 14. A method of producing uniformly sized particles of solid inorganic compounds, comprising: Items: (a) Prepare a solution by dissolving this compound in a solvent that is compatible with water. thing; (b) At a temperature between about -50°C and about 100°C, the injection rate was adjusted to a unit volume of 50 ml of solution. Add an aqueous precipitate to this solution from about 0.01 ml/min to about 3000 ml/min per minute. Injecting a liquid, provided that the particle size is uniform, selected from a particle size range of up to approximately 10 μm. produces a precipitated amorphous, non-crystalline solid compound in the form of substantially unagglomerated particles of As expected, this solid compound has essentially little solubility in the precipitation solution and The medium is compatible with this precipitation solution, and the particle size is positively related to the solution temperature during precipitation and the injection rate. negatively correlated with; and (c) separating said particles from said solvent and washing said particles with an aqueous cleaning solution; The particles are essentially poorly soluble in the washing liquid. 15. 15. The method of claim 14, wherein said precipitation solution comprises a surfactant solution. 16. The precipitate contains 5% polyvinylpyrrolidone in water and 0.1% polyvinylpyrrolidone in water. Nilpyrrolidone, 0.1% human serum albumin in water, propylene glycol started average molecular weight formed by the addition of propylene oxide to the two hydroxyl groups of the agent 0.1% of 8350 poly(oxyethylene-cooxypropylene) polymer , 0.33% gelatin in water, 0.33% gelatin in water and 0.6% Hetus hetastarch, 0.33% gelatin and 0.02% in water Propylene glycol and 0.33% gelatin and 2% sucrose in water 15. The method of claim 14, wherein the surfactant solution is selected from the group consisting of: 17. The solid compound is aluminum chloride hexahydrate, and the solvent is ethanol. and the precipitating liquid is a 0.5% polyvinylpyrrolidone aqueous solution. The method in Box 16.