CN101442987A

CN101442987A - Compositions and methods for treating dermatological conditions

Info

Publication number: CN101442987A
Application number: CNA2006800515321A
Authority: CN
Inventors: J·张; K·S·华纳; S·莎玛
Original assignee: ZARS Pharma Inc
Current assignee: ZARS Pharma Inc
Priority date: 2005-12-14
Filing date: 2006-12-14
Publication date: 2009-05-27
Also published as: CN101370453B; CN101370453A

Abstract

The invention provides a aerosol formulation and dermal delivery method. The invention relates to the aerosol formulation, dermal delivery method and solidified layer obtained by dermal delivery. The formulation may include medicament, non-volatile solvent system, solidifying agent, and propellant. The formulation may have initial viscosity suitable for being pulled out from a pressure container or a manual pump container and applied to surface of skin. After the formulation is applied to skin, evaporation of at least some of the propellant converts the formulation on the skin into a solidified layer.

Description

Spray agent and percutaneous drug delivery method

Technical field

[0001] present invention relates in general to be developed the system that is used for percutaneous drug delivery.More specifically, the present invention relates to the viscosity preparation, it has the viscosity that is suitable for to the skin surface spray application, and it forms the viscosity solidification layer that continues medication on skin.

Background technology

[0002] there are several transdermals or percutaneous drug delivery system (transdermal ordermal drug delivery systems) generally: skin patch, semi-solid as ointment, ointment and lotion, and spray agent (spray-on formulations).Common administration patch is not elastic and has fixed shape and size.They behave oneself best at relatively flat and skin area not crooked or that stretch.

[0003] general semisolid dosage form such as ointment and ointment, on being applied to skin after usually experience remove or transfer to other skin surface unintentionally.Solvent in these semi-solid preparations also tends to rapid evaporation after using, this may have a negative impact to injection speed.In addition, when semi-solid preparation was applied on the skin, its is " being rubbed into top layer (rubbed in) " usually, and it means to have only very that the preparation of thin layer is applied on the skin.This has limited the medication amount that can be applied on every square centimeter of skin, makes that it is difficult continuing medication.

[0004] spray such as those preparations in pressurizing vessel or the pump, comprises traditional semi-solid preparation composition and propellant (propellants) and/or diluent.Propellant and diluent improve the easiness that preparation is used.Therefore, except application process, they have as top listed to similar restriction and the shortcoming of semisolid.

[0005] consider the shortcoming of many existing percutaneous drug delivery systems, expectation provides such system, preparation and/or method: i) provide lasting administration during long-time; Ii) in use between during in be not easy to be not intended to remove owing to contacting with medicated clothing, other object or person; Iii) can be applied to the flexible and unfolded skin area of experience, and not cause the uncomfortable or poor of skin with contacting of skin; And/or iv) after using and using, can easily be removed.

Summary of the invention

[0006] the present invention relates to new formulation, it can be applied to skin surface by spraying, and can form agglutinating, flexible after its propellant evaporation in preparation and/or the continuous solid body layer.Although film technique has been used in cosmetics and the pharmaceutical preparation, the solvent that usually uses in this system can not last very long, and is not best for continuing to discharge using therefore.According to this point, have realized that in preparation to use and select for selected medicine and application need are special or the non-volatile solvents system of preparation, can improve or even optimization continue medication.For instance, the media solvent of medicine can be prepared or be kept and can serve as be chosen in medicament administration the duration to the non-volatile solvents in the preparation (multiple solvent).

[0007] according to this point, the spray that is used for administration can comprise medicine, comprise the non-volatile solvents system of at least a non-volatile solvents, coagulant (firming agent) and propellant.Said preparation can have such initial viscosity, described viscosity is suitable for being discharged from from pressurizing vessel or manual pump container and being applied to skin surface as layer, and further, said preparation can also form solidification layer on skin surface after at least a portion propellant is evaporated.

[0008] in another embodiment, the percutaneous drug delivery method can comprise injection viscosity coagulation agent on skin surface.Non-volatile solvents system, coagulant and propellant that said preparation can comprise medicine, medicine can be circulated.Preparation can have such initial viscosity, and described viscosity is suitable for being pushed out from pressurizing vessel or manual pump container and being applied to skin surface as layer.Other step comprises by to small part evaporation propellant preparation being solidified, to carry out percutaneous drug delivery from solidification layer to skin surface with effective speed on treating in the time durations that forms solidification layer on the skin surface and continuing.

[0009] from following detailed description---its mode by example is set forth feature of the present invention, and it is obvious that additional features of the present invention and advantage will become.

The specific embodiment

[0010] before the specific embodiment of the present invention is disclosed and describes, should understand, the invention is not restricted to concrete grammar disclosed herein and material, because these can change to a certain extent.Scope of the present invention it is also understood that term used herein only is used to describe the purpose of the specific embodiment and is not intended to is restrictive, because will only be limited by claims and its equivalent.

[0011] describing and claimed when of the present invention, following term will be used.

[0012] unless context shows in addition that clearly singulative " (a) ", " one (an) " and " being somebody's turn to do (the) " comprise that plural number refers to thing.Therefore, for instance, quoting of " a kind of medicine " comprised quoting one or more such components.

[0013] " skin " is defined as comprising application on human skin (complete, ill, ulcer or disruptive); Finger and toe nail surface; With the mucomembranous surface that is exposed to air usually to small part, as the mucosa of lip, genitals and anus and the mucosa of nose and mouth.

[0014] term " medicine (multiple medicine) " is meant and is applied to skin, uses in the skin into or any bioactivator by dermal administration, and it is applied to realize therapeutical effect.This comprises the compositions of being thought medicine by routine, and other bioactivator that is not considered to " medicine " in the traditional view usually, as peroxide, wetting agent (humectants), emollient (emollients) etc., but they can provide therapeutic effect to some disease.When mentioning " medicine " prevailingly, should understand, have the various ways of given medicine, and those various ways are included clearly.According to this point, multiple medicament forms comprises polymorph, salt, hydrate, solvate and eutectic.For some medicines, a kind of medicine of physical form may have better physicochemical characteristics, makes it more can arrive, enter or pass skin, and this particular form is defined as " being beneficial to the physical form of dermal delivery ".For instance, diclofenac sodium is high more a lot of from the steady state flux of the same non-volatile solvents that makes circulation than diclofenac from the steady state flux of the non-volatile solvents that can make circulation.Therefore, needs assessment medicine physical form is from the flux of non-volatile solvents, with physical form/non-volatile solvents combination of selecting expectation.

[0015] term " percutaneous drug delivery (dermal drug delivery) " or " percutaneous drug delivery (multiple medicine) (dermal delivery of drug (s)) " should comprise transdermal administration and topical administration the two, and comprise to percutaneous drug delivery (multiple medicine), by percutaneous drug delivery (multiple medicine) or administration (multiple medicine) in skin." transdermal administration (the Transdermal delivery) " of medicine can targeting the only skin histology under skin, the local organization under the skin or organ, body circulation and/or central nervous system.

[0016] term " flux (flux) ", such as respectively in the context of " skin flux (dermal flux) " or " transdermal flux (transdermal flux) ", be meant the medication amount that penetrates into or pass skin on the time per unit per unit area.The common unit of flux per hour is every square centimeter a micrograms.A kind of method of measuring flux is to place preparation on the known skin area of human volunteer and measure how many permeable drug enter or pass skin in the certain hour restriction.Several different methods (method in the body) also can be used for measuring.Method or other similar approach (in vitro method) described among the embodiment 1 also can be used for measuring flux.Although in vitro method uses people's epidermis film of obtaining from corpse or firm isolated skin histology from the hairless mouse, rather than the drug flux of passing skin with the human volunteer measurement, but those skilled in the art admit usually, and the result of appropriate design and the in vitro tests carried out can be used for estimating or the result of prediction in vivo test with reliability preferably.Therefore, " flux " value that this paper quoted can refer in the body or the measured amount of flux of in vitro method.

[0017] " can make circulation (flux-enabling) " about the term of the non-volatile solvents system solidification layer of non-volatile solvents system (or comprise) is meant, non-volatile solvents system (comprising one or more non-volatile solvents) is selected especially or is prepared, so that effective flux in the treatment of certain drug (multiple medicine) can be provided.For external or the local medicine of carrying, can make the non-volatile solvents of circulation be defined as such non-volatile solvents system: when this non-volatile solvents system was saturated by medicine, enough the medicine of level be conveyed through subject's skin, be sent on the subject's skin or be sent in the subject's skin on down separately just can be with treatment without any other composition auxiliary.For the whole body targeted drug, the non-volatile system that can make circulation is so non-volatile system: when this non-volatile solvents system saturated and by medicine to be not more than 500cm ²Contact area when contacting fully with subject's skin, daily dose enough in the treatment can be provided during 24 hours.Preferably, the contact area of non-volatile solvents system is for being not more than 100cm ²Can be used for measuring the ability that the non-volatile solvents system produces flux peak with this saturated test that contains medicine solvent state.In order to measure flux, the drug solvent mixture need keep the time of capacity clinically on skin.In fact, may be difficult to liquid flux is kept the time period of prolongation on human volunteer skin.Therefore, measure the optional method whether solvent system " can make circulation " and be, adopt apparatus and method measurement medicine described in the embodiment 1 in external infiltration of passing hairless mouse skin or people's corpse skin.This method and similar approach are used to estimate the permeability and the feasibility of preparation usually by those skilled in the art.Alternatively, can use the non-volatile solvents system that will have saturated medicine and remain on means on the skin, on lived people's subject's skin, measure the non-volatile solvents system and whether can make circulation, and such means may not be suitable for product.For instance, the non-volatile solvents system with saturated medicine can be dipped in the absorbent fibrous material, and it is applied on the skin and with protecting film then and protects.Such system is unpractical as drug products, but is suitable for testing the endogenous capacity that whether the non-volatile solvents system has provides enough drug flux, and perhaps whether it can make circulation.

[0018] should also be noted that, in case preparation forms solidification layer, this solidification layer also can be " can make circulation " for medicine when some non-volatile solvents are retained in the solidification layer, even also like this after volatile solvent (comprising water) has been evaporated basically.

[0019] phrase " effective dose ", " treatment effective dose ", " treatment effective speed (speed is multiple) " or similar phrase, when it relates to medicine, be meant the q.s or the delivery rate of medicine, its when the disease that this medicine of treatment is sent, reach arbitrarily can the survey level therapeutic outcome.Should understand, the business-like effect standard of any government organs approved products may be satisfied or may do not satisfied to " can survey the therapeutic outcome of level ".Should understand, the various biological factor can influence the ability that material is finished its intention task.Therefore, in some cases, " effective dose ", " treatment effective dose " or " treatment effective speed (multiple speed) " may depend on such biological factor to a certain extent.Yet for every kind of medicine, those skilled in the art have consensus usually to dosage enough in most of object or flux range.Further, can adopt evaluation methodology test known in the art by doctor or other titular healthcare givers although reach therapeutic effect, but will be appreciated that, individual variation and to the treatment reaction can be so that reach the decision that therapeutic effect becomes subjectivity.Definite treatment effective dose or medicine-feeding rate are proficient in for the those of ordinary skill of pharmacy science and medical domain.

[0020] " treat effective flux " or " treating enough flux " is defined as the permeation flux of selected medicine, its medicine with q.s is delivered in the skin or passes skin, being useful clinically.When relating to flux, " useful clinically " or " enough clinically " is meant, can obtains benefit to a certain degree in some patient populations from drug flux.This means that not necessarily most patients colony can obtain benefit to a certain degree, and perhaps this benefit is enough high to be thought " effectively " by relevant government agencies or medical expert.More specifically, for targeting skin or near the medicine of the local organization of skin surface or organ (such as joint, some muscle or be positioned at the tissue/organ of skin surface 5cm to small part), " treating effective flux " is meant in the reasonable time amount clinically that the medicine with q.s is delivered to the drug flux in the target tissue.For targeting body circulation medicine, " treat effective flux " and be meant such drug flux, it can be by suitable contact skin zone clinically, clinically in the reasonable time, and the selected medicine of sending q.s is to produce favourable clinically plasma drug level or blood substance concentration.Suitable clinically contact skin zone is defined as the dermal administration area size that most of object can be accepted.Usually, 400cm ²Or littler contact skin zone is considered to suitable.Therefore, in order in 10 hours, the 4000mcg medicine to be passed through 400cm ²Contact skin regional delivery to body circulates, and flux need be 4000mcg/400cm at least ²/ 10 hours, it equaled 1mcg/cm ²/ hr.By this definition, different pharmaceutical has different " treating effective flux "." treating enough flux " may be different for different objects, or even may be different at different time to same target.Yet for every kind of medicine, those skilled in the art have identical ideas in dosage or the flux range of most of the time usually to most of object.

[0021] below be in the treatment of some medicines effectively or more than the flux estimation of q.s:

The external steady state flux value of Table A---multiple medicine

Medicine	Indication	Effective flux in the treatment of estimating ^* (mcg/cm ²/hr)
Medicine	Indication		Ropivacaine ^**	Neuropathic pain	5
Lignocaine	Neuropathic pain	30	Ropivacaine ^**	Neuropathic pain	5
Lignocaine	Neuropathic pain	30	Acyclovir	Herpes simplex virus	3
Ketoprofen	Musculoskeletal pain	16	Acyclovir	Herpes simplex virus	3
Ketoprofen	Musculoskeletal pain	16	Diclofenac	Musculoskeletal pain	1
Clobetasol	Dermatitis, psoriasis, eczema	0.05	Diclofenac	Musculoskeletal pain	1
Clobetasol	Dermatitis, psoriasis, eczema	0.05	Betamethasone	Dermatitis, psoriasis, eczema	0.01
Testosterone	Male gonad hypofunction	0.8	Betamethasone	Dermatitis, psoriasis, eczema	0.01
Testosterone	Male gonad hypofunction	0.8	Testosterone	Hormone therapy behind the postmenopausal women	0.25
Imiquimod	Wart, basal cell carcinoma	0.92	Testosterone	Hormone therapy behind the postmenopausal women	0.25

^*The flux that the in vitro method of describing among the employing embodiment 1 is measured

^*Based on the flux estimated with respect to the known effectiveness of lignocaine

[0022] the effective amount of flux of treatment (except ropivacaine) is illustrated in the vitro system of describing among the embodiment 1 in the Table A, and the steady state flux value of hairless mouse or people's epidermis film is passed in the commercially available prod.These values are intended to estimated value and preparation research and development and the comparison basis of optimizing are provided.The effective flux of the treatment of selected medicine may be very different with different individual subject for the different phase of the various disease that will treat, disease.Should be noted that listed flux may be higher than the treatment effective dose.

[0023] shown following Examples set listed among the B, to the screening of non-volatile solvents at the made negotiability of some medicines of specifically being studied.Described in following embodiment 1, test, and the result is further discussed in embodiment 2-9 subsequently.

Many kinds of medicines of table B-are from the external steady state flux value of non-volatile solvents system

^*Meansigma methods and standard deviation that each value representation is measured for three times.

[0024] the external steady state flux value from non-volatile solvents shows surprising among the table B

Made circulation and the non-circulation solvent that makes.This information can be used to instruct formulation development.

[0025] relevant with making circulation non-volatile solvents (multiple solvent) term " plasticising (plasticizing) " is defined as, and serves as the made circulation non-volatile solvents of the plasticizer of coagulant." plasticizer " is the preparation that can increase the preparation elongation after the basic at least evaporation of volatile solvent.Plasticizer also has by making it have more flexibility and/or elasticity reduces the brittle ability of coagulation agent.For instance, propylene glycol is for being " can make circulation, plasticising non-volatile solvents " with polyvinyl alcohol as the medicine ketoprofen of the coagulant of selecting.Yet in Gantrez S-97 or the Orudis of Avalure UR 405 as coagulant, propylene glycol does not provide same plasticization.The combination compatibility difference of propylene glycol and Gantrez S-97 or Avalure UR 405 and obtaining for the not too gratifying preparation of external.Whether therefore, given non-volatile solvents is that " plastifying " depends on that selected is which kind of coagulant (multiple coagulant).

[0026] different pharmaceutical usually has different being complementary that good especially result is provided and can make circulation non-volatile solvents system.Such example is presented among the table C.Described in following embodiment 1, test, and the result is further discussed in embodiment 2-9 subsequently.

Table C-many kinds of medicines are from the external steady state flux value of the non-volatile solvents system that can make high especially circulation

Medicine	Can make the non-volatile solvents of high circulation	Average flux ^*(mcg/cm ²/h)
Medicine	Can make the non-volatile solvents of high circulation	Average flux ^*(mcg/cm ²/h)	Ropivacaine	The ISA span 20	11±2 26±8
Ketoprofen	Propylene glycol (PG)	90±50	Ropivacaine	The ISA span 20	11±2 26±8
Ketoprofen	Propylene glycol (PG)	90±50	Acyclovir	The ISA+30% triethanolamine	7±2
The betamethasone dipropionate	Propylene glycol	0.20±0.07	Acyclovir	The ISA+30% triethanolamine	7±2
The betamethasone dipropionate	Propylene glycol	0.20±0.07	Clobetasol propionate	PG+ISA (the PG:ISA ratio range is 200:1 to 1:1)	0.8±0.2

Should be noted that [0027] " non-volatile solvents that can make circulation ", " can make the plasticising non-volatile solvents of circulation " or " can make the non-volatile solvents of high circulation " can be the mixture of single chemical substance or two or more chemical substances.For instance, the steady state flux value of clobetasol propionate is the propylene glycol at 9:1 among the table C: in the isostearic acid mixture, it produces much higher clobetasol flux (referring to table B) than independent propylene glycol or ISA.Therefore, the propylene glycol of 9:1: the isostearic acid mixture is " non-volatile solvents that can make high circulation ", but independent propylene glycol or stearic acid are not.

[0028] when relating to solidification layer in this article, term " bonding " and " viscosity " is meant, between solidification layer and the skin enough bonding make intention at most of object between the operating period this layer do not come off from skin.When being used to describe solidification layer, " viscosity " or similar word can mean that also solidification layer has viscosity to the skin surface that the initial preparation layer is applied to (before volatile solvent (multiple solvent) evaporation) at first.In one embodiment, this does not mean that this solidification layer has viscosity to offside.In addition, should be noted that whether solidification layer can adhere to skin surface and reach the long situation that partly depends on skin surface period of expectation.For instance, the oily matter on excessive sweating or butyrous skin or the skin surface may make solidification layer lower to the viscosity of skin.Therefore, viscosity solidification layer of the present invention may not keep with skin surface intact contact and for each object under any condition of skin surface in duration delivering drugs.A standard is that under the normal condition of skin surface and external environment condition, for most of object, at the appointed time the stage keeps good contacting with the most skin surface as 70% of the gross area for it.

[0029] as used herein, term " flexible ", " resilient ", " elasticity " or similar terms be meant, solidification layer have enough flexibilities with elasticity so that it does not destroy or separates with skin surface between the intention operating period.For instance, present acceptable flexibility, elasticity and can be adhered to human skin on soft skin part such as elbow, finger, wrist, neck, lower back, lip, knee joint etc., and will on skin, keep basic complete behind the stretching of skin the adherent solidification layer of skin.Should be noted that in some embodiments solidification layer of the present invention not necessarily must have any elasticity.

[0030] when being used to describe solidification layer, term " strippable " means that solidification layer can be uncovered with a sheet of or several sheet from skin surface, rather than many small pieces or fragment.

[0031] term " lasting " the treatment effective speed that relates to percutaneous drug delivery reaches at least 30 minutes section continuous time, and in some embodiments, be at least about 2 hours, 4 hours, 8 hours, 12 hours, 24 hours or longer time period.

[0032] when relating to the volatile solvent evaporation, the use of term " basically " means that the most of volatile solvent that is included in the initial preparation evaporates.Similarly, when solidification layer was said to be " not having basically " volatile solvent and---comprises water---, solidification layer had the volatile solvent below the 10wt% in solidification layer as a whole, and is preferably below the 5wt%.

[0033] term " propellant " is meant such solvent, and its boiling point is can produce enough pressure so that preparation of the present invention is discharged from container in hermetic container below 20 ℃ and under the temperature more than 20 ℃.Propellant can be dissolved in the remainder of preparation, is present in the remainder of preparation as isolating phase (isolating or suspension), perhaps is present in chamber separately (type (bag in can tpye) of bag in jar) or the interval.When propellant be maintained at the preparation remainder separate mutually or at interval the time, before being applied to skin surface, it can mix with other composition of preparation, such as by shaking, put upside down, stir or other manual or mechanical mixture method.

[0034] " volatile solvent system " is meant volatile single solvent or solvent mixture, and it comprises water and has more volatile solvent than water, but it has the boiling point more than 25 ℃.

[0035] " non-volatile solvents system " can be single solvent or the solvent mixture of volatility than water difference.It can also comprise is the material of solid or liquid at room temperature, as pH or ion-pairing agent.After the volatile solvent system evaporation, major part non-volatile solvents system should remain on a certain amount of time in the solidification layer, the described time be enough to given medicine with enough flux dermal deliveries in subject's skin or by subject's skin a period of time, so that therapeutic effect to be provided.In some embodiments, for the expectation permeability that obtains active medicine and/or compatible with coagulant or other composition of preparation, the mixture of two or more non-volatile solvents can be used to form the non-volatile solvents system.In one embodiment, two or more non-volatile solvents mixture of formation solvent system provide the flux that separately this medicine is provided than each non-volatile solvents higher transdermal flux for medicine.Non-volatile solvents can also be as the plasticizer of solidification layer, so that solidification layer has elasticity and flexibility.

[0036] " viscosity coagulation agent " or " coagulation agent ", " spraying coagulation agent " and similar terms can exchange use, and be meant such compositions, it has the viscosity that is fit to be administered to skin surface before its volatile solvent (multiple solvent) evaporation, and it can become solidification layer after at least a portion volatile solvent (multiple solvent) evaporation.In a single day solidification layer forms, and it just can be very firm.In one embodiment, in a single day preparation solidifies on skin surface and just can form skin (peel).This micromicro is to be softish bonding solid, and it can be removed by several sheets of peelling off from skin for employed preparation size, and usually peels off from skin as independent a slice.Application viscosity is more sticking than water sample liquid usually, but lower than the viscosity of pliable solid.The example of preferred viscosities comprises the material with the denseness that is similar to paste, gel, ointment etc., for example flows but the viscous liquid that do not leak.Therefore,, compositions has " being fit to use " when being said to be during to the viscosity of skin surface, this means that compositions has sufficiently high viscosity so that compositions does not come off from skin basically after being administered on the skin, and having enough low viscosity on skin so that it can be sprawled easily.Satisfy this definition range of viscosities can for from about 100cP to about 3,000,000cP (centipoise), and more preferably be from about 1,000cP is extremely about 1,000,000cP.

[0037] in some embodiments of the present invention, it may be gratifying that other reagent or material are joined in the preparation so that viscous characteristics raising or that increase to be provided.Other viscous agent or material can be other non-volatile solvents or other coagulant.The non-limiting example that can be used as the material of other tackify reagent comprises the copolymer of methyl vinyl ether and maleic anhydride (Gantrez polymer), Polyethylene Glycol and polyvinylpyrrolidone, gelatin, low-molecular-weight polyisobutylene rubber, alkyl acrylsan/ octyl acrylamide base co-polymer (acrylsanalkyl/octylacrylamido) (Dermacryl 79), and various group aliphatic resin and aromatic resin.

[0038] when being used about viscosity preparation of the present invention, term " can be washed " or " removing by washing " is meant, the viscosity preparation is used the removed ability of cleaning solvent by the washing force that adopts normal or moderate.Remove the required power of preparation by washing and should not cause tangible skin irritation or wearing and tearing.Generally speaking, the soft suitable cleaning solvent of washing force concomitant administration is enough to remove viscosity preparation disclosed herein.It is numerous can being used to by washing the solvent that preparation of the present invention removes, but preferably is selected from common acceptable solvent, and it comprises the volatile solvent that this paper is listed.The preferred not obvious irritate human skin of cleaning solvent and can be used for common object usually.The example of cleaning solvent includes but not limited to water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol or its combination.In aspect of the present invention, cleaning solvent can be selected from water, ethanol, isopropyl alcohol or its combination.Surfactant is also in some embodiments available.

[0039] term " drying time " or " acceptable time length " are meant, under the skin of standard and environmental condition and adopt standard method of test, preparation forms the neatly time that coagulation surface spent of (non-messy) after on being applied to skin.Should be noted that word " drying time " in this application is not to mean the time that volatile solvent (multiple solvent) is spent that evaporates fully.On the contrary, it is meant and forms the above-mentioned clean and tidy time that coagulation surface spent.

[0040] " standard skin " be defined as surface temperature about 30 ℃ to about 36 ℃ dry healthy application on human skin.It is 20% to 80% that the standard environment condition is defined as 20 ℃ to 25 ℃ temperature range and relative humidity scope.Term " standard skin " does not limit skin type or the skin condition that preparation of the present invention can be used by any way.Preparation of the present invention can be used to treat all types of " skins ", comprises unmarred skin (standard skin), ill skin or the skin of damage.Can use preparation for treating of the present invention although have the skin condition of different qualities, the use of term " standard skin " only is used as the standard of the compositions of the various embodiments of test the present invention.As the problem of reality, also can on skin ill or damage, do well at the preparation of do well on the standard skin (as solidifying, provide the effective flux of treatment etc.).

[0041] " standard method of test " or " standard test condition " is as follows: use the viscosity coagulation agent layer of about 0.1mm and measure drying time on the standard skin under the standard environment condition.Be defined as preparation drying time and form the required time of clean and tidy surface so that preparation does not have missing mass by adhering on a slice 100% cotton, described cotton with about 5 to about 10g/cm ²Pressure by on dosage surface, continuing 5 seconds.

[0042] " solidification layer " is described in the solidification layer that at least a portion volatile solvent system has been evaporated back viscosity coagulation agent.Solidification layer keeps sticking on the skin, and preferably can keep reaching whole basically using the persistent period with good contact of subject's skin under the skin of standard and environmental condition.Solidification layer preferably also shows enough tensile strength, so that it can peel off (opposite with the layer with more weak tensile strength, it is broken into many small pieces or chip when from skin removed) from skin with a slice or a few sheet when using end.

[0043] as used herein, for simplicity, during multiple medicine, chemical compound and/or solvent can be listed in and enumerate jointly.Yet these are enumerated and should be interpreted as, as each member in enumerating as independent and unique member by individual recognition.Therefore, under situation about not pointing out on the contrary, only appear in the common set based on them, the separate member in this enumerating should not be construed as the actual equivalent of any other member in same the enumerating.

[0044] form of scope can be expressed or be expressed as to concentration, amount and other numeric data in this article.Be to be understood that, this range format is just used for convenience and succinctly, and therefore should be interpreted as neatly, not only comprise range boundary clearly the statement numerical value, and comprise all single numerical value or subranges that this scope comprises, stated clearly as each numerical value and subrange.As an example, the numerical range of " about 0.01 to 2.0mm " should be interpreted as, and not only comprises the extremely about 2.0mm of the about 0.01mm of numerical value of clearly statement, and comprises single value and subrange in the described scope.Therefore, be included in this numerical range be single value as 0.5,0.7 and 1.5 and subrange as 0.5 to 1.7,0.7 to 1.5 and from 1.0 to 1.5 etc.Same principle is applicable to the scope of only stating a numerical value.And not how are the width of scope tube and described feature, and this explanation all should be suitable for.

[0045] according to this point, the spray agent that is used for delivering drugs can comprise medicine, comprise non-volatile solvents system, coagulant and the propellant of at least a non-volatile solvents.Preparation can have such initial viscosity, described viscosity is suitable for being pushed out from pressurizing vessel or manual pump container and being applied to skin surface as layer, and further, preparation can also form solidification layer on skin surface after at least a portion propellant is evaporated.

[0046] in another embodiment, the percutaneous drug delivery method can comprise to skin surface injection viscosity coagulation agent.Said preparation can comprise medicine, can make drug flow logical non-volatile solvents, coagulant and propellant.Said preparation can have such initial viscosity, and described viscosity is suitable for it and is discharged from and is applied to skin surface as layer from pressurizing vessel.Other step comprise by be evaporated to the small part propellant make preparation solidify with form solidification layer on the skin surface and in the time period that continues with the treatment effective speed from solidification layer dermal delivery medicine to skin surface.

[0047] therefore, these embodiments illustrate the present invention who relates to novel formulation, method and solidification layer.Preparation can be ejected on the skin surface, form solidification layer, described solidification layer can be apace (under standard skin and the environmental condition from 15 seconds to about 4 minutes) become solidification layer to medium (under standard skin and environmental condition from about 4 to about 15 minutes) apace, as strippable agglutinating and pliable solid layer randomly, be used for delivering drugs.Thus the solidification layer of Xing Chenging can the persistent period section as 30 minutes in tens hours, with the treatment effective speed, deliver drugs into skin, enter in the skin or pass skin etc., after forming solidification layer, sent so that will be delivered to most of active medicine of object.

[0048] in addition, usually adhere on the skin by the formed solidification layer of preparation of the present invention, and has the minimum adherent outer surface that solidifies, it relatively promptly forms after using, and it is not transferred to or otherwise make dirty clothes or object is dressed or solidification layer may contact unintentionally other object basically.Solidification layer can also be prepared, and makes its highly flexible and extensible, and therefore, even skin is stretched during body kinematics, also can keep and the skin surface excellent contact, as locating at knee joint, finger, elbow, other joint, lip etc.

[0049] in order to use spraying coagulation agent of the present invention, user is ejected into skin surface with preparation.Preparation forms thin wettable layer on skin surface.When propellant (with optional volatile solvent (multiple solvent)) evaporation, preparation is frozen into thin, nonrigid, agglutinating, softish, successive and/or preferably resilient solid layer.Solid layer has and enough bonding of skin surface, so that it can keep reaching the long time of expectation with the skin surface excellent contact, is generally several hrs to tens hour.Because the non-volatile solvents system does not evaporate and be designed to provide medicine to pass the enough flux of skin surface, medicine can from solidification layer be delivered to the skin surface continuously or pass skin surface reach the lasting time period or use basically during the whole persistent period.

[0050] when the various compositions of selecting to be used such as medicine, non-volatile solvents system, coagulant (multiple coagulant), propellant etc., various considerations can be suitable for.For instance, propellant can be selected from the pharmacy known in the art or make up and go up acceptable solvent, uses to be used for pressure atomization.The example of the propellant that can be used comprises hydrofluoroalkane (hydrofluorocarbon), hydrogen chlorofluoromethane (hydrochlorofluorocarbon), ether or alkane.More specifically, they include but not limited to: propane, butane, iso-butane, pentane, isopentane, diethyl ether, dimethyl ether, 1,1-Difluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, 1,1,1,3,3,3-HFC-236fa, vinyl chloride, compression arbon dioxide, compressed nitrogen or its combination.Propellant can be dissolved in the preparation, as separating mutually or being present in as suspended phase in the remainder of preparation, be present in (type of bag in jar) lining, independent chamber or be present in the independent interval and and mix, to provide propulsive force in time of application with the remainder of preparation.For most of preparations, the percentage by weight of propellant can be for from about 4wt% to about 90wt%, and more preferably be to about 60wt% from about 10wt%.

[0051] some embodiments of the present invention also can comprise volatile solvent.The example of the volatile solvent that can be used includes but not limited to: isoamyl acetate, denatured alcohol, methanol, propanol, chlorobutanol, Oleum Terebinthinae, D5 (cytopentasiloxane), cyclomethicone, butanone, ethanol, isopropyl alcohol, water, ethyl acetate, acetone or its combination.In the time of in being included in preparation, these volatile solvents should be selected with compatible with the remainder of preparation.When being used, expectation be that the volatile solvent of suitable weight percentage (multiple solvent) is present in the preparation.Too many volatile solvent system prolongs drying time.

[0052] the non-volatile solvents system can also be selected or preparation, with compatible with coagulant, medicine, propellant and any other composition that may exist.For instance, coagulant can be selected, to such an extent as to it can disperse in the non-volatile solvents system or be solvable.Most of non-volatile solvents system as a whole will preparation suitably after test.For instance, some drugs has good dissolubility in the Polyethylene Glycol (PEG) (PEG400, non-volatile solvents) of molecular weight 400, but has poor dissolubility in glycerol (non-volatile solvents) and water (volatile solvent).Yet PEG400 is dissolve polyvinyl alcohol (PVA) effectively, and therefore can not be compatible well with coagulant PVA separately.For the active medicine that dissolves capacity and use PVA simultaneously as coagulant, comprise that the PEG400 of proper ratio and the non-solvent system of glycerol (compatible with PVA) can be prepared, realize that the compatibility is compromise.As the further example of the compatibility, when span 20 is formulated into the coagulation agent that comprises PVA, observe the incompatible of non-volatile solvents/coagulant.Under this combination, span 20 can be separated from preparation and form oil reservoir on the solidification layer surface.Therefore, suitable coagulant/non-volatile solvents is chosen in feasible preparation of exploitation and the compatible combination and expects.

[0053] in further detail, the non-volatile solvents (multiple solvent) that can be used alone or in combination to form the non-volatile solvents system can be selected from acceptable liquid in the multiple pharmacy.In one embodiment, the non-volatile solvents system can comprise glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, triethanolamine, tromethane, triacetin (glyceryl triacetate), Span-20, sorbitan monooleate, sorbitan monopalmitate, butanols or its combination.In another embodiment, the non-volatile solvents system can comprise benzoic acid, butanols, dibutyl sebacate, diglyceride, dipropylene glycol, acetaminol, fatty acid such as Oleum Cocois, fish oil, Petiolus Trachycarpi oil, Oleum Vitis viniferae, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglyceride, sorbitol anhydride fatty acid surfactant, triethyl citrate or its combination.In further embodiment; the non-volatile solvents system can comprise 1; 2; the 6-hexanetriol; the alkyl triol; alkyl diol; glyceryl monoacetate; tocopherol; the alkyl dioxolanes; the anethole; Oleum Anisi Stellati; almond oil; the isosorbide dimethyl ester; alkyl androstanediol; benzyl alcohol; Cera Flava; benzyl benzoate; butanediol; caprylic/capric triglyceride; caramel; Oleum Cinnamomi; Oleum Ricini; cinnamic aldehyde; Oleum Cinnamomi; Oleum Caryophylli; Oleum Cocois; cocoa butter; cocoa glyceride (cocoglycerides); Fructus Coriandri oil; Semen Maydis oil; Fructus Coriandri oil; corn syrup; Oleum Gossypii semen; cresol; cyclomethicone; Glycerine 1,3-diacetate; the diacetylation glyceryl monoacetate; diethanolamine; diethylene glycol one ether; diglyceride; ethylene glycol; Eucalyptus oil; fat; aliphatic alcohol; spice; liquid sugar; Rhizoma Zingiberis Recens extract; glycerol; high-fructose corn syrup; castor oil hydrogenated; IP cetylate (IP palmitate); Fructus Citri Limoniae oil; white lemon oil limonene; milk; monoacetin; glyceryl monoacetate; Semen Myristicae oil; octyl dodecanol; olivetol; orange oil; Petiolus Trachycarpi oil; Oleum Arachidis hypogaeae semen; the Polyethylene Glycol vegetable oil; Oleum menthae; vaseline; phenol; pinke needle oil; polypropylene glycol; Oleum sesami; Oleum menthae; soybean oil; vegetable oil; vegetable shortenings; vinyl acetate; wax; 2-(2-(octadecane oxygen base) ethyoxyl) ethanol; benzyl benzoate; Butylated hydroxyanisole; candelilla wax; Brazil wax; ceteareth-20 (ceteareth-20); hexadecanol; polyglycereol (polyglycery); two multi-hydroxy stearic acid esters (dipolyhydroxy stearate); Polyethylene Glycol-7-castor oil hydrogenated; diethyl phthalate; ethyl sebacate; dimethicone (dimethicone); dimethyl phthalate; cithrol such as polyglycol distearate; polyethylene glycol (PEG) oleate; polyethylene glycol laurate; polyethylene glycol fatty acid diester such as Polyethylene Glycol dioleate; polyglycol distearate; Polyethylene Glycol Oleum Ricini behenic acid glyceride; polyethylene glycol glycerol fatty acid ester such as Polyethylene Glycol glyceryl laurate ester; the Polyethylene Glycol tristerin; the Polyethylene Glycol olein; hexene glycerol (hexyleneglycerol); lanoline; the lauric acid diethanolamine; Lauryl lactate; lauryl sulfate; medronic acid; methacrylic acid; many sterin extract (multisterol extract); tetradecyl alchohol; neutral oil; Polyethylene Glycol octyl group phenylate; Polyethylene Glycol-alkyl ether such as Polyethylene Glycol cetyl ether; the Polyethylene Glycol stearyl ether; polyethylene glycol sorbitan fatty acid esters such as Polyethylene Glycol anhydrous sorbitol diisopstearate; the Polyethylene Glycol sorbitan monostearate; methyl glycol fatty acid ester such as propylene glycol stearate; propylene glycol caprylate/decanoin; pyrrolidone sodium carboxylate; sorbitol; Squalene; stear-o-wet; triglyceride; alkyl aryl polyether alcohol; the polyoxyethylene deriv of anhydrous sorbitol ether; saturated polyglycolysed C8-C10 glycerol; N-Methyl pyrrolidone; Mel; polyoxy ethylization glycerol; dimethyl sulfoxide; azone and related compound; dimethyl formamide; the N-methylformamide; fatty acid ester; fatty alcohol ether; alkylamide (N, N-dimethyl alkylamide); the N-Methyl pyrrolidone related compound; ethyl oleate; the bound to polyglycerol fatty acid; glyceryl monooleate; single myristin; the glyceride of fatty acid; the aminoacid of silk; PPG (polypropylene glycol)-3 methyl benzyl ether. myristinate (PPG-3benzyl ether myristate); two PPG-2 Semen Myristicae oleyl alcohol polyethers-10 adipate esters (Di-PPG2 myreth 10-adipate); Mel Moisture factor (honeyquat); sodium pyroglutamate; Caulis et Folium Brassicae capitatae oil (abyssinica oil); dimethicone; macadimia nut oil; Bai Manghua seed oil (limnanthes alba seed oil); cetearyl alcohol (cetearyl alcohol); Polyethylene Glycol-50 shea oil; shea oil; Aloe juice; Silicone DC 556; hydrolyzed wheat protein or its combination.In still further embodiment, the non-volatile solvents system can be included in the combination or the mixture of non-volatile solvents system described in any embodiment discussed above.

[0054] except these and other consideration, plasticizer also can serve as in the non-volatile solvents system in the viscosity preparation, makes that this layer is flexible, extensile and/or is " skin-friendly " in addition when forming solidification layer.

[0055] some composition of possibility chafe may be expected to be employed to realize the dissolubility and/or the permeability of medicine expectation in the preparation.Under those situations, expectation adds can prevent or reduce the chemical compound that skin irritation again can be compatible with preparation.For instance, in the preparation of propellant chafe, it will be useful that use can reduce skin irritant non-volatile solvents.The known example that can prevent or reduce skin irritant solvent includes, but not limited to glycerol, Mel and/or propylene glycol.

[0056] preparation of the present invention also can comprise two or more non-volatile solvents, and it is respectively the non-volatile solvents that does not make drug flow logical, but the part as system becomes the non-volatile solvents that can make circulation when being prepared together.The possible reason that these original non-non-volatile solvents that make circulation become the non-volatile solvents that can make circulation when being prepared together may be to have more high-throughout physical form because the ionization state of medicine is optimized to, perhaps alternatively, other cooperative mode plays a role non-volatile solvents with some together.The blended further benefit of non-volatile solvents is, it can optimize the pH of preparation or the skin histology under the ghe layer so that stimulate and minimize.The example that produces the non-volatile solvents appropriate combination of the enough non-volatile solvents systems of some drugs includes but not limited to: isostearic acid/triethanolamine, isostearic acid/diisopropylamine, oleic acid/triethanolamine, propylene glycol/isostearic acid.

[0057] selection of coagulant (multiple coagulant) be it is also conceivable that other one-tenth that exists assigns to carry out in the viscosity preparation.Coagulant can be selected or preparation with medicine and propellant and non-volatile solvents system (with randomly, be not other volatile solvent of propellant) compatible, and the physical characteristic that expectation is provided for it when solidification layer forms.Depend on medicine, solvent and/or other composition that may exist, coagulant can be selected from plurality of reagents.In one embodiment, coagulant can comprise that MW (molecular weight) scope is 20,000-70,000 polyvinyl alcohol (Amresco), the MW scope is 80,000-160, the ester of polyvinyl methyl ether/copolymer-maleic anhydride of 000 (ISP Gantrez ES-425 and Gantrez ES-225), the MW scope is 120,000-180,000 the butyl methacrylate and the neutral copolymer of methyl methacrylate (Degussa Plastoid B), the MW scope is 100,000-200, dimethylaminoethyl methacrylate-butyl methacrylate of 000-methylmethacrylate copolymer (Degussa EudragitE100), MW is 5, more than 000 or the muriatic copolymer (Degussa) of MW and the similar ethyl acrylate-methyl methacrylate of Eudragit RLPO-methacrylic acid front three amino ethyl ester, MW is 5, Zein more than 000 (prolamine) as MW greatly about 35,000 Zein (Freeman industries), pregelatinized Starch (Grain Processing Corporation) with the MW that is similar to Instant Pure-Cote B793, MW is 5, more than 000 or MW be similar to Aqualon EC N7, N10, N14, N22, the ethyl cellulose of N50 or N100 (Hercules), MW20,000-250,000 fish glue (Norland Products), gelatin, MW is 5, other animal origin more than 000, MW is more than 5,000 or MW is similar to acrylate/octyl acrylamide copolymer of NationalStarch and Chemical Dermacryl 79.

[0058] in another embodiment, coagulant can comprise ethyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, methylcellulose, polyetheramides, corn starch, pregelatinized corn starch, polyetheramides, lac, polyvinylpyrrolidone, Oppanol, poly-phthalic acid vinyl acetate or its combination.In further embodiment, coagulant can comprise ammonium methacrylate (ammonia methacrylate), chondrus ocellatus Holmes, the cellulose acetate-phthalate aqueous solution is as the CAPNF from Eastman, carbopol (carboxy polymethylene), cellulose acetate (microcrystal), cellulosic polymer, divinylbenzene-styrene, ethylene vinyl acetate, silicones, guar gum, melon Colophonium, glutelin, casein, calcium caseinate, eucasin, casein sidium, potassium caseinate, acrylic acid methyl ester., microwax, polyvinyl acetate, the polyvinylpyrrolidone ethyl cellulose, acrylate, Polyethylene Glycol/polyvinylpyrrolidone (PEG/PVP), Xanthan gun, siloxy silicic acid trimethyl, maleic acid/acid anhydride copolymer, bohr Acree woods, poloxamer, polyethylene glycol oxide, polylactic acid/poly--1-lactic acid, terpene resin (turpene resin), locust bean gum, acrylic copolymer, dispersions of polyurethanes, dextrin, the polyvinyl alcohol-polyethylene glycol copolymer, EUDRAGIT L100-55 is as the Kollicoat polymer of BASF, methacrylic acid and methacrylate based polymer such as polymethylacrylic acid or its combination.In another embodiment, coagulant can comprise any above-mentioned combination that coagulant described in the embodiment is discussed.Other polymer also can be suitable as coagulant, and this depends on solvent (multiple solvent), medicine and the specific function requirement of giving customization agent.Other polymer also can be suitable as coagulant, and this depends on solvent (multiple solvent), medicine and the specific function requirement of giving customization agent.

[0059] in one embodiment, non-volatile solvents and coagulant (multiple coagulant) should be compatible mutually.The compatibility can be defined as: i) coagulant does not have a negative impact to the function of non-volatile solvents system basically, except some minimizing of flux; Ii) coagulant can remain on the non-volatile solvents system in the solidification layer, and making does not have non-volatile solvents to ooze out this layer basically; And/or the solidification layer that iii) forms with selected non-volatile solvents system and coagulant has acceptable pliability, hardness, tensile strength, elasticity and to the viscosity of skin.The weight ratio of non-volatile solvents system and coagulant (multiple coagulant) can be the extremely about 10:1 of about 0.1:1.On the other hand, the weight ratio of non-volatile solvents system and coagulant can be the extremely about 4:1 of about 0.2:1, and more preferably, from the extremely about 2:1 of about 0.5:1.

The pliability and the extensibility of [0060] solidification layer---it randomly also is a skin (peel)---can be gratifying in some applications.For instance, some non-steroidal anti-inflammatory agent (NSAIDs) can directly be ejected on joint and the muscle to be formed for the solidification layer to joint and muscle transdermal administration.Yet the skin area on joint and some muscle group is often stretched during body kinematics significantly.This motion overslaugh not the extensibility patch keep good contact skin.For above-mentioned reasons, lotion, ointment, emulsifiable paste, gel, foam, patch or analog also can be not suitable for using.So, in joint and/or muscle percutaneous dosing, spraying coagulation agent of the present invention can provide unique advantage and benefit at NSAIDs.Can expect in some applications that although should be pointed out that good extensibility spraying coagulation agent of the present invention always need not be extensile, because some application of the present invention must not have benefited from this character.

[0061] the further feature of prepared preparation relates to drying time according to the embodiment of the present invention.If preparation is dry too slowly, restarting normal activity (for example wearing the clothes)---before it may remove not solidified preparation, object may must wait as long for.Therefore, be shorter than about 15 minutes the drying time of expectation, preferably be shorter than 3 minutes, and more preferably be shorter than 1 minute.

[0062] other benefit of solidification layer of the present invention comprises the physical barriers that existence can be formed by solidification layer itself.Under some diseases or degree of impairment, skin surface is responsive to the contact of foreign body, perhaps the attack of being infected easily when the contact foreign body.Under those situations, solidification layer can provide physical protection to skin surface.For instance, local anesthetic can be by topical with the relevant pain of treatment neuropathy, as diabetic neuropathic pain with other medicament such as clonidine.Because many such objects are felt huge pain, even when their skin area just was touched gently, therefore, the physical barriers of solidification layer can prevent or minimize with object or other thing accident and contact caused pain.

[0063] another advantage of spray agent of the present invention is, they can be used skin surface, and does not need contact or wiping skin surface.For instance, as implied above, stand the object of neuropathic pain and often feel pain, even when skin area just is touched gently, as be applied device or user (applicator) contact.The spray application of coagulation agent allows the drug administration chemical preparation, and does not need contact or wiping skin.For instance, the comparable traditional semi-solid preparation of spraying coagulation agent that is used for the treatment of bald corticosteroid more easily has been administered to some The scalp with hair zones.Wherein another example that spray application can be favourable is aspect damage or skin infection.Object with damage or skin infection or tissue may not be stood the relevant pain of non-spray agent.In addition, when preparation needed object physics contact damage or skin infection, newly infecting or increasing the risk that infects also increased.

[0064] compare with available " spray preparations (spray formulations) " or " semisolid " preparation at present, spray agent (spray-on formulations) can provide other important advantage.When comparing with other spray agent, can holding more from the solidification layer of the present invention of spraying coagulation agent formation, the medicine of a large amount continues longer administration.When comparing with traditional semi-solid preparation, sprayable coagulation agent of the present invention can be used easilier or can be applied and contacts with skin surface without application equipment such as spatula.The skin surface that preparation of the present invention can be applied includes but not limited to: skin, the mucomembranous surface of lip, genitals and anus, nail surface, wound surface, the ulcer skin surface that decubital ulcer surface and diabetes cause.

[0065] the invention provides use coagulation agent that combination has the liquefaction propellant make things convenient for mode, with the uniform solidified layer of easy formation, it will keep and use the site and contact closely and provide the active medicine medicine to send.This need use the capacity preparation to the per unit area skin surface, so that solidification layer can contain the medicine of capacity.For most of medicine, solidification layer need 0.01mm be thick at least, and preferably 0.05mm is thick at least.

[0066] these advantages and other advantage can be summarised in during following indefiniteness benefit enumerates.Preparation can be sprayed on the skin surface easily, and does not need to contact skin surface---and it can cause pain or infection that should the zone.Solidification layer comprises the non-volatile solvents system that can make this medicine circulation, so that medicine can be sent in the persistent period section to treat effective speed.In addition, because solidification layer keeps the viscosity of skin and preferably peelable, the easy removal of solidification layer can take place, and can not have the auxiliary generation down of solvent or surfactant.In some embodiments, to the elasticity of the viscosity of skin and material so so that stretch the after coagulation layer in the extensible skin area of height such as joint with skin on the muscle and will can not separate with skin.For instance, in one embodiment,, and do not break, rupture and/or separate with skin surface that this layer is applied even solidification layer can be at least one direction be stretched 5% 10% or bigger.Further, solidification layer can be by preparation with administration advantageously and protection sensitive skin zone.

[0067] in one embodiment of the invention, when the administration of expectation finished, solidification layer can be washed off with solvent such as water or ethanol.Other solvent that also can be used for washing off coagulation agent includes but not limited to the volatile solvent that this paper is listed.By washing that removed ability uses for some is particularly advantageous.For instance, if coagulation agent be applied to skin surface with many hairs (as, the coagulation agent of anti-genital herpes is applied to the genital skin zone that has pubes), therefore may cause discomfort and do not expect by peeling off removal, therefore, washing can be preferred removing method in the using of this form.In another example, if coagulation agent is injected into palm surface as the palm of hands or the sole of foot, may be second Consideration to the preparation that will adhere to skin surface by the ability of peeling off removal.In these cases, being configured to easily the solidification layer of being washed off by water or ethanol can more expect.In the washing embodiment, the solvent that is used to wash off solidification layer can dissolve this layer or make the viscosity step-down of this layer to skin, so that it can be removed from skin easily.This point is described, should be noted that in some embodiments, solidification layer can be strippable be again rinsable.

[0068] in another embodiment, the viscosity that coagulation agent has makes it can be disperseed (aerosol or pump spraying) from the container that has the control of dosing or volume, makes that the coagulation agent of controlled quentity controlled variable is disperseed.Preparation comprises the composition described in the above-mentioned embodiment.Amount averted dose deficiency or the dosage of controlling dispersive preparation are excessive---and they can cause not desired therapeutic effect and/or disadvantageous side effect.

[0069] in another embodiment of the present invention, the system with two compositions comprises having makes it can be from the coagulation agent of the dispersed viscosity of pressurizing vessel, and pressurizing vessel.Preparation comprises coagulant, at least a non-volatile solvents, medicine, propellant and volatile solvent system randomly.In case preparation is injected on the skin surface and after propellant and optional volatile solvent (multiple solvent) evaporate, preparation will form the administration solidification layer that can be removed easily after the use on the skin.In this and other embodiment, used not long ago, the aerosol container that comprises preparation and propellant can be vibrated so that the remainder of propellant and preparation is mixed into temporary transient suspension, and it has the suitable viscosity that is sprayed on the skin surface.In case be applied and after propellant and optional volatile solvent (multiple solvent) evaporation, preparation forms the administration solidification layer on skin, it can easily be removed after use.Alternatively, pressurizing vessel can comprise and causes that propellant mixes the mechanism be discharged to the mixture on the skin surface from container to form with the remainder of preparation.In case be applied and after propellant and optional volatile solvent (multiple solvent) evaporation, preparation forms the administration solidification layer on skin, it can be removed after use easily.

[0070] in another embodiment, the viscosity that has of coagulation agent can be disperseed it from manual pump automiser spray or conventional pump automiser spray.Preparation comprises coagulant, non-volatile solvents system, medicine and volatile solvent (multiple solvent) randomly.Pharmaceutical preparation has suitable viscosity, so that it can easily be pushed out and be applied to skin surface from the manual pump automiser spray.After using, said preparation will form the administration solidification layer on skin, and it can be removed after use easily.

[0071] as further shown, the specific characteristic of solidification layer of the present invention is, they can keep a large amount of non-volatile solvents systems on skin surface, and it is optimized for administration.Compare with existing product, this feature can provide unique advantage.For instance, in some semi-solid preparations, be administered on the skin surface after, volatile solvent evaporates rapidly and ghe layer is solidified into hard lacquer sample layer.Drug molecule is fixed in the hard enamelled coating and can not be used to basically and is delivered in the skin surface.The result is to think that not sending of medicine continued in long-time section.Opposite with this type preparation, keep drug molecule in the non-volatile solvents system that contacts with skin surface, suitable flowability to be arranged with the formed solidification layer of preparation of the present invention, therefore guarantee to continue to send.

[0072] instantiation of the application that can benefit from system of the present invention, preparation and method is as follows.In one embodiment, solidification layer can comprise bupivacaine, lignocaine, tetracaine and/or ropivacaine, and can be used for the treatment of diabetes and postherpetic neuralgia by preparation.Alternatively, Cinchocaine (dibucanine) and α-2 agonist such as clonidine can be formulated in and be used for the treatment of same disease in the coagulation agent.In another embodiment, tretinoin and benzoyl peroxide can be combined in and be used for the treatment of acne in the solidification layer, or alternatively, 1wt% clindamycin and 5wt% benzoyl peroxide can be combined in alternatively and be used for the treatment of acne in the solidification layer.In another embodiment, retinol coagulation agent (OTC) can be produced and be used for the treatment of wrinkle, and perhaps the lignocaine coagulation agent can be produced to be used for the treatment of and have a back ache.In another embodiment, zinc oxide coagulation agent (OTC) can be produced and be used for the treatment of diaper rash (the counterirritation urine that solidification layer provided and the physical barriers of excrement are considered to favourable), and perhaps the hydryllin solidification layer can be produced and be used for the treatment of allergic rash such as by the caused allergic rash of poison ivy.

[0073] other application comprises and is administered for some dermatosis of treatment, as dermatitis, psoriasis, eczema, skin carcinoma, bald, wrinkle, viral infection as flu rash, genital herpes, herpes zoster etc., especially occur in transdermal patch may unpractical joint or muscle on those diseases.For instance, the coagulation agent that comprises imiquimod can be used for the treatment of the skin of skin carcinoma, premature aging, the skin of photic damage, common wart and genital wart and actinicity seborrheic keratosis by preparation.The coagulation agent that comprises antiviral drugs such as acycloguanosine, penciclovir, famciclovir, valaciclovir, steroid and/or behenyl alcohol can be used for the treatment of flu rash on herpesvirus infection such as face and the genital area by preparation.The coagulation agent that comprises non-steroidal anti-inflammatory agent (NSAIDs), capsaicin, α-2 agonist and/or nerve growth factor can be used for the treatment of soft tissue injury and muscle-skeleton pain by preparation, as the arthralgia and the backache of a variety of causes.As discussed above, the patch on these skin areas does not generally have excellent contact in the persistent period section, especially for the object of body movement, and can cause discomfort.Equally, traditional semi-solid preparation such as emulsifiable paste, lotion, ointment etc. may be because the not inadvertently removals of the evaporation of solvent and/or preparation and stop administration prematurely.Coagulation agent of the present invention has solved the shortcoming of these two types of drug-supplying systems.

[0074] a kind of embodiment can need to comprise the solidification layer from the medicine of α-2 antagonist kind, its by external application with the treatment neuropathic pain.α-2 agonist discharges to provide pain relief in the persistent period section from preparation gradually.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 5 minutes, be generally several hrs to tens hour.Solidification layer is removed after intended use easily, and does not stay residual agent at skin surface.

[0075] another embodiment relates to the coagulation agent that comprises capsaicin, its by external application with the treatment neuropathic pain.Capsaicin progressively discharges from said preparation and is used in persistent period this pain of section internal therapy.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 5 minutes.Its random time after drying can easily be removed, and does not stay residual agent at skin surface.

[0076] another embodiment relates to the coagulation agent that comprises clobetasol propionate, its by external application with treatment hand dermatitis.Clobetasol propionate progressively discharges from preparation and is used in persistent period section internal therapy dermatitis.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 3 minutes.Physical barriers also protects the skin of infringement to avoid potential harmful substance.Its random time after drying can easily be removed, and does not stay residual agent at skin surface.

[0077] another embodiment relates to the coagulation agent that comprises clobetasol propionate, and it is bald to treat by external application.Clobetasol propionate progressively discharges from preparation and is used for promoting hair growth in the persistent period section.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 5 minutes.Its random time after drying is washed and can easily be removed by peeling off to watering.

[0078] another embodiment relates to the coagulation agent that comprises tazorac, is used for the treatment of flexible stricture of vagina (striae gravidarum, stretch mark), wrinkle, sebaceous hyperplasia or seborrheic keratosis disease.

[0079] in another embodiment, the coagulation agent that comprises glycerol can be produced to provide finger tip fissured protective barrier.

[0080] another embodiment can comprise comprising and is selected from local anesthesia class medicine and comprises lignocaine and ropivacaine etc., or the coagulation agent of NSAID class such as ketoprofen, piroxicam, diclofenac, indomethacin etc.These medicines can be by the symptom of external application with treatment backache, muscular tone and/or myofascial pain.Local anesthetic and/or NSAID progressively discharge to provide pain relief in the persistent period section from preparation.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 3 minutes.Its random time after drying easily is removed, and does not stay residual agent at skin surface.

[0081] further embodiment relates to the coagulation agent that comprises at least a α-2 agonist medicine, at least a tricyclic antidepressants and/or at least a local anesthetic, its by external application with the treatment neuropathic pain.Medicine (multiple medicine) progressively discharges so that provide pain relief in the persistent period section from preparation.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 3 minutes.Its random time after drying can easily be removed, and does not stay residual agent on skin surface.

[0082] similarly embodiment can comprise the coagulation agent that comprises medicine capsaicin and local anesthetic, its by external application to the skin so that pain relief to be provided.Another embodiment can comprise the coagulation agent of the combination that comprises local anesthetic and NSAID.In above-mentioned two kinds of embodiments, medicine progressively discharges so that provide pain relief in the persistent period section from preparation.Preparation can become agglutinating soft solid and maintenance and adhere to skin surface and reach the time span that it is used in about 3 minutes.Its random time after drying is easily removed, and does not stay residual agent on skin surface.

[0083] in another embodiment, the coagulation agent that is used for delivering drugs also can be benefited from system of the present invention, preparation and method, and described medicine is used for the treatment of the cause of disease or the symptom of the disease that relates to joint and muscle.These diseases that may be suitable for include but not limited to: joint and skeleton pain, myofascial pain, myalgia and the athletic injury of osteoarthritis (OA), rheumatic arthritis (RA), various other reasons.The medicine or the medicament categories that can be used to this application include but not limited to: NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is as ketoprofen and diclofenac, COX-2 selective N SAIDs and medicament, COX-3 selective N SAIDs and medicament, local anesthetic such as lignocaine, bupivacaine, ropivacaine and tetracaine and steroid such as dexamethasone.

[0084] administration that is used for the treatment of acne and other dermatosis also can have benefited from principle of the present invention, especially when sending the medicine with low percutaneous permeability.At present, local external use's biostearin, peroxide and the antibiotic major part that is used for the treatment of acne is applied as traditional semi-solid gel or emulsifiable paste.Yet because above-mentioned shortcoming, it is impossible continuing to send in many hours.For instance, only when q.s was delivered in the hair follicle, clindamycin, benzoyl peroxide and erythromycin just may be effectively.Yet traditional semi-solid preparation such as common acne medicine benzaclin gel lose its most of solvent (being water under the situation at benzaclin) usually in a few minutes after using.May damage basically a few minutes in this short period medicine continue send.Preparation of the present invention does not generally have this restriction.

[0085] in another embodiment, the sending also of medicine that is used for the treatment of neuropathic pain can be benefited from method of the present invention, system and preparation.The patch such as the Lidoderm that comprise local anesthetic ^TMBe widely used in treating neuropathic pain, as the caused pain of postherpetic neuralgia.Because as the restriction of the above-mentioned patch of discussing, prepared solidification layer provides some unique benefits according to the present invention, and provide the potential cheap optional mode of using patch.Sending the possible medicine that is used for these application includes but not limited to: local anesthetic such as lignocaine, prilocaine, tetracaine, bupivacaine, clothing are for caine; And/or other medicines, it comprises capsaicin and α-2 agonist such as clonidine, dissociation anesthesia agent such as ketamine, and/or tricyclic antidepressants such as amitriptyline.

[0086] coagulation agent of the present invention can---comprise dermatitis and psoriasis and skin rehabilitation (cosmetic skin treatment) and infection---by preparation to treat various diseases and disease such as musculoskeletal pain, neuropathic pain, bald, dermatosis and comprise virus, antibacterial and fungal infection.Therefore, preparation can transmit the medicine and the activating agent of wide region quantity and type.In one embodiment, coagulation agent can be by preparation to comprise acyclovir, econazole, miconazole, terbinafine, lignocaine, bupivacaine, ropivacaine and tetracaine, amitriptyline, Ketanserine, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, retinoic acid, Accutane, clobetasol propionate, propanoic acid halogen Beta rope, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid or its combination.

[0087] in another embodiment, preparation can comprise antifungal agent such as amorolfine, butenafine, naftifine, terbinafine, fluconazol, itraconazole, ketoconazole, posaconazole, pressgang health azoles (ravuconazole), voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole (triaconazole), tioconazole, Caspofungin, Mi Kafen clean (micafungin), anidulafungin (anidulafingin), amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate and undecylenate or its combination.

[0088] in another embodiment, preparation can comprise antifungal drug such as acyclovir, penciclovir, famciclovir, valaciclovir behenyl alcohol, trifluridine, iodouracil desoxyriboside, cidofovir, ganciclovir, podofilox (podofilox), podophyllotoxin, ribavirin, Abacavir, dilazep Wei Ding (delavirdine), didanosine, Sustiva, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir (amprenavir), indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir or its combination.

[0089] when preparation is intended to antibacterial therapy is provided, it can be by preparation to comprise antimicrobial drug such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciprofloxacin (ciproflaxin) or its combination.

[0090] be intended to ease the pain when preparation, especially during neuropathic pain, preparation can comprise local anesthetic such as lignocaine, bupivacaine, ropivacaine and/or tetracaine; And/or α-2 agonist such as clonidine.When preparation is intended to treat inflammation when ache related, it can be by preparation to comprise NSAID (non-steroidal anti-inflammatory drug) such as ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitor, common COX inhibitor, COX-2 selective depressant, COX-3 selective depressant or its combination.

[0091] in another embodiment, by comprising active agent such as anti-acne medicine such as clindamycin and benzoyl peroxide; Retinol; Vitamin A derivative such as tazarotene and isotretinoin; Ciclosporin; Anthraline; Vitamin D3; Cholecalciferol; Calitriol; Calcipotriol (calcipotriol); Tacalcitol; Calcipotrienes (calcipotriene) etc., preparation can be by preparation with treatment dermatosis or damage.

[0092] still in another embodiment, the sending of medicine that is used for the treatment of wart and other dermatosis also can be had benefited from secularly continuing medication.The example of anti-wart chemical compound includes but not limited to: imiquimod, resiquimod (rosiquimod), keratolytic agent, salicylic acid, alpha hydroxy acid, sulfur, resorcinol, carbamide, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, benzoic acid or its combination.

[0093] further embodiment relates to and uses coagulation agent and carry out the administration of sex steroid, described sex steroid includes but not limited to: by progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethynodiol diacetate, norelgestromine (norelgestromin), norgestimate, levonorgestrel, the d1-norgestrel, cyproterone acetate, dydrogesterone, medroxyprogesterone, chlormadinone acetate, megestrol, promegestone, norethindrone, lynestrenol, the gestodene, the progestagen that tibolone (tibolene) is formed, by testosterone, methyltestosterone, oxandrolone, androstenedione, the androgen that dihydrotestosterone is formed, by estradiol, ethinyl estradiol, estriol (estiol), estrone, conjugated estrogen hormone, esterified estriol, the estrogen that estropipate is formed, or its combination.

[0094] non-sex steroid also can be used formulation delivered of the present invention.The example of this steroid includes but not limited to: betamethasone dipropionate, halobetasol propionate, the bisgallic acid diflorasone, triamcinolone acetonide, desoximetasone (desoximethasone), fluocinonide (fluocinonide), halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, FLUTICASONE PROPIONATE, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, the valeric acid hydrocortisone, Aclovate, neopentanoic acid flumetasone (flumethasonepivolate), hydrocortisone, hydrocortisone acetate, or its combination.

[0095] further the embodiment control that relates to nicotine is sent, and is used for the treatment of the smoker and to the people's of nicotine addiction nicotine dependence.Preparation of the present invention will be the cheap effective means of transdermal administration effective dose nicotine.

[0096] another embodiment relates to formulation delivered hydryllin such as diphenhydramine and tripelennamine.These medicaments will cause that the histamine of itching reduces by blocking-up itches, and also by providing local analgesia to provide misery to alleviate.

[0097] other medicines sent of available coagulation agent of the present invention include but not limited to: tricyclic antidepressants such as amitriptyline; Spasmolytic such as carbamazepine and alprazolam; N-methyl-D-aspartate (NMDA) antagonist such as ketamine; 5-HT2A receptor antagonist such as Ketanserine; With immunomodulator such as tacrolimus and picrolimus.The other medicines that available preparation of the present invention and method are sent comprise wetting agent, emollient and other skin nursing chemical compound.

Embodiment

[0098] following embodiment illustrates the embodiments of the present invention of having understood very much at present.Yet, be appreciated that, only be the example used of the principle of the invention below or illustrate.Those skilled in the art can design many changes and optional compositions, method and system, and do not break away from the spirit and scope of the present invention.Claims are intended to cover these changes and arrangement.Therefore, although the present invention is described in detail in the above, the following examples provide and have been considered to the most practical further details relevant with preferred implementation of the present invention at present.

Embodiment 1

[0099] pressurizing vessel of the spraying coagulation agent that is used for administration is filled in preparation, it comprises medicine (as ketoprofen, testosterone etc.), polyvinyl alcohol coagulant (31,000-50,000Mw) the ester (80 of (Amresco) and polyvinyl methyl ether/copolymer-maleic anhydride, 000-160,000Mw) the non-volatile solvents system of (Gantrez ES-425), propylene glycol and glycerol and water and alcoholic acid volatile solvent system.It is one of following at least that propellant comprises: propane, butane, iso-butane, pentane, isopentane, fluorochlorohydrocarbon, diethyl ether, dimethyl ether, 1,1-Difluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, 1,1,1,3,3,3-HFC-236fa, vinyl chloride, compression arbon dioxide, compressed nitrogen or its combination.By adding the propellant of enough concentration, container becomes inherent and pressurizes.

Embodiment 2

[0100] object will be similar to the prepared coagulation agent of embodiment 1 and be ejected on the ankle that is subjected to by damage or caused pain of arthritis or inflammation from pressurizing vessel.After propellant and volatile solvent (multiple solvent) evaporation, the coagulation agent fast setting becomes softness, bonding and the elastic solid layer of tool, and maintenance closely contacts until being removed by object with skin part.Solidification layer is sent at the ketoprofen of effective dose during at least 2 hours and on preferably will treating during at least 8 hours and is passed skin and enter in the ankle tissue, with pain management and inflammation.Non-volatile solvents (multiple solvent) also keeps solidification layer softness, bonding and tool elasticity, and the solvent of the made circulation in the solidification layer is provided, to make the ketoprofen transmission pass skin continuously not having water or have more under the situation of volatile solvent and propellant.When during being intended to use, finishing, solidification layer since its good coherency can be removed from skin.

Embodiment 3

[0101] object is ejected into the similar embodiment 1 prepared coagulation agent that comprises testosterone on its upper arm, shoulder or the abdomen area in pressurizing vessel.Coagulation agent is rapidly solidificated into solid layer after the propellant evaporation.Solidification layer is softish, agglutinating, rubber-like, and maintenance closely contacts until it with skin part and is removed.Solidification layer will be treated the testosterone of effective dose in during at least 6 hours and be sent the body circulation of passing skin and entering object.Non-volatile solvents serves as the carrier (vehicle) of sending testosterone, and also keep solidification layer softness, bonding and tool elasticity, and the solvent of the made circulation in the solidification layer is provided, pass skin under the situation that does not have water or more volatile solvents and propellant, testosterone is sent.When during being intended to use, finishing, solidification layer since its good coherency can from skin, be removed as a sheet of or a few sheet.

Embodiment 4

[0102] object is ejected on the subject's skin site of standing neuropathic pain from the coagulation agent that pressurizing vessel will comprise tetracaine.Coagulation agent comprises tetracaine alkali, Plastoid B (120,000-180, the butyl methacrylate of 000Mw scope and the neutral copolymer of methyl methacrylate) coagulant, mineral oil and isostearic acid non-volatile solvents system, GrantrezES-425 (80,000-160, the ester of the polyvinyl methyl ether/copolymer-maleic anhydride of 000Mw scope is to increase the bonding force between solidification layer and the skin) and the dimethyl ether propellant.After ghe layer was directed onto on the skin, propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.Solidification layer is delivered to tetracaine in the skin and the control neuropathic pain reaches the persistent period section.

Embodiment 5

[0103] the object aerosol container coagulation agent that will comprise ropivacaine is ejected on the subject's skin site of standing neuropathic pain.Coagulation agent comprises ropivacaine alkali, Plastoid B (120,000-180, the butyl methacrylate of 000Mw scope and the neutral copolymer of methyl methacrylate) coagulant, comprise non-volatile solvents system at least a in tetrahydroxypropyl ethylenediamine, triacetin, span 20 and the isostearic acid.Preparation can comprise that also dimethyl ether is as propellant.After ghe layer was directed onto on the skin, propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.During a period of time that continues, ropivacaine is delivered on the skin with the treatment neuropathic pain from solidification layer.

Embodiment 6

[0104] the object coagulation agent that will comprise clobetasol propionate from pressurizing vessel is ejected into object and stands bald area of scalp.Although area of scalp is treated at bald, it has some hairs, and spray agent make use simpler than using ointment, emulsifiable paste or non-spraying coagulation agent.Coagulation agent comprises clobetasol propionate, the fish glue coagulant, and the non-volatile solvents system of propylene glycol and isostearic acid is as the fumed silica (optional) of filler with as the fluorine carbon or the dimethyl ether of propellant.After ghe layer was directed onto on the skin, propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.During at least 6 hours, the clobetasol propionate of treatment effective dose is delivered to the scalp table surface from this layer, is used to promote natural on-off cycles of hair growth.After the application of intention, preparation can be washed off in shower or hair washing, because solidification layer is soluble in water.

Embodiment 7

[0105] the object coagulation agent that will comprise clobetasol propionate from pressurizing vessel is ejected on the skin of palm of hand zone that object just standing hand dermatitis.Preparation is similar to the preparation among the embodiment 6.After ghe layer was sprayed on the skin, this propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.During at least 2 hours, clobetasol propionate from then on solidification layer is delivered in the skin of palm of hand surface, is used to suppress hand dermatitis.Solidification layer has viscosity to skin and also serves as physical barriers to protect this skin away from the exterior materials that can cause or increase the weight of dermatitis.

Embodiment 8

[0106] the object coagulation agent that will comprise the antibiotic medicament from pressurizing vessel is ejected on the skin area of ulcer of decubital ulcer or diabetes-induced.Preparation comprises antibiotic, polyvinyl alcohol coagulant, glycerol volatile solvent system and 1,1,1,2,3,3,3-heptafluoro-propane (propellant) propellant.After ghe layer was directed onto on the skin, propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.The antibiotic medicament was delivered to the impaired skin surface from this layer to treat effective speed during at least 2 hours, was used for the treatment of or prevention infection.Solidification layer has viscosity to skin surface and also serves as physical barriers and contacts with the exterior object that can be caused pain away from outside pathogen to protect impaired skin area.

Embodiment 9

[0107] the object coagulation agent that will comprise clobetasol propionate from aerosol container is ejected into object and is just standing on the psoriasic skin area.Preparation comprises clobetasol propionate, polyvinyl alcohol coagulant, glycerol, propylene glycol and oleic non-volatile solvents system, Grantrez ES-425 (80,000-160, the ester of the polyvinyl methyl ether/copolymer-maleic anhydride of 000Mw scope, to increase the bonding force between solidification layer and the skin) and hydrofluoroalkane as propellant.After ghe layer was directed onto on the skin, propellant rapid evaporation and preparation were frozen into the elastic solid layer of softness, bonding and tool.Clobetasol propionate at least 6 hour during from this layer is being delivered to psoriasis skin surface during 2 hours and preferably at least, to suppress psoriasis.

[0108], it will be apparent to those skilled in the art that and to make various changes, variation, omission and replacement, and do not break away from spirit of the present invention although the present invention is described with reference to some preferred implementation.Therefore, this invention is intended to only be subjected to the scope of claims to limit.

Claims

1. be used for the spray agent of percutaneous dosing, it comprises:

Medicine;

The non-volatile solvents system that comprises at least a non-volatile solvents;

Coagulant; With

Propellant,

Wherein, described preparation has the initial viscosity that is suitable for being pushed out and being applied to as layer skin surface from pressurizing vessel or manual pump container, and wherein after the described propellant evaporation of at least a portion, described preparation can also form solidification layer on described skin surface.

2. preparation according to claim 1, the described medicine of wherein said non-volatile solvents system transmissibility treatment effective dose enters or passes skin surface.

3. preparation according to claim 1, the described medicine of wherein said solidification layer transmissibility treatment effective dose enters or passes skin surface.

4. preparation according to claim 1, wherein said preparation is a homogeneous solution.

5. preparation according to claim 1, wherein said preparation is a suspension.

6. preparation according to claim 1, wherein when described preparation is in described pressurizing vessel, described propellant with other composition of described preparation separate mutually in exist, and wherein before releasing from described pressurizing vessel, described propellant and described other composition are mixed.

7. preparation according to claim 1, wherein when described preparation was in described pressurizing vessel, described propellant was held with other composition of described preparation and separates, and wherein said propellant and described other composition use not long ago mixed.

8. preparation according to claim 1, wherein said preparation further comprises the volatile solvent with the boiling point more than 25 ℃.

9. preparation according to claim 1, wherein said preparation further comprises volatile solvent, it improves the compatibility of the composition in the described preparation.

10. preparation according to claim 1, wherein said preparation further comprises the volatile solvent that is selected from ethanol, isopropyl alcohol and its combination.

11. preparation according to claim 1, wherein said preparation further comprise the volatile solvent of regulating described preparation viscosity.

12. preparation according to claim 1, wherein said non-volatile solvents system is the plasticizer of described coagulant.

13. preparation according to claim 1, wherein said coagulant accounts at least 10% of described total formulation weight amount.

14. preparation according to claim 1, wherein said coagulant accounts at least 20% of described total formulation weight amount.

15. preparation according to claim 1, wherein said non-volatile solvents system accounts at least 10% of described total formulation weight amount.

16. preparation according to claim 1, wherein said non-volatile solvents system accounts at least 20% of described total formulation weight amount.

17. preparation according to claim 1, wherein said medicine comprises the activating agent that is used for the treatment of neuropathic pain.

18. preparation according to claim 1, wherein said medicine comprises local anesthetic.

19. preparation according to claim 1, wherein said medicine comprises ropivacaine.

20. preparation according to claim 1, wherein said medicine comprises tetracaine.

21. preparation according to claim 1, wherein said medicine comprises lignocaine.

22. preparation according to claim 1, wherein said medicine comprises amitriptyline.

23. preparation according to claim 1, wherein said medicine comprises androgen.

24. preparation according to claim 1, wherein said medicine comprises testosterone.

25. preparation according to claim 1, wherein said medicine comprises corticosteroid.

26. preparation according to claim 1, wherein said medicine comprises clobetasol.

27. preparation according to claim 1, wherein said medicine comprises clobetasol propionate.

28. preparation according to claim 1, wherein said medicine comprises antiinflammatory.

29. preparation according to claim 1, wherein said medicine comprises ketoprofen.

30. preparation according to claim 1, wherein said medicine comprises the antibiolics agent.

31. preparation according to claim 1, wherein said medicine comprises antifungal.

32. preparation according to claim 1, wherein said medicine comprises antiviral agent.

33. preparation according to claim 1, wherein said medicine comprises immunomodulator.

34. preparation according to claim 1, wherein said medicine comprises imiquimod.

35. preparation according to claim 1, wherein said medicine comprises anti-infective.

36. comprising, preparation according to claim 1, wherein said medicine be selected from least a in acyclovir, econazole, miconazole, terbinafine, lignocaine, bupivacaine, ropivacaine and tetracaine, amitriptyline, Ketanserine, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, retinoic acid, Accutane, clobetasol propionate, propanoic acid halogen Beta rope, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid and its combination.

37. comprising, preparation according to claim 1, wherein said medicine be selected from amorolfine, butenafine, naftifine, terbinafine, fluconazol, itraconazole, ketoconazole, posaconazole, pressgang health azoles, voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole (triaconazole), tioconazole, Caspofungin, Mi Kafen is clean, anidulafungin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, undecylenate, penciclovir, famciclovir, valaciclovir behenyl alcohol, trifluridine, iodouracil desoxyriboside, cidofovir, ganciclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, dilazep Wei Ding, didanosine, Sustiva, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones, ciprofloxacin, bupivacaine, α-2 agonist, clonidine, amitriptyline, carbamazepine, alprazolam, ketamine, Ketanserine, betamethasone dipropionate, halobetasol propionate, the bisgallic acid diflorasone, triamcinolone acetonide, desoximetasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, FLUTICASONE PROPIONATE, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, the valeric acid hydrocortisone, Aclovate, the neopentanoic acid flumetasone, hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin, ciclosporin, anthraline, vitamin D3, cholecalciferol, calitriol, calcipotriol, tacalcitol, calcipotriene, piroxicam, diclofenac, indomethacin, imiquimod, resiquimod, salicylic acid, alpha hydroxy acid, sulfur, resorcinol, carbamide, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, benzoic acid, progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethynodiol diacetate, norelgestromine, norgestimate, levonorgestrel, the dl-norgestrel, cyproterone acetate, dydrogesterone, medroxyprogesterone, chlormadinone acetate, megestrol, promegestone, norethindrone, lynestrenol, the gestodene, tibolone, testosterone, methyltestosterone, oxandrolone, androstenedione, dihydrotestosterone, estradiol, ethinyl estradiol, estriol, estrone, conjugated estrogen hormone, esterified estriol, at least a in estropipate and its combination.

38. comprising, preparation according to claim 1, wherein said coagulant be selected from polyvinyl alcohol, the ester of polyvinyl methyl ether/copolymer-maleic anhydride, the neutral copolymer of butyl methacrylate and methyl methacrylate, dimethylaminoethyl methacrylate-butyl methacrylate-methylmethacrylate copolymer, the muriatic copolymer of ethyl acrylate-methyl methacrylate-methacrylic acid front three amino ethyl ester, prolamine (Zein), pregelatinized Starch, ethyl cellulose, fish glue, gelatin, at least a in acrylate/octyl acrylamide copolymer and its combination.

39. preparation according to claim 1, wherein said coagulation agent comprise be selected from ethyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, methylcellulose, polyetheramides, corn starch, pregelatinized corn starch, polyetheramides, lac, polyvinylpyrrolidone, Oppanol, poly-phthalic acid vinyl acetate and its combination at least a.

40. comprising, preparation according to claim 1, wherein said coagulation agent be selected from ammonium methacrylate, chondrus ocellatus Holmes, the cellulose acetate-phthalate aqueous solution, carbopol, cellulose acetate (microcrystal), cellulosic polymer, divinylbenzene-styrene, ethylene vinyl acetate, silicones, guar gum, melon Colophonium, glutelin, casein, calcium caseinate, eucasin, casein sidium, potassium caseinate, acrylic acid methyl ester., microwax, polyvinyl acetate, the polyvinylpyrrolidone ethyl cellulose, acrylate, Polyethylene Glycol/polyvinylpyrrolidone, Xanthan gun, siloxy silicic acid trimethyl, maleic acid/acid anhydride copolymer, bohr Acree woods, poloxamer, polyethylene glycol oxide, polylactic acid/poly--1-lactic acid, terpene resin, locust bean gum, acrylic copolymer, dispersions of polyurethanes, dextrin, the polyvinyl alcohol-polyethylene glycol copolymer, EUDRAGIT L100-55, at least a in methacrylic acid and methacrylate based polymer such as polymethylacrylic acid and its combination.

41. preparation according to claim 1, wherein said non-volatile solvents system comprises and is selected from least a in glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, triethanolamine, tromethane, triacetin, Span-20, sorbitan monooleate, sorbitan monopalmitate, butanols and its combination.

42. preparation according to claim 1, wherein said non-volatile solvents system comprises and is selected from least a in benzoic acid, butanols, dibutyl sebacate, diglyceride, dipropylene glycol, acetaminol, fatty acid, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglyceride, sorbitol anhydride fatty acid surfactant, triethyl citrate and its combination.

43. preparation according to claim 1; wherein said non-volatile solvents system comprises and is selected from 1; 2; the 6-hexanetriol; the alkyl triol; alkyl diol; glyceryl monoacetate; tocopherol; the alkyl dioxolanes; the anethole; Oleum Anisi Stellati; almond oil; the isosorbide dimethyl ester; alkyl androstanediol; benzyl alcohol; Cera Flava; benzyl benzoate; butanediol; caprylic/capric triglyceride; caramel; Oleum Cinnamomi; Oleum Ricini; cinnamic aldehyde; Oleum Cinnamomi; Oleum Caryophylli; Oleum Cocois; cocoa butter; cocoa glyceride; Fructus Coriandri oil; Semen Maydis oil; Fructus Coriandri oil; corn syrup; Oleum Gossypii semen; cresol; cyclomethicone; Glycerine 1,3-diacetate; the diacetylation glyceryl monoacetate; diethanolamine; diethylene glycol one ether; diglyceride; ethylene glycol; Eucalyptus oil; fat; aliphatic alcohol; spice; liquid sugar; Rhizoma Zingiberis Recens extract; glycerol; high-fructose corn syrup; castor oil hydrogenated; the IP cetylate; Fructus Citri Limoniae oil; white lemon oil limonene; milk; monoacetin; glyceryl monoacetate; Semen Myristicae oil; octyl dodecanol; olivetol; orange oil; Petiolus Trachycarpi oil; Oleum Arachidis hypogaeae semen; the Polyethylene Glycol vegetable oil; Oleum menthae; vaseline; phenol; pinke needle oil; polypropylene glycol; Oleum sesami; Oleum menthae; soybean oil; vegetable oil; vegetable shortenings; vinyl acetate; wax; 2-(2-(octadecane oxygen base) ethyoxyl) ethanol; benzyl benzoate; Butylated hydroxyanisole; candelilla wax; Brazil wax; ceteareth-20; hexadecanol; polyglycereol; two multi-hydroxy stearic acid esters; Polyethylene Glycol-7-castor oil hydrogenated; diethyl phthalate; ethyl sebacate; dimethicone; dimethyl phthalate; cithrol; polyglycol distearate; polyethylene glycol (PEG) oleate; polyethylene glycol laurate; the polyethylene glycol fatty acid diester; the Polyethylene Glycol dioleate; polyglycol distearate; Polyethylene Glycol Oleum Ricini behenic acid glyceride; the polyethylene glycol glycerol fatty acid ester; the Polyethylene Glycol glyceryl laurate ester; the Polyethylene Glycol tristerin; the Polyethylene Glycol olein; hexene glycerol; lanoline; the lauric acid diethanolamine; Lauryl lactate; lauryl sulfate; medronic acid; methacrylic acid; many sterin extract; tetradecyl alchohol; neutral oil; Polyethylene Glycol octyl group phenylate; Polyethylene Glycol-alkyl ether; the Polyethylene Glycol cetyl ether; the Polyethylene Glycol stearyl ether; polyethylene glycol sorbitan fatty acid esters; Polyethylene Glycol anhydrous sorbitol diisopstearate; the Polyethylene Glycol sorbitan monostearate; methyl glycol fatty acid ester; propylene glycol stearate; propylene glycol caprylate/decanoin; pyrrolidone sodium carboxylate; sorbitol; Squalene; stear-o-wet; triglyceride; alkyl aryl polyether alcohol; the polyoxyethylene deriv of anhydrous sorbitol ether; saturated polyglycolysed C8-C10 glycerol; N-Methyl pyrrolidone; Mel; polyoxy ethylization glycerol; dimethyl sulfoxide; azone and related compound; dimethyl formamide; the N-methylformamide; fatty acid ester; fatty alcohol ether; alkylamide (N, N-dimethyl alkylamide); the N-Methyl pyrrolidone related compound; ethyl oleate; the bound to polyglycerol fatty acid; glyceryl monooleate; single myristin; the glyceride of fatty acid; the aminoacid of silk; PPG-3 methyl benzyl ether. myristinate; two-PPG2 Semen Myristicae oleyl alcohol polyethers-10 adipate ester; the Mel Moisture factor; sodium pyroglutamate; Caulis et Folium Brassicae capitatae oil; dimethicone; macadimia nut oil; Bai Manghua seed oil; cetearyl alcohol; Polyethylene Glycol-50 shea oil; shea oil; Aloe juice; Silicone DC 556; at least a in hydrolyzed wheat protein and its combination.

44. preparation according to claim 1, wherein said propellant comprises dimethyl ether.

45. preparation according to claim 1, wherein said propellant comprises hydrofluoroalkane.

46. preparation according to claim 1, wherein said propellant comprises the hydrogen chlorofluoromethane.

47. comprising, preparation according to claim 1, wherein said propellant be selected from propane, butane, iso-butane, pentane, isopentane, fluorochlorohydrocarbon, diethyl ether, dimethyl ether, 1,1-Difluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-propane, 1,1,1,3,3, at least a in 3-HFC-236fa, vinyl chloride, compression arbon dioxide, compressed nitrogen and its combination.

48. preparation according to claim 1, wherein said preparation further comprise the medicament that can increase bonding force between described solidification layer and the described skin surface.

49. preparation according to claim 1, wherein said skin surface is a skin.

50. preparation according to claim 1, wherein said skin surface is a mucomembranous surface.

51. preparation according to claim 1, wherein said skin surface are the fingernail surfaces.

52. preparation according to claim 1, wherein said skin surface is a wound surface.

53. preparation according to claim 1, wherein said skin surface are the decubital ulcer surfaces.

The ulcer skin surface that 54. preparation according to claim 1, wherein said skin surface are diabetes to be caused.

55. preparation according to claim 1, the weight ratio of wherein said non-volatile solvents system and described coagulant are from about 0.5:1 to 2:1.

56. preparation according to claim 1, wherein said solidification layer provide the lasting release of described medicine to reach at least 2 hours.

57. preparation according to claim 1, wherein said solidification layer provide the lasting release of described medicine to reach at least 6 hours.

58. preparation according to claim 1, wherein said solidification layer are softish bonding solids, it is by peelling off and can take off from skin after use as a slice or a few sheet for using the zone.

59. preparation according to claim 1, wherein said preparation is comprised in the described pressurizing vessel.

60. preparation according to claim 1, wherein said preparation are comprised in the described manual pump container.

61. preparation according to claim 1, wherein said solidification layer are configured to the described medicine of dermal delivery.

62. the percutaneous drug delivery method, it comprises:

A) spray the viscosity coagulation agent to skin surface, described preparation comprises:

I) medicine,

Ii) non-volatile solvents system, it comprises at least a non-volatile solvents, described non-volatile solvents system can make circulation to described medicine,

Iii) coagulant and

Iv) propellant;

Wherein, described preparation has the initial viscosity that is suitable for being pushed out and being applied to as layer from pressurizing vessel skin surface;

B) by described propellant to small part evaporation, described preparation is solidified to form solidification layer on described skin surface;

C) in the time period that continues, with treat effective speed from described solidification layer to the described medicine of described skin surface dermal delivery.

63. according to the described method of claim 62, wherein said solidification layer was maintained on the described skin surface about at least 2 hours.

64. according to the described method of claim 62, wherein said solidification layer was maintained on the described skin surface about at least 6 hours.

65. according to the described method of claim 62, wherein said injecting step is by from pressurizing vessel described preparation being ejected on the described skin surface.

66. according to the described method of claim 62, wherein said injecting step is by using manual pump from container described preparation to be ejected on the described skin surface.

67. according to the described method of claim 62, wherein said solidification layer is that 0.01mm is thick at least.

68. according to the described method of claim 62, wherein said solidification layer is that 0.05mm is thick at least.

69. according to the described method of claim 62, wherein said skin surface is a mucomembranous surface.

70. according to the described method of claim 62, wherein said skin surface is the fingernail surface.

71. according to the described method of claim 62, wherein said skin surface is the compromised skin surface.

72. according to the described method of claim 62, wherein said skin surface is the skin surface that suffers decubital ulcer.

73. according to the described method of claim 62, wherein said skin surface is the ulcer skin surface that diabetes cause.

74. according to the described method of claim 62, wherein said step of sending described medicine mainly occurs in and does not have propellant, water basically and have more under the situation of volatile solvent than water arbitrarily.