CN101277686A - Formulations and methods for enhancing the transdermal penetration of a drug - Google Patents
Formulations and methods for enhancing the transdermal penetration of a drug Download PDFInfo
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- CN101277686A CN101277686A CNA2006800366384A CN200680036638A CN101277686A CN 101277686 A CN101277686 A CN 101277686A CN A2006800366384 A CNA2006800366384 A CN A2006800366384A CN 200680036638 A CN200680036638 A CN 200680036638A CN 101277686 A CN101277686 A CN 101277686A
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Abstract
Methods and formulations of enhancing the permeability the skin of a subject to a drug are disclosed. The method may include administering a combination of lauryl alcohol and isopropyl myristate as a penetration enhancer to the area of skin to provide synergistically enhanced penetration of the drug.
Description
The priority data
[1] the application requires the rights and interests of No. the 60/705th, 289, the U.S. Provisional Patent Application sequence submitted on August 3rd, 2005, and it incorporates this paper into as a reference.
Invention field
[2] the present invention relates to the collaborative method and formulation that promotes medicine by the subject's skin infiltration.Correspondingly, the present invention relates to chemistry, pharmaceutical science, medical science and other health science field.
Background of invention
[3] transdermal delivery of medicine has been improved the route of administration of establishing, and it typically provides and has been better than other approach such as the oral and outer many advantages of carrying of intestinal.The recognized advantages of transdermal drug delivery (transdermal administration) comprising: the administration frequency of bigger patient's comfortableness and convenience, reduction, the elimination of liver first pass metabolism and to the height control of drug plasma concentration.These all advantages cause bigger patient's compliance, and make to have bigger degree of freedom in the effective therapeutic scheme of design.
[4] although these advantages are arranged, transdermal medicine preparation typically is faced with many challenges.Skin irritation, onset time are slow, the medicine of the unstability of storage period and delivering therapeutic effective dose is by skin and enter the required skin area amount of serum, are typically to hinder the problem that most of transdermal drug delivery are made great efforts.
[5] in order to solve above-mentioned main challenge, that is, increase medicine by skin and the speed that enters serum, in transdermal administration is carried, known application chemical skin penetration promoter.The acceleration of medicine infiltration provides many advantages, as has reduced the ability that reaches the required time of curative drug serum levels and reduce the size of the skin area that medicine must be applied thereon.Unfortunately, also cause the comprising of dermal osmosis accelerator or facilitate at least above-mentioned many other challenges, for example with preparation capable of permeating skin in drug reaction, facilitate or cause skin irritation and influence the cohesive of transdermal patch.
[6] many particular compound are studied as transdermal penetration promoter, at United States Patent (USP) the 5th, 601, and 839,5,006,342,4,973,468,4,820,720,4,006,218,3,551,154 and 3,472, in No. 931, can find example as the medicament of promoter.The effectiveness of penetration enhancer is very important, because promoter is effective more, realizes that the required amount of facilitation is few more.Certainly, when the penetration enhancer of needs more after a little while, the challenge that promoter successfully is included in the preparation capable of permeating skin is weakened.
[7] therefore, seeking wide effective penetration enhancer of scope medicine height and permeation enhancer compositions always.
Summary of the invention
[8] correspondingly, the invention provides the method and formulation that promotes that medicine permeates by subject's skin.On the one hand, this method can comprise, be administered to skin area so that the collaborative drug osmotic that promotes to be provided by combination as penetration enhancer (penetrationenhancer), promote the infiltration of medicine by skin area with lauryl alcohol (lauryl alcohol) and isopropyl myristate (isopropyl myristate).
[9] cooperative effect of the combination of lauryl alcohol and isopropyl myristate can cause the infiltration facilitation of medicine, and described effect is bigger than the additive effect of each independent promoter of the equal volume that exists in the preparation.Like this, on the one hand, the transdermal penetration facilitation can be than the expection additive effect of using lauryl alcohol and isopropyl myristate high about 5% to about 150%.On the other hand, the infiltration facilitation is than intended effect high about 5% to about 75%.Another aspect, the infiltration facilitation is than intended effect high about 10% to about 50%.
[10] ratio of lauryl alcohol and isopropyl myristate can promote characteristic, the characteristic of medicine, employed special adhesive etc. to change according to the expectation medicine of preparation.On the one hand, penetration enhancer can comprise ratio be about 1: 5 to about 5: 1 lauryl alcohol and isopropyl myristate.On the other hand, penetration enhancer can comprise that ratio is about 1: 4 to 4: 1 lauryl alcohol and isopropyl myristate.On the other hand, penetration enhancer can comprise ratio be about 1: 3 to about 3: 1 lauryl alcohol and isopropyl myristate.Another aspect, penetration enhancer can comprise ratio be about 1: 2 to about 2: 1 lauryl alcohol and isopropyl myristate.On the one hand, penetration enhancer can comprise that ratio is about 1: 1 lauryl alcohol and isopropyl myristate again.Another aspect, penetration enhancer can comprise that ratio is about 4: 1 lauryl alcohol and isopropyl myristate.
[11] penetration enhancer of the present invention can improve the permeability of subject's skin to multiple medicine.The one class medicine that can have benefited from the penetration enhancer combination is a hormone.Any hormone well known by persons skilled in the art all is to be considered within the scope of the invention, but gonadal hormone merits attention especially.The instantiation of gonadal hormone includes but not limited to, testosterone, norethindrone, norethindrone acetate, estradiol, norelgestromine (norelgestromin) and their mixture, salt, isomer or analog.Testosterone is that the combination of lauryl alcohol and isopropyl myristate demonstrates the gonadal hormone of special advantage to it.
[12] lauryl alcohol can be applied to object with any order with respect to isopropyl myristate.Therefore, lauryl alcohol and isopropyl myristate can be used respectively, and perhaps, they can be used as single enhancer compositions and use.Thus, lauryl alcohol can be before isopropyl myristate, use simultaneously or afterwards.In one aspect of the invention, lauryl alcohol and isopropyl myristate are used simultaneously.Similarly, the combination of lauryl alcohol and isopropyl myristate can be before medicine, use simultaneously or afterwards.On the one hand, the combination of lauryl alcohol and isopropyl myristate and medicine are used simultaneously.On the other hand, the combination of lauryl alcohol and isopropyl myristate can before the drug administration, during and use afterwards.Another aspect, the combination of lauryl alcohol and isopropyl myristate can be used as single enhancer compositions and uses.
[13] in another aspect of this invention, also provide the permeation enhancer compositions of stating use as this paper.Such penetration enhancer can comprise the combination of lauryl alcohol and isopropyl myristate, and the infiltration of the percutaneous collaborative promotion of medicine can be provided.
[14] in addition, the present invention includes the preparation capable of permeating skin that to use according to this method.On the one hand, this preparation can comprise the medicine of pharmaceutically acceptable carrier, treatment effective dose and the permeation enhancer compositions of stating as this paper.
[15] though the amount of the lauryl alcohol that comprises in the preparation can depend on many standards and change, for example, the concrete medicine that is transferred, the chemistry of carrier constitute or the like, but on the one hand, and can respectively do for oneself about 0.5%w/w of preparation capable of permeating skin of lauryl alcohol and isopropyl myristate arrives about 20%w/w.On the other hand, lauryl alcohol and isopropyl myristate can respectively be done for oneself about 1%w/w of preparation capable of permeating skin to about 10%w/w.On the other hand, lauryl alcohol and isopropyl myristate can respectively be done for oneself about 2.5%w/w of preparation capable of permeating skin to about 7.5%w/w.Again on the one hand, lauryl alcohol and the isopropyl myristate about 5%w/w of preparation capable of permeating skin that can respectively do for oneself.Again on the one hand, lauryl alcohol and isopropyl myristate can respectively be done for oneself below about 5%w/w of preparation capable of permeating skin or be equaled about 5%w/w.
[16] pharmaceutically acceptable carrier of the present invention can be any carrier well known by persons skilled in the art.On the one hand, pharmaceutically acceptable carrier can be a biocompatible polymer.Biocompatible polymer can comprise without limitation: rubber, organosilicon polymer (siliconepolymers) and copolymer, acrylic acid base polymer and copolymer and their mixture.On the one hand, biocompatible polymer is a rubber, and it can be any useful rubber well known by persons skilled in the art, comprises natural rubber and synthetic rubber, plasticising styrene-rubber block copolymers etc. and their mixture.On the other hand, biocompatible polymer can include organosilicon polymer, polysiloxanes and their mixture.In another embodiment, biocompatible polymer can comprise acrylic polymer, polyacrylate and their mixture.In further embodiment, biocompatible polymer can comprise vinylacetate, vinyl-vinyl acetate copolymer, polyurethanes, plasticising polyether amide block copolymer and their mixture.
The present invention also considers liquid storage storehouse system (liquid reservior system, LRS) preparation.On the one hand, pharmaceutically acceptable carrier can comprise the stickum that is suitable for being included in the liquid storage storehouse.An example of stickum can comprise the material that forms gel without limitation.
[17] preparation capable of permeating skin of the present invention can be taked many specific embodiment.On the one hand, preparation can be a transdermal patch.Transdermal patch can comprise the patch of any kind well known by persons skilled in the art, comprises transdermal matrix patch, liquid storage storehouse patch or the like.On the other hand.Preparation capable of permeating skin can be a topical formulations.Topical formulations can non-limitingly comprise: emulsifiable paste (agent) (creams), lotion, ointment (agent) (ointment), gel, paste, mousse (mousses), aerosol, spray, wax, balsam (balms), suppository and their mixture or combination.For the preparation capable of permeating skin of special expectation is provided, can use the arbitrary member in many special components, for example, diluent, excipient, softening agent (emollients), plasticizer, solubilizing agent, skin irritation palliative (skin irritation reducing agents), stable compound or their mixture.
[18] on the other hand, provide a kind of method of transdermal delivery medicine, described method has enhanced infiltration of passing the subject's skin zone.This method typically comprises preparation capable of permeating skin as herein described is administered to the subject's skin zone.
[19] the present invention also considers test kit, is used for the infiltration of passing the subject's skin zone with enhanced, uses the preparation capable of permeating skin that contains medicine.On the one hand, test kit can comprise pharmaceutically acceptable carrier---wherein be mixed with medicine, the lauryl alcohol of effective dose and the isopropyl myristate of effective dose of treatment effective dose.Lauryl alcohol and isopropyl myristate can provide the collaborative transdermal drug infiltration that promotes.Test kit can also comprise the description of describing the method for using preparation capable of permeating skin.On the one hand, lauryl alcohol and isopropyl myristate can be combined as single permeation enhancer compositions.On the other hand, they also can be included in the test kit respectively.
[20] in a specific embodiment of the present invention, provide method with the enhancing infiltration transdermal delivery medicine that passes the subject's skin zone.This method comprises to skin area uses preparation capable of permeating skin, described preparation capable of permeating skin contains: account for the acrylic polymer contact adhesive (pressure sensitive adhesive) of about 55%w/w of preparation capable of permeating skin to about 85%w/w, account for the testosterone of about 5%w/w of preparation capable of permeating skin to about 12%w/w, account for the polyvinylpyrrolidone of about 8%w/w of preparation capable of permeating skin, and permeation enhancer compositions---it comprises the lauryl alcohol and about 2%w/w combination to the isopropyl myristate of about 8%w/w of about 2%w/w to about 8%w/w to about 12%w/w.The infiltration that permeation enhancer compositions can provide medicine to pass through the collaborative promotion of skin area, described infiltration is than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 10% to about 50%.
[21] in another embodiment, provide preparation capable of permeating skin with enhanced drug osmotic.Preparation capable of permeating skin can comprise: account for the acrylic polymer contact adhesive of about 55%w/w of preparation capable of permeating skin to about 85%w/w, account for the testosterone of about 5%w/w of preparation capable of permeating skin to about 12%w/w, the about 8%w/w that accounts for preparation capable of permeating skin is to the solubilizing agent of about 12%w/w, and permeation enhancer compositions---and it comprises and accounts for the about 2%w/w of preparation capable of permeating skin to the lauryl alcohol of about 8%w/w with account for the isopropyl myristate that the about 2%w/w of preparation capable of permeating skin arrives about 8%w/w.Permeation enhancer compositions can provide testosterone to pass through the infiltration of the collaborative promotion in subject's skin zone.
Term definition
[22] describing and claimed when of the present invention, following term will be according to the definition application of hereinafter setting forth.
[23] singulative " (a) ", " one (an) " and " being somebody's turn to do (the) " comprise that plural number refers to thing, indicate unless context is additionally clear.Therefore, for example, referring to of " (a kind of) binding agent (an adhesive) " comprised the referring to of one (a kind of) or a plurality of (multiple) such binding agent, referring to of " (a kind of) excipient (an excipient) " comprised referring to one (a kind of) or a plurality of (multiple) such excipient.
[24] as used herein, " lauryl alcohol " or " 1-12 (alkane) alcohol (1-Dodecanol) " is meant the chemical compound with following general chemical constitution:
Lauryl alcohol is known in the art, and
Merck Index(13
ThEd.2001) be listed in monograph 3439 (monograph 3439) in the 3443rd page, it incorporates this paper into as a reference.
[25] as used herein, " isopropyl myristate " or " IPM " is the chemical compound with following general chemical constitution:
IPM is known in the art, and
Merck Index(13
ThEd.2001) be listed in monograph 5235 in the 5238th page, it incorporates this paper into as a reference.。
[26] as used herein, " object " is meant and can benefits from using or the mammal of method of pharmaceutical composition of the present invention.The example of object comprises the mankind, can also comprise other animals such as horse, pig, cattle, Canis familiaris L., cat, rabbit and aquatic mammals.
[27] as used herein, terms " formulation " and " compositions " can be replaced mutually and be used, and are meant the mixture of two or more chemical compounds, key element or molecule.In some respects, terms " formulation " and " compositions " can be used in reference to the mixture for one or more active agents and carrier or other excipient.Term " medicine ", " medicament (medicine) ", " activating agent " and " bioactivator " also can be replaced mutually and be used, and refer to pharmacologic activity material or component.At pharmacy and medical domain, these technical terms are known.
[28] as used herein, term " transdermal " is meant the route of administration of taking through the medicine of skin Zoned application and absorption.In some respects, skin can be not damaged basically.Therefore, term " preparation capable of permeating skin " and " transdermal composition " can be replaced use mutually, are meant to be applied to skin surface and by the preparation of Transdermal absorption or compositions.The example of preparation capable of permeating skin includes but not limited to: ointment, ointment, gel, transdermal patch, spray, lotion, mousse, aerosol, nasal spray, oral cavity and sublingual tablet and adhesive plaster (tape), pessary and paste.Therefore, term " transdermal administration (transdermal administration) " is meant the transdermal application of preparation or compositions.Transdermal administration can be by using transdermal formulation or preparation, paste, roll, adhere to, topple over, push, rub at skin or mucomembranous surface is first-class finishes.In the art, these medications and other medication are known.
[29] term " transdermal delivery system (transdermal drug delivery system; transdermal deliverysystem) ", " transdermal patch " or only " patch " be meant, the transdermal delivery device of matrix type or liquid reservoir devices, it is used for the material of transdermal delivery limiting dose in specific application period.
[30] term " substrate ", " matrix system " or " matrix patch " are meant such compositions: it comprises the medicine that is dissolved in or is scattered in the effective dose in the polymer phase, and described polymer phase is contact adhesive normally; It can also comprise other compositions, as penetration enhancer, skin irritation palliative, excipient, plasticizer, solubilizing agent, softening agent and other optional ingredients.This definition is intended to comprise such embodiment: wherein such polymer phase is in turn laminated to contact adhesive or uses in upper strata binding agent (overlay adhesive).
[31] the general structure of matrix type patch preparations is known for those skilled in the art.This structure generally comprises: the impermeable sealing backing of medicine, described backing layer is pressed in the distally of solid or semisolid matrix layer, and described hypothallus comprises the homogeneous admixture of medicine, polymer pressure-sensitive adhesion agent carrier and optional one or more dermal osmosis accelerators; With the interim strippable release liner that is bonded in the hypothallus nearside (release liner).In use, before being applied to skin, patch removes release liner.Matrix patch is known in the transdermal administration transportation art.The limiting examples of gluing substrate transdermal patch (adhesive matrix transdermal patches) is a United States Patent (USP) 5,985,317,5,783,208,5,626,866,5,227,169,5,122,383 and 5, those that describe in 460, No. 820 or quote, described patent is incorporated this paper into as a reference.
[32] in addition, the general structure of liquid storage storehouse system (LRS) type patch also is known.This patch generally comprises the fluid with desired viscosity, as gel or ointment, it is configured to and is limited in the storage storehouse, described storage storehouse (Drug Storage) has impermeable backing and the permeable membrane that contacts skin, or the film adhesive laminate body (membrane adhesive laminate) that provides storage storehouse content to contact with diffusibility between the skin.Medicine and any penetration enhancer are included in the fluid with the amount of expectation.In order to use, to remove strippable release liner, and patch is pasted skin surface.In the transdermal administration transportation art, the LRS patch is known.The limiting examples of LRS transdermal patch is a United States Patent (USP) 4,849,224,4,983, and those that describe in No. 395 or quote, described patent is incorporated this paper into as a reference.
[33] term " skin ", " skin surface ", " corium ", " epidermis " and the commutative in this article use of similar term not only are meant the external skin of the object that comprises epidermis also to refer to the mucomembranous surface that pharmaceutical composition can be applied.The example of mucomembranous surface comprises the surface of respiratory apparatus (comprising nose and lung), mouthful (mouth and oral cavity), vagina, vaginal orifice (vaginal vestibule), lip and rectum.Therefore, term " transdermal " also comprises " saturating mucosa ".
[34] as used herein, " facilitation (potentiation; enhancement) ", " infiltration facilitation (infiltration potentiation; penetration enhancement) " or " seeing through facilitation (seeing through potentiation; permeation enhancement) " are meant that skin increases the permeability of medicine, to such an extent as to the percutaneous speed of drug osmotic increases.Therefore, " see through promoter ", " penetration enhancer " or only " promoter " be meant medicament or the pharmaceutical mixture that obtains such infiltration facilitation.Existing several chemical compounds are studied as penetration enhancer and use.Referring to, for example, United States Patent (USP) the 5th, 601,839,5,006,342,4,973,468,4,820,720,4,006,218,3,551,154 and 3,472, No. 931.The index of penetration enhancer by David W.Osborne and Jill J.Henke at their title be "
Skin Penetration Enhancers Cited in the Technical Literature "Publication in open, it was published in " PharmaceuticalTechnology " (in June, 1998), incorporated this paper into as a reference.
[35] term " cooperative effect (synergism) ", " working in coordination with ", " synergistically " are meant the combined effect phenomenon bigger than their additive effect of at least two kinds of active component in compositions or the mixture.That is to say, the resulting effect of the combination of composition, it is big with its resulting effect added together then to compare every kind of composition mensuration effect itself.Determining of cooperative effect is well known by persons skilled in the art.All have the situation of some effect individually for two kinds of medicaments wherein, in some aspects, can use Loewe additive value (Loewe Additivity value) (W.R.Greco etc.,
Pharmacological Reviews47:331-385 (1995)) measures the combined effect of expectation.
[36] as used herein, " effective dose " of promoter is meant is enough to increase the percutaneous amount that infiltrates into selected degree of medicine.The method that is used to analyze the characteristic of penetration enhancer is known in the art.For example, referring to, Merritt etc., " Diffusion Apparatus for SkinPenetration, "
J.of Controlled Release61 (1984), its integral body is incorporated this paper into as a reference.Therefore, " effective dose " of medicine or " treatment effective dose " are meant nontoxic but enough medication amount, so that at known this medicine of treatment it is obtained therapeutic effect in effective situation.Be appreciated that the various biological factor can influence the ability that material is finished its intention task.Therefore, in some cases, " effective dose " or " treatment effective dose " can depend on such biological factor.Further, when obtaining of treatment effect can use evaluation methodology known in the art to measure by doctor or other titular medical workers, think to make obtaining of effect of treatment have some subjective judgment to the individuality variation and the reaction for the treatment of.Effective dose fixes within the common skill of pharmacy and medical domain really.Referring to, for example, Meiner and Tonascia, " ClinicalTrials:Design, Conduct, and Analysis, "
Monographs in Epidemiology and Biostatistics, Vol.8 (1996), it incorporates this paper into as a reference.
[37] as used herein, " pharmaceutically acceptable carrier " and " carrier " commutative use are meant any inert and pharmaceutically acceptable material, the major part that it does not have biologic activity basically and constitutes preparation.Carrier can be polymer such as binding agent or non-polymer, and other compositions of common and compositions (for example, medicine, binding agent (binders), filler, penetration enhancer, counter-stimulus, softening agent, lubricant etc., on demand) preparation is formed in mixing.
[38] term " blended " is meant that medicine and/or promoter can be dissolved in, are scattered in or are suspended in the carrier.In some cases, medicine can be by uniform mixing in carrier.
[39] as used herein, for simplicity, a plurality of items, structural element, element and/or material can occur in enumerating (list) jointly.But these are enumerated and should be interpreted as, and are confirmed as independent and unique member separately as each member in enumerating.Therefore, do not having under the opposite indicated situation, the indivedual members in such enumerating should only not be interpreted as according to appearing in common group, are the actual equivalents of any other member in same the enumerating.
[40] in this article, concentration, amount and other data can be represented or occur with the form of scope.Be appreciated that, using this range format only is for convenience with succinct, therefore, it should be interpreted as neatly, not only comprise the numerical value that clearly is set fourth as the scope limit value, also comprise all single numerical value or subranges of being included in this scope, clearly stated as each numerical value and subrange.As example, the numerical range of " about 1 to about 5 " should be interpreted as, and not only comprises the numerical value of clearly stating in about 1 to about 5, is also included within each numerical value and subrange in the specified scope.Therefore, in this numerical range, comprise individual values as 2,3 and 4, and subrange such as 1-3,2-4 and 3-5 etc.
[41] identical principle is applicable to the scope of only stating a numerical value.And, no matter the width of described scope or character how, all should use this explanation.
Detailed Description Of The Invention
[42] applicant has been found that the combination of lauryl alcohol and isopropyl myristate provides the collaborative infiltration potentiation of medicine by skin area.Except the penetrating power that strengthens various medicines, the combination of lauryl alcohol and isopropyl myristate allows to use every kind of promoter of low concentration, has therefore reduced the skin irritant level relevant with higher promoter concentration usually.Therefore, the present invention includes the collaborative method and formulation that promotes medicine by the infiltration of subject's skin.This paper disclosure and description multiple preparation capable of permeating skin, it contains the lauryl alcohol and the isopropyl myristate of the effective dose in object to be administered.And, also disclosure and description the method for collaborative promotion medicine by subject's skin infiltration.
[43] for realizing the aspect of the present invention's expectation, do not disturb any pharmaceutically acceptable preparation capable of permeating skin of infiltration facilitation as herein described and medication to use.Transdermal drug delivery systems of the present invention (transdermal drug delivery system) can adopt multiple known conveying preparation, include but not limited to, transdermal patch such as gluing matrix patch, liquid storage storehouse system (LRS) patch, saturating mucosa patch or tablet and topical formulations, for example ointment, lotion, ointment, gel, paste, mousse, aerosol, spray, suppository etc.
[44] when transdermal drug delivery systems of the present invention occurred with the form of transdermal patch, it can comprise multiple constituent, as known in the art.For example, under the situation of gluing matrix patch, the distally backing is in turn laminated to base polymer layer usually.This distally backing defines matrix patch towards environment---promptly, the distally of skin or mucosa---a side.The function of backing layer is to protect base polymer layer and medicine/enhancer compositions and provide to prevent that medicine is lost to the impermeable barrier in the environment.Therefore, the selected material of backing should be compatible with polymeric layer, medicine and promoter, and should be that minimum level ground is permeable to any composition of matrix patch.Advantageously, backing can be opaque, so that the composition of protection matrix patch avoids degrading because of being exposed to ultraviolet light.And backing should be able to be bonding and the support polymer layer, but should be enough pliable and tough to adapt to the people's who uses matrix patch motion.
[45] suitable back lining materials includes but not limited to: metal forming, the poly-paper tinsel (polyfoils) of plating, the composite insulating foil that contains polyester such as polyester terephthalate or composite membrane, polyester or aluminum polyester, politef, polyether-amide block copolymers, polyethylene methyl methacrylate segmented copolymer, polyurethanes, poly-inclined to one side 1,1 dichloroethylene, nylon, silicone elastomer, rubber-based polyisobutylene, styrene, styrene-butadiene and styrene-isoprene copolymer, polyethylene and polypropylene.In addition, backing can comprise multiple foam, for example closed cell foamed plastic.Example can comprise without limitation, expanded polyolefin, polyvinyl chloride foam, polyurethane foam, polyethylene etc.In one aspect of the invention, backing layer can have about 0.0005 to 0.1 inch thickness.
[46] further, release liner can temporarily be provided at the nearside (with a side of adhering skin) of adhesive layer.Before patch and adhering skin, such liner provides the many functions identical with backing layer.In use, just before using, release liner is peeled off and discarded from adhesive layer.Release liner can be by making with the backing layer identical materials, or by making with other suitable film of suitable stripper surface coating.
[47] one general aspect, transdermal drug delivery system of the present invention can comprise pharmaceutically acceptable carrier, its intention contains the combination of medicine and lauryl alcohol and isopropyl myristate.Many pharmaceutically acceptable carriers are that those of ordinary skills are known, and can use together with the present invention.
[48] when preparation capable of permeating skin of the present invention is taked the embodiment of LRS patch, the pharmaceutically acceptable carrier of application can be the known any suitable cohesive materials of transdermal administration those skilled in the art.This carrier generally is the fluid with desired viscosity, example gel or ointment, it is configured to and is limited in the storage storehouse, and described storage storehouse has impermeable backing and the permeable membrane that contacts skin, or the film adhesive laminate body that provides diffusibility to contact between storehouse and the skin is being provided.This adhesive carrier can comprise the combination of lauryl alcohol and isopropyl myristate and treat any medicine of transdermal delivery, and other optional preparation capable of permeating skin composition.
[49] when the present invention takes the embodiment of transdermal matrix patch, the pharmaceutically acceptable carrier that is fit to use also is that those of ordinary skills are known.The present invention considers the transdermal matrix patch of multiple structure type.For example, can use its Chinese medicine and promoter directly to be included in monolithic system (monolithic system) in the single pressure sensitive adhesive layer, and the system that except pressure sensitive adhesive layer, also contains one or more polymer storage storehouse.Comprise system with a plurality of layer/layered products aspect in, can comprise rate controlled parts (rate controllingelement).Usually, the rate controlled parts are between bin-storing layer and skin.Those comprise transfer layer and bin-storing layer aspect in, the rate controlled parts can be bonded between the distally of the nearside of bin-storing layer and transfer layer.The rate controlled parts are provided for to be measured or control medicine and/or penetration enhancer are moved to speed the transfer layer from bin-storing layer.Pointed as this paper, in one aspect of the invention, the infiltration of a plurality of levels promotes can be used to increase the transfer rate of medicine, and thereby can be used to change other parameter, for example, patch size etc.
[50] on the one hand, used pharmaceutically acceptable carrier can be a biocompatible polymer in matrix patch.The biocompatible polymer of many general types is known, comprises without limitation: rubber; Organosilicon polymer and copolymer; Acrylic polymer and copolymer; And their mixture.On the one hand, biocompatible polymer can be a rubber, comprises natural rubber and synthetic rubber.An object lesson of useful rubber is plasticising styrene-rubber block copolymers.On the other hand, biocompatible polymer can comprise silicon polymer, polysiloxanes and their mixture.Another aspect, biocompatible polymer can comprise acrylic polymer, polyacrylate and their mixture.Another aspect, biocompatible polymer can comprise vinylacetate, vinyl-vinyl acetate copolymer, polyurethanes, plasticising polyether amide block copolymer and their mixture.
[51] on the one hand, the biocompatible polymer of pharmaceutically acceptable carrier can be suitable for and skin Long contact time (for example, more than 1 day, can be about 3-4 days or longer as 7 days or even 1-4 week).On the other hand, the biocompatible polymer of carrier is suitable for short-term administration (for example, continue a few minutes by several hours, 1 day with interior or equal 1 day).This biocompatible polymer must with the combination of lauryl alcohol, isopropyl myristate and any medicine that exists, and any carrier and/or vehicle or incorporate in the preparation other additives physically and chemically compatible.In one aspect of the invention, the biocompatible polymer of pharmaceutically acceptable carrier can comprise polymer adhesive.The example of this binding agent can comprise without limitation: acrylic adhesives comprises crosslinked and uncrosslinked acrylic acid series copolymer; The vinyl acetic acid ester adhesive; Natural and synthetic rubber comprises polyisobutylene, neoprene, polybutadiene and polyisoprene; The ethylene-vinyl acetate copolymer; Polysiloxanes; Polyacrylate; Polyurethanes; Plasticising amount (plasticized weight) polyether amide block copolymer and plasticising styrene-rubber block copolymers or their mixture.The invention another aspect, the contact adhesive that uses in the pharmaceutically acceptable carrier is an acrylic adhesives, for example Duro-Tak
.87-2888 binding agent (National Starch ﹠amp; Chemical Co., Bridgewater, N.J); With polyisobutylene adhesives ARcare for example
TM.MA-24 (Adhesives Research, Glen Rock is Pa.) with ethylene-vinyl acetas binding agent.The use that is considered of another aspect, gel-type or " hydrogel " binding agent.Referring to, for example, United States Patent (USP) 5,827, No. 529, it incorporates this paper into as a reference.The particular type and the quantity that will be apparent to those skilled in the art that applied polymer adhesive can be selected according to the required concrete property of final products.Yet, on the one hand, the content of the binder polymer in gluing hypothallus (adhesive stroma layer) can be adhesive phase (adhesive layer) at least about 50%w/w.On the other hand, described content can be adhesive phase at least about 60%w/w.Another aspect, described content can be adhesive phase at least about 85%w/w.Again on the one hand, described content can be adhesive phase at least about 90%w/w.Another aspect, described content can be that about 50%w/w of adhesive phase arrives about 95%w/w.
[52] when preparation capable of permeating skin of the present invention is taked the embodiment of topical formulations, can use the known multiple pharmaceutically acceptable carrier of those of ordinary skills.On the one hand, topical carrier can be the ointment that comprises lauryl alcohol and isopropyl myristate.Ointment is semisolid pharmaceutical formulation, and it is based on material known such as oleaginous bases (greasing base, oleaginous base), lanoline, emulsion or water-soluble base.The preparation of ointment is well known in the art, for example,
Remington:The Science and Practice of Pharmacy19
ThEd. (1995), vol.2 describes in the 1585-1591 page or leaf, and it incorporates this paper into as a reference.This preparation comprises vaseline or zinc oxide usually together with medicine.(substrate base) generally includes but is not limited to the oily ointment base that be fit to use among the present invention: vegetable oil, Animal fat and derive from the semi-solid hydrocarbon of oil.The ointment base that absorbs of the present invention can comprise water seldom or not comprise water, and can comprise such composition, for example but be not limited to: Oxystearin sulfate (hydroxystearinsulfate), anhydrous lanolin and hydrophilic petrolatum (vaseline).Emulsion ointment base of the present invention or water-in-oil type (W/O) Emulsion or oil-in-water type (O/W) Emulsion can include but not limited to: spermol, tristerin, lanoline, poly-alkylsiloxane and stearic acid.Be applicable to that water-soluble ointment base of the present invention can be prepared by different molecular weight polyethylene glycol.
[53] in another aspect of this invention, topical carrier can be the emulsifiable paste that comprises lauryl alcohol and isopropyl myristate.Emulsifiable paste is the class ointment for viscous liquid or semi-solid Emulsion, or oil-in-water type or water-in-oil type, as known in the art.Emulsifiable paste base water soluble, and contain oil phase, emulsifying agent, water and activating agent.In detailed aspect of the present invention, oil phase can be made up of vaseline and aliphatic alcohol such as spermol or octadecanol.In another detailed aspect of the present invention, water can be greater than oil phase on volume, and can contain wetting agent.In another detailed aspect of the present invention, the emulsifying agent in the cream preparation can be nonionic, anionic, cationic or amphoteric surfactant.
[54] in another aspect of this invention, topical carrier can be the lotion that contains lauryl alcohol and isopropyl myristate.Lotion is to be the ointment of liquid or semi-liquid preparations, wherein has the solid particle that comprises activating agent in water-based or pure substrate.Be applicable to that lotion of the present invention can be that solid suspension maybe can be an oil-in-water emulsion.In another aspect of this invention, lotion also can comprise other chemical compound of improving dispersive suspending agent or improving activating agent and contact skin for example methylcellulose, sodium carboxymethyl cellulose, or similar compound.
In still another aspect of the invention, topical carrier can be the paste that contains lauryl alcohol and isopropyl myristate.Paste of the present invention is an ointment, and a large amount of solids is wherein arranged, and described solid forms semi-solid preparation, and in described preparation, activating agent is suspended in the suitable substrate.In a detailed aspect of the present invention, paste can be made of the substrate of the fatty paste of generation or can be made by the single-phase water gel.Be applicable to that fatty paste of the present invention can be made of substrate such as vaseline, hydrophilic petrolatum or analog.Be applicable to that the paste of being made by the single-phase water gel of the present invention can mix cellulose-based polymer such as carboxymethyl cellulose or analog as substrate.
[55] in another aspect of this invention, topical gel can be produced.Gel prepared in accordance with the present invention can be the colloid for preparing thing, and wherein decentralized photo combines with continuous phase and produces sticky product.Gel can form submicroscopic crystal grain group, and it is retained in solvent in the space.As known to the personnel that work in this area, gel is semi-solid, floating type system.Single-phase gels can contain the organic macromolecule that distributes substantially equably in whole carrier liquid, it can be aqueous or non-water and contain alcohol or oil.
[56] except containing promoter combination and medicine, the pharmaceutically acceptable carrier of the preparation capable of permeating skin of this paper statement can comprise many other additives, for example diluent, excipient, softening agent, plasticizer, solubilizing agent, skin irritation palliative, stable compound, or their mixture.The composition of these types and other composition of not specifically noting are known in the art and are used for being included in multiple preparation capable of permeating skin, and can join in the transdermal drug delivery system of the present invention with particular type and content as required, to obtain the result of hope.For example, polyvinylpyrrolidone can be used as solubilizing agent in the pharmaceutically acceptable carrier, is used to the amount of about 12%w/w with about 8%w/w of accounting for preparation capable of permeating skin.On the one hand, polyvinylpyrrolidone can exist with about 10% amount of preparation capable of permeating skin.
[57] in addition, when medicine to be carried is subject to the acid catalysis degraded, for example some androgens and progesterone (progestins), the carrier that does not comprise the carrier of acid functional group and do not form any acid functional group in storage can be used, so that improve stability of formulation.An object lesson of this carrier is the EHA polymer, as at United States Patent (USP) the 5th, 780, describes in No. 050, and it incorporates this paper into as a reference.
[58] the present invention can be used for carrying to object the multiple medicine of wide region.The inventor has been found that when being used to carry hormone the synergistic combination of lauryl alcohol and isopropyl myristate can be effective especially.So, on the one hand, hormone is a gonadal hormone.The diversity hormone comprises that androgen, estrogen and progesterone can be promoted and conveying by collaborative, as disclosed herein.
[59] concrete androgen for example the example of testosterone and related compound comprise without limitation: testosterone, methyltestosterone, androstenedione (androstenedione), Reichstein's compound G, dehydroepiandrosterone, adroyd, fluoxymesterone, protobolin, testosterone, methyltestosterone, androstenedione, Reichstein's compound G, dehydroepiandrosterone, adroyd, fluoxymesterone, protobolin, teslac, pregnenolone pregnant (steroid) enol ketone, 17 Alpha-Methyl nortestosterones, norethandrolone, dihydrotestosterone, danazol, adroyd, androsterone, the 19-nortestosterone, stanozolol, ethylestrenol, oxandrolone, 7 α, 17-clausterone and mesterolone, Testosterone Propionate, depo-testosterone, testosteroni phenylacetas, testosterone enanthate (testosterone enanthate), the acetic acid testosterone, testosterone buciclate, testosterone enanthatas (testosterone heptanoate), capric acid testosterone (testosterone decanoate), testosterone decanoate (testosterone caprate), isodecyl acid testosterone and their combination.These testosterone chemical compounds can be to be lower than saturated concentration or low concentration exists.The example that comprises the compositions that is lower than saturated testosterone is known in the art.Referring to, for example, 5,164,190 and 5,152,997, it incorporates this paper into as a reference.
[60] concrete estrogen for example the example of estradiol and related compound comprise without limitation: 17 beta estradiols, 17 alpha-estradiols, in conjunction with premarin, esterified estriol, micronize estradiol, sodium sulfate estrogen (sodium estrogen sulfate), ethinyl estradiol, estrone, tibolone, selective estrogen receptor instrumentality (SERM), phytoestrogen (phytoestrogen) and their mixture.
[61] example of concrete progesterone comprises without limitation: progesterone (progesterone), hydroxyprogesterone, megestrol acetate, dimethisterone, norgestrel, left-handed 18-methyl norgestrel, medroxyprogesterone acetate, desogestrel, norgestimate, ethynodiol diacetate, norethindrone, norethindrone acetate, Norethynodrel and their derivant.
The concentration of hormone that comprises in the preparation capable of permeating skin of the present invention can change according to the intended use of concrete hormone composition, employed concrete carrier and preparation.The capable fully preparation of those skilled in the art is included in the correct hormone concentration in the preparation capable of permeating skin.So, any treatment effective dose of hormone or medicine all considered to be within the scope of the present invention.For example, in comprising an embodiment of testosterone, testosterone can exist to about 15%w/w with about 0.5%w/w.In another embodiment, testosterone can exist to about 10%w/w with about 1%w/w.In another embodiment.Testosterone can exist to about 12%w/w with about 5%w/w.In an embodiment again, testosterone can exist to about 10%w/w with about 7%w/w.
[62] as described herein, have been found that the collaborative infiltration that promotes medicine by subject's skin of combination of lauryl alcohol and isopropyl myristate.Should be appreciated that,, can have the variation of synergism level between them because the chemical composition of different preparation capable of permeating skin is different fully.For example, when different pharmaceutical or carrier and promoter combinatorial association of the present invention, described medicine or carrier can show different infiltration facilitations.Therefore, intention is, prove have synergistic any level promotion all within the scope of the present invention.More specifically, on the one hand, collaborative enhanced osmosis can be than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 5% to about 150%.On the other hand, collaborative enhanced infiltration can be than expectation effect high about 5% to about 75%.Another aspect, collaborative enhanced infiltration can be than expectation effect high about 10% to about 50%.Another aspect, collaborative enhanced infiltration can be high more about below 5% or equal about 5% than the expectation effect.
The amount of the promoter combination that [63] comprises in the preparation capable of permeating skin can change according to many factors, for example, and to the effectiveness of the desired enhanced level of certain drug, medicine, the use persistent period of preparation capable of permeating skin etc.The correct promoter concentration of preparation in reaching the required preparation of specific infiltration facilitation, this can easily be determined by those skilled in the art.Therefore, any amount that shows the promoter combination of the present invention of collaborative facilitation all is to be considered within the scope of the invention.More specifically, on the one hand, preparation capable of permeating skin can comprise lauryl alcohol and isopropyl myristate, and they account for about 0.5%w/w of preparation capable of permeating skin separately to about 20%w/w.On the other hand, lauryl alcohol and isopropyl myristate can account for about 1%w/w of preparation capable of permeating skin separately to about 10%w/w.On the other hand, lauryl alcohol and isopropyl myristate can account for about 22%w/w of preparation capable of permeating skin separately to about 78%w/w.Another aspect, lauryl alcohol and isopropyl myristate can account for about 5%w/w of preparation capable of permeating skin separately.Again on the one hand, lauryl alcohol and isopropyl myristate can account for below about 5%w/w of preparation capable of permeating skin separately or equal about 5%w/w.
[64] for given preparation capable of permeating skin, except the concentration of the combination of the promoter in the preparation capable of permeating skin, the multiple ratio of lauryl alcohol and isopropyl myristate is considered, and can be by meticulous adjusting (fine setting), so that realize required infiltration promotion level.Described is can obtain the lauryl alcohol of synergistic results and any ratio of isopropyl myristate and all be to be considered within the scope of the invention.On the one hand, described ratio can be from about 1: 5 to about 5: 1.On the other hand, described ratio can be from about 1: 4 to about 4: 1.On the other hand, described ratio can be from about 1: 3 to about 3: 1.Another aspect, ratio can be from about 1: 2 to about 2: 1.More specifically aspect one, ratio can be about 1: 1.Again one more specifically aspect, ratio can be about 4: 1.
[65] the multiple time sequencing of using the composition of promoter combination all is possible, and any such order of administration that obtains synergistic results all is contemplated within the scope of the present invention.On the one hand, lauryl alcohol and isopropyl myristate can be used simultaneously, or as single compositions or as independent chemical compound.This while administration intention is included in substantially the same every kind of chemical compound of time use.In this while administration, the promoter combination can be carried simultaneously with medicine, or separates conveying with medicine.Under the situation of promoter combination and medicine administration simultaneously, the promoter combination can be with medicament mixed or as independent compound administration.Similarly, one of lauryl alcohol and isopropyl myristate can with medicament mixed, the residual components of promoter combination can be used as independent compound administration.Under the situation that promoter combination is used separately with respect to medicine, lauryl alcohol and isopropyl myristate can before the drug administration, afterwards or before and use afterwards.
[66] on the other hand, lauryl alcohol and isopropyl myristate can be used in the time that differs from one another, and still provided collaborative infiltration accelerating effect as long as separately use.Therefore, can before or after using isopropyl myristate, use lauryl alcohol.Can consider that multiple time sequencing is with respect to medicinal application promoter.For example, can before the drug administration, afterwards or before and the two uses lauryl alcohol and isopropyl myristate afterwards.Also consider, one of medicine and promoter component can be used simultaneously.
[67] preparation capable of permeating skin of the present invention can be prepared to extended release preparation, and it is at the medicine of the time durations administering therapeutic effective dose that prolongs.Therefore, on the one hand, the lasting conveying phase of progesterone can be at least 7 days.On the other hand, the lasting conveying phase can be at least 5 days.Another aspect, the lasting conveying phase can be at least 3 days.On the other hand, continuing the conveying phase can be at least one sky.Again on the one hand, continuing the conveying phase can be for below one day.Another aspect, the lasting conveying phase can be about 1 to about 4 weeks.
[68] except method and preparation that the collaborative promotion that provides medicine to pass through subject's skin is permeated, the present invention also comprises the aspect that relates to test kit, and described test kit is used for providing the collaborative drug osmotic that promotes according to method disclosed herein.Test kit can comprise the pharmaceutically acceptable carrier of the medicine that has wherein mixed the treatment effective dose, the lauryl alcohol of effective dose, the isopropyl myristate of effective dose, with the description of describing use preparation capable of permeating skin method, wherein lauryl alcohol and isopropyl myristate provide the collaborative drug transdermal infiltration that promotes.On the one hand, lauryl alcohol and isopropyl myristate can be combined into single permeation enhancer compositions, or separate or and medicament mixed with medicine.On the other hand, lauryl alcohol and isopropyl myristate can be provided as the independent chemical compound in the test kit, or separate or a kind of chemical compound and medicament mixed with medicine.
Embodiment
[69] Xia Mian example of formulations provides the collaborative promotion infiltration of medicine by subject's skin, provides them more to be expressly understood some embodiments of the present invention with help, and never in any form as the restriction to embodiment of the present invention.
[70] embodiment 1
The transdermal matrix system that contains lauryl alcohol (LA) and isopropyl myristate (IPM) can be prepared as follows: acryloid cement solution (Duro-Tak
Solids content 87-9301) is following to be determined: small volume of solution is put in the preweighted aluminum dish, and (Model A4718-Q, BlueM), 75 ℃ are spent the night subsequently the aluminum dish to be placed convection oven.After the solvent evaporation, obtain the weight of dry adhesive, solids content is calculated the ratio for dry weight and weight in wet base.
An amount of polyvinylpyrrolidone K-12 (PVP) that forms 10%w/w in desciccator diaphragm is had in the vial that is calculated as the minimum dehydrated alcohol that dissolves PVP fully direct the adding.According to the solids content of measuring before, in the binding agent adding bottle with known quantity.An amount of testosterone (TS) is added in the bottle, and dry back produces the TS concentration of about 8.5%w/w.LA is solid at normal temperatures, and a small amount of LA that can be kept in the bottle by heating in water-bath before use melts.An amount of LA and IPM are added in the bottle, and dry back produces has the expectation compositions of about 5%w/w LA and 5%w/w IPM.Tight each bottle of lid spends the night with paraffin sealing film phonograph seal and rotation, and during this period, all the components dissolving produces limpid solution.
[71] height that an amount of compositions (about 10 gram) is placed on thick polyester (PET) release liner of 3 mils (Mil) that have been coated with fluoropolymer polymer discharges side, and is the manual curtain coating of casting knife (casting knife) of 10 mils with the slit.With curtain coating thing (cast) in 75 ℃ draft furnace dry 15 minutes.Make film room temperature cooling 10 minutes.After the drying, make the lamination backing film lamination of curtain coating thing and 2 mils (PET/EVA) subsequently.Cut curtain coating thing and backing film subsequently so that suitable delivered dose is provided.
Embodiment 2
[72] research of vitro skin flow can use the Franz diffusion cell of modification to carry out.Can use people's corpse epidermis film of thermal release.Downcut 0.71cm from the matrix patch of embodiment 1
2Round property hole.Release liner is peeled off and discarded, circular hypothallus is pressed on the horny layer of epidermis film.Subsequently skin-matrix device is clipped between the supply chamber of diffusion cell and the receiving chamber and fixing, the epidermis side is to receiving chamber.Fill the sodium azide solution of 0.02%w/w in the receiving chamber.Subsequently diffusion cell is placed on and remains in about 37 ℃ circulator bath.
At the time point of preliminary election, it is quantitative that all the elements thing of collection receiving chamber carries out medicine.Receiving chamber recharges the fresh receiver media (NaN of 0.02%w/w subsequently
3Aqueous solution).After sample being carried out the HPLC analysis, calculate the interval flow and the cumulative amount of the medicine of infiltration per unit area.Cumulative amount (Qt, the μ g/cm of the medicine of the per unit area of t infiltration at any time
2) obtain by following formula:
[73] C wherein
nBe the drug level in the receiver media under corresponding sample time, represent with μ g/ml that V is the volume (≈ 6.3ml) of receiving chamber, A is the diffusion area (0.64cm of diffusion cell
2).
[74] average discharge and 24 hours accumulative total is permeated the result and is illustrated respectively in table 1 and the table 2.
Table 1: testosterone, in the 87-9301 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Average discharge | Promote % |
| 8.5％TS | 10 | 0 | 0 | 2.55 | Baseline |
| 8.5％TS | 10 | 5 | 0 | 3.37 | 32％ |
| 8.5％TS | 10 | 0 | 5 | 3.03 | 19％ |
| *51％ | |||||
| 8.5％TS | 10 | 5 | 5 | 4.36 | 71％ |
| **39％ |
*Addition
*Increase percent
Table 2: testosterone, in the 87-9301 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Accumulative total infiltration in 24 hours | % promotes |
| 8.5％TS | 10 | 0 | 0 | 56.4 | Baseline |
| 8.5％TS | 10 | 5 | 0 | 80.8 | 43％ |
| 8.5％TS | 10 | 0 | 5 | 72.8 | 29％ |
| *72％ | |||||
| 8.5％TS | 10 | 5 | 5 | 104.7 | 86％ |
| **19％ |
*Addition
*Increase percent
[75] from data as can be seen, exist the amazing collaborative increase that skin area average discharge and infiltration promote of striding.The addition percentage ratio of pointing out in the table is represented the expection additive effect of LA and IPM promoter.The value added percentage ratio of pointing out in the table represents because the observed facilitation value added that is higher than addition percentage ratio of actual effect of LA and IPM combination.This numerical evaluation goes out the synergistic percent of promoter combination results just.The following examples show in the preparation capable of permeating skin that comprises TS and other hormone in multiple binding agent, and the infiltration of LA and IPM promotes character.In these cases, also observe similar or higher levels of collaborative infiltration facilitation.
Embodiment 3
[76] as embodiment 1 preparation patch, except binding agent is Duro-Tak
87-900A.Detect patch as described in Example 2.Average discharge and 24 hours accumulative total are permeated the result and are presented in table 3 and the table 4 respectively.
Table 3: testosterone, in the 87-900A binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Meansigma methods | % promotes |
| 8.5％TS | 10 | 0 | 0 | 2.68 | Baseline |
| 8.5％TS | 10 | 5 | 0 | 3.52 | 31％ |
| 8.5％TS | 10 | 0 | 5 | 3.12 | 16％ |
| *47％ | |||||
| 8.5％TS | 10 | 5 | 5 | 4.53 | 69％ |
| **47％ |
*Addition
*Increase percent
Table 4: testosterone, in the 87-900A binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Accumulative total infiltration in 24 hours | % promotes |
| 8.5％TS | 10 | 0 | 0 | 64.4 | Baseline |
| 8.5％TS | 10 | 5 | 0 | 84.6 | 31％ |
| 8.5％TS | 10 | 0 | 5 | 75.1 | 17％ |
| *48％ | |||||
| 8.5％TS | 10 | 5 | 5 | 108.8 | 69％ |
| **44％ |
*Addition
*Increase percent
Embodiment 4
[77] as embodiment 1 preparation patch, except binding agent is silicone adhesive MD7-4502 (Dow Corning
).Detect patch as described in Example 2.Average discharge and 24 hours accumulative total are permeated the result and are presented in table 5 and the table 6 respectively.
Table 5: testosterone, in silicone adhesive MD7-4502
| The % medicine | ％PVP | ％LA | ％IPM | Average discharge | % promotes |
| 1％TS | 10 | 0 | 0 | 1.23 | Baseline |
| 1％TS | 10 | 5 | 0 | 1.78 | 45％ |
| 1％TS | 10 | 0 | 5 | 1.44 | 17％ |
| *62％ | |||||
| 1％TS | 10 | 5 | 5 | 2.13 | 73％ |
| **18％ |
*Addition
*Increase percent
Table 6: testosterone, in silicone adhesive MD7-4502
| The % medicine | ％PVP | ％LA | ％IPM | Accumulative total infiltration in 24 hours | % promotes |
| 1％TS | 10 | 0 | 0 | 29.5 | Baseline |
| 1％TS | 10 | 5 | 0 | 42.8 | 45％ |
| 1％TS | 10 | 0 | 5 | 34.5 | 17％ |
| *62％ | |||||
| 1％TS | 10 | 5 | 5 | 51.7 | 75％ |
| **21％ |
*Addition
*Increase percent
Embodiment 5
[78] as embodiment 1 preparation patch, except hormone is estradiol (ES).Detect patch as described in Example 2.The result of average discharge, accumulative total infiltration in 72 hours and the 3rd day is presented in table 7, table 8 and the table 9 respectively.
Table 7: estradiol, in the 87-9301 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Average discharge | % promotes |
| 5％ES | 10 | 0 | 0 | 0.39 | Baseline |
| 5％ES | 10 | 5 | 0 | 0.67 | 72％ |
| 5％ES | 10 | 0 | 5 | 0.46 | 18％ |
| *90％ | |||||
| 5％ES | 10 | 5 | 5 | 0.88 | 126％ |
| **40％ |
*Addition
*Increase percent
Table 8: estradiol, in the 87-9301 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Accumulative total infiltration in 72 hours | % promotes |
| 5％ES | 10 | 0 | 0 | 31.5 | Baseline |
| 5％ES | 10 | 5 | 0 | 52.6 | 67％ |
| 5％ES | 10 | 0 | 5 | 37.2 | 18％ |
| *85％ | |||||
| 5％ES | 10 | 5 | 5 | 67.5 | 114％ |
| **34％ |
*Addition
*Increase percent
Table 9: estradiol, in the 87-9301 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | The 3rd day Infiltration | % promotes, from the 3rd It data *** |
| 5％ES | 10 | 0 | 0 | 8.7 | Baseline |
| 5％ES | 10 | 5 | 0 | 14.6 | 68％ |
| 5％ES | 10 | 0 | 5 | 10.6 | 22％ |
| *90％ | |||||
| 5％ES | 10 | 5 | 5 | 19.5 | 124％ |
| **38％ |
*Addition
*Increase percent
* *Based on only the 3rd day infiltration
Embodiment 6
[79] as embodiment 1 preparation patch, except hormone is norethindrone acetate (NEA).Detect patch as described in Example 2.The result of average discharge, accumulative total infiltration in 168 hours and the 7th day is presented in table 10, table 11 and the table 12 respectively.
Table 10: norethindrone acetate, in the 87-900A binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Average discharge | % promotes |
| 10％NEA | 10 | 0 | 0 | 0.35 | Baseline |
| 10％NEA | 10 | 5 | 0 | 0.52 | 49％ |
| 10％NEA | 10 | 0 | 5 | 0.42 | 20％ |
| *69％ | |||||
| 10％NEA | 10 | 5 | 5 | 0.68 | 94％ |
| **36％ |
*Addition
*Increase percent
Table 11: norethindrone acetate, in the 87-900A binding agent
| The % medicine | ％PVP | ％LA | ％IPM | 168 hours integrated fluxs | % promotes |
| 10％NEA | 10 | 0 | 0 | 62.5 | Baseline |
| 10％NEA | 10 | 5 | 0 | 90.5 | 45％ |
| 10％NEA | 10 | 0 | 5 | 73.3 | 17％ |
| *62％ | |||||
| 10％NEA | 10 | 5 | 5 | 119.0 | 90％ |
| **45％ |
*Addition
*Increase percent
Table 12: norethindrone acetate, in the 87-900A binding agent
| The % medicine | ％PVP | ％LA | ％IPM | The 7th day Infiltration | % promotes, from the 7th It data *** |
| 10％NEA | 10 | 0 | 0 | 7.5 | Baseline |
| 10％NEA | 10 | 5 | 0 | 11.4 | 52％ |
| 10％NEA | 10 | 0 | 5 | 9.2 | 23％ |
| *75％ | |||||
| 10％NEA | 10 | 5 | 5 | 15.0 | 100％ |
| **33％ |
*Addition
*Increase percent
* *Based on only the 7th day infiltration
Embodiment 7
[80] as embodiment 1 preparation patch, except binding agent is Duro-Tak
87-2516 and hormone be norelgestromine (norelgestromin, NG).Detect patch as described in Example 2.The result of average discharge, accumulative total infiltration in 168 hours and the 7th day is presented in table 13, table 14 and the table 15 respectively.
Table 13: norelgestromine, in the 87-2516 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Average discharge | % promotes |
| 10％NG | 10 | 0 | 0 | 0.2 | Baseline |
| 10％NG | 10 | 5 | 0 | 0.26 | 30％ |
| 10％NG | 10 | 0 | 5 | 0.22 | 10％ |
| *40％ | |||||
| 10％NG | 10 | 5 | 5 | 0.36 | 80％ |
| **100％ |
*Addition
*Increase percent
Table 14: norelgestromine, in the 87-2516 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | Accumulative total infiltration in 168 hours | % promotes |
| 10％NG | 10 | 0 | 0 | 35.6 | Baseline |
| 10％NG | 10 | 5 | 0 | 44.5 | 25％ |
| 10％NG | 10 | 0 | 5 | 38.6 | 8％ |
| *33％ | |||||
| 10％NG | 10 | 5 | 5 | 60.8 | 71％ |
| **115％ |
*Addition
*Increase percent
Table 15: norelgestromine, in the 87-2516 binding agent
| The % medicine | ％PVP | ％LA | ％IPM | The 7th day Infiltration | % promoted, from the 7th day Data *** |
| 10％NG | 10 | 0 | 0 | 4.2 | Baseline |
| 10％NG | 10 | 5 | 0 | 5.4 | 29％ |
| 10％NG | 10 | 0 | 5 | 4.5 | 7％ |
| *36％ | |||||
| 10％NG | 10 | 5 | 5 | 7.7 | 83％ |
| **131％ |
*Addition
*Increase percent
* *Based on only the 7th day infiltration
[81] as from as described in embodiment 2-7 the result as can be seen, the LA in the combination and IPM produce the collaborative facilitation of the promoter summation action that is higher than expectation.This cooperative effect all is observed in all detected hormones.
[82] be appreciated that above-described compositions and the application mode preferred embodiment of the present invention of only having demonstrated.Under the situation that does not deviate from the spirit and scope of the present invention, those skilled in the art can carry out many modifications and optionally adjustment to it, and appended claims is intended to comprise such modification and adjustment.Therefore, though the present invention is described at being considered to the present invention feature and details the most practical and preferred embodiment at present, but for those of ordinary skills, can carry out many modifications, include but not limited to the modification aspect size, material, shape, form, function and operational approach, device and use, these revise principle and the notion that does not deviate from this paper statement.
Claims (63)
1. promote the method for medicine, comprising: the combination of lauryl alcohol and isopropyl myristate is administered to described skin area as penetration enhancer, so that the collaborative promotion infiltration of described medicine to be provided by the infiltration of skin area.
2. the described method of claim 1, wherein said collaborative promotion infiltration is than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 1% to about 150%.
3. the described method of claim 2, wherein said collaborative promotion infiltration is than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 5% to about 75%.
4. the described method of claim 3, wherein said collaborative promotion infiltration is than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 10% to about 50%.
5. the described method of claim 1, wherein said penetration enhancer comprise ratio be about 1: 5 to about 5: 1 lauryl alcohol and isopropyl myristate.
6. the described method of claim 5, wherein said penetration enhancer comprise ratio be about 1: 4 to about 4: 1 lauryl alcohol and isopropyl myristate.
7. the described method of claim 6, wherein said penetration enhancer comprise ratio be about 1: 3 to about 3: 1 lauryl alcohol and isopropyl myristate.
8. the described method of claim 7, wherein said penetration enhancer comprise ratio be about 1: 2 to about 2: 1 lauryl alcohol and isopropyl myristate.
9. the described method of claim 1, wherein said penetration enhancer comprises that ratio is about 1: 1 lauryl alcohol and isopropyl myristate.
10. the described method of claim 1, wherein said penetration enhancer comprises that ratio is about 4: 1 lauryl alcohol and isopropyl myristate.
11. the described method of claim 1, wherein said medicine is a hormone.
12. the described method of claim 11, wherein said hormone is a gonadal hormone.
13. the described method of claim 12, wherein said gonadal hormone are to be selected from following member: testosterone, norethindrone, norethindrone acetate, estradiol, ethinyl estradiol, norelgestromine and their mixture, salt, isomer or analog.
14. the described method of claim 13, wherein said gonadal hormone is a testosterone.
15. the described method of claim 1 is wherein before using described isopropyl myristate, use described lauryl alcohol simultaneously or afterwards.
16. the described method of claim 15, wherein said lauryl alcohol and described isopropyl myristate are used simultaneously.
17. the described method of claim 1 is wherein before using described medicine, use the combination of described lauryl alcohol and isopropyl myristate simultaneously or afterwards.
18. the described method of claim 17, the combination and the medicine of wherein said lauryl alcohol and isopropyl myristate are used simultaneously.
19. the described method of claim 1 is wherein before using described medicine and the combination of using described lauryl alcohol and isopropyl myristate afterwards.
20. the described method of claim 1, the combination of wherein said lauryl alcohol and isopropyl myristate is applied as single permeation enhancer compositions.
21. as the permeation enhancer compositions of application as described in the claim 20, it comprises: the combination of lauryl alcohol and isopropyl myristate, wherein said combination provide medicine percutaneous collaborative promotion infiltration.
22. preparation capable of permeating skin, it comprises:
Pharmaceutically acceptable carrier;
The medicine of treatment effective dose; With
Permeation enhancer compositions as claimed in claim 21, wherein said permeation enhancer compositions provide the collaborative promotion transdermal penetration of described medicine.
23. the described preparation capable of permeating skin of claim 22, wherein said medicine is a hormone.
24. the described preparation capable of permeating skin of claim 23, wherein said hormone is a gonadal hormone.
25. the described preparation capable of permeating skin of claim 24, wherein said gonadal hormone are to be selected from following member: testosterone, norethindrone, norethindrone acetate, estradiol, ethinyl estradiol, norelgestromine and their mixture, salt, isomer or analog.
26. the described preparation capable of permeating skin of claim 25, wherein said gonadal hormone is a testosterone.
27. the described preparation capable of permeating skin of claim 22, wherein said lauryl alcohol and described isopropyl myristate account for about 0.5%w/w of described preparation capable of permeating skin separately to about 20%w/w.
28. the described preparation capable of permeating skin of claim 27, wherein said lauryl alcohol and described isopropyl myristate account for about 1%w/w of described preparation capable of permeating skin separately to about 10%w/w.
29. the described preparation capable of permeating skin of claim 28, wherein said lauryl alcohol and described isopropyl myristate account for about 2.5%w/w of described preparation capable of permeating skin separately to about 7.5%w/w.
30. the described preparation capable of permeating skin of claim 29, wherein said lauryl alcohol and described isopropyl myristate account for about 5%w/w of described preparation capable of permeating skin separately.
31. it is following or equal about 5%w/w that the described preparation capable of permeating skin of claim 28, wherein said lauryl alcohol and described isopropyl myristate account for about 5%w/w of described preparation capable of permeating skin separately.
32. the described preparation capable of permeating skin of claim 22, wherein said pharmaceutically acceptable carrier is a biocompatible polymer.
33. the described preparation capable of permeating skin of claim 32, wherein said biocompatible polymer are to be selected from following member: rubber; Organosilicon polymer and copolymer; Acrylic polymer and copolymer; With their mixture.
34. the described preparation capable of permeating skin of claim 33, wherein said biocompatible polymer are to be selected from following rubber: natural rubber and synthetic rubber, plasticising styrene-rubber block copolymers and their mixture.
35. the described preparation capable of permeating skin of claim 33, wherein said biocompatible polymer are to be selected from following member: organosilicon polymer, polysiloxanes and their mixture.
36. the described preparation capable of permeating skin of claim 33, wherein said biocompatible polymer are to be selected from following member: acrylic polymer, polyacrylate and their mixture.
37. the described preparation capable of permeating skin of claim 32, wherein said biocompatible polymer are to be selected from following member: vinylacetate, vinyl-vinyl acetate copolymer, polyurethanes, plasticising polyether amide block copolymer and their mixture.
38. the described preparation capable of permeating skin of claim 22, wherein said pharmaceutically acceptable carrier comprise the cohesive material that is suitable as liquid storage storehouse.
39. the described preparation capable of permeating skin of claim 38, wherein said cohesive material forms gel.
40. the described preparation capable of permeating skin of claim 22 further comprises being selected from following member: diluent, excipient, softening agent, plasticizer, skin irritation palliative, stable compound or their mixture.
41. the described preparation capable of permeating skin of claim 22, wherein said preparation is a transdermal patch.
42. the described preparation capable of permeating skin of claim 41, wherein said transdermal patch are the transdermal matrix patches.
43. the described preparation capable of permeating skin of claim 41, wherein said transdermal patch are liquid storage storehouse patches.
44. the described preparation capable of permeating skin of claim 22, wherein said preparation is a topical formulations.
45. the described preparation capable of permeating skin of claim 44, wherein said topical formulations are to be selected from following member: ointment, lotion, ointment, gel, paste, mousse, aerosol, spray, wax, balsam, suppository and their mixture or combination.
46. to permeate the method for transdermal delivery medicine by the enhancing in subject's skin zone, it comprises:
Use preparation capable of permeating skin as claimed in claim 22 to described skin area.
47. test kit is used for using the preparation capable of permeating skin that contains medicine with the enhancing infiltration by the subject's skin zone, described test kit comprises:
Pharmaceutically acceptable carrier, it has the medicine of the treatment effective dose that is mixed in the described carrier;
The lauryl alcohol of effective dose;
The isopropyl myristate of effective dose;
Describe the description of the method for using described preparation capable of permeating skin, wherein said lauryl alcohol and described isopropyl myristate provide the collaborative drug transdermal infiltration that promotes.
48. the described test kit of claim 47, wherein said lauryl alcohol and described isopropyl myristate are combined into single permeation enhancer compositions.
49. promote the method for medicine by the transdermal penetration in subject's skin zone, it comprises:
Use preparation capable of permeating skin to described skin area, described preparation capable of permeating skin comprises:
Pressure-sensitive acrylic base polymer, its content are that about 55%w/w of described preparation capable of permeating skin arrives about 85%w/w;
Testosterone, its content are that about 5%w/w of described preparation capable of permeating skin arrives about 12%w/w;
Polyvinylpyrrolidone, its content are that about 8%w/w of described preparation capable of permeating skin arrives about 12%w/w; With
Permeation enhancer compositions, it comprises the lauryl alcohol and about 2%w/w combination to the isopropyl myristate of about 8%w/w of about 2%w/w to about 8%w/w, the collaborative promotion infiltration that wherein said combination provides medicine to pass through skin area, described collaborative promotion infiltration is than the expectation additive effect of using lauryl alcohol and isopropyl myristate high about 10% to about 50%.
50. have the preparation capable of permeating skin that medicine promotes infiltration, it comprises:
Pressure-sensitive acrylic base polymer, its content are that about 55%w/w of described preparation capable of permeating skin arrives about 85%w/w;
Testosterone, its content are that about 5%w/w of described preparation capable of permeating skin arrives about 12%w/w;
Solubilizing agent, its content are that about 8%w/w of described preparation capable of permeating skin arrives about 12%w/w; With
Permeation enhancer compositions, it comprises: content is the lauryl alcohol of about 2%w/w of described preparation capable of permeating skin to about 8%w/w; With content be about 2%w/w of described preparation capable of permeating skin to the isopropyl myristate of about 8%w/w, wherein said permeation enhancer compositions provides the collaborative promotion infiltration of described testosterone by the subject's skin zone.
51. the described preparation of claim 50, wherein said pressure-sensitive acrylic base polymer account for about 70%w/w of described preparation capable of permeating skin to about 73%w/w.
52. the described preparation of claim 50, wherein said testosterone account for about 7%w/w of described preparation capable of permeating skin to about 10%w/w.
53. the described preparation of claim 50, wherein said solubilizing agent is a polyvinylpyrrolidone.
54. the described preparation of claim 53, wherein said polyvinylpyrrolidone account for about 10%w/w of described preparation capable of permeating skin.
55. the described preparation of claim 50, wherein said lauryl alcohol account for about 5%w/w of described preparation capable of permeating skin.
56. the described preparation of claim 50, wherein said isopropyl myristate account for about 5%w/w of described preparation capable of permeating skin.
57. have the preparation capable of permeating skin that medicine promotes infiltration, it comprises:
Pressure-sensitive acrylic base polymer, its content are that about 55%w/w of described preparation capable of permeating skin arrives about 85%w/w;
Norethindrone acetate, its content are that about 5%w/w of described preparation capable of permeating skin arrives about 15%w/w;
Solubilizing agent, its content are that about 8%w/w of described preparation capable of permeating skin arrives about 12%w/w; With
Permeation enhancer compositions, it comprises: content is the lauryl alcohol of about 2%w/w of described preparation capable of permeating skin to about 8%w/w; With content be about 2%w/w of described preparation capable of permeating skin to the isopropyl myristate of about 8%w/w, wherein said permeation enhancer compositions provides the collaborative promotion infiltration of described testosterone by the subject's skin zone.
58. the described preparation of claim 57, wherein said pressure-sensitive acrylic base polymer account for about 68%w/w of described preparation capable of permeating skin to about 72%w/w.
59. the described preparation of claim 57, wherein said norethindrone acetate account for about 8%w/w of described preparation capable of permeating skin to about 12%w/w.
60. the described preparation of claim 57, wherein said solubilizing agent is a polyvinylpyrrolidone.
61. the described preparation of claim 60, wherein said polyvinylpyrrolidone account for about 10%w/w of described preparation capable of permeating skin.
62. the described preparation of claim 57, wherein said lauryl alcohol account for about 5%w/w of described preparation capable of permeating skin.
63. the described preparation of claim 57, wherein said isopropyl myristate account for about 5%w/w of described preparation capable of permeating skin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70528905P | 2005-08-03 | 2005-08-03 | |
| US60/705,289 | 2005-08-03 | ||
| US11/461,377 | 2006-07-31 |
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| Publication Number | Publication Date |
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| CN101277686A true CN101277686A (en) | 2008-10-01 |
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| CNA2006800366384A Pending CN101277686A (en) | 2005-08-03 | 2006-08-02 | Formulations and methods for enhancing the transdermal penetration of a drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289859A (en) * | 2015-11-30 | 2018-07-17 | 椭圆疗法有限公司 | System and method for cutaneous penetration |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289859A (en) * | 2015-11-30 | 2018-07-17 | 椭圆疗法有限公司 | System and method for cutaneous penetration |
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