CN101466355A

CN101466355A - Nanostructured compositions having antibacterial, anti-fungal, anti-yeast, and/or anti-viral properties

Info

Publication number: CN101466355A
Application number: CNA2007800213152A
Authority: CN
Inventors: 迪尼什·施诺伊; 罗伯特·李; 克雷格·赖特
Original assignee: Novavax Inc
Current assignee: Novavax Inc
Priority date: 2006-04-07
Filing date: 2007-04-03
Publication date: 2009-06-24
Also published as: AU2007240983A1; JP2009533341A; EP2010149A1; CA2648360A1; WO2007123790A1

Abstract

The invention provides nanostructured compositions having antibacterial, anti-fungal, anti-yeast, and/or anti-viral properties. The compositions are useful as drug delivery carriers for one or more active agents or, in the absence of an active agent, in methods where such compositions are desirable.

Description

Nanorize compositions with antibacterium, antifungal, anti-yeast and/or antiviral properties

Technical field

The present invention relates to have antibacterium, the nanorize compositions (nanostructured composition) of antifungal, anti-yeast and/or antiviral properties.Said composition can be used as the drug administration carrier of one or more activating agents, and perhaps being used for above-mentioned composition when not having activating agent is desired method.

Background technology

A. about the background technology of the purposes of antibacterial agent in pharmaceutical dosage form and consumer goods

Thereby microbiological antiseptic is added to make them avoid microbial growth in the dosage form of sterilized or avoid making in the middle of the course of processing or non-ly afterwards having a mind to the microorganism introduced.With regard to regard to the sterile product of using in the multi-dose container, add anti-microbial preservative to suppress by extracting the individually dosed microbial growth of being introduced repeatedly.

All spendable antimicrobials all are toxicants.Referring to USP 26 (the 26th edition American Pharmacopeia), general rules, 51 joints, " antimicrobial efficacy test (Antimicrobial Effectiveness Testing) ".In order farthest to protect the patient, the concentration that shows effective antiseptic in the packaging product of final preparation should be lower than may be to the deleterious level of people.

The guide of U.S. food and Drug Administration (U.S.Food and Drug Administration) requires: no matter be the antimicrobial efficacy that intrinsic antimicrobial efficacy in the product (promptly for antibiotic) still produces because of the interpolation antimicrobial, for with all injections of multi-dose container packing or contain the other products of anti-microbial preservative, all mandatory declaration antimicrobial efficacy.For multiple dose part and peroral dosage form, and for other dosage form such as eye usefulness, ear usefulness, nose usefulness, lavation and dialysis fluid, also mandatory declaration antimicrobial efficacy.Referring to USP 26, general rules, 51 joints, " antimicrobial efficacy test ".

Adding antimicrobial may be out of season in therapeutic dosage forms, because above-claimed cpd may be toxic and they may interact undesirably with main activating agent to be sent.In addition, the use of microbicide can promote the generation of antibiotic-resistant bacteria, Drug resistance yeast, Drug resistance fungus etc.In being extensive use of of antibacterium washing liquid, soap, cleaning product etc., observed this situation.

Antibiotic resistance in the antibacterial increases in recent years, thereby people have improved developing the concern that cross tolerance owing to being exposed to antibiotic or biocide in antibacterial or other microorganism.Rutala, W.A., " APIC Guideline for Selection and Use of Disinfectants; " American J., people such as 24:313-342 (1996) and Russell, " Do Antiseptics andDisinfectants Select for Antibiotic Resistance? " J.of Medicinal Microbiology, 48:613-615 (1999).More effective disinfectant may be to stimulate very much with toxic, and this causes health complications such as contact dermatitis and mucous membrane irritation in the people.Hansen, K.S., " OccupationalDermatoses in Hospital Cleaning Women; " Contact Dermatitis, people such as P:343-351 (1983) and Beauchamp, " A Critical Review of the Toxicology of Glutaraldehyde, Critical Reviews in Toxicology, 22:143-174 (1992).Therefore, along with the variation of microorganism and the development of resistant strain, constantly need the effective and safe biocide that is used for local and surface sterilization.

B. about the background technology of fungus, antibacterial, yeast and viral chance organism

USP describes the measure to the test of killing escherichia coli (E.coli), Pseudomonas aeruginosa (P.aeruginosa) and staphylococcus aureus (S.aureus) effectiveness and control and restriction white candida mycoderma (C.albicans) and aspergillus niger (A.niger) growth in detail, thereby measures the antimicrobial efficacy of dosage form.Referring to USP 26, general rules, 51 joints, " antimicrobial efficacy test ".These concrete microorganisms have been represented and have been a problem most and thorny antibacterial, fungus and yeast.

Aspergillus niger is a kind of fungus and is one of modal kind in the aspergillus.It causes the black mycete on the fruits and vegetables of some type, and is the common pollutant of food.

The white candida mycoderma is people's a main fungal pathogens.Infection can be partial, and as vaginal infection and oral cavity infection, it causes the discomfort of certain degree.In some patient groups (premature infant, leukaemic and fire victim) that its system of defense is badly damaged, described yeast becomes fatal pathogen and causes systemic infection-result is nearly 50% infected patient death.Above-mentioned incidence of infection increases apace, especially in the patient who seeks medical advice.In New Zealand, above-mentioned infection is now than before 15 years frequent 10 times.And the candidate target of anti-candida mycoderma medicine is very limited, and these medicines may have serious adverse.

Escherichia coli are a kind of ubiquitous antibacterials, and it has a large amount of known bacterial strains.Wu Hui coli strain is an Escherichia coli O 157 especially: H7 is that EHEC is a member in the enterohemorrhagic Escherichia coli.Thereby enterohemorrhagic is meant the intestinal related organisms that causes hemorrhage blood loss.Escherichia coli O 157: H7 produces toxin, is called shiga-like toxin (SLT) or Vero toxin.This toxin is a kind of protein that causes the enterocyte grievous injury.This situation is especially dangerous for the younger ones in an age group child, and may be fatal, can not bear a large amount of blood and fluidic loss because the child is too little.In some cases, relate to another kind of syndrome, be called hemolytic uremic syndrome (HUS), it is characterized in that renal failure and erythrocyte run off.About Child Development of 5% to 10% is to this stage of disease.Under serious situation, this disease causes permanent injury of kidney.The existence of above-mentioned antibacterial also may extremely endanger in older or weakling.HUS can make up with the other factors that relates to blood system, and this may be 50% fatal for the older.Evidence show Escherichia coli O 157: H7 comes into vogue.

Pseudomonas aeruginosa is a kind of gram negative bacteria, this antibacterial with its environment polytropy, in tetchy individuality, cause disease ability with and antagonism give birth to plain resistance and clear.The severe complication of cystic fibrosis is to be the respiratory tract infection that Pseudomonas aeruginosa causes by ubiquitous antibacterial.Cancer and fire victim also usually suffer from the severe infections that is caused by this organism, and some other individuality of suffering from immune system defect also is like this.Be different from many environmental bacteria, Pseudomonas aeruginosa has the outstanding ability that causes disease in the master of responsive place.It can adapt to the multiple Ecological niche (organizing to plant and animal from water and soil earth) and grow vigorously these Ecological niches.This antibacterial can utilize widely organic compound as food source, thereby gives the unusual ability that it is settled in the limited Ecological niche of nutrient.Pseudomonas aeruginosa can produce multiple toxic protein, and these toxic proteins not only cause tissue injury widely but also disturb the defense mechanism of human immune system.These protein are contained from entering and kill in the settlement or the digestive enzyme of near the toxin of the host cell the settlement cell membrane the various organs and connective tissue to permanent damage.

Staphylococcus aureus is soft tissue infection and toxic shock syndrome (TSS) and the inducement of scalding sample skin syndrome.Staphylococcic pathogenic effects is main relevant with the toxin of its generation.Great majority in these toxin result from the plateau of growth curve of bacteria.In fact, commonly infected place does not contain the aureus cell of any survival.The enterotoxin of staphylococcus aureus causes the burst alimentary toxicosis that can cause spasm and serious vomiting.Infection can be traced to the source to incomplete ripe contaminated meat.Leukocidin is also secreted in these microorganisms, and it destroys leukocyte and cause pus and the toxin of acne formation for a kind of.Especially, found that staphylococcus aureus is the inducement of disease such as pneumonia, meningitis, furuncle, arthritis and osteomyelitis (chronic infection of bone).Most of staphylococcus aureuses are penicillin resistances, but known vancomycin (vancomycin) and nafcillin (nafcillin) resist most of bacterial strains effectively.

Mycete such as Aspergillus fumigatus (Aspergillus fumigatus) are filamentous fungis.They especially generally grow in the soil on the abiotic organic substance.They scatter and are called conidial asexual spore in air.Most of aspergillosis are harmless to the people, and Aspergillus fumigatus is especially not harmless by the people that disease, medication or hereditary disease are damaged to immune system.Be exposed to the anaphylaxis that Aspergillus fumigatus can cause sensitive individual.The more important thing is that Aspergillus fumigatus is the opportunistic pathogen of bone marrow transplantation patient, AIDS patient and other immunocompromised individuals.

Worldwide, Aspergillus fumigatus is to cause the most common mycete that infects.It is the Edinburg that aspergilloma was reported in 1842 that the first routine people of record infects, and has reported many cases of invasion property disease in the non-immunocompromised patient.These cases and nearest epidemic data emphasize that Aspergillus fumigatus is people's a main pathogens, although this is uncommon.Be recorded in the London of nineteen fifty-two first by the microbial anaphylactic disease of aspergillosis.And the British Medical Journal that is described in nineteen fifty-three is infected in the invasion (and mortality) in the first routine non-immunocompromised patient, and wherein the patient is from the Gloucester.

Judge that from non-selective obduction after death the sickness rate of invasion property disease was compared with 1992 over 12 years and risen about 14 times.In Europe, invasion property aspergillosis has replaced candidiasis and has become modal fungal pathogens in the postmortem of tertiary care hospital.That is to say that 4% among all dead patients suffer from invasion property aspergillosis, about by contrast 2% suffers from invasion property candidiasis.The patient who is in the risk based on sickness rate comprises the patient (25-40%) who suffers from chronic granulomatous disease, lung transplantation receiver (17-26%), allos bone marrow transplantation patient (4-30%), with leukemic neutrophilic granulocytopenia patient (5-25%), heart transplantation receiver (2-13%), pancreas is transplanted receiver (1-4%), the Europe and the renal transplant recipients of U.S.'s (～1%) and India's (～10%) and suffer from AIDS, the patient of multiple myeloma and the comprehensive immunodeficiency of severe (～4%).The whole world surpasses 500,000 examples every year and transplants.Acute leukemia influences about 3/100,000 population, and average every patient accepts 3 chemotherapy cycles, and each cycle is revealed as the principal risk phase.In the face of the senior lymphoma patient of invasion property aspergillosis height risk, also observe similar sickness rate for also.Only in industrialized country, these treatment protocol just produce about 250,000 principal risk phases in every year.Expection AIDS case surpasses 4,000 ten thousand to the year ends 2000, and it can cause about 1,400,000 example invasion property aspergillosis, although developing country's Most patients can not live long enough and this disease.

The rough mortality rate of invasion property aspergillosis is approximately 85%, if the words of treatment can reduce to about 50%.New drug in the test (voriconazole (voriconazole) etc.) can reduce mortality rate (about 10%) slightly, but the patient in the test often is better than the patient who treats in the clinical practice.Except invasion property disease, aspergillosis causes multiple other disease in the people.These diseases comprise the postoperative infection of sinusitis, anaphylaxis broncho-pulmonary and sinus infection, keratitis (it usually causes the blind of place eyes and is common in developing world) and immunocompetent patient among aspergilloma (promptly there is pulmonary cavity in " cluster (colonization) "), the normal person.The case load of aspergilloma increases significantly owing to the increase of incidence of tuberculosis, and these aspergilloma cases are difficult to treat as everyone knows.In the patient of 15-20% (in Britain), 2cm or bigger cavity develop into aspergilloma subsequently after the tuberculosis.Aspergilloma patient's 5 annual survival rates are about 40%.Allergic bronchopulmonary aspergillosis betides (number is also increasing) among the patient who suffers from cystic fibrosis and asthma, and this causes pulmonary fibrosis and death in 10 years after diagnosis usually.

Aspergillus flavus (Aspergillus flavus) is the pathogen of a variety of infection, and these infection comprise mycotoxicosis, hypersensitivity pneumonia, otitis, sinusitis and the invasion disease that is caused by aflatoxin (aflotoxin).Some report demonstration aflatoxin can be strengthened lysis, especially in the host that immunocompromised host/neutrophilic granulocyte reduces.This organism has extremely strong vascular invasion and causes necrosis and infraction.

C. medication of the prior art

The convenience of active medicine administration is exploitation treatment product and makes it the major issue that business-like drugmaker faces.For example, activating agent soluble in water is easy to be mixed with suitable dosage form.Yet it but is great challenge that weak water-soluble active agent is mixed with suitable dosage form.This is because human body is based on the system of water, thereby as the condition that produces therapeutic activity, medicine must dissolving after administration.

Some weak water-soluble active agent are never by commercialization, and this is because they can not dissolve effectively thereby can not show acceptable interior therapeutic activity.Perhaps, with respect to the weak water solublity of activating agent, administration may be excessive with the amount of the needed weak water-soluble active agent of the therapeutic activity that reaches acceptable level, and may cause unacceptable toxicity.Even activating agent is mixed with liquid (wherein activating agent being dissolved in the solvent), above-mentioned dosage form effect sometimes neither be best.For example, above-mentioned dosage form may have the character that is difficult to expect or cause the side effect of not expecting.

There is the method that improves the activating agent dissolubility in the prior art.For example, thereby the granularity that can reduce activating agent increases the surface area that activating agent exposed, and this causes the rate of dissolution that increases and bigger water solubility.A kind of existing method that reduces granularity is wet grinding.Come activating agent is ground by the pearl ball made from Bohemian glass, pottery material, porcelain, zirconium oxide, Zirconium orthosilicate., polymer resin or other suitable substance in need be a little less than the activating agent molten medium (as water) of this method.Activating agent is converted into much smaller granule physically, and it still is suspended in the abrasive media.Then can be by the active agent particle of resulting micron or nano-scale being separated from abrasive media such as method such as filter or centrifugal, and be mixed with suitable dosage form.Referring to United States Patent (USP) 5,145,684,5,518,187; 5,862,999 and 5,718,388.One or more chemical compounds that in the medium that activating agent is ground, comprised the effect of activating agent surface stabilizer usually.Described surface stabilizer is adsorbed in the surface of activating agent, and sterically hindered as the activating agent particle size growth.

Therefore, conventional wet grinding technology produces " biphase " system, and wherein the activating agent nanoparticle (nanoparticulate) of stabilisation is suspended in the water-bearing media.(King of Prussia is PA) with trade name for Elan Drug Delivery

Business-like nanoparticle medicine-feeding technology of technology and SkyePharma, the Insoluble Drug Delivery of plc The technology example above-mentioned wet grinding technology.But the wet grinding of activating agent has many shortcomings, mainly is the cost of this method.Utilize wet grinding that the fringe cost that weak water-soluble active agent is mixed with nano-particle composition may have been hindered its application.In addition, amorphous compound is unsuitable for the wet grinding technology.

Other known method of preparation nanoparticle surfactant composition comprises precipitation, homogenize and supercritical fluid processes.Microdeposit (microprecipitation) is a kind of method of the stabilising dispersions of the weak insoluble active agent of preparation.Said method comprises activating agent is dissolved in the solvent, makes in the agent from solution to be precipitated out again.Homogenize is a kind of technology of not using grinding or abrasive media.Activating agent in the liquid medium constitutes the process streams that is pulled in the processing district, and described processing district exists

(Microfluidics is called the interaction chamber in Inc.).The geometry of interaction chamber produces powerful shearing force, impact force and air pocket power, and these power cause reducing of granularity.United States Patent (USP) 5,510,118 relate to utilization Obtain the biphase technology of nanoparticle active agent particle.At last, the supercritical fluid processes of preparation nanoparticle surfactant composition comprises activating agent is dissolved in the solution.Then this solution and supercritical fluid are incorporated in the granule formation container jointly.The control temperature and pressure, thus by supercritical fluid be used for making the dispersion of media and extracting basically take place simultaneously.The example of the known supercritical process of preparation nanoparticle comprises International Patent Application WO 97/144407 and United States Patent (USP) 6,406,718.

This area need have the form of administration of intrinsic antibacterium, anti-yeast, antifungal and/or antiviral properties.In addition, also need to have above-mentioned intrinsic antibacterium, anti-yeast, antifungal and/or antiviral properties and can be in the compositions that does not have to use under the situation of activating agent.The present invention has satisfied these needs.

Summary of the invention

The present invention relates to have antimicrobial, the nanorize compositions of antifungal, anti-yeast and/or antiviral properties.Said composition comprises at least a oil, at least a surfactant, at least a solvent and water.In addition, said composition also can comprise activating agent.For example, this activating agent useful as drug, diagnostic agent or cosmetics.

Another aspect of the present invention relates to pharmaceutical composition, it comprises according to nanorize compositions of the present invention and one or more needed pharmaceutically suitable carrier and/or needed excipient, and described pharmaceutically suitable carrier and/or excipient can comprise viscosity modifier, pigment, flavoring agent, spice etc.

One aspect of the present invention relates to the nanorize preparation of unique activity ingredient, and it comprises the solid particulate components of mixture that (1) micelle component, (2) water-alkoxide component are water and water-miscible solvent, (3) emulsion oil-in-water drop component and optional (4) activating agent.Can comprise needed active medicine, diagnostic agent, cosmetics or other active component arbitrarily or all in these components.Therefore, shown in component 1-3, activating agent can be in the solution; Perhaps shown in component 4, activating agent can be sedimentary form of suspension.

In one embodiment, when said composition was imposed on skin, dissolved (solubilized) form was passed skin and is entered darker skin layer as entering corium.Other component such as micelle, oil part and/or granule medicament can make the horny layer that himself is positioned to towards skin layer usually.Based on various physics and chemical property, some chemical compound can make in the different layers that himself is positioned at epidermis and corium, and other chemical compound may directly pass skin.

This compound formulation needn't be sneaked into chemical penetrating agent, and for other preparation, chemical penetrating agent is to impel the active pharmaceutical ingredient transdermal penetration necessary.

Another aspect of the present invention relates to preparation nanorize method for compositions of the present invention, this method comprises that (a) makes up to form emulsion matrix the mixture of at least a oil, at least a solvent and at least a surfactant (also being referred to as surface stabilizer), (b) add water to described emulsion matrix, and (c) described mixture is carried out homogenize or vigorous stirring.If activating agent is used for compositions, the illustrative methods that then prepares said composition comprises that (a) is added into described activating agent in the mixture of oil, solvent and surfactant or stabilizing agent to form emulsion matrix, wherein this activating agent is dissolved in oil or the solvent, perhaps be dissolved among both, but water fast, (b) add water to described emulsion matrix, and (c) described mixture is carried out homogenize or vigorous stirring.

At last, the experimenter (subject) who uses compositions of the present invention to treat to need or also be that the present invention is contained as the method that the wide spectrum antimicrobial compositions is used for part or surface sterilization.

The general introduction of front and the description of drawings of back and detailed description all are exemplary and explanat, and are intended to further specify claimed the present invention.Based on following detailed description the in detail of the present invention, other purpose, advantage and new feature are conspicuous for those skilled in the art.

Description of drawings

Fig. 1 has shown according to USP 25,＜51 〉, the antibacterial efficacy result of the test of the placebo Composition of the present invention that illustrated rules are carried out in the 1869-1871 page or leaf (being the non-activity agent) (testing) with escherichia coli (ATCC8739), Pseudomonas aeruginosa (ATCC 9027), staphylococcus aureus (ATCC 6538), white candida mycoderma (ATCC 10231) and aspergillus niger (ATCC 16404).

Fig. 2 has shown according to USP 25,＜51 〉, the antibacterial efficacy result of the test of the placebo Composition of the present invention that illustrated rules are carried out in the 1869-1871 page or leaf (being the non-activity agent), but test with other microorganism (Pseudomonas aeruginosa (ATCC 13388), Pseudomonas aeruginosa (ATCC 25619), Aspergillus flavus and Aspergillus fumigatus).

Fig. 3 has shown according to USP 25, the antibacterial efficacy result of the test of estradiol of the present invention (estradiol) compositions that＜51 〉, illustrated rules are carried out in the 1869-1871 page or leaf (testing) with escherichia coli (ATCC8739), Pseudomonas aeruginosa (ATCC 9027), staphylococcus aureus (ATCC 6538), white candida mycoderma (ATCC 10231) and aspergillus niger (ATCC 16404).

Fig. 4 has shown according to USP 25, the antibacterial efficacy result of the test of testosterone of the present invention (testosterone) compositions that＜51 〉, illustrated rules are carried out in the 1869-1871 page or leaf (testing) with escherichia coli (ATCC8739), Pseudomonas aeruginosa (ATCC 9027), staphylococcus aureus (ATCC 6538), white candida mycoderma (ATCC 10231) and aspergillus niger (ATCC 16404).

Fig. 5 has shown the estradiol granularity in the nanorize compositions after the homogenize.

Fig. 6 has shown the estradiol granularity in the nanorize compositions after the Silverson method.

Fig. 7 has shown the testosterone granularity in the nanorize compositions after the homogenize.

The specific embodiment

A. general introduction of the present invention

The present invention relates to the nanorize compositions, it has antimicrobial, antifungal, anti-yeast and/or antiviral properties unexpectedly.Nanorize compositions of the present invention comprises at least a solvent, at least a oil, at least a surface stabilizer (also being referred to as surfactant) and water-bearing media.Said composition can contain one or more activating agents in addition, and described activating agent dissolves in or is scattered in in described oil, solvent or the water any.For example, these activating agent useful as drug or cosmetics.Need not to add any external antibacterial agent or antiseptic is given antimicrobial, anti-yeast, antifungal and/or antiviral properties to compositions of the present invention.

Compositions of the present invention satisfies the antimicrobial efficacy test standard that American Pharmacopeia (USP-general rules, 51 joints) is described.This illustrates by the test that following embodiment 4 describes, wherein cultivated various microorganisms (testing with escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC9027), staphylococcus aureus (ATCC 6538), white candida mycoderma (ATCC 10231), aspergillus niger (ATCC 16404), Pseudomonas aeruginosa (ATCC 13388), Pseudomonas aeruginosa (ATCC 25619), Aspergillus flavus and Aspergillus fumigatus) in the presence of the present composition.Result of the test also is shown among Fig. 1, and it illustrates the remarkable anti-microbial properties of the present composition.

5 kinds of microorganisms of standard USP test needs assessment: aspergillus niger (ATCC 16404), white candida mycoderma (ATCC 10231), escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027) and staphylococcus aureus (ATCC 6538).Use other bacterial strain to confirm antimicrobial efficacy in Aspergillus flavus, Aspergillus fumigatus, Pseudomonas aeruginosa (ATCC 25619) and Pseudomonas aeruginosa (ATCC 13388).As shown Fig. 2 of this result of the test indicated, the antimicrobial efficacy in these other bacterial strains has confirmed that without doubt the said composition media itself is antimicrobial.

And the introducing of activating agent does not damage the antimicrobial efficacy of the present composition.Particularly, shown in embodiment 3 and 4, the present composition that comprises estradiol and testosterone has also shown significant anti-microbial effect, and satisfies the USP test requirements document that is used to confirm antimicrobial acivity.Also referring to Fig. 3 and 4.

At the product that is used for topical therapeutic infection, wound healing etc., compositions of the present invention is useful especially, and this is that media itself plays microbicide because in above-mentioned composition the pharmacological properties of activating agent.Above-mentioned composition can cause synergism, and reduces the development probability of Drug resistance microorganism.And above-mentioned composition can make the use of low dosage activating agent realize.

At present, various types of cosmetics and pharmaceutical composition need add antimicrobial and stop microbial growth.Because the potential interaction between activating agent and the antimicrobial, it may be challenging selecting suitable antimicrobial agents in order.And antimicrobial may be toxic, and may cause side effect in the patient.

In one embodiment of the invention, said composition comprises activating agent, and described activating agent is selected from but is not limited to fenofibrate (fenofibrate), estradiol, alendronic Acid (alendronic acid), acycloguanosine (acyclovir), paclitaxel and cyclosporin (cyclosporine).

In another embodiment; described grease separation from but be not limited to almond oil (almond oil) (sweet); almond oil (apricot seed oil); borage oil (borage oil); Semen Brassicae Campestris oil (canola oil); Oleum Cocois (coconut oil); Semen Maydis oil; cotton seed oil; fish oil; Jojoba Oleum Glycines (jojoba bean oil); Adeps Sus domestica; Semen Lini oil (ripe) (linseed oil (boiled)); macadimia nut oil (Macadamia nut oil); medium chain triglyceride (medium chain triglyceride); mineral oil; olive oil; Oleum Arachidis hypogaeae semen; safflower oil; Oleum sesami; soybean oil; Squalene; Oleum Helianthi; tricaprylin (1; 2,3-three caprylyl glycerol) and Semen Tritici aestivi germ oil (wheat germ oil).

In one embodiment, described solvent is selected from but is not limited to isopropyl myristate, glycerol triacetate, N-Methyl pyrrolidone, aliphatic alcohol and aromatic alcohol, Polyethylene Glycol and propylene glycol.Other example of useful solvent is a long-chain alcohol.Ethanol and benzylalcohol are other examples that can be used for alcohol of the present invention.

In another embodiment, described stabilizing agent or surfactant be selected from but be not limited to sorbitan ester, glyceride, macrogol ester, block polymer, acrylate copolymer (as

The ethoxylated fat ester (as

RH-40), ethoxylated alcohol (as Ethoxylated fatty acid (as Tween20), monoglyceride, based on the surfactant and the polysorbate of silicon.In another embodiment, described sorbitan ester stabilizing agent is

Or

Described glyceride is glyceryl monostearate; Described macrogol ester is a polyglycol distearate; Described block polymer is

Described acrylate copolymer is

Described ethoxylated fat ester is

RH-40; Described ethoxylated alcohol is

Described ethoxylated fatty acid is

20; Or their combination.

In another embodiment, 1,000-40 carries out the homogenize step under the condition of 000psi (pound/square inch) by high-pressure system.

In one embodiment, the particle mean size of active agent particle, the drop that comprises activating agent or its combination is less than about 10 microns.In other embodiments of the present invention, active agent particle, the particle mean size that comprises the drop of activating agent or its combination is less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less than about 2900nm, less than about 2800nm, less than about 2700nm, less than about 2600nm, less than about 2500nm, less than about 2400nm, less than about 2300nm, less than about 2200nm, less than about 2100nm, less than about 2000nm, less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, perhaps less than about 100nm, less than about 90nm, less than about 80nm, less than about 70nm, less than about 60nm, less than about 50nm, less than about 40nm, less than about 30nm, less than about 20nm, perhaps less than about 10nm.In one embodiment, the particle mean size of active agent particle, the drop that comprises activating agent or its combination in diameter less than about 3 microns.

The application has described three kinds of methods of the preparation present composition.First method does not need the existence of activating agent.In the method, (a) at least a oil, at least a solvent and at least a surfactant are made up to form emulsion matrix; (b) add water to described emulsion matrix; And (c) described mixture is carried out homogenize or vigorous stirring.

If activating agent is used for compositions, the illustrative methods that then prepares said composition comprises that (a) is added into described activating agent in the mixture of oil, solvent and surfactant or stabilizing agent to form emulsion matrix, wherein this activating agent is dissolved in oil or the solvent, perhaps be dissolved among both, but water fast, (b) add water to described emulsion matrix, and (c) described mixture is carried out homogenize or vigorous stirring.

Two kinds of concrete grammars of preparation surfactant composition of the present invention have been described herein.In first method (" approach I "), in emulsion matrix, activating agent is ground (being that homogenize or vigorous stirring are to reduce the granularity of activating agent).This method requires to be dissolved in a little less than activating agent or is insoluble to oil phase/lipophilic mutually and each phase in water or the buffer.In second method (" approach II "), observe in emulsion matrix and simultaneously activating agent is ground (being that homogenize or vigorous stirring are to reduce the granularity of activating agent) and precipitation.Second method requires activating agent to be dissolved in or is partially soluble in the phase of one in the emulsion matrix or heterogeneous, and promptly activating agent is dissolved in oil, solvent or water or buffer.

Compare with art methods such as wet grinding, a benefit for preparing the method for the present composition is that this method is applicable to water-soluble active agent and weak water-soluble active agent.Another benefit of the inventive method is that they do not need abrasive media or special grinding technics or equipment.The use of above-mentioned abrasive media can increase cost and increase the complexity of the particle size reduction technology that is used for activating agent.Another benefit of the inventive method is that it can be used to process amorphous substance.

For approach I, at first activating agent is suspended in the mixture of nonmiscibility liquid (such as oil and solvent) and water or buffer to form emulsion matrix, then this emulsion matrix is carried out homogenize or vigorous stirring.Available reciprocal injection device (reciprocating syringe instrumentation), continuous-flow instrument (continuous flow instrumentation) or high-speed mixer (high speed mixing equipment) produce nanoparticle.Preferred high speed homogenizing method or the vigorous stirring method that produces high shear force and cavitation.Preferred high shear process, this is because the low technology of shearing can cause bigger activating agent granularity.Resultant composition is to be suspended in the activating agent in the emulsion droplet (nanoemulsions part) and to be in the crystallite (microcrystalline) of the spatial stability in the medium and/or to receive the compound mixture of crystalline substance (nanocrystalline) activating agent.This three-phase system comprises granule medicament, oil and water or buffer.Effective particle mean size of resulting micro-/ nano grain activating agent is less than about 3 microns.As described below, also can obtain littler seed activity agent.

Can activating agent be precipitated out from oil droplet by adding more nonmiscibility liquid.Usually, effective particle mean size of sedimentary activating agent is less than about 3 microns.If need, can stop active agent particle to be assembled or caking by sneaking into surfactant or emulsifying agent (i.e. " surface stabilizer ").

Approach II is applicable to the activating agent that dissolves at least a portion emulsion matrix (as solvent).For approach II, activating agent is dissolved in the mixture of oil, solvent and stabilizing agent to form the emulsion premix.If water or buffer are not added to this mixture, then this activating agent keeps soluble form.In case add water or buffer and applied shear force, this activating agent then is precipitated as effective particle mean size less than about 3 microns micro-/ nano grain.Available reciprocal injection device, continuous-flow instrument or high-speed mixer produce nanoparticle.The high-energy input of being undertaken by high speed homogenize or vigorous stirring is preferred technology.This high-energy technology has reduced the size of emulsion droplet, thereby makes big surface area exposure in aqueous environment on every side.Preferred high shear process, this is because the low technology of shearing can cause bigger granularity.Make the nanoparticle surfactant precipitate that before had been embedded in the emulsion matrix then.Final product comprises activating agent and the particle suspensions under the solution state, and both are distributed between solvent, oil and water or the buffer.In one embodiment, the nanoparticle activating agent has at least a and surface stabilizer its surface association.

Weak water-soluble but example that be dissolved in the activating agent of another kind of liquid comprise dissolve in the estradiol in the ethanol and be soluble in 1-Methyl-2-Pyrrolidone or N-Methyl pyrrolidone [NMP] in, be slightly soluble in oil and the stabilizing agent and the fenofibrate of water fast.

If need, can will utilize the water miscibility oil droplet and the activating agent nanoparticle of approach I or approach II preparation to filter 0.2 or 0.45 micron filter.Can be by increasing water content simply, reducing oil-stabilizing agent-solvent or change and form the cutting method that fluid drips in the process and generate bigger oil droplet and/or active agent particle.

For being used for the emulsion matrix of approach I or approach II as antimicrobial compositions or as drug administration carrier, by weight the weight meter, oil: stabilizing agent: the preferred proportion of solvent is about 23: about 5: about 4.The preferred proportion that contains oil phase and water or buffer is about 2: about 1.In other embodiments of the present invention, oil can exist by about 5% to about 50% (w/w); Solvent can exist by about 0.5% to about 10% (w/w); Stabilizing agent or surfactant can exist by about 0.5% to about 10% (w/w); Water can exist by about 20% to about 80% (w/w); Or their combination in any.

B. compositions of the present invention

Method of the present invention can produce several dissimilar compositionss.First compositions comprises (1) at least a oil; (2) at least a solvent; (3) at least a surfactant or surface stabilizer; And (4) water.Said composition has shown broad-spectrum anti-microbial activity, so said composition can be used as universal decontaminant.

The present composition of other type comprises at least a activating agent.For example, second compositions can comprise (1) nanoparticle activating agent, and its surface association has at least a surface stabilizer; (2) water or buffer; (3) comprise the emulsion premix of at least a oil and optional at least a solvent or oil phase or lipophilic mutually; And optional (4) micron grain (microparticulate) activating agent.This micron grain activating agent can be same as or be different from described nanoparticle activating agent.Described seed activity agent can be present in water or buffer, oil, solvent or their combination.Above-mentioned composition utilizes approach I preparation.

The 3rd compositions comprises (1) nanoparticle activating agent, and its surface association has at least a surface stabilizer; (2) water or buffer; And (3) comprise the emulsion premix of at least a oil, optional at least a solvent and dissolved activating agent or oil phase or lipophilic mutually.Said composition also can comprise micron grain activating agent.Described dissolved activating agent can be present in water or buffer, oil, solvent or their combination.In addition, the nanoparticle activating agent can be present in water or buffer, oil, solvent or their combination.Above-mentioned composition utilizes approach II preparation.In another embodiment of the invention, dissolved activating agent can be precipitated out from emulsion droplet.Effective particle mean size of sedimentary activating agent is preferably less than about 3 microns.

Three-phase compositions of the present invention is owing to following reason but favourable.At first, the preparation that is obtained by approach II method comprises solid form and the dissolved form with a kind of activating agent.The sustained release that this makes resulting pharmaceutical preparation can provide the instant-free of composition activity agent that the composition activity agent also can be provided provides fast initial (fast onset) activity of activating agent and the prolongation activity of activating agent thus.

And, when the solid activator nanoparticle being mixed with for example ointment or lotion when being locally applied to skin, this solid activator nanoparticle can provide instant local therapeutic effects at skin surface, and dissolved activating agent passes skin/barrier cell in the emulsion matrix, and this makes activating agent enter body system.That is to say, dissolved activating agent passes skin apace and infiltrates in the darker layer, and solid portion does not infiltrate in the darker skin layer, but plays chamber, local storehouse (depot), and provides as bank (reservoir) and to enter the more medicine of deep layer.Therefore, both having comprised the preparation that the activating agent nanoparticle also comprises dissolved activating agent can provide local therapeutic effects and whole body therapeutic effect, and it is particularly advantageous in the percutaneous dosage form.

If need, the different component of above-mentioned two based compositions of separable and independent use.

The present invention allows the activating agent with number of different types to be mixed with preparation based on emulsion.The example of above-mentioned activating agent includes but not limited to acycloguanosine, cyclosporin, estradiol, fenofibrate, cetirizine (ceterizine), nicotine (nicotine), naltrexone (naltrexone) and alendronic Acid.

1. activating agent nanoparticle

Can be from aqueous suspension medium and/or emulsion ball (emulsion globule) for example by filtering or centrifugally coming separating solids activating agent nanoparticle.This provides the facilitated method of the nanoparticle that obtains weak water solublity or water-insoluble activating agent.And when surface stabilizer was used for particle size reduction technology, it had avoided the activating agent nanoparticle to assemble, thereby makes the activating agent nanoparticle be stabilized in the nanoparticle size.If need, the activating agent nanoparticle can be mixed with any suitable dosage form again.Can use the food stage, USP level or the NF level material that are suitable for human purposes application to prepare the activating agent nanoparticle.

Exemplary dosage form includes but not limited to liquid dispersant, oral suspensions, tablet, gel, aerosol, ointment, ointment, capsule, dry powder doses, many granules (multiparticulate), spray agent (sprinkle), wafer, lozenge and syrup.And dosage form of the present invention can be solid dosage forms, liquid dosage form, semiliquid dosage form, quick-release formulation (immediate release formulation), improve delivery formulations (modified release formulation), the sustained release preparation, melt preparation, lyophilized formulations, delayed release preparation, prolongation delivery formulations, pulsation-releasing preparation, blended rapid release and sustained release preparation or their combination in any fast.Compositions of the present invention can be mixed with by any suitable method and come administration, as intestinal inject (being intravenous, intramuscular or subcutaneous) administration outward, with (intracisternal) administration in solid, liquid or aerosol form oral administration, vagina administration, nasal administration, rectally, ophthalmic administration, ear administration, part (powder, ointment or drop) administration, oral administration, the pond, intraperitoneal administration or topical etc.

Because effective particle mean size of described activating agent nanoparticle is less than about 3 microns, than the crystallite activating agent, this activating agent nanoparticle can be easier to pass absorption barrier such as skin usually.Similarly, little activating agent granularity enables to pass the blood/tissue and the blood/tumor barrier of various organs.

2. the emulsion ball that comprises activating agent nanoparticle and/or dissolved activating agent

If need, also can from water on every side or buffering liquid phase, isolate the emulsion ball that comprises dissolved activating agent, activating agent nanoparticle or its combination, and be used for the treatment of dosage form.Can use the food stage, USP level or the NF level material that are suitable for human purposes application to prepare the emulsion ball.Nanoparticle oil ball that comprises dissolved activating agent and preparation method thereof is described in United States Patent (USP) 5,629, and 021 (' 021 patent) is introduced into as a reference at this.Emulsion ball of the present invention comprises (1) at least a oil usually; (2) at least a solvent; (3) at least a surface stabilizer or surfactant; And optional (4) dissolved activating agent, seed activity agent or its combination.If need, can for example separate the emulsion ball that comprises dissolved activating agent, seed activity agent or its combination by filtering.The emulsion ball that comprises dissolved activating agent is to be particularly suited for transporting activating agent to make it to pass the media that skin barrier enters blood.Therefore, the ball that comprises dissolved activating agent provides the system approach of active agent delivery in individuality.

In general; the diameter that comprises the emulsion ball of dissolved activating agent, activating agent nanoparticle or its combination is about 10 to about 1000nm; and comprise the activating agent of a great deal of; wherein preferred average diameter is less than about 1 micron, and wherein minimum ball can filter such as 0.2 micron filter that is generally used for the microorganism purification.The scope of surfactant concentration can be about 1% to about 50% in the ball.This emulsion ball can be stored in about 20 to about 40 ℃.In one embodiment of the invention, in the preparation at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about the diameter of 90% described ball less than about 1 micron, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, or less than about 100nm.

By changing the various parameters of approach I and approach II, can adjust the size and the integrity of above-mentioned ball.Therefore, can change the stability of the ball that comprises dissolved activating agent, thus can be with solution or sedimentary form release bioactive agent.This is little bank-dissolving-controlled system, and wherein medical solid plays the chamber, storehouse, and when dissolved part depletion, more medicine enters the solution from chamber, granule storehouse.Therefore, comprising the emulsion ball of dissolved activating agent can be in time and the release of control activating agent.

The compatibility that comprises the small size of emulsion ball of dissolved activating agent, activating agent nanoparticle or its combination and they and tissue makes it can be applicable to multiple use.For example, because emulsion ball skin permeation apace, so they can be used as the topical carrier.This ball is still unusual general, and promptly employed activating agent can be to suspend or to be dissolved in any activating agent in any in water or buffer, oil or the solvent.These character make this system be used in the activating agent that is difficult to prepare in other drug-supplying system.

In addition, comprise dissolved activating agent, activating agent nanoparticle or its combination the emulsion ball can with aqueous solution dilute and do not have stability loss.This can realize the use of high reactivity reagent concentration (promptly up to about 30%) product, if need, described product can dilute and use.Yet the concentration of activating agent depends on the dissolubility of actual drug and is used for dissolving the amount of its solvent.

In one embodiment of the invention, this emulsion ball comprises estradiol, acycloguanosine or the testosterone as activating agent, and is mixed with the dosage form that is used for percutaneous dosing.

C. the composition of the composition of the inventive method and the present composition

1. active pharmaceutical ingredient

A. character

Any suitable activating agent can be used for the compositions and methods of the invention.With regard to the activating agent that is used for approach I method, this activating agent is dissolved in or is insoluble to each phase of grinding (being homogenize or vigorous stirring) system a little less than must being, comprises the employed water of this method, solvent and oil.With regard to the activating agent that is used for approach II, this activating agent must be a weak water solublity or water-insoluble, but dissolves at least one solution such as oil or solvent and stabilizing agent or stabilizing agent in the emulsion matrix.

" weak water solublity " or " water-insoluble " are meant under ambient temperature and ambient pressure and pH are about 7 condition, the dissolubility of activating agent in water is less than about 20mg/mL, less than about 10mg/mL, less than about 1mg/mL, less than about 0.1mg/mL, less than about 0.01mg/mL, or less than about 0.001mg/mL.

The activating agent that is used for the inventive method and is present in the present composition can be amorphous, half amorphous, crystal, semi-crystal or their mixture.

B. activating agent granularity

Measure the employed activating agent granularity of this paper by routine techniques well-known to those skilled in the art, described mensuration is based on the weight average granularity, described technology such as sedimentation field flow fractionation (sedimentationfield flow fractionation), photon correlation spectroscopy (photon correlation spectroscopy), laser diffraction (laser diffraction) or disk centrifugal (disk centrifugation).

This paper employed " nanoparticle activating agent " is meant that effective particle mean size is less than about 3 microns activating agent." crystallite activating agent " is meant that effective particle mean size is greater than about 3 microns activating agent.

This paper uses " effectively particle mean size " active agent particle size below it for about 50% at activating agent.Therefore, if effectively particle mean size is less than about 3 microns, then in the compositions size of at least 50% active agent particle less than about 3 microns.In other embodiments of the present invention, effective particle mean size of active agent particle can be less than about 2900nm, less than about 2800nm in the compositions of the present invention, less than about 2700nm, less than about 2600nm, less than about 2500nm, less than about 2400nm, less than about 2300nm, less than about 2200nm, less than about 2100nm, less than about 2000nm, less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, or less than about 100nm.

In other embodiments of the present invention, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or at least about the size of 99% active agent particle less than effective particle mean size, promptly less than about 3 microns, less than about 2900nm, less than about 2800nm etc.

C. exemplary activating agent

Any suitable activating agent can be used for method and composition of the present invention.The examples of types of spendable activating agent includes but not limited to therapeutic agent and diagnostic agent, pigment, coating, ink, dyestuff, sensitive material, cosmetic composition etc.

Amphiphilic class activating agent can be incorporated in the preparation of the present invention.That is to say, can with ionizable and dissolve in polarity or the medicine of non-polar solven or the treatment chemical compound be incorporated in the preparation of the present invention.Therefore, above-claimed cpd both also dissolved in (amphiphile) in the aqueous environment in the oil-soluble.The example of above-claimed cpd comprises nicotine and cetirizine.

Also the hydrophilic active agent can be incorporated in the preparation of the present invention.Above-claimed cpd includes but not limited to Naltrexone Hydrochloride, alendronic Acid and cetirizine hydrochloride.

Described activating agent can be a hormone, such as testosterone, progesterone (progesterone) and estrogen.Other hormone comprises the deutero-hormone of (1) amine, as catecholamine, epinephrine, dopamine, norepinephrine (or noradrenaline), tryptophan derivative, melatonin (N-acetyl group-5-methoxytryptamine), 5-hydroxy tryptamine (5-HT), tyrosine derivative, thyroxine (T4), trilute (T3); (2) peptide hormone, (antimullerian hormone AMH) (is also referred to as mullerian duct inhibitory factor or hormone) such as AMH, adiponectin (being also referred to as Acrp30), thyroliberin (ACTH) (being also referred to as close cortin), proangiotensin and angiotensin, vassopressin (ADH) (being also referred to as vasopressin or arginine-vasopressin (AVP)), atrial natriuretic peptide (ANP) (being also referred to as atrial natriuretic peptide), calcitonin, cholecystokinin (CCK), corticotropin releasing hormone (CRH), erythropoietin (EPO), follicle stimulating hormone (FSH), gastrin, glucagon, gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH), human chorionic gonadotropin (hCG), growth hormone (GH or hGH), insulin, insulin like growth factor (IGF) (being also referred to as somatomedin), leptin, interstitialcellstimulating hormone (ICSH) (LH), melanotropin (MSH or α-MSH), neuropeptide tyrosine, oxytocin, parathyroid hormone (PTH), prolactin antagonist (PRL), relaxin, Chymosin, secretin, Somat, thrombopoietin, thyrotropin (TSH), thyrotrophin-releasing hormone (TRH); (3) steroid hormone is such as glucocorticoid, hydrocortisone, mineralocorticoid, aldosterone, sex steroid, androgen, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), ANDROSTENEDIONE, dihydrotestosterone (DHT), estrogen, estradiol, progestogen, progesterone, Progesterone; (4) sterol hormone is such as vitamin D-derivatives and calitriol; (5) lipid and phospholipid hormone (eicosanoid) are such as prostaglandin, leukotriene, prostacyclin and thromboxane.

Therefore, in one embodiment of the invention, described activating agent is estradiol, fenofibrate, acycloguanosine, alendronic Acid or testosterone.The instantiation that can be used for the activating agent of the inventive method includes but not limited to insulin, calcitonin, calcitonin gene is regulated albumen, atrium natriuresis albumen, betaserori, erythropoietin, interferon-alpha, interferon-, IFN-, growth hormone, growth hormone, somatostatin, insulin like growth factor, luteinising hormone-releasing hormo, Factor IX, interleukin, interleukin analog, blood substance (hematological agent), anticoagulant, the hemopoietic agent, hemorrhage, thrombolytic agent, the endocrine agent, antidiabetic, antithyroid drug, the receptor, blocker, growth hormone, growth hormone releasing hormone, gonadal hormone, thyroid, the parathyroid gland calcitonin, bisphosphonate, the uterus activating agent, cardiovascular agents, anti-arrhythmic agents, the antianginal agent, depressor, vasodilation, the medicine that is used for the treatment of heart disease, the heart contraction agent, the kidney medicine, the urogenital agent, antidiuretic, medicine for respiratory system, hydryllin, antitussive, intend the parasympathetic agent, intend sympathetic dose, xanthine, medicine for central nervous system, analgesic, anesthetis, antiemetic, anoretics, antidepressants, the migraine agent, Anti-epileptics, dopaminergic, anticholinergic, the Antiparkinsonian agent, muscle relaxant, narcotic antagonist, tranquilizer, analeptic, the medicine that is used for the treatment of attention deficit disorder, BA4311, fluvoxamine (fluoxamine), bisoprolol (bisolperol), tacrolimus, sacrolimus, cyclosporin, the gastrointestinal agent, the general anti-infectives, the medicine that is used for the treatment of acquired immune deficiency syndrome (AIDS), anthelmintic, the mycobacteria agent, immunizing agent, vaccine, hormone, dermatosis treating medicine, the antibiotic medicine, elastase inhibitor, muscarine antagonist, lipid regulating agent, blood products, the blood substitute, antitumor drug, leuprorelin acetate, chemotherapeutics, anti-tumor medicine, nutrient, nutrient, chelating agen, interleukin II, interleukin-1 receptor antagonist (IL-Ira), heparin, hirudin, colony stimulating factor, tissue plasminogen activator, oxytocin, nitroglycerin, diltiazem

Clonidine, nifedipine, verapamil, isosorbide 5-Mononitrate, organic nitrates, diuretic, Desmopressin, vassopressin, expectorant, mucolytic, fentanyl, sufentanil, butorphanol; buprenorphine; levorphanol; morphine; hydromorphone; hydrocodone; oxymorphone; methadone; lignocaine; bupivacaine; diclofenac; naproxen; eupaverine; scopolamine; ondansetron; motilium; metoclopramide; sumatriptan; peptide; benzodiazepine

, phenothiazine, prostaglandin, antibiotic, antiviral agent, antifungal, immunosuppressant, anti-allergic agent, astringent, 17-hydroxy-11-dehydrocorticosterone, fluorouracil, vincristine or deferoxamine.Described activating agent can be used for treating wound healing.

2. oily

For method and the compositions of the present invention of approach I and approach II, can use any suitable oil.Exemplary spendable oil comprises for example vegetable oil, macadamia nut oil, fish oil, Adeps Sus domestica, mineral oil, squalane, tricaprylin and their mixture.The instantiation of spendable oil includes but not limited to almond oil (sweet), almond oil, borage oil, Semen Brassicae Campestris oil, Oleum Cocois, Semen Maydis oil, cotton seed oil, fish oil, Jojoba Oleum Glycines, Adeps Sus domestica, Semen Lini oil (ripe), macadimia nut oil, medium chain triglyceride, mineral oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum sesami, soybean oil, Squalene, Oleum Helianthi, tricaprylin (1; 2,3-three caprylyl glycerol), Semen Tritici aestivi germ oil and their mixture.

3. surface stabilizer or surfactant

Compositions of the present invention also comprises at least a surface stabilizer or surfactant.When said composition also comprised the nanoparticle activating agent, the employed surface stabilizer of method and composition of the present invention associated or is adsorbed in the surface of nanoparticle activating agent, but not with this activating agent covalent bond.Surface stabilizer in the preferred water soluble.One or more surface stabilizers can be used for the compositions and methods of the invention.Term as used herein " stabilizing agent ", " surface stabilizer " and " surfactant " are used interchangeably.

Any suitable nonionic or ionic surfactant can be used for compositions of the present invention, and it comprises anion, cation and zwitterionic surfactant.Can be used for not containing the present composition of activating agent and comprise the exemplary stabilizing agent of the present composition of activating agent or surfactant comprises but is not limited to non-phospholipid surfactant, such as

(polyoxyethylene deriv of sorbitan fatty esters) the class surfactant (promptly

20,

60 Hes

80), non-phenol polyglycol ether (nonphenol polyethylene glycol ether), Isosorbide Dinitrate (such as

With

Glycerine ester (such as glyceryl monostearate), macrogol ester (such as polyglycol distearate), block polymer (such as

Acrylate copolymer (such as

The ethoxylated fat ester (such as

RH-40), ethoxylated alcohol (such as

Ethoxylated fatty acid, monoglyceride, surfactant, polysorbate based on silicon and

NP-40 (poly-(Oxy-1,2-ethane two bases), α-(4-nonyl phenol), ω-hydroxyl, branching [mean molecule quantity 1980]) and

(blended surfactant-AQ=70%).

4. solvent

Any suitable solvent can be used for method and composition of the present invention.Exemplary solvent includes but not limited to that isopropyl myristate, glycerol triacetate, N-Methyl pyrrolidone, long-chain alcohol, Polyethylene Glycol, propylene glycol, diethylene glycol monoethyl ether (diethyleneglycol monoethyl ether) and long-chain and short chain alcohol are such as ethanol.Can use other short chain alcohol and/or amide and aliphatic alcohol and aromatic alcohol such as benzylalcohol.The mixture of solvent also can be used for the compositions and methods of the invention.

5. water or buffer

If method of the present invention and/or compositions are used or comprised water or buffer, then aqueous solution is preferably the solution of physical compatibility, as water or phosphate buffered saline (PBS).

6. other composition

Various other materials can be added in the compositions of the present invention.Can use ethereal oil (as volatile fragrant oil (flavor oil)) replace as described in the oil some, perhaps except original oil, can add ethereal oil.Can be used for exemplary ethereal oil of the present invention or spice and include but not limited to face cream oil (balm oil), laurel oil, bergamot oil, Cedar oil, Fructus Pruni pseudocerasi oil, Oleum Cinnamomi, Oleum Caryophylli, Herba Origani oil and Oleum menthae.Also can use for example food color of coloring agent.The exemplary food colour that can be used for the present composition includes but not limited to green pigment, xanthein, red pigments and blue pigment.Employed food colour is food-grade material (McCormick), although can replace from the material in other source.In addition, the seasoning extract can be used for method and composition of the present invention.Exemplary seasoning extract includes but not limited to pure Fructus Foeniculi extract (73% ethanol), imitation Fructus Musae extract (40% ethanol), imitation Fructus Pruni pseudocerasi extract (24% ethanol), chocolate extract (23% ethanol), pure citron extract (84% ethanol), pure orange extract (80% ethanol), pure Folium Menthae extract (89% ethanol), imitation pineapple extract (42% ethanol), imitation rum extract (35% ethanol), imitation Fructus Fragariae Ananssae extract (30% ethanol) and pure vanilla extract or imitation vanilla extract (35% ethanol).Usually, employed extract is food-grade material (McCormick), although can replace from the material in other source.

D. use the method for the present composition

Compositions of the present invention can be used as broad-spectrum antimicrobial agent.For example, they can be used for the part or the surface sterilization on biological and abiotic surface.Said composition can be used to the surface that may be exposed to microorganism (such as any surface in cooking surface, have meal surface, the hospital, be exposed to child's surface etc.) carried out disinfection.Biological surface comprises skin, hair, mucosa, wound surface, lnsect bite injury etc.

Described compositions also can be used as the delivery vector of activating agent (as medicine and cosmetics).Said composition need not to add antimicrobial and stops microbial growth.When being mixed with when being used to deliver medicine to mammal such as people's dosage form, compositions of the present invention can deliver medicine to the experimenter via the mode of any routine.Said composition can be used for preparing the activating agent that is intended to handle wound and wound surface.In these activating agents some are incompatible with common antimicrobial.Therefore, the media with inherent anti-microbial properties can be ideal drug-supplying system.

Term as used herein " experimenter (subject) " is used in reference to animal, and preferred mammal comprises the mankind or non-human.Term " patient " and " experimenter " are used interchangeably.In addition, compositions of the present invention can be mixed with any suitable dosage form, as liquid dispersion, oral suspensions, tablet, gel, aerosol, ointment, capsule, dry powder doses, many granules, spray agent, wafer, lozenge and syrup.And dosage form of the present invention can be solid dosage forms, liquid dosage form, semiliquid dosage form, quick-release formulation, improvement delivery formulations, sustained release preparation, melt preparation, lyophilized formulations, delayed release preparation, prolongation delivery formulations, pulsation-releasing preparation, blended rapid release and sustained release preparation or their combination in any fast.

Compositions of the present invention also can comprise adjuvant, as anticorrosion base, wetting agent, emulsifying agent and dispersant.Can be by the absorption of using absorption delay agent (such as aluminum monostearate (aluminum monostearate) and gelatin) to come the prolong drug injection.

Liquid dosage form comprises pharmaceutically acceptable Emulsion, solution, suspensoid, syrup and elixir.Except activating agent, liquid dosage form can comprise this area inert diluent (as water or other solvent), solubilizing agent and emulsifying agent commonly used.Exemplary emulsifying agent has the mixture of ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (such as Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, mazola oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, oxolane alcohol, Polyethylene Glycol, sorbitan fatty ester or these materials etc.Except above-mentioned inert diluent, said composition also can comprise adjuvant, as wetting agent, emulsifying agent, suspending agent, sweeting agent, flavoring agent and flavouring agent.

The dosage that this paper provides concrete pharmacology to reply when using " treatment effective dose " to be meant to give this activating agent in most of experimenters of needs treatments about activating agent dosage.What should emphasize is, " the treatment effective dose " that delivers medicine to concrete experimenter under concrete condition may not be all effective for 100% patient who accepts the disease specific treatment, always be not effective in treatment disease described herein, even those skilled in the art think that above-mentioned dosage is " treatment effective dose " yet.

It will be understood by those skilled in the art that the effective dose that can by virtue of experience take to determine activating agent, and the activating agent that can use effective dose by the form (when these forms exist) of pure form or pharmaceutically acceptable salt, ester or prodrug.Can change the actual dose level of activating agent in the compositions of the present invention, thereby the amount of activating agent is effective in obtain concrete compositions and the desired treatment of medication is replied.Therefore, selected dosage level depends on the effectiveness of the activating agent of desired curative effect, route of administration, administration, desired treatment persistent period and other factor.

Dosage unit compositions can comprise above-mentioned amount or its factor, and described factor can be used for constituting the dosage of every day.Yet it should be understood that the concrete dosage level that is used for any particular patient depends on multiple factor: the cell that reach or the type of physiologic response and degree; The activity of employed concrete activating agent or compositions; Employed concrete material or compositions; Patient's age, body weight, general health, sex and diet; The discharge rate of administration time, route of administration and described material; The treatment persistent period; With described concrete material coupling or the medicine that uses simultaneously; And known other factors in the field of medicaments.

Provide the following example with explanation the present invention.But it should be understood that and the invention is not restricted to concrete condition or the details that these embodiment describe.In entire description, any and all documents that will disclose in the obtainable data (comprising United States Patent (USP)) all are incorporated herein by reference clearly.

Embodiment

Embodiment 1

The purpose of present embodiment is to describe exemplary nanorize preparation of compositions of the present invention.

Ethanol, soybean oil and polysorbate80 are mixed.Then water is added to this mixture, and resultant composition is mixed fully with paddle stirrer.The amount of each component is shown in the following table 1.

Then with the said composition feed in high-pressure homogenizer (high-pressure homogenizer) (APVInvensys, APV-1000 type), and pressure transferred to 10,000psi.Mixture is handled 2 and is taken turns in homogenizer.

Perhaps, can utilize the rotor-stator assembly that is installed on the Silverson mixer, (10,000rpm, 15 minutes) add to water in the mixture of ethanol, oil and polysorbate80 under the condition of high-speed stirred.

Resultant composition can perhaps can be mixed with said composition another kind of suitable dosage form directly as local lotion or ointment with antibacterium, antiviral, antifungal and/or anti-yeast character.

Embodiment 2

The purpose of present embodiment is to describe the exemplary nanorize preparation of compositions of the present invention that comprises the activating agent estradiol.

Estradiol chemically is being described as female steroid-1,3,5 (10)-triolefins-3,17-isoallopregnane-3.The molecular formula of estradiol is C ₁₈H ₂₄O ₂, and structural formula is

The molecular weight of estradiol is 272.39.

The estradiol product of U.S. food and Drug Administration (FDA) approval at present comprises oral administration pills

The percutaneous patch

Pessary

And local Emulsion

This medicine is used for hormone replacement therapy, with the moderate of treatment hectic fever relevant and night sweat with climacteric to the severe symptom and avoid pregnancy.

Estradiol is dissolved in the ethanol.Oil and polysorbate80 are added in the solution of estradiol, water is added in the mixture of estradiol/ethanol/oil/polysorbate80, and resultant composition is fully mixed with paddle stirrer.The amount of each component is shown among the following table 2A.

The said composition feed in high-pressure homogenizer (APV Invensys, APV-1000 type), and is transferred to 10,000psi with pressure.Mixture is handled 2 and is taken turns in homogenizer.The granularity of said composition is detailed to be shown among the following table 2B, and further is shown among Fig. 5.

Perhaps, estradiol can be dissolved in the ethanol, oil and polysorbate80 can be added in the solution of estradiol, and can utilize the rotor-stator assembly that is installed on the Silverson mixer, (10,000rpm, 15 minutes) add to water in the resultant composition under the condition of high-speed stirred.

Be shown among the following table 2C according to the granularity of the compositions of Silverson method is detailed, and further be shown among Fig. 6.

Resultant composition can perhaps can be mixed with said composition another kind of suitable dosage form directly as local lotion of the estradiol with antibacterium, antiviral, antifungal and/or anti-yeast character or ointment.

Embodiment 3

The purpose of present embodiment is to describe the exemplary nanorize preparation of compositions of the present invention that comprises the activating agent testosterone.

Testosterone USP is the extremely almost crystalline powder of white of white, chemically is being described as 17-β hydroxy-androstane-4-alkene-3-ketone.

Testosterone

Its chemical formula is C ₁₉H ₂₈O ₂, and molecular weight is 288.42.The commercial testosterone of buying for example is injection, percutaneous gel Transdermal delivery device

And buccal delivery system

For example, testosterone is used for hormone replacement therapy.

Testosterone is dissolved in the ethanol.Oil and polysorbate80 are added in the solution of testosterone, and water is added in the resultant composition.Resultant composition is fully mixed with paddle stirrer.The amount of each component is shown among the following table 3A.

The compositions feed of testosterone/ethanol/oil/polysorbate80/water in high-pressure homogenizer (APVInvensys, APV-1000 type), and is transferred to 10,000psi with pressure.Mixture is handled 2 and is taken turns in homogenizer.The granularity of said composition is detailed to be shown among the following table 3B, and further is shown among Fig. 7.

Perhaps, testosterone can be dissolved in the ethanol, and oil and polysorbate80 can be added in the solution of testosterone.Can utilize the rotor-stator assembly that is installed on the Silverson mixer, (10,000rpm, 15 minutes) add to water in the compositions of testosterone/ethanol/oil/polysorbate80 under the condition of high-speed stirred.

Resultant composition can perhaps can be mixed with said composition another kind of suitable dosage form directly as local lotion of the testosterone with antibacterium, antiviral, antifungal and/or anti-yeast character or ointment.

Embodiment 4

The purpose of present embodiment is to determine the effect of the concentration of excipient to the anti-microbial properties of preparation.Water dilutes 10 times with the compositions of embodiment 1, and the test antimicrobial efficacy.The amount of each component is shown in the following table 4.

When testing according to USP antimicrobial efficacy test standard, said preparation does not satisfy the standard that is proposed.Resultant composition can not can not be mixed with said composition other suitable dosage form to give anti-microbial properties directly as local lotion or ointment with antibacterium, antiviral, antifungal and/or anti-yeast character.

Embodiment 5

The purpose of present embodiment is to determine the effect of the concentration of excipient to the anti-microbial properties of preparation.Water dilutes 50 times with the compositions of embodiment 1, and the test antimicrobial efficacy.The amount of each component is shown in the following table 5.

Embodiment 6

Ethanol, soybean oil and Pluronic F-68 are mixed.Then water is added in this mixture, and resultant composition is fully mixed with paddle stirrer.The amount of each component is shown in the following table 6.

The said composition feed in high-pressure homogenizer (APV Invensys, APV-1000 type), and is transferred to 10,000psi with pressure.Mixture is handled 2 and is taken turns in homogenizer.

Perhaps, can utilize the rotor-stator assembly that is installed on the Silverson mixer, (10,000rpm, 15 minutes) add to water in the mixture of ethanol, oil and Pluronic F-68 under the condition of high-speed stirred.

Embodiment 7

Ethanol, benzylalcohol, isopropyl myristate, light mineral oil and Pluronic F-68 are mixed.Then water is added in this mixture, and resultant composition is fully mixed with paddle stirrer.The amount of each component is shown in the following table 7.

Then with the said composition feed in high-pressure homogenizer (APV Invensys, APV-1000 type), and pressure transferred to 10,000psi.Mixture is handled 2 and is taken turns in homogenizer.

Embodiment 8

The purpose of present embodiment is to describe to comprise the nanorize preparation of compositions that propofol (propofol) is the model active pharmaceutical ingredient, and said composition does not satisfy USP antimicrobial efficacy test standard.

Propofol, ethanol, soybean oil and polysorbate80 are mixed.Then saline (saline) is added in this mixture, and resultant composition is fully mixed with paddle stirrer.The amount of each component is shown in the following table 8.

When testing according to USP antimicrobial efficacy test standard, said preparation does not satisfy the standard that is proposed.

Embodiment 9

The purpose of present embodiment is the anti-microbial effect of determining as the compositions of preparation as described in the embodiment 1.

Anti-microbial test is according to USP 25,＜51 〉, the 1869-1871 page or leaf carries out.Test a certain amount of compositions with various bacteria, yeast or fungus: aspergillus niger (fungus), white candida mycoderma (yeast), escherichia coli (antibacterial), Pseudomonas aeruginosa (antibacterial), staphylococcus aureus (antibacterial), Aspergillus fumigatus (fungus) and Aspergillus flavus (fungus) as preparation as described in the embodiment 1.

Before test, in the stock culture of the nearest recovery of every kind of organism shown in the surface seeding following table 4 of the solid agar culture medium of suitable volumes.For every test, be shown in the following table 4 as the inoculum concentration of compositions of preparation among the embodiment 1.When inoculation, the 7th day, the 14th day and the 28th day, measure antibacterial, fungus or zymic amount.According to USP 25,＜51 〉, the 1869-1871 page or leaf is implemented condition of culture.The results are shown in the table 4 of test.In addition, the result is illustrated among Fig. 1 and 2.

Table 4: antimicrobial efficacy test

^*The ATCC=American type culture collection (Manassas, VA)

The result has shown the surprising effectiveness of compositions of the present invention as antibacterium, antifungal and anti-yeast agent significantly.For all the biological subject bodies except that a kind of (aspergillus niger), all organisms all were uprooted after 7 days, and for aspergillus niger, have reduced the growth of this organism significantly, only measured 70cfu/g at the 28th day.And described result shows that said composition satisfies the requirement of USP 25 combating microorganisms potency tests.

Embodiment 10

The purpose of present embodiment is the anti-microbial effect of determining as the compositions of preparation as described in the embodiment 2, and whether the interpolation of definite activating agent such as estradiol influences the antimicrobial of the present composition, anti-yeast, antifungal and/or antiviral properties.Present embodiment has also been estimated the active influence of alcohol amount combating microorganisms that changes in the compositions of the present invention.

Anti-microbial test is according to USP 25,＜51 〉, the 1869-1871 page or leaf carries out.Test a certain amount of compositions with various bacteria, yeast or fungus: aspergillus niger (fungus), white candida mycoderma (yeast), escherichia coli (antibacterial), Pseudomonas aeruginosa (antibacterial) and staphylococcus aureus (antibacterial) as preparation as described in the embodiment 2.

Before test, in the stock culture of the nearest recovery of every kind of organism shown in the surface seeding following table 5 of the solid agar culture medium of suitable volumes.For every test, be shown in the following table 5 as the inoculum concentration of the compositions of preparation as described in the embodiment 2.When inoculation, the 14th day (table 5) and the 28th day (table 6), measure antibacterial, fungus or zymic amount.According to USP 25,＜51 〉, the 1869-1871 page or leaf is implemented condition of culture.The results are shown in table 5 and 6 of test.In addition, the result is illustrated among Fig. 3.

Embodiment 11

The purpose of present embodiment is the anti-microbial effect of determining as the compositions of preparation as described in the embodiment 3, and whether the interpolation of definite activating agent such as testosterone influences the antimicrobial of the present composition, anti-yeast, antifungal and/or antiviral properties.

Anti-microbial test is according to USP 25,＜51 〉, the 1869-1871 page or leaf carries out.Test a certain amount of compositions with various bacteria, yeast or fungus: aspergillus niger (fungus), white candida mycoderma (yeast), escherichia coli (antibacterial), Pseudomonas aeruginosa (antibacterial) and staphylococcus aureus (antibacterial) as preparation among the embodiment 2.

Before test, the stock culture of bringing back to life recently separately surface seeding aspergillus niger, white candida mycoderma, escherichia coli, Pseudomonas aeruginosa and the staphylococcus aureus of the solid agar culture medium of suitable volumes.When inoculation, the 7th day, the 14th day and the 28th day, measure antibacterial, fungus or zymic amount.According to USP 25,＜51 〉, the 1869-1871 page or leaf is implemented condition of culture.The result who is shown among Fig. 4 shows that significantly when compositions of the present invention was used as drug administration carrier, said composition had surprising effectiveness as antibacterium, antifungal and anti-yeast agent.Unexpectedly, the existence of activating agent disappears the anti-microbial effect of the present composition.And the result shows that said composition satisfies the requirement of USP 25 combating microorganisms potency tests.

Under the situation that does not deviate from the subject or scope of the present invention, those skilled in the art obviously can carry out various modifications and variations to method and composition of the present invention.Therefore, if to these modifications and variations of the present invention fall into appended claims and the scope that is equal in, then it also is that the present invention is intended to contain.

Claims

1. antimicrobial compositions, it comprises emulsion, and described emulsion comprises:

(a) at least a solvent;

(b) at least a surfactant;

(c) at least a oil; And

(d) water;

Wherein said compositions satisfies the test requirements document that American Pharmacopeia (USP) combating microorganisms is renderd a service.

2. the compositions of claim 1, it has antimicrobial efficacy in escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), staphylococcus aureus (ATCC 653S), white candida mycoderma (ATCC 10231) and the aspergillus niger (ATCC 16404) one or more.

3. the compositions of claim 2, it has antimicrobial efficacy in Pseudomonas aeruginosa (ATCC 13388), Pseudomonas aeruginosa (ATCC 25619), Aspergillus flavus and the Aspergillus fumigatus one or more.

4. the compositions of claim 1, it comprises by weight weight meter ratio is about 23: about 5: about 4 oil: stabilizing agent: solvent.

5. the compositions of claim 1, it comprises ratio is about 2: about 1 contain oil phase: water or contain oil phase: buffer.

6. the compositions of claim 1, it comprises:

(a) about 10% oil to about 30% (w/w);

(b) about 0.5% solvent to about 10% (w/w);

(c) about 1% surfactant to about 8% (w/w);

(d) about 20% water to about 80% (w/w); Or

(e) their combination in any.

7. the compositions of claim 1, it also comprises:

(a) at least a activating agent that is dissolved in the described solvent;

(b) at least a activating agent that is dissolved in the described oil;

(c) at least a activating agent that is dissolved in the described water;

(d) be present in the granule of at least a activating agent in the described solvent;

(e) be present in the granule of at least a activating agent in the described oil;

(f) be present in the granule of at least a activating agent in the described water; Or

(g) their combination.

8. the compositions of claim 7, wherein said activating agent is acycloguanosine, cyclosporin, naltrexone, alendronic Acid, cetirizine, nicotine, testosterone, progesterone or estradiol.

9. the compositions of claim 7, the butyraceous ball of wherein said compositions bag, the ball of described oil comprises dissolved activating agent.

10. the compositions of claim 9, the granularity of the ball of wherein said oil is selected from down group in diameter: less than about 1 micron, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, and less than about 100nm.

11. the compositions of claim 7, the particle mean size of wherein said active agent particle, the oil droplet that contains dissolved activating agent, the water droplet that contains dissolved activating agent or their combination in diameter less than about 10 microns.

12. the compositions of claim 11, the particle mean size of wherein said active agent particle, the oil droplet that contains dissolved activating agent, the water droplet that contains dissolved activating agent or their combination is selected from down group in diameter: less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, and about 3 microns or more very.

13. the compositions of claim 7, the particle mean size of wherein said active agent particle, the oil droplet that contains dissolved activating agent, the water droplet that contains dissolved activating agent or their combination in diameter less than about 3 microns.

14. the compositions of claim 13, wherein said active agent particle, the oil droplet that contains dissolved activating agent, contain the water droplet of dissolved activating agent or the particle mean size of their combination and be selected from down group: less than about 2900nm, less than about 2800nm in diameter, less than about 2700nm, less than about 2600nm, less than about 2500nm, less than about 2400nm, less than about 2300nm, less than about 2200nm, less than about 2100nm, less than about 2 microns, less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1 micron, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, less than about 100nm, less than about 90nm, less than about 80nm, less than about 70nm, less than about 60nm, less than about 50nm, less than about 40nm, less than about 30nm, less than about 20nm, and less than about 10nm.

15. the compositions of claim 1, wherein said solvent is selected from down group: isopropyl myristate, glycerol triacetate, N-Methyl pyrrolidone, aliphatic alcohol and aromatic alcohol, ethanol, dimethyl sulfoxide, dimethyl acetylamide, ethoxydiglycol, Polyethylene Glycol and propylene glycol.

16. the compositions of claim 1; wherein said oil is the oil that is selected from down group: almond oil (sweet), almond oil, borage oil, Semen Brassicae Campestris oil, Oleum Cocois, Semen Maydis oil, cotton seed oil, fish oil, Jojoba Oleum Glycines, Adeps Sus domestica, Semen Lini oil (ripe), macadimia nut oil, medium chain triglyceride, mineral oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum sesami, soybean oil, Squalene, Oleum Helianthi, tricaprylin (1; 2,3-three caprylyl glycerol) and Semen Tritici aestivi germ oil.

17. the compositions of claim 1, wherein said surfactant is selected from down group: sorbitan ester, glyceride, macrogol ester, block polymer, acrylate copolymer (as Pemulen), ethoxylated fat ester (as Cremophor RH-40), ethoxylated alcohol (as Brij), ethoxylated fatty acid (as Tween 20), monoglyceride, based on the surfactant and the polysorbate of silicon.

18. the compositions of claim 17, wherein said sorbitan ester surfactant is Span and Arlacel; Wherein said glyceride is glyceryl monostearate; Wherein said macrogol ester is a polyglycol distearate; Wherein said block polymer is Pluronic, and wherein said acrylate copolymer is Pemulen; Wherein said ethoxylated fat ester is Cremophor RH-40; Wherein said ethoxylated alcohol is Brij; And wherein said ethoxylated fatty acid is Tween 20.

19. to biological surface or abiotic surperficial method of disinfecting, it comprises that described surface is exposed to comprises the compositions of group material down:

(a) at least a solvent;

(b) at least a surfactant;

(c) at least a oil; And

(d) water;