CN105435227A - Liquid preparation composition and preparation method and use and solid preparation thereof - Google Patents

Liquid preparation composition and preparation method and use and solid preparation thereof Download PDF

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Publication number
CN105435227A
CN105435227A CN201410390825.9A CN201410390825A CN105435227A CN 105435227 A CN105435227 A CN 105435227A CN 201410390825 A CN201410390825 A CN 201410390825A CN 105435227 A CN105435227 A CN 105435227A
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liquid preparation
preparation composition
acid
surfactant
solvent
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于莉
詹姆斯·格瑞·弗格森
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Shanghai Hightide Biopharmaceutical Ltd
Shenzhen Jun Shengtai Bioisystech Co Ltd
Shenzhen Hightide Biopharmaceutical Ltd
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Shanghai Hightide Biopharmaceutical Ltd
Shenzhen Jun Shengtai Bioisystech Co Ltd
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Priority to CN201410390825.9A priority Critical patent/CN105435227A/en
Priority to JP2016564568A priority patent/JP2017529313A/en
Priority to SG11201700484SA priority patent/SG11201700484SA/en
Priority to BR112017002356A priority patent/BR112017002356A2/en
Priority to MX2017001812A priority patent/MX2017001812A/en
Priority to NZ728487A priority patent/NZ728487A/en
Priority to US15/303,451 priority patent/US20170182063A1/en
Priority to AU2014403039A priority patent/AU2014403039B2/en
Priority to PCT/CN2014/088010 priority patent/WO2016019627A1/en
Priority to EP14899487.4A priority patent/EP3177271A4/en
Priority to KR1020177006157A priority patent/KR20230019268A/en
Priority to CA2945604A priority patent/CA2945604C/en
Publication of CN105435227A publication Critical patent/CN105435227A/en
Priority to ZA2017/00697A priority patent/ZA201700697B/en
Priority to IL250510A priority patent/IL250510B/en
Priority to JP2019116824A priority patent/JP6876100B2/en
Priority to US16/853,492 priority patent/US20200261472A1/en
Priority to US17/372,436 priority patent/US11559531B2/en
Priority to US18/076,012 priority patent/US20230147517A1/en
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Abstract

The present invention provides a liquid preparation composition, which is emulsion comprising a solvent and surfactant-containing liquid droplets distributed in the solvent, the volume average particle diameter of the liquid droplet is 100mum or less, the surface tension of the liquid preparation composition is less than 60mN / m, and the absolute value of the zeta potential is more than 15mV. The present invention also discloses a preparation method of the liquid preparation composition and use of the liquid preparation composition in treatment of otitis media, otitis externa, rhinitis, nasosinusitis, lower respiratory tract inflammation, xerostomia, xerophthalmia and dry noses. The present invention also discloses a preparation prepared from the liquid preparation composition. The liquid preparation composition can effectively relieve the otitis media, the otitis externa, the rhinitis, the nasosinusitis, the lower respiratory tract inflammation, the xerostomia, the xerophthalmia, the dry noses and other symptoms, can be used in the form of sprays or liquid droplets, can be applied to an effective site without use of a propellant or an atomization device, is easy to operate, and can effectively avoid stimulation and injury caused by the propellant and use inconvenience of the atomization device.

Description

A kind of liquid preparation composition and preparation method thereof, purposes and solid preparation
Technical field
The present invention relates to a kind of liquid preparation composition and preparation method thereof, and the purposes of this liquid preparation composition and the solid preparation that obtained by this liquid preparation composition.
Background technology
Otitis media, otitis externa, rhinitis and sinusitis are all common otorhinolaryngology diseases.Wherein, otitis media (Otitismedia) is the inflammatory lesion of involving middle ear (comprising pharyngotympanic tube, tympanum, tympanic antrum and mastoid air cell) all or part of structure, is apt to occur in child.Apyetous and suppurative two large classes can be divided into.Apyetous person comprises secretory otitis media, barotraumatic otits media (because the change of takeoff and landing pressure, the increase of diving hydraulic pressure etc. cause); Suppurative person has acute and chronic dividing.External otitis (Otitisexterna) is the inflammation of infection of external auditory meatus, often because digging wound, ear is scratched or sewage enters caused by after external auditory meatus.External otitis can cause the swelling of external auditory meatus local skin and be attended by pain or tenderness sense, external ear is scratched where it itches, outer ear discharge increases.There are diffusivity and limitation two kinds.Rhinitis is that the symptom produced by nasal mucosa irriate or inflammation is referred to as, and can be divided into allergic rhinitis, sinusitis, acute rhinitis etc.The symptom of rhinitis comprises nasal obstruction, many tears, itches, sneeze, seriously can cause headache, dizzy and olfactory sensation decline.Pathogenic factor and the symptom of above disease are summarized as follows:
Otitis media normally causes due to salpingian periodicity open function generation obstacle.Pharyngotympanic tube is unique passage of MEV drain.Major function guides nasopharynx part gas to enter tympanum, to maintain tympanum pressure at both sides balance, thus ensures the normal vibration of tympanum.Pharyngotympanic tube mucosa continues mutually with nasopharynx part mucosa of tympanic cavity, is made up of pseudostratified ciliated columnar epithelium cell, has considerable secretory cell.The wash (mucus) of these emiocytosises, pharyngotympanic tube both not exclusively openings can be made, but can in suitable chance, opening once in a while during as dehisced, swallow, yawn or chewing, regulate bulging room pressure with this, thus keep the balance of tympanum external and internal pressure.When eustachian tube function generation obstacle, tympanum pressure at both sides disequilibrium on the one hand, tract hydrops cannot be discharged in time on the other hand, and then brings angor to patient.Wherein otalgia is its early clinic symptom, deafness, tinnitus, the symptom such as dizzy all cover by otalgia time, easily out in the cold.General Symptoms is different because of the virulence of patient's resistance and bacterial infection, often has the uncomfortable and inappetence of fear of cold, heating, body etc.Headache feature shows as the violent otalgia of their early stage formerly, then to the temporo top occipitalia radiation of suffering from ear homonymy, causes insufferable half side headache.If pharyngotympanic tube obturation also can cause tympanum pressure to reduce, ambient pressure increases relatively, thus makes otopiesis and affect audition.
Domestic and international research report, in the sample of patients with secretory otitis media, represent the content of phospholipid minimizing more obvious than Normal group of surfactant, its difference has statistical significance (p<0.01), confirm that the surfactant of patients with secretory otitis media reduces and be mainly manifested in nasopharynx, middle ear and pharyngotympanic tube local, force that salpingian opening pressure increases, compliance becomes possibility, thus cause tympanum hydrops, hydrops stores, and secretory otitis media occurs.[research of nasopharynx part surfactant and secretory otitis media relation. West China medical university journal .1999; 30 (3): 310-311] content of phospholipid reduces also has report in patients with rhinitis.[ JLaryngolOtol.2000Apr；114(4):254-9.Studyofsurfactantlevelincasesofprimaryatrophicrhinitis.SayedRH1,Abou-ElhamdKE,Abdel-KaderM,SaleemTH.； AnnOtol RhinolLaryngolSuppl.2006Sep；196:40-4.Surfactantanditsroleinchronicsinusitis.SchlosserRJ.]
Cause the reason of external otitis to have multiple, wherein great majority are bacteriological infection, and minority is fungal infection, and noninfective dermatosis causes.When suffering from external otitis, the chief complaint of patient is to itch in external ear Dodge, swelling, pain and stiff, white or yellow transudate.If transudate blocks auditory meatus, then there will be part hearing disability.
Under normal physiological conditions, the mucus that bronchia mucosal produces, can stick as dust, pollen, dust and the material such as microorganism as antibacterial and virus.Mucus can flow out from nose front portion or throat rear portion flows down.When nasal mucosa irriate or inflammation, it is excessive that mucus produces, and cannot remove in time and cause nasal obstruction, many tears, itch, sneeze.
Normal paranasal sinus (Paranasalsinuses) is the gassiness cavity in craniofacial bone around nasal cavity, and totally four is right: maxillary sinus, sinus frontalis, sieve hole and sphenoid sinus, their inwall is all lined with mucosa, and they respectively have certain position, shape and outlet.When suffering from sinusitis, the mucosa of patient is congested, swelling, and nasal cavity has a large amount of glutinous pus or purulence nasal mucus, causes serious nasal obstruction, pus tears, headache, giddy and olfactory sensation to decline.
Lower respiratory tract inflammation mainly comprises: bronchitis, chronic bronchitis, pneumonia, bronchiectasis etc., and cardinal symptom is cough, expectoration, asthma, chest pain, heating etc.Current clinical treatment mostly is antibiotic, cough-relieving and phlegm-eliminating medicine.
Dryness in the nasal cavity disease take dry nasal cavity as the nose illness of main manifestations.Doctor trained in Western medicine is called rhinitis sicca, is with the nasal cavity Chronic inflammatory conditions that nasal mucosa is dry, nasal discharge is reduced to main manifestations.Symptom is that intranasal is dry, and nasal secretion reduces, and intranasal has prodding and itching feeling or foreign body sensation, often causes sneeze, burning sensation, often lures that patient digs nose into, and cause epistaxis in a small amount, olfactory sensation is not generally gone down.Before nasal septum, inferior segment mucosa is often rotten to the corn, and can have the thin crust attachment of small pieces, that goes is often hemorrhage.The cause of disease is still unclear, thinks relevant with working environment and outside climatic more, and vitamin deficiency, anemia, a large amount of smoking, drinking can cause nasal mucosa and change, and causes primary disease.The treatment of primary disease, local can be dripped with lubrication medicinal liquid by intranasal, and whole body vitimin supplement A, vitamin B2, vitamin C, vitamin E etc. can strengthen nutrition.
Xerophthalmia refers to that the tear matter that any reason causes or amount exception or kinetics are abnormal, causes tear film stability to decline, and the general name of various diseases with ophthalmic uncomfortable and (or) eye table organization characteristics of lesion.Also known as angle conjunctival xerosis.Common symptom comprise eyes dry and astringent, easily tired, ophthalmic pruritus, have that foreign body sensation, pain burning sensation, secretions are sticky, aversion to wind, photophobia, to external world stimulate very sensitive; Sometimes eyes are too dry, basic oligodacrya, stimulate reflexive lacrimal secretion on the contrary, and cause and usually shed tears; More severe case eyes can redness, hyperemia, keratinization, corneal epithelium broken skin and have filament to stick, this damage with the passing of time then can cause angle conjunctive disorder, and can affect one's power of vision.
Tear film is primarily of phospholipid, protein, mucoprotein, electrolyte and water composition.The composition of lipid layer is mainly derived from tarsal glands, twinkle (nictation) time, lipid is gathered on the water liquid layer of inferior cornea by eyelid compression, distribute in horizontal band-like, twinkle at the end of (nictation), lipid is laid in rapidly water liquid layer with the speed opened faster than eyelid disease, water liquid layer is not directly exposed in air, decreases the evaporation of tear.Current bibliographical information causes the most common cause of xerophthalmia to be meibomian gland dysfunction (MeibomianGlandDysfunction, MGD), and MGD can affect the function of tear film, causes xerophthalmia.[ survOphthalmol.2007Jul-Aug (4): 369-74.TheCorrelationBetweentheTearFilmLipidLayerandDryE yeDisease, FoulksGN; chinese Journal of Ophthalmology.the abnormal clinical progress with xerophthalmia of tear lipid layer March 48 (3): 282-5. in 2012, Xiao Xinye, Liu Zuguo .]
The treatment means of current xerophthalmia mainly comprises artificial tears, inflammation-inhibiting, promotion lacrimal secretion etc., and wherein artificial tears is the most frequently used, the most acceptable therapeutic modality of patient.Commercially available artificial tears has liposic (Bausch-Lomb company of the U.S.) main component to be 1% medium chain triglyceride, 0.2% Carbopol, sorbitol, sodium hydroxide etc., and antiseptic is 0.01% cetrimonium bromide; RefreshDryEyeTherapy (predecessor RefreshEndura, Allergan company of the U.S.) main component is 1% polyoxyethylene sorbitan monoleate, 1% glycerol, carbomer, Oleum Ricini, mannitol, sodium hydroxide etc.
Xerostomia is a kind of symptom in oral cavity caused by aptyalism.The generation of saliva and secretion by whole body, locally, the impact of extraneous and self each factor.Because salivation reduces, patient feels xerostomia, has foreign body sensation, burn feeling, at laboratory rodent chow, during particularly drier food, can not form food group and impact is swallowed.Salivation amount is few, also little to the souring of tooth and oral mucosa, and oral cavity self-cleaning action is deteriorated.Thus, the caries prevalence rate of xerostomia patient is higher.The sense of taste of most xerostomia patient is also affected, and effectively can not stimulate appetite, and can affect the function of whole digestive system.
The treatment of current xerostomia comprises etiological treatment and symptomatic treatment.Etiological treatment is the most effective when the clear and definite cause of disease, as Drug xerostomia, by adjustment medicine and dosage thereof, can alleviate xerostomia.Saliva being consumed and increases and the xerostomia of generation, solving by eliminating the reasons such as mouth breathing.If the xerostomia caused by salivary gland parenchymal destruction, as after head-neck malignant tumor radiotherapy, Sjogren syndrome, alleviate xerostomia mainly through symptomatic treatment at present, reduce complication.
By above description, we can see: the common feature of these diseases is that tract (ear or nose) is owing to infecting or inflammatory reaction, the liquid secreted by cavity mucous membrane is caused to increase, cannot discharge in time, and cause tract to block, and then produce the malaise symptoms such as earplug, nasal obstruction, pain, cough.Or to be reduced by the secretions (nasal discharge, tear film, saliva) of corresponding site or stability declines that the eye that causes is done, xerostomia and the malaise symptoms such as dryness in the nasal cavity, asthma.
At present, in clinical treatment, use antibiotic, steroid hormone and operative treatment more.But in these Therapeutic Method, except operation, all can not within the short time (minute-hour), the malaise symptoms such as the earplug of rapid reduction of patient, nasal obstruction, pain, cough, asthma, eye are dry, xerostomia and dryness in the nasal cavity.Therefore, need badly at present a kind of can at short notice effectively the earplug of reduction of patient, nasal obstruction, pain, cough, asthma, eye do, the product of the malaise symptoms such as xerostomia and dryness in the nasal cavity.
Summary of the invention
Technical problem to be solved by this invention be to provide a kind of can at short notice effectively the earplug of reduction of patient, nasal obstruction, pain, cough, asthma, eye do, the liquid preparation composition of the product of the malaise symptoms such as xerostomia and dryness in the nasal cavity.
It is as follows that the present invention solves the problems of the technologies described above adopted technical scheme:
There is provided a kind of liquid preparation composition, described liquid preparation composition is emulsion, and described liquid preparation composition comprises solvent and is distributed in the drop containing surfactant in solvent; The volume average particle size of described drop is less than 100 μm; The surface tension of described liquid preparation composition is less than 60mN/m, and the absolute value of the zeta current potential of described liquid preparation composition is more than 15mV.
In the past between the more than ten years, people once attempted to utilize surfactant to solve the problem such as otitis media, rhinitis, but there is various problem in technology and application aspect, such as, utilize the nasal wash product that artificially synthesised surfactant prepares for component, although patient can be helped to remove nasal cavity mucus, reduce nasal obstruction symptom, but contained by product, the toxic and side effects of component causes the anosmia of patient, and consequence is serious; The research such as Jang reports the effect of Curosurf at Cavia porcellus otitis media model of atomization, [Efficacyoftransnasalnebulizedsurfactantonexperimentaloti tismediawitheffusioninguineapig. intJ pediatrOtorhinolaryngol.2010Jan; , but atomising device is complicated, uses inconvenience 74 (1): 71-4].Chandrasekhar etc. report surfactant aerosol for treating otitis media zoopery [Otitismedia:treatmentwithintranasalaerosolizedsurfactant. laryngoscope.2004Mar; 114 (3): 472-85.], but this preparation not only needs to use propellant, and active component exists in solid form, for reaching curative effect, must first in the moistening attachment of target site, therefore increase onset time, propellant may cause the nasal cavity having local inflammation to react simultaneously stimulates and injury.In addition, the aerosol products described in literary composition needs the canned production equipment of particular pressure, and production cost is expensive, uses inconvenience.
When liquid preparation composition provided by the invention is applied to tubal mucosa place, surfactant and middle ear effusion surface contact.Because the surface tension (being less than 60mN/m) of liquid preparation composition is lower, the surface tension of tubal mucosa place transudate can be reduced fast, pharyngotympanic tube is more easily opened, simultaneously, liquid preparation composition is paid on the cavity mucous membrane, produce lubrication, therefore middle ear effusion is able to smooth outflow.The elimination of hydrops, can reduce ear pressure, eliminates tinnitus, headache syndromes; Reduce simultaneously and infect probability, promote that inflammation is eliminated, promote recovery from illness.For external auditory meatus pus, liquid preparation composition by reducing the surface tension of pus, is attached on external auditory meatus mucosa on the one hand on the other hand, produces lubrication, impels pus to flow out smoothly, alleviate earplug, bulge of the ear symptom.Based on same purpose mechanism, liquid preparation composition can be attached to nasal mucosal surface, promotes that nasal cavity mucus is removed, alleviates nasal obstruction symptom.
As everyone knows, salpingian one end enters tympanum by antetheca, and the other end then enters nasopharynx part, and its position is very hidden, is unfavorable for treatment.Liquid preparation composition provided by the invention is used in the form of a spray by aerosol apparatus, can effectively arrive the target sites such as pharyngotympanic tube, nasal cavity, paranasal sinus thus play curative effect, also can be applied to external auditory meatus and nasal cavity with the form of [Dan and nasal drop.
The present invention be used for lower respiratory tract inflammation treatment mainly surfactant can reach trachea by aerosol form, moistening trachea, reduce disease to the stimulation of tunica mucosa tracheae, dilution sputum, is beneficial to sputum expectoration, reduces pulmonary surface tension, alleviate asthma, adopt the preparation of Natural Surfactant-Lecithin both can moistening trachea, reduce pulmonary surface tension, damaged mucosa can be repaired again.
The present invention be used for dryness in the nasal cavity disease (or rhinitis sicca) treatment mainly surfactant effectively can reach nasal cavity by aerosol apparatus or nasal drop form, reduce the surface tension of nasal cavity and mucus, supplement the liquid of disappearance, adopt the preparation prepared of Natural Surfactant-Lecithin both can moistening nasal cavity, damaged mucosa can be repaired again.
The present invention is used for the treatment of xerophthalmia, mainly utilizes surfactant to reduce capillary character, increases the thickness of tear lipid layer, is conducive to keeping tear film stability, extends breakup time of tear film, reduce tear evaporation, keeps eye table tear content.The preparation adopting Natural Surfactant-Lecithin to prepare can supplement the disappearance of lecithin in tear lipid layer.
Have result of study to show, the saliva of buccal cavity surface tension of xerostomia patient apparently higher than normal person [ sleep, Vol.31, No.3,2008.UpperAirwaySurfaceTensionbutnotUpperAirwayCollapsib ilityisElevatedinPrimary syndrome.CassieJ.Hilditch, R.DougMcEvoy, etc.].Surfactant in the present invention can reduce the surface tension of xerostomia patient saliva of buccal cavity, and the present invention simultaneously can supplement saliva fluid, alleviates xerostomia symptom.
Compare with nebulization therapy with aerosol, spray without using the atomising device of propellant and complexity, the power produced by compressed air by means of only nasal spray device and produce droplet, and a kind of water type spray of ejection.Its advantage is that the droplet of ejection is comparatively thin, is evenly distributed, not easily runs off, adhesion speed is fast, onset is rapid at nasal cavity; And aerosol apparatus service condition is simple, and cost is low.But when adopting spray pattern to treat, the stability of liquid preparation composition has considerable influence to spray agent, when especially there is the phenomenons such as sedimentation when liquid preparation composition, it is very unfavorable normally to use for it.
Explore through great many of experiments, liquid preparation composition entirety provided by the invention is emulsion, and comprise liquid flux and be distributed in the drop in solvent, drop contains the surfactant with excellent surface activity.Further, the absolute value of the zeta current potential of liquid preparation composition is more than 15mV, and the volume average particle size of drop is less than 100 μm.Have above-mentioned feature drop can in solvent Stable distritation, avoid the sedimentation phenomenon that solid powder surfactant easily occurs.
This liquid preparation composition is the colloidal dispersion system that surfactant is formed in a solvent, and zeta current potential is an important indicator characterizing dispersion stability.The volume average particle size at drop of liquid preparation composition provided by the invention is under the prerequisite of less than 100 μm, and the absolute value of the zeta current potential of liquid preparation composition is more than 15mV.The dispersion with above-mentioned feature can keep comparatively steady statue, not easily occurs condensation, coacervation.
Meanwhile, when using with spray pattern, the surfactant containing drop sprays from aerosol apparatus with droplet form together with solvent.After arriving the target areas such as such as pharyngotympanic tube, nasal cavity, paranasal sinus, liquid surfactant is directly scattered in middle ear effusion and nasal cavity mucus, reduce the surface tension of middle ear effusion and nasal cavity mucus, simultaneously, be attached on mucous membrane surface and play lubrication, work along both lines, middle ear effusion and nasal cavity mucus are removed smoothly, the malaise symptoms of rapid recovery patient.
In addition, liquid preparation composition provided by the invention has good stability, active component is all can eat general non-toxic components by medicine, surfactant is present in solvent in liquid form, when using with spray pattern, requiring low to service conditions such as atomisation pressures, adopting conventional aerosol apparatus, without the need to adopting propellant and special atomizing device.Further, the liquid preparation composition existed in liquid form, without the need to through the necessary course of dissolution of solid state surface activating agent, shortens responding time; Simultaneously also without the need to accelerating its dissolving at target site by other materials.Therefore liquid preparation composition provided by the invention has novelty and can practicality concurrently.
Meanwhile, present invention also offers the preparation method of aforesaid liquid preparation compositions, comprising:
S1, by the ultrasonic middle dispersion 1-3min of the surfactant of liquid state at 40-60KHZ;
S2, at rotating speed be more than 3000rpm stirring condition under, the surfactant of liquid state is mixed homogeneously with solvent, form the liquid preparation composition being dispersed with the drop containing surfactant in solvent, and the absolute value that described liquid preparation composition surface tension is less than 60mN/m, zeta current potential is more than 15mV.
In addition, the invention discloses the purposes that aforesaid liquid preparation compositions is used for the treatment of otitis media, external otitis, rhinitis, sinusitis, lower respiratory tract inflammation, xerostomia, xerophthalmia, dryness in the nasal cavity disease.
According to the difference of purposes, use auxiliary treatment rhinitis, sinusitis, lower respiratory tract inflammation, otitis media, dryness in the nasal cavity disease by nasal cavity, the xerostomia using auxiliary treatment a variety of causes to cause by oral cavity, uses auxiliary treatment xerophthalmia by eyes.
And a kind of solid preparation, by foregoing liquid preparation composition through super-dry, obtains except desolventizing.Further, aforesaid liquid preparation compositions provided by the invention through super-dry, except desolventizing, can also become solid-state form, uses front redissolution.
Accompanying drawing explanation
Fig. 1 is during sedimentation stability of the present invention detects, the sedimentation stability comparison diagram of embodiment 2, embodiment 4 and comparative example 2.
Detailed description of the invention
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Liquid preparation composition provided by the invention is emulsion, and described liquid preparation composition comprises solvent and is distributed in the drop containing surfactant in solvent; The volume average particle size of described drop is less than 100 μm; The surface tension of described liquid preparation composition is less than 60mN/m, and the absolute value of the zeta current potential of described liquid preparation composition is more than 15mV.
In aforesaid liquid preparation compositions, solvent and to be distributed in solvent and drop containing surfactant is the main body of liquid preparation composition.
For whole liquid preparation composition system, its surface tension should be less than 60mN/m.As previously mentioned, when the surface tension of liquid preparation composition is less than 60mN/m, the surface tension of tubal mucosa place transudate can be reduced, middle ear effusion is flowed out smoothly, reduce ear pressure, eliminate tinnitus, headache syndromes; Reduce simultaneously and infect probability, promote that inflammation is eliminated, promote recovery from illness.
According to the present invention, for faster and better plays therapeutic effect, under preferable case, the surface tension of described liquid preparation composition is less than 40mN/m, more preferably the surface tension of described liquid preparation composition is less than 30mN/m, and the surface tension most preferably being described liquid preparation composition is less than 27mN/m.The surface tension of liquid preparation composition is less, is more beneficial to the surface tension reducing tubal mucosa place transudate, is more conducive to the outflow of middle ear effusion.
But found by great many of experiments, liquid preparation composition surface tension is less, liquid preparation composition is more unstable, surfactant in solvent more easily assembles even layering and sedimentation, poor stability, cannot effectively use with spraying or drop-wise.
Therefore, for ensureing that liquid preparation composition provided by the invention has enough stability, spraying or drop-wise can be adopted to use, and the volume average particle size of described drop is less than 100 μm, the volume average particle size being more preferably described drop is less than 10 μm, even less than 6 μm.
According to the present invention, for making liquid preparation composition more stable, under preferable case, the volume average particle size of described drop is 1-100 μm, and the volume average particle size being more preferably described drop is 1-10 μm, even 1-6 μm.
Above-mentioned volume average particle size is defined as: refer to identical with the grain shape of this particle swarm, cumulative volume is identical, and granule number is identical, but the particle diameter of an even-grained imaginary particle swarm.
When the particle diameter of the drop in solvent meets above-mentioned condition, the dispersion in a solvent that drop can be more stable.
In the present invention, under preferable case, the volume average particle size of described drop is 50-500nm, and the volume average particle size being more preferably described drop is 100-500nm, even 200-400nm.Now, drop stability is in a solvent better.
For ensureing that liquid preparation composition provided by the invention has enough stability, under technique ensures that particle diameter meets the prerequisite of above-mentioned condition, other materials that surfactant in liquid preparation composition and the relative amount of solvent and selectivity add will affect the size of zeta current potential, find after deliberation, during zeta current potential more than the absolute value 15mV of liquid preparation composition provided by the invention, liquid preparation composition has good stability.
As known in the art, zeta current potential (Zetapotential) is again electrokinetic potential or eletrokinetic potential (Zeta-potential or ζ-electromotive force), refers to the current potential of shear surface (ShearPlane).More preferably, in situation, the zeta current potential absolute value of described liquid preparation composition is more than 20mV, even more than 40mV.Now, liquid preparation composition has more excellent stability.
According to liquid preparation composition provided by the invention, in order to improve the stability of this liquid preparation composition, reduce the stimulation to user, under preferable case, the pH value of aforesaid liquid preparation compositions is 5.0-7.4, is more preferably 6.0-7.4 simultaneously.
In the present invention, the various materials that the surfactant adopted can select the field such as medicine, food known, safe, such as, described surfactant is selected from, but be not limited to that natural phospholipid, sterol, Curosurf, stearic acid, oleic acid, lauric acid, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, fatty acid Pyrusussuriensis are smooth, one or more in Polysorbate, Myrj 45, polyoxyethylene aliphatic alcohol ether, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol.For ensureing the safety in utilization of liquid preparation composition provided by the invention, therefore, above-mentioned surfactant preferably adopts high, the active excellent material of safety, such as above-mentioned surfactant is selected from, but is not limited to one or more in lecithin, sterol, Curosurf, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol.
When adopting above-mentioned various material (such as phospholipid) as surfactant, on the basis realizing the object of the invention, the composition (such as phospholipid) of otitis media and patients with rhinitis's nasopharynx part disappearance can also be supplemented.
For preparation compositions provided by the invention, especially when surfactant is above-mentioned various material, excessive or too small pH value will cause surfactant to be hydrolyzed, and the stability of preparation compositions will reduce greatly.
Above-mentioned various material is all by commercially available.
For the solvent in liquid preparation composition provided by the invention, being not particularly limited, can be one or more in water, ethanol, glycerol, Medical silicone oil, edible vegetable oil.Such as described solvent is water.
According to the present invention, in aforesaid liquid preparation compositions, the relative amount of solvent and surfactant can change in a big way, as is known in the art, solvent is different with the relative amount of surfactant, and the surface tension of liquid preparation composition is also different.In the present invention, the surface tension of liquid preparation composition and zeta current potential only need be made to meet described requirement above, those skilled in the art, when preparing this liquid preparation composition, make the surface tension of liquid preparation composition and zeta current potential fall into described scope above by the relative amount of adjustment solvent and surfactant.Usually, for corresponding disease, after determining the material composition needed for liquid preparation composition, by constantly changing the addition of each material composition, make the final liquid preparation composition obtained meet condition of the present invention, now, the addition of each raw material components can be recorded.During the liquid preparation composition of follow-up preparation same composition, only directly need prepare according to the addition of known each raw material components.
Under preferable case, in described liquid preparation composition, surface-active contents is 0.1-25.0wt%, and solvent is 75.0-99.9wt%.When aforesaid surfactant adopt many kinds of substance with the use of time, the relative amount of various material does not limit, and only needs the surface tension of liquid preparation composition entirety and zeta current potential to meet described condition above.
In the present invention, for better ensureing the stability of liquid preparation composition, preventing the generation of sedimentation, extending its memory time, under preferable case, in liquid preparation composition provided by the invention, also comprise stabilizing agent.The edible stabilizing agent that the stabilizing agent applied is known in the field such as lecithin, poloxamer, saponarin, tannin, fatty acid glyceride, sucrose fatty acid ester, methyl glycol fatty acid ester, cholesterol, cholesteryl ester, Polyethylene Glycol, cellulose and derivant, dextrin, arabic gum, Tragacanth class, pecto-cellulose cheese, gelatin, alginic acid.
In above-mentioned adoptable stabilizing agent, the material that moieties and surfactant adopt is identical, such as lecithin, poloxamer, cholesterol, cholesteryl ester.In the present invention, above-mentioned each material has good stability in liquid preparation composition provided by the invention, and himself can simultaneously as surfactant and stabilizing agent.
The addition of aforementioned stable agent can change in a big way, only need ensure that the surface tension of liquid preparation composition is in described scope above.Under preferable case, stabiliser content is 0.01-5.0wt%.
In order to improve the compliance of product, also comprise aromatic in liquid preparation composition provided by the invention, such as, but not limited to Mentholum, Borneolum Syntheticum, Fructus Citri Limoniae oil, patchouli oil, Oleum Cinnamomi, red date tincture, vanillin, Oleum menthae, geranium absolute, eucalyptus oil, Oleum Menthae Rotundifoliae, eugenol, citral, concrete of jasmine, Hang Zhou chrysanthemum flower extract, osmanthus concrete, benzyl alcohol, phenethanol, terpineol, methyl cyclopentenyl ketone, jasminal, butanoic acid, caproic acid, isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate, ethyl n-butyrate., isoamyl butyrate, benzyl butyrate, iso-amyl iso-valeriate, ethyl hexanoate, cognac oil, ethyl lactate, allyl hexanoate, nonyl lactone, ethyl maltol, allyl cyclohexyl propionate, maltol, gamma-undecalactone (peach aldehyde), raspberry ketone (4-(4-hydroxyphenyl)-2-butanone), benzyl propionate, butyl butyrate, ethyl isovalerate, Ethyl formate, benzyl benzoate, methylpyrazine, 2,3-dimethyl pyrazine, trimethylpyrazine, 2-acetyl group pyrazine, 4-methyl-5-(beta-hydroxyethyl) thiazole, 2-acetylthiazole, 2，3，5，6-tetramethylpyrazine, hexadecanoyl (strawberry aldehyde, strawberry aldehyde), ethyl vanillin, hydroxycitronellal, and the correctives known in field, one or more in essence.
The addition of above-mentioned aromatic can change in a big way, only need ensure that the surface tension of liquid preparation composition is in described scope above.Under preferable case, fragrance level is 0.01-5.0wt%.
For improving the memory time of liquid preparation composition, avoid breed bacteria, under preferable case, also antibacterial is comprised in liquid preparation composition provided by the invention, such as, but be not limited to parabens and salt, benzoic acid and salt, benzyl alcohol, phenethanol, phenylacetic acid, phenoxyethanol, glycerol monolaurate, chlorobutanol, sorbic acid and salt, calcium propionate, sodium propionate, dehydroactic acid and salt, sodium diacetate, lauric monoglyceride fat, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, chlorhexidine acetate, propylene glycol, carbon dioxide, nisin, natamycin, Charantin, thimerosal, one or more in Mercury pernitrate..
The addition of above-mentioned antibacterial can change in a big way, only need ensure that the surface tension of liquid preparation composition is in described scope above.Under preferable case, antibacterial content is 0.01-2.0wt%.
Antioxidant can also be comprised in liquid preparation composition provided by the invention.Described antioxidant is selected from, but is not limited to one or more in butylhydroxy anisole, dibenzylatiooluene, tert-butyl hydroquinone, propyl gallate, ascorbyl palmitate, thiodipropionic acid dilauryl cinnamic acid ester, 4-hexyl resorcin, tocopherol (vitamin E), L-AA, sodium D-isoascorbate, tea polyphenols, Herba Rosmarini Officinalis extract, Rhizoma Zingiberis Recens extract, sugar alcohols saccharide, aminoacid and dipeptide aminoacid.
The addition of above-mentioned antioxidant can change in a big way, only need ensure that the surface tension of liquid preparation composition is in described scope above.Under preferable case, antioxidant content is 0.001-5.0wt%.
In the present invention, when liquid preparation composition contains above-mentioned antibacterial, aromatic, stabilizing agent, antioxidant, in liquid preparation composition, each constituent content can change in a big way, such as, for liquid preparation composition generally speaking, surface-active contents can be 0.1-25.0wt%, solvent can be 58.0-99.869wt%, antibacterial content can be 0.01-2.0wt%, fragrance level can be 0.01-5.0wt%, stabiliser content can be 0.01-5.0wt%, and antioxidant content can be 0.001-5.0wt%.
For improving the combined therapy effect of liquid preparation composition provided by the invention, under preferable case, can also ingredient be contained in liquid preparation composition in the present invention, described ingredient comprise treatment rhinitis, sinusitis, lower respiratory tract inflammation, otitis media, external otitis, xerostomia, xerophthalmia, dryness in the nasal cavity disease medicine in one or more.
Conventional treatment rhinitis, sinusitis, the medicine of lower respiratory tract inflammation, such as, treatment rhinitis, the medicine of lower respiratory tract inflammation comprises, but be not limited to cortisone, hydrocortisone, beclometasone, triamcinolone acetonide, mometasone, dexamethasone, fluocinolone acetonide, budesonide, the glucocorticoidss such as fluticasone, ephedrine hydrochloride, the vasoconstrictors such as xylometazoline hydrochloride, hydrochloric acid levocabastine, the antihistaminics such as A-5610, and etc. Fructus Xanthii, dandelion, Radix Scutellariae, Fructus Lagenariae gourdae, Herba Ephedrae, Flos Magnoliae, Herba Asari, the Radix Angelicae Dahuricae, Rhizoma Acori Graminei, Catechu, dragon well green tea, one or more in the Chinese medicines such as Cortex Phellodendri and extract thereof.
More than treat rhinitis, sinusitis, lower respiratory tract anti-inflammatory drugs consumption for being no more than its conventional effective dose.
Similar, can also containing conventional treatment external otitis in liquid preparation composition in the present invention, otitis media, the medicine of lower respiratory tract inflammation, such as, treatment external otitis, otitis media, the medicine of lower respiratory tract inflammation comprises, but be not limited to ofloxacin, levofloxacin, norfloxacin, lomefloxacin, tosufloxacin, Sparfloxacin, Roxithromycin, chloromycetin, penicillin, clindamycin, nitrofural, amoxicillin, ampicillin, clavulanate potassium, cefaclor, cefixime, cefdinir, cefradine, cefalexin, Cefpodoxime Proxetil, CEFUROXIME AXETIL, cefprozil, azithromycin, minocycline, Acetylmidecamycin, the antibioticses such as acetylspiramycin, the antiviral classes such as metronidazole, cortisone, the glucocorticoidss such as triamcinolone acetonide, Moschus moschiferous is fragrant, dried Alumen, Calamina, sheet brain, dry kermes, Cacumen Platycladi, Echinacea root, counterfeit indigo root, Deng one or more in Chinese medicine and extract thereof.
More than treat external otitis, otitis media, lower respiratory tract anti-inflammatory drugs consumption for being no more than its conventional effective dose.
Similar, can also medicine containing conventional treatment external otitis, lower respiratory tract inflammation, dryness in the nasal cavity disease, xerostomia and xerophthalmia in liquid preparation composition in the present invention, these medicines include, but are not limited in D-panthenol, glycerol, hyaluronic acid, butanediol, Polyethylene Glycol, propylene glycol, hexanediol, xylitol, Sorbitol one or more.
More than treat external otitis, lower respiratory tract inflammation, dryness in the nasal cavity disease, xerostomia and xerophthalmia the consumption of medicine for being no more than its usual amounts.
Exemplary, in aforesaid liquid preparation compositions, the content of ingredient can be 0.001-5.0wt%.As previously mentioned, in liquid preparation composition, surface-active contents is 0.1-25.0wt%, and solvent is 70.0-99.899wt%, and the content of described ingredient is 0.001-5.0wt%.When in liquid preparation composition also containing above-mentioned antibacterial, aromatic, stabilizing agent, one or more in antioxidant time, for liquid preparation composition generally speaking, surface-active contents can be 0.1-25.0wt%, solvent can be 53.0-99.868wt%, antibacterial content can be 0.01-2.0wt%, fragrance level can be 0.01-5.0wt%, stabiliser content can be 0.01-5.0wt%, antioxidant content can be 0.001-5.0wt%, and the content of described ingredient is 0.001-5.0wt%.
Meanwhile, present invention also offers the preparation method of aforesaid liquid preparation compositions, comprising:
S1, by the ultrasonic middle dispersion 1-3min of the surfactant of liquid state at 40-60KHZ;
S2, at rotating speed be more than 3000rpm stirring condition under, the surfactant of liquid state is mixed homogeneously with solvent, form the liquid preparation composition being dispersed with the drop containing surfactant in solvent, and the absolute value that described liquid preparation composition surface tension is less than 60mN/m, zeta current potential is more than 15mV.
In above-mentioned preparation method, for surfactant, concrete adoptable material as previously mentioned, can be one or more in lecithin, sterol, Curosurf, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol.The above-mentioned various surfactant met the demands can directly be commercially available.
Above-mentioned solvent can be one or more in water, ethanol, glycerol, Medical silicone oil, edible vegetable oil.Preferred employing water, can reduce the stimulation to user.
According to the present invention, in described step S1, when being liquid under the surfactant base room temperature state adopted, can directly by the ultrasonic middle dispersion 1-3min of surfactant at 40-60KHZ.Now, only the surface tension of liquid preparation composition and zeta current potential need be made to fall into described scope above by the relative amount of adjustment solvent and surfactant.Under preferable case, in described liquid preparation composition, surface-active contents is 0.1-25.0wt%, and solvent is 75.0-99.9wt%.
When being solid-state under the surfactant base room temperature adopted, needing is first liquid by solid state surface activating agent Feedstock treating.Then by the ultrasonic middle dispersion 1-3min of the surfactant of liquid state at 40-60KHZ.
Above-mentioned is that liquid method can adopt method conventional in prior art by solid state surface activating agent Feedstock treating, such as, mixed by the material of this solid state surface activating agent raw material of solid state surface activating agent raw material and solubilized, dissolved.Understandable, for different solid active materials, the material of above-mentioned solubilized solid state surface activating agent raw material may be different, and in the present invention, those skilled in the art can know, and only need to dissolve above-mentioned solid state surface activating agent raw material.
According to the present invention, in described step S2, be preferably under the stirring condition of more than 3000rpm at rotating speed, surfactant is mixed homogeneously with solvent.Now, the drop containing surfactant that volume average particle size is less than 100 μm can be formed in a solvent.Such as can form the drop that volume average particle size is 1-100 μm.Above-mentioned drop can stable existence in a solvent, and liquid preparation composition entirety exists with emulsion form.For different liquid surfactants, when formation volume average particle size is the drop of 1-100 μm in a solvent, required rotating speed is different, and those skilled in the art can adjust according to practical situation.As known to those skilled in the art, along with the raising of speed of agitator and the prolongation of time, the volume average particle size of the drop that can be formed is less.
Concrete, solvent is mixed with surfactant, such as, surfactant is added in solvent.During mixing, detect surface tension and the zeta current potential of solvent/surfactant mixture, when surface tension is less than 60mN/m (or the target surface tension value preset) and the absolute value of zeta current potential is more than 15mV, stop mixing, liquid preparation composition disclosed by the invention can be obtained.The surface tension of liquid preparation composition obtains by automatic surface tension measuring device (USKino, A601) test.The zeta current potential of liquid preparation composition obtains by zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) test.In above-mentioned preparation method, as mentioned before, such as, in described liquid preparation composition, surface-active contents is 0.1-25.0wt%, and solvent is 75.0-99.9wt% for the concrete material that surfactant and solvent adopt and its relative amount.
Under preferable case, after described step S2, also comprise ultrasonication or high pressure homogenization step.Concrete, the method for above-mentioned ultrasonication or high-pressure homogenization is conventional in prior art, is not particularly limited in the present invention.
Can, by further for drop homogenize, make drop less by ultrasonication or high-pressure homogenization, forming volume average particle size be the drop of 50-500nm.Wherein, what drop can be more stable is scattered in solvent.The volume average particle size of above-mentioned drop can directly be obtained by existing various particle diameter testing equipment (such as laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain)) test.
Understandable, the drop in liquid preparation composition may be the drop formed by surfactant, also may be the drop jointly formed by other materials in surfactant and liquid preparation composition.And what obtained by the test of above-mentioned testing equipment is the volume average particle size of drop in whole liquid preparation composition, comprise the drop that other materials in the drop and surfactant and liquid preparation composition formed by surfactant are formed jointly.
According to the present invention, the pH value by rearrange liquids preparation compositions improves the stability of liquid preparation composition further within the scope of 6.0-7.4.Understandable, when preparing liquid preparation composition, the pH value comprising the original mixture of each material composition adopting different raw materials to obtain can be different, if when the pH value of original mixture is in above-mentioned scope, and can without the need to adjusting pH value again.If not in above-mentioned scope, under preferable case, adjust by the pH value of existing method to liquid preparation composition.Such as, the mode by adding buffer solution adjusts.In the present invention, alternative buffer system is citric acid-Fructus Citri Limoniae sodium buffer, Acetic acid-sodium acetate buffer, phosphate buffer, HEPES and Tris-citrate buffer solution, and preferred buffer system is HEPES and the Tris-citrate buffer solution of pH6.0-7.4.
The addition of above-mentioned various buffer solution meets above-mentioned condition to make the pH value of liquid preparation composition.
According to the present invention, when preparing aforesaid liquid preparation compositions, also can according to actual user demand, add in antibacterial, aromatic, stabilizing agent, antioxidant one or more.
The concrete material of the employing of above-mentioned antibacterial, aromatic, stabilizing agent, antioxidant as mentioned before, does not repeat them here.
The addition of above-mentioned antibacterial, aromatic, stabilizing agent, antioxidant also can be as mentioned before, the addition of such as described surfactant is 0.1-25.0wt%, the addition of solvent is 58.0-99.869wt%, the addition of antibacterial is 0.01-2.0wt%, the addition of aromatic is 0.01-5.0wt%, the addition of stabilizing agent is 0.01-5.0wt%, and the addition of antioxidant is 0.001-5.0wt%.
According to the present invention, when preparing liquid preparation composition, one or more in the medicine of conventional treatment rhinitis, sinusitis, lower respiratory tract inflammation, otitis media, external otitis, xerostomia, xerophthalmia, dryness in the nasal cavity disease can also be added as ingredient, make liquid preparation composition have better combined therapy effect.Concrete, the concrete material that ingredient adopts as mentioned before, does not repeat them here.
Concrete, the step of adding ingredient is not particularly limited, such as, said medicine composition and surfactant etc. can be mixed together and be prepared.
The consumption of said medicine composition is no more than its conventional effective dose.During concrete preparation, those skilled in the art can adjust according to practical situation, and such as, the concrete material of said medicine composition and addition in all cases can be as previously mentioned.
The above-mentioned various materials added for improving liquid preparation composition combination property may exist with various form in a solvent, comprise drops.Because the addition of above-mentioned various material belongs to trace relative to surfactant and solvent, the volume average particle size impact of various materials on drop in liquid preparation composition of above-mentioned interpolation is less, in the present invention, ignores on above-mentioned impact.
According to the present invention, under preferable case, described container is anti-pollution aerosol apparatus or anti-pollution liquid-drop machine.
According to the present invention, the anti-pollution doser of the above-mentioned container for receiving fluids preparation compositions, such as anti-pollution aerosol apparatus or anti-pollution liquid-drop machine.Above-mentioned anti-pollution doser is commonly known in the art, such as, can adopt the anti-pollution doser of the eye of A Puta company (OSD).Above-mentioned anti-pollution doser, based on pure theory of mechanics, by drip nozzle Sealing Technology and air filtration technology, effectively prevents microbial contamination liquid preparation composition and keeps the pressure balance inside and outside whole packaging.Above-mentioned anti-pollution aerosol apparatus or anti-pollution liquid-drop machine can avoid liquid preparation composition by environmental pollution largely, adopt during this device simultaneously and existing method still can be used to carry out fill.
Due to encapsulation aforesaid liquid preparation compositions is anti-pollution doser, is beneficial to and ensures the long-acting stable of liquid preparation composition.
In concrete commercial production, after preparing liquid preparation composition by said method, liquid preparation composition is poured into jetmizer or liquid-drop machine (those skilled in the art can select whether to adopt anti-pollution aerosol apparatus or anti-pollution liquid-drop machine as required), sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), sedimentation volume ratio, microbial limit after testing, outer package after meeting the requirements, to obtain final product.
Above-mentioned outer package can adopt existing conventional packaging, comprises charge cask, pump (or valve) and toucher.
Liquid preparation composition provided by the invention can fill in aerosol apparatus, use in the form of a spray.
Liquid preparation composition provided by the invention also can adopt nasal drop or ear drop to use, and the packaging of nasal drop or ear drop adopts the conventional packaging of nasal drop or ear drop, comprises charge cask, dropper.
The packaging process of above liquid preparation composition knows in field.
According to the present invention, when adopting anti-pollution aerosol apparatus or anti-pollution liquid-drop machine as container, the preparation process for liquid preparation composition does not affect.When liquid preparation composition being filled into anti-pollution aerosol apparatus or anti-pollution liquid-drop machine, packaging process is also know in field.
It is to be understood that in the present invention, the employing of anti-pollution aerosol apparatus or anti-pollution liquid-drop machine does not have an impact to the content of the component in liquid preparation composition and effect.
The object of this invention is to provide a kind of stable, spraying and drop-wise can be adopted to carry out liquid preparation composition used and preparation method thereof.This liquid preparation composition has that treatment otitis media, external otitis, rhinitis, sinusitis, lower respiratory tract inflammation, xerostomia, eyes are dry and astringent, the purposes of dry nasal cavity.
Liquid preparation composition action principle provided by the invention for providing lower surface tension in site of administration, thus plays the object of relief of symptoms.Only be described to be applied to otitis media in description of the present invention.Those skilled in the art are knowing after in the present invention, can know and adopt liquid preparation composition provided by the invention to other beyond otitis media because mucilage secretion is too much, cause tract to block and the disease (such as external otitis, rhinitis, sinusitis etc.) that causes is effective equally.
Liquid preparation composition provided by the invention is highly stable, can preserve for a long time.In the present invention, in order to improve retention cycle further, under preferable case, can be dry by aforesaid liquid preparation compositions, except desolventizing, form solid powdery or tabletting formation lamellar solid preparation.During use, only solid preparation need be dissolved again and can use in a solvent.
By the following examples the present invention is further detailed.
Embodiment 1
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take hydrogenated phospholipid 2.38g, sterol 0.12g, methyl hydroxybenzoate 0.4g, ethyl hydroxybenzoate 0.2g and Mentholum 0.1g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, and under high-speed stirred (6000rpm) state, mix homogeneously, continues to add water to final volume 100ml, mix homogeneously, pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 48.851mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 2.342 μm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-28.5mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.2.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 2
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 2.35g, poloxamer 0.15g, vitamin E 0.08g and phenethanol 0.5g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, even in high-speed stirred (6000rpm), continues to add water to final volume 100ml, mix homogeneously, pours into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 16.252mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 5.712 μm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-25.8mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.1.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 3
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 3.75g and vitamin E 0.64g is positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, above-mentioned alcoholic solution is joined in the Tris-citrate buffer solution of the pH6.0-7.4 of 0.05g glycerol monolaurate and 99ml, more evenly ultrasonic in Ultrasonic Cell Disruptor.Pour into anti-pollution doser (OSD), sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 26.225mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure particle size distribution, result is volume average particle size 223nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-32.2mV.The pH value of mixed liquor through adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.5.
Through 3750rpm after centrifugal 5 hours, there is not obvious sediment in bottom.
Embodiment 4
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 3.75g, vitamin E 0.013g, Mentholum 0.1g is positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, above-mentioned alcoholic solution is joined in 99ml water, mix homogeneously, adopt high pressure homogenizer homogenate 10min, pour into anti-pollution doser (OSD), sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 28.253mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure particle size distribution, result is volume average particle size 252nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-21.2mV.The pH value of mixed liquor through adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.0.
Through 3750rpm after centrifugal 5 hours, there is not obvious sediment in bottom.
Embodiment 5
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 2.5g, vitamin E 0.01g, methyl hydroxybenzoate 0.4g, ethyl hydroxybenzoate 0.2g, phenethanol 0.5g and Mentholum 0.1g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, and mix homogeneously; Poloxamer 0.12g is dissolved in 5ml water, the aqueous solution containing poloxamer is mixed with above-mentioned alcoholic solution under high velocity agitation, and continue to add water to final volume 100ml, mix homogeneously, pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 20.185mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 4.422 μm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-19.8mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.1.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 6
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 3.75g and vitamin E 0.64g, phenethanol 0.5g is positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, and under high-speed stirred (6000rpm) state, is added by above-mentioned alcoholic solution and is dissolved with in the 99ml water of poloxamer 0.15g, more evenly ultrasonic in Ultrasonic Cell Disruptor.Pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 16.425mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure particle size distribution, result is volume average particle size 275nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-17.8mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 5.9.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 7
The present embodiment is for illustration of liquid preparation composition disclosed by the invention and preparation method thereof.
Take hydrogenated phospholipid 1.38g, soybean phospholipid 1.0g, sterol 0.12g, methyl hydroxybenzoate 0.4g, ethyl hydroxybenzoate 0.2g and Mentholum 0.1g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, mix homogeneously, continues to add water to final volume 100ml, mix homogeneously, adopt high pressure homogenizer homogenate 10min, pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 28.518mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 356nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-35.8mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 6.2.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 8
The present embodiment is for illustration of liquid preparation composition disclosed by the invention (containing treatment rhinitis, sinusitis medicine) and preparation method thereof.
Take soybean phospholipid 1.0g, sterol 0.12g, triamcinolone acetonide 4mg, methyl hydroxybenzoate 0.4g, ethyl hydroxybenzoate 0.2g and Mentholum 0.1g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, mix homogeneously, continues to add water to final volume 100ml, mix homogeneously, adopt high pressure homogenizer homogenate 10min, pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 24.518mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 305nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-25.8mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 5.7.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Embodiment 9
The present embodiment is for illustration of liquid preparation composition disclosed by the invention (containing treatment otitis media medicine) and preparation method thereof.
Take soybean phospholipid 1.0g, sterol 0.12g, methyl hydroxybenzoate 0.4g, ethyl hydroxybenzoate 0.2g and Mentholum 0.1g to be positioned in container.Add dehydrated alcohol 1ml, ultrasonic (40KHZ) dissolves, under high-speed stirred (6000rpm) state, mix homogeneously, continue to add aqueous solution containing 0.3wt% levofloxacin hydrochloride (by levofloxacin) to final volume 100ml, mix homogeneously, adopts high pressure homogenizer homogenate 10min, pour into aerosol apparatus or liquid-drop machine, sealing.The mass parameter such as appearance character, loading amount, main constituent content, often discharge rate (or often dripping amount), microbial limit after testing, outer package after meeting the requirements, to obtain final product.
The surface tension of finished product is 27.184mN/m through adopting automatic surface tension measuring device (USKino, A601) to detect its surface tension.Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 235nm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-43.9mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 5.8.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment does not appear in bottom.
Comparative example 1
This comparative example is used for comparative illustration liquid preparation composition disclosed by the invention and preparation method thereof.
Take hydrogenated phospholipid 2.5g to be positioned in container.Add water to final volume 100ml, ultrasonic (40KHZ) dissolves, and under magnetic agitation state, stirs 30min.
Through the particle size distribution adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure product, result is volume average particle size 525.234 μm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-2.5mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 5.7.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment appears in bottom.
Comparative example 2
This comparative example is used for comparative illustration liquid preparation composition disclosed by the invention and preparation method thereof.
Take soybean phospholipid 5.0g, vitamin e1 .0g, phenethanol 0.5g is positioned in container, under hand operated mixing state, add 100ml water, mix homogeneously.
Through adopting laser particle analyzer Mastersizer2000 (MalvernInstrumentsLtd, Britain) to measure particle size distribution, result is volume average particle size 785.347 μm.Through the zeta current potential adopting zeta potential measurement instrument NANOTRACWAVE (MicroTrac, the U.S.) to measure product, result is-2.2mV.Through the pH value adopting pH meter (Shanghai thunder magnetic, PHSJ3F) to measure product, result is 5.7.
Mixed liquor is through 3750rpm after centrifugal 5 hours, and obvious sediment appears in bottom.
Performance test
Following performance test is carried out to the above-mentioned liquid preparation composition prepared:
1, otitis media Function detection
Intramuscular injection ketamine 70mg/kg and subcutaneous injection pentobarbital 30mg/kg general anesthesia, adopt the hemophilus influenza Injection in Tympanic Cavity of deactivation, set up Secretory Otitis Media model.Laboratory animal is variegated Cavia porcellus, random packet, and intact animal organizes 10, and modeling success animal 30, is divided into each 10 of non-processor group, normal saline group, treatment group at random.The liquid preparation composition spray nose adopting embodiment 2 to prepare is used, every Cavia porcellus, and each spray nose 2.5mg, bilateral nasal cavity 5mg, sprays 2 every day, continuous 7 days.Record acoustic immitance tympanogram and auditory brainstem response (ABR) threshold value, statistical analysis adopts one factor analysis of variance.
Table 1 is group tympanum pressure (daPa) respectively
Group Quantity Meansigma methods SD
Intact animal's group 20 33.06 18.75
Animal pattern group 20 140.6 26.00
Normal saline group 20 129.0 21.94
Treatment group 20 28.21 16.78
Table 2 is group tympanum pressure multiple comparisons LSD respectively
Group Comparable group Equal value difference P value
Treatment group Animal pattern group 112.4* 0.000
Treatment group Normal saline group 100.8* 0.000
Animal pattern group Intact animal's group 107.6* 0.000
Animal pattern group Normal saline group 11.62 0.252
Note: * difference has statistical significance (P<0.05)
Table 3ABR threshold value (dB)
Group Quantity Meansigma methods SD
Intact animal's group 10 14.9 3.0
Animal pattern group 10 53.0 4.3
Normal saline group 10 52.6 4.9
Treatment group 10 24.6 3.6
Table 4 each group reaction threshold value multiple comparisons LSD
Group Comparable group Equal value difference P value
Treatment group Animal pattern group 28.4* 0.000
Treatment group Normal saline group 28.0* 0.000
Treatment group Intact animal's group 9.73* 0.000
Animal pattern group Normal saline group 0.400 0.513
Note: * difference has statistical significance (P<0.05)
Result shows, and intact animal organizes ABR threshold value for (14.9 ± 3.0) dBHL.
Animal pattern non-processor group ABR threshold value is increased to (53.0 ± 4.3) dBHL, has statistical significance with intact animal's group.
Normal saline group ABR threshold value is (52.6 ± 4.9) dBHL, compares no difference of science of statistics with animal pattern non-processor group.
After inhalation treats 7 days, treatment group ABR threshold value is down to (24.6 ± 3.6) dBHL, and with animal pattern non-processor group, normal saline group compares statistical significance.
Therefore, adopt liquid preparation composition provided by the invention to treat Negative middle ear pressure and the ABR threshold value that significantly can reduce secretory otitis media Cavia porcellus, the improvement conversion of these indexs had both been the rapid alleviation of previously described otitis media symptom clinically.
Based on similar principles, liquid preparation composition provided by the invention plays effect equally for external otitis, rhinitis and sinusitis remission.
2, sedimentation stability detects
Each 2 of the finished product of Example 2, embodiment 4 and comparative example 2,0.5ml/ props up, through 3750rpm centrifugal 5 hours, detects sedimentation stability.By the naked eye, as shown in Figure 1, do not find that obvious sediment occurs in embodiment 2 and embodiment 4, in comparative example 2, find that there is obvious sediment.
In above-mentioned test, under 3750rpm is similar to normal condition for centrifugal 5 hours, preserve the effect of a year.As can be seen from Figure 1, liquid preparation composition provided by the invention has excellent stability.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.

Claims (34)

1. a liquid preparation composition, is characterized in that, described liquid preparation composition is emulsion, and described liquid preparation composition comprises solvent and is distributed in the drop containing surfactant in solvent;
The volume average particle size of described drop is less than 100 μm; The surface tension of described liquid preparation composition is less than 60mN/m, and the absolute value of the zeta current potential of described liquid preparation composition is more than 15mV.
2. liquid preparation composition according to claim 1, is characterized in that, the absolute value of the zeta current potential of described liquid preparation composition is more than 20mV.
3. liquid preparation composition according to claim 1, is characterized in that, the absolute value of the zeta current potential of described liquid preparation composition is more than 40mV.
4. liquid preparation composition according to claim 1, is characterized in that, the volume average particle size of described drop is 1-100 μm.
5. liquid preparation composition according to claim 1, is characterized in that, the volume average particle size of described drop is 50-500nm.
6. according to the liquid preparation composition in claim 1-5 described in any one, it is characterized in that, the pH value of described liquid preparation composition is 5.0-7.4.
7. liquid preparation composition according to claim 6, is characterized in that, the pH value of described liquid preparation composition is 6.0-7.4.
8. according to the liquid preparation composition in claim 1-5,7 described in any one, it is characterized in that, the surface tension of described liquid preparation composition is less than 40mN/m.
9. according to the liquid preparation composition in claim 1-5,7 described in any one, it is characterized in that, the surface tension of described liquid preparation composition is less than 30mN/m.
10. according to the liquid preparation composition in claim 1-5,7 described in any one, it is characterized in that, the surface tension of described liquid preparation composition is less than 27mN/m.
11., according to the liquid preparation composition in claim 1-5,7 described in any one, is characterized in that, described surfactant be selected from natural or synthetic surfactant one or more.
12. liquid preparation compositions according to claim 11, it is characterized in that, described surfactant comprises that natural phospholipid, sterol, Curosurf, stearic acid, oleic acid, lauric acid, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, fatty acid Pyrusussuriensis are smooth, one or more in Polysorbate, Myrj 45, polyoxyethylene aliphatic alcohol ether, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol.
13. liquid preparation compositions according to claim 11, it is characterized in that, described surfactant comprise in lecithin, sterol, Curosurf, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol one or more.
14. liquid preparation compositions according to claim 12, is characterized in that, described solvent is one or more in water, ethanol, glycerol, Medical silicone oil, edible vegetable oil.
15., according to the liquid preparation composition in claim 12,13,14 described in any one, is characterized in that, in described liquid preparation composition, surface-active contents is 0.1-25.0wt%, and solvent is 75.0-99.9wt%.
16., according to the liquid preparation composition in claim 1-5,7,12,13,14 described in any one, is characterized in that, also containing one or more in antibacterial, aromatic, stabilizing agent, antioxidant in described liquid preparation composition.
17. liquid preparation compositions according to claim 16, it is characterized in that, described antibacterial comprise in parabens and salt, benzoic acid and salt, benzyl alcohol, phenethanol, phenylacetic acid, phenoxyethanol, glycerol monolaurate, chlorobutanol, sorbic acid and salt, calcium propionate, sodium propionate, dehydroactic acid and salt, sodium diacetate, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, chlorhexidine acetate, propylene glycol, carbon dioxide, nisin, natamycin, Charantin, thimerosal, Mercury pernitrate. one or more;
Described aromatic comprises Mentholum, Borneolum Syntheticum, Fructus Citri Limoniae oil, patchouli oil, Oleum Cinnamomi, red date tincture, vanillin, Oleum menthae, geranium absolute, eucalyptus oil, Oleum Menthae Rotundifoliae, eugenol, citral, concrete of jasmine, Hang Zhou chrysanthemum flower extract, osmanthus concrete, benzyl alcohol, phenethanol, terpineol, methyl cyclopentenyl ketone, jasminal, butanoic acid, caproic acid, isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate, ethyl n-butyrate., isoamyl butyrate, benzyl butyrate, iso-amyl iso-valeriate, ethyl hexanoate, cognac oil, ethyl lactate, allyl hexanoate, nonyl lactone, ethyl maltol, allyl cyclohexyl propionate, maltol, gamma-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate, ethyl isovalerate, Ethyl formate, benzyl benzoate, methylpyrazine, 2,3-dimethyl pyrazine, trimethylpyrazine, 2-acetyl group pyrazine, 4-methyl-5-(beta-hydroxyethyl) thiazole, 2-acetylthiazole, 2，3，5，6-tetramethylpyrazine, hexadecanoyl, ethyl vanillin, one or more in hydroxycitronellal,
Described stabilizing agent comprise in lecithin, poloxamer, saponarin, tannin, fatty acid glyceride, sucrose fatty acid ester, methyl glycol fatty acid ester, cholesterol, cholesteryl ester, Polyethylene Glycol, cellulose and derivant, dextrin, arabic gum, Tragacanth class, pecto-cellulose cheese, gelatin, alginic acid one or more;
Described antioxidant comprise in butylhydroxy anisole, dibenzylatiooluene, tert-butyl hydroquinone, propyl gallate, ascorbyl palmitate, thiodipropionic acid dilauryl cinnamic acid ester, 4-hexyl resorcin, tocopherol, L-AA, sodium D-isoascorbate, tea polyphenols, Herba Rosmarini Officinalis extract, Rhizoma Zingiberis Recens extract, sugar alcohols saccharide, aminoacid one or more.
18. liquid preparation compositions according to claim 17, it is characterized in that, in described liquid preparation composition, surface-active contents is 0.1-25.0wt%, solvent is 58.0-99.869wt%, and antibacterial content is 0.01-2.0wt%, and fragrance level is 0.01-5.0wt%, stabiliser content is 0.01-5.0wt%, and antioxidant content is 0.001-5.0wt%.
The preparation method of 19. liquid preparation compositions as claimed in claim 1, is characterized in that, comprising:
S1, by the ultrasonic middle dispersion 1-3min of the surfactant of liquid state at 40-60KHZ;
S2, at rotating speed be more than 3000rpm stirring condition under, the surfactant of liquid state is mixed homogeneously with solvent, form the liquid preparation composition being dispersed with the drop containing surfactant in solvent, and the absolute value that described liquid preparation composition surface tension is less than 60mN/m, zeta current potential is more than 15mV.
20. preparation methoies according to claim 19, is characterized in that, after described step S2, also comprise ultrasonication or high pressure homogenization step, and forming volume average particle size is in a solvent the drop of 50-500nm.
21. preparation methoies according to claim 19 or 20, it is characterized in that, the addition of described surfactant is 0.1-25.0wt%, and the addition of solvent is 75.0-99.9wt%.
22. preparation methoies according to claim 19 or 20, is characterized in that, also comprise and be scattered in solvent by one or more in antibacterial, aromatic, stabilizing agent, antioxidant;
The addition of described surfactant is 0.1-25.0wt%, the addition of solvent is 58.0-99.869wt%, the addition of antibacterial is 0.01-2.0wt%, the addition of aromatic is 0.01-5.0wt%, the addition of stabilizing agent is 0.01-5.0wt%, and the addition of antioxidant is 0.001-5.0wt%.
23. preparation methoies according to claim 22, it is characterized in that, described antibacterial comprise in parabens and salt, benzoic acid and salt, benzyl alcohol, phenethanol, phenylacetic acid, phenoxyethanol, glycerol monolaurate, chlorobutanol, sorbic acid and salt, calcium propionate, sodium propionate, dehydroactic acid and salt, sodium diacetate, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, chlorhexidine acetate, propylene glycol, carbon dioxide, nisin, natamycin, Charantin, thimerosal, Mercury pernitrate. one or more;
Described aromatic comprises Mentholum, Borneolum Syntheticum, Fructus Citri Limoniae oil, patchouli oil, Oleum Cinnamomi, red date tincture, vanillin, Oleum menthae, geranium absolute, eucalyptus oil, Oleum Menthae Rotundifoliae, eugenol, citral, concrete of jasmine, Hang Zhou chrysanthemum flower extract, osmanthus concrete, benzyl alcohol, phenethanol, terpineol, methyl cyclopentenyl ketone, jasminal, butanoic acid, caproic acid, isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate, ethyl n-butyrate., isoamyl butyrate, benzyl butyrate, iso-amyl iso-valeriate, ethyl hexanoate, cognac oil, ethyl lactate, allyl hexanoate, nonyl lactone, ethyl maltol, allyl cyclohexyl propionate, maltol, gamma-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate, ethyl isovalerate, Ethyl formate, benzyl benzoate, methylpyrazine, 2,3-dimethyl pyrazine, trimethylpyrazine, 2-acetyl group pyrazine, 4-methyl-5-(beta-hydroxyethyl) thiazole, 2-acetylthiazole, 2，3，5，6-tetramethylpyrazine, hexadecanoyl, ethyl vanillin, one or more in hydroxycitronellal,
Described stabilizing agent comprise in lecithin, poloxamer, saponarin, tannin, fatty acid glyceride, sucrose fatty acid ester, methyl glycol fatty acid ester, cholesterol, cholesteryl ester, Polyethylene Glycol, cellulose and derivant, dextrin, arabic gum, Tragacanth class, pecto-cellulose cheese, gelatin, alginic acid one or more;
Described antioxidant comprise in butylhydroxy anisole, dibenzylatiooluene, tert-butyl hydroquinone, propyl gallate, ascorbyl palmitate, thiodipropionic acid dilauryl cinnamic acid ester, 4-hexyl resorcin, tocopherol (vitamin E), L-AA, sodium D-isoascorbate, tea polyphenols, Herba Rosmarini Officinalis extract, Rhizoma Zingiberis Recens extract, sugar alcohols saccharide, aminoacid one or more.
24. according to the preparation method in claim 19,20,23 described in any one, it is characterized in that, described surfactant comprises that natural phospholipid, sterol, Curosurf, stearic acid, oleic acid, lauric acid, benzalkonium chloride, benzalkonium bromide, cetrimonium bromide, fatty acid Pyrusussuriensis are smooth, one or more in Polysorbate, Myrj 45, polyoxyethylene aliphatic alcohol ether, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol.
25. preparation methoies according to claim 24, it is characterized in that, described surfactant comprise in lecithin, sterol, Curosurf, poloxamer, dipalmitoyl phosphatidyl choline, cholesterol, cholesteryl ester, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Polyethylene Glycol one or more; Described solvent is one or more in water, ethanol, glycerol, Medical silicone oil, edible vegetable oil.
26. 1 kinds of solid preparations, is characterized in that, by the liquid preparation composition in claim 1-18 described in any one through super-dry, obtain except desolventizing.
27. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of otitis media.
28. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of external otitis.
29. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of rhinitis.
30. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of sinusitis.
31. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of xerostomia.
32. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of xerophthalmia.
33. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of dryness in the nasal cavity disease.
34. liquid preparation compositions as described in claim 1-18 or solid preparation as claimed in claim 26 are used for the treatment of the purposes of lower respiratory tract inflammation.
CN201410390825.9A 2014-08-08 2014-08-08 Liquid preparation composition and preparation method and use and solid preparation thereof Pending CN105435227A (en)

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CN106037016A (en) * 2016-08-05 2016-10-26 广西中烟工业有限责任公司 Blueberry-flavor electronic cigarette liquid
CN108567737A (en) * 2017-03-10 2018-09-25 深圳君圣泰生物技术有限公司 Liquid composition and its use device
CN110876807A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Spray containing surfactant for anticholinergic medicine
CN110876722A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Tiotropium bromide and oxdarterol spray containing surfactant
CN110876720A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Application of edetate to properly change surface tension of tiotropium bromide spray
CN110876724A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Application of edetate for properly changing surface tension of tiotropium bromide and oxdarterol spray
CN110876723A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Isopropyl tropium bromide spray containing surfactant
CN110876721A (en) * 2018-09-06 2020-03-13 天津金耀集团有限公司 Tiotropium bromide spray containing surfactant

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