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

Abstract

The present invention discloses a composition of a stable suspension of a poorly water soluble pharmaceutical agent or cosmetic in the form of particles of the pharmaceutical agent or cosmetic suspended in a frozen aqueous matrix and method for its preparation. The composition is stable for a prolonged period of time, preferably six months or longer and is suitable for parenteral, oral, or non-oral routes such as pulmonary (inhalation), ophthalmic, or topical administration.

Description

In chilled water substrate, comprise particulate stable composition

The cross reference of relevant application

The application requires the priority of the provisional application 60/347,548 submitted in October 19 calendar year 2001, and this application is introduced into this paper for your guidance and constitute the part of this paper.

The research or the development of federal patronage

Inapplicable.

Background of invention

Technical field

The invention discloses the stable suspersion fluid composition of the relatively poor chemical compound of a kind of water solublity, and preparation method thereof, described compositions comprises the compound particle that is suspended in the chilled water substrate.Said composition keeps stable in preferred six months or longer time in long-time.

Background technology

The poor solubility of preparing in aqueous solution or the quantity of insoluble medical compounds increase just day by day.Carry these chemical compounds that certain difficulty is arranged with injection form.When water-fast modification of drug is become the stable suspension of submicron particles, has obvious benefit.For utilizing these preparations safely and effectively, accurately control particle diameter and be absolutely necessary.In order not cause thromboembolism safely by capillary tube, particle diameter must be less than 7 microns (people such as Allen, 1987; Davis and Taube, 1978; People such as Schroeder, 1978; People such as Yokel, 1981).One of solution of this problem is the superfine granule of the insoluble drug candidate of preparation and produces micron particle or the suspension of nano-particle.The medicine that can not allocate in aqueous based systems before like this, just making is fit to intravenously administrable.What be fit to intravenously administrable comprises little particle diameter (＜7 μ m), the bioavailability of drug particles after hypotoxicity (when using poisonous formulation components or residual solvent) and the administration.

That suspension also is fit to is oral, intramuscular, lung, part or subcutaneous administration.When by these administrations, favourable particle diameter is in the 5-100 mu m range.

When the suspension long term storage, they may lack enough physics and chemical stability.Physical instability appears when particle aggregation forms larger particles (generally being that small particle diameter causes).The Ostwald-Mie ripening may be owing to little particle radius and the surface-active increase of following (causing the increase of dissolubility thus) produce.Particularly, nano-particle has very high surface volume ratio, and this has increased their rate of dissolution and dissolubility.As a result, granule can be dissolved in the suspension, forms megacryst by recrystallization subsequently.Coalescent and crystal growth produces the suspension of nano-particle, and described nano-particle has bigger and particle diameter that changing.Granule no longer is fit to intravenously administrable greater than the suspension of 7 μ m.

In suspension, active component also may be degraded owing to interacting with suspension media, reduces activity along with the prolongation of time.Even the dissolving of trace also may promote the degraded of active component.Chemical degradation speed depends on the chemical property of particle diameter, intrinsic solubility and active component.

For physics and chemical stability aspect, expect very much a kind of water slurry pharmaceutical preparation, preferred minimum storage period with six months with long storage period.

Coalescent and the crystal growth that several method limits nano-particle in the suspension is disclosed in the prior art, with physical stability and the storage period that improves them.A kind of method comprises the step that adds surface stabilizer in preparation.Suitable surface stabilizer comprise surfactant, polymer, cloud point modifier (referring to United States Patent (USP) 5,298,262,5,346,702 and 5,470,583), crystal growth modifier is (referring to United States Patent (USP) 5,665,331) and cryoprotector (referring to United States Patent (USP) 5,302,401).Although having been found that these methods is successful for restriction particles coalesce and crystal growth, also there is not discovery can prolong the suitable surfactant of the storage period of suspension in room temperature or refrigerator under the liquid condition.Perhaps, if can find this stabilizing agent, they also have undesirable toxicity profile.

Described in people's such as Liversidge United States Patent (USP) 6,267,989, suppressing nano-particle coalescent is that mean diameter is restricted to about 150nm to the close limit of about 350nm with another kind of method crystal growth.This patent points out that when granule was in this particle size range, coalescent and crystal growth was minimized.Yet the particle diameter of close limit has limited its application.Use for some, advantageously particle diameter surpasses the nano granule suspension of 400nm.These application include, but not limited to oral, subcutaneous or the muscle administration, and wherein ideal particle diameter is the 5-100 micron.In other preparation, ideal particle diameter may be less than 100nm.For hiding the granule that RES (reticuloendothelial system) designs, this point is right for for example.This long-term circulation granule also can move by lax, foraminous vascular system, as the vascular system relevant with some cancerous tumour.This will help these tumors of passive sensing.

People such as Yiv are at United States Patent (USP) 6,245, disclose the stabilization formulations of the lipid nano-particle of lipophilic and both sexes medicine in 349.Said preparation is a kind of oil-in-water microemulsion, is made up of phosphide, propylene glycol, Polyethylene Glycol, surfactant and water.Can choose wantonly and use a kind of oil ingredient such as triglyceride.Each component is mixed the formation emulsion.For the preparation of wanting filtration sterilization, mean diameter should be less than 200nm.Said composition or store with conc forms or with dilute form.Dilute form comprises aqueous buffer agent, is stable at about-50 ℃ to about 40 ℃ temperature range.In embodiment 1, compositions-20 ℃ down store 21 days and do not occur significantly being separated, change of size or drug crystallization.Yet this method only limits to the oil-in-water dispersion liquid of particle diameter less than 200nm, and wherein all components all is a liquid.This dispersion liquid is generally sterilized by filtration sterilization, and this requires dispersion liquid is the filter of 220nm by hole size.

Prior art also discloses to prolonging storage period and has improved the method for the chemical stability of nanoparticle formulations.Universal method is to remove aqueous medium by lyophilization, and stores this nano-particle with freeze-dried.One of example is a United States Patent (USP) 5,091,187 embodiment 6.Need to dialyse as last in lyophilization, to remove for example salt of any undesired solute, perhaps in order to prevent concentrating of these solutes during the lyophilization.Because dialysis is the methods that method very consuming time and lyophilization are a kind of power consumption, therefore dialysis and cryodesiccated additional step have increased production cost.In addition, cryodesiccated preparation need be prepared with suitable disperse medium again by before injecting (intravenous, intramuscular or subcutaneous) or oral administration.This needs more manpower when the administration of medicament, introduced the potential mistake that may occur in the redistribution process simultaneously.

Stablizing the part effort of these suspensions, we find as the exploitation new method, by drug particles being wrapped in the chilled water substrate, freezingly can avoid these unstable mechanism.Under so low temperature, drug solubility reduces, and the viscosity that aqueous medium is very high is unfavorable for that the solute medicine spreads out from solid particle.This diffusion comprises nucleation, crystal growth and Ostwald (Ostwald) ripening.By reducing the decomposition of medicine in aqueous medium, lower temperature also can increase chemical stability.For example, when being lower than the eutectic point of mixture, the crystallization of water also may occur, this has got rid of the probability that forms the solution phase that contains medicine, and described medicine can carry out secondary nucleation, crystal growth and Ostwald ripening.

Nano-particle among the present invention can prepare by any method known in the art.A kind of method focuses on reducing the particle diameter of carrying medicine.Comprising United States Patent (USP) 6,228,399,6,086,376,5,922,355 and 5,660, in one of patent of 858 series, people such as Parikh disclose, and can utilize ultrasonic technique to prepare the microgranule of water-insoluble compound.In these patents, United States Patent (USP) 5,922,355 disclose a kind of more short grained improving one's methods of ultrasonic technique preparation of utilizing.This method improvement comprises, in the single-phase water system active agents is mixed with phosphide and surfactant, and this system is applied energy to make more granule.Yet this patent is not openly by the freeze-stable suspension.

The United States Patent (USP) 5,091,188 of authorizing Haynes also discloses and has reduced the particle diameter that the pharmacology goes up active water-insoluble drug, and uses the lipid coating to form solid form on granule.This patent relates to a kind of pharmaceutical composition of being made up of the particulate water slurry of medical solid basically, and described particulate diameter is about 0.05 to about 10 μ m.The lipid coating that sticks on the particle surface is used to stablize these granules.In the presence of film forming lipid surfactant, medicine is added in the entry, in water slurry, reduce particle diameter then, thus the compositions of making.Yet frozen suspension liquid is not described as antihunt means.

United States Patent (USP) 5,858,410 disclose the medicament nano suspension of suitable parenteral.This patent disclosure, at least a solid therapeutical active compound that is dispersed in the solvent is carried out the high pressure homogenize in the homogenizer of piston slit (piston-gap), the average diameter that forms by photon correlation spectroscopy (PCS) test is the granule of 10nm to 1000nm, granule ratio greater than 5 microns in total particle is lower than 0.1% (distributed number that coulter counter is measured), do not melt body and change in advance, wherein reactive compound at room temperature is a solid, and is insoluble or only seldom be dissolved in or moderate water soluble, aqueous medium and/or organic solvent.The embodiment of this patent carries out jet grinding before disclosing homogenize.

United States Patent (USP) 5,145,684 disclose another kind of method, and it is by reducing the nano-particle that particle diameter is provided for the insoluble drugs that parenteral sends.This patent disclosure, in the presence of surface modifier, the wet lapping insoluble drugs obtains the drug particles that the average effective particle diameter is lower than 400nm.This patent has emphasized not use in this method the necessity of any solvent.This patent disclosure be adsorbed on the surface modifier on drug particles surface amount to be enough to prevent to be agglomerated into larger particle.

Except reducing the big or small of drug particles physically and, can also preparing nano-particle by multiple intermediate processing with the surface stabilizer coated particle.These methods typically comprise with medicine dissolution in solvent as continuous phase, subsequently by solution condition is changed into discontinuous phase, the medicine fine grained just is precipitated out and enters in the discontinuous phase like this.Coating reagent or surface stabilizer generally be used for the medicine co-precipitation with stable particle.The example of these intermediate processings is that solvent and anti-solvent microdeposit (microprecipitation), phase inversion precipitation, pH change precipitation, supercritical fluid precipitation and variations in temperature precipitation.

The example of suitable sedimentation comprises the preparation nano granule suspension, and it is disclosed in U.S. Patent application 60/258,160,09/874,799,09/874,637,09/874,499 and 09/953, in 979, these documents are introduced into this paper for your guidance and form the part of this paper.These applications disclose by following method and have formed the granule organic compound: with organic compound be dissolved in water-soluble mixed organic solvent in, then organic compound is deposited in and forms pre-suspension in the aqueous medium, in pre-suspension, apply energy then with stable particle coating, the particulate lattice structure of change or reduction particle diameter.This method is optimized for the suspension of the chemical compound of the pharmaceutically active for preparing poorly water-soluble.

United States Patent (USP) 5,118,528 disclose the method for preparing nano-particle by the anti-solvent precipitation of solvent.This method comprises the steps: the liquid phase of (1) a kind of material of preparation in solvent or solvent mixture, wherein can add one or more surfactants, (2) second liquid phase of preparation non-solvent or non-solvent mixture, the solvent or the solvent mixture of non-solvent and this material are miscible, (3) by stirring solution (1) and (2) are added to together and (4) remove the soliquid that undesired solvent obtains nano-particle.This patent points out that it has been made less than the material grains of 500nm does not need to provide energy.Particularly, this patent has shown that it is disadvantageous utilizing high energy equipment such as ultrasonoscope and homogenizer.

United States Patent (USP) 4,826,689 disclose by water-insoluble drug or other organic compound and have prepared particulate method of uniform size.At first, in organic solvent, this solution can dilute with non-solvent with suitable SOLID ORGANIC compound dissolution.Then, inject this aqueous precipitation liquid, be settled out and have basically the not agglomerate particles of average diameter uniformly.Then granule is separated from organic solvent.According to organic compound and required particle diameter, can change the parameters such as ratio, charge velocity, stir speed (S.S.) and volume of temperature, non-solvent and organic solvent according to the present invention.This patent points out that this method has formed metastable medicine, and it is unsettled on thermodynamics.This patent is pointed out, this method makes medicine become metastable state by adopting crystallization inhibitor (for example polyvinyl pyrrolidone) and surfactant (for example polyethylene glycol oxide-common-propylene oxide), gives the enough stability of metastable state precipitate to separate by centrifugal, membrane filtration or reverse osmosis.

United States Patent (USP) 5,780,062 discloses by following step and has prepared the short grained method of insoluble drugs: (1) with medicine dissolution with the water-soluble first mixed solvent in, (2) preparation polymer and second solution of amphiphile in moisture second solvent, its Chinese medicine is soluble basically, formed polymer/amphiphile complex and (3) thus the solution of the first step and preparation in second step has been mixed aggregation with precipitation medicine and polymer/amphiphile complex.

United States Patent (USP) 4,997,454 disclose by the evenly big or small particulate method of solid chemical compound preparation.Method in this patent comprises the steps: solid chemical compound is dissolved in the suitable solvent, then injects precipitation and uses liquid, has precipitated thus to have basically the non-agglomerate particles of average diameter uniformly.Then granule is separated from solution.This patent disapprove forms the granule of crystalline state, and this is because in the precipitation process, crystal can dissolve and recrystallize, and particle size distribution range is broadened.This patent is agreed with, and in precipitation process, granule is become unsettled granule on the thermodynamics.

All authorize people's such as Mathiowitz United States Patent (USP) 6,235,224B1 and 6,143,211 disclose the microgranule that utilizes the microencapsulation of phase inversion phenomenon precipitation.This method comprises polymer and medicine and solvent.This mixture is introduced in the miscible non-solvent of effective dose the product of spontaneous thus formation microencapsulation.

The microdeposit that changes by pH is another technology that is used to prepare the dispersion of nano-particle medicament.Referring to United States Patent (USP) 5,766,635,5,716,642,5,665,331,5,662,883,5,560,932 and 4,608,278.This technology relates to medical compounds is dissolved in the water-based with non-neutral pH value, then with this substrate neutralization with compound precipitation in water-based.

In another approach, for example authorize people's such as Spenlenhauer United States Patent (USP) 5,766, disclosed such in 635, nano-particle is preparation like this: polyethylene glycol oxide and/or polypropylene oxide/polyactide copolymer are dissolved in the organic solvent, organic solution and aqueous solution with forming like this are precipitated out nano-particle from solution, mobile this suspension of microcosmic under the situation of not using surfactant.So just make the carrier granular of forming by solid polymer substrate, wherein can add the medicament of co-precipitation.

Supercritical fluid precipitation is disclosed in people's such as Krukonis United States Patent (USP) 5,360,478 and 5,389,263 and the WO97/14407 of Johnston in.This technology is similar to the anti-solvent precipitation of solvent.In the method, be that the supercritical fluid of gas or liquid is as anti-solvent more than critical point with pressure, temperature.Supercritical fluid is joined the solution of solute in solvent, and this can cause that solute reaches or near the over-saturation attitude, and is precipitated out with fine grain form.

The variations in temperature sedimentation method are disclosed in the United States Patent (USP) 5,188,837 of Domb.This method relates to thermally-stabilised medicine is joined in the polymer.This polymer is (for example phosphide, the synthetic wax) of oil base normally, and has low melting point.Medicine is heated to the fusing point of a little higher than polymer with polymer, to form the warm emulsion of medicine in molten polymer.Then, for example bathe in the water and cool off emulsion fast, utilize thermal agitation to make emulsion form drop, and solidify activating agent is entered in the suspension by emulsion being joined cold non-solvent.

The another kind of method of the submicron particles of the organic compound of preparation poorly water-soluble is to form the chemical compound emulsion.Organic compound is dissolved in the organic facies.Organic facies and water form emulsion.The emulsion method of evaporating is disclosed in the U.S. Patent application 09/964,273.This method comprises the steps: that (1) provides the heterogeneous system with organic facies and water, contain the pharmacology in the organic facies and go up compounds effective, (2) this system of supersound process makes the compound precipitation of water with the evaporation section organic facies, and its average effective particle diameter is lower than about 400nm.

United States Patent (USP) 5,605,785 disclose the method for preparing the nanometer amorphous dispersion of the chemical compound that is used to take a picture.The method that forms nanometer amorphous dispersion comprises emulsive any known method, produces to have the particulate decentralized photo of amorphous state.

Another method of submicron order nano granule suspension of preparation pharmaceutical active compounds is, in precipitation process, sows crystal seed at certain on a bit, produces the crystal of required form.(referring to U.S. Patent application 10/035,821).This method comprise the steps: with the first quantitative pharmaceutical active compounds be dissolved in the first miscible organic solvent of water in form first solution.Then first solution is sowed crystal seed.Perhaps, second solvent is sowed crystal seed.Also can utilize the crystal seed chemical compound on the point At All Other Times in precipitation process.Then with first solution and second solvent.First solution precipitates with required form with causing pharmaceutical active compounds mixing of second solvent.

Another kind method relates to preparation and is coated with proteinic particle.The United States Patent (USP) 5,916,596 of authorizing people such as Desai discloses organic facies that wherein is dispersed with pharmaceutically active agents and the mixture that contains the aqueous medium of bioavailable polymer has been applied high shear force.This mixture in the high pressure homogenizer, about 3,000 to about 30, is sheared in the pressure limit of 000psi.This patent requires this mixture to go up substantially not contain surfactant, and this causes formation big, aciculiform crystal grain owing to surfactant and proteinic being used in combination, and institute's crystal grain size in depositing process becomes big.Referring to the 17-18 hurdle, embodiment 4.

The United States Patent (USP) 5,560,933 of authorizing people such as Soon-Shiong forms polymer shell disclose the water-insoluble drug of sending in being used for body around.This method discloses, to comprising the aqueous medium that contains polymer and wherein be dispersed with basically that the mixture of the dispersant of water-fast medicine applies supersound process.In this list of references, supersound process is used to impel and forms disulfide bond in polymer, makes crosslinked polymer, to form polymer shell in the medicine periphery.The time of supersound process will be enough to form disulfide bond.

In people's such as Grinstaff the United States Patent (USP) 5,665,383, disclosing single-phase B is that aqueous medium applies supersound process, and immunostimulant is encapsulated in the polymer shell to send in vivo.Excusing from death is handled and has been promoted encapsulation agent to form shell by disulfide bond crosslinking.

United States Patent (USP) 5,981,719 and 6,268,053 discloses the method for preparation particle diameter less than 10 microns macromole microgranule.In the presence of the energy of preferred heat, macromole is mixed the scheduled time with the mixture (for example albumin) of soluble polymer or soluble polymer under the pH value near the macromole isoelectric point, IP.The microgranule that this method forms enters wherein aqueous fluid, and dissolved macromole and polymer are left wherein, and can have short-term or secular release dynamics, provides macromolecular thus and discharges fast or lastingly.

The invention summary

One of shortcoming of aqueous nano granule suspension is that its physical and chemical stability is very poor.Physical instability is because particles coalesce and crystal growth.Chemical instability is that this degraded is owing to the interaction between active component and excipient such as surfactant and the buffer agent strengthens owing to be dissolved in the degraded of the active component in the solution on every side (it and the solid phase balance that suspends).Because these stability problems, many aqueous nanoparticle system are not suitable for use in pharmaceutical preparation.For example, if dissolved reactive compound because hydrolysis and chemically unstable, the decomposition in the solution will make chemical equilibrium move towards the direction of degrading gradually and lose active component so.

We find that by drug particles being wrapped in the chilled water substrate, freezing method can be avoided these unstability mechanism.Under such low temperature, drug solubility reduces, and the viscosity that aqueous medium is very high is unfavorable for that the solute medicine spreads out from solid particle.This diffusion comprises nucleation, crystal growth and Ostwald ripening.Lower temperature has also reduced the spontaneous degraded of drug molecule in aqueous medium, has increased their chemical stability.Low temperature has also slowed down the degraded of the active component that the interaction owing to active component and excipient causes.For example, be lower than the eutectic point of mixture, also the crystallization of water may occur, thereby got rid of the probability that forms the solution phase that contains medicine, described medicine can carry out secondary nucleation, crystal growth and Ostwald ripening.

The preparation method of the medicament that the invention provides poorly water-soluble stabilized nano particle suspending fluid composition and said composition in water-based.Plan of the present invention provides such as cosmetics, takes a picture with the stable suspension of other chemical compounds such as reagent.Said composition can be in storage in long-term preferred six months or longer time.

The present invention can be used for any nanoparticle system known in the art.Nano granule suspension can be made by any known method, and described method for example physical grinding, homogenize, high shear mixing, emulsion evaporation precipitation, the anti-solvent deposition of solvent, supercritical fluid precipitation, variations in temperature precipitation, pH changes precipitation, fusion precipitation and crystal sowing.

The present invention also is applicable to and contains the nanoparticle system that a large amount of compositions for example comprise surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

Said composition does not need to carry out redistribution with suitable dispersant before using, and is applicable to multiple route of administration, includes but not limited to injection (intravenous, intramuscular, subcutaneous), pulmonary administration, dosing eyes, part and oral.

These and other aspect of the present invention and feature will be discussed with the explanation of back with reference to the accompanying drawings.

Detailed Description Of The Invention

Although the present invention admits of multiple multi-form embodiment, and will describe in detail in this article, it is disclosed that but the preferred embodiments of the invention are based on following position, be that content disclosed by the invention will be considered to inventive principle is illustrated, rather than the scope that the present invention is very wide is defined as described embodiment.

The invention discloses and be used for intravenously administrable or oral pharmaceutical composition, and said composition is as the preparation method of nano granule suspension in the water-based.Parenteral comprises in the intravenous, intra-arterial, sheath, in the intraperitoneal, ophthalmic, intraarticular, dura mater, intramuscular, intradermal or subcutaneous injection.Said composition also is applicable to other non-oral administration route, for example comprises part, eyes, nose, oral cavity, suction, rectum etc.

Pharmacy optimization is the chemical compound of poorly water-soluble.When compositions when long-term preferred a year or longer time deposit in refrigerator or under the room temperature, it is in physics and instability chemically.Deposit said composition by freezing this aqueous nano granule suspension and with cold moving state, can realize static stabilization.Under such low temperature, drug solubility reduces, and the viscosity that aqueous medium is very high is unfavorable for that the solute medicine spreads out from the solid particle that contains this medicine.This diffusion comprises nucleation, crystal growth and Ostwald ripening.Lower temperature has also reduced the spontaneous decomposition of drug molecule in aqueous medium, has increased their chemical stability.For example, be lower than the eutectic point of mixture, also the crystallization of water may occur, thereby got rid of the probability that forms the solution phase that contains medicine, described medicine can carry out secondary nucleation, crystal growth and Ostwald ripening.

Can also implement the present invention with the suspension that is not the material (for example comprising photographic compound) of other poorly water-soluble of medicament.

A. nano granule suspension compositions

The present composition comprises the nano-particle that is suspended in the medicament in the chilled water substrate.As required, said composition can contain one or more excipient, and this depends on concrete medicament, prepares the method and the route of administration of nano granule suspension.

1. medicament

The present invention can implement with many medicaments, and described medicament can be therapeutic agent, diagnostic agent or cosmetics.They comprise organic and inorganic compound and biological preparation such as protein, peptide, saccharide, polysaccharide, polypeptide, nucleotide and oligonucleotide.

Medicament can exist with crystalline phase or non-crystalline amorphous phase.Pharmacy optimization is a poorly water-soluble." poorly water-soluble " is meant, the dissolubility of medicament in water is lower than 10mg/ml, preferably is lower than 1mg/ml.Because the medicament of these poorly water-solubles limited preparation alternative in aqueous medium, so their major parts are applicable to aqueous nano granule suspension preparation.

By with these kit in solid carrier substrate (for example polylactic acid salt-polyglycolic acid salt copolymer, albumin, starch), perhaps by these kit are enclosed in the outer insaccation, described capsule is impermeable for medicament, can also implement the present invention with water soluble medicament thus.This encapsulation can be a for example polyacrylate of polymer coating.In addition, nano-particle and the microgranule made by these water soluble medicaments can carry out modification with the raising chemical stability, and control its pharmacokinetics character by the release of control medicament from granule.The example of water soluble medicament includes, but not limited to simple organic compound, protein, peptide, nucleotide, oligonucleotide and carbohydrate.

Therapeutic agent can be selected from the medicine of a large amount of known kinds, and described medicine comprises for example analgesic, antiinflammatory, anthelmintic (antihelmintics), antiarrhythmics, antibiotic (comprising penicillin), anticoagulant, antidepressant, antidiabetic drug, antuepileptic, antifungal, antihistaminic, antihypertensive, the muscarine antagonist agent, anti-mycobacteria agent, antineoplastic agent, antiprotozoal, immunosuppressant, immunostimulant, antithyroid drug, antiviral agents, anti-worried tranquilizer (sleeping pill and neuroleptic), astringent, β-adrenoreceptor blocker, blood products and succedaneum, myocardial contraction agent (cardic inotropic agent), contrast agent, corticosteroid, cough suppressant's (expectorant and mucolytic agent), diagnostic agent, the diagnosis developing agent, diuretic, dopaminergic (Mirapexin), hemorrhage, immune substance, the lipid regulator, muscle speeds to delay medicine, parasympathomimetic agent, parathyroid gland calcitonin and diphosphonate, prostaglandin, radiopharmaceutical, gonadal hormone (comprising steroid), antiallergic agent, analeptic and anorexigenic, sympathomimetic, thyroid drug, vasodilation, vaccine and xanthine.

Diagnostic agent comprises X ray developing agent and contrast agent.The example of X ray developing agent comprises WIN-8883 (3,5-diacetylamino-2,4,6-phenyl triiodide Ethyl formate), is also referred to as the ethyl ester (EEDA) of amidotrizoic acid; WIN 67722 i.e. (6-ethyoxyl-6-oxo-hexyl-3,5-two (acetylamino)-2,4,6-phenyl triiodide formic acid esters; 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formic acid) ethyl n-butyrate. (WIN 16318); Amidotrizoic acid ethyl acetate (WIN 12901); 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formyl) ethyl propionate (WIN 16923); N-ethyl 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formyl) acetamide (WIN65312); Isopropyl 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formyl) acetamide (WIN 12855); Diethyl 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formyl) malonate (WIN 67721); [[3,5-two (acetylamino)-2,4,5-phenyl triiodide formyl] oxygen] two (1-methyl) ester (WIN 68165) of 2-(3,5-two (acetylamino)-2,4,6-phenyl triiodide formyl) phenylacetic acid ethyl ester (WIN 67585), malonic acid; With benzoic 3,5-two (acetylamino)-2,4,6-three iodos-4-(ethyl-3-ethyoxyl-2-butylene acid) ester (WIN 68209).Preferred contrast agent comprises that those expects very fast the decomposition under physiological condition, thereby any inflammatory reaction relevant with granule is reduced to the material of minimum.Decomposition can be solubilising or other mechanism owing to carboxylic acid under enzyme hydrolysis, the physiology pH value.Therefore, the iodo carboxylic acid of preferred dissolution difference is adipiodone, amidotrizoic acid and metrizoic acid for example, and the iodo class that is easy to hydrolysis for example WIN 67721, WIN 12901, WIN 68165 and WIN 68209 or other material.

Antineoplastic agent or anticarcinogen include but not limited to, paclitaxel and derivative compound thereof and other be selected from alkaloid, antimetabolite, alkylating agent and antibiotic antineoplastic agent.

Preferred therapeutic agent or diagnostic agent comprise and are used for oral and those reagent intravenously administrable.To the description of the therapeutic agent of these kinds and diagnostic agent and in the material tabulation of these kinds apoplexy due to endogenous wind referring to Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, ThePharmaceutical Press, London, 1989, the document is incorporated herein by reference, and constitutes the part of this paper.Therapeutic agent and diagnostic agent are commercially available, and/or can make by technology known in the art.

Cosmetics are any active active components of cosmetic that have.The example of these active components specifically can be, emollient, wetting agent, free radical inhibitors, antiinflammatory, vitamin, remove toner, go acne agent, seborrhea to go out agent (antiseborrhoeics), keratolytic, appetrol, dye agent and sunscreen, particularly linoleic acid, retinol, tretinoin, ascorbic acid Arrcostab, poly-unsaturated fatty acid, nicotinate, tocopheryl nicotinate; Not rice, Semen Glycines or Adeps Bovis seu Bubali resin (shea) not saponified; Ceramide, hydroxy acid such as glycolic, selenium derivant, antioxidant, bata-carotene, γ-orizanol (orizanol) and glyceric acid stearyl ester.Cosmetics can be by commercially available acquisition, and/or makes by technology known in the art.

With composition weight meter, the content of medicament is about 0.01% to about 50%, more preferably from about 0.1% to about 30%, most preferably from about 0.5% to about 5%.

2. excipient

Excipient of the present invention is chosen wantonly.Can comprise one or more excipient in the compositions.The example of excipient comprises buffer agent, surface modifier, pH regulator agent, crystal growth modifier, freezing preservative agent, penetrating agent, cosolvent and viscosity modifier.

Suitable surface modifier preferred known organic and inorganic drug excipient, for example anion surfactant, cationic surfactant, non-ionic surface active agent or Bio-surface active molecule.

Suitable anion surfactant includes but not limited to, potassium laurate, sodium lauryl sulfate, sodium lauryl sulphate, alkyl polyoxyethylene sulfate, sodium alginate, dioctyl sodium sulphosuccinate, glyceride, sodium carboxymethyl cellulose, cholic acid and other bile acid (for example cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodesoxycholic acid) and salt thereof (for example NaTDC etc.).Suitable cationic surfactants includes but not limited to, quaternary ammonium compound, for example benzalkonium chloride, cetyl trimethylammonium bromide, lauryl dimethyl benzyl ammonium chloride, acetyl group carnitine hydrochlorate or alkyl pyridine halogenide.

Suitable ionic surfactant pack is drawn together: the ether of polyoxyethylene aliphatic alcohol (Macrogoland Brij), polyoxyethylene sorbitan fatty acid ester (Polysorbates), the ester of polyoxyethylene fatty acid (Myrj), the fat of polyoxyethylene derivative or phosphide, the ester of anhydro sorbitol (Span), glyceryl monostearate, Polyethylene Glycol, polypropylene glycol, spermol, spermol stearyl alcohol mixture, stearyl alcohol, the aryl alkyl Aethoxy Sklerol, polyoxyethylene-polyoxypropylene copolymer (poloxamers), polaxamines, methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, the amorphous cellulose element, comprise for example polysaccharide of hetastarch (HES) of starch and starch derivatives, polyvinyl alcohol, and polyvinyl pyrrolidone.In optimal way of the present invention, non-ionic surface active agent is polyoxyethylene and polyoxypropylene copolymer, the block copolymer of preferred propylene glycol and ethylene glycol.This polymer is sold with trade name POLOXAMER (being also referred to as PLURONIC  sometimes), and wherein several suppliers are Spectrum Chemical and Ruger.In the ester of polyoxyethylene fatty acid, comprise that those have the ester of short alkyl chain.One of example of this surfactant is the SOLUTOL  HS15 that BASFAktiengesellschaft makes, i.e. polyethylene-660-hydroxy stearic acid ester.

The surface activity biomolecule comprises such as albumin, casein, heparin, hirudin or other suitable proteinic molecule.

Other representative example of surface modifier comprises gelatin, casein, arabic gum, cholesterol, Tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, spermol stearyl alcohol mixture, cetomacrogol (cetomacrogol) emulsifing wax, Isosorbide Dinitrate, polyxyethylated ester for example polyglycol ether such as cetomacrogol 1000, for example commercially available Tweens of castor oil derivatives, polyoxyethylene sorbitan fatty acid ester ^TM, Polyethylene Glycol, Myrj 45, silica sol, phosphate ester, sodium lauryl sulphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, amorphous cellulose element, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol and polyvinyl pyrrolidone (PVP).Great majority in these surface modifiers are known drug excipient, be described in detail in Handbook ofPharmacertical Excipients, by American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press was in combined publication in 1986, and the document is incorporated herein by reference and constitutes the part of this paper.

Surface modifier can obtain from the market, and/or prepares with technology known in the art.Can use two or more surface modifiers simultaneously in the said composition.

Suitable pH regulator agent includes but not limited to buffer agent, sodium hydroxide, hydrochloric acid, three (methylol) aminomethane (tris), citrate, acetate, lactate, meglumine etc.Buffer agent also includes but not limited to aminoacid such as glycine, leucine, alanine, lysine etc.

Suitable crystal growth modifier is described in United States Patent (USP) 5,665, in 331.Crystal growth modifier is defined as a kind of like this chemical compound, and promptly it is introduced in the microdeposit crystal structure of medicament in coprecipitation method, suppresses sedimentary growth of crystallite or increase by being called the Ostwald ripening method thus.Some crystal growth modifier on molecular basis with the medicament structural similarity.What be suitable as the crystal modification agent equally is polymer, and for example United States Patent (USP) 4,826, disclosed crystallization inhibitor polyvinylpyrrolidone in 689.Crystal growth modifier can also play a role by following manner, promptly with the over-saturation state under solute form complex, prevent thus or suppress crystal nucleation and/or growth.

The freezing preservative agent that is used for nano granule suspension is disclosed in United States Patent (USP) 5,302, in 401.In this patent, freezing preservative agent stops nano-particle coalescent in freezing dry process.The example of suitable freezing preservative agent comprises carbohydrate for example sucrose, xylose, glucose and sugar alcohol such as mannitol and sorbitol, surfactant such as polysorbate (tween (Tweens)), and glycerol and dimethyl sulfoxide.Freezing preservative agent also comprises for example for example Polyethylene Glycol, polypropylene glycol and poloxamer of polyvinyl pyrrolidone (PVP), starch and poly-alkoxyl ether of water-soluble polymer.Biologically-derived freezing preservative agent comprises albumin.Another kind of freezing preservative agent comprises for example Solutol of Pegylation lipid (pegylated lipids).Preferred freezing preservative agent is a carbohydrate.Preferred carbohydrate is monosaccharide or disaccharide.Preferred disaccharide is a sucrose.Another kind of preferred freezing preservative agent comprises polymer, such as but not limited to list above those.Another preferred freezing preservative agent is an albumin.

Viscosity modifier is the reagent that influences composition viscosity.The example of this regulator is carbohydrate (for example cellulose, natural gum, sugar, a sugar alcohol), polymer (for example poloxamer, poloxamines, polyvinyl pyrrolidone), protein (for example albumin, lactoprotein).These reagent are listed among the Handbook of Pharmaceutical Additives that is published by Gower, at Thickeners, Viscosity control agents, Consistency regulators, Bodying agents, in the chapters and sections such as Antigellants, the document is introduced into this paper for your guidance, and constitutes the part of this paper.

Suitable penetrating agent comprises sugar (for example glucose, sucrose), sugar alcohol (for example mannitol, sorbitol), salt (for example sodium chloride), glycerol and glycerol derivatives etc.

The example of suitable cosolvent is ethanol, dimethyl sulfoxide and N-N-methyl-2-2-pyrrolidone N-.Other example comprises lactic acid, acetic acid and other liquid carboxylic.

With composition weight meter, the content of excipient is about 0.001% to about 20%, preferred about 0.01% to about 5%.

Excipient can join in the aqueous medium in the preparation of nanoparticles process, directly joins in the medicament before perhaps mixing with aqueous medium.If medicament with aqueous anti-solvent before be dissolved in the organic facies, so excipient can the precipitation before join in the organic facies.

3. the shape of particle diameter and nano-particle

In the present invention, particle diameter is measured (for example, photon correlation spectroscopy, laser diffraction, little angle laser light scattering (LALLS), middle angle laser light scattering (MALLS), shading method (light obscuration) (for example Coulter method), rheology or the microscopic method in above-mentioned scope (optical microscope or ultramicroscope)) by the dynamic light scattering method.The present invention is applicable to particle diameter nano-particle and microparticle suspending liquid in very large range.Particulate preferred average effective particle diameter is lower than about 100 μ m, more preferably less than about 7 μ m, more preferably less than about 2 μ m, most preferably is lower than about 400nm, even more preferably less than any range or combination in about 200nm or this scope.

4. the preparation method of nano granule suspension

The moisture nano granule suspension of medicament can be by comprising the mechanical lapping activating agent the method for any means, sedimentation or suspended medicament prepare.As United States Patent (USP) 5,145, disclosed in 684 like that mechanical lapping comprises the technology of grinding (pearlmilling), ball milling, sledge mill, fluid energy mill or wet grinding such as jet grinding, beadlet, and the document is introduced into this paper for your guidance and constitute the part of this paper.

Settling step can be used to prepare particle suspension liquid, this suspension is further applied the step of energy.As United States Patent (USP) 5,091,188 disclosed like that (document be introduced into this paper for your guidance and constitute the part of this paper), the step that applies energy comprises and particle dispersion is placed shear conditions, cavitation, shearing or the impulsive force of for example utilizing microcosmic fluidisation device, piston slit homogenizer or adverse current homogenizer to apply.Suitable piston slit homogenizer can have been bought on market, for example those homogenizers sold with trade name EMULSIFLEX by Avestin and the French Pressure Cells that is sold by Spectronic Instruments.Suitable microcosmic fluidisation device can derive from Microfiuidics Corp.The crystal that describes below sowing step can be placed in whenever carrying out in the process of shear conditions at solution, most preferably carries out before applying the energy step.

The step that applies energy also can utilize ultrasonic technique to finish.Ultrasound treatment step can be utilized any suitable ultrasonic device, and for example Branson Model S-450A or Cole-Parmer500/750 Watt Model carry out.These equipment industrial be well-known.Typically, ultrasonic device has ultrasonic angle or probe, and it is inserted in the solution that contains medicine, launches acoustic energy in solution.In a preferred embodiment of this invention, ultrasonic device is to about 90kHz, more preferably from about 20kHz extremely works under the frequency of about 40kHz or wherein any range or its combination at about 1kHz.Probe size can change, preferably the different size of 1/2 inch or 1/4 inch etc. for example.In the supersound process process, it also is favourable that solution is cooled to subambient temperature.The crystal that describes below sowing step can be placed in whenever carrying out in the process under the shear conditions at solution, most preferably carries out before applying the energy step.

Intermediate processing

In intermediate processing, medicament is dissolved in obtains solution in the solvent.Then solution is mixed with aqueous medium and obtain the fine grain pre-suspension of medicament.Aqueous medium can randomly comprise one or more excipient, and described excipient is selected from surface modifier, pH regulator agent, freezing preservative agent, crystal growth modifier, penetrating agent, cosolvent and viscosity modifier.Before settling step, also excipient can be included in the solvent that wherein is dissolved with medicament.As required, can apply energy with the stable pharmaceutical coating, change lattice structure, perhaps further reduce the size of precipitate particles pre-suspension.That energy source includes but not limited to is ultrasonic, homogenize, microcosmic flow, adverse current homogenize or other method of impact, shearing or cavitation force is provided.The energy also comprises with heating or refrigerative form or imports the method for heat by variations in temperature (for example circulate) continuously.

Some known intermediate processings are emulsion evaporation precipitation, microdeposit, the anti-solvent deposition of solvent, supercritical fluid precipitation, variations in temperature precipitation, pH variation precipitation and crystal sowing.

Emulsion evaporation precipitation

The emulsion evaporation is disclosed in the U.S. Patent application 09/964,273, and the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the steps: that (1) provides the heterogeneous system that comprises organic facies and water, contains compounds effective on the pharmacopedics in the organic facies; (2) this system of supersound process makes the compound precipitation of aqueous phase to evaporate a part of organic facies, and its average effective particle diameter is less than about 2 μ m.(1) will mix with compounds effective on the pharmacopedics with the immiscible solvent of water (oil phase) and obtain organic solution to provide the step of heterogeneous system to comprise the steps:, (2) prepare group water solution and (3) with one or more surface active cpds organic solution and aqueous solution are formed heterogeneous system.Stir or mix heterogeneous system and form thick emulsion.In this thick emulsion, will contain the approximate oil droplet of diameter in the water less than about 1 μ m.This thick emulsion is obtained microemulsion by supersound process, finally obtains the submicron particles suspension.

Being selected from carbon number with the immiscible solvent of water 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, all or part of halogenated hydrocarbon, ether, ester, ketone, monoglyceride, two glyceride or triglyceride, natural oil, alcohol, aldehyde, acid, amine, linearity or annular siloxane, hexamethyl disiloxane, or the combination in any of these solvents.Preferred and the immiscible solvent of water is a dichloromethane.

Ultrasound treatment step can provide the mode of energy to replace with any other, and the example of other energy sources is that ultrasonic, homogenize, microcosmic flow, the adverse current homogenize, or other method of impact, shearing or cavitation force is provided.

Microdeposit

The microdeposit method is disclosed in U.S. Patent application 60/258,160,09/874,799,09/874,637,09/874,499 and 09/953,979.The organic compound granule forms by following method, organic compound is deposited in the aqueous medium forms pre-suspension, with after-applied energy with the stable particle coating or change particulate lattice structure.This method is preferred for preparing the suspension of active chemical compound on the pharmacopedics of poorly water-soluble, and described chemical compound is fit to parenteral or oral administration.

This method can be divided into two classes, method A and method B.

Method A

In method A, at first organic compound (" medicine ") is dissolved in and forms first solution in first solvent.According to the dissolubility of organic compound in first solvent, the addition of organic compound is that about 0.1% (w/v) is to about 50% (w/v).Be dissolved in fully in first solvent in order to ensure chemical compound, be necessary concentrated solution is heated to about 100 ℃ from about 30 ℃.

To wherein adding one or more optional surface modifiers to obtain second aqueous solution, described surface modifier is selected from for example anion surfactant, cationic surfactant, non-ionic surface active agent or Bio-surface active molecule.

It also is favourable adding the pH regulator agent in second solution, and described pH regulator agent is selected from for example buffer, sodium hydroxide, hydrochloric acid, three (methylol) aminomethane buffer solution, citrate, acetate, lactate, meglumine etc.Other buffer agent comprises aminoacid such as glycine, leucine, alanine, lysine etc.The pH value of second solution about 2 to about 11 scope.

In optimal way of the present invention, the particulate method of organic compound of preparation submicron order comprises the step that first solution is added second solution.Add speed and depend on the size in batches and the precipitation kinetics of organic compound.Typically, for small scale experiments chamber preparation method (preparation 1L), adding speed is that about 0.05cc/min is to about 10cc/min.In adition process, solution should be under the constant agitation.Arrive by observation by light microscope, formed amorphism granule, hypocrystalline solid or subcooled liquid, obtain pre-suspension.This method also comprises the steps, pre-suspension is carried out annealing steps, to change amorphism granule, subcooled liquid or hypocrystalline solid into more stable crystalline solid state.The gained granule will have the average effective particle diameter, and this measures by dynamic light scattering method (for example related power spectrum of the photon in above-mentioned scope, laser diffraction, little angle laser light scattering (LALLS), middle angle laser light scattering (MALLS), light shading method (for example Coulter method), rheology or microscope (optics or electronics)).

The method that applies energy relates to by ultrasonic, homogenize, adverse current homogenize, microcosmic is mobile or other provides the method for impulsive force, shearing force or cavitation force to add energy.Can be in this stage with sample cooling or heating.In an optimal way of the present invention, annealing steps carries out with piston slit homogenizer, described homogenizer for example by Avestin Inc. with trade name EmulsiFlex-C160 sell the sort of.In another optimal way of the present invention, annealing is finished by supersound process with ultrasonic processor, described processor for for example by Sonics andMaterials, the Vibra-Cell Ultrasonic Processor (600W) that Inc makes.In another optimal way of the present invention, annealing is to adopt United States Patent (USP) 5,720,551 described emulsifying devices to finish, and described document is introduced into this paper for your guidance and constitute the part of this paper.

According to annealing rate, the temperature that advantageously will handle sample is adjusted at approximately-30 ℃ to 30 ℃ scope.In addition, in order in handling solid, to realize required phase transformation, in the annealing process pre-suspension is heated to about 30 ℃ to about 100 ℃ temperature also be necessary.

Except amorphous solid, hypocrystalline solid or subcooled liquid, also may contain frangible crystal in the pre-suspension, this crystal before precipitation than the easier fragmentation of its solid state.Like this, applying the energy step is required size with these particle splitings.

Method B

Method B is different from method A following aspect several.First difference is, the compositions of surfactant or surfactant is joined in first solution.Surfactant can be selected from nonionic, anion and cationic surfactant.

Except amorphism granule, hypocrystalline solid or subcooled liquid, also may contain frangible crystal in the pre-suspension, this crystal before precipitation than the easier fragmentation of its solid state.Like this, applying the energy step is required size with these particle splitings.

A kind of suitable emulsion sedimentation is disclosed in the common U. S. application 09/964273 unsettled, common transfer, and the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the steps: that (1) provides the heterogeneous system that comprises organic facies and water, contain compounds effective on the pharmacopedics in the organic facies, (2) this system of supersound process causes the compound precipitation of water with the evaporation section organic facies, and its average effective particle diameter is lower than about 2 μ m.(1) will mix with compounds effective on the pharmacopedics with the immiscible solvent of water and obtain organic solution to provide the step of heterogeneous system to comprise the steps:, (2) prepare group water solution and (3) with one or more surface active cpds organic solution and aqueous solution are formed heterogeneous system.The blend step of organic facies and water comprises and uses flow device or other of piston slit homogenizer, colloid mill, high-speed mixing equipment, extrusion equipment, manual stirring or oscillator device, microcosmic that the equipment or the technology of shear conditions are provided.In the water of thick emulsion, contain diameter approximately less than the oil droplet of 1 μ m.This thick emulsion is obtained microemulsion by supersound process, finally obtains the submicron particles suspension.

The optional polymorphic controlled step of describing in detail below can be undertaken by in any one of these steps.The polymorphic controlled step can be carried out before or after this system of supersound process.In most preferably mode of the present invention, the polymorphic controlled step is carried out in the supersound process process.

The another kind of method that prepare submicron particles is disclosed in jointly in the U. S. application 10/183,035 unsettled, common transfer, and the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the steps: that (1) provides the heterogeneous thick dispersion liquid that comprises organic facies and water, contains medical compounds in the organic facies; (2) the diffusing liquid application of rough segmentation is added energy and form finely divided liquid; (3) freezing this finely divided liquid; (4) this finely divided liquid of lyophilization obtains the submicron particles of active compound on the pharmacopedics.(1) will mix with compounds effective on the pharmacopedics with the immiscible solvent of water and obtain organic solution to provide the step of heterogeneous system to comprise the steps:, (2) prepare group water solution and (3) with one or more surface active cpds organic solution and aqueous solution are formed heterogeneous system.The blend step of organic facies and water comprises and uses flow device or other of piston slit homogenizer, colloid mill, high-speed mixing equipment, extrusion equipment, manual stirring or oscillator device, microcosmic that the equipment or the technology of shear conditions are provided.

The polymorphic controlled step of describing in detail below can be carried out among any one step of these steps.In most preferably mode of the present invention, the polymorphic controlled step is by providing the blend step (3) in the heterogeneous system step to carry out.

The anti-solvent deposition of solvent

The anti-solvent deposition technology of suitable solvent is disclosed in United States Patent (USP) 5,118, and in 528 and 5,100,591, the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the steps: the liquid phase of (1) preparation bioactive substance in solvent or solvent mixture, can be to wherein adding one or more surfactants; (2) second liquid phase of preparation non-solvent or non-solvent mixture, the solvent or the solvent mixture of non-solvent and this material are miscible, (3) by stirring solution (1) and (2) are added to together and (4) remove the soliquid that undesired solvent obtains nano-particle.This patent points out that it has been made less than the material grains of 500nm does not need to provide energy.

As mentioned above, the optional polymorphic controlled step of describing in detail below can be carried out in any one step of these steps.In most preferably mode of the present invention, the polymorphic controlled step was carried out in step (3) before being added to solution (1) and (2) together.

The phase inversion precipitation

A kind of suitable phase inversion intermediate processing is disclosed in United States Patent (USP) 6,235, and 224,6,143,211 and U.S. Patent application 2001/0042932, described document is introduced into this paper for your guidance and constitute the part of this paper.Phase inversion is the term that is used to describe following physical phenomenon, and the polymer transition that promptly is dissolved in the continuous phase dicyandiamide solution is the solid macromolecular network, and wherein polymer is a continuous phase.A kind of method of inducing phase inversion is to add non-solvent in continuous phase.Polymer becomes unsettled two-phase mixture by single-phase: rich in polymers part and poor polymer moieties.In polymer-rich phase, the micelle drop of non-solvent is as the nucleation position, and is aggregated thing and coats.Patent 6,235,224 point out, under certain conditions, the phase inversion of polymer solution can spontaneous formation discrete particles, comprises nano-particle.This patent disclosure with a kind of polymer dissolution or be scattered in a kind of solvent.Medicament also is dissolved or dispersed in the solvent.For the effectively optional polymorphic controlled step of the present invention, wish that medicament is dissolved in the solvent.Polymer, medicament and solvent form the mixture that comprises continuous phase together, and wherein solvent is a continuous phase.Then mixture is added in the excessive at least 10 times miscible non-solvent, spontaneous formation mean diameter is the microgranule of microencapsulation of the medicament of 10nm to 10 μ m.Particle diameter is subjected to the influence of the right characteristic of viscosity, polymer molecular weight and the solvent non-solvent of solvent and non-solvent volume ratio, polymer concentration, polymer-solvent solution.This method has been omitted for example by forming the step that emulsion produces the little drop of solvent.This method has also been removed stirring and/or shearing force from.

The optional polymorphic controlled step that describes in detail below can be carried out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step is before adding non-solvent in continuous phase or carry out in the process.

PH changes precipitation

PH changes sedimentation and typically comprises the steps: medicine dissolution in having the solution of certain pH, and this moment, medicine was soluble, changed pH subsequently and made medicine no longer solvable.According to concrete medical compounds, pH can be tart or alkaline.Then with in the solution and form the particulate pre-suspension of pharmaceutical active compounds of submicron order.A kind of suitable pH changes intermediate processing and is disclosed in United States Patent (USP) 5,665, and in 331, the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the steps, medicament is dissolved in the alkaline solution with crystal growth modifier (CGM), forms the fine grained dispersion liquid of medicament then in the presence of the surfactant of suitable surface modification with this solution of acid neutralization.Can be the membrane permeation purification step of dispersion liquid after settling step, the concentration with dispersion liquid be adjusted to desired concn then.This report method has obtained the microcrystal grain of Z average diameter less than 400nm (measuring with photon correlation energy spectrum).

The optional polymorphic controlled step of describing in detail below can be carried out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step before the neutralization procedure or among carry out.

The example that other pH changes intermediate processing is disclosed in United States Patent (USP) 5,716, and in 642,5,662,883,5,560,932 and 4,608,278, described document is introduced into this paper for your guidance and constitute the part of this paper.

Inject intermediate processing

Suitable injection sedimentation is disclosed in United States Patent (USP) 4,997, and in 454 and 4,826,689, these documents are introduced into this paper for your guidance and constitute the part of this paper.At first, suitable solid chemical compound is dissolved in forms solvent mixture in the appropriate organic solvent.Then, to be infused in the solvent mixture with non-solvent with the miscible precipitation of organic solvent, temperature is-10 ℃ to about 100 ℃ approximately, charge velocity is that the about 0.01ml/min of every 50ml volume is to about 1000ml/min, make the particulate suspension of sedimentary non-coalescent compound solid, it has the uniform basically average diameter less than 10 μ m.Preferably, when the injection that precipitates with non-solvent, carry out the stirring (for example stirring) of solution.Can contain surfactant in the non-solvent comes stable particle coalescent to prevent.Then granule is separated from solvent.According to solid chemical compound and required particle diameter, the present invention can change ratio, charge velocity, stir speed (S.S.) and the volume parameter of temperature, non-solvent and solvent.The volume ratio and the implantation temperature of particle diameter and non-solvent and solvent are in direct ratio, and are inversely proportional to charge velocity and stir speed (S.S.).Precipitation can be aqueous or non-water with non-solvent, and this depends on the relative solubility of chemical compound and required suspension excipient.

The optional polymorphic controlled step of describing in detail below can be carried out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step before non-solvent injects or among carry out.

The variations in temperature precipitation

The variations in temperature sedimentation is also referred to as hot-melt technology, is disclosed in the United States Patent (USP) 5,188,837 of Domb, and the document is introduced into this paper for your guidance and constitute the part of this paper.In one embodiment of the invention, the fat ball is made by following method: (1) fusion or dissolving will form by the liquid of delivered substance by substance for delivery such as medicine in the fusion excipient; (2) under the temperature of the fusing point that is higher than material or excipient, phosphide is joined in fused material or the excipient together with aqueous medium; (3) under the temperature that is higher than the excipient fusing point mixing suspension until obtaining uniform fine-grained agent; (4) cool off preparation fast to room temperature or below the room temperature then.

The optional polymorphic controlled step of describing in detail below can be carried out among any one of these steps, as long as treatment temperature is not higher than the fusing point of medicine.In most preferably mode of the present invention, the polymorphic controlled step is to carry out before the warm medicament dispersion liquid of cooling.

The solvent evaporation precipitation

The solvent evaporation sedimentation is disclosed in United States Patent (USP) 4,973, and in 465, the document is introduced into this paper for your guidance and constitute the part of this paper.This patent disclosure prepare the method for crystallite, described method comprises the steps: that (1) provides the pharmaceutical composition that is dissolved in ordinary organic solvents or the solvent mixture and the solution of phosphide; (2) vigorous stirring will be carried out by the film that evaporating solvent or solvent mixture obtain in evaporating solvent or solvent mixture and (3) in aqueous solution, and it is suspended in the aqueous solution.Can desolvate thereby remove by in solution, applying energy, make chemical compound produce precipitation with the evaporation sufficient amount of solvent.Also can for example apply vacuum or on solution, be blown into nitrogen, desolvate thereby remove by other known technology to solution.The optional polymorphic controlled step of describing in detail below can be carried out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step was carried out before evaporation step.

Reaction precipitation

Reaction precipitation comprises the step that medical compounds is dissolved in formation solution in the suitable solvent.The addition of chemical compound should be and chemical compound is reached saturation point or the amount below the saturation point in solvent.By reacting with chemical reagent, perhaps relevant with applying energy (for example heat or UV light etc.) method of modifying makes modified compound have being precipitated out than low solubility and from solution in this solvent with compound modified.The optional polymorphic controlled step of describing in detail below can be carried out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step be before the settling step or among carry out.

The compressed fluid precipitation

Be disclosed among the WO97/14407 of Johnston by the sedimentary a kind of appropriate technology of compressed fluid, the document is introduced into this paper for your guidance and constitute the part of this paper.This method comprises the step that water-insoluble drug is dissolved in formation solution in the solvent.Then solution is sprayed in the compressed fluid, this fluid can be gas, liquid or supercritical fluid.Compressed fluid is added solute in the solution of solvent, and this can make solute reach or near the over-saturation state, and is precipitated out with fine grain form.Here, compressed fluid is as anti-solvent, and it has reduced the cohesion energy density that wherein is dissolved with the solvent of medicine.

Perhaps, medicine can be dissolved in the compressed fluid, then it is sprayed into aqueous phase.The rapid expanding of compressed fluid has reduced fluidic solvability, and this makes solute be deposited in aqueous phase with fine grained successively.Here, compressed fluid serves as solvent.

Coalescent for stable particle to prevent, can comprise surface modifier such as surfactant in this technology.Granule by this technology preparation is generally 500nm or littler.

The optional polymorphic controlled step that describes in detail below can be by carrying out among any one of these steps.In most preferably mode of the present invention, the polymorphic controlled step before granule forms step or among carry out.

Suspension process

Other method for preparing aqueous nano granule suspension is a suspension process.In the method, by granule is directly added in the aqueous medium, thereby pharmacy particle is dispersed in the aqueous medium, to obtain pre-suspension.This granule generally is coated with surface modifier and suppresses particulate coalescent.Can in medicament or aqueous medium, add one or more other excipient.

Can in medicament or pre-suspension, apply energy so that the medicament particle diameter is reduced to required size.The example of energy source includes but not limited to, ultrasonic, homogenize, microcosmic flow, adverse current homogenize or other provide the method for impulsive force, shearing force or cavitation force.

The polymorphic control method

The method of supending also comprises the step of crystal sowing, with the crystal structure of control medicine.Term " crystal structure " is meant the arrangement and/or the conformation of molecule in the lattice.The chemical compound that can crystallize into the different crystal structure is known as multi-crystalline compounds.Polymorphous evaluation is an important step in the medication preparation process, because the different polymorphs of same medicine show different dissolubility, therapeutic activity, bioavailability and suspending power.Equally, the different polymorphs of identical excipient also show different dissolubility, with by the compatibility of delivering drugs, chemical stability and suspension stability.Therefore, for the repeatability of guaranteeing between product purity and the batch, the polymorphic of control chemical compound is important.

In said method, the polymorphic of chemical compound can be controlled by the additional step of crystal sowing.Crystal sowing comprises utilizing the seed chemical compound or applying energy and forms the seed chemical compound.In optimal way of the present invention, the seed chemical compound is an active chemical compound on required polymorphous pharmacopedics.Perhaps, the seed chemical compound also can be inert impurities or the organic compound with required polymorphic similar.

The seed chemical compound can be precipitated out from the solution that comprises medicine arbitrary any method.This method comprises the steps: active chemical compound on the pharmacopedics is added with enough amounts that surpasses its dissolubility in first solution, forms supersaturated solution.Handle supersaturated solution with active chemical compound on the required polymorphic precipitation pharmacopedics.Handle supersaturated solution comprise with solution ripening a period of time crystal formation until observing, obtain the crystal seed mixture.Treatment Solution also comprises temperature or the pH value that changes solution.Can also apply energy to supersaturated solution, make that active chemical compound is precipitated out with required polymorphic on the pharmacopedics from solution.Can be with comprising that the several different methods that above-mentioned energy applies step applies energy.In addition, energy can also be by heating pre-suspension or being exposed to electromagnetic energy, particle beam or the method in electron beam source applies.Electromagnetic energy comprises uses laser beam, dynamic electromagnetic energy or other radiation source.Also considered to utilize ultrasonic, electrostatic field and electromagnetostatic field to apply the source as the energy.

In optimal way of the present invention, the method for preparing crystal seed by the supersaturated solution of ripening comprises the steps: that (i) adds in drug solution that active chemical compound obtains supersaturated solution on a certain amount of pharmacopedics, (ii) the ripening supersaturated solution forms detectable crystal, produces the crystal seed mixture; (iii) the precipitation seed mixture forms pre-suspension.Then, further handle pre-suspension, with the aqueous suspension of active chemical compound on the pharmacopedics that obtains having required polymorphic and required particle size range according to methods described herein.

The step of crystal sowing can also be finished by the method that applies energy formation seed chemical compound in first solution or pre-suspension, as long as the liquid or the liquid mixture that expose contain medical compounds or seed material.Can apply energy to supersaturated solution according to above-mentioned identical method.

Therefore, the invention provides a kind of compositions with required polymorphous medical compounds, it is substantially free of unspecified polymorph.Estimate that the inventive method can be used for optionally preparing the required polymorphic of multiple medical compounds.

6. the sterilization of compositions

According to the heat stability of the concrete component of compositions and the particle diameter of compositions, before freezing, can carry out heat sterilization or filter the processing of sterilization more earlier compositions.The method for optimizing of preparation sterile product is to filter selected component, carries out sterilization treatment then before freezing.Another kind of sterilizing methods of the present invention is to carry out gamma-radiation before or after freezing.

Embodiment

Embodiment 1: adopt microdeposit method A, by homogenize then frozen suspension liquid prepare the itraconazole suspension

Surfactant solution: in the 4L flask, add 3500mL distilled water, 22g glycerol, 22g poloxamer 407 and 22g poloxamer 188.Heat this surfactant solution, and the stirring and dissolving solid.Become 4L with the surfactant solution cooling and with distilled water diluting.

The itraconazole concentrated solution: in the 100mL beaker, mix 15g itraconazole and 67.5g lactic acid.Heating blends is with dissolved solid.The itraconazole concentrated solution is cooled to room temperature.

Pre-suspension: the itraconazole concentrated solution is transferred in the 60mL syringe.The 1.5L surfactant solution is transferred in the homogenizer funnel of chuck.Overhead is put into dilute solution to immerse fully until hybrid blade.Utilize syringe pump, under agitation the itraconazole concentrated solution is slowly added in the dilute solution.

The homogenize suspension: with the homogenize at once of pre-suspension (10,000psi) about 20 minutes.

Final suspension: with the centrifugal homogenize of suspension 20 minutes, thereby excessive lactic acid is removed.Supernatant is outwelled, solid is suspended in the surfactant solution of being made up of the unsalted surface activator solution once more.Suspension is mixed and centrifugal 20 minutes.Supernatant is outwelled, solid is suspended in the surfactant solution of being made up of the unsalted surface activator solution once more.10, homogenize is about 20 minutes under the 000psi with the sample that suspends once more.The final pH of suspension is about 4.Suspension is collected in the bottle of 50mL, and with the plug seal of posting Teflon .

Refrigerated suspension: the suspension sample that 3-50mL is final is put into-20 ℃ of icy devices, and the final suspension sample of 3-50mL is deposited under 2-8 ℃.After about 1 month, sample is taken out down from-20 ℃, it is melted under environmental condition.With sample transfer under 2-8 ℃.Do not observe be separated, tangible coalescent or caking.The comparative sample of carrying out refrigerated sample and leave under 2-8 ℃ is tested its particle size distribution with laser scattering method.Freezing sample and comparative sample do not have recognizable difference (as follows) on particle size distribution.

Sample ID	Mean diameter	99% particle diameter
			The ultrasonic processing of the ultrasonic processing of the comparative sample-1 comparative sample-1 ultrasonic processing of the 1 minute comparative sample-2 comparative sample-2 1 minute comparative sample-3 comparative sample-3 ultrasonic processing of freezing sample-1 freezing sample-1 in the 1 minute ultrasonic processing of freezing sample-2 freezing sample-2 in the 1 minute ultrasonic processing of freezing sample-3 freezing sample-3 in 1 minute 1 minute	0.243 0.238 0.240 0.247 0.250 0.266 0.246 0.261 0.232 0.245 0.236 0.241	0.510 0.510 0.510 0.510 0.510 0.510 0.510 0.510 0.510 0.510 0.510 0.510

Have reason to infer that frozen suspension liquid can be stablized and deposited 1 year or the longer time under such storage condition.

Embodiment 2: amorphism Itraconazole nanometer suspension carries out stabilisation by depositing under-70 ℃

The 4.0g itraconazole is dissolved in the 20mL dichloromethane and mixes with the albumin solution (solution dilution by 25% comes) of 400mL 5%.Mixed solution is manually vibrated with two kinds of liquid of effective dispersion.Then with thick emulsion supersound process (T=5 ℃) 6 minutes (with 1 " probe carried out supersound process every 30 seconds under 40% amplitude).With the solution of supersound process vacuum (house vacuum) (about 100 holders) about 1/2 hour of rotary evaporation (rotovapped) down in doors, then at pump vacuum (＜20 holder) about 2 hours of rotary evaporation down.The product of rotary evaporation is detected (Horiba) analysis with light scattering, show that average diameter of particles is 406nm.Then this product is sent into Galbraith Laboratories Inc. and carried out the GC headspace analysis, show that concentration dichloromethane is 12.3ppm.The visible optical microscopic examination shows that granule is spherical, does not have the crystallization sign.In addition, the granule that this method is made carries out the X-ray powder diffraction analysis, has further proved it is amorphous state fully.

About 35mL product was deposited under-70 ℃ 32 days.Check suspension with HORIBA light scattering detection method and microscope inspection and the analysis showed that once more, particle diameter does not change (meansigma methods is 427nm) basically.Have reason to infer that under such storage condition, frozen suspension liquid is stable in 1 year or longer time.

Embodiment 3: 1% budesonide in PEG-phosphide surfactant system

Composition: 1% budesonide

1.2%mPEG-PSPE, molecular weight 2000

2.25% glycerol

0.14% sodium hydrogen phosphate

Ready-made 2.25% glycerol and 0.14% sodium hydrogen phosphate, the pH of containing is 8.6 aqueous solution with the mPEG-PSPE (palmityl-stearoyl-phosphatidyl ethanolamine) of weighing and a volume, and stirs with high-shear mixer.Add medicine, and the pre-suspension of formation that under high shear stirs the mixture.25, under the pressure of 000psi, pre-suspension is disperseed homogenize 30 times.

A part of sample was descended freezing 24 hours at-20 ℃, make it then at room temperature to melt fully.

Particle diameter test result (fixed) with the laser diffraction instrumentation

Diameter (in volume-weight)	Initially (micron)	After freeze thaw (micron)
			On average	0.8472	0.8371
99％	1.688	1.685

Embodiment 4: 1% the nabumetone that contains the albumin surfactant

Composition: 5% human albumin

1% nabumetone

With the medicament mixed of 1 volume albumin solution and weighing, and under high shear mix the pre-suspension of formation.25, under the pressure of 000psi, pre-suspension is disperseed homogenize 30 times.

A part of sample was descended freezing 24 hours at-20 ℃, it is at room temperature melted fully.

Particle diameter test result (fixed) with the laser diffraction instrumentation

Diameter (in volume-weight)	Initially (micron)	After freeze thaw (micron)
			On average	0.7721	0.7940
99％	1.889	1.936

Embodiment 5: 1% the nabumetone that contains poly-alkoxyl ether surface active agent and bile salts

Composition:

2.2% poloxamer 188

0.1% dexycholate

2.2% glycerol

1% nabumetone

The medicine and a volume solution of weighing are mixed, and described solution contains 2.2% poloxamer 188,0.1% NaTDC and 2.2% glycerol, and pH value of solution is adjusted into 8.7, and mixes the pre-suspension of formation down with high shear force.25, under the pressure of 000psi, pre-suspension is disperseed homogenize 20 times.

A part of sample was descended freezing 24 hours at-20 ℃, it is at room temperature melted fully.

Particle diameter test result (fixed) with the laser diffraction instrumentation

Diameter (in volume-weight)	Initially (micron)	After freeze thaw (micron)
			On average	1.0498	1.085
99％	2.423	2.484

Embodiment 6: 1% the budesonide that contains the PEG-fatty acid ester

Composition:

0.125％Solutol

2.25% glycerol

1% budesonide

The medicine of weighing and a volume solution are mixed, and described solution contains 0.125%Solutol and 2.25% glycerol, and pH value of solution is adjusted into 8.7, and carries out high shear mixing and form pre-suspension.25, under the pressure of 000psi, pre-suspension is disperseed homogenize 30 times.

A part of sample was descended freezing 24 hours at-20 ℃, it is at room temperature melted fully.

Particle diameter test result (fixed) with the laser diffraction instrumentation

Diameter (in volume-weight)	Initially (micron)	After freeze thaw (micron)
			On average	0.7587	0.7641
99％	1.460	1.480

Embodiment 7:

Composition: 1% vitamin E TPGS (d-alpha tocopherol cetomacrogol 1000 succinate)

1% nabumetone

2.25% glycerol

0.14% sodium hydrogen phosphate

With the vitamin E TPGS and the ready-made aqueous solution of 1 volume of weighing, described solution contains 2.25% glycerol and 0.14% sodium hydrogen phosphate, and pH is 8.6.Mixture is stirred with vortex agitator, dissolve until vitamin E TPGS.Add also powerful stirring (ultraturraxed) mixture of medicine and form pre-suspension.Under the pressure of 25kpsi, pre-suspension is disperseed homogenize 30 times with the AvestinB3 homogenizer.

A part of sample was descended freezing 24 hours at-20 ℃, it is at room temperature melted fully.

The particle diameter test result

Diameter (in volume-weight)	Initially (micron)	After freeze thaw (micron)
			Not 99% of supersound process	2.372μm	2.593μm
99% of excusing from death processing	2.266μm	2.398μm
			Supersound process meansigma methods	1.0332μm	1.0333μm

Although illustrate and described specific embodiment, can make multiple change in the case of without departing from the spirit of the present invention, and protection domain only limits to the scope of back claim.

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.