TW201016220A - Micronization form of 7α-[9-(4,4,5,5,5-pentafluoropentylsufinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol and process for the preparation thereof - Google Patents

Abstract

The present invention relates to a micronization form of 7 α -[9-(4, 4, 5, 5, 5-pentafluoropentylsufinyl)nonyl]estra-1, 3, 5(10)-triene-3, 17 β -diol (also known as fulvestrant) and process for the preparation of fulvestrant utilizing a supercritical anti-solvent precipitation process. The invention also provides a pharmaceutical composition comprising the micronization form of fulvestrant and the use of the micronization form of fulvestrant for treating a hormone dependent benign or malignant disease of the breast or reproductive tract.

Description

201016220 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl) fluorenyl] estrone _1 , micronized form of 3,5(10)-triene_3,1邛-diol and preparation method thereof. In particular, the present invention relates to the micronization of 7〇1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl) fluorenyl] females by continuous supercritical antisolvent deposition. Indole-1,3,5(10)-triene-3,173-diol. [Prior Art] Deprivation of estrogen is the basis for the treatment of many benign or malignant breast and genital diseases. Many breast cancer cells have estrogen receptors, and the growth of such tumors can be stimulated by estrogen. The current method commonly used to reduce estrogen is to use the antiestrogens agent β EP 〇 138 5〇4 to reveal some steroid derivatives as potent antiestrogenic agents. Ep 〇13 8 5 04 Example 3 5 Specific disclosure of compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)indolyl]Essence _1'3'5 (1 〇)-diene_3170_diol. 7(]1_[9_(4,4,5,5,5-pentafluoropentylsulfenyl fluorenyl) fluorenyl] female _1,3,5(10)triene·3,ΐ7β-diol Also known as fulvestrant - (fulvestrant) 'has the following chemical structure:

Gasulite is an estrogen receptor antagonist with comparable affinity to estradiol, and competes with estradiol for binding to estrogen receptors, 133051.doc 201016220 indirectly inhibits the division of cancer cells Estrogen receptors that can destroy breast cancer cells, therapeutic drugs (see Kansra recept〇r antagonists on and growth), so they have been medically used as differential effects of estrogen pituitary lactotroph proliferation and prolactin release, M〇/. C , / /. Heart Office (7) · (10) / ·, 2005, 239: 27 · 36). Fulvestrant is known to be useful in the treatment of hormonal-dependent benign or malignant breast or genital diseases. This is used in applications where other hormonal therapies are ineffective.

Patients with cancer recurrence and metastasis can delay the duration of chemotherapy, but they are currently very expensive. Like other steroids, fulvestrant has some physical properties that make it difficult to make a pharmaceutical formulation. Group I (4) is a lipophilic molecule that is particularly low in water solubility compared to other steroids, only about 1 ng ng/mL (see US 6,774,122 Β 2). Although there is a commercialized fulvestrant formula, the bioavailability rate (bi〇availabimy), dosage and drug release controllability of fulvestrant need to be improved, & One of the means to achieve this. At the same temperature and pressure, the material will have three-phase changes of solid, liquid and gas. When the temperature and pressure of the substance exceed the critical temperature and the critical pressure, the fluid phase is called supercritical fluid. The physical properties of a supercritical fluid are between gas and liquid. Its density is close to that of liquid. The diffusion coefficient is between gas and liquid. Its viscosity and compressibility are close to that of gas. Table i is a commonly used supercritical fluid. In the application of supercritical fluids, carbon dioxide is most commonly used. 'The main advantage is that carbon dioxide can reach supercritical state under milder (4) (1>31.rc, Pe = 7.4 hall) and has the advantages of non-combustible 133051.doc 201016220, non-toxic and low price. Table 1 Critical temperature of commonly used supercritical fluid liquids 艽) Critical pressure Pc (MPa) Dipole moment μ (Debye) C〇2 31.0 7.4 0 N20 36.6 7.2 0.2 c3H8 96.8 4.2 0 c5h10 196.6 3.3 0 C2H4 9.4 5.0 0 nh3 132.4 11.2 1.5 h2o 374.1 22.1 1.8 C2H50H 243.1 6.4 1.7 CH30H 239.4 7.8 1.7 chf3 26.0 4.7 1.6 CHC1F2 96.2 4.8 1.3 References: Subraj P. and Jestin, P., Powders elaboration in supercritical media: comparison with conventional routes, (1999) Powder Technol 103: 2-9.

The application of supercritical fluid technology is very extensive. For example, supercritical fluids can be applied to Supercritical Fluid Extraction (SFE) to extract specific components from substances, such as Mendiola et al. Extracting vitamin E from spiral households/aiews/i·) "Enrichment of vitamin E from Spirulina platensis microalga by SFE," J. Supercrit. Fluids, 2008, 43: 484-489); G0mez-Prieto et al. Extracting β-carotene from Mentha Spicata L. And lutein (see Application of Chrastil's model to the extraction in SC-CO2 of β-carotene and lutein in Mentha spicaia L., " J··Swinccn'i. 2007, 43: 32-36). Or apply supercritical fluids to supercritical fluid reactions (Supercritical Fluid 133051.doc 201016220

Reaction, SFR), the use of supercritical fluids in place of general organic solvents during the reaction, or as a medium to reduce mass transfer limitations. For example, Prajapati and Gohain use supercritical reactions for the synthesis of organic molecules (refer to "Recent advances in the application of supercritical fluids for carbon-carbon bond formation in organic synthesis, " 2004, 60: 815-83 3). Or supercritical fluids (Supercritical Fluid Chromatography (SFC)), supercritical fluids are used to replace the liquid mobile phase in general chromatographic operations for chromatographic separation of mixtures, such as Pettinello et al. Fluid Chromatography Separates Ethyl Eicosapentaenoate (EPA-EE) from Silicone (refer to "Production of EPA enriched mixtures by supercritical fluid chromatography: from the laboratory scale to the pilot plant," J· iSwpercrz 'i. 2000, 19:51-60). Or apply supercritical fluids to emerging supercritical fluid material technologies that have been popular in the past decade. For example, Alavia et al. use supercritical fluids to make foamed materials (see "Process dynamics of starch-based microcellular foams produced by supercritical fluid". I. Model development,” Foot/2003, 36:309-3 19 and "Process dynamics of starch-based microcellular foams produced by supercritical fluid extrusion. II. Numerical simulation and experimental evaluation," Food Res. Inter, , 2003, 36:321-330); Fricke and Tillotson use a supercritical fluid to make aerogels (see 'Aerogels: production, characterization, and applications," Thin Solid Films, \99Ί, 29Ί'2\2- 2ΐν)专. 133051.doc 201016220 The supercritical fluid preparation microparticle technology that has received considerable attention in recent years is in the process of particle formation, using the aid of supercritical fluid to generate particles, small and distributed micro- or nano Grade material particles. How to improve the availability of raw materials and reduce medication in the development of medical music Dose-modifying drug routes and improving the controllability of drug release are the research directions in this field. In order to improve the solubility and dissolution rate of the drug, micronization can be carried out to increase the surface area, and then increase the surface area. Increasing the rate of dissolution, oral drugs are more rapidly dissolved and absorbed in the stomach. Traditionally, the most common physical method for preparing drug particles is to use a mechanical method, which is to pass the particles of the particles to the physical side such as grinding, grinding, and ball milling. However, during the grinding process, the grinding machine may cause contamination of the drug due to abrasion and peeling, and the mechanical force pulverizes the drug particles (4), and may also destroy the original crystal face and crystal form of the drug itself, thereby affecting the drug efficacy or : The physical and chemical stability of the substance. $ The traditional chemical method for preparing drug particles is to reduce the solubility in the drug solute by evaporation, enthalpy, cold ginseng, or by adding a component to the solution. The drug solute is deposited by supersaturation to form a crystalline or probiotic powder. However, the drug prepared by these methods is obtained. Particles, to particles with a narrow particle size distribution, may also have problems with solvent residues and are prone to different crystal forms. Therefore, there is still an urgent need to find a drug particle preparation technique which can effectively control the particle size, distribution and crystallization properties, and can stabilize the properties of the drug. By using supercritical fluid technology for micronization, the size and distribution of particles can be effectively controlled by changing operating conditions. Taking carbon dioxide as the super 133051.doc • 10-201016220 boundary fluid as an example, it can be operated at room temperature and is non-toxic, has little impact on the environment, and can obtain dry, solvent-free particles at the same time in operation, exempting Complex post-processing. Based on the above advantages, the application of supercritical fluid technology in the manufacture of microparticles or nanopowders has become a very popular research topic in recent years. - Supercritical fluid powder manufacturing technology, according to the role of supercritical fluids, can be divided into four categories, respectively, Rapid Expansion of Supercritical Solution (RESS), gas saturated solution ❹ · deposition method (Particle from Gas Saturated Solution, PGSS), Supercritical Anti-Solvent (SAS) and Supercritical Assisted Atomization (SAA). Supercritical solution rapid expansion is the earliest supercritical powder manufacturing technology. In this method, supercritical fluid plays the role of solvent (see Kayrak et al. "Micronization of ibuprofen by RESS," J. Supercrit. Fluids, 2003, 26·.17-31) β The advantage of this method is that no organic solvent is used, so the environmental pollution problem caused by the use of the organic solvent can be reduced. The disadvantage is that the method is limited to the solubility of the solute in the supercritical fluid. If the solubility of the solute in the supercritical fluid is too low, the method cannot be used to make particles. In gas saturated solution deposition operations, supercritical fluids act as solutes (see Kerc et al. "Micronization of drugs using supercritical carbon dioxide, " 1999, 182: 33-39). The disadvantage of this method is that the supercritical fluid dissolves in the material to be micronized and reaches equilibrium, which takes a long time. The supercritical fluid-assisted atomization method was developed in recent years and is developed by 133051.doc -11- 201016220

Based on the PGSS method, Reverchon proposed a new supercritical fluid particle preparation technology (please refer to "Supercritical antisolvent precipitation of micro- and nano-particles," J. Supercrit. Fluids, 1999, 15:1-21 ). In this method, the supercritical fluid acts as an atomizing medium (Atomizing. Medium). In this operation, whether a uniform phase can be formed between the supercritical fluid, the solute to be treated, and the organic solvent is critical. In supercritical antisolvent operation, the supercritical fluid acts as an anti-solvent. According to different operation modes, it can be subdivided into Gas _ Anti-Solvent (GAS), Aerosol Solvent Extraction System (ASES), Supercritical Anti-Solvent (SAS). And the Solution Enhanced Dispersion by Supercritical Fluids > SEDS, etc. Up to now, the supercritical antisolvent method has two operations, which are classified according to the solution feeding method, and are respectively batch operation and Continuous operation. Zhang Yunju (please refer to "Study on Microparticles of Drugs by Supercritical Antisolvent Deposition Method", Master's Thesis, Institute of Chemical Engineering, National Taiwan University, 2005) Index * Execution using continuous supercritical antisolvent method The operation can result in smaller drug particles because the batch operation is accomplished by adding an anti-solvent to the quiescent solution to supersaturate the solute during the pressurization process. Under this circumstance, the anti-solvent and the solution have a high mass transfer resistance, and the disturbance caused by the supercritical anti-solvent rushing into the solution is not enough to achieve uniform mixing, and only a small part of the precipitation tank is supersaturated. The number of crystal nuclei is insufficient, and most of the solute adheres to the crystal nucleus to grow the crystal, so that fine particles cannot be obtained. In addition, during the boosting process, the supersaturation of the solute continues to change, meaning that the nucleation rate and growth are 133051.doc -12- 201016220 The rate changes with pressure, so particles with a narrow particle size distribution cannot be obtained. In continuous operation, a small amount of solution is sprayed into a large amount of continuous flow of anti-solvent medium by a capillary tube. The mixing of the solution and the anti-solvent is easier than batch operation, and the pressure of the solution at the outlet of the capillary is the pressure of the precipitation tank. After the anti-solvent contact, it is highly supersaturated to produce a large number of crystal nuclei, and only a small part of the solute causes the crystal to grow, so that the drug particles having a smaller particle size distribution can be obtained than the batch operation. As can be seen from the above description, the continuous supercritical antisolvent method can obtain smaller drug particles than the batch type supercritical antisolvent method. The present invention uses a continuous supercritical antisolvent deposition method to micronize fulvestrant to increase its dissolution rate. The method of the present invention does not destroy the original crystalline properties of fulvestrant under prolonged operation. Therefore, the method of the present invention can be used for mass production of micronized fulvestrant drug particles. SUMMARY OF THE INVENTION The object of the present invention is to provide a method for preparing a fluorofibrin group in a micronized form, characterized in that the method for micronizing gas by supercritical antisolvent deposition comprises the following method in the present invention. A preferred embodiment of the steps of: (4) (b) an agent; and providing a supercritical fluid antisolvent deposition system; formulating a drug solution comprising fulvestrant and at least one organic solution (c) system to feed the drug solution The supercritical fluid antisolvent of step (4) is fed to obtain micronized fulvestrant drug particles. Shen 133051.doc 201016220 In another preferred embodiment of the invention, the operating pressure of the supercritical antisolvent deposition method is controlled to be from about 1 Torr to 140 bar, preferably about 1 Torr bar. In another preferred embodiment of the present invention, the operating temperature of the 'supercritical antisolvent deposition method is controlled to be about 3 to 6 ° C, preferably about 35 to 55 ° C, more preferably about 35 ° C. . In another preferred embodiment of the invention, the anti-solvent used in the supercritical antisolvent deposition system is carbon dioxide. In another preferred embodiment of the present invention, the organic solvent used in the supercritical antisolvent deposition method is an ester, and most preferably ethyl acetate. In another preferred embodiment of the present invention, the drug solution flow rate of the supercritical antisolvent deposition method is about MU mL / min, preferably about U (4) minutes 0, in a further preferred embodiment of the present invention. The drug cold solution concentration of the supercritical antisolvent deposition method is about 11 mg/mL, preferably about 5. Another object of the present invention is to provide a dendritic group in a micronized form which is obtained by the supercritical antisolvent deposition method of the present invention. In the preferred embodiment of the present invention, the micronized form has a particle size of about 1 to 6 μm, preferably about (1) (d). In another preferred embodiment of the invention, the micronized form of fulvestrant has a crystal morphology of an irregular or rod-like structure. In the further preferred embodiment of the present invention, the dissolution rate of the micronized group is about 1.2 times that of the non-micronized '·,5.乍J group is - 'better than the other object of the invention, the rabbit is said to provide - for the treatment of hormone-dependent good I33051.doc -14- 201016220 sexual or malignant breast or reproductive tract disease A pharmaceutical composition comprising a fulvestrant of the micronized form of the invention. Another object of the present invention is to provide a granulide group of the micronized form of the present invention for use in the preparation of a medicament for the treatment of a hormonal-dependent benign or malignant breast or a disease of the skin. It is still another object of the present invention to provide a method of treating a hormone-dependent benign or malignant breast or genital tract disease comprising administering to a subject in need thereof a fulvestrant of the micronized form of the present invention. The invention is described in detail in the following sections. Other features, objects, and advantages of the invention are apparent from the embodiments of the invention and the appended claims. [Embodiment] The science and technology used in connection with the present invention, unless otherwise defined herein, should have the meaning commonly understood by those of ordinary skill in the art. The meaning and scope of such terms should be clear, but if there is any potential ambiguity, the definitions provided herein take precedence over any dictionary or foreign definition. Unless otherwise stated, the following terms as used herein shall be understood to have the term "supercritical antisolvent deposition method" as used herein, meaning that the solute is dissolved in a solvent and the solute is further treated with a supercritical fluid as an antisolvent. The method of crystallizing the temple. The term "dissolution rate" as used herein is defined as the reciprocal of the time required for Loth and Hemgesbefg (1986) to start the dissolution of the drug in simulated gastric juice by 63.2% from the Weibull model. Dissolution rate coefficient (dissolve rate coefficient > indicates. 133051.doc -15- 201016220 The term "hormone-dependent benign or philosophical breast or genital tract disease" as used herein refers to the use of an anti-estrogen agent (eg An estrogen-like remedy for the treatment of a disease, such as breast cancer. ° The term "treatment" as used herein means reversal, sedation, prevention of disease symptoms or inhibition of disease progression. An individual"is an animal, especially a mammal. In a preferred aspect, the term "individual" means "human". As used herein, the term "therapeutically effective amount" means either alone or in combination with The amount of the therapeutic agent used to treat the same condition can be used to demonstrate the therapeutic effect, depending on the individual in need of treatment, the severity of the disease, the rate of administration, and The judgment of the division determines that, in general, the therapeutically effective amount of fulvestrant is at least 2.5 ng/mL, preferably at least 3 ng/mL, more preferably at least 8.5 ng/mL, most preferably in the individual plasma. Preferably, it is at least 12 ng/mL and does not exceed 15 ng/mL. The term "carrier" or "pharmaceutically acceptable carrier" means a diluent, excipient or the like which is manufactured The singular term should include the plural and the plural term should include the singular unless the context requires otherwise. The operating principle of the supercritical antisolvent method of the present invention is similar to that of the prior art in the art. In order to dissolve the micronized solute in the solvent, the supercritical fluid must be soluble in the solvent, and the solute must be insoluble in the supercritical fluid. When the solution is in contact with the anti-solvent (supercritical fluid), the volume expansion of the solution is caused. Decreasing the density of the solution phase, so that the solvent's ability to dissolve is reduced, and the equilibrium solubility of the solute in the liquid phase is reduced. 'The solute is precipitated by supersaturation. After the particles are formed, at the high pressure. Under the circumstances, 'continuously enter the supercritical anti-solvent to remove organic solvents, avoid residual and pollution of organic solvents, and obtain solvent-free residual solute particles. Figure 1 is a schematic diagram of the operation of the supercritical anti-solvent method. The principle of operation is similar to that of general crystallization and can be illustrated by Figure 2 (see Mtiller et al. "Experimental study of the effect of process parameters in the recrystallization of an organic compound using compressed carbon dioxide as antisolvent, " ❹ CTzew. 2000, 39:2260-226). The stable solution in the figure refers to an unsaturated region, a meta-stable zone is a supersaturated region and does not reach a supersaturated region, and a nucleation region is a supersaturated region. Solutes have spontaneous crystal nucleation and crystal growth in the nucleation region; in the sub-stable region, because the solute is in a homogeneous phase environment, the nucleation rate is extremely slow, most solute undergoes crystal growth; and crystal nucleation and Growth will not occur in stable areas. At the beginning, the solute concentration is lower than the saturation concentration, that is, the α point of the Tushen; when the supercritical fluid is in contact with the solution, the volume expansion of the solution is generated, and the supersaturated region is reached, that is, the defect point in the figure, after reaching the β point, there is Two different effects, one is the effect of antisolvent mass transfer', that is, the solution volume expansion rate (v〇lume expansion) caused by the antisolvent mass transfer to the solution, and the other effect is the crystal nucleation and growth effect. The competitive effect produces three possible ways to reach the end point ω. When the mass transfer rate of the anti-solvent is greater than the crystal nucleation and growth rate, it will increase the supersaturation of the solution, that is, the path in the figure, the system will rapidly produce volume expansion, reaching a very large supersaturation in a short period of time. At this time, 133051.doc 17- 201016220 crystal nucleation and growth effect began. Due to the effect of anti-solvent mass transfer, the system takes a long time in the nucleation zone. Because a large number of crystal nuclei are generated, the solubility of the solute in the solvent decreases rapidly. After reaching the sub-stable zone, the crystal no longer nucleates, but only grows and decreases. The solubility declines and finally arrives at • End of Experiment®. The path is simple to stay in the area where the nucleus grows, so the number of particles produced is large, the particle size is small, and the distribution is uniform. Conversely, if the mass transfer rate of the reverse solvent is less than the crystal nucleation and growth rate, then the path of (4) 2 is indicated by c. The system will still reach supersaturation before it begins to produce crystal nucleation and enthalpy I'. However, due to the slow rate of the anti-solvent mass transfer, the crystal nucleation and growth begin to function. The system cannot provide sufficient supersaturation for the crystal. Nuclear and growth, the number of crystal nuclei produced is small, and the growth of the nucleus at a faster rate 'gradually consumes the solute until reaching the end point of the experiment ω. Since the c-path is not much nucleus and mainly dominates crystal growth, the particles produced are large particles and quantitative particles; I: the knives are also relatively uneven. If the mass transfer rate of the anti-solvent is equivalent to the crystal nucleation and growth rate, that is, the path B in Fig. 2, the resulting knot money will be between the media diameter A#c, and the medium particle is obtained, and the particle size distribution is presented. Double bee phenomenon. It can be seen from Fig. 2 that if a better micronization effect is desired, the system reverse rate and mass transfer rate are important indicators. When the mass transfer rate of the antisolvent is greater than the crystal nucleation and growth rate, the particle size can be obtained. More uniform distribution of particles. The factors affecting the supercritical anti-solvent method are: anti-solvent flow rate, solvent selection, operating waste force, operating temperature, solution concentration and solution flow rate, etc., in addition to the operation mode, 1^ nozzle structure 'volume expansion degree and solvent density, etc. , will affect the supercritical anti-solvent program, familiar with one of the technical fields of the invention 133051.doc -18· 201016220 people can adjust the above factors to control the particle size and particle size and distribution according to the known technical means. For the solvent effect, it is necessary to find out the proper affinity of the drug for the presence of strong crystallization, which may result in a combination of the precursor and solvent in the continuous supercritical antisolvent operation. Different solvents have the same solute to the drug, so the drug solute has different crystal forms and particle sizes in different solvent environments. Pressure and temperature effects

The pressure and temperature effects have a regular behavior for particle size and branching, and there is currently no definitive answer. Generally speaking, some scholars believe that it is easy to form smaller particles by increasing the force; some scholars believe that the willingness has a significant influence on the particle size'; however, some scholars believe that the operating pressure increases and the particle size will become larger. This is because when the force is increased, it will facilitate the diffusion of the anti-solvent to the solvent, so that the volume of the solution will be expanded, and the rate of nucleation will be accelerated, so that particles having a small particle size and uniform distribution are easily obtained; When the pressure is increased, the density of the system will increase. At this time, the diffusion of the anti-solvent to the solvent will be slowed down, and particles having a larger particle size and a less uniform distribution are easily obtained. It can be seen that the pressure effect is a competitive effect. The same is true for temperature effects on particle size and distribution. In general, some scholars believe that 'reducing temperature tends to produce smaller particles. 1 Some scholars believe that temperature has no significant effect on particle size; but some scholars believe that the operating temperature is reduced and the particle size will become larger. This is because when the temperature is increased, the density of the anti-solvent is reduced, the solubility of the anti-solvent in the solvent is lowered, and the degree of volume expansion of the solution is lowered, thereby reducing the supersaturation of the system 133051.doc •19-201016220, which helps When the solute crystal grows, it is easy to obtain particles with a smaller particle size and a more uneven cloth. On the other hand, increasing the temperature increases the degree of vaporization of the solvent, and the effect of mass transfer is increased, which facilitates the mixing and mass transfer between the solution and the reverse solution. , and particles having a smaller particle size and a uniform distribution are obtained. It can be seen from this that the dish effect is a competitive effect. Due to the pressure and temperature conditions, it can be determined whether the solvent and the anti-solvent are in the range of the homogeneous phase (supercritical phase) or in the gas-liquid coexisting phase, that is, the critical point of the mixture of the mixture/reverse mixture (Mixture Critical Point). , MCP) Judgment ¥ operating point is located above the mcp of the solvent / anti-solvent mixture, is a single-phase operation, that is, the solute is nucleated and grown in the homogeneous phase; conversely, if under the MCP, it is two-phase operation. The particle size obtained during the operation in the single-phase region is relatively uniform, and larger block particles are obtained when operating in the two-phase region, and the particle size distribution is uneven. This is because the gas-liquid interface still exists during the operation of the two-phase region, increasing the mass transfer resistance of the solvent_anti-solvent, so that the solute cannot be quickly supersaturated. It can be seen that the pressure and temperature _ effect of the supercritical anti-solvent method will affect the volume expansion ratio of the solution and the vaporization effect, so the two should be considered together. Solution Concentration vs. Solution Flow Rate In general, the probability of collision between solute increases at high solution concentrations, requiring only a low volume expansion to achieve the desired degree of supersaturation. However, at most high concentrations, the nucleation rate of the nucleus is greater than the nucleation rate, so the solution concentration effect is a competitive effect. Under the condition of low solution flow rate, when the solution is mixed with the supercritical fluid, the solution precipitates the solute due to volume expansion, and the nucleation step consumes most of the solute, which is available in the subsequent crystal growth process of 133051.doc -20- 201016220 The solute used is less, and the hexahydrate is easily increased and the particle size is increased. When the concentration of the solution increases, 35 nucleation (4) is consumed (4), there is still a solute for crystal growth, and the average particle size will become larger. Therefore, 'at a low flow rate', the average particle size will decrease with the solution concentration in the high solution flow (four) τ, the relative velocity of the solution and the super fluid will be smaller, and the mixture of the solution and the supercritical fluid is not as good as the low flow rate. Therefore, the solute with higher supersaturation first nucleates, and the solute with lower supersaturation cannot be nucleated and moves toward the surface of the nucleus for crystal growth because of insufficient driving force. When the concentration of the solution is high, the solute is allowed to reach supersaturation, so the gradient of the degree of supersaturation is small, and a small particle size is easily obtained. At that time, the gradient of overrun and degree is large, and it is easy to obtain a large lower. Under the condition of high solution flow rate, the average particle size decreases with the increase of the solution concentration.

The present invention discusses the preferred parameters of micronized fulvestrant drug powder by the continuous performance supercritical antisolvent method and the fulfilmentation of fulvestrant by continuous supercritical antisolvent method by the following non-limiting examples. Analysis of the nature before and after. These examples are not to be construed as limiting the invention in any way. Modifications and variations of the embodiments discussed herein may be made without departing from the spirit and scope of the invention, and still fall within the scope of the invention. EXAMPLES Continuous Supercritical Antisolvent Deposition Apparatus The experimental apparatus used in the present invention is shown in FIG. The experimental device is mainly divided into three parts: 133051.doc •21· 201016220: (1) The first part is the high-pressure section where the precipitation of particles occurs, which is composed of steel pipes, adapters and stainless steel pipes of various sizes. a carbon dioxide transfer line and a sink tank; (b) the second part is a solution feed section for continuously delivering the drug solution through a high pressure pump to the settling tank; and (c) the third part is a solvent for separating the solvent and the antisolvent under reduced pressure. The back end line, the solvent recovery section. ❹ ❹

The carbon dioxide sent from the carbon dioxide cylinder (C〇2 cylinder, 1) is further purified by a filter with a pore size of 7 # m and an adsorption cylinder filled with molecular sieves (estimated purity is greater than 99.8 ° / ❶), after about 〇 ° C After the refrigeration cycle (cooler' 2) is completely cooled to liquid, it is pressurized with a high pressure pump (HpLC pump, 3) (maximum flow rate is 99.9 mL/min at 3000 psi) via a check valve (B2) Entering the system, the system pressure is regulated by a back pressure regulator (C). A pressure gauge is installed at the outlet end of the high pressure pump to monitor the outlet pressure of the pressure pump and install a safety rupture disc. The carbon dioxide is output from the high-pressure pump and preheated by a preheater (5). The three-way ball valve (D) above the / yogyo trough enters the sedimentation tank (precipitation, 7), and the pressure is transmitted. The pressure transducer and indicator (8) and the thermocouple temperature measuring element (thermometer, 9) are used to measure the temperature and pressure values in the sedimentation tank. The sedimentation tank consists of a high-pressure steel pipe and a adapter and a filter. The filter (stainless frit' 10) has a pore size of 0.5 μηι, which has two functions: one is used as an anti-solvent for particle formation, and the other is Supercritical drying and 133051.doc -22· 201016220 Decompression as a barrier drug particle and sampling. The system temperature is controlled by a constant temperature water bath (4). The drug solution was placed in the sample reservoir (6) and pressurized with high pressure pump (HPLC pump' 3) (maximum flow rate 9.9 mL/min at 6000 psi). Check valve (B3) The capillary nozzle is sprayed into the sedimentation tank. The hair-thin nozzle is a double-casing structure in which the inner tube is a 1/16-inch capillary (inner diameter 127 μηι) for transporting the drug solution; the outer tube is connected to the sedimentation tank for transporting carbon dioxide and drug solution to the nozzle The outlet is mixed with supercritical carbon dioxide to form drug particles, which are deposited on the filter on the bottom of the sedimentation tank or on the wall of the sedimentation tank. A micro-metering valve (E) in the back-end line can be used to regulate the flow of fluid leaving the settling tank to control the flow of supercritical carbon dioxide. The fluid leaving the settling tank is separated from the anti-solvent by condensation of the solvent in the back-end line due to a sudden drop in pressure and a sudden drop in temperature. The supercritical carbon dioxide is also depressurized into gaseous carbon dioxide and finally passed into a condenser trap (11) which is filled with five points of water and used to recover the solvent. The carbon dioxide flow rate is measured by a float meter (rotameter, i 2). The components of the experimental device, the specifications of the instrument, the description, model and manufacturer's data are described in Table 2. 133051.doc -23- 201016220 Table 2 Description of the components of the continuous supercritical anti-solvent deposition device Name Specification Model (1) Valve assembly Back pressure valve Hiccup valve Axle system pressure suspension * Shop 笳懕 six psi Tescom~~26-1762-24-014 Ensure flow direction is free of reverse flow withstand pressure 6000 psi

Swagelok S S-5 3 -series - Directions to the needle control line Bi-directional needle valve SiT Li Withstand pressure 11500 psi, 1/8

Autoclave 10V2075 (two) to help Pu Chusheng j pipe switch - 彳〗 55 ^ si ~, 丨 / 8 " - Autoclave 10Y2071 Dad volume control flow pressure 11 〇 0 ^ ^ si, Γ / F Autoclave 10VRMM2812 high pressure Pu high pressure pump solution up to 600 (^ 丨 (1〇11117 minutes) 881 Series II Pressurization 3 1 3000 psi (100 mL / min) SSI Prep 100 ❹ and ink: - Jiqin cooling fluid ' ϋ 31 L / min f Vacuum pump pair (3) measuring original

Iwaki

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Swagelok Taiwan-24 - 201016220 Continuous supercritical anti-solvent deposition method: The steps can be divided into five steps (1) Step 1: Equipment assembly, pre-cleaning and leak detection First wash and dried precipitate The tank is assembled, and then carbon dioxide is introduced to degas (PU (10) into the (four) system _ cleaning, impurities in the n system removed. After the pre-cleaning is completed, the carbon dioxide is introduced to the experiment.

Pressure, let stand for about - hour, check if there is any change in the pressure inside the system. If the system pressure does not change, it means there is no gas leakage in the system. (2) Step 2: Supercritical carbon dioxide feed operation uses a constant temperature water bath to control the system temperature. When the system temperature reaches the temperature to be tested, the oil pressure lift truck will raise the constant temperature water bath until the sediment tank body is completely Immerse yourself in the water bath. After that, the carbon dioxide in the cylinder is pumped by the local pressure pump (7). The system pressure is regulated by the back I valve (C). After the carbon dioxide is pumped by the high pressure, it passes through a preheater (5) from the sedimentation tank. The top enters, when the sedimentation tank reaches the pressure to be operated, the carbon dioxide is removed from the bottom of the sedimentation tank by the opening of the two-way needle valve 'A4', and the flow rate of carbon dioxide is carried out by the micrometering valve (E). Fine-tuning 'read by the float flow meter (12). (III) Step 3: Operation of Solution Feeding When the system temperature and pressure reach the conditions to be tested and the flow rate of the supercritical body is stable, the feed to the feed end is carried out. The residual solvent and air in the solution feed line must be removed before the drug solution is transferred to the precipitation tank. The drug solution is transferred by the high-pressure pump (3) and then adjusted by the three-way ball valve (D), so that the residual solvent in the pipeline, the air and the drug solution are discharged from the bypass. After ensuring that the feed line is filled with the drug solution, the three-way ball valve is adjusted to the feed direction, and the drug solution is sprayed into the sedimentation tank via the capillary. (4) Step 4: Supercritical Drying After all the drug solutions prepared are in the sedimentation tank, the solution is stopped. In order to obtain drug-free residual drug particles, supercritical carbon dioxide is continuously supplied, and the generated drug microparticles are supercritically dried. The residual solvent of the drug microparticles t will volatilize into the supercritical carbon dioxide fluid, which is then carried out by the supercritical carbon dioxide. The resulting drug particles are collected on a filter having a pore size of 0.5 μηη, and the supercritical drying time is between about 3 minutes and 60 minutes. (5) Step 5: After the solvent for decompression and post-cleaning is removed from the sedimentation tank by supercritical carbon dioxide, the carbon dioxide is stopped, and the system is depressurized. The pressure is reduced from the operating pressure to the atmospheric pressure. Fast, otherwise it will take about 1 hour to carry out the sedimentation tank after the pressure is released to the normal pressure. Granules, causing particle aggregation. = Unloading' and taking the drug particles out of the sedimentation tank. The sink and the pipeline are then cleaned and dried to prepare for the next operation. Fulvestrant original drug The fulvestrant original drug used in the present invention example

Analytical method of drug particles 133051.doc -26 - 201016220 Before and after treatment with fulvestrant by supercritical antisolvent deposition method, the physical properties such as grain size and particle size, crystallization characteristics, thermal effect and drug analysis were analyzed. A. Particle morphology and particle size 1. Scanning electron microscope (Scanning. .Ele+c.tran Microscopy, SEM) analysis Microscopic analysis before and after drug treatment using a scanning electron microscope. The analysis process is as follows: Take a certain amount of drug powder, stick it on the sample tray with carbon tape, and after gold plating in vacuum, take a scanning electron microscope to take the grain crystal appearance. Scanning electron microscope analysis was performed using a JSM-5600 (JEOL) electron microscope and a JSM-6700F (JOEL) electron microscope. 2. Particle Size Distribution (PSD) analysis using image analysis software ImageJ (see Abramoff et al. Image Processing with ImageJ, " Biophotonics Inter., 2004, 11:36-42) on the SEM image, More than 200 intact crystal particles were selected, and the particle size was measured by ❹. The average particle size and particle size distribution were determined by statistical methods. B. Analysis of crystallization characteristics X-ray Diffraction (XRD) analysis using a X'pert (PANalytical) X-Ray Diffractometer for continuous treatment of pharmaceutical powders by continuous supercritical antisolvent treatment Crystal quality before and after measurement. The analysis process is as follows: Take a certain amount of drug powder and fill it into the sample tank for X-ray diffraction. The X-ray diffraction angle is scanned from 5 degrees to 40 degrees, and the scanning rate is 133051.doc • 27- 201016220 is 3 degrees per minute. C. Thermal effect analysis The TA 2010 (DuPont) Differential Scanning Calorimeter (DSC) was used to carry out the supercritical anti-solvent of the drug powder. Whether the polymorphism of the drug changed before and after treatment. The differential sweep type thermal card has a scan rate of 5 ° C per minute. D. Qualitative analysis of the drug 1. Infrared spectrophotometry (IR) analysis © Qualitative analysis of the drug using a Spectrum 100 FTIR-ATR (PerkinElmer) Fourier Transform Infrared Spectrometer (FTIR). The absorption of infrared rays by drug molecules causes molecular vibration and rotational energy level migration, and the energy absorbed by them is discontinuous (quantization). Different functional groups have different vibration and rotational energy, and absorb infrared light of a specific frequency. Therefore, different absorption positions can be used to identify functional groups and their contents in drug molecules. The analysis procedure is as follows: a certain amount of drug powder is placed on a zinc-zinc (ZnSe) single crystal, and the scanning wave number ranges from 4000 to 700 cm·1, and the number of scans is 8 times, and the resolution is 4 cm. ·1. Drug Dissolution Rate Test - To investigate the effectiveness of the drug before and after continuous supercritical antisolvent operation, the drug dissolution rate test was performed. . The dissolution tester used in the dissolution rate test was Dissolution Tester DT3 (Shin Kwang Machinery), and the dissolution medium was a buffer of pH 1.2 and 6.8. The former consisted of 2.0 g of sodium carbonate and 37% by weight of concentrated hydrochloric acid. Distilled water to 1000 mL, formulated into simulated stomach 133051.doc -28 - 201016220 (Simulated Gastric Fluid) with pH value of 1.2; the latter is 6.8 g filled with acid dihydrogen and 0.2 N sodium hydroxide plus distilled water to 1000 mL It was formulated into Simulated Intestinal Fluid with a pH of 6.8. The above method was formulated according to the method described in the United States Pharmacopeia (2008). Before performing the dissolution rate test, a calibration curve must be prepared. The preparation of the calibration curve first dissolves the drug in the simulated stomach/intestinal fluid, and the absorption spectrum of the full-band scan of the UV spectrometer can be used to find the maximum absorption wavelength of the drug. The drug is then formulated into different concentrations, and at this maximum absorption wavelength, a calibration curve is produced. The dissolution rate test method used in the present invention is a paddle type, the rotation speed is set to 50 rpm, the dissolution solution is simulated gastric/intestine liquid 900 mL, and the temperature is set at 37 ± 0.5 °C. Approximately 20 mg of the original and continuous supercritical antisolvent treated drug was directly placed in the buffer of the dissolution tester. 2.5 mL was sampled at fixed time intervals, and the sample taken was transferred through a φ μηη Syringe Filter to remove the drug powder that may be taken during the sampling process. The filtered sample solution was appropriately diluted. Concentration analysis was performed using a uv spectrometer. Example 1 Operational parameters of micronization and recrystallization of fulvestrant by continuous-performance supercritical antisolvent deposition method This experiment is based on the effect of pressure and temperature parameters of fulvestrant by continuous supercritical antisolvent method. It is desirable to obtain optimal operating conditions for smaller and more uniformly distributed particles. 1. Solvents Due to the high solubility of fulvestrant in supercritical carbon dioxide, the fluorine group 133051.doc -29- 201016220 is easy to be carried away by supercritical carbon dioxide during the experimental operation, resulting in a low rate of A. The recovery rate of the sorghum group is selected as the solvent of the volatile sulphuric acid 乙», and the recovery rate is less than 3 (four). When using ethanol, lysine and DMSO as a substitute solvent, it may be due to the inability of the solvent to vaporize the micro-:: together with the drug # is taken away by carbon dioxide without collecting particles or recycling - the rate is extremely low (less than 1%) 0 2. Pressure: The experiment used ethyl acetate as the solvent, the concentration of the solution was 5 mg/mL, and the solution flow rate: under the degree of (6) job i4〇bar π test operation pressure' to test the effect of pressure effect on the micronization process. πFig. 5(4) is a continuous supercritical antisolvent operation under the conditions of a solvent of ethyl acetate, a pressure of (10) (8), a dish of 35 C, a solution concentration of 5 mg/mL, and a solution flow rate of μ cents. The fulvestrant microparticles are rod-shaped, and the particle size is expected to be 2 in 19 phases. Called) is in the operation, the conditions of the solvent is ethyl acetate, the force is 12 〇 _, temperature deduction, lysing solution; the agricultural degree is 5 mg / mL, the solution flow rate is 0.5 mL / min, continuous $ The fulvestrant microparticles operated by the supercritical antisolvent method have a crystal appearance of a rod shape and a broad size of about 3. 9 ± 2.22 (four). Figure 5 (4) is the continuous supercritical antisolvent operation under the operating conditions of the solvent is ethyl b vinegar: the force is "0-, temperature tree, solution concentration is 5mg / mL, 'l rate is 0.5 mL / min" The fulvestrant microparticles have a crystal shape with a rod shape and a particle size of about ] Μ Μ T Fig. 6 is the particle size and distribution result of the micronized fulvestrant, and the condition τ at the solid temperature is 3 generations. The particle size will increase with the increase of pressure. Figure 7 (4) is the solvent in the operating conditions is ethyl acetate, dust force is _ (6), 133051.doc • 30- 201016220 temperature is 55t, solution concentration is 5 mg / mL, solution flow The fulvestrant microparticles subjected to continuous supercritical antisolvent operation at a rate of mL5 mL/min: the crystal morphology is irregular, and the particle size is about 12 Μ±6 58 . Figure 7^) The operating condition solvent is ethyl acetate, the pressure is 12〇bar, the temperature is “C, the solution concentration is 5 mg/mL, the solution flow rate is 〇·5 mL/min, and the continuous supercritical antisolvent method is operated. The fulvestrant microparticles have an irregular crystal morphology with a particle size of about 2.62 ± 2.16 μη ΐ β. Figure 7 (4) is a solvent in the operating conditions. Ethyl acetate, a pressure of 140 bar, a temperature of 55 r, a solution concentration of 5 mg/mL, a solution flow rate of 〇·5 mL/min τ, and a continuous supercritical antisolvent operation of fulvestrant microparticles The crystal appearance is irregular, and the size of the grain control is about 5·〇5±2.26 μιη. Figure 8 shows the particle size and distribution of the micronized fulvestrant at a fixed temperature of 55. Under the condition of 〇, when the pressure is 120 bar, the particles with smaller average particle size distribution and the average particle size of about 2.65 μηι can be obtained. When the pressure is 14 〇bar, the average particle size can be obtained. A particle of about 5.05 μηι; when the pressure is 1 〇〇 bar, the ruthenium has a larger particle size distribution, and the average particle size is about 12.14 μηι. 3. Temperature The experiment was carried out with ethyl acetate as solvent, solution concentration of 5 mg/mL, solution flow rate of 0.5 mL/min and fixed pressure, with 35 ° lt;) and 55 匸 as experimental operating temperature. The effect of the effect on the micronization process. The operating conditions were ethyl acetate, the pressure was 丨〇〇bar, the solution concentration was 5 mg/mL, the solution flow rate was mL5 mL/min, and the temperature was 55t. Under the conditions of micronization, the obtained fulvestrant particles have a particle size of 133051.doc •31 - 201016220 and the sizes are 2.08±1,19 μηη and 12.14±6.58 μιη, respectively, and their crystal appearances are rod-shaped and irregular. The operating conditions were ethyl acetate, a pressure of ΐ2〇bar, a solution concentration of 5 mg/mL, a solution flow rate of 0.5 mL/min, and a micronization operation at a temperature of 35 C and 55 ° C, respectively. The particle size of fulvestrant particles was 3.19 soil 2.22 from melon and 2 62±2 16, and the crystal appearance was rod-shaped and irregular. The solvent was ethyl acetate, the pressure was 140 bar, and the solution concentration was under the operating conditions. 5 mg/mL, solution flow rate 〇5 m L / min The particle size of the fulvestrant particles was 3.91±2_33 μπι and 5.05±2.26 μιη, respectively, at a temperature of 3 5 art and 5 5 〇c. The crystallites were rod-shaped and respectively. Irregularity. It can be observed from the /Ri effect that the crystal appearance of fulvestrant will change from rod to irregular with increasing temperature. Two operating variables of temperature and pressure, for the micronization of fulvestrant In other words, there are factors of interaction. From the above results, it can be known that the solvent is ethyl acetate, the pressure is bar, the temperature is 35 ° C, the solution concentration is 5 mg / mL, and the solution flow rate is 〇 5 mL / ❹ min. In the case, the minimum average particle size of fulvestrant can be obtained is 2.08±1.19 μηη. Thermal effect analysis, crystallization characteristic analysis and qualitative analysis of the micronized product of Example 2, the melting point of the original drug of fulvestrant is 114_118〇c, such as Figure 9(a) shows the results of DSC analysis of fulvestrant after continuous supercritical antisolvent recrystallization procedure under all operating conditions, as shown in Figure 9(b), melting point is 1〇8112 :C Analysis by DSC#, via the continuous-supercritical anti-solvent method The melting point of the drug before and after the treatment is the same, and there is no deterioration of the drug during the recrystallization process. Figure 133051.doc •32· 201016220 10 is the XRD pattern of the fluorine (tetra) group of drug powder before and after continuous supercritical antisolvent treatment (1〇(4) treatment Before; after 1Q(b) treatment, the analysis results show that the drug after continuous supercritical antisolvent operation has the same characteristic peak as the original drug, but the crystallinity after continuous operation is significantly lower than that of the original drug. The situation. This situation indicates that when the drug is continuously operated, the solute rapidly crystallizes under supersaturation, so that it cannot be arranged neatly on the crystal lattice. Figure 11 is a R image of the fulvestrant powder before and after continuous supercritical antisolvent treatment. Figure u(4) is the a vesistrant original drug y ❻® spectrum and ll(b) is the FT-IR spectrum of the fluorine (four) group after continuous supercritical antisolvent operation. The functional groups CF2 and CF of fulvestrant were shown in the FT_IR spectrum before and after the continuous supercritical antisolvent operation, and no signal due to solvent residue was detected. Example 3 Comparison of small amounts and large amounts of products Table 3 shows the particle size, distribution and recovery of the resulting fulvestrant microparticles under different operating conditions. The foregoing example shows that the experimental results of collecting a small amount of product are as shown in Tables 3(a) to (7). Table 3 (4) shows the results of the product collection of 36. The particle size is 2.08 ± 1.19 μιη, and the SEM is shown in Fig. 12. Table 3 (Imaginary product collection of 832 mg results in a particle size of 3 63 ± 23 ι μηι, the SEM of which is shown in Figure 13. As can be seen from Figures 12 and 13, when a small amount of product is collected, The particle size distribution is more uniform than when a large amount of product is collected. There are three reasons for the uneven particle size distribution: the first possible reason is that Table 3 (g) operating conditions are using a higher solution flow rate (1 mL / min), high The solution volume flow rate solution volume expansion rate effect is lower, the flow rate distribution is poor, thus causing the particle size distribution to be uneven, and the solution flow rate is selected to be 丨mL/min, which is to serve 133051.doc -33- 201016220 More products 'avoid solute that has not yet nucleated into the body growth day. For this reason, the product of Table 3 (g) is collected about 832 Γ = = substance powder will be stacked in the sinking tank In the lowermost layer, the aggregate is: the body is squeezed to a greater extent than the uppermost layer of the drug powder, which is easy to make, and the second layer of the drug powder is less squeezed, longer and shorter, when collecting Xiao Dongzhi Experiment; == collection of the injection time of the liquid is greatly injected when the cold liquid is injected To 40 minutes, when ❷: a large number of experiments, the solution nozzle into the operating room, there is enough time to help the solute, BU when 3〇 knife clock 'to obtain the large crystals # ^ long duration, it is easy to

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From the results of XRD analysis, whether it is collecting a small amount of experiments, or collecting a large number of experiments, the characteristic peaks are consistent, and no crystal-type transition is caused. The fulvestrant was processed in a short time (36 mg collected) or long-term (collected 832 mg), and the DSC analysis showed the same melting point and the characteristic peaks of the XRD analysis were consistent. Therefore, it can be known that fulvestrant does not affect the original crystalline property due to the long-term supercritical antisolvent operation. Regarding the recovery rate, the recovery rate is less than 30% when collecting a small amount of experiments, but when a large number of experiments are collected, the recovery rate is increased to more than 40%, and the recovery rate should be due to the drug in the sedimentation tank. The stack continues to accumulate, causing blockages, so fewer drugs are carried away by supercritical carbon dioxide. *V Example 4 Dissolution rate test of micronized product - From the results of Example 1, it is known that the solvent is acetic acid, the pressure is 100 bar, the temperature is 35 ° C, the solution concentration is 5 mg / mL, and the solution flow rate At 0.5 mL/min, the minimum average particle size of fulvestrant was 2.08 ± 1.19 μηη. In this test, the dissolution rate of the drug particles obtained under the operating conditions was compared, thereby comparing the change in the dissolution rate before and after the operation of the fulvestrant by the continuous supercritical antisolvent method. The fulvestrant standard curve must be prepared prior to the dissolution test. Figure 133051.doc -36- 201016220 is the absorption spectrum of Fluvi 34 in the simulated gastric juice after full-band scanning by UV-Vis spectrometer. It can be seen from Fig. 16 that the maximum absorption wavelength of the gas viscer group is 2 〇 inm. Further, different concentrations of the fulvestrant solution were prepared, and the standard curve was prepared at the maximum absorption wavelength. The results are shown in Fig. 7. Figure ig is the experimental results of the aerosols of the gas viscer group and the dissolution rate of the gas-wrist particles obtained by the continuous supercritical anti-solvent method under the optimal operating conditions (i.e., the conditions of Table 3 (4)). It can be seen from the figure that the fulvestrant microparticles obtained by the continuous supercritical antisolvent treatment under the optimum operating conditions have a higher dissolution rate than the fluorine (four) group of original drugs. β In the test of the present invention, the empirical formula for describing the dissolution behavior is commonly used: the Weibull model is used to describe the dissolution behavior of the drug. The pattern is as follows: m = l- exp- j_ a where m is the specific sampling time below, the drug is dissolved fraction and α and 6 are two-mode parameters, which can be obtained by regression of the dissolution curve. And Loth and Hemgesberg (please refer to "Properties and dissolution of drugs micronized by crystallization from supercritical gases," /«i. «/· P/mrw., 1986, 32: 265-267) from the Wilbur mode The reciprocal of the time required to dissolve the drug up to 63.2% is defined as the dissolution rate coefficient (匕), and the coefficient of drug dissolution rate is compared by this coefficient. In the form of the IWBER mode, the dissolution rate coefficient 匕 can be calculated from the two mode parameters α and 6, ie: }ς ="~ W— $ 133051.doc -37- 201016220 In this test, the regression of the dissolution data is The dissolution rate coefficient of the original fulvestrant group was 0.0043 minutes, and the dissolution rate coefficient of the fulvestrant microparticles treated by the continuous supercritical antisolvent method was increased to 0.0052 minutes." Continuous supercritical antisolvent method After the micronization operation, the rate of dissolution rate of fulvestrant is increased by about 1.2 times that of the original drug. [Simplified Schematic] Fig. 1 is a schematic diagram of the operation of the supercritical antisolvent method. Fig. 2 illustrates the supercritical antisolvent method. Fig. 3 is a schematic view of the apparatus of the continuous supercritical antisolvent deposition method of the present invention. Fig. 4 is a scanning electron micrograph of the original drug particles of fulvestrant. Fig. 5 is continuous under different pressure conditions. Scanning electron micrograph of fulvestrant micronized by supercritical antisolvent method (solvent is ethyl acetate, solution concentration is 5 mg/mL, solution flow rate is 0.5 mL/min, temperature is 35°) C) (a) pressure is 100 bar; (b) pressure is 120 bar; (c) pressure is 140 bar. Figure 6 shows the particle size and distribution of fulvestrant micronized under different pressure conditions (solvent is Ethyl acetate, solution concentration of 5 mg / mL, solution flow rate of 0.5 * W mL / min, temperature of 35 ° C) - Figure 7 is the continuous supercritical antisolvent micronization under different pressure conditions. Scanning electron micrograph of fulvestrant (solvent is ethyl acetate, solution concentration 5 mg/mL, solution flow rate 0.5 mL/min, temperature 55 ° C). (a) Pressure is 100 bar; (b) The waste force is 120 bar; (c) The pressure is 140 bar. Figure 8 shows the particle size and distribution of fulvestrant micronized under different pressure conditions (solvent is ethyl acetate, solution concentration is 5 mg) /mL, solution flow rate is 0.5 mL / min, temperature is 55 ° C). 133051.doc -38- 201016220 Figure 9 (4) and (b) is the DSC chart of the powder of the complex (a boundary anti-solvent treatment before and after fluoride The vesis group is a continuous fluorosis group: the DSC spectrum of the original drug of fluvostatin and (b) Fig. 10(4) and (b) are the D after the critical antisolvent operation. SC map. XRD_ of powders (a ^ before and after the anti-solvent treatment), the fulvestrant is the XRD pattern of the original fulvestrant group of fulvestrant, and (b) F11UU and / supercritical antisolvent XRD pattern after the operation of the method. ❺ 续 Continued supercritical solution of the powder of the substance. Before and after treatment, the fulvestrant group (b) is fulvestrant and 9 a) is the FT- of the original drug of fulvestrant. m map, and Fig. 12 (8) to (4) are the spectrum of the less anti-solvent method after the h-th boundary. Scanning electron microscopy of the gas-wound group of microparticle products. Figures 13(a) and (b) are a large number of figures. Scanning Electron Microscopy of Vesonic Microparticles Figure 14 (a) and (b) compare the results of a small amount of analysis. (4) A small amount: the result of DSC analysis of the viscous fraction of the fulvestrant microparticle product obtained by the vitamin 51 group microparticle product. The results of the analysis of a large number of fulvestrant microparticle products. Figures 15(a) and (b) show the XRD analysis of a small amount of monthly + θ & 罝 罝 维 群 微粒 颗粒 颗粒 颗粒 颗粒. The result of the comparison is that (a) is the result of the analysis of the J fulvestrant microparticle product. (8) Analysis results for a large number of fluorine (tetra) group particulate products. Figure 16 shows the absorption spectrum of H-Wissler in simulated gastric juice after UV-visible (four) full-band scanning. Figure 17 is a standard curve (y = 〇. 〇 623ix, r2 = 999 99912) of different concentrations of Dunvis's solution at 201 run absorption wavelength. Figure 18 is an experimental result of the dissolution rate of fulvestrant microparticles obtained under optimal operating conditions using a gas-assisted group of scorpion scorpion». music and continuous supercritical antisolvent method 133051.doc -39· 201016220. [Main component symbol description] A1, A2, A3 and A4 Bidirectional needle valves Bl, B2 and B3 Check valve C Back pressure valve D Three-way ball valve E Micro-metering valve Θ 1 Carbon dioxide cylinder 2 Refrigeration circulation tank 3 High-pressure pump 4 Constant temperature water Bath 5 Preheater 6 Vial 7 Precipitation tank 8 w 9 Pressure transfer and display thermocouple temperature measuring element 10 Filter 11 Conical flask 12 Float flowmeter 133051.doc • 40-

Claims (1)

201016220 X. Patent application scope: 1. A method for preparing a fulvestrant in a micronized form, characterized in that the fulvestrant is micronized by supercritical antisolvent deposition. 2. The method of claim 1, comprising the steps of: - (a) providing a supercritical fluid antisolvent deposition system; (b) formulating a pharmaceutical solution comprising fulvestrant and at least one organic soluble agent; (c) feeding the drug solution to the supercritical fluid antisolvent deposition system of step (a) to obtain micronized fulvestrant drug particles. 3. The method of claim 2, wherein the operating pressure of the supercritical antisolvent deposition method performed in step (c) is controlled to be about 100 to 140 bar. 4. The method of claim 3, wherein the operating pressure is about 100 bar. 5. The method of claim 2, wherein the operating temperature of the supercritical antisolvent deposition method carried out in step (c) is controlled at about 30 to 60 °C. 6. The method of claim 5, wherein the operating temperature is between about 35 and 55 °C. 7. The method of claim 6, wherein the operating temperature is about 35 °C. 8. The method of claim 2, wherein the organic solvent is an ester. 9. The method of claim 8, wherein the ester is ethyl acetate. 10. The method of claim 2, wherein the anti-solvent is carbon dioxide. 11. The method of claim 2, wherein the solution flow rate of the supercritical fluid antisolvent deposition method performed in step (c) is about 0.1 to 1 mL/min. 12. The method of claim 11, wherein the solution flow rate is about 0.5 mL/min. 13. The method of claim 2, wherein the concentration of the solution of step (b) is about 1 to 10 mg/mL. 133 051051.doc 201016220 14. The method of claim 13, wherein the solution has a concentration of about 5 mg/mL. The method of any one of claims 1 to 14, wherein the micronized fulvestrant has a particle size of from about 1 to 6 μηη. 16. The method of claim 15, wherein the micronized fulvestrant has a particle size of from about 2 to 3 μηη. The method of any one of claims 1 to 14, wherein the micronized fulvestrant has an irregular appearance or a rod-like structure. The method of any one of claims 1 to 14, wherein the micronized fulvestrant has a higher dissolution rate than the unmicronized fulvestrant. 19. The method of claim 18, wherein the fulvestrant form of the micronized form has a dissolution rate that is about 1.2 times higher than the unmicronized fulvestrant. 20. A micronized fulvestrant produced by the method of any one of claims 1 to 14. 21. The micronized fulvestrant of claim 20 having a particle size of from about 1 to 6 μηη. 22. The micronized fulvestrant of claim 21 having a particle size of from about 2 to 3 μηη. 23. The micronized fulvestrant of any one of claims 20 to 22 having a crystalline appearance of an irregular or rod-like structure. 24_ The micronized fulvestrant according to any one of claims 20 to 22, which has a higher dissolution rate than the unmicronized fulvestrant. 25. The fulvestrant of micronized as claimed in item 24 has a dissolution rate about 1.2 times higher than that of the unmicronized fulvestrant. 26. A pharmaceutical composition for the treatment of a hormonal dependent benign or malignant breast or genital tract disease comprising a therapeutically effective amount of a micronized fluorochemical group as claimed in any one of claims 20 to 25. And a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 26, wherein the hormonal-dependent benign or malignant breast or genital tract disease is breast cancer. 28. The use of the micronized fulvestrant according to any one of claims 20 to 25 for the manufacture of a medicament for the treatment of a hormone-dependent benign or malignant breast or genital tract disease. 29. The use of claim 28, wherein the hormonal dependent benign or malignant breast or genital tract disease is breast cancer. Participation .© 133051.doc