Apparatus and method for transdermal delivery of parathyroid hormone agents 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
EP1744683 B1 2016-03-16 [EP1744683]EP1744683 A4 2010-09-29 [EP1744683]EP1744683 A2 2007-01-24 [EP1744683] / 2016-03-162010-09-292007-01-24
申请号/申请日
2005EP-0727716 / 2005-03-18
发明人
AMERI MAHMOUD;CORMIER MICHEL J N;MAA YUH-FUN;KAMBERI MARIKA;DADDONA PETER;
申请人
ALZA;
主分类号
IPC分类号
A61K-009/00A61K-038/29A61K-047/12A61K-047/18A61K-047/26A61M-031/00A61M-037/00
摘要
(EP1744683) An apparatus and method for transdermally delivering a biologically active agent comprising a delivery system having a microprojection member (or system) that includes a plurality of microprojections (or array thereof) that are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers.  In one embodiment, the PTH-based agent is contained in a biocompatible coating that is applied to the microprojection member.  (From US7556821 B2)
机翻摘要
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地址
代理人
代理机构
;
优先权号
2004US-60571304 2004-05-13 2004US-60585276 2004-07-01 2005US-60643660 2005-01-12 2005WO-US09147 2005-03-18
主权利要求
(EP1744683) 1. A device for transdermally delivering a PTH-based agent to a patient, comprising: a microprojection member having a plurality of microprojections that are adapted to pierce the stratum corneum of the patient; and a biocompatible coating disposed on said microprojection member, said coating being formed from a coating formulation having at least one PTH-based agent, wherein said PTH based agent is selected from the group consisting of hPTH(1-34), hPTH (1-34) salts and analogs, teriparatide and related peptides at a dose of 10-100 \.1g and wherein delivery of the PTH-based agent results in a plasma C max of at least 50 pg/mL after one application and a decreased T max as compared to subcutaneous administration. 2. The device of Claim 1, wherein said coating is disposed on at least one of said plurality of microprojections. 3. The device of Claim 1, wherein said microprojection member has a microprojection density of (i) at least approximately 10 microprojections/cm **2, or (ii) in the range of approximately 200-2000 microprojections/cm **2. 4. The device of Claim 1, wherein said microprojection member is constructed out of a material selected from the group consisting of stainless steel, titanium and nickel titanium alloys. 5. The device of Claim 4, wherein said microprojection member is coated or constructed with a non-conductive material. 6. The device of Claim 1, wherein said coating formulation comprises an aqueous formulation or a non- aqueous formulation. 7. The device of Claim 1, wherein said hPTH(1-34) salt is selected from group consisting of acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarballylicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpropinate, tiglicate, glycerate, methacrylate, isocrotonate, P hydroxibutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, methane sulfonate, sulfate and sulfonate. 8. The device of Claim 1, wherein the pH of said coating formulation is below approximately pH 6, and optionally is in the range of approximately pH 2 - pH 6. 9. The device of Claim 8, wherein said coating formulation includes at least one low volatility counterion and optionally wherein said coating formulation includes a plurality of low volatility counterions. 10. The device of Claim 9, wherein said PTH-based agent has a positive charge at said coating formulation pH and said viscosity-enhancing counterion comprises a first acid having at least two acidic pKas and optionally wherein said first acid is selected from the group consisting of maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, tartronic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid and phosphoric acid, 11. The device of Claim 1, wherein said PTH-based agent has a positive charge at said coating formulation pH and said coating formulation includes at least a second counterion comprising a second acid with one or more pKas, and optionally wherein said second acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid, methane sulfonic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, acetic acid, propionic acid, petanoic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid. 12. The device of Claim 9, wherein the amount of said low volatility counterion present in said coating formulation is sufficient to neutralize the charge of said PTH-based agent. 13. The device of Claim 1, wherein said PTH-based agent comprises hPTH (1-34) and wherein said coating formulation comprises at least one viscosity-enhancing counterion. 14. The device of Claim 13, wherein (i) said viscosity-enhancing counterion is selected from the group consisting of citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic acid and acetic acid, or (ii) said coating formulation has a viscosity in the range of approximately 20 - 200 cp. 15. The device of Claim 1, wherein said coating formulation includes a viscosity-enhancing counterion comprising an acidic counterion. 16. The device of Claim 15, wherein said acidic counterion comprises a low volatility weak acid that exhibits at least one acidic pKa. 17. The device of Claim 16, wherein said low volatility weak acid (i) has a melting point higher than about 50 deg.C, or (ii) has a boiling point higher than about 170 deg.C at P atm, or (iii) is selected from the group consisting of citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, and fumaric acid. 18. The device of Claim 15, wherein said acidic counterion comprises a first strong acid that exhibits at least one pKa lower than about 2. 19. The device of Claim 18, wherein said first strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid. 20. The device of Claim 15, further comprising a plurality of acidic counterions, wherein at least a first counterion comprises a strong acid and at least a second counterion comprises a low volatility weak acid. 21. The device of Claim 15, further comprising a plurality of acidic counterions wherein at least a first counterion comprises a strong acid and at least a second counterion comprises a high volatility weak acid with at least one pKa higher than about 2. 22. The device of Claim 21, wherein said high volatility weak acid (i) has a melting point lower than about 50 deg.C, or (ii) has a boiling point lower than about 170 deg.C at P atm, or (iii) is selected from the group consisting of acetic acid, propionic acid and pentatonic acid. 23. The device of Claim 1, wherein said coating formulation includes at least one buffer selected from the group consisting of ascorbic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, maleic acid, phosphoric acid, tricarbally acid, malonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, citramalic acid, dimethylopropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid,P-hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine, and mixtures thereof. 24. The device of Claim 1, wherein said coating formulation includes at least one antioxidant selected from the group consisting of sequestering agents and free radical scavengers. 25. The device of Claim 24, wherein (i) said sequestering agent is selected from the group consisting of sodium citrate, citric acid and ethylene dinitrilo-tetraacetic acid, or (ii) said free radical scavenger is selected from the group consisting of ascorbic acid, methionine and sodium ascorbate. 26. The device of Claim 24, wherein the concentration of said antioxidant is in the range of approximately 0.01-20 wt. % or 0.03-10 wt. % of said coating formulation. 27. The device of Claim 1, wherein said coating formulation includes at least one surfactant selected from the group consisting of sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbates, sorbitan derivatives, sorbitan lauratealkoxylated alcohols, polyoxyethylene castor oil derivatives and mixtures thereof, and optionally wherein the concentration of said surfactant is in the range of approximately 0.01-20 wt. % of said coating formulation. 28. The device of Claim 1, wherein said coating formulation includes at least one polymeric material having amphiphilic properties. 29. The device of Claim 28, wherein said polymeric material comprises a cellulose derivative, and optionally wherein said cellulose derivative is selected from the group consisting of hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose(HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethyl- methycellulose (HEMC), or ethylhdroxy-ethylcellulose (EHEC), and pluronics. 30. The device of Claim 28, wherein the concentration of said polymer is in the range of approximately 0.01-20 wt. % of said coating formulation. 31. The device of Claim 1, wherein said coating formulation includes a hydrophilic polymer selected from the following group consisting of hydroxyethyl starch, carboxymethyl cellulose and salts of, dextran, poly(vinyl alcohol), poly(ethylene oxide), poly (2-hydroxyethyl-methacrylate), poly(n-vinyl pyrolidone), polyethylene glycol and mixtures thereof, and optionally wherein the concentration of said hydrophilic polymer is in the range of approximately 1-30 wt. % of said coating formulation. 32. The device of Claim 1, wherein said coating formulation includes a biocompatible carrier selected from the group consisting of bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffmose, stachyose, mannitol and like sugar alcohols, and optionally wherein said biocompatible carrier comprises in the range of approximately 2-70 wt. % of said coating formulation. 33. The device of Claim 32, wherein the concentration of said biocompatible carrier is in the range of approximately 5-50 wt. % of said coating formulation. 34. The device of Claim 1, wherein said coating formulation includes a stabilizing agent selected from the group consisting of a non-reducing sugar, a polysaccharide and a reducing sugar. 35. The device of Claim 34, wherein (i) said non-reducing sugar is selected from the group consisting of sucrose, trehalose, stachyose and raffinose, or (ii)said polysaccharide is selected from the group consisting of dextran, soluble starch, and dextrin. 36. The device of Claim 34, wherein said reducing sugar is selected from group consisting of monosaccharides and disaccharides. 37. The device of Claim 36, wherein (i) said monosaccharide is selected from the group consisting of apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, gulose, hamamelose, idose, mannose and tagatose, or (ii) said disaccharide is selected from the group consisting of primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose and turanose. 38. The device of Claim 34, wherein the concentration of said stabilizing agent in said coating formulation is at a ratio approximately 0.01 - 2.0: 1 with respect to said PTH- based agent. 39. The device of Claim 1, wherein said coating formulation includes at least one vasoconstrictor selected from the group consisting of amidephrine, cafaminol, cyclopentaimine, deoxyepinephrine, epinephrine, felypressin, indanzoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, ornipressin, oxymethazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline, and mixtures thereof, and optionally wherein the concentration of said vasoconstrictor is in the range of approximately 0.1-10 wt. % of said coating formulation. 40. The device of Claim 1, wherein said coating formulation includes at least one pathway patency modulator selected from the group consisting of osmotic agents, zwitterionic compounds, anti-inflammatory agents and anticoagulants. 41. The device of Claim 40, wherein said anti-inflammatory agent is selected from the group consisting of betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate disodium salt, methylprednisolone 21-succinaate sodium salt, paramethasone disodium phosphate and prednisolone 21-succinate sodium salt, or wherein said anticoagulant is selected from the group consisting of citric acid, citrate salts, dextrin sulfate sodium, aspirin and EDTA. 42. The device of Claim 1, wherein said coating formulation includes a solubilising/complexing agent selected from the group consisting of Alpha-Cyclodextrin,Beta-Cyclodextrin, Gamma-Cyclodextrin, glucosyl-alpha Cyclodextrin, maltosyl-alpha-Cyclodextrin, hydroxyethyl-beta-Cyclodextrin, methyl-beta-Cyclodextrin, sulfobutylether-alpha-Cyclodextrin, sulfobutylether-beta-Cyclodextrin, and sulfobutylether-gamma-Cyclodextrin, and optionally wherein the concentration of said solubilising/complexing agent is in the range of approximately 1 - 20 wt. % of said coating formulation. 43. The device of Claim 1, wherein (i) said coating formulation has a viscosity in the range of approximately 3 - 500 centipose, or (ii) wherein the thickness of said biocompatible coating is less than approximately 25 microns. 44. The device of any of claims 1 to 44 for transdermally delivering a PTH-based agent to a patient, comprising the steps of; applying said microprojection member to a skin site of said patient, whereby said plurality of stratum corneum-piercing microprotrusions pierce the stratum corneum and deliver said PTH-based agent to said patient; and  removing said microprojection member from said skin site. 45. The device of Claim 44, wherein (i) said microprojection member remains applied to said skin site for a period of time in the range of 5 sec. to 24 hrs, or (ii) wherein applying said microprojection member comprises applying said microprojection member to said skin site with an impact applicator. 46. The device of Claim 44, wherein said PTH-based agent is selected from the group consisting of hPTH (1-34), hPTH salts and analogs, teriparatide and related peptides, and optionally wherein said hPTH salt is selected from group consisting of acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, methane sulfonate, sulfate and sulfonate. 47. The device of Claim 44, wherein said delivery of said PTH-based agent exhibits (i) rapid on-set of biological action, or (ii) sustained biological action for a period of up to 8 hours. 48. A microprojection member for improving the pharmacokinetics of a transdermally delivered PTH-based agent, said microprojection member having a plurality of stratum corneum-piercing microprotrusions and a coating disposed thereon including at least one PTH-based agent; and comprising  applying said microprojection member to a skin site of said patient,  whereby said plurality of stratum corneum-piercing microprotrusions pierce the stratum corneum and deliver said PTH-based agent to said patient; and  removing said microprojection member from said skin site;  wherein said delivery of the PTH-based agent has improved pharmacokinetics compared to pharmacokinetics characteristic of subcutaneous delivery. 49. The microprojection member of Claim 48, wherein said improved pharmacokinetics comprises: (i) increased bioavailability of said PTH-based agent, or (ii) increased Cmax, or (iii) decreased Tmax, or (iv) an enhanced absorption rate of said PTH-based agent. 50. The device of claim 1, wherein the biocompatible coating comprises 20% PTH, 20% sucrose, 12.7% HCl, 0.2% Tween 20, and 0.03% EDTA. 51. The device of claim 1, wherein said PTH-based agent is synthetic hPTH(1-34).
法律状态
(EP1744683) LEGAL DETAILS FOR EP1744683  Actual or expected expiration date=2025-03-18    Legal state=ALIVE    Status=GRANTED     Event publication date=2005-03-18  Event code=EP/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=EP EP05727716  Application date=2005-03-18  Standardized application number=2005EP-0727716     Event publication date=2007-01-24  Event code=EP/A2  Event type=Examination events  Application published without search report  Publication country=EP  Publication number=EP1744683  Publication stage Code=A2  Publication date=2007-01-24  Standardized publication number=EP1744683     Event publication date=2007-01-24  Event code=EP/17P  Event indicator=Pos  Event type=Examination events  Request for examination filed Pruefungsantrag gestellt  Effective date of the event=2006-11-10     Event publication date=2007-01-24  Event code=EP/AK  Event indicator=Pos  Event type=Designated states  Designated contracting states: Benannte vertragsstaaten AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR    Event publication date=2007-08-22  Event code=EP/DAX  Event indicator=Neg  Event type=Designated states  Request for extension of the european patent (to any country) deleted    Event publication date=2008-10-01  Event code=EP/RAP1  Event type=Change of name or address  Event type=Reassignment  Transfer of rights of an EP application Anmelder uebertragung (korr.) OWNER: ALZA CORPORATION    Event publication date=2010-09-29  Event code=EP/A4  Event indicator=Pos  Event type=Examination events  Supplementary search report Ergaenzender recherchenbericht  Publication country=EP  Publication number=EP1744683  Publication stage Code=A4  Publication date=2010-09-29  Standardized publication number=EP1744683     Event publication date=2010-09-29  Event code=EP/A4  Event indicator=Pos  Event type=Administrative notifications  Supplementary search report Despatch of supplementary search report  Effective date of the event=2010-08-27     Event publication date=2010-09-29  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61B  17/20        20060101AFI20061115BHEP    Event publication date=2010-09-29  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61K   9/00        20060101ALI20100823BHEP    Event publication date=2010-09-29  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61K  38/29        20060101ALI20100823BHEP    Event publication date=2011-10-05  Event code=EP/RAP1  Event type=Change of name or address  Event type=Reassignment  Transfer of rights of an EP application Anmelder uebertragung (korr.) OWNER: ALZA CORPORATION    Event publication date=2012-07-25  Event code=EP/17Q  Event indicator=Pos  Event type=Examination events  First examination report Erster pruefungsbescheid  Effective date of the event=2012-06-20     Event publication date=2013-12-04  Event code=EP/RAP1  Event type=Change of name or address  Event type=Reassignment  Transfer of rights of an EP application Anmelder uebertragung (korr.) OWNER: ALZA CORPORATION    Event publication date=2015-06-03  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61M  37/00        20060101ALI20150429BHEP    Event publication date=2015-06-03  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61K  47/12        20060101AFI20150429BHEP    Event publication date=2015-06-03  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61K  47/18        20060101ALI20150429BHEP    Event publication date=2015-06-03  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) IPC: A61K  47/26        20060101ALI20150429BHEP    Event publication date=2015-07-01  Event code=EP/RIC1  Event type=Classification modifications  Classification (correction) Klassifikation (korr.) 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