CN1993092A - Dermal peel-forming formulation - Google Patents

Abstract

The present invention is drawn to adhesive peel-forming formulations for dermal delivery of a drug. The formulation can include a drug, a solvent vehicle, and a peel-forming agent. The solvent vehicle can include a volatile solvent system having one or more volatile solvent, and a non-volatile solvent system having one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility for the drug that is within a window of operable solubility for the drug such that the drug can be delivered at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system. When applied to the skin, the formulation can form a solidified peelable layer after at least a portion of the volatile solvent system is evaporated.

Description

Dermal peel forms preparation

Invention field

The present invention relates generally to the system that develops for the dermal delivery medicine.More specifically, the present invention relates to have adhesivity epithelium formation (peel-forming) preparation that is fit to be applied to the viscosity of skin surface and can on skin, forms the adhesivity curing strippable coating that continues delivering drugs.

Background of invention

Conventional dermal drug delivery system generally can be divided into two kinds of forms: semi-solid preparation and skin patch dosage form.Semi-solid preparation can adopt several different forms, comprises ointment, ointment, paste, gel or lotion, and can be applied topically to skin.Skin (comprising percutaneous) patch dosage form also can adopt several different forms, comprises matrix patch structure and liquid storage storehouse patch structure.In matrix patch, active medicine is blended in the adhesive of coating backing film.The adhesive layer that is added with medicine directly is applied on the skin usually, both as the means that patch are fixed on the skin, is used as the solvent of medicine again.Different therewith, in the patch of liquid storage storehouse, usually medicine is mixed in the solvent system by thin bag splendid attire, described thin bag can be the flexible receptacle that approaches.Thin bag can comprise that the permeable membrane or the semipermeable membrane that stick with glue the agent coating are surperficial so that film is fixed on the skin.This film often is called as speed limit film (but its in fact be not maximum speed limits in delivery process all) in all cases, medicine can be transferred to skin to carry out dermal delivery in thin bag.

Though patch and semi-solid preparation be widely used in medicine send into and by skin, they all have tangible limitation.For example, most of semi-solid preparation contains solvent usually, and as water and ethanol, they are volatile, therefore will evaporate soon after application.The evaporation of this kind solvent can cause remarkable minimizing that dermal drug sends or or even stop, this may be undesirable under many circumstances.In addition, semi-solid preparation regular meeting is by " wiping is advanced " skin, and this must not mean that pharmaceutical preparation is really sent into skin.On the contrary, this phrase often means extremely thin one deck pharmaceutical preparation and is used on the skin surface.Be applied to this class conventional medicine preparation thin layer on the skin and may do not contain the active medicine that realization continues the capacity of sending for a long time.In addition, owing to contact with object such as clothes, the conventional semi-solid preparation is unconsciously removed through regular meeting, and this can damage and continue to send and/or the clothes of undesirably making dirty.The medicine that exists in the semi-solid preparation also may unconsciously be delivered to the people who contacts with the patient who treats with semi-solid preparation with this part.

For matrix patch, in order suitably to be sent, medicine should have enough dissolubility in adhesive, just mainly be because have only dissolved drug that the driving force of skin permeation can be provided.Unfortunately, the dissolubility of many medicines in adhesive all is not enough to high to producing enough dermal osmosis driving forces.In addition, for example liquid flux and penetration enhancer can not be impregnated in many adhesive substrates system with the q.s of onset to many compositions that can be used for helping dissolved substance or increase cutaneous permeability.For example, under functional level, the great majority in these materials have the tendency of the wearability that changes adhesive unfriendly.Thereby in the matrix patch based on adhesive, the selection and the admissible amount of additive, promoter, excipient etc. may be restricted.For example, for many medicines, when medicine is dissolved in some liquid solvent system, can obtain best percutaneous flow, but in common matrix patch, the skim adhesive often can not be contained in suitable drugs and/or the additive that effective capacity is gone up in treatment.And the characteristic of adhesive such as cohesiveness and viscosity also may significantly be changed owing to there is liquid flux.

For liquid storage storehouse patch, even entrained particular fluid or the semi-solid solvent system of the thin bag of medicine and patch is the compatibility, this solvent system also must be compatible with the adhesive layer that is coated on permeable membrane or the semipermeable membrane; Otherwise adhesive layer may have a negative impact or the drug/solvent system may reduce the viscosity of adhesive layer to medicine.Except these dosage forms are considered item, to compare with matrix patch, storage storehouse patch volume is huger, and manufacturing cost is higher usually.

Another shortcoming of many patches is that they neither have enough extensibilities usually and also do not have enough pliabilities, because backing film (in matrix patch) and thin fluid bag (in the patch of storage storehouse) are normally made by relative material of not having extensibility.If patch is applied in the body kinematics process skin area such as the joint of significantly stretching, may take place separating between patch and the skin, thus the sending of infringement medicine.In addition, the patch that is present in skin surface may hinder the expansion of skin in the body kinematics process and cause discomfort.Because these in addition, for the skin area that in the body kinematics process expansion takes place and stretch, patch is not ideal dosage form.

In view of many present shortcomings that delivery system had, need provide system, preparation and/or method, its i with following characteristic) can provide secular more lasting medicine to send; Ii) during using, be not easy owing to contact and unconsciously removed with clothes, other object or person; Iii) can be applied to stretch and not cause discomfort with the skin area of expansion or contact with the bad of skin; And/or iv) can easily be removed in application with after using.

Summary of the invention

It is favourable that the verified form with adhesivity epithelium formation compositions or preparation provides dermal delivery preparation, system and/or method, described adhesivity epithelium forms compositions or preparation has the viscosity that is fit to be applied to skin surface, and can form on skin after using can be by the curing strippable coating of the delivering drugs of easily peeling off or removing.In view of the above, the adhesivity epithelium that is used for the dermal delivery medicine forms preparation and can comprise medicine, solvent carrier and epithelium and form agent.Solvent carrier can comprise the volatile solvent system with one or more volatile solvents and have the non-volatile solvents system of one or more non-volatile solvents, wherein the non-volatile solvents system provide medicine feasible dissolubility window (windowof operable solubility) in case can be in a period of time with treatment effective dose delivering drugs, even after most of volatile solvent evaporation, also be like this.Preparation can have the viscosity that is fit to be applied to skin surface before the evaporation of at least a volatile solvent, and can further dispose (configure) to preparation and form the curing strippable coating at least a portion volatile solvent evaporation back preparation when being applied to skin surface with box lunch.

In an alternative embodiment, can comprise: the adhesivity epithelium is formed preparation be applied to individual skin surface the method for individual's skin delivering drugs; In a period of time and with required speed from solidifying strippable coating dermal delivery medicine; Remove the curing strippable coating from skin after a period of time or behind the medicine of having sent aequum in the past.The peelable preparation of adhesivity can comprise that medicine, solvent carrier and epithelium form agent.Solvent carrier can comprise the volatile solvent system with one or more volatile solvents and have the non-volatile solvents system of one or more non-volatile solvents, wherein the non-volatile solvents system have the feasible dissolubility window that is arranged in medicine drug solubility in case can a period of time with treatment effective dose delivering drugs, even after most of volatile solvent evaporation, also be like this.Preparation can have the viscosity that is fit to be applied to skin surface before the volatile solvent evaporation.When preparation was applied to skin surface, preparation can form the curing strippable coating at least a portion volatile solvent system evaporation back.

In another embodiment, the preparation method that is used for the peelable preparation of adhesivity that dermal drug sends can may further comprise the steps: the medicine of selecting to be suitable for dermal delivery; The non-volatile solvents system that selection is made up of a kind of non-volatile solvents basically with the drug solubility that is positioned at feasible dissolubility window; With medicine and non-volatile solvents are mixed with the adhesivity epithelium and form preparation.The adhesivity epithelium forms the volatile solvent system that preparation can comprise epithelium formation agent and comprise at least a volatile solvent.The adhesivity epithelium forms preparation can have the viscosity that is fit to be applied to skin surface before the volatile solvent system evaporation, and can be applied to skin surface, and it forms and solidifies strippable coating at least a portion volatile solvent system evaporation back.In this embodiment, evaporating the back medicine basically in volatile solvent system continues to be sent with the treatment effective dose.

In another embodiment, preparation is used for the method that adhesivity epithelium that dermal drug sends forms preparation and can may further comprise the steps: the medicine of selecting to be suitable for dermal delivery; By selecting at least two kinds of non-volatile solvents to form the non-volatile solvents system according to the ratio that the dissolubility that makes medicine in the non-volatile solvents system is positioned at feasible dissolubility window; Medicine and non-volatile solvents system are mixed with adhesivity epithelium formation preparation.The adhesivity epithelium forms the volatile solvent system that preparation can comprise epithelium formation agent and comprise at least a volatile solvent.The adhesivity epithelium forms preparation can also have the viscosity that is fit to be applied to skin surface before the volatile solvent system evaporation, and can be applied to skin surface, forms at least a portion volatile solvent system evaporation back and solidifies strippable coating.Basically evaporating the back medicine in volatile solvent system can continue to be sent with the treatment effective dose.

In another embodiment, the curing strippable coating that is used for delivering drugs can comprise medicine, non-volatile solvents system and epithelium and forms agent.The non-volatile solvents system can comprise one or more non-volatile solvents, and can provide feasible dissolubility window so that can be to treat the effective dose delivering drugs at least 2 hours for medicine.And, strippable coating can at least one direction, stretch 10% and do not rupture, break or with solidify the skin surface that strippable coating is employed thereon and separate.

In another embodiment, the adhesivity epithelium that is used for the dermal delivery medicine forms that preparation can comprise medicine, epithelium forms agent and solvent carrier.Solvent carrier can comprise: comprise one or more volatile solvents volatile solvent system, comprise the non-volatile solvents system of one or more non-volatile solvents.After adhesivity epithelium formation preparation was applied to skin surface, the adhesivity epithelium formed the curing strippable coating that preparation forms the contact surface with first area size.To solidify strippable coating can be extensile so as the first area size tensible to not breaking, rupture than the second area size of first area size big 10% and/or separating with skin surface that epithelium formation preparation is employed thereon.And after the curing strippable coating forms and after volatile solvent system is evaporated basically, medicine continues to be sent with the treatment effective dose.

By the following detailed description and the accompanying drawing of setting forth feature of the present invention with way of example, other features and advantages of the present invention will become apparent.

Brief Description Of Drawings

Fig. 1-the 4th independently solidifies the diagram of the cumulant-time of the external medicine of sending by biomembrane the adhesivity preparation from four kinds of embodiment of the present invention.

DESCRIPTION OF THE PREFERRED

Before particular of the present invention is carried out disclosure and description, should be understood that the present invention is not limited to ad hoc approach disclosed herein and material, because it can change to a certain extent.It is to be further understood that term used herein only is used to describe the purpose of particular, and be not to be intended to limit, because scope of the present invention is only determined by appended claim and equivalent thereof.

In description and claimed the present invention, will use following term.

Unless it is really not so that context is clearly indicated,, singulative refers to thing otherwise comprising plural number.Therefore, for example, referring to of " a kind of medicine " comprised referring to one or more these based compositions.

For convenience, multiple medicine used herein, chemical compound and/or solvent can provide with the form of common list.But these tabulations just are interpreted as each member in will tabulating as independently differentiating with unique memberwise.Therefore, under the situation that does not have opposite explanation, can not only be present in the single member who just thinks in same group in this type of tabulation according to them is the actual equivalent of any other member in the same tabulation.

" skin " is defined as comprising people's skin, fingernail and toenail surface and the mucomembranous surface that is exposed to air usually to small part, as lip, genitals and anal mucosa and nasal cavity and oral mucosa.

In this article, concentration, amount and other numeric data can be represented or provide with range format.Should be understood that, use this class range format only be for convenience with succinct purpose, therefore should explain neatly this class range format, it not only comprises the numerical value of clearly being enumerated as this scope limit, and comprise included all single numerical value or inferior scope in this scope, just clearly enumerated as each numerical value and inferior scope.For example, numerical range " about 0.01 to 2.0mm " should be interpreted as not only comprising about 0.01mm of clearly being enumerated value to about 2.0mm, and is included in this specified scope interior single numerical value and inferior scope.Therefore, this numerical range comprise single value as 0.5,0.7 and 1.5 and inferior scope as 0.5 to 1.7,0.7 to 1.5 and 1.0 to 1.5 etc.Same principle also is applicable to the scope of only having enumerated a numerical value.In addition, regardless of the width or the described feature of scope, all be suitable for this type of explanation.

" effective dose " of phrase medicine, " treatment effective dose " or " treatment effective speed " be meant nontoxic but treatment send this medicine at disease in realize the q.s or the delivery rate of the medicine of therapeutic outcome.Should be understood that various biological factors can influence the ability that material is finished its preplanned mission.Therefore, effective dose ", " treatment effective dose " or " treatment effective speed " may depend on this quasi-biology factor in some cases.And, though the realization of therapeutic effect can use evaluation methodology known in the art to measure by doctor or other titular medical worker, be recognized that individual variation and can make the realization of therapeutic effect become subjective decision the response for the treatment of.Determining fully in the common skill scope of pharmacy and medical domain of treatment effective dose or delivery rate.

Phrase " dermal drug is sent " or " dermal delivery medicine " will comprise percutaneous and localized drug delivery, should mean with medicine be delivered to skin, by skin or send into skin.When the dermal delivery medicine, tissue, the local organization under the skin or organ, body circulation and/or the central nervous system that can for example be positioned under the skin with skin, just are target.

Term " medicine " is meant and is applied to, use into or by skin to realize any bioactivator of therapeutic effect.It comprises conventional the discriminating to the compositions of medicine and other always are not considered to the therapeutic effect of bioactivator " medicine " still can provide to(for) some disease on traditional sense, for example, and peroxide, wetting agent, softening agent etc.

The solubility range that is provided for selected medicine by the non-volatile solvents system is provided term " feasible dissolubility window ".The medicine that is dissolved in non-volatile solvents system (dissolubility of medicine is arranged in feasible dissolubility window) can provide acceptable dermal osmosis driving force, comprises the best or approaching best dermal osmosis driving force.The suitable selection of the non-volatile solvents system in the peelable preparation of adhesivity of the present invention or preparation are used to guarantee that the dissolubility of medicine is positioned at the required skin of generation or " the feasible dissolubility window " of dermal delivery speed.In other words, in order to realize that acceptable dermal delivery or percutaneous flow/medicine arrives or enter the driving force of skin surface, the dissolubility (it be the maximum medication amount that may be dissolved in unit volume solvent system) of medicine in the non-volatile solvents system should be in this feasible dissolubility window, for example, can not dissolubility too big, can not dissolubility too poor.

Generally speaking, the transdermal penetration driving force of medicine increases with the increase of the concentration of medicine in the non-volatile solvents system usually, and is saturated until solution.Different therewith, for consoluet given drug level, driving force reduces with the increase of dissolubility or the reduction of saturation usually.This can make an explanation according to some physical and chemical principle, and its Chinese medicine tends to rest in its solution with better dissolubility.Change a kind of saying, if medicine and solution have good affinity (as high-dissolvability reflects), then medicine will tend to rest in the solution rather than deviate from solution outer and infiltrate through skin.Therefore, low percutaneous flow not only may be medicine does not have enough dissolubility in the non-volatile solvents system result, and may be medicine result of " comfortable " (high medicine-non-volatile solvents affinity) too in the non-volatile solvents system.Therefore, send in order to realize acceptable drug, have feasible dissolubility window for given medicine, and the dissolubility of medicine in the non-volatile solvents system should be positioned at this window so that provide enough or required (its often but always do not mean near maximum) percutaneous driving force for medicine.This feasible dissolubility window individuation normally for every kind of medicine.But it is generally 0.01 weight % to 40 weight % of the peelable preparation of adhesivity generally, and for a lot of medicines, is 0.5 weight % to 20 weight %.

For this principle is described more fully, can consider two kinds of preparations, a kind of have the non-volatile solvents system (dissolubility is 100mg/mL) that can dissolve the 100mg medicine in every mL solvent, and another kind has that dissolubility is the non-volatile solvents system of 6mg/mL for same medicine.If in each system of 1mL, put into the 5mg medicine, both all complete dissolved substances, but the driving force of medicine in 6mg/mL non-volatile solvents system usually will be more much bigger than the driving force that is provided by 100mg/mL non-volatile solvents system.In other words, even medicine is dissolved in two kinds of systems fully, the system of medicine and 100mg/mL will have better affinity, therefore will provide lower dermal osmosis driving force.

This also can obtain the support of thermodynamics and diffusion notion, and wherein " feasible dissolubility window " reflected the medicine of enough flows or quantity is sent by skin or the required field of activity of medicine (solute) in non-volatile solution of mucosa.

More quantitatively, seepage discharge is defined in the medication amount of permeating in the unit length time (being generally one hour) by unit are skin (being generally one square centimeter), and it is provided by following formula:

J＝PC (1)

Wherein C is the concentration of institute's dissolved drug, and P is the infiltration coefficient that medicine passes through skin or mucosa, and is irrelevant with drug level.P is relevant with medicine and preparation, and still, according to all data that the inventor understands, it is not higher than 10 usually ^-5Cm/ second, even also be like this for the transdermal drug delivery system of abundant optimization.

Formula (1) and if the upper limit of viewed P prompting drug level too low, then can not reach enough flows.Because drug level is subjected to the solubility limit of medicine in preparation, this just means that preparation must have certain solubility so that have enough flows to medicine.

Therefore, formula (1) provides support for such notion, promptly has a solubility range, exceeds this scope preparation and can not produce required or feasible dermal osmosis driving force.In the present invention, utilization guarantees that to the suitable selection and/or the preparation of non-volatile solvents system in the epithelium preparation dissolubility is positioned at be somebody's turn to do " the feasible dissolubility window " that produces required percutaneous characteristic.

When relating to medicine " continuing to send ", phrase " substantial constant " can according to external by people or hairless mouse skin or epidermis permeability or use the data of collecting by 12 or more a plurality of human individuals' set to define, wherein at the appointed time in the section (2 hours or longer) average drug delivery rate compare with the peak value drug delivery rate to descend and be no more than 50%.Therefore, the compositions of sending with " substantial constant " speed comprises and goes up the preparation that significant speed delivering drugs reaches for example 2 hours, 4 hours, 8 hours, 12 hours, 24 hours lasting a period of time etc. with substantial constant with treatment.The non-volatile solvents system that use has above defined feasible dissolubility window can send with this continuing of significant speed realization in the treatment in a period of time that continues.

" volatile solvent system " can be volatile single solvent or solvent mixture, comprises water and than the more volatile solvent of water.

" non-volatile solvents system " can be single solvent or the solvent mixture than water volatility difference.Solidifying in volatile solvent system evaporation back and should remain most of non-volatile solvents system in the strippable coating and reach a period of time, thus this section period be enough to given medicine in a period of time with enough flows be delivered to, send into or skin by individuality therapeutic effect is provided.In some embodiments, in order to obtain required active medicine dissolubility and/or to form the compatibility of other composition in agent or the preparation, can use the mixture of two or more non-volatile solvents to form the non-volatile solvents system with epithelium.

The compositions that comprises volatile solvent system and non-volatile solvents system described in term " solvent carrier ".Volatile solvent system is selected so that thereby rapid evaporation form to be solidified strippable coating from the peelable preparation of adhesivity, thereby and to the non-volatile solvents system prepare or select so as after the volatile solvent system evaporation basically with solidify the remaining realization of strippable coating medicine continue send.Usually, medicine can partially or completely be dissolved in solvent carrier or the whole preparation.Equally, in case the volatile solvent system evaporation, medicine also can partially or completely be dissolved in the non-volatile solvents system.The preparation that only is partly dissolved in the non-volatile solvents system at volatile solvent system evaporation back medicine has the potentiality that keep the longer time to continue to send, because along with dissolved medicine is consumed from solidify strippable coating in delivery process, undissolved medicinal soluble is separated in the non-volatile solvents system.

" the peelable preparation of adhesivity " or " the adhesivity epithelium forms preparation " is meant to have before its volatile solvent evaporation and is fit to be applied to the viscosity of skin surface and becomes the compositions of solidifying strippable coating (or epithelium) after the evaporation of at least a portion volatile solvent.

Term " drying time " is meant the neat required time of (non-messy) solidified surface of formation after preparation is applied to skin under standard skin and the environmental condition of using standard method of test to measure.It is 32 ℃ to 36 ℃ drying, healthy application on human skin that " standard skin " or " normal skin " are defined as surface temperature; The standard environment condition is defined as 20 ℃ to 25 ℃ temperature and 20% to 80% relative humidity.Standard method of test is as follows: one deck adhesivity epithelium to the about 0.2mm of standard dermal application under the standard environment condition forms preparation, measures drying time.Be defined as that preparation forms neat surface drying time so as with 5 to 10g/cm ²The pressure time that preparation can not cause mass loss because of adhesion when one 100% cotton is pushed 5 seconds on dosage surface.

When mentioning that compositions has " be fit to use " during in the viscosity of skin surface, this mean that compositions has sufficiently high viscosity so that after being applied to skin compositions can not come off basically from skin, and have enough low viscosity so that it can easily spread on the skin.The range of viscosities that satisfies this definition can be 100cP to 3,000, and 000cP (centipoise), more preferably 1,000cP to 1,000,000cP.

" curing strippable coating " or " epithelium " have been described at least a portion volatile solvent system and have been evaporated curing or the drying layer that back adhesivity epithelium forms preparation.Epithelium keeps adhering on the skin, preferably can keep excellent contact with patient's skin during whole application basic under normal skin and the environmental condition.Epithelium also show enough hot strengths in case when use finishing can with the form of one or several bulks from skin peel off (with have the layer different of weak hot strength, when the fault rupture that has weak hot strength when skin is removed is many fritters or chip).

These definition have been understood, the present invention relates to new preparation, there be (comprising ointment, gel, paste, ointment and other viscous liquid) in it with semisolid original form usually, it can easily be applied to skin with the form of layer, and can be fast (under normal skin and the environmental condition 15 seconds to 4 minutes) solidify strippable coating or epithelium to medium becoming (under normal skin and environmental condition 4 minutes to 15 minutes) fast, for example cohesion and pliable solid layer is sent to carry out medicine.Thus curing strippable coating of Xing Chenging or epithelium can a period of time that continues for example a few hours with the speed of substantial constant medicine is delivered to skin, sends into skin, sends by skin etc. in to tens of hours so that send most of active medicine after strippable coating forms solidifying.In addition, solidifying strippable coating adheres on the skin usually, but the outer surface with solidified minimum adhesion, it is forming and can not transfer to basically on clothes or patient other object that dress or that epithelium can touch carelessly quickly or is making them dirty after application.Solidify strippable coating and can also be prepared, thereby can keep excellent contact, even skin stretches in the body kinematics process, for example at knee, finger, elbow or other joint with skin surface so that it has high degree of flexibility and extensibility.

When selecting operable various components for example solvent carrier, the epithelium of medicine, volatile solvent system and non-volatile solvents system form agent etc., various considerations can be arranged.For example, volatile solvent system can be selected from pharmaceutically known in the art or acceptable solvent is gone up in beauty treatment.The example of this class volatile solvent comprises water, ethanol, propanol, ethyl acetate, acetone etc.In addition, should select so that all the other compositions in itself and the preparation are compatible these volatile solvents.Desirable is the volatile solvent that uses suitable percetage by weight in preparation.Too many volatile solvent system can prolong drying time.Volatile solvent system very little can make preparation be difficult to sprawl on skin.For most of preparation, the percetage by weight of volatile solvent can for about 2 weight % to about 50 weight %, more preferably from about 4 weight % are to about 30 weight %.

Also can to the non-volatile solvents system select or prepare so as itself and epithelium to form agent, medicine, volatile solvent compatible with any composition that other may exist.For example, can form that agent is selected so that it can be dispersed or dissolved in the non-volatile solvents system to epithelium.Most of non-volatile solvents system and whole solvent carrier are prepared after experiment aptly.For example, some drugs has good dissolubility in the Polyethylene Glycol (PEG) (PEG 400, non-volatile solvents) of molecular weight 400, but has poor dissolubility in glycerol (non-volatile solvents) and water (volatile solvent).Yet PEG 400 is dissolve polyvinyl alcohol (PVA) effectively, and therefore, independent PEG 400 is not very compatible with PVA (a kind of epithelium formation agent).For the active medicine that dissolves q.s also uses PVA to form agent as epithelium simultaneously, can comprise the non-solvent system of PEG 400 and glycerol (compatible) with suitable ratio preparation, thereby obtain the compatibility of compromise with PVA.As another example of the compatibility, when Span 20 was formulated in the epithelium preparation that contains PVA, it was incompatible to observe non-volatile solvents/film former.Make up, Span 20 can separate out and form on the epithelium surface oiliness layer from preparation at this point.Therefore, the film former/non-volatile solvents that needs to suit in the combination of the feasible preparation of exploitation and the compatibility is selected.

Can be used alone or be combined and use non-volatile solvents can be selected from various pharmaceutically acceptable liquid, including, but not limited to Polyethylene Glycol, mineral oil, vaseline, Oleum Ricini, quintessence oil such as acetaminol, menthol, eucalyptole or the Oleum Rosae Rugosae of glycerol, the about 200MW to 800MW of weight average molecular weight, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, the polyoxyethylene deriv of Isosorbide Dinitrate, saturated Pegylation C to form the non-volatile solvents system ₈To C ₁₀Glyceride (polyglycolyzed C ₈To C ₁₀Glyceride), polyoxy ethylization fatty glyceride, oleic acid, dimethyl sulfoxide (DMSO), aliphatic alcohol, isopropyl myristate (IPM), glyceryl triacetate, ethyl oleate, isostearic acid, medium-chain fatty acid and other fatty acid, and their mixture.Except these and other was considered, when the non-volatile solvents system also can be used as plasticizer with the formation of box lunch curing strippable coating in the peelable preparation of adhesivity, this layer was flexible, extensile and/or " skin friendliness ".

May need to use the volatility and/or dissolubility and/or the permeability of non-volatile solvents of some chafe to obtain required medicine.Also may need to add and to prevent or to reduce compatible with the preparation again chemical compound of skin irritation.For example, in the preparation of volatile solvent energy chafe, it is useful that use can reduce skin irritant non-volatile solvents therein.Knownly can prevent or reduce the example of skin irritant solvent including, but not limited to glycerol, Mel and propylene glycol.

During other component of in considering the peelable preparation of adhesivity, existing, also can carry out the selection that epithelium forms agent.Can to epithelium form agent select or prepare so that itself and medicine is compatible with solvent carrier (comprising volatile solvent and non-volatile solvents system) and in case form to solidify strippable coating and be it required physical characteristic is provided.According to medicine, solvent carrier and/or other component that may exist, epithelium forms agent can be selected from various materials, including, but not limited to polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, gelatin, guar gum, polyethylene glycol oxide, starch, xanthan gum, comprise hydroxyethyl-cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose is interior cellulose derivative, the Kollicoat polymer of polyvinyl alcohol-polyethylene glycol copolymer and EUDRAGIT L100-55 such as BASF, with methacrylic acid and methacrylate is polymer based as poly-(methacrylic acid) copolymer and methylmethacrylate copolymer, comprises Rohm ﹠amp; The Eudragit polymer of Haas, but for example Eudragit E, Eudragit RL, Eudragit RS and have identical or similar chemical property have common name or have different trade (brand) names or the polymer of chemical name, and their mixture.According to solvent carrier component, medicine and the specific function requirement of giving customization agent, many other film forming polymers form agent as epithelium and also may be fit to.

It should be the compatibility each other that non-volatile solvents system and epithelium form agent.The compatibility is defined as i) epithelium forms the function that agent can negatively not influence the non-volatile solvents system basically; Ii) epithelium forms agent and the non-volatile solvents system can be retained in and solidify in the strippable coating so that there is not non-volatile solvents to ooze out and iii) have acceptable pliability, rigidity, hot strength, elasticity and cohesiveness with the curing strippable coating of selected non-volatile solvents system and epithelium formation agent formation from this layer basically.The weight ratio that non-volatile solvents system and epithelium form agent can be about 0.01: 1 to about 2: 1.On the other hand, the ratio between non-volatile solvents system and the epithelium formation agent can be about 0.2: 1 to about 1.2: 1.

For some practical parameter are provided, usually, the concentration of active medicine in topical formulations seldom surpasses 10 weight % (by the weight of active medicine in total weight of formulation).In one embodiment, if the non-volatile solvents system in the preparation accounts for 30 weight % of total weight of formulation, this means that the concentration of active medicine in the non-volatile solvents system is about 25 weight %.In this class preparation, if the non-volatile solvents system is much higher than 25 weight % for the dissolubility of medicine, then osmotic drive power will significantly reduce.At many natures and being purchased in the feasible product, maximum drug level significantly is lower than 10 weight %, and this means for the upper limit of the feasible dissolubility window of those systems significantly lower again, more may be in 1 weight % to 10 weight % scope.

Send the consideration item for given preparation and required medicine, the thickness that is applied to the ghe layer of skin also should suit.If this layer is too thin, the amount of medicine may be not enough to continue to send in required time span.If this layer is too thick, forming neat curing strippable coating outer surface may need the long time.If medicine is very effective and epithelium has very high hot strength, then the thin layer of 0.01mm may be just enough.If medicine has lower effectiveness and epithelium has low hot strength, then may need the thick layer of 2-3mm.Therefore, for most of medicine and preparation, suitable thickness may for about 0.01mm to about 3mm, but be more typically extremely about 1mm of about 0.05mm.

The pliability and the extensibility of solidifying strippable coating or epithelium may need in some applications.For example, some non-steroidal anti-inflammatory agent (NSAID) can directly apply on joint and the muscle and go into joint and muscle with dermal delivery.Yet the skin area of joint and some muscle group stretches in the body kinematics process of being everlasting significantly.This type games has hindered non-extensibility patch to keep the advantages of good skin contact.Since more than enumerate, lotion, ointment, ointment, gel, paste etc. also may be inapplicable.Therefore, go in the process of joint and/or muscle at the NSAID dermal delivery, epithelium of the present invention forms preparation can provide unique advantage and benefit.Though should be pointed out that in some applications to need good extensibility, it is extensile that epithelium formation preparation of the present invention does not always need, because some application of the present invention must not benefit from this characteristic.For example, spend the night with the treatment acne if preparation is applied to little facial zone, even epithelium is not extensible, the patient will experience, and not accommodate that preparation-skin separates also be minimum because skin of face usually in sleep cycle stretching, extension minimum.

Another feature of preparation is relevant with drying time.If the preparation drying is too fast, user before preparation solidifies, may not have time enough with preparation at skin surface upper berth generate thin layer, thereby cause the contact skin of difference.If the preparation drying is slow excessively, the patient is restarting normal activity (for example, putting on clothes) the necessary wait of possibility before for a long time, and described normal activity may be removed uncured preparation.Therefore, be longer than about 15 seconds but be shorter than about 15 minutes, preferred about 0.5 minute to about 4 minutes drying time be desirable.

Other benefit of curing strippable coating of the present invention comprises the physical barriers that existence can be formed by material itself.For example, local anesthetic can be by local delivery with the treatment pain relevant with neuropathy, as diabetic neuropathic pain with other activating agent such as clonidine.Because many this class patients feel great pain, even also be so during their skin area of just slight contact, the physical barriers that therefore solidifies strippable coating can prevent owing to contact the pain that causes accidentally or it is dropped to minimum level with object or other thing.

These and other advantage can be summarized as follows.Curing strippable coating of the present invention can be prepared with the original form of the semisolid dosage form that is easy to use.In addition, after the volatile solvent system evaporation, this dosage form is thicker and can contain much more active medicine than the common layer of conventional ointment, gel, lotion, ointment, paste etc., and can unconsciously not removed.In volatile solvent evaporation and form solidify strippable coating after, can provide required drug delivery rate in a period of time that continues at the medicine of remaining non-volatile solvents system (its dissolubility to medicine is arranged in the feasibility dissolubility window of medicine).And, because the curing strippable coating is keeping cohesiveness and is being strippable,, do not need the help of solvent or surfactant usually so can easily remove the curing strippable coating.In some embodiments, material makes that to the adhesion of skin and its elasticity solidifying strippable coating can not separate with skin when skin generation skin on the muscle stretches in highly extensile skin area such as joint.For example, in one embodiment, solidify strippable coating and can stretch 10% or bigger and do not break, rupture and/or separate in one direction with skin surface that strippable coating is employed thereon.In another embodiment, may spread to area with the area of the curing strippable coating of contact skin and increase by 10% and do not break, rupture and/or separate with skin surface that strippable coating is employed thereon.In addition, can be configured with delivering drugs advantageously and protect the sensitive skin zone and do not break or rupture solidifying strippable coating.

Can be as follows by the application-specific example that system of the present invention, preparation and method benefit.In one embodiment, can prepare the curing strippable coating that comprises bupivacaine, lignocaine or ropivacaine with treatment diabetic neuralgia and postherpetic neuralgia.Select as an alternative, cincaine can be formulated in the epithelium to treat identical disease with α-2 agonist such as clonidine.In another embodiment, tretinoin and benzoyl peroxide can be combined in and solidify in the strippable coating, perhaps select as an alternative, the clindamycin of 1 weight % and the benzoyl peroxide of 5 weight % can be combined in the epithelium with the treatment acne with the treatment acne.In another embodiment, can prepare the retinol epithelium and form preparation (OTC), perhaps can prepare the lignocaine epithelium and form preparation with the treatment backache with the treatment wrinkle.

Application in addition comprises delivering drugs to treat some skin disorder, and for example psoriasis, skin carcinoma etc. are particularly in the unpractical joint of percutaneous patch or the described disease that takes place of muscle place.For example, can prepare the epithelium that contains imiquimod and form preparation with treatment skin carcinoma, verruca vulgaris and genital wart and actinic keratosis.Can prepare the epithelium that contains antiviral agents such as acyclovir, penciclovir, famciclovir, valaciclovir, steroid, behenyl alcohol and form the herpes labialis of preparation with treatment herpesvirus infection such as face and genital area.Can prepare the epithelium that contains NSAID (non-steroidal anti-inflammatory drug) (NSAID), capsaicin, α-2 agonist and/or nerve growth factor and form arthralgia and the backache of preparation with treatment soft tissue injury and muscle-skeletal pain such as a variety of causes.As discussed above like that do not have excellent contact in a period of time that the patch on these skin areas is continuing usually, especially for the patient of body movement, and can cause discomfort.Similarly, possibilities such as Chang Gui semi-solid preparation such as ointment, lotion, ointment are because the evaporation of solvent and/or unconsciously remove preparation and stop medicine prematurely and send.Curing adhesivity preparation of the present invention has solved the shortcoming of this delivery system of two types.

Embodiment relates to and containing from the topical application of the medicine of the α-2 antagonist class epithelium with the treatment neuropathic pain.α-2 agonist was little by little discharged so that the pain relief effect to be provided from preparation in a period of time that continues.Said preparation can become cohesive pliable solid and keeping adhering to body surface during it be used after 2-4 minute.It can not stayed remaining preparation on skin surface can easily removing after the drying.

Another embodiment relates to the topical application that the contains capsaicin epithelium preparation with the treatment neuropathic pain.Capsaicin was little by little discharged to treat this pain from preparation in a period of time that continues.Said preparation can become cohesive pliable solid and keeping adhering to body surface during it be used after 2-4 minute.It can not stayed remaining preparation on skin surface can easily removing after the drying.

The topical application that also has an embodiment to relate to contain the medicine that is selected from the NSAID class such as piroxicam, diclofenac, indomethacin is with treatment backache, muscular tension or the symptom of myofascial pain (myofascial pain) or the epithelium preparation of its combination.NSAID was little by little discharged so that the pain relief effect to be provided from preparation in a period of time that continues.Said preparation can become cohesive pliable solid and keeping adhering to body surface during it be used after 2-4 minute.It can easily be removed and can not stayed remaining preparation on skin surface in the dried any time.

Another embodiment relates to the topical application that contains at least a α-2 agonist medicine and at least a local anesthetic epithelium preparation with the treatment neuropathic pain.Medicine was little by little discharged so that the pain relief effect to be provided from preparation in a period of time that continues.Said preparation can become cohesive pliable solid and keeping adhering to body surface during it be used after 2-4 minute.It can easily be removed and can not stayed remaining preparation on skin surface in the dried any time.

Similarly embodiment can comprise contain capsaicin and local anesthetic be applied topically to skin so that the epithelium preparation of pain relief effect to be provided.Another embodiment can comprise the epithelium preparation of the combination that contains local anesthetic and NSAID.In above-mentioned two embodiments, medicine was little by little discharged so that the pain relief effect to be provided from preparation in a period of time that continues.Said preparation can become cohesive pliable solid and keeping adhering to body surface during it be used after 2-4 minute.It can easily be removed and can not stayed remaining preparation on skin surface in the dried any time.

In another embodiment, being used for epithelium that delivery treatments relates to the medicine of the cause of disease of disease of joint and muscle or symptom forms preparation and also can benefit from system of the present invention, preparation and method.This class disease that can be suitable for is including, but not limited to joint and skeletal pain, myofascial pain, myalgia and the athletic injury of osteoarthritis (OA), rheumatoid arthritis (RA), various other reasons.Can be used for medicine that this class uses or medicament categories including, but not limited to NSAID (non-steroidal anti-inflammatory drug) (NSAID) as ketoprofen and diclofenac, COX-2 optionally NSAID and activating agent, local anesthetic such as lignocaine, bupivacaine, ropivacaine and tetracaine, steroid such as dexamethasone of NSAID and activating agent, COX-3 optionally.

Delivering drugs also can be by benefiting in the principle of the present invention, especially when sending the medicine with low percutaneous permeability with treatment acne and other skin disorder.At present, use with the semi-solid gel agent of routine or the form of ointment with retinoid, peroxide and antibiotic major part the part that is used for the treatment of acne.Yet because aforesaid shortcoming, it is impossible that continuing in many hours sent.For example, clindamycin, benzoyl peroxide and erythromycin only are only when enough amounts are sent into hair follicle effectively.Yet semi-solid preparation such as common acne medicine benzaclin gel are just lost its most of solvent (under the situation of benzaclin, solvent is a water) usually in a few minutes after application, this may damage greatly medicine continue send.Preparation of the present invention does not have this limitation usually.

In another embodiment, delivering drugs also can be by benefiting in method of the present invention, system and the preparation with the treatment neuropathic pain.The patch such as the Lidoderm that contain local anesthetic ^TMBe widely used in treating neuropathic pain, as the pain that causes by postherpetic neuralgia and the neuropathic pain of diabetes-induced.Because the limitation of patch discussed above, curing strippable coating prepared in accordance with the present invention provides some unique benefits, and for using patch that a kind of alternative that may be more cheap is provided.This class is used the possible medicine sent including, but not limited to local anesthetic such as lignocaine, prilocaine, tetracaine, bupivacaine, etidocaine; And other medicines, comprise capsaicin and α-2 agonist such as clonidines.

In another embodiment, delivering drugs also will be sent middle benefit by the long-term medicine that continues with treatment wart and other skin disorder.Can be used on this class medicine in the preparation of the present invention including, but not limited to salicylic acid and imiquimod.

In another embodiment, natural materials and nutrient such as retinol (vitamin A) and can benefit by system of the present invention, preparation and method at wetting agent or sending also of softening agent that cosmetic purpose is used for skin.

Another embodiment relates to and antifungal such as ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives such as butenafine, naphthalene husband is delivered to skin for sweet smell and terbinafine so that eliminate or alleviate various fungal diseases.This is sent and can finish by system of the present invention, preparation and method.

In another embodiment, send antiviral agent such as acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir and their combination.Antiviral therapy can be used for treating partial and viral infection general.

Another embodiment relates to anti-infective such as the antibiotic epithelium formation preparation that is used to send local and general targeting.

Other operable medicine comprises wetting agent, softening agent and other skin care chemical compound.

For the purpose of giving an example, the feasible dissolubility window of some drugs and drug categories below is provided, but should considerablely has been that specific non-volatile solvents system can influence these scopes to a certain extent.For example, local anesthetic can have the feasible dissolubility window of about 50 μ g/g to about 400mg/g, preferred 100 μ g/g to 200mg/g.Antiviral agent can have the feasible dissolubility window of about 50 μ g/g to about 400mg/g, preferred 100 μ g/g to 200mg/g.Non-steroidal anti-inflammatory agent has the feasible dissolubility window of about 200 μ g/g to about 400mg/g, preferred 1mg/g to 200mg/g.Imiquimod can have the feasible dissolubility window of about 100 μ g/g to about 400mg/g, preferred 1mg/g to 200mg/g.Testosterone can have the feasible dissolubility window of about 0.5mg/g to about 400mg/g, preferred 1mg/g to 200mg/g.α-2 agonist can have the feasible dissolubility window of about 10 μ g/g to about 400mg/g, preferred 1mg/g to 200mg/g.Antibiotic can have the feasible dissolubility window of about 10 μ g/g to about 400mg/g, preferred 1mg/g to 200mg/g.Capsaicin can have the feasible dissolubility window of about 10 μ g/g to about 400mg/g, preferred 100 μ g/g to 200mg/g.Retinoid can have the feasible dissolubility window of about 5 μ g/g to about 400mg/g, preferred 100 μ g/g to 200mg/g.

Embodiment

Following example has been set forth the present invention's abundant known embodiment at present.Yet, should be understood that following examples only are the demonstrations of the application principle of the invention or give an example.Those skilled in the art can design many variants and select as an alternative under the situation that does not break away from spirit of the present invention and scope compositions, method and system.Appended claim is intended to contain this class variant and arrangement.Therefore, though above the present invention is described in detail, the present invention is the most practical to provide further details with embodiment preferred to following examples at being considered at present.

Embodiment 1-dermal osmosis methodology

With the replica of hairless mouse skin (HMS) as extracorporeal flow quantity research as herein described.The epidermis of the fresh separated that will be downcut by the hairless mouse abdominal part is fixed between the donor compartment and receiving chamber of Franz diffusion cell carefully.In receiving chamber, pack into the phosphate buffered saline (PBS) (PBS) of pH 7.4.Begin experiment on the horny layer (SC) of skin samples by being placed on for test preparation (preparation of embodiment 2-5).The Franz pond put into 37 ℃ heater and with the HMS temperature maintenance at 35 ℃.Take out 800 μ L aliquots at interval and replace fresh PBS solution with preset time.Stable state slope by accumulation infiltration capacity-time graph is determined skin flow (μ g/cm ²/ h).Should be noted in the discussion above that the extracorporeal flow quantity research personnel selection corpse skin described in the embodiment 10 is as replica.Used skin is fixing identical with aforementioned HMS research with sampling technique.

Embodiment 2-5-comprises that the adhesivity epithelium of ketoprofen forms preparation and in vitro tests

Preparation is used for the peelable preparation of extensile adhesivity (it is suitable for via sending that the skin on joint and the muscle carries out) of dermal delivery ketoprofen, said preparation comprises the ketoprofen (the more ketoprofen of the dissolved ketoprofen of energy in than excipient mixture) of saturation capacity in the excipient mixture that forms the peelable preparation of adhesivity, wherein some prepare according to embodiment of the present invention.Composition shown in the use table 1 prepares excipient mixture, and it is thickness and transparent liquid.

Table 1. ketoprofen epithelium forms formulation components

Composition *	Embodiment
					2	3	4	5
	PVA (polyvinyl alcohol)	1	2	2					2
PEG-400 (Polyethylene Glycol)					1	1	0.27	1.75
	PVP-K90 (polyvinylpyrrolidone)	1	0	0					0

Glycerol	1	1	1.8	0.27
					Water	2.6	5.3	5.4	5.4
Ethanol	3	0	0	0
					Ketoprofen

^*Composition is represented with weight portion

Each ketoprofen flow in the compositions of embodiment 2-5 is studied, as shown in the following Table 2:

Table 2. under 35 ℃ from the peelable preparation of various adhesivities

Ketoprofen steady state flow by hairless mouse skin

Preparation	Average discharge mcg/cm 2/h *
		Embodiment 2	8±3
Embodiment 3	21±6
		Embodiment 4	3±1
Embodiment 5	1±0.4

^*Flow value is represented the meansigma methods and the SD that measure three times.

Infiltration is passed through cuticular ketoprofen amount-time of hairless mouse skin as shown in Figure 1.

About the preparation described in the embodiment 2, the second alcohol and water has formed volatile solvent system, and 1: 1 glycerol and PEG 400 mixture have formed the non-volatile solvents system.Be determined by experiment that PEG 400 is than the better solvent of glycerol for ketoprofen, yet glycerol is more much better than PEG400 with the compatibility of PVA.Therefore, the non-volatile solvents system that uses glycerol and PEG 400 together simultaneously has the rational compatibility with PVA so that the appropriate drug dissolubility to be provided.In the preparation of embodiment 2, form agent as epithelium with PVA and PVP.And in this embodiment, glycerol and PEG 400 also are used as plasticizer in the peelable preparation of the volatile solvent evaporation formed adhesivity in back.Under the situation that does not have glycerol and PEG 400, the thin film that is formed separately by PVA and PVP is inflexible and not extensible.As can be seen from Figure 1, the linear relationship between cumulant-time shows in ketoprofen 8 hours after at least a portion volatile solvent evaporation and is sent with constant relatively speed.

About the preparation of embodiment 3, the peelable preparation of formed adhesivity has the physical characteristic similar to preparation 1, but higher by the percutaneous flow of hairless mouse skin.Epithelium formation agent among this prompting embodiment 2, promptly 1: 1 PVA: the pure PVA among PVP-K-90 and the embodiment 3 is influential to permeating.

The preparation of embodiment 4 than the formulation delivered of embodiment 2 or 3 ketoprofen still less.A reason that causes this difference may be that it can cause dissolved ketoprofen amount lower, thereby causes lower skin flow owing to the PEG 400 (good solvent of ketoprofen) of low concentration in the non-volatile solvents system.If the medicine that this low skin flow can not Supporting Therapy's effective dose, then this embodiment understands that for example dissolubility wherein is lower than the scheme of " feasible dissolubility window ".

The preparation of embodiment 5 than the formulation delivered of embodiment 2 and 3 ketoprofen of much less.Think that a possible reason that causes flow to reduce is that osmotic drive power reduces, this is that PEG 400 by non-volatile solvents system middle and high concentration is caused, and the PEG400 of non-volatile solvents system middle and high concentration causes the dissolubility of ketoprofen too high.This for example clear wherein dissolubility is higher than the scheme of " feasible dissolubility window ".Therefore, when attempting to reach the skin flow, too low dissolubility is not unique consideration item.In this case, medicine too " comfortable " or in the non-volatile solvents system dissolubility very good so that effective skin flow can't be provided.Therefore, the high-dissolvability of ketoprofen make medicine be positioned at feasible dissolubility outside window outside and can not be effective.

Unique significant difference is respectively non-volatile solvent system in the preparation of embodiment 3,4 and 5, perhaps more specifically, is PEG 400: the glycerol weight ratio.These results have reflected the non-volatile solvents system to the influence of skin flow and for above-mentioned principle provides support, promptly the non-volatile solvents system provide the drug solubility that is positioned at feasible dissolubility window with the medicine that will treat effective dose be delivered to, send into or send and pass through skin.

Embodiment 6-comprises peelable preparation of the adhesivity of lignocaine and in vitro tests

Prepare the peelable preparation of extensile adhesivity that is used for the dermal delivery lignocaine according to embodiment of the present invention, it comprises the lignocaine of saturation capacity in the excipient mixture that forms the peelable preparation of adhesivity.This epithelium preparation is prepared by the composition shown in the table 3.

Table 3. lignocaine epithelium forms the component of preparation

Composition *	Embodiment
		6
	PVA		1
Eudragit E-100 **		1
	PVP-K90		0.5
Glycerol		0.75
	PEG-400		0.75
Water		2
	Ethanol		2
Lignocaine

^*Composition is represented with weight portion

^*From Rohm ﹠amp; Haas

Table 4. forms the preparation from various adhesivity epitheliums under 35 ℃

Lignocaine steady state flow by hairless mouse skin

Preparation	Average discharge mcg/cm 2/h *
		Embodiment 6	47±3

Infiltration is passed through cuticular lignocaine amount-time of hairless mouse skin as shown in Figure 2.

The peelable preparation of lignocaine adhesivity in the present embodiment has the physical characteristic similar to the preparation of embodiment 2-5.Percutaneous flow by hairless mouse skin is acceptable and kept stable state to send in 8 hours.

Embodiment 7-uses the ropivacaine flow of non-volatile solvents

As described in embodiment 1, in a plurality of saturated non-volatile solvents, measure the ropivacaine alkali flow that passes through hairless mouse skin.

Table 5. under 35 ℃ from saturated non-volatile solvents system

Ropivacaine steady-state flow value by hairless mouse skin

Non-volatile solvents	Average discharge mcg/cm 2/h *
		ISA (isostearic acid)	1 1±2
Glycerol	1.2±0.7
		Tween 20	2.4±0.1
Mineral oil	8.9±0.6
		Span 20	26±8

^*Flow value is represented the meansigma methods and the SD that measure three times

It is estimated that in order to treat cutaneous nerve pain, flow need be at 10 μ g/cm ²More than/the h.Some solvents of range specification from the ropivacaine flow value in the various non-volatile solvents have the dissolubility that is positioned at feasible dissolubility window.

Embodiment 8-9-contains the peelable preparation of adhesivity of ropivacaine

Prepare the peelable preparation of extensile adhesivity that is used for the dermal delivery ropivacaine according to embodiment of the present invention, it comprises the ropivacaine of ormal weight in the excipient mixture that forms the peelable preparation of adhesivity.This epithelium preparation contains following component:

The composition of the peelable preparation of table 6. ropivacaine

Composition *	Embodiment
			8	9
	Eudragit RL-100	1			1
Ethanol			0.6	0.6
	ISA (isostearic acid)	0.34			0.34
PG (propylene glycol)			0.2	0.1
	Trolnitrate	0.1			0.1
Glycerol			0.2	0.3
	Ropivacaine	0.085			0.085

^*Composition is represented with weight portion

As described in embodiment 1, these preparations are applied to HMS skin, and measure the ropivacaine flow.Being summarised in the table 7 of result of the extracorporeal flow quantity research that carries out with the preparation of embodiment 8 and 9 listed.

Table 7. under 35 ℃ from the peelable preparation of various adhesivities

Ropivacaine steady state flow by hairless mouse skin

Preparation	Average discharge mcg/cm 2/h *
		Embodiment 8	36±5
Embodiment 9	32±2

^*Flow value is represented the meansigma methods and the SD that measure three times

As the infiltration of the function of the time ropivacaine amount by hairless mouse skin as shown in Figure 3.About the preparation described in embodiment 8 and 9, as volatile solvent, use ISA, glycerol and PG mixture as the non-volatile solvents system with ethanol.By experiment, determining to use together ISA and propylene glycol so that the appropriate drug dissolubility to be provided, is compatible with Eudragit RL-100 film former simultaneously.And in this embodiment, glycerol is used as plasticizer in ethanol (volatile solvent) evaporation back in peelable preparation.Trolnitrate exists as the pH regulator agent provides the drug solubility that is positioned at feasible dissolubility window to send into skin with the medicine that will treat effective dose.The linearity of cumulant-time graph shows that ropivacaine was sent 8 hours with constant relatively speed.

Embodiment 10-comprises that the adhesivity epithelium of diclofenac forms preparation

Prepare the peelable preparation of extensile adhesivity that is used for the dermal delivery diclofenac according to embodiment of the present invention, it comprises the diclofenac of saturation capacity in the excipient mixture that forms the peelable preparation of adhesivity.This epithelium forms preparation and contains following component:

The composition of the peelable preparation of table 8. diclofenac

Composition *	Embodiment
		10
	PVA		1
Water		1.5
	Eudragit E-100		1

Ethanol	1
		Span 20	0.6

^*Composition is represented with weight portion

Said preparation is applied to people's corpse skin samples, and measures percutaneous flow with the method described in the embodiment 1, the result is 5 ± 2 μ g/cm ²/ h.Diclofenac amount-the time of infiltration by people's epidermis film as shown in Figure 4.The peelable preparation of the adhesivity of diclofenac and embodiment 2-6 and 8 have similar physical characteristic with 9 preparation.By 30 hours percutaneous flow of application on human skin is acceptable.

The pliability of the peelable preparation of embodiment 11-adhesivity

Preparation that will be similar to the preparation of embodiment 2 compositionss (no ketoprofen) is used the skin surface of the pure man elbow joint and articulations digitorum manus, forms thin, transparent, flexible and extensile thin film.Volatile solvent (second alcohol and water) forms strippable curing strippable coating after evaporating a few minutes.This extensile thin film has the advantages of good skin cohesiveness, does not separate with joint skin when arthrogryposis, and can easily peel off from skin.

Embodiment 12-non-volatile solvents system and epithelium form the compatibility of agent

Shown that in the present embodiment dissolubility forms the influence of the compatibility between the agent to infiltration, non-volatile solvents system and epithelium.Be slightly larger than 1: 4 through the dissolubility of measuring ropivacaine alkali in isostearic acid (ISA), this means that 1 Crow piperazine caine alkali can be dissolved in the 4 gram isostearic acids fully.In an experiment, prepare two kinds of solution: solution A comprises 1 part of ropivacaine alkali and 4 parts of isostearic acids.Solution B comprises 1 part of ropivacaine alkali, 4 parts of isostearic acids and 1 part of trolnitrate.(all umbers all by weight).Ropivacaines all in the solution A all dissolve, but only some ropivacaine dissolving in the solution B.Measured the percutaneous flow that passes through hairless mouse skin that solution produced with common Franz cell system, the result is as follows:

Table 9. is by the flow of hairless mouse skin, and is external, μ g/hr/cm ²

	Pond 1	Pond 2	Pond 3	On average
					Solution A	13.1	9.9	9.1	10.7
Solution B	43.2	35.0	50.0	42.7

As can be seen, the flow that is produced by solution B is about 4 times of the flow that produces of solution A.These result's proofs have increased the percutaneous flow significantly by adding the dissolubility of trolnitrate minimizing ropivacaine in isostearic acid (non-volatile solvents system).Yet, this system mixed based on the trial of the epithelium preparation of polyvinyl alcohol (PVA) failed, because the PVA in the preparation is as the strong pH buffer agent that suppresses the trolnitrate effect.Adding more trolnitrate causes the epithelium of required PVA to form the characteristic forfeiture with the pH buffer capacity of attempting to overcome PVA.When form agent EudragitRL 100 (Rohm ﹠amp with another kind of epithelium; When Haas) replacing PVA, the effect of trolnitrate is not suppressed, and has obtained to produce about 30 μ g/hr/cm ²The preparation of flow.This has proved that non-volatile solvents system and epithelium form the benefit of the compatibility between the agent.

Embodiment 13-has the peelable preparation of adhesivity of ropivacaine

The peelable preparation of extensile adhesivity that is used for dermal delivery ropivacaine (it is suitable for via sending that the skin on joint and the muscle carries out) by the following ingredients preparation:

Table 10. ropivacaine epithelium forms the component of preparation

Composition *	Embodiment
		13
	Ropivacaine HCl		0.096
Eudragit RL-100		1.0
	Ethanol		0.7
Isostearic acid		0.34
	Glycerol		0.3
Propylene glycol		0.1
	Trolnitrate		0.15

^*Composition is represented with weight portion

Above ingredients listed is mixed in accordance with the following methods.Eudragit RL-100 and ethanol mixed in glass jar and be heated to about 60 ℃ and finish dissolving until Eudragit RL-100.After Eudragit solution is cooled to room temperature, add the ropivacaine HCl and abundant the mixing 1 minute of Sq.In this solution, add isostearic acid (ISA) and with mixture vigorous stirring 2-3 minute.After one hour, solution was acutely mixed 2-3 minute once more.In this solution, add glycerol, propylene glycol and trolnitrate successively.After adding every kind of composition, with solution stirring 1 minute.

Embodiment 14-ropivacaine flow

To as described in embodiment 1, be applied on the HMS according to the preparation of embodiment 13 preparations, and measure the ropivacaine flow.Being summarized as follows in table 11 of result listed:

Table 11. under 35 ℃ from the peelable preparation of various adhesivities

Ropivacaine steady state flow by hairless mouse skin

Preparation	Average discharge mcg/cm 2/h *
		Embodiment 13	43±4

^*Flow value is represented the meansigma methods and the SD that measure three times

Ropivacaine epithelium preparation according to embodiment 13 preparation has acceptable application characteristic, for example, from the easiness that sample cell is removed epithelium, spreads over easiness on the dermal application position of expection etc., and formed cured film in 2-3 minute.This curing strippable coating became easier and peels off in 2 hours, and epithelium keeps sticking on skin surface, any unconscious epithelium does not take place removes and reach at least 12 hours.After the use of expection finished, epithelium was easily removed with one successive.

Though invention has been described with reference to some embodiment preferred, one of ordinary skill in the art will recognize that and under the situation that does not break away from spirit of the present invention, to carry out various modifications, variation, omission and alternative.Therefore, the present invention is only limited by the scope of claims.

Claims (62)

1. the adhesivity epithelium that is used for the dermal delivery medicine forms preparation, and it comprises

A) medicine;

B) solvent carrier, it comprises

I) comprise one or more volatile solvents volatile solvent system and

The non-volatile solvents system that ii) comprises one or more non-volatile solvents, wherein the non-volatile solvents system have the drug solubility that is arranged in feasible dissolubility window in case can a period of time that continues with treatment effective speed delivering drugs; With

C) epithelium forms agent,

Wherein said preparation has the viscosity that is fit to use and be adhered to skin surface before the volatile solvent system evaporation, and the said preparation that wherein is applied to skin surface forms to small part evaporation back in volatile solvent system and solidifies strippable coating, wherein evaporates the back medicine basically in volatile solvent system and continues to be sent.

2. the preparation of claim 1 wherein forms agent for described epithelium, and the non-volatile solvents system is as plasticizer.

3. the preparation of claim 1, wherein said volatile solvent system comprises water and at least a than the more volatile solvent of water, and it is selected from ethanol, isopropyl alcohol, ethyl acetate, acetone, their mixture, and their mixture.

4. the preparation of claim 1, wherein the non-volatile solvents system comprises the multiple non-volatile solvents that mixes, these non-volatile solvents provide the drug solubility that is positioned at feasible dissolubility window.

5. the preparation of claim 1, wherein the non-volatile solvents system comprises one or more solvents that is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, oleyl alcohol, isostearic acid, comprise the fatty acid of medium-chain fatty acid and their mixture.

6. the preparation of claim 1, wherein epithelium forms agent and is selected from down group: polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, guar gum, xanthan gum, weight average molecular weight is greater than about 5, the polyethylene glycol oxide of 000Mw, starch, cellulose derivative, hydroxyethyl-cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, the copolymer of methyl vinyl ether and maleic anhydride, the polyvinyl alcohol-polyethylene glycol copolymer, methacrylate polymers, with methacrylic acid and methacrylate is based copolymers, comprise poly-(methacrylic acid) copolymer, methylmethacrylate copolymer, EUDRAGIT L100-55, and their combination.

7. the preparation of claim 1, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises aciclovir, penciclovir, famciclovir, valaciclovir steroid; He behenyl alcohol; And their combination.

8. the preparation of claim 1, its Chinese medicine is the steroid that is used for the treatment of herpes infection.

9. the preparation of claim 1, its Chinese medicine is the medicine that is used for the treatment of herpes labialis.

10. the preparation of claim 1, its Chinese medicine is the medicine that is used for the treatment of genital wart.

11. the preparation of claim 1, its Chinese medicine are the medicines that is used for the treatment of musculoskeletal pain.

12. the preparation of claim 1, its Chinese medicine is an antifungal agent.

13. the preparation of claim 12, wherein antifungal agent is selected from down group: ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and comprise butenafine, the naphthalene husband allylamine derivatives for sweet smell and terbinafine, and their combination.

14. the preparation of claim 1, its Chinese medicine is an antiviral agents.

15. the preparation of claim 14, wherein antiviral agents is selected from down group: acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, acyclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and their combination.

16. the preparation of claim 1 wherein solidifies strippable coating and is fully flexible and when having cohesiveness to be applied to person joint's skin with box lunch to skin, solidifying strippable coating when arthrogryposis will intactly remain on the skin basically.

17. the preparation of claim 1, wherein peelable preparation are configured to form the back with the speed delivering drugs of substantial constant at least 2 hours at described curing strippable coating.

18. the preparation of claim 1, wherein peelable preparation are configured to form the back with the speed delivering drugs of substantial constant at least 8 hours at described curing strippable coating.

19. the preparation of claim 1, wherein the weight ratio of non-volatile solvents system and epithelium formation agent is about 0.2: 1 to about 1.2: 1.

20. the preparation of claim 1, wherein volatile solvent system can cause that application on human skin stimulates and described non-volatile solvents system at least a non-volatile solvents can reduce skin irritation.

21. the preparation of claim 20 wherein can reduce skin irritant non-volatile solvents and be selected from down group: glycerol, propylene glycol and Mel.

22. the preparation of claim 1 wherein is being applied to skin surface and is forming in 15 minutes solidifying strippable coating under standard skin and the environmental condition.

23. the preparation of claim 1 wherein is being applied to skin surface and is forming in 4 minutes solidifying strippable coating under standard skin and the environmental condition.

24. the preparation of claim 1, wherein said preparation has about 100 initial viscosities to about 3,000,000 centipoise before dermal application.

25. the preparation of claim 1, wherein the percetage by weight of volatile solvent system is that about 4 weight % are to about 30 weight %.

Be used for the treatment effective speed medicine being delivered to individual purposes in a period of time that continues 26. be applied to the adhesivity epithelium formation preparation of skin surface, described preparation comprises:

A) medicine;

B) solvent carrier, it comprises

I) comprise one or more volatile solvents volatile solvent system and

The non-volatile solvents system that ii) comprises one or more non-volatile solvents, wherein the non-volatile solvents system have the drug solubility that is arranged in feasible dissolubility window in case can a period of time that continues with treatment effective speed delivering drugs; With

C) epithelium forms agent,

Wherein said preparation has the viscosity that is fit to use and be adhered to skin surface before the volatile solvent system evaporation, and the said preparation that wherein is applied to skin surface forms to small part evaporation back in volatile solvent system and solidifies strippable coating, wherein evaporates the back medicine basically in volatile solvent system and continues to be sent.

27. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein the adhesivity epithelium forms preparation by with the thickness application of about 0.01mm to about 2mm.

28. the adhesivity epithelium of claim 27 forms the purposes of preparation, wherein thickness is that about 0.05mm is to about 1mm.

29. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein the non-volatile solvents system comprises the multiple non-volatile solvents that mixes with the formation mixture, and described mixture provides the drug solubility that is positioned at feasible dissolubility window.

30. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein the non-volatile solvents system comprises one or more solvents that is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, isostearic acid, fatty acid and medium-chain fatty acid, and their mixture.

31. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein epithelium forms agent and is selected from down group: polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, guar gum, xanthan gum, weight average molecular weight is greater than about 5, the polyethylene glycol oxide of 000Mw, starch, cellulose derivative, hydroxyethyl-cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, the copolymer of methyl vinyl ether and maleic anhydride, the polyvinyl alcohol-polyethylene glycol copolymer, methacrylate polymers, with methacrylic acid and methacrylate is based copolymers, comprise poly-(methacrylic acid) copolymer, methylmethacrylate copolymer, EUDRAGIT L100-55, and their combination.

32. the adhesivity epithelium of claim 26 forms the purposes of preparation, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises aciclovir, penciclovir, famciclovir, valaciclovir steroid; He behenyl alcohol; And their mixture.

33. the adhesivity epithelium of claim 26 forms the purposes of preparation, its Chinese medicine is the medicine that is used for the treatment of herpes infection, herpes labialis or genital wart.

34. the adhesivity epithelium of claim 26 forms the purposes of preparation, its Chinese medicine is the medicine that is used for the treatment of skeletal pain.

35. the adhesivity epithelium of claim 26 forms the purposes of preparation, its Chinese medicine is the antifungal agent that is selected from down group: ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and comprise butenafine, naphthalene husband for allylamine derivatives fragrant, terbinafine, and their combination.

36. the adhesivity epithelium of claim 26 forms the purposes of preparation, its Chinese medicine is the antiviral agents that is selected from down group: acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, acyclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and their combination.

37. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein solidify strippable coating and be fully flexible and when having cohesiveness to be applied to person joint's skin with box lunch to skin, solidifying strippable coating when arthrogryposis will intactly remain on the skin basically.

38. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein peelable preparation is configured to form the back with the speed delivering drugs of substantial constant at least 2 hours at described curing strippable coating.

39. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein peelable preparation is configured to form the back with the speed delivering drugs of substantial constant at least 8 hours at described curing strippable coating.

40. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein the weight ratio of non-volatile solvents system and epithelium formation agent is about 0.2: 1 to about 1.2: 1.

41. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein solidifies strippable coating and forms in 4 minutes being applied to skin surface.

42. the adhesivity epithelium of claim 26 forms the purposes of preparation, wherein said preparation has about 100 initial viscosities to about 3,000,000 centipoise.

43. preparation is used for the method that adhesivity epithelium that dermal drug sends forms preparation, it comprises:

A) selection is suitable for the medicine of dermal delivery;

B) select the non-volatile solvents system form by a kind of non-volatile solvents basically with the drug solubility that is positioned at feasible dissolubility window; With

C) medicine and non-volatile solvents are mixed with adhesivity epithelium formation preparation, it also comprises the volatile solvent system that epithelium forms agent and comprises at least a volatile solvent, described adhesivity epithelium forms preparation and have the viscosity that is fit to be applied to skin surface before the volatile solvent system evaporation, and the said preparation that wherein is applied to skin surface forms at least a portion volatile solvent system evaporation back and solidifies strippable coating, and wherein evaporates the back medicine basically in volatile solvent system and continue to be sent with the treatment effective speed.

44. the method for claim 43, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents, comprise acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, acyclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and their combination; Antifungal agent comprises ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and allylamine derivatives such as butenafine, naphthalene husband for sweet smell and terbinafine, and their combination.

45. the method for claim 43, wherein non-volatile solvents is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, oleyl alcohol, isostearic acid, fatty acid and medium-chain fatty acid.

46. preparation is used for the method that adhesivity epithelium that dermal drug sends forms preparation, it comprises:

A) selection is suitable for the medicine of dermal delivery;

B) by selecting at least two kinds of non-volatile solvents to form the non-volatile solvents system according to the ratio that the dissolubility that makes medicine in the non-volatile solvents system is positioned at feasible dissolubility window; With

C) medicine and non-volatile solvents system are mixed with adhesivity epithelium formation preparation, it also comprises the volatile solvent system that epithelium forms agent and comprises at least a volatile solvent, described adhesivity epithelium forms preparation and have the viscosity that is fit to be applied to skin surface before the volatile solvent system evaporation, and the said preparation that wherein is applied to skin surface forms at least a portion volatile solvent system evaporation back and solidifies strippable coating, and wherein evaporates the back medicine basically in volatile solvent system and continue to be sent with the treatment effective speed.

47. the method for claim 46, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises aciclovir, penciclovir, famciclovir, valaciclovir steroid; He behenyl alcohol; And their mixture.

48. the method for claim 46, wherein the non-volatile solvents system comprises the member who is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, isostearic acid, fatty acid and medium-chain fatty acid, and their mixture.

49. be used for the curing strippable coating of delivering drugs, it comprises

A) medicine;

B) have the non-volatile solvents system of one or more non-volatile solvents, wherein this non-volatile solvents system provides feasible dissolubility window for medicine so that can be with treatment effective speed delivering drugs at least 2 hours; With

C) epithelium forms agent,

Wherein said strippable coating can stretch 10% and do not rupture or break at least one direction.

50. the curing strippable coating of claim 49 wherein forms agent for epithelium, the non-volatile solvents system is as plasticizer.

51. the curing strippable coating of claim 49, wherein the non-volatile solvents system comprises the member who is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, isostearic acid, fatty acid and medium-chain fatty acid, and their mixture.

52. the curing strippable coating of claim 49, wherein epithelium formation agent comprises the member who is selected from down group: dextrin, guar gum, xanthan gum, weight average molecular weight is greater than about 5, the polyethylene glycol oxide of 000Mw, starch, cellulose derivative, hydroxyethyl-cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, methacrylate polymer, EUDRAGIT L100-55, the polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, guar gum, xanthan gum, polyethylene glycol oxide, starch, cellulose derivative, the copolymer of methyl vinyl ether and maleic anhydride, and their mixture.

53. the curing strippable coating of claim 49, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir; Antifungal agent comprises ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and comprises that butenafine, naphthalene husband replace the allylamine derivatives of sweet smell and terbinafine; And their combination.

Form preparation 54. be used for the adhesivity epithelium of dermal delivery medicine, it comprises:

A) medicine;

B) epithelium forms agent; With

C) solvent carrier, it comprises

I) comprise one or more volatile solvents volatile solvent system and

The non-volatile solvents system that ii) comprises one or more non-volatile solvents,

Wherein when described adhesivity epithelium formation preparation is applied to skin surface, the adhesivity epithelium forms preparation and forms the curing strippable coating with contact surface, described contact surface has first area size, described curing strippable coating be extensile in case the first area size tensible to not breaking, rupture or separate with skin surface than the second area size of first area size big 10%; And wherein after described curing strippable coating forms and after volatile solvent system is evaporated basically, medicine continues to be sent with the treatment effective speed.

55. the preparation of claim 54, wherein said volatile solvent system comprise the member who is selected from down group: water, ethanol, isopropyl alcohol, ethyl acetate, acetone, and their mixture.

56. the preparation of claim 54, wherein the non-volatile solvents system comprises one or more solvents that is selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, isostearic acid, medium-chain fatty acid and other fatty acid, and their mixture.

57. the preparation of claim 54, wherein epithelium formation agent comprises the member who is selected from down group: polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, guar gum, xanthan gum, weight average molecular weight are greater than about 5, the polyethylene glycol oxide of 000Mw, starch, cellulose derivative, and their mixture.

58. the preparation of claim 54, its Chinese medicine is selected from down group: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine and zanamivir; Antifungal agent comprises ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and comprises that butenafine, naphthalene husband replace the allylamine derivatives of sweet smell and terbinafine; And their combination.

59. the preparation of claim 54, wherein the weight ratio of non-volatile solvents system and epithelium formation polymer is about 0.2: 1 to about 1.2: 1.

60. the preparation of claim 54 wherein is being applied to skin surface and is forming in 15 minutes solidifying strippable coating under standard skin and the environmental condition.

61. the preparation of claim 54 wherein solidifies strippable coating and forms in being applied to skin surface 4 minutes.

Form preparation 62. be used for the adhesivity epithelium of dermal delivery medicine, it comprises:

A) be selected from down the medicine of organizing: NSAID (non-steroidal anti-inflammatory drug) (NSAID) comprises ketoprofen and diclofenac; COX-2 is NSAID and activating agent optionally; COX-3 is NSAID and activating agent optionally; Local anesthetic comprises lignocaine, bupivacaine, ropivacaine and tetracaine; Steroid comprises dexamethasone; Antibiotic; Retinoid; Clonidine; Peroxide; Retinol; Salicylic acid; Imiquimod; Wetting agent; Softening agent; Antiviral agents comprises acyclovir, trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir, ganciclovir, valaciclovir, podofilox, podophyllotoxin, ribavirin, Abacavir, delavirdine, Didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, viracept see nelfinaivr, ritonavir, Saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine and zanamivir; Antifungal agent comprises ciclopirox, imidazoles, miconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and comprises that butenafine, naphthalene husband replace the allylamine derivatives of sweet smell and terbinafine; And their combination;

B) solvent carrier, it comprises:

I) comprise the volatile solvent system of one or more volatile solvents, described one or more volatile solvents are selected from down group: water, ethanol, isopropyl alcohol, ethyl acetate, acetone, their mixture and

The non-volatile solvents system that ii) comprises one or more non-volatile solvents, wherein the non-volatile solvents system have the drug solubility that is arranged in feasible dissolubility window in case can a period of time that continues with treatment effective speed delivering drugs; And described one or more non-volatile solvents are selected from down group: the polyoxyethylene deriv of the Polyethylene Glycol of glycerol, the about 200MW to 800MW of weight average molecular weight, mineral oil, vaseline, Oleum Ricini, n-methyl pyrrolidone, vegetable oil, Mel, oleyl alcohol, dipropylene glycol, Isosorbide Dinitrate, saturated Pegylation C ₈To C ₁₀Glyceride, polyoxy ethylization fatty glyceride, dimethyl sulfoxide, aliphatic alcohol, isopropyl myristate, ethyl oleate, the quintessence oil that comprises acetaminol and Oleum Rosae Rugosae, oleic acid, oleyl alcohol, isostearic acid, comprise the fatty acid of medium-chain fatty acid and their mixture; With

C) epithelium that is selected from down group forms agent: the copolymer of polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, dextrin, guar gum, xanthan gum, polyethylene glycol oxide, hydroxyethyl-cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, methyl vinyl ether and maleic anhydride, polyvinyl alcohol-polyethylene glycol copolymer, be based copolymers with methacrylic acid and methacrylate, comprise poly-(methacrylic acid) copolymer, methylmethacrylate copolymer, EUDRAGIT L100-55;

Wherein said preparation has the viscosity that is fit to use and be adhered to skin surface before the volatile solvent system evaporation, and the said preparation that wherein is applied to skin surface forms to small part evaporation back in volatile solvent system and solidifies strippable coating, wherein evaporating the back medicine basically in volatile solvent system continues to be sent, wherein said preparation had 5 minutes or shorter drying time under standard skin and environmental condition, wherein to form the weight ratio of polymer be about 0.2: 1 to about 1.2: 1 for non-volatile solvents system and epithelium, and wherein solidify strippable coating can stretch 10% and do not break at least one direction, fracture or separate with skin.

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