CN100566669C

CN100566669C - The transdermal release device of parathyroid hormone agents

Info

Publication number: CN100566669C
Application number: CNB2005800232224A
Authority: CN
Inventors: M·阿梅里; M·J·N·科尔米尔; Y·-F·马; M·坎贝里; P·达多纳
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 2004-05-13
Filing date: 2005-03-18
Publication date: 2009-12-09
Anticipated expiration: 2025-03-18
Also published as: CN1997319A; ZA200610412B

Abstract

The apparatus and method of transdermal release biologically active drug, comprise the delivery system of (30) (or the system) that have microprojection member, this microprojection member (or system) comprises many microprojection (32) (or its array) that pierce through horny layer and enter subcuticle or epidermis and skin corium that are applicable to.In one embodiment, in being coated to the biocompatible coating of microprojection member (35), contain medicine based on PTH.

Description

The transdermal release device of parathyroid hormone agents

The cross reference of related application

The application requires the U.S. Provisional Application No.60/571 that submits on May 13rd, 2004, and 304; The U.S. Provisional Application No.60/585 that on July 1st, 2004 submitted, 276; The U.S. Provisional Application No.60/643 that on January 12nd, 2005 submitted, 660 rights and interests.

Invention field

The present invention relates in general to transdermal drug delivery system and method.More especially, the present invention relates to the transdermal release apparatus and method of parathyroid hormone agents.

Background of invention

The most usually, give activating agent (or medicine) by oral or injection.Regrettably, when oral, the fully invalid or curative effect of many activating agents significantly reduces, because they are not absorbed before entering blood flow or affect adversely, thereby does not have ideal activity.On the other hand, direct intravenous injection or subcutaneous injection medicine, though medicine does not change during can guaranteeing administration, but difficulty, inconvenience, pain and uncomfortable process, it causes patient's compliance poor sometimes.

Therefore, in principle, releasing medicine through skin penetration provides the method that need not to give by subcutaneous injection or venoclysis activating agent.Generic term used herein " transdermal " is to instigate activating agent (therapeutic agent medicine for example for example, or immune-active agent vaccine for example) passing skin is released into local organization or systemic circulation system, basically do not need cutting or pierce through skin, for example cut or thrust by hypodermic needle skin with scalpel.Transdermal drug discharges and comprises by the release of passive diffusion with based on for example release of the outside resources of electricity (for example ionotherapy) and ultrasonic (for example ultrasonic introductory technique).

Passive transdermal drug delivery system is more common, generally includes the drug-reservoir that contains the high concentration active medicine.This bank is fit to and contact skin, thereby makes medicine can pass through skin diffusion, and enters patient's body tissue or blood flow.

Just as known in the art, the transdermal drug flux depends on the size of skin condition, drug molecule and physical/chemical, percutaneous Concentraton gradient.Because many medicines are low to percutaneous permeability, the application of releasing medicine through skin penetration is restricted.This hypotonicity is the outermost skin layer owing to horny layer mainly, and it is made up of the dead cell (being horn cell) smooth, that be full of keratin fiber that lipid bilayer surrounds.The height orderliness structure of lipid bilayer provides impervious relatively characteristic to horny layer.

Promote a common methods of passive transdermal diffusion drug flux, relate to dermal osmosis accelerator pretreatment skin or with this promoter and discharging altogether.When being applied to medicine through the surface of its release, penetration enhancer promotes the flux that medicine passes through.But these methods promote that the effect of albumen transdermal flux is limited, at least for bigger albumen, because of its molecule is more greatly like this.

Also develop many technology and device, their machinery pierces through or destroys outermost skin layers, thereby hews out the path that enters skin, so that promote the medication amount of transdermal release.Illustration has U.S. Patent No. 3,964, disclosed drug release device in 482.

Other adopt small skin-piercing element, improve system that transdermal drug discharges and device in U.S. Patent No. 5,879,326,3,814,097,5,250,023,3,964,482, second edition No.25,637 and PCT announce among No.WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298 and the WO 98/29365 open; All documents all are attached to herein by reference.

Disclosed system and device use the outermost layer (being horny layer) that element pierces through skin that thrusts of different shape and size.The disclosed element that thrusts is usually by thin, flat elements in these lists of references, and for example pad or sheet vertically launch.At some in this type of device to thrust element extremely small, the microprojection length that some has only is about 25-400 μ m, the only about 5-50 μ of microprojection thickness m.These small thrusting/cutting elements are used to promote transdermal drug to discharge and pass at the corresponding little microfissure/micro-incision of horny layer preparation.

Disclosed system also typically comprises the bank of storage of pharmaceutical and for example transports the medicine-releasing system of medicine by the hollow tooth of device itself from bank by horny layer.An example of this device is open in WO 93/17754, and it has liquid agent reservoir.But, must pressurize to bank, force liquid medicine by microtubular members with enter skin.The inferior position of this type of device comprises that adding the fluid under pressure bank increases complexity and expense, and owing to has the complexity of pressure-driven delivery system.

Disclosed such as Application No. 10/045,842, the document is attached to herein by reference, also active medicine to be discharged can be coated on the microprojection, but not be included in the physics bank.This just omits the necessity of separating physics bank and exploitation bank special-purpose medicaments preparation or compositions.

As known in the art, osteoporosis is to be characterized as the osteopathia that carrying out property bone mass loss increases individual risk of fractures, generally occurs in buttocks, spinal column and wrist.Carrying out property bone mass loss is generally from the 30-40 age in year, and is most of asymptomatic until fracturing, and causes high patient's M ﹠ M.80% is the women in the patients with osteoporosis, based on nearest research, and during menopause takes place back 6 years, women's bone amount loss 1/3rd.

Equally, as known in the art, parathyroid hormone (PTH) is the hormone of interior calcium of the control agent of pth secretion and phosphate metabolism.Because it promotes osteoplastic ability, PTH produces very big effect in the treatment osteoporosis, therefore significantly reduces fracture and takes place.Extensive clinical trial has shown PTH effectively also the reduction osteoporosis women's of safety vertebra and non-vertebral fracture generation percentage rate.

Because the ability of their accelerated bone healing is based on the also generation effect in treatment fracture (masculinity and femininity) of PTH medicine.

So far, developed the various stabilized preparations based on the PTH medicine, but recomposition is used for subcutaneous injection, as discussed below, subcutaneous injection is conventional method for releasing.Example is referring to U.S. Patent number 5,563,122 (stabilisation parathyroid hormone promotor compositions) and the disclosed preparation of U.S. Patent Application Publication No. 2002/0107200 (agent of stabilisation teriparatide solutions), and they are bonded to herein by reference.

Approval is FORTEO based on the PTH drug injection at present ^TM(the deutero-teriparatide injection of rDNA), it contains recombinant human parathyroid hormone (1-34) (rhPTH (1-34)).FORTEO ^TMGenerally be used to have women's prescription of osteoporotic fracture history, described women has multiple risk of fractures factor, or based on doctor's evaluation, its previous osteoporosis treatment failure or do not tolerate.In the postmenopausal osteoporosis women, FORTEO ^TMDiscovery has increased bone mineral density (BMP), has reduced the danger of vertebra and non-vertebral fracture.

In initial stage that is in high risk of fractures or hypogonadism osteoporosis male, FORTEO ^TMAlso find to increase the bone amount.These comprise the male with osteoporotic fracture history, or have the male of multiple risk of fractures, or to the failure of previous osteoporosis treatment or do not tolerate.In the early stage or among the hypogonadism osteoporosis male, find FORTEO ^TMIncreased BMD equally.Allowance for bark down outside the injection, also studied the method for other releases based on the PTH medicine.For example, pulmonary's release (promptly sucking) method has been discussed: " the medicine pulmonary that is used for osteopathia discharges " in following document, Advanced Drug Delivery Reviews, Vol 42, Issue 3, pp239-248 (on August 31st, 2000), Patton " pulmonary's release peptide and albumen :-interferon; the bioavailability of calcitonin and parathyroid hormone ", Journal of Controlled Release, Vol 28, Issue 1-3, pp.79-85 (in January, 1994), Patton etc., " pulmonary's delivery formulations and method absorb the influence of parathyroid hormone (1-34) to induced lung ", Journal ofPharmaceutical Sciences Vol 93, Issue 5, pp 1241-1252 (in May, 2004), Codrons etc., " in rat, discharging parathyroid hormone (1-34) " with sucking the dry powder whole body, Journal of Pharmaceutical Sciences Vol 92, Issue 5, pp 938-950 (in May, 2003) and Pf ü tzner, A etc., " examination research Technosphere/PTH (1-34)-effectively pulmonary discharges the new method of parathyroid hormone (1-34) ", Horm.Metab.Res., Vol 35 (5), pp 319-23.

The whole bag of tricks of active transdermal release based on the PTH medicine also has been discussed in following document: " electroporation to Eontophoretic transdermal release calcium-regulating hormone influence ", Journalof Controlled Release, Vol 66, Issues 2-3, pp.127-133 (on May 15th, 2000) and Chang etc., " by the osteopathia of the ovariectomized rat of pulse transdermal iontophoretic therapy administration of human PTH (1-34) prevention ", Journal ofPharmaceutical Sciences Vol 91, Issue 2, pp 350-361 (in February, 2002).

Although effectively, there is injection under some shortcomings and the inferior position, particularly percutaneous in disclosed PTH method for releasing prior art to PTH in treatment disease such as osteoporosis.Hypodermic major defect is difficulty and uncomfortable process, and this causes patient's compliance poor usually.

Existing document record gives medicine with the microprojection systems Intradermal, and hGH for example observes similar pharmacokinetic curve after hGH and subcutaneous administration are provided.See, Cormier etc., U.S. Patent Application Publication No. 2002/0128599, title " has the transdermal drug releasing device that applies the micro-protuberance body ".

To body, cause active bone heavily to absorb based on PTH medicine continuous infusion.Therefore, give based on the PTH medicine extremely important with pulse mode.Based on the effectiveness that subcutaneous injection once a day produces, what the PTH blood concentration that the alternative route that any PTH discharges provides all should be than subcutaneous injection PTH is slow.

Therefore, expectation provides and helps minimally-invasive and give drug delivery system based on the PTH medicine.Further expectation provide that drug delivery system, this system provide based on observed similar behind PTH drug pharmacokinetics curve and the subcutaneous administration.

Therefore, the purpose of this invention is to provide transdermal drug releasing device and method, provide Intradermal to discharge based on the PTH medicine to the patient.

Another object of the present invention provides transdermal drug releasing device and method, provides than the observed similar or fast pharmacokinetic curve based on the PTH medicine behind the subcutaneous administration.

Another object of the present invention provides transdermal drug releasing device and method, provides to reach 8 hours the pharmacologically active blood concentration based on the PTH medicine.

Another object of the present invention provide be used for Intradermal discharge to the patient based on PTH pharmaceutical preparation.

Another object of the present invention provides transdermal drug releasing device and method, and it comprises the microprojection that applies with biocompatible coating, and this coating comprises at least a biologically active drug, is preferably based on the PTH medicine.

Summary of the invention

According to above purpose and following will mentioning and conspicuous those purposes, transdermal release of the present invention comprises the delivery system with microprojection member (or system) usually based on the apparatus and method of PTH medicine, and this microprojection member comprises many microprojection (or its array) that pierce through horny layer and enter subcuticle or epidermis and skin corium that are applicable to.In preferred embodiments, this microprojection member comprises having at least a biocompatible coating based on the PTH medicine that is placed in one.

In one embodiment of the invention, the microprojection density of microprojection member is at least about 10 microprojection/cm ², more preferably at least about 200-2000 microprojection/cm ²Scope in.

In one embodiment, microprojection member is made of rustless steel, titanium, Nitinol or similar biocompatible material.

In another embodiment, microprojection member is by non-conducting material, and for example polymeric material constitutes.Perhaps, microprojection member can be used non-conducting material, for example

Or hydrophobic material, for example

Silicon or other low energy material apply.

Be coated to microprojection member to form the coating agent of solid biologic compatiblizing coatings, can comprise water and non-water formulation.The preferred coatings preparation comprises at least a based on the PTH medicine, and described medicinal soluble is separated in physiologically acceptable carrier and maybe can be suspended in this carrier.

In preferred embodiments, be selected from hPTH (1-34), hPTH salt and analog, teriparatide and related peptides based on the PTH medicine.In this application, term " based on the PTH medicine " and " hPTH (1-34) medicine " hPTH (1-34) that includes but not limited to recombinate, synthetic hPTH (1-34), PTH (1-34), teriparatide, hPTH (1-34) salt; The simple derivatives of hPTH (1-34), for example hPTH (1-34) amide and closely-related molecule, for example hPTH (1-33) or hPTH (1-31) amide; Or any other closely-related one-tenth bone peptide.Synthetic hPTH (1-34) is most preferred PTH medicine.

Pharmaceutically acceptable hPTH salt example includes but not limited to acetate, propionate, butyrate, valerate, caproate, enanthate, levulinate, hydrochlorate, hydrobromate, citrate, succinate, maleate, oxyacetate, gluconate, glucuronate, the 3-hydroxyisobutyrate, tricarballylic acid salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalic acid salt, dihydromethyl propionic acid salt (dimethylolpropinate), tiglic acid salt, glycerate, methacrylate, iso-crotonic acid salt, beta-hydroxy-butanoic acid salt, cronate, the Radix Angelicae Sinensis hydrochlorate, hydracrylate, Ascorbate, aspartate, glutamate, Glu, the 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, mesylate, sulfate and sulfonate.

Preferably, be present in the coating agent based on the PTH drug level for about 1-30% weight.

More preferably, contained amount based on the PTH medicine is about 1 μ g-1000 μ g in solid biologic compatiblizing coatings (being microprojection member or product), also 10 μ g-100 μ g more preferably from about.

Also the pH of preferred coatings preparation is at about pH below 6.More preferably the pH of coating agent is in the scope of about pH 2-6.Also more preferably the pH of coating agent in the scope of about pH 3-6.

In certain embodiments of the invention, improve the viscosity of coating agent that coating microprojctions adopts by the gegenion that adds low volatility.In one embodiment, positively charged under preparation pH based on the PTH medicine, and the gegenion of raising viscosity comprises the acid with at least two acid pKa.Suitable acid comprises maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, 1,3-propanedicarboxylic acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, hydroxymalonic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulphuric acid and phosphoric acid.

Another embodiment preferred relates to the gegenion mixture that improves viscosity, and wherein positively charged under preparation pH based on the PTH medicine, and at least a gegenion comprises the acid with at least two acid pKa.Other gegenions comprise the acid with one or more pKa.The example of appropriate acid comprises hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid, fumaric acid, acetic acid, propanoic acid, valeric acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulic acid, 1,3-propanedicarboxylic acid, the itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

In the embodiment that the present invention mentioned, during the amount of preferred gegenion is enough to and the electric charge of PTH.In this type of embodiment, electrically charged during the amount of preferred gegenion or gegenion mixture is enough under preparation pH with the institute of medicine.In other embodiments, can in peptide, add excessive gegenion (for free acid or for salt) with control pH and suitable buffer capacity is provided.

In another preferred embodiment, medicine comprises hPTH (1-34), and gegenion comprises the raising viscosity mixture of the gegenion that is selected from citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic and acetic acid.Preferably, in preparation, add gegenion so that viscosity in the scope of about 20-200cp.

In a preferred embodiment, the gegenion that improves viscosity comprises acid gegenion, low volatility weak acid for example, this low volatility weak acid gegenion has at least one acid pKa and fusing point is higher than about 50 ℃, or boiling point under atmospheric pressure is higher than about 170 ℃.This type of sour example comprises citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid and fumaric acid.

In another preferred embodiment, gegenion comprises strong acid, and this strong acid has at least one and is lower than about 2 pKa.This type of sour example comprises hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.

Another embodiment preferred relates to the gegenion mixture, and wherein at least a gegenion comprises strong acid, and at least a gegenion comprises low volatility weak acid.

Another embodiment preferred relates to the gegenion mixture, wherein at least a gegenion comprises strong acid, at least a gegenion comprises weak acid, this weak acid has high volatile volatile, and have at least one and be higher than about 2 pKa and be lower than about 50 ℃ fusing point, or under atmospheric pressure be lower than about 170 ℃ boiling point.This type of sour example comprises acetic acid, propanoic acid, valeric acid etc.

Preferably, acid gegenion exists with the amount of positive charge on being enough to neutralize based on the PTH medicine under the preparation pH.In other embodiments, can add excessive gegenion (for free acid or for salt) with control pH and suitable buffer capacity is provided.

In another embodiment of the invention, coating agent comprises at least a buffer agent.The example of this type of buffer agent includes but not limited to ascorbic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid., fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, 1,3-propanedicarboxylic acid (glutaratic acid), the itaconic acid, mesaconic acid, citramalic acid, dihydromethyl propionic acid, tiglic acid, glyceric acid, methacrylate, iso-crotonic acid, beta-hydroxy-butanoic acid, .beta.-methylacrylic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine or its mixture.

In one embodiment of the invention, coating agent comprises at least a antioxidant, and this antioxidant can comprise for example for example ascorbic acid, methionine, sodium ascorbate etc. of sodium citrate, citric acid, EDTA (ethylenediaminetetraacetic acid) or free radical scavenger of chelating agen.Preferred anti-oxidants comprises EDTA and methionine at present.

In mentioned embodiment of the present invention, preferably in coating agent, the concentration of antioxidant is about 0.01-20% weight.More preferably in coating agent, the concentration of antioxidant is about 0.03-10% weight.

In one embodiment of the invention, coating agent comprises at least a surfactant, this surfactant can be amphion, both sexes, cation, anion or nonionic surfactant, include but not limited to lauroyl both sexes sodium acetate, sodium lauryl sulphate (SDS), cetylpyridinium chloride (CPC), Dodecyl trimethyl ammonium chloride (TMAC), benzalkonium chloride (benzalkonium, chloride), polysorbate such as polysorbas20 and Tween 80, other sorbitan derivatives are the sorbitan laurate alcohol alcoxylates for example, laureth4 (laureth-4) for example, and castor oil derivatives, as Cremophor

In mentioned embodiment of the present invention, preferably in coating agent, surfactant concentrations is about 0.01-20% weight.Preferably in coating agent, surfactant concentrations is about 0.05-1% weight.

In another embodiment of the present invention, coating agent comprises at least a polymeric material or polymer with amphipathic characteristic, it can include but not limited to cellulose derivative, for example hydroxyethyl-cellulose (HEC), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxyethylmethyl-cellulose (HEMC) or ethyl hydroxyl-ethyl cellulose (EHEC) and poloxamer.

In one embodiment of the invention, in coating agent, in coating agent, provide the polymer concentration of amphipathic characteristic to be preferably about 0.01-20% weight, more preferably about 0.03-10% weight.

In another embodiment, coating agent comprises and is selected from following hydrophilic polymer: hetastarch, carboxymethyl cellulose and salt thereof, glucosan, poly-(vinyl alcohol), poly-(oxirane), poly-(methacrylate 2-hydroxyethyl ester), poly-(n-vinyl pyrrolidone), Polyethylene Glycol and composition thereof and similar polymerization thing.

In preferred embodiments, in coating agent, the concentration of hydrophilic polymer is about 1-30% weight in the coating agent, more preferably from about 1-20% weight.

In another embodiment of the invention, coating agent comprises physiologically acceptable carrier, and this carrier can include but not limited to human albumin, biological engineering human albumin, polyglutamic acid, poly-aspartate, polyhistidyl, pentosane polysulfate ester, polyamino acid, sucrose, trehalose, melezitose, Raffinose and stachyose.

In coating agent, the concentration of physiologically acceptable carrier is about 2-70% weight in the preferred coatings preparation, more preferably from about 5-50% weight.

In another embodiment, coating agent comprises stabilizing agent, and this stabilizing agent can include but not limited to non-reducing sugar, polysaccharide or reducing sugar.

The suitable non-reducing sugar that is used for the inventive method and compositions comprises, for example sucrose, trehalose, stachyose or Raffinose.

The suitable polysaccharide that is used for the inventive method and compositions comprises, for example glucosan, soluble starch, dextrin and insulin (insulin).

The suitable reducing sugar that is used for the inventive method and compositions comprises, for example for example apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, chinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, her shut out sugar, mannose, Tagatose etc. of monosaccharide; Reach disaccharide for example 6-(.beta.-D-xylosido)-D-glucose., vicianose, 6-O-.alpha.-L-rhamnosyl-D-glucose., scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, 6-(.alpha.-D-galactosido)-D-glucose., sophorose and turanose etc.

Preferably, the concentration of stabilizing agent is about 0.1-2.0 with respect to the ratio based on the PTH medicine in the coating agent: 1, and be about 0.25-1.0 more preferably: 1 with respect to ratio based on the PTH medicine.

In another embodiment, coating agent comprises vasoconstrictor, and this vasoconstrictor can include but not limited to amidefrine, 8-(.beta.-oxyethyl)methylaminocaffeine, cyclopentamine, phenylephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, isoadrenaline, octodrine, ornipressin, oxymetazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vassopressin, xylometazoline and composition thereof.Most preferred vasoconstrictor comprises epinephrine, naphazoline, tetrahydrozoline indanazoline, metizoline, tramazoline, tymazoline, oxymetazoline and xylometazoline.

If adopt, in coating agent, the concentration of vasoconstrictor is preferably about 0.1-10% weight.

In another embodiment of the invention, coating agent comprises at least a " pathway patency modulator ", this regulator can include but not limited to penetrating agent (for example sodium chloride), zwitterionic compound (for example aminoacid) and anti-inflammatory agent, betamethasone 21-disodic alkaliine for example, Aristosol (Lederle)., hydrocortamate hydrochloride, hydrocortisone 21-disodic alkaliine, Medrol Stabisol (Upjohn)., methylprednisolone 21-succinic acid sodium salt, paramethasone disodium hydrogen phosphate and prednisolone 21-succinic acid sodium salt reach for example citric acid of anticoagulant, citrate (for example sodium citrate), dextran sodium sulfate, aspirin and EDTA.

In also another embodiment of the present invention, coating agent comprises solubilising/chelating agent, and this solubilising/chelating agent can comprise alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, glucosyl group-alpha-cyclodextrin, malt-base-alpha-cyclodextrin, glucose group-beta-cyclodextrin, malt sugar group-beta-cyclodextrin, HP-, 2-hydroxypropyl-beta-schardinger dextrin-, 2-hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-, methyl-beta-schardinger dextrin-, sulfo group butyl ether-alpha-cyclodextrin, sulfo group butyl ether-beta-schardinger dextrin-and sulfo group butyl ether-gamma-cyclodextrin.Most preferred solubilising/chelating agent is beta-schardinger dextrin-, hydroxypropyl, 2-hydroxypropyl-beta-schardinger dextrin-and sulfo group butyl ether 7 beta-schardinger dextrin-s.

If adopt, in coating agent, the concentration of solubilising/chelating agent is preferably about 1-20% weight.

In another embodiment of the invention, coating agent comprises at least a nonaqueous solvent, for example ethanol, isopropyl alcohol, methanol, propanol, butanols, propylene glycol, dimethyl sulfoxide, glycerol, N, dinethylformamide and PEG400.In coating agent, the preferred amount of nonaqueous solvent in coating agent is about 1-50% weight.

The viscosity of preferred coatings preparation is less than about 500 centipoises, and greater than 3 centipoises.

In one embodiment of the invention, less than 25 microns, be more preferably less than 10 microns from the biocompatible coating thickness of microprojection surface measurement.

According to one embodiment of the invention, to comprise for patient's method based on the PTH drug release: microprojection member (i) is provided, this element has many cuticular microprojection that pierce through, this microprojection member has biocompatible coating placed on it, and this coating comprises at least a based on the PTH medicine; (ii) described microprojection member is administered to the patient skin position, described microprojection is thrust horny layer thus, and will give described patient based on the PTH drug release.

Preferably, the microprojection member that applies is administered to skin part through impacting applicator.

Also preferably the microprojection member that applies is placed on the skin part, continue 5 seconds-24 hours.After reaching desired service time, take off microprojection member.In certain embodiments, be about 1 μ g-1000 μ g based on the PTH medicine in the biocompatible coating.

In addition, afterwards observed pharmacokinetic curve is similar to subcutaneous releases at least to be preferably based on the pharmacokinetic curve that the PTH drug transdermal discharges.

In a preferred embodiment, be selected from hPTH (1-34), hPTH salt and analog, teriparatide and related peptides based on the PTH medicine.Also preferred hPTH salt is selected from acetate, propionate, butyrate, valerate, caproate, enanthate, levulinate, hydrochlorate, hydrobromate, citrate, succinate, maleate, oxyacetate, gluconate, glucuronate, the 3-hydroxyisobutyrate, tricarballylic acid salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalic acid salt, dihydromethyl propionic acid salt, tiglic acid salt, glycerate, methacrylate, iso-crotonic acid salt, beta-hydroxy-butanoic acid salt, cronate, the Radix Angelicae Sinensis hydrochlorate, hydracrylate, Ascorbate, aspartate, glutamate, Glu, the 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, mesylate, sulfate and sulfonate.

In the methods of the invention, transdermal release preferably has the biological agent of rapid onset based on the PTH medicine.Also preferred having based on the PTH medicine of transdermal release reaches 8 hours lasting biological agent.

In one embodiment, transdermal release comprise teriparatide (hPTH (1-34)) based on the PTH medicine, the dosage that biocompatible coating comprises based on the PTH medicine is about 10-100 μ g dosage, wherein behind the applied once, produces the plasma C of 50pg/ml at least based on the release of PTH medicine _Max

The present invention also comprises the method based on the pharmacokinetics of PTH medicine of improving transdermal release, this method comprises: microprojection member is provided, this element has many cuticular microprojection that pierce through, this microprojection member has biocompatible coating placed on it, and this coating comprises at least a based on the PTH medicine; Described microprojection member is administered to the patient skin position, described microprojection is thrust horny layer thus, and will give described patient based on the PTH drug release, thus compare with the pharmacokinetics feature of subcutaneous release, have the pharmacokinetics of improvement based on the PTH drug release.

In mentioned embodiment, the pharmacokinetics of improvement can comprise based on the PTH bioavailability of medicament and improving.The pharmacokinetics of improving also can comprise C _MaxImprove.In addition, the pharmacokinetics of improvement can comprise T _MaxDescend.The pharmacokinetics of improving can comprise that also the absorption rate based on the PTH medicine improves.

Therefore, in osteoporosis and treatment of fractures, can be safely and use apparatus and method of the present invention effectively.

The accompanying drawing summary

Press description of drawings, by following and the preferred embodiment of the invention more specifically described, further feature and advantage will be apparent, wherein as the character of quoting typically refer to the same section of whole view or element and wherein:

Fig. 1 is the sketch map of pulse concentration curve of the present invention;

Fig. 2 is the part perspective view of a microprojection member embodiment of the present invention;

Fig. 3 is the perspective view of microprojection member of the present invention shown in Fig. 2, and this microprojection member has the coating on the microprojection of being deposited on;

Fig. 4 has the microprojection member side view that viscosity is served as a contrast for the present invention;

Fig. 5 puts microprojection member for the side view of localizer of the present invention in this localizer;

Fig. 6 is the perspective view of localizer shown in Figure 4;

Fig. 7 is the decomposition diagram of applicator of the present invention and localizer;

Fig. 8 is for showing according to the electric charge curve synoptic diagram that the present invention is based on the PTH medicine;

Fig. 9 is for showing that band net charge class is based on the mol ratio sketch map of PTH medicine according to the present invention;

Figure 10 is for showing that acetic acid and neutral form are based on the mol ratio sketch map of PTH medicine according to the present invention;

Figure 11 is the plasma concentration comparison diagram after basis the present invention is based on PTH drug transdermal and subcutaneous release;

Figure 12 the present invention is based on the aggregation percentage rate sketch map that the PTH medicine contains and do not contain the sucrose stabilizing agent for basis;

Figure 13 the present invention is based on the sketch map that the PTH medicine contains and do not contain antioxidant oxidation in time for basis;

Figure 14 is according to the plasma concentration figure that the present invention is based on after the PTH drug transdermal discharges;

Figure 15 is the cAMP urine concentration figure that reflects according to the present invention based on the PTH drug bioavailability;

Figure 16 is for the PTH drug transdermal discharges and subcutaneous release back blood plasma concentration ratio another figure according to the present invention is based on.

Detailed Description Of The Invention

Before describing the present invention in detail, should understand and the invention is not restricted to specifically exemplify material, method or structure, so they can change certainly.Therefore, although implementing can to use when of the present invention and described those similar or be equal to many materials and methods herein, described herein is preferred material and method.

Should understand term used herein yet and only be used to describe specific embodiment purpose of the present invention, be not to be used for limiting.

Except that other had definition, all technology used herein and scientific terminology had the identical meanings of the those of ordinary skill common sense in the relevant field of the present invention.

In addition, all publications, patent and the patent application of quoting herein, no matter above or hereinafter all by reference integral body be attached to herein.

At last, except that other had clearly regulation, the singulative that uses in this description and claims " " and " being somebody's turn to do " comprised plural indicant.Therefore, " a kind of active medicine " that for example relate to comprises two or more this type of medicines; " a kind of microprojection " that relate to comprises two or more these type of microprojection etc.

Definition

Term used herein " transdermal " refers to drug release is entered and/or pass through skin for part or whole body therapeutic purpose.

Term used herein " transdermal flux " refers to the speed of transdermal release.

After term used herein " pulse release curve " and " pulse concentration curve " the expression administration, 1 minute in 4 hours, rise to the concentration of about 50-1000pg/ml based on the plasma concentration of PTH medicine from base concentration, wherein reach C _Max, and at C _MaxIn 1-8 hour, plasma concentration is from C after reaching _MaxReduce to base concentration.As shown in Figure 1, the concentration of being indicated (or pharmacokinetics) curve generally reflects administration bleeding from anus slurry concentration raise rapidly (being the first area) and C _MaxReach the back and descend slightly slowly (being second area) C with respect to the first area _MaxUsually the spike by concentration curve reflects.

Other concentration curves that produce pulse release also might produce the beneficial effect of expectation, and this pulse release was included in after the administration in 12 hours, rose to the C of 50-1000pg/ml based on the blood concentration of PTH medicine _Max, therefore within the scope of the present invention.

As going through herein, in one embodiment of the invention, illustrated " pulse release curve " is by the host's plasma concentration-time graph reflection (or proof) based on the PTH medicine, for the microprojection member that contains 30 μ g PTH (1-34) usually, the area under curve of this curve (AUC) is about 0.014-5.24 h ng/ml, C _MaxBe about 0.13-0.72ng/ml.

Term used herein " discharge altogether " be illustrated in release based on the PTH medicine before, before flowing into based on the PTH drug transdermal and during, flow into based on the PTH drug transdermal during, flow into based on the PTH drug transdermal during and afterwards and/or based on after the inflow of PTH drug transdermal, one or more supplement of transdermal administration.In addition, two or more can be mixed with coating and/or preparation based on the PTH medicine, cause discharging altogether based on the PTH medicine.

Term used herein " based on the PTH medicine " includes but not limited to hPTH (1-34), hPTH salt, hPTH analog, teriparatide, closely related peptide with " hPTH (1-34) medicine " and has the medicine of the peptide sequence that the mode identical with 34N-terminal amino acid (biologically active zone) sequence in the 84-aminoacid human parathyroid hormone work.Therefore term " based on the PTH medicine " and " hPTH (1-34) medicine " hPTH (1-34) that includes but not limited to recombinate, synthesize hPTH (1-34), PTH (1-34), hPTH (1-34) salt, teriparatide; The simple derivatives of hPTH (1-34), for example hPTH (1-34) amide and closely-related molecule, for example hPTH (1-33) or hPTH (1-31) amide; Become bone peptide with closely-related.

The example of suitable hPTH salt includes but not limited to acetate, propionate, butyrate, valerate, caproate, enanthate, levulinate, hydrochlorate, hydrobromate, citrate, succinate, maleate, oxyacetate, gluconate, glucuronate, the 3-hydroxyisobutyrate, tricarballylic acid salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalic acid salt, dihydromethyl propionic acid salt, tiglic acid salt, glycerate, methacrylate, iso-crotonic acid salt, beta-hydroxy-butanoic acid salt, cronate, the Radix Angelicae Sinensis hydrochlorate, hydracrylate, Ascorbate, aspartate, glutamate, Glu, the 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, mesylate, sulfate and sulfonate.

Describedly also can be various forms, as the composition or the non-irritating pharmaceutically acceptable salt of free alkali, acid, electrically charged or uncharged molecule, molecular complex based on the PTH medicine.

It is to be understood that in drug source of the present invention, bank and/or coating, to add more than a kind of, use term " based on the PTH medicine " never to get rid of two or more these type of medicines of use based on the PTH medicine.

Term used herein " microprojection " be meant suitable thrust or cut wear live animal, especially mammal and the more specifically horny layer of application on human skin enter the element that thrusts of subcuticle or epidermis and skin corium.

In one embodiment of the invention, thrust the ejectisome length of element less than 1000 microns.In another embodiment, the ejectisome length of thrusting element is more preferably less than 250 microns less than 500 microns.Microprojection also has width (being designated as " W " in Fig. 1) and the thickness in about 10-100 micrometer range in about 25-500 micrometer range.Microprojection can be made into difformity, for example pin, blade, nail, borer and combination thereof.

Term used herein " microprojection member " generally is meant to comprise and is used to thrust the cuticular microprojection array of lining up many microprojection of array.Can pass through etching or punching on many microprojection thin slices, and folding or crooked microprojection forms structure for example shown in Figure 2 away from plate plane, thus the formation microprojection member.Also available other known method is for example pressed U.S. Patent number 6,050, and is open in 988 (integral body is attached to herein by reference), by forming one or more with microprojection along every edge, and forms microprojection member.

Term used herein " coating agent " is meant and comprises free flowing composition or the mixture that is used for coating microprojctions and/or its array.The preferred coatings preparation comprises at least a based on the PTH medicine, can be solution or suspension based on the PTH medicine in preparation.

Term used herein " biocompatible coating " and " solid cladding " are meant and comprise " coating agent " of solid state basically.

As above illustrated, the present invention generally includes delivery system, this delivery system comprises the have many microprojection microprojection member (or system) of (or its array), and this microprojection (or its array) is applicable to that piercing through horny layer enters subcuticle or epidermis and skin corium.

Go through as this paper, key advantages of the present invention be with based on the PTH drug release to mammalian hosts, people patient's delivery system particularly wherein shows preferred pulse concentration curve based on the PTH medicine in patient's blood plasma after the administration.This delivery system also be suitable for self giving at least 1 time every day 20 μ g bullet (bolus) dosage based on the PTH medicine.

Refer now to Fig. 2, this figure shows that the present invention uses an embodiment of microprojection member 30.As shown in Figure 2, microprojection member 30 comprises the microprojection array 32 with many microprojection 34.Microprojection 34 is preferably extended from this sheet with an angle of 90 degrees basically, comprises hole 38 in illustrated embodiment.

According to the present invention, sheet 36 can be bonded to release patch, comprises the backing 40 of sheet 36, and can comprise tack coat 16 (see figure 4)s that make patch and skin-adherent in addition.In this embodiment, microprojection 34 is by etching on foil 36 or many microprojection 34 of punching out, and with microprojection 34 from the plane outside sweep of sheet 36 and form.

In one embodiment of the invention, the microprojection density of microprojection member 30 is at least about 10 microprojection/cm ², more preferably at least about 200-2000 microprojection/cm ²Scope in.The hole count that preferred per unit area medicine passes through is at least about 10 holes/cm ², and be less than about 2000 holes/cm ²

As explanation, the ejectisome length of microprojection 34 is preferably less than 1000 microns.In one embodiment, the ejectisome length of microprojection 34 is more preferably less than 250 microns less than 500 microns.The width of preferred microprojection 34 is about 25-500 micron, and thickness is about 10-100 micron.

In another embodiment of the present invention, the biocompatibility that can improve microprojection member 30 minimizes the hemorrhage and stimulation that is applied to behind the patient skin or eliminate.Particularly, the length of microprojection 34 can be less than 145 microns, more preferably about 50-145 micron, also more preferably about 70-140 micron.The array that also preferred microprojection member 30 comprises has greater than 100 microprojection/cm ²Microprojection density, more preferably about 200-3000 microprojection/cm ²See the U.S. Patent application serial number 60/______[ALZ5174 PSP that submitted on February 15th, 2005 about more details with microprojection member of improving biocompatibility], its by reference integral body be bonded to herein.

Microprojection member 30 can be by various metals, for example rustless steel, titanium, Nitinol or similarly biocompatible material preparation.

According to the present invention, microprojection member 30 also can by non-conducting material for example polymeric material constitute.Perhaps, microprojection member can be with non-conducting material for example

Or hydrophobic material for example

Silicon or other low energy material apply.Hydrophobic material of knowing and relevant substrate (for example photoreist) layer be at U.S. Provisional Application No.60/484, proposes in 142, and this provisional application is attached to herein by reference.

Can include but not limited to U.S. Patent No. 6,083 by the microprojection member that the present invention adopts, disclosed element in 196,6,050,988 and 6,091,975, these patents are by reference and integral body is attached to herein.

Can comprise by other microprojection member that the present invention adopts by with silicon chip etching technology etching silicon or the element that forms with the little mould moulded plastic of etching, for example at U.S. Patent number 5,879, disclosed element in 326, document integral body by reference is attached to herein.

In some embodiment of the present invention, preferred microprojection 34 is configured to reduce the transmutability of institute's applying coating 35.Suitable microprojection generally comprises the specific region of the Breadth Maximum with transversal longitudinal axis, is positioned at the position apart from the terminal about 25%-75% length range of microprojection.Near the ad-hoc location of Breadth Maximum, the width of microprojection is decreased to minimum widith gradually.See the U. S. application serial number 60/649,888 that on January 31st, 2005 submitted to about the more details of described microprojection structure, document integral body by reference is attached to herein.

Now, Fig. 3, Fig. 3 show microprojection member 30, and it has the microprojection 34 that comprises biocompatible coating 35, and biocompatible coating 35 comprises the medicine based on PTH.According to the present invention, coating 35 can partly or entirely cover each microprojection 34.For example, coating 35 can be dried pattern (pattern) coating on microprojection 34.Coating 35 also can apply before or after microprojection 34 forms.

According to the present invention, coating 35 can be coated to microprojection 34 by various known method.Preferably, coating only is coated to microprojection member 30 or microprojection 34 and thrusts those parts of skin (for example most advanced and sophisticated 39).

A kind of such coating process comprises invading and is coated with.Invade to be coated with and to be described to by microprojection 34 partly or entirely being immersed in the method for coming coating microprojctions in the coating solution.By using part immersion technology, can limit coating 35 and only be coated on the tip 39 of microprojection 34.

Another coating process comprises roller coat, and this method adopts roller coat mechanism, similarly limits coating 35 and only is coated on the tip 39 of microprojection 34.Method of roll coating is open in U. S. application number 10/099,604 (publication No. 2002/0132054), and this application integral body by reference is attached to herein.As going through in the application of being mentioned, disclosed method of roll coating provides and be not easy the smooth finish that comes off from microprojection 34 when thrusting skin.

According to the present invention, microprojection 34 also can comprise the means of accepting and/or increasing coating 35 volumes that are applicable to, for example hole (not shown), groove (not shown), surface irregularity (not shown) or similarly improvement, wherein these means provide the surface area of increase, on can deposit more substantial coating.

Another coating process that can use within the scope of the present invention comprises spraying.According to the present invention, spraying can comprise the formation of the aerosol suspension of coating composition.In one embodiment, the aerosol suspension that will have about 10-200 picoliter drop size is sprayed on the microprojection 10, and is dry then.

Also can use pattern application method coating microprojctions 34.Can adopt the pattern application method, use distribution system that deposited liquid is positioned on the microprojection surface.The amount of preferred deposition liquid is 0.1-20 millilambda/microprojection.The example of suitable accurate quantitative liquid distributor is in U.S. Patent number 5,916,524; 5,743,960; 5,741,554; With 5,738, open in 728; These patents all are attached to herein by reference.

The ink-jet technology coating microprojection coating agent or the solution of the known solenoid valve allotter of also available use, optional by using the fluid flow method and the localization method of electric field controls usually.Known class quasi-liquid distribution technique can be used for being coated with patterned coatings of the present invention in the liquid distribution technique of other printing industry or this area.

Refer now to Fig. 5 and 6, be storage and application, microprojection member 30 preferably is suspended on the loop mapping device 40 by viscosity draw ring (tabs) 6, as U. S. application No.09/976, describe in detail in 762 (publication No. 2002/0091357) like that, this application is by reference and integral body is attached to herein.

After microprojection member 30 places loop mapping device 40, microprojection member 30 is applied to patient skin.Preferably with impacting applicator 45 microprojection member 30 is applied to patient skin, described in for example shown in Figure 7 and common pending trial U. S. application number 09/976,978, this application integral body by reference is attached to herein.

As explanation,, be coated to microprojection member 30 and have at least a aqueous and non-aqueous preparation based on the PTH medicine to form the coating agent of solid biologic compatiblizing coatings, can comprise according to one embodiment of the invention.According to the present invention, separate in physiologically acceptable carrier or be suspended in this carrier based on the PTH medicinal soluble.

See Fig. 8 now, show the hPTH (1-34) that is predicted among the figure, promptly show the electric charge curve of the peptide of 11 acid pKa and 6 alkaline pKa.As shown in Figure 8, this peptide provides zero net charge when pH 9.This point is also referred to as isoelectric point, IP or pI.

See Fig. 9 now, this figure shows the mol ratio of net charge class hPTH (1-34) medicine of being predicted.As shown in Figure 8, neutral class medicine only exists in pH 6.5-11.5 scope in a large number.In this pH scope, the water solublity of peptide reduces, and can separate out from solution.HPTH and closely related analog thereof show similarly feature and the behavior with hPTH (1-34).

Therefore, reflection hPTH (1-34) deliquescent data can obtain being lower than about pH 6 or being higher than under the pH of pH11.5, and the acceptable preparation of coating is compatible on described dissolubility and the microprojection array of the present invention.Therefore, in preferred embodiments, the pH of coating agent is in the scope of about pH 2-6.

Refer now to Figure 10, this figure shows the mol ratio stack of hPTH (1-34) acetic acid and neutral form.As shown in Figure 8, the pH of six acetic acid PTH (mol ratio 1: 6) solution is about pH 5.At pH 5, the PTH of negligible quantity exists with PTH zero net charge (PTH 0).Very soluble in water above PTH under 20% the concentration.In drying with between the storage life subsequently, free acetic acid evaporates inwardness, causes water-insoluble PTH 0 to form.Recomposition will not allow all PTH dissolvings in water subsequently.Therefore, use the low volatility gegenion that the solid dissolubility preparation of PTH is provided, as long as pH maintains the PI 2.5pH unit at least that is lower than PTH, preferred 3pH unit.Preferably, this can realize by providing for per molecule PTH at least about 2 molecule low volatility gegenions.

Therefore, in one embodiment of the invention, coating agent comprises gegenion or gegenion mixture.In addition, in the pH scope of preferred pH 3-6, based on the PTH medicine with positively charged.

In preferred embodiments, be selected from hPTH (1-34), hPTH salt and analog, teriparatide and related peptides, comprise reorganization hPTH (1-34), synthetic hPTH (1-34), PTH (1-34), teriparatide, hPTH (1-34) salt based on the PTH medicine; The simple derivatives of hPTH (1-34), for example hPTH (1-34) amide and closely-related molecule, for example hPTH (1-33) or hPTH (1-31) amide; Closely-relatedly become bone peptide with any other.Synthetic hPTH (1-34) is most preferred based on the PTH medicine.

Suitable hPTH salt example includes but not limited to acetate, propionate, butyrate, valerate, caproate, enanthate, levulinate, hydrochlorate, hydrobromate, citrate, succinate, maleate, oxyacetate, gluconate, glucuronate, the 3-hydroxyisobutyrate, tricarballylic acid salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalic acid salt, dihydromethyl propionic acid salt, tiglic acid salt, glycerate, methacrylate, iso-crotonic acid salt, beta-hydroxy-butanoic acid salt, cronate, the Radix Angelicae Sinensis hydrochlorate, hydracrylate, Ascorbate, aspartate, glutamate, Glu, the 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, mesylate, sulfate and sulfonate.

More preferably, contained amount based on the PTH medicine is 1 μ g-1000 μ g in the biocompatible coating on microprojection member, also more preferably 10 μ g-100 μ g.

The pH of preferred coatings preparation is at about pH below 6.More preferably the pH of coating agent is in the scope of pH2-6.Also more preferably the pH of coating agent in the scope of about pH 3-6.

In certain embodiments of the invention, improve the viscosity of coating agent by the gegenion that adds low volatility.In one embodiment, positively charged under preparation pH based on the PTH medicine, and the gegenion of raising viscosity comprises the acid with at least two acid pKa.Suitable acid includes but not limited to maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, 1,3-propanedicarboxylic acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, hydroxymalonic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulphuric acid and phosphoric acid.

Another embodiment preferred relates to the gegenion mixture that improves viscosity, and wherein positively charged under preparation pH based on the PTH medicine, and at least a gegenion comprises the acid with at least two acid pKa.Other gegenions are the acid with one or more pKa.The example of appropriate acid includes but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid, fumaric acid, acetic acid, propanoic acid, valeric acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulic acid, 1,3-propanedicarboxylic acid, the itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

In the embodiment that the present invention mentioned, during the amount of preferred gegenion is enough to and the electric charge of PTH.In this type of embodiment, electrically charged during preferred gegenion or gegenion mixture are enough under preparation pH with the institute of medicine.In other embodiments, can in peptide, add excessive gegenion (for free acid or for salt) with control pH and suitable buffer capacity is provided.

In a preferred embodiment, medicine comprises hPTH (1-34), and gegenion comprises the raising viscosity mixture of the gegenion that is selected from citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic and acetic acid.Preferably, in preparation, add gegenion to obtain the viscosity in about 20-200cp scope.

In a preferred embodiment, the gegenion that improves viscosity comprises acid gegenion, for example low volatility weak acid.Preferred this low volatility weak acid gegenion has at least one acid pKa and fusing point is higher than about 50 ℃, or boiling point under atmospheric pressure is higher than about 170 ℃.This type of sour example includes but not limited to citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid and fumaric acid.

In another embodiment, gegenion comprises strong acid.Preferred this strong acid has at least one and is lower than about 2 pKa.This type of sour example includes but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.

Another embodiment preferred relates to the gegenion mixture, and wherein at least a gegenion comprises strong acid, and at least a gegenion comprises and has high-volatile weak acid.Preferred this volatility weak acid gegenion has at least one and is higher than about 2 pKa and is lower than about 50 ℃ fusing point, or under atmospheric pressure is lower than about 170 ℃ boiling point.This type of sour example includes but not limited to acetic acid, propanoic acid, valeric acid etc.

In another embodiment of the invention, coating agent comprises at least a buffer agent.The example of this type of buffer agent includes but not limited to ascorbic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid., fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, 1,3-propanedicarboxylic acid, the itaconic acid, mesaconic acid, citramalic acid, dihydromethyl propionic acid, tiglic acid, glyceric acid, methacrylate, iso-crotonic acid, beta-hydroxy-butanoic acid, .beta.-methylacrylic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and composition thereof.

In one embodiment of the invention, coating agent comprises at least a antioxidant, this antioxidant can be chelating agen, for example for example ascorbic acid, methionine, sodium ascorbate etc. of sodium citrate, citric acid, EDTA (ethylenediaminetetraacetic acid) or free radical scavenger.Preferred anti-oxidants comprises EDTA and methionine at present.

In mentioned embodiment of the present invention, in coating agent, the concentration of antioxidant is about 0.01-20% weight.Preferably in coating agent, antioxidant accounts for about 0.03-10% weight.

In one embodiment of the invention, coating agent comprises at least a surfactant, this surfactant can be amphion, both sexes, cation, anion or nonionic surfactant, include but not limited to lauroyl both sexes sodium acetate, sodium lauryl sulphate (SDS), cetylpyridinium chloride (CPC), Dodecyl trimethyl ammonium chloride (TMAC), benzalkonium chloride, polysorbate such as polysorbas20 and Tween 80, other sorbitan derivatives are sorbitan laurate for example, alcohol alcoxylates, laureth4 for example, and castor oil derivatives, as Cremophor

In one embodiment of the invention, in coating agent, surfactant concentrations is about 0.01-20% weight.Preferred surfactant accounts for the about 0.05-1% weight of coating agent.

In another embodiment of the invention, coating agent comprises physiologically acceptable carrier, and this carrier can include but not limited to human albumin, biological engineering human albumin, polyglutamic acid, poly-aspartate, polyhistidyl, pentosane polysulfate ester, polyamino acid, sucrose, trehalose, melezitose, Raffinose, stachyose, mannitol and other sugar alcohols.

The suitable polysaccharide that is used for the inventive method and compositions comprises, for example glucosan, soluble starch, dextrin and insulin.

Therefore, as those of ordinary skills recognize, in coating agent of the present invention and solid biologic compatiblizing coatings, add vasoconstrictor, hemorrhage particularly useful to what prevent from after using microprojection member or array, may occur, and the blood flow by reducing site of administration and reduce the absorption rate that enters systemic circulation from skin part prolongs the pharmacokinetics based on the PTH medicine.

Other known formulation auxiliary agents also can join in the coating agent, as long as they do not cause adverse effect to the dissolubility of coating agent needs and the physical integrity of viscosity characteristics and dry coating.

In one embodiment of the invention, coating layer thickness less than 25 microns, is more preferably less than 10 microns from the microprojection surface measurement.

Ideal coating layer thickness depends on Several Factors, comprises desired dosage and therefore discharges the density of microprojection on the necessary coating layer thickness of this dosage, the per unit area sheet, viscosity and the concentration and the selected coating process of coating composition.

According to one embodiment of the invention, on the microprojection member in the biocompatible coating contained method for releasing based on the PTH medicine may further comprise the steps: at first the microprojection member that applies is applied to patient skin by driver, wherein microprojection pierces through horny layer.Preferably the microprojection member that applies is placed on the skin, continue 5 seconds-24 hours.After reaching desired service time, take off microprojection member.

Contained amount based on the PTH medicine (being dosage) is the about 1 μ g-1000 μ g of every dosage unit, more preferably from about 10 μ g-200 μ g in the preferred biocompatible coating.Also more preferably in the biocompatible coating contained amount based on the PTH medicine be the about 10 μ g-100 μ g of every dosage unit.

As described, according to the present invention, will therefore show the pharmacokinetics that produces the pulse concentration curve based on the PTH drug release to the patient with pulse mode.In one embodiment of the invention, the pulse concentration curve is by the host's plasma concentration-time graph reflection (or proof) based on the PTH medicine, for the microprojection member that contains 30 μ g PTH (1-34) usually, the area under curve of this curve (AUC) is about 0.014-5.24 h ng/ml, C _MaxBe about 0.13-0.72ng/ml.

In another embodiment of the present invention, the pulse concentration curve is by the host's plasma concentration-time graph reflection (or proof) based on the PTH medicine, for the microprojection member that contains 30 μ g PTH (1-34) usually, the area under curve of this curve (AUC) is about 0.014-5.24h ng/ml, C _MaxBe about 0.13-0.72ng/ml, T _MaxBe 5-15min.

In present embodiment preferred, by microprojection member being placed suitable position, kept 15 minutes or time still less, with pulse mode discharge 20 μ g bullet dosage based on the PTH medicine.

Preferably obtain at mentioned pulse concentration curve, more preferably overall pulse every day (or dosage) through the PTH release embodiments of (promptly every other day once)-2 pulses every day 0.5.Yet, being familiar with as those of ordinary skills, PTH also can discharge through various other dosage regimens.

In all situations, behind the applying coating, dry coating agent on microprojection 34 ins all sorts of ways.In the preferred embodiment of the invention, the microprojection member 30 of coating is dry at ambient temperature.Yet the coating agent on the dry microprojection can use all temps and humidity level.In addition, coated element can adopt heating, lyophilization, lyophilizing or similar techniques to remove moisture in the coating.

Those of ordinary skill in the art will recognize that in order to promote medicine to pass the skin barrier transmission, the present invention also can with various ionotherapies or fax delivery system applied in any combination because in this respect, the invention is not restricted to any way.Exemplary electrical is transmitted drug delivery system in U.S. Patent No. 5,147, and is open in 296,5,080,646,5,169,382 and 5,169,383, and its disclosure by reference and integral body is attached to herein.

Usually, term " fax is passed " refers to beneficial drugs, and for example medicine or prodrug are through body surface, and for example skin, mucosa, fingernail etc. passes through.The transmission of medicine is by applying electromotive force and induce or improving, and this electromotive force causes the application of electric current, and this electric current discharges or promote the release of medicine, perhaps, " reverse " fax is passed sampling or promote the sampling of medicine.The medicine electricity is transmitted into human body or passes out human body and can obtain in every way.

Method-ionotherapy is passed in a kind of widely used fax, and the electricity that relates to charged ion is induced transmission.Method (for example, the sampling of the transdermal of glucose) is passed in the fax of electro-osmosis-the relate to another kind of type of neutral or electric neutrality molecule transdermal delivery, relates under electric field effects, and solvent and medicine are by the motion of film.Another type that electroporation-fax is passed relates to medicine and passes passing through of hole, and this hole is by being applied to electric pulse, high voltage pulse on the film and forming.

In many cases, can there be different scopes simultaneously more than a kind of described method.Therefore, its possible extensive interpretation given in term herein " fax is passed ", comprises at least a electrically charged or neutral medicine, or the transmission of inducing or promoting of the electricity of its mixture, no matter the concrete mechanism that in fact this medicine is transmitted.

In addition, other transmit the promotion for example ultrasonic introductory technique of method (sonophoresis) or piezo-electric device can be used in combination with the present invention.

Embodiment

Provide the following example, make those skilled in the art can more be expressly understood and implement the present invention.They should not be considered to limit the scope of the invention, and are illustrated as just its representative.

Embodiment 1

With there not being the release of hair Cavia porcellus (HGP) model evaluation hPTH (1-34) from the microprojection array of coating.Make to use up/chemical etching and molding prepare microprojection array.The microprojection array area 2cm that this research is used ², 320 microprojection/cm ², ejectisome length 200 μ m.Microprojection array is pressed every 2cm with 25% aqueous solution of hPTH (1-34) ² Array 40 ± 10 μ g apply, and solid cladding is limited to the initial 100 μ m of microprojection.The microprojection array of each coating is installed flexible polymer viscosity backing.The gained patch is placed on the loop mapping device, and when being applied to HGP, install on the reusable impact applicator.

The HGP of every anesthesia accepts patch, and this patch is applied to the skin area of cleaning, 1 hour service time.Each interval after using patch is taked blood sample.Measure hPTH (1-34) blood plasma level with enzyme immunoassay (EIA) (Peninsula Lab).

To accept the HGP blood plasma level of microprojection array patch (applying), and give 20 μ g hPTH (1-34) with subcutaneous (SC) and compare (seeing Figure 11) with 40 μ g hPTH (1-34).

In 5 animals of another group, also carry out intravenous (IV) injection 23 μ g hPTH (1-34), use area under curve (AUC), calculate the amount of all absorption/releases after SC or the microneedle array administration as reference.The pharmacokinetic parameter of hPTH (1-34) is shown in Table 1 after IV, SC and the microneedle array administration.

SC is similar with immunocompetence hPTH (1-34) pharmacokinetics (PK) curve that microprojection array discharges both; t _Max(SC:10min is to 20min), C _Max(SC:4.6 ± 1.5ng/ml is to 3.4 ± 1.0ng/ml); AUC _240min(SC:8.2 ± 2.9 μ g are to 6.6 ± 1.8 μ g) (the n=10/ group, meansigma methods ± SD).

Data show that the PK curve of hPTH (1-34) transdermal release can be with hypodermic similar, and explanation is with the practicality of microprojection array technology transdermal release hPTH (1-34), and it can become patients with osteoporosis alternative method more easily.

Table 1

Embodiment 2

Embodiment 2 proof hPTH (1-34) drug use weak acid have improved viscosity.Weak acid anion and positively charged hPTH (1-34) drug interaction cause forming second key, and as hydrogen bond, this causes solution viscosity to increase.The number of acidic-group is many more, and second number of keys that forms between anion and hPTH (1-34) medicine is many more, so the viscosity increase is many more.Therefore, when monoacid relatively, binary acid, ternary acid and tetra-atomic acid, theoretical viscosity raising ability increases.

In this test, add various weak acid buffer agents in hPTH (1-34) preparation.Also preparation comprises the control formulation of acetic acid PTH (1-34) and sucrose.This experimental study the physicochemical characteristicss that provide of the various mixture of hPTH (1-34) and monoacid, binary acid and ternary acid, and pharmaceutical solutions is at 48 hours, the stability under 2-8 ℃.PTH (1-34) preparation is buffered to pH 5.2.

Now, referring to table 2, table 2 has shown the viscosity results of preparation.(lot number 7528069A) compares with control formulation, and the buffered preparation of citric acid and malic acid shows maximum viscosity and improves.The citric acid of ternary acid obtains the most full-bodied preparation.

The digital proof of table 2: compare with the control formulation of 20%PTH, 20% sucrose, 0.2% polysorbas20, the gegenion mixture of citric acid/acetic acid, malic acid/acetic acid, tartaric acid/acetic acid and hydrochloric acid/acetic acid has improved the viscosity of hPTH (1-34).According to the result of table 2, add viscosity improves behind the weak acid buffer agent trend be preferably ternary acid to binary acid to monoacid.

Table 2

The preparation lot number	Viscosity (cP)
The preparation lot number	Viscosity (cP)	20%PTH, 20% sucrose, 0.2% polysorbas20	68
20%PTH, 20% sucrose, 0.5%HCl, 0.2% polysorbas20	87	20%PTH, 20% sucrose, 0.2% polysorbas20	68
20%PTH, 20% sucrose, 0.5%HCl, 0.2% polysorbas20	87	20%PTH, 20% sucrose, 1.2% glycolic, 0.2% polysorbas20	53
20%PTH, 20% sucrose, 1.4% malic acid, 0.2% polysorbas20	116	20%PTH, 20% sucrose, 1.2% glycolic, 0.2% polysorbas20	53
20%PTH, 20% sucrose, 1.4% malic acid, 0.2% polysorbas20	116	20%PTH, 20% sucrose, 1.2% tartaric acid, 0.2% polysorbas20	77
20%PTH, 20% sucrose, 1.7% citric acid, 0.2% polysorbas20	172	20%PTH, 20% sucrose, 1.2% tartaric acid, 0.2% polysorbas20	77

Embodiment 3

Embodiment 3 proof hPTH (1-34) medicines improve based on dissolution in the body of hPTH medicine with the gegenion mixture.

In the solid cladding, medicine generally exists with the amount of per unit dosage less than about 1mg on microprojection array.After adding excipient and gegenion, the gross mass per unit dosage of solid cladding can be less than 3mg.

Array is present on the viscosity backing usually, and this viscosity backing sticks on the disposable polymer ring localizer.This combination is generally packed separately with pouch or polymer shell.Except that this combination, this packing contains provides the atmosphere of 3ml volume (inertia usually) at least.This large volume (comparing with the coating volume) is as the absorber of any volatile component.For example, in the time of 20 ℃,, there is the amount of acetic acid in the 3ml atmosphere because its vapour pressure is about 0.15mg.If use acetic acid as gegenion, this amount is generally the amount that exists in the solid cladding.In addition, the assembly of this combination, for example adhesive may be used as the other absorption cell of volatile component.As a result, in the long term storage process, the concentration of any volatile component that exists in the coating may acute variation.When wherein there was the medicinal compound of a large amount of excipient in packing usually, these situations were typically.Even if as the activity of injection very Johnson ﹠ Johnson's thing technical compound, a large amount of buffer agents and excipient exist with dried cheese formula for lyophilizing.

At solution or solid-state, the volatilization of gegenion occurs in the interface between solution or solid and the atmosphere.The solute of high diffusibility makes the concentration difference between interface and the whole solution minimize usually.Therefore, solid-state, diffusibility is very low, obtains bigger volatility gegenion Concentraton gradient between interface and whole solution.At last, compare with initial drying regime, the outer field gegenion of coating reduces, and the gegenion of solid cladding integral body is constant relatively.If the largely insoluble medicine of gegenion net charge state neutral with it associates, this situation can cause extremely insoluble external skin.Really, the volatilization of gegenion causes the formation of water-insoluble neutral species.When being exposed to biological fluid, this endangers the stripping of medicine from solid cladding again.Therefore, this experimental study adds the deliquescent effect of low volatility gegenion raising coating.

Prepare several aqueous formulations that contain hPTH (1-34), see Table 3 and describe.These preparations contain volatility gegenion acetic acid.Some preparation contains other low volatility gegenion hydrochloric acid, glycolic or tartaric acid.The contact skin area of microprojection array (microprojection length 200mm, 595 microprojection/arrays) is about 2cm ²With U.S. Patent application serial number 10/099,604 disclosed apparatus and method (this application is bonded to herein by reference), by the array process being loaded with the rotation of PTH preparation, with the tip of the preparation coating microprojctions of describing.

At 2-8 ℃, on each microprojection array, carry out 4 times and apply continuously.By using ultraviolet spectrophotometry,, estimate the amount that is coated in the peptide on the array in the 275nm wavelength.Electron scanning microscope shows that solid cladding has very slick surface, flawless evidence.In addition, observing between the microprojection coating has good homogeneous, and coating is limited to the most advanced and sophisticated initial 100 μ m of microprojection.

Then, the array that the tip for preparing is according to the method applied does not carry out drug release studies in having hair Cavia porcellus (HPG).By intramuscular injection xylazine (8mg/kg) and ketalar (44mg/kg) HPG is anaesthetized.The HPG of anesthesia is inserted conduit through carotid artery.Conduit condenses preventing with heparinized saline (20IU/ml) flushing.By pentobarbital sodium (32mg/ml) being injected directly into conduit (0.1ml/ injection), make HPG in entire test, remain on narcotism.Before the application, blood sample is placed heparinization bottle (the heparin final concentration is 15IU/ml), used as 0 sample or authentic specimen.

With the impact applicator of flexible drive (gross energy=0.4 joule, release time is less than 10 milliseconds) microprojection array that applies is applied to the flank of anesthetized animal, described impact applicator is a U.S. Patent application serial number 09/976,798 disclosed types, this application are by reference and integral body is bonded to herein.The system that is used comprises the microprojection array device of coating, and this device is bonded to the center of LDPE backing with adhesive (7cm, 2 dishes).Patch keeps 1 hour (n=4-5) on skin.Control animals (n=5) is accepted intravenous injection 22 μ g hPTH.

After patch is used, collect blood sample by carotid duct at each interval.All blood samples are centrifugal immediately, collect blood plasma, then the latter is used when-80 ℃ of storages are to be analyzed.Measure blood plasma hPTH with EIA, EIA is Peninsula Lab (San Carlos, hPTH CA) EIA enzyme immunoassay test kit commodity.Calculate according to the area under curve of comparing with hPTH IV administration (AUC), calculate the hPTH dosage that discharges through microprojection array.

As shown in table 3, the PTH amount that each solid preparation discharges is different.The solid preparation that only contains acetic acid PTH on average discharges and is less than 2mg, adds the low volatility gegenion and significantly improve release in acetic acid PTH, adds to improve as many as 11.2mg behind the low volatility gegenion glycolic.Two kinds of other non-gegenions of test, promptly tartaric acid and hydrochloric acid have also increased PTH release.Particularly, compare with the control formulation of 21.2%PTH, 3.8% acetic acid, the gegenion mixture of glycolic/acetic acid, tartaric acid/acetic acid and hydrochloric acid/acetic acid has increased the amount that hPTH (1-34) discharges.

Table 3

Formulation soln (wt%)

(PTH: acetate (ester): low volatility is anti-for ratio

Be coated in amount (μ the g) ± SD of the PTH on the array

Burst size (μ g) ± SD

	Charge ions)
	Charge ions)			21.2%PTH, 3.8% acetic acid, water (in right amount)	1∶3∶0	28.0±6.6	1.1±1.1
21.2%PTH, 3.8% acetic acid, water	1∶3∶0	35.0±11.4	1.5±1.7	21.2%PTH, 3.8% acetic acid, water (in right amount)	1∶3∶0	28.0±6.6	1.1±1.1
21.2%PTH, 3.8% acetic acid, water	1∶3∶0	35.0±11.4	1.5±1.7	22.3%PTH, 2.7% acetic acid, 0.4%HCl, water	1∶2∶2	40.0±9.8	5.9±2.5
16.2%PTH, 3.8% acetic acid, 0.5%HCl, 20.2% excipient, water	1∶3∶3	30.5±2.3	6.1±4.0	22.3%PTH, 2.7% acetic acid, 0.4%HCl, water	1∶2∶2	40.0±9.8	5.9±2.5
16.2%PTH, 3.8% acetic acid, 0.5%HCl, 20.2% excipient, water	1∶3∶3	30.5±2.3	6.1±4.0	6.2%PTH, 3.8% acetic acid, 2.1% glycolic, 12.2% excipient, water	1∶3∶4	45.9±11.7	11.2±2.7
16.2%PTH, 3.8% acetic acid, 1.2% tartaric acid, 20.23% excipient, water	1∶3∶2	29.0±4.3	4.2±1.5		1∶3∶4	45.9±11.7	11.2±2.7

Embodiment 4

Embodiment 4 proof hPTH (1-34) drug use stabilizing agents improve hPTH (1-34) stability of drug.

10 preparations shown in the table 4 are coated on the titanium, and in 40 ℃ of chemical stabilities of observing 60 days.The pH that contains the weak acid buffer formulations is about pH 5.2, and the pH of chloride preparation is about pH 5.4.By reversed-phase high-performance liquid chromatography (RPHPLC) and size exclusion chromatography (SEC) (SEC), detect oxidation product and the solubility of purity, PTH (1-34) respectively and assemble thing, be the function of time.The 5-14 that the results are shown in Table of each preparation sums up.

The stability data that produces shows that the main mechanism of solid-state PTH degraded passes through accumulation process.In addition, stability data shows that adding sucrose prevents the gathering of hPTH (1-34).Figure 12 shows and to add and not with hPTH (1-34) preparation of the sucrose aggregation percentage rate at 60 days time points.

Table 4

Preparation	Preparation compositions (%w/w)
Preparation	Preparation compositions (%w/w)	A	20％PTH，12.7％HCl
B	20％PTH，12.7％HCl，0.01％EDTA	A	20％PTH，12.7％HCl
B	20％PTH，12.7％HCl，0.01％EDTA	C	20%PTH, 12.7%HCl, 1% methionine, 0.01%EDTA
D	20%PTH, 12.7%HCl, 1.2% tartaric acid, 1% methionine, 0.2% polysorbas20,0.01%EDTA	C	20%PTH, 12.7%HCl, 1% methionine, 0.01%EDTA
D		E	20%PTH, 20% sucrose, 12.7%HCl, 0.2% polysorbas20
F	20%PTH, 20% sucrose, 12.7%HCl, 0.2% polysorbas20,0.03%EDTA	E	20%PTH, 20% sucrose, 12.7%HCl, 0.2% polysorbas20
F	20%PTH, 20% sucrose, 12.7%HCl, 0.2% polysorbas20,0.03%EDTA	G	20%PTH, 20% sucrose, 12.7%HCl, 2% methionine, 0.2% polysorbas20,0.03%EDTA
H	20%PTH, 20% sucrose, 1.2% tartaric acid, 2% methionine, 0.2% polysorbas20,0.03%EDTA	G
H		I	20%PTH, 20% sucrose, 1.2% glycolic, 2% methionine, 0.2% polysorbas20,0.03%EDTA
J	20%PTH, 20% sucrose, 1.7% citric acid, 2% methionine, 0.2% polysorbas20,0.03%EDTA	I

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Embodiment 5

Embodiment 5 proofs are used the oxidation of antioxidants retard hPTH (1-34) medicine.Table 15 is listed 7 kinds of preparations that preparation is used for stability study.

Table 15

Preparation	Preparation compositions (%w/w)
Preparation	Preparation compositions (%w/w)	A	25％PTH，
B	25%PTH, 0.5% methionine	A	25％PTH，
B	25%PTH, 0.5% methionine	C	25%PTH, 1% methionine
D	25%PTH, 3% methionine	C	25%PTH, 1% methionine
D	25%PTH, 3% methionine	E	25％PTH，0.5mM EDTA
F	25％PTH，1mM EDTA	E	25％PTH，0.5mM EDTA
F	25％PTH，1mM EDTA	G	25％PTH，3mM EDTA

The result of 3 months stability studies of table 16 explanation.RPHPLC belongs to the oxide of hPTH (1-34) at relative retention time 0.36,0.53 and 0.68 detected three peaks, and is denoted as

oxide

1,2 and 3.In all situations, oxide 3 is main oxidation product.

Table 16

In a word, total oxidation product percentage rate that the preparation of no antioxidant produces is the highest, and adding methionine or EDTA have delayed oxidation.The result shows that methionine delays oxidation in the concentration dependent mode.But EDTA does not show this phenomenon.In preparation, add 0.5mM EDTA delay aspect the oxidation the same with 3mM effective.And the result shows that EDTA more effectively stops oxidation than methionine.These results as shown in figure 13, this figure provides hPTH the total oxide of (1-34).

Embodiment 6

In this embodiment, will be with the microprojection member transdermal release that applies based on the PTH medicine, with the subcutaneous release teriparatide of routine PTH (Forteo ^TM) compare.Carry out dosage-discovery research with 10 health, young woman, described women accepts at least 5 days, treats according to two groups of independences of random packet: subcutaneous release 20 μ g Forteo ^TMWith with the microprojection transdermal release 30 μ g that apply based on the PTH medicine.Measure the bioavailability of transdermal release PTH in 20 health, young woman, described women is given at least 5 days, treats according to two groups of independences of random packet: subcutaneous release 40 μ g Forteo ^TMWith with the microprojection transdermal release 30 μ g that apply based on the PTH medicine.

In this dosage-discovery research, there are two participants to withdraw from, 11 experimenters participate in research, have 8 to produce useful data.After measured, there are 3 experimenters behind subcutaneous injection, to have measurable PTH blood plasma level, have measurable PTH blood plasma level after 8 experimenter's transdermal release.In bioavailability study, 20 experimenters have finished research, and 15 experimenters record measurable PTH blood plasma level after subcutaneous release, and 20 experimenters record measurable PTH blood plasma level after transdermal release.

As shown in figure 14, discharge the back based on the PTH drug transdermal and entered blood flow by effective the absorption.Figure 12 also reflects the preferred pulse concentration curve of PTH medicine, and promptly rapid onset is also reaching C _MaxThe back is skew (off-set) rapidly.In addition, as shown in figure 15, the biological activity of PTH and subcutaneous release back is suitable after the transdermal release, and this improves by urine cAMP Excreta level proves.

Figure 16 has compared the plasma concentration of PTH after subcutaneous release and the transdermal release, and it absorbs rapidly after further proving transdermal release.Figure 16 has reflected the preferred pulse concentration curve based on the PTH medicine equally, and promptly rapid onset is also reaching C _MaxThe back is skew rapidly.

Table 17 also provides the PK/PD result of subcutaneous release and transdermal release, and it shows similar PTH bioavailability.

Table 17

Parameter	Forteo ^TMSubcutaneous release 40 μ g	The microprojection transdermal release 30 μ g that apply	The P-value
Parameter	Forteo ^TMSubcutaneous release 40 μ g	The microprojection transdermal release 30 μ g that apply	The P-value	T _max(hr)	0.58	0.13	＜0.0001
C _max(ng/ml)	0.22 ^*	0.32	0.04	T _max(hr)	0.58	0.13	＜0.0001
C _max(ng/ml)	0.22 ^*	0.32	0.04	AUC(h ng/mL)	0.75(cv＝152％)	0.94(cv＝216％)	0.28
ΔcAMP (μM)	117(n＝19) p＜0.0001	121(n＝18) p＝0.0014	0.90	AUC(h ng/mL)	0.75(cv＝152％)	0.94(cv＝216％)	0.28

^*Be normalized to 30 μ g dosage

This duration of test has also been estimated the safety of transdermal release.Generally speaking, the microprojection transdermal release through applying is better than conventional subcutaneous release, and experimenter's untoward reaction ratio of report is similar, but none is serious.Nausea and vomiting is more common in subcutaneous release.

Those of ordinary skill in the art will appreciate that, the invention provides many advantages.For example, have transdermal release based on the PTH medicine based on the apparatus and method of microprojection, should be based on the similar advantage of observing behind the pharmacokinetic curve of PTH medicine and the subcutaneous administration.Another advantage that discharges based on the PTH drug transdermal is the biological agent of rapid onset.Also another advantage that discharges based on the PTH drug transdermal is to have to reach 8 hours lasting biological agent.In addition, behind the applied once, the microprojection array transdermal release with 10-100 μ g dosage teriparatide (hPTH (1-34)) applies produces the plasma C of 50pg/ml at least _Max

Those of ordinary skill can carry out variations and modifications to the present invention, making it being applicable to various uses and condition, and does not deviate from aim of the present invention and scope.Therefore, these variations and revise suitable, fair and will be in claims are equal to the four corner of claim.

Claims

1. one kind will discharge device to the patient based on the PTH drug transdermal, and described device comprises:

Microprojection member, this element have many being applicable to and pierce through the cuticular microprojection of described patient; And

Place the biocompatible coating on the described microprojection member, described coating is formed by coating agent, and this coating agent comprises at least a based on the PTH medicine, and described is hPTH (1-34) or its salt based on the PTH medicine, dosage is 10-1000 μ g, causes plasma C after single administration _MaxBe at least 50pg/ml.

2. the device of claim 1, wherein said being coated with at least one that is placed on described many microprojection.

3. the device of claim 1, wherein said microprojection member has at least 10 microprojection/cm ²Microprojection density.

4. the device of claim 1, wherein said microprojection member has 200-2000 microprojection/cm ²Microprojection density.

5. the device of claim 1, wherein said microprojection member constitutes by being selected from following material: rustless steel, titanium and Nitinol.

6. the device of claim 5, the non-conducting coated materials of wherein said microprojection member.

7. the device of claim 6, wherein said non-conducting material is selected from

And silicon.

8. the device of claim 1, wherein said microprojection member is made of non-conducting material.

9. the device of claim 1, wherein said coating agent comprises aqueous formulation.

10. the device of claim 1, wherein said coating agent comprises non-aqueous preparation.

11. the device of claim 1, wherein said hPTH salt is selected from acetate, propionate, butyrate, valerate, caproate, enanthate, levulinate, hydrochlorate, hydrobromate, citrate, succinate, maleate, oxyacetate, gluconate, glucuronate, the 3-hydroxyisobutyrate, tricarballylic acid salt, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalic acid salt, dihydromethyl propionic acid salt, tiglic acid salt, glycerate, methacrylate, iso-crotonic acid salt, beta-hydroxy-butanoic acid salt, cronate, the Radix Angelicae Sinensis hydrochlorate, hydracrylate, Ascorbate, aspartate, glutamate, Glu, the 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartrate, nitrate, phosphate, benzene sulfonate, mesylate, sulfate and sulfonate.

12. the device of claim 1 wherein saidly accounts for described coating agent 1-30% weight based on the PTH medicine.

13. it is described based on the PTH medicine that the device of claim 1, wherein said biocompatible coating comprise 10 μ g-100 μ g.

14. the device of claim 1, the pH of wherein said coating agent are at pH below 6.

15. the device of claim 14, the described pH of wherein said coating agent is in the scope of pH 2-6.

16. the device of claim 14, wherein said coating agent comprise at least a low volatility gegenion.

17. the device of claim 16, wherein said coating agent comprise many low volatility gegenions.

18. the device of claim 16 is wherein said positively charged under described coating agent pH based on the PTH medicine, and described low volatility gegenion comprises first kind of acid with at least one acid pKa.

19. the device of claim 18, wherein said first kind of acid is selected from maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, 1,3-propanedicarboxylic acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, hydroxymalonic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulphuric acid and phosphoric acid.

20. the device of claim 18 is wherein said positively charged under described coating agent pH based on the PTH medicine, and described coating agent comprises at least the second kind of gegenion, this gegenion comprises second kind of acid with one or more pKa.

21. the device of claim 20, wherein said second kind of acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid, fumaric acid, acetic acid, propanoic acid, valeric acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulic acid, 1,3-propanedicarboxylic acid, itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

22. the device of claim 16, the amount of the described low volatility gegenion that wherein exists in described coating agent are enough to the described electric charge based on the PTH medicine of balance.

23. the device of claim 1 wherein saidly comprises hPTH (1-34) based on the PTH medicine, and described coating agent comprises the gegenion of at least a raising viscosity.

24. the device of claim 23, the gegenion of wherein said raising viscosity is selected from citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic and acetic acid.

25. the device of claim 23, the viscosity of wherein said coating agent are 20-200cp.

26. the device of claim 1, wherein said coating agent comprises the gegenion that improves viscosity, and this gegenion comprises acid gegenion.

27. the device of claim 26, wherein said acid gegenion comprises the low volatility weak acid with at least one acid pKa.

28. the device of claim 27, the faintly acid fusing point of wherein said low volatility is higher than 50 ℃.

29. the device of claim 27, the faintly acid boiling point of wherein said low volatility under atmospheric pressure is higher than 170 ℃.

30. the device of claim 27, wherein said low volatility acid is selected from citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid and fumaric acid.

31. the device of claim 26, wherein said acid gegenion comprises first kind of strong acid, and this strong acid has at least one and is lower than 2 pKa.

32, the device of claim 31, wherein said first kind of strong acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid.

33. the device of claim 26, described device also comprise many acid gegenions, wherein at least the first gegenion comprises strong acid, and at least the second gegenion comprises low volatility weak acid.

34. the device of claim 26, described device also comprise many acid gegenions, wherein at least the first gegenion comprises strong acid, and at least the second gegenion comprises high volatile volatile weak acid, and this weak acid has at least one and is higher than 2 pKa.

35. the device of claim 34, the faintly acid fusing point of wherein said high volatile volatile is lower than 50 ℃.

36. the device of claim 34, the faintly acid boiling point of wherein said high volatile volatile under atmospheric pressure is lower than 170 ℃.

37. the device of claim 34, wherein said high volatile volatile weak acid is selected from acetic acid, propanoic acid and valeric acid.

38. the device of claim 1, wherein said coating agent comprise at least a following buffer agent that is selected from: ascorbic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid., fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, 1,3-propanedicarboxylic acid, the itaconic acid, mesaconic acid, citramalic acid, dihydromethyl propionic acid, tiglic acid, glyceric acid, methacrylate, iso-crotonic acid, beta-hydroxy-butanoic acid, .beta.-methylacrylic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and composition thereof.

39. the device of claim 1, wherein said coating agent comprise at least a following antioxidant that is selected from: chelating agen and free radical scavenger.

40. the device of claim 39, wherein said chelating agen is selected from sodium citrate, citric acid and ethylenediaminetetraacetic acid.

41. the device of claim 39, wherein said free radical scavenger is selected from ascorbic acid, methionine and sodium ascorbate.

42. the device of claim 39, the concentration of wherein said antioxidant is counted 0.01-20% weight with described coating agent.

43. the device of claim 39, the concentration of wherein said antioxidant is counted 0.03-10% weight with described coating agent.

44. the device of claim 1, wherein said coating agent comprise at least a following surfactant that is selected from: lauroyl both sexes sodium acetate, sodium lauryl sulphate (SDS), cetylpyridinium chloride (CPC), Dodecyl trimethyl ammonium chloride (TMAC), benzalkonium chloride, polysorbate, sorbitan derivatives, sorbitan laurate alcohol alcoxylates, castor oil derivatives and composition thereof.

45. the device of claim 44, wherein said surfactant concentrations is counted 0.01-20% weight with described coating agent.

46. the device of claim 1, wherein said coating agent comprise at least a polymeric material with amphipathic characteristic.

47. the device of claim 46, wherein said polymeric material comprises cellulose derivative.

48. the device of claim 47, wherein said cellulose derivative are selected from hydroxyethyl-cellulose (HEC), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxyethylmethyl-cellulose (HEMC) or ethyl hydroxyl-ethyl cellulose (EHEC) and poloxamer.

49. the device of claim 46, the concentration of wherein said polymer is counted 0.01-20% weight with described coating agent.

50. comprising, the device of claim 1, wherein said coating agent be selected from following hydrophilic polymer: hetastarch, carboxymethyl cellulose and salt thereof, glucosan, poly-(vinyl alcohol), poly-(oxirane), poly-(methacrylate 2-hydroxyethyl ester), poly-(n-vinyl pyrrolidone), Polyethylene Glycol and composition thereof.

51. the device of claim 50, the concentration of wherein said hydrophilic polymer is counted 1-30% weight with described coating agent.

52. comprising, the device of claim 1, wherein said coating agent be selected from following physiologically acceptable carrier: biological engineering human albumin, polyglutamic acid, poly-aspartate, polyhistidyl, pentosane polysulfate ester, polyamino acid, sucrose, trehalose, melezitose, Raffinose, stachyose and mannitol.

53. the device of claim 52, wherein said physiologically acceptable carrier account for described coating agent 2-70% weight.

54. comprising, the device of claim 1, wherein said coating agent be selected from following stabilizing agent: non-reducing sugar, polysaccharide and reducing sugar.

55. the device of claim 54, wherein said non-reducing sugar is selected from sucrose, trehalose, stachyose and Raffinose.

56. the device of claim 54, wherein said polysaccharide is selected from glucosan, soluble starch and dextrin.

57. the device of claim 54, wherein said reducing sugar is selected from monosaccharide and disaccharide.

58. the device of claim 57, wherein said monosaccharide are selected from apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, chinovose, rhamnose, allose, altrose, fructose, galactose, gulose, hamamelose, her shut out sugar, mannose and Tagatose.

59. the device of claim 57, wherein said disaccharide is selected from 6-(.beta.-D-xylosido)-D-glucose., vicianose, 6-O-.alpha.-L-rhamnosyl-D-glucose., scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, 6-(.alpha.-D-galactosido)-D-glucose., sophorose and turanose.

60. the device of claim 54, the concentration of stabilizing agent described in the wherein said coating agent is 0.01-2.0 with respect to described ratio based on the PTH medicine: 1.

61. the device of claim 1, wherein said coating agent comprise at least a following vasoconstrictor that is selected from: amidefrine, 8-(.beta.-oxyethyl)methylaminocaffeine, cyclopentamine, phenylephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, isoadrenaline, octodrine, ornipressin, oxymetazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vassopressin, xylometazoline and composition thereof.

62. the device of claim 61, the concentration of wherein said vasoconstrictor is counted 0.1-10% weight with described coating agent.

63. the device of claim 1, wherein said coating agent comprise at least a following pathway patency modulator that is selected from: penetrating agent, zwitterionic compound, anti-inflammatory agent and anticoagulant.

64. the device of claim 63, wherein said anti-inflammatory agent are selected from betamethasone 21-disodic alkaliine, Aristosol (Lederle)., hydrocortamate hydrochloride, hydrocortisone 21-disodic alkaliine, Medrol Stabisol (Upjohn)., methylprednisolone 21-succinic acid sodium salt, paramethasone disodium hydrogen phosphate and prednisolone 21-succinic acid sodium salt.

65. the device of claim 63, wherein said anticoagulant are selected from citric acid, citrate, dextran sodium sulfate, aspirin and EDTA.

66. comprising, the device of claim 1, wherein said coating agent be selected from following solubilising/chelating agent: alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, glucosyl group-alpha-cyclodextrin, malt-base-alpha-cyclodextrin, hydroxyethyl-, methyl-beta-schardinger dextrin-, sulfo group butyl ether-alpha-cyclodextrin, sulfo group butyl ether-beta-schardinger dextrin-and sulfo group butyl ether-gamma-cyclodextrin.

67. the device of claim 66, the concentration of wherein said solubilising/chelating agent is counted 1-20% weight with described coating agent.

68. the device of claim 1, the viscosity of wherein said coating agent are the 3-500 centipoise.

69. the device of claim 1, the thickness of wherein said biocompatible coating is less than 25 microns.

70. the device of claim 1, wherein said is reorganization hPTH (1-34) or synthetic hPTH (1-34) based on the PTH medicine.

71. the device of claim 1, wherein said coating make the pulse release curve 1 minute in 4 hours, basic haemoconcentration is 50-1000pg/ml.

72. the device of claim 71, wherein said coating make C _MaxIn 1-8 hour, serum-concentration is from C after reaching _MaxReduce to base concentration.

73. the device of claim 72, wherein C _MaxBe 0.13-0.72ng/mL.

74. the device of claim 1, wherein biocompatible coating comprises 20%PTH, 20% sucrose, 12.7%HCL, 0.2%Tween 20 and 0.03%EDTA.

75. one kind will discharge device to the patient based on the PTH drug transdermal, described device comprises:

Place the biocompatible coating on the described microprojection member, described coating comprises based on PTH medicine, low volatility gegenion, surfactant, stabilizing agent and antioxidant.

76. the device of claim 75, wherein said is hPTH or its salt based on the PTH medicine.

77. the device of claim 75, wherein said is reorganization hPTH (1-34) or synthetic hPTH (1-34) based on the PTH medicine.

78. the device of claim 75, wherein said stabilizing agent is a non-reducing sugar.

79. the device of claim 75, wherein said is hPTH (1-34) acetate based on the PTH medicine, and described gegenion is acid.

80. the device of claim 75, wherein said is hPTH (1-34) acetate based on the PTH medicine, and described gegenion is a hydrochloric acid, and described surfactant is a tween, and described stabilizing agent is a sucrose, and described antioxidant is EDTA.

81. one kind will discharge device to the patient based on the PTH drug transdermal, described device comprises:

Place the biocompatible coating on the described microprojection member, described coating is formed by coating agent, and described coating agent comprises at least a low volatility gegenion and at least a based on the PTH medicine, and wherein said is hPTH or its salt based on the PTH medicine.

82. the device of claim 81, wherein the low volatility gegenion is acid.

83. the device of claim 82, wherein the low volatility gegenion is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, maleic acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, citric acid, succinic acid, glycolic, gluconic acid, glucuronic acid, lactic acid, malic acid, acetone acid, tartaric acid, hydroxymalonic acid, fumaric acid, acetic acid, propanoic acid, valeric acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulic acid, 1,3-propanedicarboxylic acid, itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

84. the device of claim 82, wherein the low volatility gegenion is hydrochloric acid, glycolic or tartaric acid.