CN1750811A - Stable composition comprising particles in a frozen aqueous matrix - Google Patents

Abstract

This invention discloses a stable suspension composition for pharmaceuticals or cosmetics with poor water solubility, and a method for preparing the same. The composition is in the form of pharmaceutical or cosmetic particles suspended in a frozen water matrix. The composition remains stable over a long period, preferably six months or longer, and is suitable for parenteral, oral, or non-oral administration routes, such as pulmonary (inhalation), ophthalmic, or topical administration.

Description

Stabilized compositions comprising particles in a frozen water matrix

Cross-references for applications

This application claims priority to Provisional Application 60/347,548, filed October 19, 2001, which is incorporated herein by reference and constitutes a part hereof.

Federally Sponsored Research or Development

not applicable.

Background of the invention

technical field

The present invention discloses a stable suspension composition of a poorly water soluble compound comprising particles of the compound suspended in a frozen water matrix, and a method for preparing the same. The composition remains stable over an extended period of time, preferably six months or more.

Background technique

An increasing number of pharmaceutical compounds are being formulated that have poor or insoluble solubility in aqueous solutions. Delivery of these compounds in injectable form presents certain difficulties. There are clear benefits when formulating water-insoluble drugs as stable suspensions of submicron-sized particles. Precise control of particle size is essential for the safe and effective utilization of these formulations. Particles must be smaller than 7 microns in size in order to pass through capillaries safely without causing embolism (Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981). One of the solutions to this problem is to prepare extremely fine particles of insoluble drug candidates and generate suspensions of microparticles or nanoparticles. In this way, drugs that could not previously be formulated in water-based systems could be made suitable for intravenous administration. Suitability for intravenous administration includes small particle size (<7 μm), low toxicity (when toxic formulation components or residual solvents are used), and bioavailability of drug particles after administration.

Suspensions are also suitable for oral, intramuscular, pulmonary, topical or subcutaneous administration. When administered by these routes, advantageous particle sizes are in the range of 5-100 [mu]m.

When suspensions are stored for long periods of time, they may lack sufficient physical and chemical stability. Physical instability occurs when particles aggregate to form larger particles (typically due to small particle size). Ostwald-Mie ripening is likely due to the small particle radius and the concomitant increase in surface activity (and thus solubility). In particular, nanoparticles have a very high surface-to-volume ratio, which increases their dissolution rate and solubility. As a result, particles can be dissolved in suspension and subsequently form large crystals by recrystallization. Coalescence and crystal growth produce a suspension of nanoparticles with larger and varying particle sizes. Suspensions with particles larger than 7 μm are no longer suitable for intravenous administration.

In suspension, active ingredients may also degrade due to interaction with the suspension medium, reducing activity over time. Even trace amounts of dissolution may facilitate the degradation of the active ingredient. The rate of chemical degradation depends on the particle size, intrinsic solubility, and chemical nature of the active ingredient.

In terms of physical and chemical stability, it is highly desirable for an aqueous suspension pharmaceutical formulation to have a long shelf life, preferably a minimum of six months.

Several approaches have been disclosed in the prior art to limit the agglomeration and crystal growth of nanoparticles in suspension in order to improve their physical stability and shelf life. One method includes the step of adding a surface stabilizer to the formulation. Suitable surface stabilizers include surfactants, polymers, cloud point modifiers (see US Pat. . Although these methods have been found to be successful in limiting particle agglomeration and crystal growth, no suitable surfactants have been found that can extend the shelf life of suspensions in the liquid state at room temperature or in the refrigerator. Or, if such stabilizers can be found, they also have an undesirable toxicity profile.

Another approach to inhibit nanoparticle agglomeration and crystal growth is to limit the average particle size to a narrow range of about 150 nm to about 350 nm, as described in US Patent 6,267,989 to Liversidge et al. The patent states that when the particles are in this size range, agglomeration and crystal growth are minimized. However, the narrow range of particle sizes limits its applications. For certain applications, nanoparticle suspensions with particle sizes in excess of 400 nm are advantageous. These applications include, but are not limited to, oral, subcutaneous, or intramuscular administration, where the ideal particle size is 5-100 microns. In other formulations, the ideal particle size may be less than 100 nm. This is true for eg particles designed to hide from the RES (reticuloendothelial system). Such chronically circulating particles are also able to migrate through loose, porous vasculature, such as that associated with certain cancerous tumors. This would facilitate passive targeting of these tumors.

Yiv et al. in US Patent 6,245,349 disclose stable formulations of lipid nanoparticles of lipophilic and amphoteric drugs. The formulation is an oil-in-water microemulsion consisting of phospholipids, propylene glycol, polyethylene glycol, surfactants and water. An oily component such as triglycerides may optionally be used. The components are mixed together to form an emulsion. For formulations to be filter sterilized, the average particle size should be less than 200 nm. The composition is stored either in concentrated or diluted form. Diluted forms include aqueous buffers and are stable at temperatures ranging from about -50°C to about 40°C. In Example 1, the composition was stored at -20°C for 21 days without significant phase separation, particle size change, or drug crystallization. However, this method is limited to oil-in-water dispersions with particle sizes smaller than 200 nm, where all components are liquids. Such dispersions are generally sterilized by filter sterilization, which requires passing the dispersion through a filter with a pore size of 220 nm.

The prior art also discloses methods of increasing the chemical stability of nanoparticle formulations for extended shelf life. A common approach is to remove the aqueous medium by freeze-drying and store the nanoparticles in freeze-dried form. One example is Example 6 of US Patent 5,091,187. Dialysis is generally required prior to lyophilization to remove any unwanted solutes such as salts, or to prevent concentration of such solutes during lyophilization. The additional steps of dialysis and freeze-drying add to production costs, since dialysis is a very time-consuming process and freeze-drying is an energy-intensive process. Furthermore, lyophilized formulations require reconstitution with a suitable dispersion medium prior to administration by injection (intravenous, intramuscular or subcutaneous) or oral administration. This requires more manpower at the time of administration of the medicament, while introducing potential human error that may arise during the reconstitution process.

As part of an effort to develop new methods to stabilize these suspensions, we found that freezing circumvents these destabilizing mechanisms by encapsulating drug particles in a frozen water matrix. At such a low temperature, the solubility of the drug decreases, and the very high viscosity of the aqueous medium is not conducive to the diffusion of the solute drug from the solid particles. This diffusion includes nucleation, crystal growth and Ostwald ripening. Lower temperatures may also increase chemical stability by reducing the decomposition of the drug in aqueous media. For example, crystallization of water may also occur below the eutectic point of the mixture, which rules out the formation of a solution phase containing a drug capable of secondary nucleation, crystal growth and Ostwald mature.

Nanoparticles in the present invention can be prepared by any method known in the art. One approach focuses on reducing the particle size of the drug being delivered. In one of the series of patents comprising US Patents 6,228,399, 6,086,376, 5,922,355, and 5,660,858, Parikh et al. disclose that ultrasonic techniques can be used to prepare microparticles of water-insoluble compounds. Among these patents, US Patent No. 5,922,355 discloses an improved method of producing smaller particles using ultrasonic technology. The method modification involves mixing the active agent with a phospholipid and a surfactant in a single-phase aqueous system, applying energy to the system to make smaller particles. However, this patent does not disclose stabilization of the suspension by freezing.

US Patent 5,091,188 to Haynes also discloses reducing the particle size of pharmacologically active water-insoluble drugs and applying a lipid coating to the particles to form a solid form. This patent relates to a pharmaceutical composition consisting essentially of an aqueous suspension of solid particles of the drug, said particles having a diameter of from about 0.05 to about 10 [mu]m. A lipid coating affixed to the surface of the particles serves to stabilize these particles. Compositions are prepared by adding the drug to water in the presence of a film-forming lipid surfactant and then reducing the particle size in the aqueous suspension. However, freezing suspensions has not been described as a stabilization method.

US Patent 5,858,410 discloses drug nanosuspensions suitable for parenteral administration. This patent discloses that at least one solid therapeutically active compound dispersed in a solvent is subjected to high-pressure homogenization in a piston-gap homogenizer to form an average diameter measured by photon correlation spectroscopy (PCS) of Particles of 10 nm to 1000 nm, the proportion of particles larger than 5 microns in the total particles is less than 0.1% (number distribution determined by Coulter counter), without prior transformation into a melt, in which the active compound is solid at room temperature, insoluble , or only sparingly soluble, or moderately soluble in water, aqueous media and/or organic solvents. The examples of this patent disclose jet milling prior to homogenization.

US Patent 5,145,684 discloses another approach to provide nanoparticles of insoluble drugs for parenteral delivery by reducing particle size. The patent discloses that, in the presence of a surface modifier, wet grinding of an insoluble drug yields drug particles with an average effective particle size of less than 400 nm. The patent emphasizes the necessity of not using any solvents in the process. The patent discloses that the amount of surface modifier adsorbed on the surface of drug particles is sufficient to prevent agglomeration into larger particles.

In addition to physically reducing the size of drug particles and coating the particles with surface stabilizers, nanoparticles can be prepared by a variety of precipitation methods. These methods typically involve dissolving the drug in a solvent as the continuous phase, followed by changing the solution conditions to the discontinuous phase so that fine particles of the drug precipitate out into the discontinuous phase. Coating agents or surface stabilizers are generally used to co-precipitate with the drug to stabilize the particles. Examples of such precipitation methods are solvent and anti-solvent microprecipitation, phase inversion precipitation, pH change precipitation, supercritical fluid precipitation and temperature change precipitation.

Examples of suitable precipitation techniques include the preparation of nanoparticle suspensions, which are disclosed in U.S. Patent Application Nos. part of this article. These applications disclose the formation of small particulate organic compounds by dissolving the organic compound in a water-miscible organic solvent, followed by precipitating the organic compound in an aqueous medium to form a presuspension, and then applying energy to the presuspension to Stabilize particle coatings, change the lattice structure of particles, or reduce particle size. This method is preferably used to prepare suspensions of poorly water soluble pharmaceutically active compounds.

US Patent No. 5,118,528 discloses a method of preparing nanoparticles by solvent-anti-solvent precipitation. The method comprises the steps of: (1) preparing a liquid phase of a substance in a solvent or solvent mixture to which one or more surfactants may be added, (2) preparing a second liquid phase of a non-solvent or non-solvent mixture phase, the non-solvent is miscible with the solvent or solvent mixture of the material, (3) adding solutions (1) and (2) together by stirring, and (4) removing unwanted solvent to obtain a colloidal suspension of nanoparticles. The patent states that it produces particles of matter smaller than 500nm without the need to provide energy. In particular, the patent shows that the use of high energy equipment such as sonicators and homogenizers is disadvantageous.

US Patent No. 4,826,689 discloses a process for preparing uniformly sized particles from water insoluble drugs or other organic compounds. First, an appropriate solid organic compound is dissolved in an organic solvent, which solution may be diluted with a non-solvent. The aqueous precipitating liquid is then injected to precipitate unagglomerated particles having a substantially uniform average diameter. The particles are then separated from the organic solvent. Depending on the organic compound and desired particle size, parameters such as temperature, ratio of non-solvent to organic solvent, injection rate, stirring rate and volume can be varied according to the invention. The patent states that this approach forms a metastable drug, which is thermodynamically unstable. The patent states that the method renders the drug metastable by employing a crystallization inhibitor (e.g., polyvinylpyrrolidone) and a surfactant (e.g., polyethylene oxide-co-propylene oxide), imparting sufficient stability to the metastable precipitate can be separated by centrifugation, membrane filtration or reverse osmosis.

U.S. Patent No. 5,780,062 discloses a method for preparing small particles of insoluble drugs by (1) dissolving the drug in a first water-miscible solvent, (2) preparing a mixture of the polymer and the amphiphile in a second aqueous solvent. The second solution, wherein the drug is substantially insoluble, thereby forming a polymer/amphiphile complex, and (3) mixing the solutions prepared in the first and second steps to precipitate the drug and the polymer/amphiphile Aggregates of biophilic complexes.

US Patent 4,997,454 discloses a process for preparing uniformly sized particles from solid compounds. The method of this patent comprises the steps of dissolving a solid compound in a suitable solvent followed by injection of a precipitating liquid whereby non-agglomerated particles having a substantially uniform mean diameter are precipitated. The particles are then separated from the solution. The patent does not favor the formation of crystalline particles because during precipitation the crystals can dissolve and recrystallize, thereby broadening the particle size distribution. This patent favors, during the precipitation process, changing the particles to thermodynamically unstable particles.

US Patents 6,235,224 B1 and 6,143,211, both to Mathiowitz et al., disclose the use of the phase inversion phenomenon to precipitate microencapsulated particles. The method involves mixing a polymer and drug with a solvent. This mixture is introduced into an effective amount of a miscible non-solvent whereby the microencapsulated product forms spontaneously.

Microprecipitation by pH change is another technique used to prepare dispersions of nanoparticulate medicaments. See US Patents 5,766,635, 5,716,642, 5,665,331, 5,662,883, 5,560,932, and 4,608,278. This technique involves dissolving a pharmaceutical compound in an aqueous matrix with a non-neutral pH, and then neutralizing the matrix to precipitate the compound in the aqueous matrix.

In another method, such as disclosed in U.S. Patent 5,766,635 to Spenlenhauer et al., nanoparticles are prepared by dissolving polyoxyethylene and/or polyoxypropylene/polylactide copolymers in an organic solvent , the organic solution thus formed is mixed with an aqueous solution, the nanoparticles are precipitated out of solution, and the suspension is microscopically flowed without the use of surfactants. This produces carrier particles consisting of a solid polymer matrix into which co-precipitated agents can be added.

Supercritical fluid precipitation is disclosed in US Patents 5,360,478 and 5,389,263 to Krukonis et al. and WO 97/14407 to Johnston. This technique is similar to solvent-anti-solvent precipitation. In this method, the supercritical fluid whose pressure and temperature are above the critical point is gas or liquid is used as an anti-solvent. The addition of a supercritical fluid to a solution of a solute in a solvent causes the solute to reach or approach supersaturation and precipitate out as fine particles.

The temperature change precipitation method is disclosed in Domb, US Patent 5,188,837. The method involves adding a heat-stable drug to the polymer. The polymers are usually oil based (eg phosphoesters, synthetic waxes) and have a low melting point. The drug is heated with the polymer to slightly above the melting point of the polymer to form a warm emulsion of the drug in the molten polymer. The emulsion is then rapidly cooled by adding it to a cold non-solvent bath such as water, the emulsion forms droplets using vigorous shaking, and solidifies to bring the active agent into suspension.

Another method of preparing submicron particles of poorly water soluble organic compounds is to form compound emulsions. Organic compounds are dissolved in the organic phase. The organic phase forms an emulsion with the aqueous phase. Emulsion evaporation methods are disclosed in US Patent Application Serial No. 09/964,273. The method comprises the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase containing a pharmacologically effective compound, and (2) sonicating the system to evaporate part of the organic phase, leaving the aqueous phase Compounds precipitated with an average effective particle size below about 400 nm.

US Patent 5,605,785 discloses a method of preparing nano-amorphous dispersions of compounds useful in photography. Methods of forming nano-amorphous dispersions include any known method of emulsification, resulting in a dispersed phase with amorphous particles.

Yet another approach to preparing a suspension of submicron nanoparticles of a pharmaceutically active compound is to seed crystals at a certain point during the precipitation process to produce crystals of the desired morphology. (See US Patent Application 10/035,821). The method comprises the steps of dissolving a first amount of a pharmaceutically active compound in a first water-miscible organic solvent to form a first solution. The first solution is then seeded. Alternatively, the second solvent is seeded. Seeding compounds can also be utilized at other points in the precipitation process. The first solution is then mixed with the second solvent. Mixing of the first solution with the second solvent causes the pharmaceutically active compound to precipitate in the desired form.

Another method involves the preparation of protein-coated suspended particles. US Patent 5,916,596 to Desai et al. discloses applying high shear forces to a mixture of an organic phase in which a pharmaceutically active agent is dispersed and an aqueous medium containing a biocompatible polymer. The mixture is sheared in a high pressure homogenizer at a pressure ranging from about 3,000 to about 30,000 psi. The patent requires that the mixture be substantially free of surfactants, since the combination of surfactants and proteins causes the formation of large, needle-shaped grains which increase in size during storage. See columns 17-18, Example 4.

US Patent 5,560,933 to Soon-Shiong et al. discloses forming a polymer shell around a water insoluble drug for in vivo delivery. The method discloses applying sonication to a mixture comprising an aqueous polymer-containing medium and a dispersant in which a substantially water-insoluble drug is dispersed. In this reference, sonication is used to induce the formation of disulfide bonds in the polymer, cross-linking the polymer to form a polymer shell around the drug. Sonicate for a time sufficient to form disulfide bonds.

US Patent No. 5,665,383 to Grinstaff et al. discloses the application of sonication to a single phase B, aqueous medium, to encapsulate immunostimulants within a polymer shell for in vivo delivery. Ultrasonic treatment promotes the cross-linking of the encapsulants to form shells through disulfide bonds.

US Patent Nos. 5,981,719 and 6,268,053 disclose methods for preparing macromolecular microparticles with particle sizes less than 10 microns. In the presence of preferably thermal energy, the macromolecule is mixed with a soluble polymer or a mixture of soluble polymers (eg albumin) for a predetermined time at a pH close to the isoelectric point of the macromolecule. The microparticles formed by this process allow entry of aqueous fluids and exit of dissolved macromolecules and polymers, and can have short- or long-term release kinetics, thereby providing rapid or sustained release of macromolecules.

Brief description of the invention

One of the disadvantages of aqueous nanoparticle suspensions is their poor physicochemical stability. Physical instability is due to particle coalescence and crystal growth. Chemical instability is due to the degradation of the active ingredient dissolved in the surrounding solution (which is in equilibrium with the suspended solid phase) due to the interaction between the active ingredient and excipients such as surfactants and buffers enhanced. Due to these stability issues, many aqueous nanoparticle systems are not suitable for use as pharmaceutical formulations. For example, if the dissolved active compound is chemically unstable due to hydrolysis, then decomposition in solution will shift the chemical equilibrium towards gradual degradation and loss of the active ingredient.

We found that freezing methods circumvent these instability mechanisms by encapsulating drug particles in a frozen water matrix. At such a low temperature, the solubility of the drug decreases, and the very high viscosity of the aqueous medium is not conducive to the diffusion of the solute drug from the solid particles. This diffusion involves nucleation, crystal growth, and Ostwald ripening. Lower temperatures also reduce the spontaneous degradation of drug molecules in aqueous media, increasing their chemical stability. Low temperature also slows down the degradation of the active ingredient due to the interaction of the active ingredient with the excipients. For example, below the eutectic point of the mixture, crystallization of water may also occur, ruling out the possibility of forming a solution phase containing the drug, which is capable of secondary nucleation, crystal growth and Ostwald ripening.

The invention provides a stable nano particle suspension composition of a poorly water-soluble medicament in a water matrix and a preparation method of the composition. The present invention contemplates providing stable suspensions of other compounds such as cosmetics, photographic agents and the like. The composition can be stored for a long term preferably six months or more.

The present invention can be used with any nanoparticle system known in the art. Nanoparticle suspensions can be made by any known method such as physical milling, homogenization, high shear mixing, emulsion evaporation precipitation, solvent antisolvent precipitation, supercritical fluid precipitation, temperature change precipitation, pH change precipitation, Melt precipitation and crystal seeding.

The invention is also applicable to nanoparticle systems containing a number of ingredients such as surface modifiers, pH regulators, crystal growth modifiers, cryopreservatives, osmotic agents, co-solvents and viscosity modifiers.

The composition does not require reconstitution with suitable dispersing agents prior to use and is suitable for a variety of routes of administration including, but not limited to, injection (intravenous, intramuscular, subcutaneous), pulmonary, ophthalmic, topical and oral.

These and other aspects and features of the invention will be discussed with reference to the drawings and description that follows.

Detailed description of the invention

While the invention is susceptible to many different forms of embodiment and will be described in detail herein, preferred embodiments of the invention are disclosed on the basis that the disclosure of the invention is to be considered as an illustration of the principles of the invention The embodiments are presented by way of illustration, but not limitation of the broad scope of the invention.

The invention discloses a pharmaceutical composition for intravenous administration or oral administration, and a method for preparing the composition as a nanoparticle suspension in a water matrix. Parenteral administration includes intravenous, intraarterial, intrathecal, intraperitoneal, intraocular, intraarticular, intradural, intramuscular, intradermal or subcutaneous injection. The composition is also suitable for other parenteral routes of administration, including topical, ophthalmic, nasal, oral, inhalational, rectal, etc., for example.

The pharmaceutical agent is preferably a poorly water soluble compound. When the composition is stored in a refrigerator or at room temperature for a long period, preferably one year or more, it is physically and chemically unstable. Stabilization can be achieved by freezing the aqueous nanoparticle suspension and storing the composition in a cold state. At such a low temperature, the solubility of the drug decreases, and the very high viscosity of the aqueous medium is not conducive to the diffusion of the solute drug from the solid particles containing the drug. This diffusion involves nucleation, crystal growth, and Ostwald ripening. Lower temperatures also reduce the spontaneous decomposition of drug molecules in aqueous media, increasing their chemical stability. For example, below the eutectic point of the mixture, crystallization of water may also occur, ruling out the possibility of forming a solution phase containing the drug, which is capable of secondary nucleation, crystal growth and Ostwald ripening.

The invention may also be practiced with suspensions of other poorly water soluble substances other than pharmaceuticals, including, for example, photographic compounds.

A. Nanoparticle Suspension Compositions

Compositions of the invention include nanoparticles of an agent suspended in a chilled water matrix. The composition may contain one or more excipients as desired, depending on the particular agent, method of preparing the nanoparticle suspension, and route of administration.

1. Pharmacy

The present invention can be practiced with many agents, which may be therapeutic, diagnostic or cosmetic. They include organic and inorganic compounds and biological agents such as proteins, peptides, carbohydrates, polysaccharides, polypeptides, nucleotides and oligonucleotides.

Agents can exist in a crystalline phase or an amorphous phase. The agent is preferably poorly water soluble. "Poor water solubility" means that the solubility of the agent in water is lower than 10 mg/ml, preferably lower than 1 mg/ml. Since these poorly water-soluble agents have limited formulation alternatives in aqueous media, they are mostly suitable for aqueous nanoparticle suspension formulations.

By encapsulating these agents in a solid carrier matrix (e.g., polylactate-polyglycolate copolymer, albumin, starch), or by encapsulating these agents in a peripheral capsule that is inert to the agent Osmotic, thus the invention can also be practiced with water soluble agents. Such encapsulation may be a polymer coating such as polyacrylate. Furthermore, nanoparticles and microparticles made from these water-soluble agents can be modified to enhance chemical stability and control their pharmacokinetic properties by controlling the release of the agent from the particles. Examples of water-soluble agents include, but are not limited to, simple organic compounds, proteins, peptides, nucleotides, oligonucleotides, and carbohydrates.

Therapeutic agents can be selected from a large number of known classes of drugs including, for example, pain relievers, anti-inflammatory agents, antihelmintics, antiarrhythmics, antibiotics (including penicillin), anticoagulants, antidepressants antidiabetic, antiepileptic, antifungal, antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antineoplastic, antiprotozoal, immunosuppressant, immune Stimulants, antithyroid agents, antivirals, antianxiety sedatives (hypnotics and neuroleptics), astringents, beta-adrenergic blockers, blood products and substitutes, cardiac inotropic agents, contrast imaging agents, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic contrast agents, diuretics, dopaminergic agents (anti-Parkinson's disease agents), hemostatic agents, immunological agents, lipid modulators , muscle relaxants, parasympathomimetics, parathyroid calcitonin and bisphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids), antihistamines, stimulants and anorectics, sympathomimetics , thyroid medicines, vasodilators, vaccines and xanthines.

Diagnostic agents include X-ray contrast agents and contrast agents. Examples of X-ray imaging agents include WIN-8883 (ethyl 3,5-diacetamido-2,4,6-triiodobenzoate), also known as ethyl ester of diatrizoic acid (EEDA); WIN 67722 is (6-Ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6-triiodobenzoate; 2-(3,5-bis(acetylamino)- 2,4,6-triiodobenzoic acid) ethyl butyrate (WIN 16318); diatrizoic acid ethyl acetate (WIN 12901); 2-(3,5-di(acetylamino)-2,4,6 -Ethyl triiodobenzoyl)propionate (WIN 16923); N-ethyl 2-(3,5-di(acetylamino)-2,4,6-triiodobenzoyl)acetamide ( WIN65312); Isopropyl 2-(3,5-bis(acetylamino)-2,4,6-triiodobenzoyl)acetamide (WIN 12855); Diethyl 2-(3,5-bis (Acetamido)-2,4,6-triiodobenzoyl)malonate (WIN 67721); 2-(3,5-bis(acetylamino)-2,4,6-triiodobenzene Formyl) ethyl phenylacetate (WIN 67585), [[3,5-bis(acetylamino)-2,4,5-triiodobenzoyl]oxy]bis(1-methyl) of malonate ) ester (WIN 68165); and 3,5-bis(acetylamino)-2,4,6-triiodo-4-(ethyl-3-ethoxy-2-butenoic acid) ester of benzoic acid (WIN 68209). Preferred contrast agents include those for which rapid decomposition is expected under physiological conditions, thereby minimizing any particle-related inflammatory response. Decomposition can be due to enzymatic hydrolysis, increased carboxylic acid at physiological pH, Solubility or other mechanisms.Therefore, preferred soluble iodocarboxylic acids such as cholateic acid, diatrizoic acid and metrizoic acid, and easily hydrolyzed iodos such as WIN 67721, WIN 12901, WIN 68165 and WIN 68209 or others substance.

Antineoplastic or anticancer agents include, but are not limited to, paclitaxel and its derivative compounds, and other antineoplastic agents selected from the group consisting of alkaloids, antimetabolites, alkylating agents, and antibiotics.

Preferred therapeutic or diagnostic agents include those for oral and intravenous administration. A description of these classes of therapeutic and diagnostic agents and a listing of substances within these classes can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, which is incorporated herein by reference and constitutes an integral part of this text part. Therapeutic and diagnostic agents are commercially available and/or can be prepared by techniques known in the art.

A cosmetic is any active ingredient that has cosmetic activity. Examples of such active ingredients may be, in particular, emollients, humectants, free radical inhibitors, anti-inflammatory agents, vitamins, depigmentation agents, anti-acne agents, antiseborrhoeics, keratin softeners, slimming agents , skin colorants and sunscreens, especially linoleic acid, retinol, retinoic acid, alkyl ascorbates, polyunsaturated fatty acids, nicotinate, tocopheryl nicotinate; rice, soybean or shea butter ( shea); ceramides, hydroxy acids such as glycolic acid, selenium derivatives, antioxidants, beta carotene, gamma-ferulic acid (orizanol) and stearyl glycerate. Cosmetics are commercially available, and/or prepared by techniques known in the art.

The agent is present in an amount of from about 0.01% to about 50%, more preferably from about 0.1% to about 30%, most preferably from about 0.5% to about 5%, by weight of the composition.

2. Excipients

The excipients of the present invention are optional. One or more excipients may be included in the composition. Examples of excipients include buffers, surface modifiers, pH regulators, crystal growth modifiers, cryopreservatives, osmotic agents, solubilizers and viscosity regulators.

Suitable surface modifiers are preferably known organic and inorganic pharmaceutical excipients, such as anionic surfactants, cationic surfactants, nonionic surfactants or biosurfactant molecules.

Suitable anionic surfactants include, but are not limited to, potassium laurate, sodium lauryl sulfate, sodium lauryl sulfate, alkylpolyoxyethylene sulfate, sodium alginate, sodium dioctyl sulfosuccinate, glycerides , sodium carboxymethylcellulose, cholic acid and other bile acids (such as cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and their salts (such as sodium deoxycholate, etc.) . Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryldimethylbenzyl ammonium chloride, acetylcarnitine hydrochloride salt or alkylpyridinium halide.

Suitable nonionic surfactants include: ethers of polyoxyethylene fatty alcohols (Macrogoland Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), esters of polyoxyethylene fatty acids (Myrj), polyoxyethylene-derived lipids or phosphoester, sorbitan ester (Span), glycerol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetearyl stearyl alcohol mixture, stearyl alcohol, arylalkyl polyether Alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), polaxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, non-crystalline cellulose, including starch and starch derivatives Polysaccharides such as hydroxyethyl starch (HES), polyvinyl alcohol, and polyvinylpyrrolidone. In a preferred mode of the present invention, the nonionic surfactant is a polyoxyethylene and polyoxypropylene copolymer, preferably a block copolymer of propylene glycol and ethylene glycol. Such polymers are sold under the tradename POLOXAMER (also sometimes called PLURONIC(R)) and several suppliers are Spectrum Chemical and Ruger. Among the esters of polyoxyethylene fatty acids are those with short alkyl chains. One example of such a surfactant is SOLUTOL(R) HS 15, polyethylene-660-hydroxystearate, manufactured by BASFAktiengesellschaft.

Surface active biomolecules include molecules such as albumin, casein, heparin, hirudin or other suitable proteins.

Other representative examples of surface modifiers include gelatin, casein, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl stearate Alcohol mixtures, cetomacrogol emulsifying waxes, sorbitan esters, polyoxyethylene alkyl esters such as polyethylene glycol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan Alcohol fatty acid esters such as commercially available Tweens ^™ , polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate esters, sodium lauryl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose Sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients, described in detail in the Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, which is incorporated herein by reference are provided for reference and form a part of this article.

Surface modifiers are commercially available and/or prepared using techniques known in the art. Two or more surface modifiers may be used simultaneously in the composition.

Suitable pH adjusting agents include, but are not limited to, buffers, sodium hydroxide, hydrochloric acid, tris (hydroxymethyl) aminomethane (tris), citrate, acetate, lactate, meglumine, and the like. Buffering agents also include, but are not limited to, amino acids such as glycine, leucine, alanine, lysine, and the like.

Suitable crystal growth modifiers are described in US Patent 5,665,331. A crystal growth modifier is defined as a compound that is incorporated into the microprecipitated crystal structure of a pharmaceutical agent in a co-precipitation process, thereby inhibiting the growth or enhancement of microcrystalline precipitates by a process known as Ostwald ripening. big. Some crystal growth modifiers are structurally similar to agents on a molecular basis. Also suitable as crystal modifiers are polymers such as the crystallization inhibitor polyvinylpyrrolidone disclosed in US Patent 4,826,689. Crystal growth modifiers can also function by forming complexes with solutes at supersaturation, thereby preventing or inhibiting crystal nucleation and/or growth.

Cryopreservatives for use in nanoparticle suspensions are disclosed in US Patent 5,302,401. In this patent, the cryopreservative prevents the nanoparticles from agglomerating during the freeze-drying process. Examples of suitable cryopreservatives include carbohydrates such as sucrose, xylose, glucose and sugar alcohols such as mannitol and sorbitol, surfactants such as polysorbate (Tweens), and glycerol and dimethylsulfoxide . Cryopreservatives also include water-soluble polymers such as polyvinylpyrrolidone (PVP), starch and polyalkoxyethers such as polyethylene glycol, polypropylene glycol and poloxamers. Biologically derived cryopreservatives include albumin. Another class of cryopreservatives includes pegylated lipids such as Solutol. Preferred cryopreservatives are carbohydrates. Preferred carbohydrates are monosaccharides or disaccharides. A preferred disaccharide is sucrose. Another preferred cryopreservative includes polymers such as, but not limited to, those listed above. Yet another preferred cryopreservative is albumin.

Viscosity modifiers are agents that affect the viscosity of a composition. Examples of such regulators are carbohydrates (eg cellulose, gums, sugars, sugar alcohols), polymers (eg poloxamers, poloxamines, polyvinylpyrrolidone), proteins (eg albumin, milk proteins). These agents are listed in the Handbook of Pharmaceutical Additives, published by Gower, in the chapters Thickeners, Viscosity control agents, Consistency regulators, Bodying agents, Antigellants, etc., which is incorporated herein by reference and constitutes a part hereof.

Suitable osmotic agents include sugars (eg, glucose, sucrose), sugar alcohols (eg, mannitol, sorbitol), salts (eg, sodium chloride), glycerol and glycerol derivatives, and the like.

Examples of suitable co-solvents are ethanol, dimethylsulfoxide, and N-methyl-2-pyrrolidone. Other examples include lactic acid, acetic acid and other liquid carboxylic acids.

Excipients comprise from about 0.001% to about 20%, preferably from about 0.01% to about 5%, by weight of the composition.

Excipients can be added to the aqueous medium during nanoparticle preparation, or added directly to the medicament prior to mixing with the aqueous medium. If the agent is dissolved in the organic phase prior to mixing with the aqueous anti-solvent, the excipients can be added to the organic phase prior to precipitation.

3. Particle size and shape of nanoparticles

In the present invention, particle size is determined by dynamic light scattering methods (e.g., photon correlation spectroscopy, laser diffraction, small angle laser light scattering (LALLS), medium angle laser light scattering (MALLS), light obscuration (e.g. Coulter method), rheology or microscopy (optical or electron microscopy) within the above ranges). The invention is applicable to nanoparticle and microparticle suspensions over a wide range of particle sizes. The particles preferably have an average effective particle size of less than about 100 μm, more preferably less than about 7 μm, more preferably less than about 2 μm, most preferably less than about 400 nm, even more preferably less than about 200 nm or any range or combination within this range.

4. Preparation method of nanoparticle suspension

Aqueous nanoparticle suspensions of pharmaceutical agents may be prepared by any method including mechanical grinding of the active agent, precipitation techniques, or methods of suspending the pharmaceutical agent. Mechanical milling includes techniques such as jet milling, pearl milling, ball milling, hammer milling, fluid energy milling, or wet milling, as disclosed in U.S. Patent No. 5,145,684, which is incorporated herein by reference and constituted herein. part.

A precipitation step may be used to prepare a suspension of particles, which is further subjected to a step of applying energy. As disclosed in U.S. Patent No. 5,091,188 (which is incorporated herein by reference and constitutes a part hereof), the step of applying energy includes subjecting the particle dispersion to high shear conditions, such as using a microfluidizer, piston gap uniformity, etc. Cavitation, shear or impact forces applied by a homogenizer or countercurrent homogenizer. Suitable piston gap homogenizers are commercially available, such as those sold under the tradename EMULSIFLEX by Avestin and French Pressure Cells by Spectronic Instruments. Suitable microfluidizers are available from Microfiuidics Corp. The crystal seeding step described below may be performed at any time during which the solution is subjected to high shear conditions, most preferably prior to the energy applying step.

The step of applying energy can also be accomplished using ultrasound techniques. The sonication step can be performed using any suitable ultrasonic equipment such as a Branson Model S-450A or a Cole-Parmer 500/750 Watt Model. These devices are well known in the industry. Typically, an ultrasound device has an ultrasound horn or probe that is inserted into a solution containing the drug and emits acoustic energy into the solution. In a preferred embodiment of the present invention, the ultrasonic device operates at a frequency of about 1 kHz to about 90 kHz, more preferably about 20 kHz to about 40 kHz, or any range or combination thereof. The probe size can vary, preferably different sizes such as 1/2 inch or 1/4 inch. During sonication, it is also advantageous to cool the solution to a temperature below room temperature. The crystal seeding step described below may be performed at any time during which the solution is subjected to high shear conditions, most preferably prior to the energy applying step.

precipitation method

In the precipitation method, the agent is dissolved in a solvent to obtain a solution. The solution is then mixed with an aqueous medium to obtain a pre-suspension of fine particles of the medicament. The aqueous medium may optionally contain one or more excipients selected from surface modifiers, pH regulators, cryopreservatives, crystal growth modifiers, osmotic agents, solubilizers, and viscosity regulators agent. Excipients may also be included in the solvent in which the agent is dissolved prior to the precipitation step. Energy can be applied to the pre-suspension to stabilize the agent coating, change the lattice structure, or further reduce the size of the precipitate particles, as desired. Energy sources include, but are not limited to, ultrasound, homogenization, microflow, countercurrent homogenization, or other methods of providing impact, shear, or cavitation forces. Energy sources also include methods for the continuous input of heat in the form of heating or cooling, or through temperature changes (eg cycling).

Some known precipitation methods are emulsion evaporation precipitation, microprecipitation, solvent-anti-solvent precipitation, supercritical fluid precipitation, temperature change precipitation, pH change precipitation, and crystal seeding.

Emulsion Evaporation and Precipitation

Emulsion evaporation methods are disclosed in US Patent Application Serial No. 09/964,273, which is incorporated herein by reference and made a part hereof. The method comprises the steps of: (1) providing a multiphase system comprising an organic phase and an aqueous phase, the organic phase containing a pharmaceutically effective compound; and (2) sonicating the system to evaporate a portion of the organic phase, leaving the aqueous phase The compound in precipitates with an average effective particle size of less than about 2 μm. The step of providing a heterogeneous system comprises the following steps: (1) mixing a water-immiscible solvent (oil phase) with a pharmaceutically effective compound to obtain an organic solution, (2) using one or more surface-active compounds A water-based solution is prepared, and (3) the organic solution is mixed with the aqueous solution to form a multiphase system. Agitation or mixing of heterogeneous systems forms macroemulsions. In this macroemulsion, the water will contain oil droplets approximately less than about 1 μm in diameter. The coarse emulsion is ultrasonically treated to obtain a microemulsion, and finally a suspension of submicron particles.

The water-immiscible solvent is selected from linear, branched or cyclic alkanes having 5 or more carbon atoms, linear, branched or cyclic alkenes having 5 or more carbon atoms, the number of carbon atoms 5 or more linear, branched or cyclic alkynes, aromatic hydrocarbons, fully or partially halogenated hydrocarbons, ethers, esters, ketones, mono-, diglycerides or triglycerides, natural oils, alcohols, aldehydes , acids, amines, linear or cyclic siloxanes, hexamethyldisiloxane, or any combination of these solvents. A preferred water immiscible solvent is dichloromethane.

The sonication step can be replaced by any other means of providing energy, examples of other sources of energy being ultrasound, homogenization, microflow, countercurrent homogenization, or other methods of providing impact, shear or cavitation forces.

microprecipitation

Microprecipitation methods are disclosed in US patent applications 60/258,160, 09/874,799, 09/874,637, 09/874,499, and 09/953,979. Small particles of organic compounds are formed by precipitating the organic compound in an aqueous medium to form a presuspension, followed by application of energy to stabilize the coating of the particles or change the lattice structure of the particles. This method is preferably used for the preparation of suspensions of poorly water soluble pharmaceutically active compounds suitable for parenteral or oral administration.

The methods can be divided into two categories, method A and method B.

Method A

In Method A, an organic compound ("drug") is first dissolved in a first solvent to form a first solution. The organic compound is added in an amount of about 0.1% (w/v) to about 50% (w/v) depending on the solubility of the organic compound in the first solvent. To ensure complete dissolution of the compound in the first solvent, it is necessary to heat the concentrate from about 30°C to about 100°C.

Adding thereto one or more optional surface modifiers selected from, for example, anionic surfactants, cationic surfactants, nonionic surfactants or biosurfactant molecules to obtain a second aqueous solution .

It is also advantageous to add a pH adjusting agent to the second solution, selected from the group such as buffer, sodium hydroxide, hydrochloric acid, tris (hydroxymethyl) aminomethane buffer, citrate, acetate, milk salt, meglumine, etc. Other buffering agents include amino acids such as glycine, leucine, alanine, lysine, and the like. The pH of the second solution is in the range of about 2 to about 11.

In a preferred mode of the present invention, the method for preparing submicron-sized organic compound particles includes the step of adding the first solution to the second solution. The rate of addition depends on the size of the batch and the kinetics of precipitation of the organic compound. Typically, for a small scale laboratory preparation process (1 L prepared), the rate of addition is from about 0.05 cc/min to about 10 cc/min. During the addition, the solution should be under constant stirring. The formation of amorphous particles, semi-crystalline solids or supercooled liquids, as observed by light microscopy, gave presuspensions. The method also includes the step of subjecting the presuspension to an annealing step to convert the amorphous particles, supercooled liquid or semi-crystalline solid to a more stable crystalline solid state. The resulting particles will have an average effective particle size as determined by dynamic light scattering methods such as photon correlation spectroscopy, laser diffraction, small angle laser light scattering (LALLS), medium angle laser light scattering (MALLS), shading methods such as Coulter method), rheology, or microscopy (optical or electronic)).

Methods of applying energy involve adding energy by sonication, homogenization, countercurrent homogenization, microscopic flow, or other methods that provide impact, shear, or cavitation forces. The sample can be cooled or heated during this stage. In a preferred form of the invention, the annealing step is carried out with a piston gap homogenizer such as that sold by Avestin Inc. under the tradename EmulsiFlex-C160. In another preferred mode of the present invention, the annealing is accomplished by ultrasonic treatment with an ultrasonic processor, such as Vibra-Cell Ultrasonic Processor (600W) manufactured by Sonics and Materials, Inc. In yet another preferred embodiment of the present invention, annealing is performed using emulsification equipment as described in US Patent No. 5,720,551, which is incorporated herein by reference and constitutes a part of this document.

Depending on the annealing rate, the temperature of the treated sample is advantageously adjusted in the range of about -30°C to 30°C. Additionally, heating of the pre-suspension to a temperature of about 30°C to about 100°C during annealing is also necessary in order to achieve the desired phase transition in the processed solid.

In addition to amorphous solids, semi-crystalline solids or supercooled liquids, pre-suspensions may contain friable crystals that break more easily than their solid state before settling. Thus, an energy application step breaks up the particles to the desired size.

Method B

Method B differs from Method A in the following ways. The first difference is that the surfactant or combination of surfactants is added to the first solution. Surfactants may be selected from nonionic, anionic and cationic surfactants.

In addition to amorphous particles, semi-crystalline solids or supercooled liquids, pre-suspensions may contain friable crystals that break more easily than their solid state before settling. Thus, an energy application step breaks up the particles to the desired size.

One suitable emulsion precipitation technique is disclosed in co-pending, commonly assigned US Application Serial No. 09/964,273, which is incorporated herein by reference and made a part hereof. The method comprises the steps of: (1) providing a multiphase system comprising an organic phase and an aqueous phase, the organic phase containing a pharmaceutically effective compound, and (2) sonicating the system to evaporate a portion of the organic phase, causing the aqueous phase to Compounds precipitated with an average effective particle size of less than about 2 μm. The step of providing a heterogeneous system comprises the steps of: (1) combining a water immiscible solvent with a pharmaceutically effective compound to obtain an organic solution, (2) preparing an aqueous solution with one or more surface active compounds , and (3) mixing the organic solution with the aqueous solution to form a heterogeneous system. The step of mixing the organic phase with the aqueous phase includes the use of piston gap homogenizers, colloid mills, high speed mixing equipment, extrusion equipment, hand mixing or shaking equipment, microfluidizers, or other equipment or techniques that provide high shear conditions. The water in the coarse emulsion contains oil droplets with a diameter of approximately less than 1 μm. The coarse emulsion is ultrasonically treated to obtain a microemulsion, and finally a suspension of submicron particles.

The optional polymorph control step described in detail below can be performed by any of these steps. The polymorph control step can be performed before or after sonicating the system. In the most preferred form of the invention, the polymorph control step is performed during sonication.

Another method of making submicron sized particles is disclosed in co-pending, commonly assigned US application Ser. No. 10/183,035, which is incorporated herein by reference and made a part hereof. The method comprises the steps of: (1) providing a heterogeneous coarse dispersion comprising an organic phase and an aqueous phase, the organic phase comprising a pharmaceutical compound; (2) applying energy to the coarse dispersion to form a fine dispersion; (3) freezing the a fine dispersion; and (4) freeze-drying the fine dispersion to obtain submicron particles of the pharmaceutically effective compound. The step of providing a heterogeneous system comprises the steps of: (1) combining a water immiscible solvent with a pharmaceutically effective compound to obtain an organic solution, (2) preparing an aqueous solution with one or more surface active compounds , and (3) mixing the organic solution with the aqueous solution to form a heterogeneous system. The step of mixing the organic phase with the aqueous phase includes the use of piston gap homogenizers, colloid mills, high speed mixing equipment, extrusion equipment, hand mixing or shaking equipment, microfluidizers, or other equipment or techniques that provide high shear conditions.

The polymorph control step described in detail below can be performed during any of these steps. In the most preferred mode of the present invention, the polymorph control step is performed by the mixing step (3) in the step of providing a multiphase system.

Solvent Anti-Solvent Precipitation

Suitable solvent anti-solvent precipitation techniques are disclosed in US Patent Nos. 5,118,528 and 5,100,591, which are incorporated herein by reference and made a part of this disclosure. The method comprises the following steps: (1) preparing a liquid phase of a biologically active substance in a solvent or a solvent mixture, to which one or more surfactants may be added; (2) preparing a second liquid phase of a non-solvent or a non-solvent mixture. Liquid phase, non-solvent miscible with a solvent or solvent mixture of the substance, (3) adding solutions (1) and (2) together by stirring, and (4) removing unwanted solvent to obtain a colloidal suspension of nanoparticles liquid. The patent states that it produces particles of matter smaller than 500nm without the need to provide energy.

As noted above, the optional polymorph control step described in detail below may be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is carried out in step (3) before adding solutions (1) and (2) together.

phase inversion precipitation

A suitable phase inversion precipitation method is disclosed in US Patent Nos. 6,235,224, 6,143,211 and US Patent Application 2001/0042932, which are incorporated herein by reference and made a part hereof. Phase inversion is a term used to describe the physical phenomenon of a polymer dissolved in a continuous phase solvent system transforming into a solid macromolecular network in which the polymer is the continuous phase. One way to induce phase inversion is to add a non-solvent to the continuous phase. The polymer changes from a single phase to an unstable two-phase mixture: a polymer-rich fraction and a polymer-poor fraction. In the polymer-rich phase, non-solvent micellar droplets serve as nucleation sites and are encapsulated by the polymer. Patent 6,235,224 states that, under certain conditions, phase inversion of a polymer solution can spontaneously form discrete microparticles, including nanoparticles. This patent discloses dissolving or dispersing a polymer in a solvent. Agents are also dissolved or dispersed in solvents. For the optional polymorph control step to be effective in the present invention, it is desirable that the agent be dissolved in the solvent. Together the polymer, agent and solvent form a mixture comprising a continuous phase, wherein the solvent is the continuous phase. The mixture is then added to at least a 10-fold excess of a miscible non-solvent to spontaneously form microencapsulated particles of the agent with an average particle size of 10 nm to 10 μm. Particle size is influenced by the solvent to non-solvent volume ratio, polymer concentration, viscosity of the polymer-solvent solution, polymer molecular weight and the nature of the solvent-non-solvent pair. This method omits the step of generating solvent droplets, eg by forming an emulsion. This method also eliminates agitation and/or shearing forces.

The optional polymorph control step detailed below can be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is performed before or during the addition of the non-solvent to the continuous phase.

PH change precipitation

The pH change precipitation technique typically involves the steps of dissolving the drug in a solution having a pH at which the drug is soluble, followed by changing the pH so that the drug is no longer soluble. Depending on the particular pharmaceutical compound, the pH can be acidic or basic. The solution is then neutralized to form a presuspension of submicron sized particles of the pharmaceutically active compound. A suitable pH change precipitation method is disclosed in US Patent No. 5,665,331, which is incorporated herein by reference and made a part hereof. The method comprises the steps of dissolving an agent in an alkaline solution together with a crystal growth modifier (CGM) and then neutralizing the solution with an acid in the presence of a suitable surface-modifying surfactant to form fine particles of the agent Dispersions. The precipitation step may be followed by a membrane permeation purification step of the dispersion, followed by adjustment of the concentration of the dispersion to the desired concentration. The reported method yields crystallite particles with a Z-average diameter of less than 400 nm (measured by photon correlation spectroscopy).

The optional polymorph control step described in detail below may be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is performed before or during the neutralization step.

Examples of other pH change precipitation methods are disclosed in US Patent Nos. 5,716,642, 5,662,883, 5,560,932 and 4,608,278, which are incorporated herein by reference and made a part hereof.

Injection Precipitation Method

Suitable injection precipitation techniques are disclosed in US Patent Nos. 4,997,454 and 4,826,689, which are incorporated herein by reference and made a part hereof. First, a suitable solid compound is dissolved in a suitable organic solvent to form a solvent mixture. Then, inject the precipitate miscible with the organic solvent into the solvent mixture with a non-solvent, the temperature is about -10°C to about 100°C, and the injection rate is about 0.01ml/min to about 1000ml/min per 50ml volume, to prepare A suspension of precipitated non-agglomerated compound solid particles having a substantially uniform mean diameter of less than 10 μm. It is preferable to perform agitation (for example, stirring) of the solution when injecting the non-solvent for precipitation. The non-solvent may contain surfactants to stabilize the particles against agglomeration. The particles are then separated from the solvent. Depending on the solid compound and desired particle size, the present invention can vary temperature, non-solvent to solvent ratio, injection rate, stirring rate and volume parameters. The particle size is directly proportional to the volume ratio of non-solvent and solvent, and the injection temperature, and inversely proportional to the injection rate and stirring rate. The non-solvent for precipitation can be aqueous or non-aqueous, depending on the relative solubility of the compounds and the desired suspending vehicle.

The optional polymorph control step described in detail below can be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is performed before or during the injection of the non-solvent.

temperature change precipitation

The temperature change precipitation technique, also known as the hot melt technique, is disclosed in Domb, US Pat. No. 5,188,837, which is incorporated herein by reference and made a part hereof. In one embodiment of the invention, lipid globules are made by (1) melting or dissolving a substance to be delivered, such as a drug, in a molten excipient to form a liquid of the substance to be delivered; (2) At a temperature above the melting point of the substance or excipient, the phospholipids are added to the molten substance or excipient together with an aqueous medium; (3) the suspension is mixed at a temperature above the melting point of the excipient until obtaining Uniform fine particle formulation; then (4) rapid cooling of the formulation to room temperature or below.

The optional polymorph control step described in detail below can be performed during any of these steps as long as the processing temperature is not above the melting point of the drug. In the most preferred form of the invention, the polymorph control step is performed prior to cooling the warm dispersion of the pharmaceutical agent.

solvent evaporation

Solvent evaporation precipitation techniques are disclosed in US Pat. No. 4,973,465, which is incorporated herein by reference and made a part hereof. This patent discloses a method for preparing microcrystals, said method comprising the steps of: (1) providing a solution of a pharmaceutical composition and a phospholipid dissolved in a common organic solvent or solvent mixture; (2) evaporating the solvent or solvent mixture, and (3) vigorously stirring the film obtained by evaporating the solvent or the solvent mixture in the aqueous solution to suspend it in the aqueous solution. The compound can be precipitated by applying energy to the solution to evaporate a sufficient amount of the solvent, thereby removing the solvent. The solvent can also be removed by other known techniques such as applying a vacuum to the solution or blowing nitrogen over the solution. The optional polymorph control step described in detail below can be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is performed before the evaporation step.

reaction precipitation

Reaction precipitation involves the step of dissolving the drug compound in a suitable solvent to form a solution. The compound should be added in such an amount that the compound reaches the saturation point or less in the solvent. Compounds are modified by reaction with chemical reagents, or modification methods associated with the application of energy (eg, heat or UV light, etc.), so that the modified compound has a lower solubility in the solvent and precipitates out of solution. The optional polymorph control step described in detail below can be performed during any of these steps. In the most preferred form of the invention, the polymorph control step is performed before or during the precipitation step.

Compressed Fluid Sedimentation

A suitable technique for precipitation by compressing fluids is disclosed in WO 97/14407 to Johnston, which is incorporated herein by reference and made a part hereof. The method includes the step of dissolving the water-insoluble drug in a solvent to form a solution. The solution is then sprayed into a compressed fluid, which can be a gas, liquid or supercritical fluid. Adding a compressed fluid to a solution of a solute in a solvent causes the solute to reach or approach supersaturation and precipitate out as fine particles. Here, the compressed fluid acts as an anti-solvent, which reduces the cohesive energy density of the solvent in which the drug is dissolved.

Alternatively, the drug can be dissolved in a compressed fluid, which is then sprayed into the aqueous phase. The rapid expansion of the compressed fluid reduces the solvency of the fluid, which in turn causes the solute to precipitate as fine particles in the aqueous phase. Here, the compressed fluid acts as a solvent.

To stabilize the particles against agglomeration, surface modifiers such as surfactants may be included in the technique. Particles produced by this technique are typically 500 nm or smaller.

The optional polymorph control step detailed below may be performed by any of these steps. In the most preferred form of the invention, the polymorph control step is performed before or during the particle formation step.

suspension method

Another method of preparing an aqueous nanoparticle suspension is the suspension method. In this method, medicament particles are dispersed in an aqueous medium by adding the particles directly to the aqueous medium to obtain a presuspension. The particles are typically coated with a surface modifier to inhibit particle agglomeration. One or more other excipients may be added to the medicament or to the aqueous medium.

Energy can be applied to the agent or pre-suspension to reduce the particle size of the agent to a desired size. Examples of energy sources include, but are not limited to, ultrasound, homogenization, microflow, countercurrent homogenization, or other methods of providing impact, shear, or cavitation forces.

Polymorph Control Methods

The method of preparing the suspension also includes a crystal seeding step to control the crystal structure of the drug. The term "crystal structure" refers to the arrangement and/or conformation of molecules within a crystal lattice. Compounds that are capable of crystallizing into different crystal structures are known as polymorphs. The identification of polymorphic forms is an important step in the drug manufacturing process, because different polymorphic forms of the same drug exhibit different solubility, therapeutic activity, bioavailability, and suspension capacity. Likewise, different polymorphs of the same excipient exhibit different solubility, compatibility with the drug being delivered, chemical stability, and suspension stability. Therefore, controlling the polymorphic form of a compound is important to ensure product purity and batch-to-batch reproducibility.

In the methods described above, the polymorphic form of a compound can be controlled by an additional step of crystal seeding. Crystal seeding involves utilizing a seed compound or applying energy to form a seed compound. In a preferred embodiment of the invention, the seed compound is a pharmaceutically active compound in the desired polymorphic form. Alternatively, the seed compound may also be an inert impurity or an organic compound that is structurally similar to the desired polymorph.

The seed compound can be precipitated from the drug-containing solution in any of the methods. The method comprises the steps of: adding a pharmaceutically active compound in an amount sufficient to exceed its solubility in a first solution to form a supersaturated solution. The supersaturated solution is processed to precipitate the pharmaceutically active compound in the desired polymorph. Treating a supersaturated solution involves aging the solution for a period of time until crystal formation is observed, resulting in a seed mixture. Treating the solution also includes changing the temperature or pH of the solution. Energy can also be applied to supersaturated solutions to precipitate the pharmaceutically active compound from solution in the desired polymorphic form. Energy can be applied by various methods including the energy application step described above. Alternatively, energy can be applied by heating the presuspension or exposing it to a source of electromagnetic energy, particle beam or electron beam. Electromagnetic energy includes the use of laser beams, dynamic electromagnetic energy, or other sources of radiation. The use of ultrasound, electrostatic fields, and electrostatic magnetic fields as sources of energy application has also been considered.

In a preferred mode of the present invention, the method for preparing seed crystals from a matured supersaturated solution comprises the following steps: (i) adding a certain amount of a pharmaceutically active compound to a drug solution to obtain a supersaturated solution, (ii) ripening The supersaturated solution forms detectable crystals, producing a seed mixture; and (iii) precipitating the seed mixture forms a presuspension. The presuspension is then further processed as described herein to obtain an aqueous suspension of the pharmaceutically active compound in the desired polymorphic form and in the desired particle size range.

The step of seeding the crystals can also be accomplished by applying energy to the first solution or pre-suspension to form the seed compound, so long as the exposed liquid or liquid mixture contains the drug compound or seed material. Energy can be applied to a supersaturated solution in the same manner as above.

Accordingly, the present invention provides a composition of a pharmaceutical compound having a desired polymorph substantially free of unspecified polymorphs. It is contemplated that the methods of the present invention can be used to selectively prepare desired polymorphic forms of a variety of pharmaceutical compounds.

6. Sterilization of the composition

Depending on the thermal stability of the particular components of the composition and the particle size of the composition, the composition may be heat sterilized or filtered and then sterilized prior to freezing. A preferred method of preparing a sterile product is to filter selected components and then sterilize before freezing. Another sterilization method of the present invention is gamma irradiation before or after freezing.

Example

Example 1: Preparation of itraconazole suspension by homogenization and then freezing the suspension using microprecipitation method A

Surfactant solution : Into a 4 L flask was added 3500 mL of distilled water, 22 g of glycerin, 22 g of poloxamer 407, and 22 g of poloxamer 188. The surfactant solution was heated and stirred to dissolve the solids. The surfactant solution was cooled and diluted to 4 L with distilled water.

Itraconazole concentrate : In a 100 mL beaker, mix 15 g of itraconazole and 67.5 g of lactic acid. The mixture was heated to dissolve the solids. Cool the itraconazole concentrate to room temperature.

Pre-suspension : Transfer the itraconazole concentrate to a 60 mL syringe. Transfer 1.5 L of the surfactant solution to the jacketed homogenizer funnel. Place the overhead agitator into the diluted solution until the mixing blades are fully immersed. Using a syringe pump, slowly add the itraconazole concentrate to the diluted solution with stirring.

Homogenize the Suspension : The pre-suspension was immediately homogenized (10,000 psi) for about 20 minutes.

Final Suspension : The suspension was homogenized by centrifugation for 20 minutes to remove excess lactic acid. The supernatant was poured off and the solid was resuspended in a surfactant solution consisting of fresh surfactant solution. The suspension was mixed and centrifuged for 20 minutes. The supernatant was poured off and the solid was resuspended in a surfactant solution consisting of fresh surfactant solution. The resuspended sample was homogenized at 10,000 psi for approximately 20 minutes. The final pH of the suspension was about 4. The suspension was collected into 50 mL bottles and sealed with Teflon(R) taped stoppers.

Frozen Suspensions: Place 3-50 mL final suspension samples in a -20°C ice freezer, store 3-50 mL final suspension samples at 2-8°C. After approximately 1 month, samples were removed from -20°C and allowed to thaw at ambient conditions. Samples were transferred to 2-8°C. No phase separation, apparent coalescence or agglomeration was observed. The particle size distribution of the samples subjected to freezing and the comparative samples stored at 2-8°C were measured by laser light scattering method. There was no discernible difference in particle size distribution between the frozen and comparative samples (below). Sample ID The average particle size 99% particle size Comparative sample-1Comparative sample-1Sonication for 1 minuteComparative sample-2Comparative sample-2Sonication for 1 minuteComparative sample-3Comparative sample-3Sonication for 1 minuteFrozen sample-1Frozen sample-1Sonication for 1 minuteFrozen sample -2 frozen sample -2 sonication for 1 minute frozen sample -3 frozen sample -3 sonication for 1 minute 0.2430.2380.2400.2470.2500.2660.2460.2610.2320.2450.2360.241 0.5100.5100.5100.5100.5100.5100.5100.5100.5100.5100.5100.510

It is reasonable to speculate that frozen suspensions are stable for 1 year or more under these storage conditions.

Example 2: Stabilization of Amorphous Itraconazole Nanosuspensions by Storage at -70°C

4.0 g of itraconazole was dissolved in 20 mL of dichloromethane and mixed with 400 mL of 5% albumin solution (diluted from a 25% solution). The mixed solution was shaken manually to effectively disperse the two liquids. The crude emulsion was then sonicated (T = 5°C) for 6 minutes (sonication was performed every 30 seconds with a 1" probe at 40% amplitude). The sonicated solution was placed under house vacuum (about 100 Torr) ) for about 1/2 hour, and then for about 2 hours under pump vacuum (<20 torr). The rotovapped product was analyzed with light scattering detection (Horiba) and showed an average particle diameter of 406 nm. The product is then sent to Galbraith Laboratories Inc. for GC headspace analysis, showing that the dichloromethane concentration is 12.3ppm.Visible optical microscope inspection shows that the particles are spherical without crystallization signs.In addition, the particles made by the method are X-rayed X-ray powder diffraction analysis further proved that it is completely amorphous.

Store approximately 35 mL of product at -70°C for 32 days. Reanalysis of the suspension by HORIBA light scattering detection and microscopy showed essentially no change in particle size (427 nm average). It is reasonable to speculate that under such storage conditions, frozen suspensions are stable for a year or more.

Example 3: 1% budesonide in PEG-phosphoester surfactant system

Ingredients: Budesonide 1%

1.2% mPEG-PSPE, molecular weight 2000

2.25% glycerin

0.14% Disodium Hydrogen Phosphate

A weighed amount of mPEG-PSPE (palmitoyl-stearoyl-phosphatidylethanolamine) and a volume of a pre-made aqueous solution containing 2.25% glycerol and 0.14% disodium hydrogen phosphate, pH 8.6 were mixed and stirred with high shear stirrer. The drug is added and the mixture is stirred under high shear to form a pre-suspension. The pre-suspension was homogenized 30 times under a pressure of 25,000 psi.

A portion of the sample was frozen at -20°C for 24 hours and then allowed to thaw completely at room temperature.

Particle size test results (measured by laser diffractometer) Diameter (by volume-weight) Initial (microns) After freeze-thaw (microns) average 0.8472 0.8371 99% 1.688 1.685

Example 4: 1% Nabumetone Containing Albumin Surfactant

Ingredients: 5% Human Albumin

1% Nabumetone

Mix 1 volume of albumin solution with weighed drug and mix under high shear to form a pre-suspension. The pre-suspension was homogenized 30 times under a pressure of 25,000 psi.

A portion of the sample was frozen at -20°C for 24 hours and then allowed to thaw completely at room temperature.

Particle size test results (measured by laser diffractometer) Diameter (by volume-weight) Initial (microns) After freeze-thaw (microns) average 0.7721 0.7940 99% 1.889 1.936

Example 5: 1% Nabumetone Containing Polyalkoxyether Surfactant and Bile Salt

Element:

2.2% Poloxamer 188

0.1% deoxycholate

2.2% glycerin

1% Nabumetone

Mix a weighed amount of drug with a volume of a solution containing 2.2% poloxamer 188, 0.1% sodium deoxycholate, and 2.2% glycerol, adjust the pH of the solution to 8.7, and mix under high shear to form a presuspension liquid. The pre-suspension was homogenized 20 times under a pressure of 25,000 psi.

A portion of the sample was frozen at -20°C for 24 hours and then allowed to thaw completely at room temperature.

Particle size test results (measured by laser diffractometer) Diameter (by volume-weight) Initial (microns) After freeze-thaw (microns) average 1.0498 1.085 99% 2.423 2.484

Example 6: Budesonide 1% Containing PEG-Fatty Acid Ester

Element:

0.125% Solutol

2.25% glycerin

1% budesonide

A weighed amount of drug was mixed with a volume of solution containing 0.125% Solutol and 2.25% glycerin, the pH of the solution was adjusted to 8.7, and high shear mixing was performed to form a pre-suspension. The pre-suspension was homogenized 30 times under a pressure of 25,000 psi.

A portion of the sample was frozen at -20°C for 24 hours and then allowed to thaw completely at room temperature.

Particle size test results (measured by laser diffractometer) Diameter (by volume-weight) Initial (microns) After freeze-thaw (microns) average 0.7587 0.7641 99% 1.460 1.480

Embodiment 7:

Ingredients: 1% Vitamin E TPGS (d-alpha tocopheryl macrogol 1000 succinate)

1% Nabumetone

2.25% glycerin

0.14% Disodium Hydrogen Phosphate

A weighed amount of vitamin E TPGS was mixed with 1 volume of a pre-made aqueous solution containing 2.25% glycerol and 0.14% disodium hydrogen phosphate at a pH of 8.6. Stir the mixture with a vortex mixer until the vitamin E TPGS dissolves. The drug is added and the mixture is ultraturraxed to form a pre-suspension. The pre-suspension was homogenized 30 times with an Avestin B3 homogenizer under a pressure of 25 kpsi.

A portion of the sample was frozen at -20°C for 24 hours and then allowed to thaw completely at room temperature.

Particle Size Test Results Diameter (by volume-weight) Initial (microns) After freeze-thaw (microns) 99% unsonicated 2.372μm 2.593μm 99% of Ultrasound Treatment 2.266μm 2.398μm Sonicated mean 1.0332μm 1.0333μm

While particular embodiments have been illustrated and described, various changes may be made without departing from the spirit of the invention, and the scope of protection is limited only by the scope of the following claims.

Claims (104)

1. the suspension composition of the chemical compound of a poorly water-soluble, described compositions comprises the compound particle that is suspended in the chilled water substrate.

2. according to the compositions of claim 1, the dissolubility of wherein said chemical compound in water is lower than 10.0mg/ml.

3. according to the compositions of claim 1, wherein said chemical compound is selected from crystalline phase medicament, amorphous phase medicament, crystalline phase cosmetics and amorphous phase cosmetics.

4. according to the compositions of claim 1, wherein medicament is selected from therapeutic agent and diagnostic agent.

5. according to the compositions of claim 4, wherein therapeutic agent is selected from analgesic, antiinflammatory, anthelmintic, antiarrhythmics, antibiotic, anticoagulant, antidepressant, antidiabetic drug, antuepileptic, antifungal, antihistaminic, antihypertensive, the muscarine antagonist agent, the mycobacteria agent, antineoplastic agent, antiprotozoal, immunosuppressant, immunostimulant, antithyroid drug, antiviral agents, anti-worried tranquilizer, astringent, β-adrenoreceptor blocker, contrast agent, corticosteroid, the cough suppressant, diagnostic agent, the diagnosis developing agent, diuretic, dopaminergic, hemorrhage, immune substance, the lipid regulator, muscle speeds to delay medicine, parasympathomimetic agent, the parathyroid gland calcitonin, prostaglandin, radiopharmaceutical, gonadal hormone, antiallergic agent, analeptic, sympathomimetic, thyroid drug, vasodilation, vaccine and xanthine.

6. according to the compositions of claim 4, wherein said therapeutic agent is selected from itraconazole, nabumetone and budesonide.

7. according to the compositions of claim 1, wherein in composition total weight, chemical content is that about 0.01wt% is to about 50wt%.

8. according to the compositions of claim 1, wherein the particle diameter of medicament is about 50nm to 50 μ m.

9. according to the compositions of claim 1, wherein the average diameter of pharmacy particle is about 50nm to 2 μ m.

10. according to the compositions of claim 1, wherein surpass 99% particle grain size approximately less than about 5 μ m.

11. according to the compositions of claim 1, described compositions also comprises one or more excipient, described excipient is selected from surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

12. according to the compositions of claim 11, wherein surface modifier is selected from anion surfactant, cationic surfactant, non-ionic surface active agent and the agent of surface activity bio-modification.

13. according to the compositions of claim 12, wherein non-ionic surface active agent is selected from: the ether of polyoxyethylene aliphatic alcohol, polyoxyethylene sorbitan fatty acid ester; the ester of polyoxyethylene fatty acid, the lipid of polyoxyethylene derivative be mPEG-PSPC (palmityl-stearoyl-phosphatidyl choline) for example; mPEG-PSPE (palmityl-stearoyl-phosphatidyl ethanolamine), the ester of anhydro sorbitol; glyceryl monostearate; Polyethylene Glycol, polypropylene glycol, spermol; spermol stearyl alcohol mixture; stearyl alcohol, aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer; polaxamines; methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose; hydroxypropyl emthylcellulose; the amorphous cellulose element, polysaccharide, starch; starch derivatives; hetastarch, polyvinyl alcohol, and polyvinylpyrrolidone.

14. according to the compositions of claim 12, wherein anion surfactant is selected from potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulphosuccinate, glyceride, sodium carboxymethyl cellulose, bile acid and salt, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodesoxycholic acid and carboxymethylcellulose calcium.

15. according to the compositions of claim 12, wherein cationic surfactant is selected from quaternary ammonium compound, benzalkonium chloride, cetyl trimethylammonium bromide, chitosan, lauryl dimethyl benzyl ammonium chloride.

16. according to the compositions of claim 12, wherein the agent of surface activity bio-modification is selected from albumin, casein, heparin, hirudin or other protein.

17. compositions according to claim 11; wherein the pH regulator agent is selected from buffer agent, sodium hydroxide, hydrochloric acid, three (methylol) aminomethane, citrate, acetate, lactate, meglumine, aminoacid, and described aminoacid is selected from glycine, alanine, leucine, isoleucine, lysine, methionine, tyrosine, phenylalanine, tryptophan, histidine, proline, serine, glutamic acid, aspartic acid, agedoite, glutamine, cysteine and taurine.

18. according to the compositions of claim 11, wherein freezing preservative agent is selected from surfactant and other surfactant of carbohydrate, glycerol, poly-alkoxyl ether, PEG-fatty acid and lipid, bio-based.

19. according to the compositions of claim 18, wherein carbohydrate is selected from saccharide, disaccharide and sugar alcohol.

20. according to the compositions of claim 19, wherein disaccharide is a sucrose.

21. according to the compositions of claim 19, wherein sugar alcohol is a mannitol.

22. according to the compositions of claim 18, wherein surfactant is selected from polysorbate (tween), glycerol, poly-alkoxyl ether, PEG-fatty acid, PEG-lipid, albumin, starch and dimethyl sulfoxide.

23. according to the compositions of claim 11, wherein viscosity modifier is selected from carbohydrate, polymer and protein.

24. according to the compositions of claim 11, wherein in composition total weight, excipient content is about 0.001% to about 20%.

25. according to the compositions of claim 11, wherein in composition total weight, excipient content is about 0.01% to about 5%.

26. according to the compositions of claim 1, wherein suspension was stablized 6 months at least.

27. the method for the suspension of the aqueous medium of the chemical compound of a stable water soluble difference, described method comprises the steps:

Be provided at the suspension in the water-based; With

Freezing this aqueous suspension.

28. according to the method for claim 27, wherein the dissolubility of chemical compound in water is lower than 10.0mg/ml.

29. according to the method for claim 27, wherein chemical compound is selected from crystalline phase medicament, amorphous phase medicament, crystalline phase cosmetics and amorphous phase cosmetics.

30. according to the method for claim 27, wherein medicament is selected from therapeutic agent and diagnostic agent.

31. according to the method for claim 30, wherein therapeutic agent is selected from antifungal, analgesic, antiinflammatory, anthelmintic, antiarrhythmics, antibiotic, anticoagulant, antidepressant, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, the muscarine antagonist agent, antigen is given birth to biological medicine, the mycobacteria agent, antineoplastic agent, immunosuppressant, immunostimulant, antithyroid drug, antiviral agents, anti-worried tranquilizer, astringent, β-adrenoreceptor blocker, contrast agent, corticosteroid, the cough suppressant, diagnostic agent, the diagnosis developing agent, diuretic, dopaminergic, hemorrhage, immune substance, the lipid regulator, muscle speeds to delay medicine, parasympathomimetic agent, the parathyroid gland calcitonin, prostaglandin, radiopharmaceutical, gonadal hormone, antiallergic agent, analeptic, sympathomimetic, thyroid drug, vasodilation, vaccine and xanthine.

32. according to the method for claim 30, wherein therapeutic agent is selected from itraconazole, budesonide and nabumetone.

33. according to the method for claim 27, wherein in composition total weight, chemical content is that about 0.01wt% is to about 50wt%.

34. according to the method for claim 27, wherein the particle diameter of medicament is about 50nm to 50 μ m.

35. according to the method for claim 27, wherein the average diameter of pharmacy particle is about 50nm to 2 μ m.

36., wherein surpass 99% particle grain size approximately less than about 5 μ m according to the method for claim 27.

37. according to the method for claim 27, described method also is included in freezing step of sterilizing by filtration sterilization before.

38. according to the method for claim 27, described method also is included in freezing step of sterilizing by heat sterilization before.

39. according to the method for claim 27, described method also comprises the step of sterilizing by gamma-radiation.

40., wherein provide the step of suspension to be selected from following method according to the method for claim 27:

Medicament is deposited in obtains pre-suspension in the aqueous medium; With

Medicament is suspended in obtains pre-suspension in the aqueous medium.

41. according to the method for claim 40, wherein settling step is selected from: microdeposit, emulsion evaporation, the anti-solvent deposition of solvent, supercritical fluid precipitation, variations in temperature precipitation, pH change precipitation and crystal sowing.

42. according to the method for claim 40, the step that wherein suspends comprises the step that medicament is added aqueous medium.

43. according to the method for claim 42, described method also comprises the step that medicament or pre-suspension is applied energy.

44. method according to claim 43, wherein the step that medicament is applied energy comprises and is selected from that ultrasonic, homogenize, microcosmic flow, the method for adverse current homogenize, with impulsive force, shearing force or cavitation force are provided, or in a continuous manner or the method by variations in temperature input heat energy.

45. according to the method for claim 43, wherein pharmacy particle had first mean diameter before applying the energy step, and had second mean diameter after applying the energy step, wherein second mean diameter is less than first mean diameter.

46. according to the method for claim 40, wherein pre-suspension also comprises one or more excipient, described excipient is selected from surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

47. according to the method for claim 46, wherein surface modifier is selected from: anion surfactant, cationic surfactant, non-ionic surface active agent and the agent of surface activity bio-modification.

48. according to the method for claim 45, wherein non-ionic surface active agent is selected from: the ether of polyoxyethylene aliphatic alcohol, polyoxyethylene sorbitan fatty acid ester; the ester of polyoxyethylene fatty acid, the lipid of polyoxyethylene derivative be mPEG-PSPC (palmityl-stearoyl-phosphatidyl choline) for example; mPEG-PSPE (palmityl-stearoyl-phosphatidyl ethanolamine), the ester of anhydro sorbitol; glyceryl monostearate; Polyethylene Glycol, polypropylene glycol, spermol; spermol stearyl alcohol mixture; stearyl alcohol, aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer; polaxamines; methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose; hydroxypropyl emthylcellulose; the amorphous cellulose element, polysaccharide, starch; starch derivatives; hetastarch, polyvinyl alcohol, and polyvinylpyrrolidone.

49. according to the method for claim 47, wherein anion surfactant is selected from potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulphosuccinate, glyceride, sodium carboxymethyl cellulose, bile acid and salt, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodesoxycholic acid and carboxymethylcellulose calcium.

50. according to the method for claim 47, wherein cationic surfactant is selected from quaternary ammonium compound, benzalkonium chloride, cetyl trimethylammonium bromide, chitosan and lauryl dimethyl benzyl ammonium chloride.

51. according to the method for claim 47, wherein the agent of surface activity bio-modification is selected from albumin, casein, heparin, hirudin or other protein.

52. method according to claim 46; wherein the pH regulator agent is selected from sodium hydroxide, buffer agent, hydrochloric acid, three (methylol) aminomethane, citrate, acetate, lactate, meglumine, aminoacid, and described aminoacid is selected from glycine, alanine, leucine, isoleucine, lysine, methionine, tyrosine, phenylalanine, tryptophan, histidine, proline, serine, glutamic acid, aspartic acid, agedoite, glutamine, cysteine and taurine.

53. according to the method for claim 46, wherein freezing preservative agent is selected from surfactant and other surfactant of carbohydrate, glycerol, poly-alkoxyl ether, PEG-fatty acid and lipid, bio-based.

54. according to the method for claim 53, wherein carbohydrate is selected from saccharide, disaccharide and sugar alcohol.

55. according to the method for claim 54, wherein disaccharide is a sucrose.

56. according to the method for claim 54, wherein sugar alcohol is a mannitol.

57. according to the method for claim 53, wherein surfactant is selected from polysorbate (tween), glycerol, poly-alkoxyl ether, PEG-fatty acid, PEG-lipid, albumin, starch and dimethyl sulfoxide.

58. according to the method for claim 46, wherein viscosity modifier is selected from carbohydrate, polymer and protein.

59. according to the method for claim 46, wherein in pre-suspension gross weight, excipient content is about 0.001% to about 20%.

60. according to the method for claim 46, wherein in pre-suspension gross weight, excipient content is about 0.01% to about 5%.

61. method according to claim 43, wherein the step that pre-suspension is applied energy comprises the step of implementing following method, described method is selected from: ultrasonic, homogenize, microcosmic flow, adverse current homogenize and provide impulsive force, shearing force or cavitation force or in a continuous manner or the method by variations in temperature input heat energy.

62. according to the method for claim 41, wherein the emulsion method of evaporating comprises the steps:

With medicament be dissolved in the immiscible volatile solvent of water in form solution;

Solution is combined the formation emulsion with aqueous medium;

Emulsion is mixed the formation microemulsion; With

Remove in the microemulsion and form aqueous suspension with the immiscible volatile solvent of water.

63. according to the method for claim 62, wherein aqueous suspension also comprises one or more excipient, described excipient is selected from surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

64. according to the method for claim 63, wherein surface modifier is selected from: anion surfactant, cationic surfactant, non-ionic surface active agent and the agent of surface activity bio-modification.

65. according to the method for claim 64, wherein non-ionic surface active agent is selected from: the ether of polyoxyethylene aliphatic alcohol, polyoxyethylene sorbitan fatty acid ester; the ester of polyoxyethylene fatty acid, the lipid of polyoxyethylene derivative be mPEG-PSPC (palmityl-stearoyl-phosphatidyl choline) for example; mPEG-PSPE (palmityl-stearoyl-phosphatidyl ethanolamine), the ester of anhydro sorbitol; glyceryl monostearate; Polyethylene Glycol, polypropylene glycol, spermol; spermol stearyl alcohol mixture; stearyl alcohol, aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer; polaxamines; methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose; hydroxypropyl emthylcellulose; the amorphous cellulose element, polysaccharide, starch; starch derivatives; hetastarch, polyvinyl alcohol, and polyvinylpyrrolidone.

66. according to the method for claim 64, wherein anion surfactant is selected from: potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulphosuccinate, glyceride, sodium carboxymethyl cellulose, bile acid and salt, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodesoxycholic acid and carboxymethylcellulose calcium.

67. according to the method for claim 64, wherein cationic surfactant is selected from quaternary ammonium compound, benzalkonium chloride, cetyl trimethylammonium bromide, chitosan, lauryl dimethyl benzyl ammonium chloride.

68. according to the method for claim 64, wherein the agent of surface activity bio-modification is selected from: albumin, casein, heparin, hirudin or other protein.

69. method according to claim 63; wherein the pH regulator agent is selected from: buffer agent, sodium hydroxide, hydrochloric acid, three (methylol) aminomethane, citrate, acetate, lactate, meglumine and aminoacid, described aminoacid is selected from glycine, alanine, leucine, isoleucine, lysine, methionine, tyrosine, phenylalanine, tryptophan, histidine, proline, serine, glutamic acid, aspartic acid, agedoite, glutamine, cysteine and taurine.

70. according to the method for claim 63, wherein freezing preservative agent is selected from: surfactant and other surfactant of carbohydrate, glycerol, poly-alkoxyl ether, PEG-fatty acid and lipid, bio-based.

71. according to the method for claim 70, wherein carbohydrate is selected from saccharide, disaccharide and sugar alcohol.

72. according to the method for claim 71, wherein disaccharide is a sucrose.

73. according to the method for claim 71, wherein sugar alcohol is a mannitol.

74. according to the method for claim 70, wherein surfactant is selected from polysorbate (tween), poly-alkoxyl ether, PEG-fatty acid, PEG-lipid, albumin, starch, glycerol and dimethyl sulfoxide.

75. according to the method for claim 63, wherein viscosity modifier is selected from carbohydrate, polymer and protein.

76. according to the method for claim 63, wherein in the suspension gross weight, excipient content is about 0.001% to about 20%.

77. according to the method for claim 63, wherein in the suspension gross weight, excipient content is about 0.01% to about 5%.

78. method according to claim 62, wherein be selected from the immiscible volatile solvent of water: carbon number is 5 or more straight chain, side chain or cyclic alkane, carbon number is 5 or more straight chain, side chain or cyclic olefin, carbon number is 5 or more straight chain, side chain or ring-type alkynes, aromatic hydrocarbons, part or all of halogenated hydrocarbon, ether, ester, ketone, monoglyceride, two glyceride or triglyceride, natural oil, alcohol, aldehyde, acid, amine, straight chain or annular siloxane, hexamethyl disiloxane, or the combination in any of these solvents.

79., be dichloromethane wherein with the immiscible volatile solvent of water according to the method for claim 62.

80. according to the method for claim 62, described method also comprises emulsion is cooled to about 4 ℃ step.

81. method according to claim 62, wherein blend step comprises the step that applies energy, the described energy that applies is implemented by being selected from following method: ultrasonic, homogenize, microcosmic flow, adverse current homogenize and provide impulsive force, shearing force or cavitation force or in a continuous manner or the method by variations in temperature input heat energy.

82., wherein remove with the step of the immiscible volatile solvent of water and undertaken by supersound process according to the method for claim 62.

83., wherein remove with the step of the immiscible volatile solvent of water and undertaken by microemulsion is put under the fine vacuum according to the method for claim 62.

84. according to the method for claim 62, wherein pharmacy particle is normally spherical.

85. according to the method for claim 39, wherein the anti-solvent method of solvent comprises the steps:

With medicament be dissolved in the miscible solvent of water in form non-aqueous solution; With

Non-aqueous solution is combined with aqueous medium with the precipitation medicament, obtain pre-suspension.

86. also comprising, 5 method according to Claim 8, described method stir the step that pre-suspension forms suspension.

87. 6 method according to Claim 8, wherein whipping step comprises the step that pre-suspension is applied energy.

88. 7 method according to Claim 8, the step that wherein applies energy comprises makes the step that with the following method pre-suspension is applied energy, that described method is selected from is ultrasonic, homogenize, microcosmic flow, adverse current homogenize and provide impulsive force, shearing force or cavitation force or in a continuous manner or the method by variations in temperature input heat energy.

89. 5 method according to Claim 8, wherein aqueous suspension also comprises one or more excipient, and described excipient is selected from surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

90. 9 method according to Claim 8, wherein surface modifier is selected from: anion surfactant, cationic surfactant, non-ionic surface active agent and the agent of surface activity bio-modification.

91. 4 method according to Claim 8, wherein non-ionic surface active agent is selected from: the ether of polyoxyethylene aliphatic alcohol, polyoxyethylene sorbitan fatty acid ester; the ester of polyoxyethylene fatty acid, the lipid of polyoxyethylene derivative be mPEG-PSPC (palmityl-stearoyl-phosphatidyl choline) for example; mPEG-PSPE (palmityl-stearoyl-phosphatidyl ethanolamine), the ester of anhydro sorbitol; glyceryl monostearate; Polyethylene Glycol, polypropylene glycol, spermol; spermol stearyl alcohol mixture; stearyl alcohol, aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer; polaxamines; methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose; hydroxypropyl emthylcellulose; the amorphous cellulose element, polysaccharide, starch; starch derivatives; hetastarch, polyvinyl alcohol, and polyvinylpyrrolidone.

92. according to the method for claim 90, wherein anion surfactant is selected from: potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulphosuccinate, glyceride, sodium carboxymethyl cellulose, bile acid and salt, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodesoxycholic acid and carboxymethylcellulose calcium.

93. according to the method for claim 90, wherein cationic surfactant is selected from: quaternary ammonium compound, benzalkonium chloride, cetyl trimethylammonium bromide, chitosan and lauryl dimethyl benzyl ammonium chloride.

94. according to the method for claim 90, wherein the agent of surface activity bio-modification is selected from albumin, casein, heparin, hirudin or other protein.

95. 9 method according to Claim 8; wherein the pH regulator agent is selected from: buffer agent, sodium hydroxide, hydrochloric acid, three (methylol) aminomethane, citrate, acetate, lactate, meglumine and aminoacid, described aminoacid is selected from glycine, alanine, leucine, isoleucine, lysine, methionine, tyrosine, phenylalanine, tryptophan, histidine, proline, serine, glutamic acid, aspartic acid, agedoite, glutamine, cysteine and taurine.

96. 9 method according to Claim 8, wherein freezing preservative agent are selected from the surfactant of carbohydrate, glycerol, poly-alkoxyl ether, PEG-fatty acid and lipid and bio-based.

97. according to the method for claim 96, wherein carbohydrate is selected from saccharide, disaccharide and sugar alcohol.

98. according to the method for claim 97, wherein disaccharide is a sucrose.

99. according to the method for claim 97, wherein sugar alcohol is a mannitol.

100. according to the method for claim 96, wherein surfactant is selected from polysorbate (tween), poly alkyl ether, PEG-fatty acid, PEG-lipid, albumin, starch, glycerol and dimethyl sulfoxide.

101. 8 method according to Claim 8, wherein viscosity modifier is selected from carbohydrate, polymer and protein.

102. 8 method according to Claim 8, wherein in pre-suspension gross weight, excipient content is about 0.001% to about 20%.

103. 8 method according to Claim 8, wherein in pre-suspension gross weight, excipient content is about 0.01% to about 5%.

104. the method that the medicament or the suspension of cosmetics in chilled water substrate of poorly water-soluble are dosed a patient with, described method comprises the steps:

The frozen suspension liquid of medicament or cosmetics is provided;

The melting chilling suspension; With

By following approach the suspension that melts is dosed a patient with, described approach is selected from parenteral injection (in intravenous, intra-arterial, the sheath, in the intraperitoneal, ophthalmic, intraarticular, dura mater, intramuscular, intradermal or subcutaneous injection), oral, pulmonary administration, dosing eyes or topical.