KR20070017197A - Apparatus and method for transdermal delivery of parathyroid hormone agents - Google Patents

Abstract

A device for transdermal delivery of a biologically active agent comprising a delivery system having a microprojection member (or system) comprising a built-in epidermal layer or a plurality of microprojections (or arrays thereof) adapted to puncture the stratum corneum into the epidermal and dermal layers. And method. In one embodiment, the PTH-based agent is included in a biocompatible coating applied to the microprojection member.

Description

Apparatus and method for transdermal delivery of parathyroid hormone agents}

Related Applications

The present invention discloses U.S. Provisional Application No. 60 / 571,304, filed May 13, 2004, U.S. Provisional Application No. 60 / 585,276, filed Jul. 1, 2004, and U.S. Provisional Application No. 60 / 643,660, filed Jan. 12, 2005. Claim merit.

The present invention generally relates to transdermal drug delivery systems and methods. More particularly, the present invention relates to devices and methods for transdermal delivery of parathyroid hormone drugs.

The active agent (or drug) is most traditionally administered orally or by infusion. Unfortunately, many active agents are not absorbed upon oral administration or are adversely affected prior to entering the bloodstream and thus do not have the desired activity, resulting in a completely invalid or radically diminished effect. On the one hand, direct intravenous or subcutaneous infusion of the drug ensures no modification of the drug during dosing but is a difficult, inconvenient, painful, cumbersome process, sometimes showing poor patient compliance.

Therefore, in principle, transdermal delivery provides a method of administering the active agent, which needs to be delivered via subcutaneous injection or intravenous infusion. As used herein, “transdermal” refers to the actuation of an active agent (eg, a therapeutic agent such as a drug, an immunoactive agent such as a vaccine) through local skin or a significant amount of cutting or penetration of the skin, for example surgical It is a generic term that refers to the delivery to a circulatory system that does not penetrate the skin with a knife cut or subcutaneous needle. Transdermal drug delivery includes delivery through passive diffusion as well as delivery based on external energy sources such as electricity (ion osmotherapy) and ultrasound (negtophoresis).

Passive transdermal drug delivery systems more often include drug reservoirs that typically contain high concentrations of active agent. The reservoir is adapted to contact the skin, which allows the medicament to diffuse through the skin into the patient's body tissues or blood stream.

As is known in the art, transdermal drug flux is dependent on the condition of the skin, the size and physical / chemical properties of the drug molecules, and the concentration gradient across the skin. Because of the low permeability to many drugs of the skin, transdermal delivery has been of limited application. This low permeability preferentially contributes to the stratum corneum (the outermost skin layer consisting of flat dead cells filled with keratin fibers (ie keratinocytes) surrounded by a fatty bilayer). The highly ordered structure of these fatty bilayers confers a relatively impermeable property to the stratum corneum.

One conventional method of increasing passive transdermal drug flux includes a skin permeation enhancer, delivered to pretreated skin or with a medicament. Permeation enhancers, when applied to the body surface through which the drug is delivered, increase the flow rate of the drug therethrough. However, in the promotion of transdermal protein flow rates, the efficiency of these methods is limited because of their size, at least for large proteins.

In addition, a number of techniques and devices have been developed for mechanically piercing or rupturing the outermost skin layer by forming a pathway into the skin to enhance the amount of drug delivered transdermally. As an example, a drug delivery device is disclosed in US Pat. No. 3,964,482.

Other systems and devices with small skin perforation elements to enhance transdermal drug delivery are described in US Pat. Nos. 5,879,326, 3,814,097, 5,250,023, 3,964,482, Reissue 25,637, and PCT Publication Nos. WO96 / 37155, WO96 / 37256, WO96 / 17648. , WO97 / 03718, WO98 / 11937, WO98 / 00193, WO97 / 48440, WO97 / 48441, WO97 / 48442, WO98 / 00193, WO99 / 64580, WO98 / 28037, WO98 / 29298, and WO98 / 29365; All of which are incorporated herein by reference in their entirety.

The disclosed systems and devices are equipped with puncturing elements of various shapes and sizes to puncture the outermost layer of skin (ie, the stratum corneum). The perforation elements disclosed in these references generally widen vertically from thin, flat members, such as pads or sheets. In some of these devices, the perforation element is extremely small and has a microprojection of about 25-400 μm in length and about 5-50 μm in thickness. These small perforations / cutting elements make corresponding small microgaps / microcuts to promote transdermal drug delivery to the stratum corneum.

The disclosed system further includes a reservoir for containing the medicament, and also includes a delivery system for delivery from the reservoir through the stratum corneum, such as by an empty tine of the device itself. One example of such a device is disclosed in WO93 / 17754, which has a liquid pharmaceutical reservoir. The reservoir must be pressurized to push the liquid medicament into the skin through a small tubular element. Disadvantages of such devices include the cost and complexity of adding pressurized liquid reservoirs and the complexity due to the presence of a pressure-propelled delivery system.

As disclosed in US patent application Ser. No. 10 / 045,842, which is incorporated herein by reference in its entirety, it is possible to have an active agent that is coated and delivered on microprojection instead of contained in a physical reservoir. This obviates the need for separate physical reservoirs and the development of specific compositions or pharmaceutical formulations in the reservoirs.

As is known in the art, osteoporosis is a bone disease characterized by a gradual loss of bone that makes individuals more prone to increased risk in fractures, typically the hips, spine and wrist. Progressive bone loss, typically starting at ages 30-40, is mainly asymptomatic until bone fractures occur, leading to high patient morbidity and mortality. 80% of people with osteoporosis are women, and according to a recent study, during the six years after menopause, women lose one third of their bone mass.

As is also known in the art, parathyroid hormone (PTH) is a hormone secreted by the parathyroid glands that regulates the metabolism of calcium and phosphate in the body. PTH has generated great interest in treating osteoporosis because of its ability to promote bone formation and thus dramatically reduce the incidence of fractures. Large clinical trials have shown that PTH effectively and safely reduces the rate of spinal and non-vertebral fractures in women with osteoporosis.

PTH-based drugs have also been of interest in the treatment of bone fractures (both male and female) because of their ability to accelerate bone healing.

To this end, various stabilized formulations of PTH based agents have been developed that can be rebuilt for subcutaneous injection, which is a traditional delivery means, as described below. Examples are formulations disclosed in U.S. Patent 5,563,122 ("Stabilized Parathyroid Hormone Composition") and U.S. Patent Application Publication 2002/0107200 ("Stabilized Teriparatide Solutions"), which is incorporated herein by reference in its entirety.

Recently approved injectable PTH-based drugs are FORTEO ^™ (rDNA derived from teriparatide injection) including recombinant human parathyroid hormone (1-34), (rhPTH (1-34)). FORTEO ^™ is typically prescribed to women with a history of osteoporotic fractures, who have multiple risks of fracture or who cannot tolerate or fail previous osteoporosis treatment based on physician evaluation. Among postmenopausal women of osteoporosis, FORTEO ^™ has been found to increase bone mineral density (BMD) and reduce the risk of spinal and non-vertebral fractures.

FORTEO ^™ has also been found to increase bone mass in men with primary or hypogonadal osteoporosis at high risk of fracture. This includes men with a history of osteoporotic fractures, or people with multiple risk factors, or those who cannot tolerate or fail previous treatment for osteoporosis. Among men with primary or hypogonadal osteoporosis, FORTEO ^™ was similarly found to increase BMD. In addition to subcutaneous injection, other means of delivering PTH-based drugs have also been investigated. For example, various methods of pulmonary delivery (ie, inhalation) are described in “Pulmonary Delivery of Drugs for Bone Disorders,” Advanced Drug Delivery Reviews, Vol. 42, Issue 3, pp. 239-248 (August 31,2000), Patton, "Bioavailability of Pulmonary Delivered Peptides and Proteins: -Interferon, Calcitonins and Parathyroid Hormones," Journal of Controlled Release, Vol. 28, Issues 1-3, pp. 79- 85 (January 1994), Patton, et al., "Impact of Formulation and Methods of Pulmonary Delivery on Absorption of Parathyroid Hormone (1-34) from Rat Lungs," Journal of Pharmaceutical Sciences, Vol. 93, Issue 5, pp. 1241-1252 (May 2004), Codrons, et al., "Systemic Delivery of Parathyroid Hormone (1-34) Using Inhalation Dry Powders in Rats," Journal of Pharmaceutical ~ Sciences, Vol. 92, Issue 5, pp. 938-950 (May 2003) and Pfutzner, A, et al., "Pilot Study with Technosphere / PTH (1-34) -A New Approach for Effective Pulmonary Delivery of Parathyroid Hormone (1-34)", Horm. Metab. Res., Vol. 35 (5), pp. Discussed in 319-23.

Various methods of active transdermal delivery of PTH based agents are also described in "The Effect of Electroporation on Eontophoretic Eransdermal Delivery of Calcium Regulating Hormones," Journal of Controlled Release, Vol. 66, Issues 2-3, pp. 127-133 (May 15, 2000) and Chang, et al., "Prevention of Bone Loss in Ovariectomized Rats by Pulsatile Transdermal Iontophoretic Administration of Human PTH (1-34)," Journal of Pharmaceutical Sciences, Vol. 91, Issue 2, pp. Also discussed at 350-361 (February 2002).

Despite the efficacy of PTH in the treatment of diseases such as osteoporosis, there are some drawbacks and drawbacks associated with the methods of delivery of PTH of the disclosed prior art, in particular through subcutaneous injection. The main drawback is that subcutaneous injection is a difficult and inconvenient process and often results in poor patient compliance.

Intradermal dosing of drugs such as hGH using a microprojection system has already been documented to provide a pharmacokinetic profile of hGH similar to that observed after subcutaneous dosing. See, eg, Cormier, et al., US Patent Application Publication No. 2002/0128599, entitled “Transdermal Drug Delivery Devices Having Coated Microprotrusions”.

Continued in vivo infusion of PTH based agents indicates active bone uptake. It is very important that PTH-based drugs be administered in Pulsatile fashion. Based on the efficacy caused by one subcutaneous injection every day, any alternative route of PTH delivery should provide a blood concentration of PTH no slower than that for subcutaneously injected PTH.

Therefore, a drug delivery system that utilizes minimally invasive dosing of PTH-based drugs is desirable. It is further desirable to provide a drug delivery system that provides a pharmacokinetic profile of a PTH-based drug similar to that observed after subcutaneous dosing.

It is an object of the present invention to provide a transdermal drug delivery device and method for providing intradermal delivery of a PTH-based drug to a patient.

It is another object of the present invention to provide a transdermal drug delivery device and method that provides a pharmacokinetic profile of PTH-based drugs that is faster or similar to that observed after subcutaneous dosing.

Another object of the present invention is to provide a transdermal drug delivery device and method for providing a pharmaceutically active blood concentration of a PTH-based drug for a period of up to 8 hours.

Another object of the present invention is to provide a PTH-based pharmaceutical formulation for intradermal delivery to a patient.

Another object of the present invention is to provide a transdermal drug delivery device and method comprising microprojection coated with a biocompatible coating comprising at least one biologically active agent, which is preferably a PTH-based drug.

Summary of the invention

Apparatus and methods for transdermal delivery PTH-based medicaments according to the invention, which are mentioned in accordance with the above objectives and will become apparent below, generally comprise a plurality of microprojections (or adapted to perforate the stratum corneum to the underlying epidermal or epidermal and dermal layers). A delivery system having a microprojection member (or system) comprising an array thereof. In a preferred embodiment, the microprojection member comprises a biocompatible coating having at least one PTH based pharmaceutical disposed therein.

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

In one embodiment, the microprojection member is made of stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials.

In another embodiment, the microprojection member is made of a non-conductive material, for example a polymeric material. Alternatively, the microprojection member can be coated with a non-conductive material such as Parylene®, or a hydrophobic material such as Teflon®, silicone or other low energy material.

Coating formulations applied to the microprojection members to form a solid biocompatible coating can include aqueous and non-aqueous formulations. Preferably, the coating formulation comprises at least one PTH based agent, which may be dissolved in or suspended in the biocompatible carrier.

In a preferred embodiment, the PTH based agent is selected from the group consisting of hPTH (1-34), hPTH salts and analogs, teriparatide and associated peptides. Throughout this application, the terms "PTH-based medicament" and "hPTH (1-34) medicament", without limitation, recombinant hPTH (1-34), synthetic hPTH (1-34), PTH (1-34), terry Paratide, hPTH (1-34) salt, simple derivatives of hPTH (1-34), for example hPTH (1-34) amide, and closely related molecules such as hPTH (1-33) or hPTH (1 -31) amides, or any other closely related osteogenic peptide. Synthetic hPTH (1-34) is the most preferred PTH agent.

Examples of pharmaceutically acceptable hPTH salts include, without limitation, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, Glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarvalilicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, Dimethylolpropionate, tiglycate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, Glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, po And a sulfate, benzene sulfonate, methane sulfonate, sulfate and sulfonate.

Preferably, the PTH based agent is present in the coating formulation at a concentration in the range of about 1-30% by weight.

More preferably, the amount of PTH based agent included in the solid biocompatible coating (ie, microprojection member or product) is in the range of about 1 μg-1000 μg, more preferably in the range of about 10-100 μg.

Also preferably, the pH of the coating formulation is about pH 6 or below. More preferably, the coating formulation has a pH in the range of about pH 2- pH 6. More preferably, the coating formulation has a pH in the range of about pH 3-pH 6.

In any embodiment of the present invention, the viscosity of the coating formulation used to coat the microprojection is enhanced by adding low volatility counterions. In one embodiment, the PTH-based agent has a positive charge at the formulation pH and the viscosity-enhancing counterion comprises an acid having at least two acidic pKa. Suitable acids are maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramal acid, tartronic acid, citric acid , Tricarvallylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid and phosphoric acid.

Another preferred embodiment relates to a viscosity-enhancing mixture of counterions, wherein the PTH-based agent has a positive charge at the formulation pH and at least one counterion comprises an acid having at least two acidic pKa. Other counterions include acids with one or more pKa. Examples of suitable acids are 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, tart Lonic acid, fumaric acid, acetic acid, propionic acid, pentanic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramal acid, citric acid, aspartic acid , Glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

In the mentioned embodiments of the invention, the amount of counterion is preferably sufficient to neutralize the charge of the PTH. In such embodiments, the amount of counterion or counterion mixture is preferably sufficient to neutralize the charge present in the agent at the pH of the formulation. In additional embodiments, excess counterion (as free acid or salt) is added to the peptide to adjust pH and provide adequate buffering capacity.

In another preferred embodiment, the medicament comprises hPTH (1-34) and comprises a viscosity-enhancing mixture of counterions selected from the group consisting of citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic acid and acetic acid. Preferably, the counterion is added to the formulation to achieve a viscosity in the range of about 20-200 cps.

In a preferred embodiment of the present invention, the viscosity-enhancing counterion comprises at least one acidic pKa at acidic counterions, eg, _atm , and a low volatility weak acid exhibiting a boiling point above 50 ° C. or a boiling point above 170 ° C. . Examples of such acids include citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, and fumaric acid.

In another preferred embodiment, the counterion includes a strong acid that exhibits at least one pKa, less than two. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid.

Another preferred embodiment relates to a mixture of counterions, wherein at least one counterion comprises a strong acid and at least one counterion comprises a low volatility weak acid.

Another preferred embodiment relates to a mixture of counterions, wherein at least one counter ion comprises a strong acid, and at least one counter ion has a high volatility and is at least one pKa higher than 2 at P _atm and greater than 50 ° C. It contains a weak acid having a low melting point or a boiling point lower than 170 ℃. Examples of such acids include acetic acid, propionic acid, pentanic acid, and the like.

The acidic counterion is preferably present in an amount sufficient to neutralize the positive charge present on the PTH-based drug at the pH of the formulation. In additional embodiments, excess counterion (as free acid or salt) is added to adjust pH and provide adequate buffering capacity.

In another embodiment of the present invention, the coating formulation comprises at least one buffer. Examples of such buffers include, without limitation, 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, tricarvalic acid, mal Lonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, citramal acid, dimethylolpropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, β- Hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and mixtures thereof.

In one embodiment of the invention, the coating formulation comprises at least one antioxidant, which is a metal ion inhibitor, such as sodium citrate, citric acid, EDTA (ethylene-dinitrolo-tetraacetic acid) or free radicals Cabins such as ascorbic acid, methionine, sodium ascorbate and the like. Presently preferred antioxidants include EDTA and methionine.

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

In one embodiment of the invention, the coating formulation comprises at least one surfactant, which includes, without limitation, sodium lauroampoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium Zwitterionic, amphoteric, cationic, anionic, or nonionic, other sorbitan derivatives, including polysorbates such as chloride (TMAC), benzalkonium, chloride, Tween 20 and Tween 80, eg example include sorbitan laurate alkoxylated alcohols such as laureth-4 and polyoxyethylene castor oil derivatives, for example, Cremophor ^® EL.

In the mentioned embodiments of the invention, the concentration of the surfactant is preferably in the range of about 0.01-20% by weight of the coating formulation. Preferably the concentration of surfactant is in the range of about 0.05-1% by weight of the coating agent.

In a further embodiment of the invention, the coating formulation is at least one polymeric material or polymer with amphiphilic properties, which, without limitation, not only pluronics but also cellulose derivatives such as hydroxyethylcellulose (HEC) , Hydroxypropylmethylcellulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxy-ethylcellulose (EHEC). The polymer exhibiting amphiphilic properties in the coating formulation is preferably in the range of about 0.01-20% by weight, more preferably in the range of about 0.03-10% by weight of the coating formulation.

In another embodiment, the coating formulation comprises a hydrophilic polymer selected from the group: hydroxyethyl starch, carboxymethyl cellulose and salts thereof, dextran, poly (vinyl alcohol), poly (ethylene oxide), poly (2- Hydroxyethyl-methacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and similar polymers.

In a preferred embodiment, the concentration of hydrophilic polymer in the coating formulation is in the range of about 1-30 wt%, more preferably in the range of about 1-20 wt% of the coating formulation.

In another embodiment of the invention, the coating formulation comprises a biocompatible carrier, which includes, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acid, Sucrose, trehalose, melezitose, raffinose and stachiose.

Preferably, the concentration of biocompatible carrier in the coating formulation is in the range of about 2-70 wt%, more preferably in the range of about 5-50 wt% of the coating formulation.

In other embodiments, the coating formulation includes a stabilizer, which may include, without limitation, non-reducing sugars, polysaccharides or reducing sugars.

Suitable non-reducing sugars useful in the methods and compositions of the present invention include, for example, sucrose, trehalose, starchiose, or raffinose.

Suitable polysaccharides useful in the methods and compositions of the present invention include, for example, dextran, soluble starch, dextrin, and insulin.

Suitable reducing sugars useful in the methods and compositions of the present invention are, for example, monosaccharides such as apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinobose, rhamnose , Allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; And disaccharides such as primeberose, bicyanos, lutinos, silaviose, cellobiose, genthiobiose, lactose, lactulose, maltose, melibiose, sophorose, and turanose and the like.

Preferably, the concentration of stabilizer in the coating formulation is in a ratio of about 0.1-2.0: 1 for PTH based agents, more preferably about 0.25-1.0: 1 for PTH based agents.

In another embodiment, the coating formulation includes vasoconstrictors, which include, but are not limited to, amidefrin, capaminol, cyclopentamine, deoxyepinephrine, epinephrine, felipressin, indazolin, metizoline, mididorin , Napazoline, nordephrine, octodrine, ornipressin, oxymethazolin, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexerine, sudoephedrine, tetrahydrozoline, tramazoline, 2aminoheptane , Thimazoline, vasopressin, xylometazoline and mixtures thereof. Most preferred vasoconstrictive agents include epinephrine, napazoline, tetrahydrozoline indanazoline, methizoline, tramazoline, timozoline, oxymethazolin and xylmethazolin.

The concentration of vasoconstrictor, if used, is preferably in the range of about 0.1% to 10% by weight of the coating agent.

In another embodiment of the present invention, the coating formulation comprises at least one "path modifier", which includes, without limitation, osmotic agents (eg sodium chloride), zwitterionic compounds (eg amino acids), and anti-inflammatory Agents such as betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate disodium salt, methyl Prednisolone 21-succinate sodium salt, paramethasone disodium phosphate and prednisolone 21-succinate sodium salt, and anticoagulants such as citric acid, citrate salts such as sodium citrate, dextrin sulfate sodium, aspirin and EDTA can do. .

In another embodiment of the invention, the coating formulation comprises a solubilizing / complexing agent, which is alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin , Glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, hydroxyethyl -Beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin. Most preferred solubilizing / complexing agents are beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether7 beta-cyclodextrin.

The concentration of the solubilizing / complexing agent, if used, is preferably in the range from about 1% to 20% by weight of the coating formulation.

In another embodiment of the invention, the coating formulation comprises at least one non-aqueous solvent such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethisulfoxide, glycerin, N, N-dimethylformamide and polyethylene Glycol 400. Preferably, the non-aqueous solvent is present in the coating formulation in the range of about 1% to 50% by weight of the coating formulation.

Preferably, the coating formulation has a viscosity of less than about 500 centipoise and greater than 3 centipoise.

In one embodiment of the present invention, the thickness of the biocompatible coating is measured from the microprojection surface and is less than 25 μm, more preferably less than 10 μm.

In one embodiment of the invention, a method for delivering a PTH-based agent to a subject comprises (i) a microprojection member having a plurality of stratum corneum-perforated microprojections on which a biocompatible coating comprising at least one PTH-based agent is arranged. And (ii) applying the microprojection member to the skin site of the subject, wherein the microprojection perforates the stratum corneum and delivers the PTH-based agent to the subject.

Preferably, the coated microprojection member is applied to the skin via an impact applicator.

Also preferably, the coated microprojection member is left on the skin area, preferably for 5 seconds-24 hours. After the desired wear time, the microprojection member is removed. In some embodiments, wherein the PTH-based agent is present in the range of about 1 μg-1000 μg of the biocompatible coating.

In addition, the pharmacokinetic profile of the PTH-based drug delivered transdermally is preferably at least similar to the pharmacokinetic profile observed after subcutaneous delivery.

In one embodiment, the PTH based agent is selected from the group consisting of hPTH (1-34), hPTH salts and analogs, teriparatides and associated peptides.

Also preferably, the hPTH salt is acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, Glucuronate, 3-hydroxyisobutyrate, tricarvalilicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpropionate, Tiglycate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, Lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, methane Selected from the group consisting of sulfonates, sulfates and sulfonates.

In the methods of the present invention, transdermal delivery of PTH based agents preferably indicated rapid onset of biological function. Also preferably, transdermal delivery of PTH-based agents exhibited a biological function lasting for a period of up to 8 hours.

In one embodiment, the transdermal PTH-based agent comprises terryparatide (hPTH (1-34)), the biocompatible coating comprises a dose of the PTH-based agent in a dosage ranging from about 10-100 μg, The delivery of PTH-based medicaments here exhibited a plasma C _max of at least 50 pg / mL after one application.

The invention also includes a method for improving the pharmacokinetics of a transdermally delivered PTH-based medicament comprising the provision of a microprojection member having a plurality of stratum corneum-perforated microprojections. The microprojection member with the biocompatible coating arranged thereon comprises at least one PTH-based agent and applies the microprojection member to the skin area of the subject such that the microprojection perforates the stratum corneum and delivery of the PTH-based agent is subcutaneous. PTH-based drugs are delivered to the subject to have improved pharmacokinetics compared to pharmacokinetic properties.

In the mentioned embodiments, the improved pharmacokinetics can include increased bioavailability of PTH based agents. Improved pharmacokinetics can also include increased C _max . In addition, the improved pharmacokinetics may include reduced T _max . Improved pharmacokinetics may additionally include enhanced absorption rates of PTH-based drugs.

Thus, the devices and methods of the present invention can be used safely and effectively in the treatment of osteoporosis and bone fractures.

Additional features and advantages will be apparent in the following and in a more specific description of preferred embodiments of the invention, as illustrated in the accompanying drawings, and generally refer to the same parts and elements throughout the time point as the properties recited herein, From here:

1 is a schematic illustration of a pulsar tile concentration profile according to the present invention;

2 is a perspective view of a portion of an example of a microprojection member in accordance with the present invention;

3 is a perspective view of the microprojection member shown in FIG. 2 with a coating deposited on the microprojection according to the invention;

4 is a side view of a microprojection member having an adhesive backside, in accordance with the present invention;

5 is a side view of a holding device having a microprojection member arranged therein according to the present invention;

6 is a perspective view of the holding device shown in FIG. 4;

7 is an exploded perspective view of an applicator and retention device according to the invention;

8 is a graph illustrating the charge profile for a PTH-based drug, in accordance with the present invention;

9 is a graph illustrating the molar ratio of net charged species of a PTH-based drug, according to the present invention;

FIG. 10 is a graph illustrating the molar ratios of acetic acid and the neutral form of PTH based agents, in accordance with the present invention; FIG.

11 is a graph comparing plasma concentrations of PTH-based drugs according to transdermal and subcutaneous delivery, according to the present invention;

12 is a graph illustrating the aggregation rate of PTH-based drugs with and without sucrose as stabilizer, according to the present invention;

FIG. 13 is a graph illustrating over time the oxidation of PTH based agents with and without antioxidants in accordance with the present invention; FIG.

14 is a graph illustrating plasma concentrations of PTH-based drugs after transdermal delivery, in accordance with the present invention;

FIG. 15 is a graph illustrating the concentration of urine in cAMP reflecting the bioavailability of a PTH-based drug in accordance with the present invention; FIG.

Figure 16 is an additional graph comparing the plasma concentration of PTH-based drugs after transdermal and subcutaneous delivery according to the present invention.

Before describing the present invention in detail, it should be understood that the present invention is not limited to the specifically exemplified materials, methods or structures, but may be modified in its own way. In addition, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are those described herein.

It is also to be understood that the terminology used herein for the purpose of describing particular embodiments of the invention is not intended to be limiting.

Unless stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In addition, all publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety, either before or after.

Finally, as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural objects unless the context clearly dictates otherwise. Thus, for example, reference to “active agent” includes two or more such agents; Reference to "microprojection" includes two or more such microprojections and the like.

Justice

As used herein, the term “transdermal” means delivery of a medicament through or to the skin for topical or systemic treatment.

As used herein, the term "transdermal flow rate" means the rate of transdermal delivery.

As used herein, the terms “pulsartile delivery profile” and “pulsartile concentration profile” refer to serum concentrations of PTH-based agents after dosing at a baseline concentration in the range of about 50-1000 pg / mL in the range of 1 minute-4 hours. means for increasing, in which C _max is achieved, the serum concentration is achieved by reduction of the baseline concentration for a range of 1-8 hours in the C _max C _max. As illustrated in FIG. 1, the concentration (or pharmacokinetic) profile mentioned typically reflects a sharp rise in serum concentration (ie, the first region) after dosing and a slightly less steep slope compared to the first region after C _max is reached. Ie, the second region), which is generally reflected by protrusions in the concentration profile.

Other concentration profiles resulting in pulsartile delivery, including elevated blood levels of PTH-based drugs to C _max of 50-1000 pg / mL within 12 hours after dosing, can also result in the desired beneficial effects, which It is in range.

As discussed in detail herein, in one embodiment of the present invention, the mentioned "pulsar tile delivery profile" is defined as an area under the curve (AUC) and nominally 30 μg PTH (1) in the range of about 0.014 to 5.24 h · ng / mL. -34) is reflected (confirmed) by the curve of the concentration of PTH based agent in the host's serum over time, with a C _max in the range of about 0.13-0.72 ng / mL for the microprojection members.

The term "co-delivering" herein means before and during the transdermal flow rate of the PTH agent, during the transdermal flow rate of the PTH agent, during and after the transdermal flow rate of the PTH agent, before delivery of the PTH agent. , And / or adjuvant (s) to be transdermally administered following the transdermal flow rate of a PTH-based agent. In addition, two or more PTH based agents will be formed in the coatings and / or formulations and exhibit co-delivery of PTH based agents.

The terms “PTH-based medicament” and “hPTH (1-34) medicament” herein include, without limitation, hPTH (1-34), hPTH salts, hPTH analogs, teriparatide, closely related peptides and 84-amino acid human parathyroid glands. Pharmaceutical agents having a peptide sequence that functions in the same sense as the 34 N-terminal amino acid (biologically active region) sequence of the hormone. The terms "PTH-based medicament" and "hPTH (1-34) medicament", without limitation, recombinant hPTH (1-34), synthetic hPTH (1-34), PTH (1-34), hPTH (1-34) Salts, teriparatide, simple derivatives of hPTH (1-34), for example hPTH (1-34) amides and closely related molecules such as hPTH (1-33) or hPTH (1-31) amides and Associated osteogenic peptides.

Examples of suitable hPTH salts include, without limitation, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate Nate, Glucuronate, 3-hydroxyisobutyrate, Tricarvalilicate, Malonate, Adipate, Citraconate, Glutarate, Itaconate, Mesaconate, Citramalate, Dimethylolpropio Nate, Tiglycate, Glycerate, Methacrylate, Isocrotonate, β-hydroxybutyrate, Crotonate, Angelate, Hydracrylate, Ascorbate, Aspartate, Glutamate, 2-hydroxyiso Butyrate, lactate, maleate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate , Methane sulfonate, sulfate and sulfonate.

The PTH-based agents mentioned may also be in various forms, for example free bases, acids, charged or uncharged molecules, components of molecular complexes or non-irritating, pharmacologically acceptable salts. One or more PTH-based agents may be included in the drug source, reservoir, and / or coating of the present invention, and the use of the term “PTH-based agent” does not exclude the use of two or more such agents in any way.

The term “microprojection” means here a puncturing element adapted to puncture or cut the stratum corneum into the epidermis or underlying epidermis of a living animal, in particular a mammal and more particularly a human.

In one embodiment of the invention, the perforation element has a projection length of less than 1000 μm. In further embodiments, the puncture element has a projection length of less than 500 μm, more preferably less than 250 μm. The microprojection further has a width in the range of about 25-500 μm (indicated by “W” in FIG. 1) and a thickness in the range of about 10-100 μm. Microprojections can be formed in other forms, for example needles, blades, pins, punches, and combinations thereof.

The term "microprojection member" generally refers to a microprojection array comprising a plurality of microprojection members arranged in a stratum corneum array. The microprojection member may form a plurality of microprojections from the thin sheet by etching or punching, and may also form a structure by folding or bending the microprojection out of the surface of the sheet, for example, shown in FIG. The microprojection members may also be formed by other known methods, for example one or more strips with microprojection along the edge of each strip, disclosed in US Pat. No. 6,050,988, which is incorporated herein by reference in its entirety. To form.

The term "coating agent" herein means and includes freely flowing compositions or mixtures used to coat microprojections and / or arrays thereof. Preferably the coating formulation comprises at least one PTH-based medicament, which may be present in solution or in suspension in the formulation.

The terms "biocompatible coating" and "solid coating" refer to and include "coating agents" in a substantially solid state.

As indicated above, the present invention generally includes a microprojection member (or system) having a plurality of microprojections (or arrays) adapted to puncture the stratum corneum with the underlying epidermal layer or epidermal and dermal layer. It includes.

As discussed in detail herein, the heart of the present invention is a delivery system for delivering PTH based agents to mammalian hosts, particularly human patients, whereby PTH based agents in the serum of a patient after dosing exhibit a desired pulsartile concentration profile. The delivery system further follows self-administration of a bolus dose of 20 g of PTH based agent at least once a day.

Referring now to FIG. 2, one embodiment of a microprojection member 30 for use in the present invention is shown. As shown in FIG. 2, the microprojection member 30 includes a microprojection array 32 having a plurality of microprojections 34. Microprojection 34 preferably extends at an angle of 90 degrees from the sheet, which in the mentioned embodiment comprises opening 38.

In accordance with the present invention, sheet 36 may be included into a delivery patch comprising a backside 40 of sheet 36, and additionally may include adhesive 16 for adhering the patch to the skin (FIG. 4). In this embodiment, the microprojection 34 is formed by etching or punching a plurality of microprojections 34 in the metal sheet 36 and bending the microprojection 34 out of the face of the sheet 36.

In one embodiment of the invention, microprojection member 30 has a microprojection density of at least about 10 microprojections / cm ² , more preferably in the range of about 200-2000 microprojections / cm ² . Preferably, the aperture per unit area through which the medicament passes is at least about 10 openings / cm ² and less than about 2000 openings / cm ² .

As shown, microprojection 34 preferably has a projection length of less than 1000 μm. In one embodiment, microprojection 34 has a projection length of less than 500 μm, more preferably less than 250 μm. Microprojection 34 also preferably has a width in the range of about 25-500 μm and a thickness in the range of about 10-100 μm.

In a further embodiment of the invention, the biocompatibility of microprojection member 30 can be improved to reduce or eliminate bleeding and irritation after application to the subject's skin. In particular, microprojection 34 may have a length of less than 145 μm, more preferably about 50-145 μm and more preferably in the range of about 70-140 μm.

In addition, microprojection member 30 preferably comprises an array having a microprojection density of greater than 100 microprojections / cm ² , more preferably in the range of about 200-3000 microprojections / cm ² . Further details regarding microprojection members with improved biocompatibility can be found in US application 60 / ________ [ALZ5174 PSP], filed February 15, 2005, which is incorporated herein by reference in its entirety. It became.

Microprojection member 30 may be constructed from various metals, such as stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials.

According to the invention, microprojection member 30 may also consist of a non-conductive material, for example a polymeric material. Alternatively, the microprojection member may be coated with a non-conductive material, for example Parylene®, or a hydrophobic material such as Teflon®, silicone or other low energy material. The hydrophobic materials and associated base (eg photoresist) layers mentioned are described in US application 60 / 484,142, which is incorporated herein by reference in its entirety.

Microprojection members that can be used in the present invention are disclosed in US Pat. Nos. 6,083,196, 6,050,988 and 6,091,975, which are incorporated by reference in their entirety.

Other microprojection members that can be used in the present invention include members formed by silicon etching using silicon chip etching techniques, and by molding plastic using etched micro-molds, for example, the members are herein incorporated in their entirety. US Pat. No. 5,879,326, which is incorporated by reference. .

In any embodiment of the present invention, microprojection 34 is preferably formed to reduce variability in the applied coating 35. Suitable microprojection generally includes a position having a maximum width across the longitudinal axis from a distal tip at a position in the range of about 25% -75% of the length of the microprojection.

Closest to the position of the maximum width, the width of the microprojection is tapered to the minimum width. Further details regarding the microprojections mentioned can be found in US application 60 / 649,888, filed Jan. 31, 2005, which is incorporated herein by reference in its entirety.

Referring now to FIG. 3, a microprojection member 30 with a microprojection 34 comprising a biocompatible coating comprising a PTH based agent is shown. According to the invention, the coating 35 partially or completely covers each microprojection 34. For example, coating 35 can be in a dry pattern coating on microprojection 34. Coating 35 may also be applied before or after microprojection 34 is formed.

According to the present invention, coating 35 can be applied to microprojection 34 according to various known methods. Preferably, the coating is applied only to the portion of the microprojection member 30 or microprojection 34 that punctures the skin (eg tip 39).

One such coating method includes dip-coating. Dip-coating may be described as a means of coating the microprojection by partially or totally immersing microprojection 34 in the coating solution. Using partial immersion techniques, it is possible to limit the coating 35 to only the tip 39 of the microprojection 34.

Additional coating methods include roller coating, which uses a roller coating mechanism that similarly limits coating 35 to tip 39 of microprojection 34.

Roller coating methods are disclosed in US Application No. 10 / 099,604 (Publication 2002/0132054), which is incorporated herein by reference in its entirety. As discussed in detail in the mentioned application, the disclosed roller coating method provides a smooth coating that is not easily removed from microprojection 34 during skin perforation.

According to the present invention, microprojection 34 may further comprise means adapted to enhance and / or accommodate the volume of coating 35, for example gaps (not shown), grooves (not shown), surface irregularities ( Not shown) or a similar variant, wherein this means provides increased surface area so that a greater amount of coating can be deposited.

Additional coating methods that can be used within the scope of the present invention include spray coating. According to the present invention, the spray coating may comprise the formation of an aerosol suspension of the coating composition. In one embodiment, an aerosol suspension having a droplet size of about 10-200 picoliters was sprayed onto microprojection 10 and then dried.

Pattern coating can also be used to coat microprojection 34. The pattern coating can be applied using a dispensing system that places liquid deposited onto the microprojection surface. The amount of liquid deposited is preferably in the range of 0.1-20 nanoliters / microprojection. Suitable finely measured liquid distributors are described in US Pat. No. 5,916,524; 5,743,960; 5,741,554; And 5,738,728.

Microprojection coating formulations or solutions may also be applied using inkjet techniques using known solenoid valve dispensers, any fluid power means, and positioning means generally controlled by the use of an electric field. Other liquid dispensing techniques in the printing industry or similar dispensing techniques known in the art can be applied to the pattern coating of the present invention.

Referring now to FIG. 5, for storage and application, microprojection member 30 is provided by a tacky tab 6 as described in US application Ser. No. 09 / 976,762 (Publication 2002/0091357), which is incorporated herein by reference in its entirety. Preferably it is suspended in the retainer ring 40.

After placing the microprojection member 30 in the retainer ring 40, the microprojection member 30 is applied to the skin of the patient. Preferably, microprojection member 30 is applied to the skin of a patient using impact applicator 45, for example shown in FIG. 7, and co-pending US application 09 / 976,978, incorporated herein by reference in its entirety. Has been described.

As shown, according to one embodiment of the present invention, the coating formulation applied to the microprojection member 30 to form a solid biocompatible coating may comprise aqueous and non-aqueous formulations with at least one PTH based agent. According to the present invention, the PTH-based agent may be dissolved in the biocompatible carrier or suspended in the carrier.

Referring now to FIG. 8, the predicted charge profile of peptide hPTH (1-34) showing acidic pKa 11 and basic pKa 5 is shown. As illustrated in FIG. 8, at pH 9 the peptide exhibits zero net electric charge. This point is also called isoelectric point or pI.

Referring now to FIG. 9, the predicted mole ratio of net charged species of hPTH (1-34) is shown. As illustrated in FIG. 9, the neutral species is present in substantial amounts only in the pH range pH 6.5-pH 11.5. In this pH range, the peptide loses water solubility and precipitates out of solution. hPTH and its closely related analogs exhibit similar properties and act similarly to hPTH (1-34).

Data reflecting hPTH (1-34) solubility compatible with acceptable formulations for coating on the microprojection arrays of the present invention is achieved at pH below 6 or above pH 11.5. Thus, in a preferred embodiment, the pH of the coating formulation is in the range of about pH 2-pH 6.

Referring now to FIG. 10, an overlap of molar ratios for the neutral form of acetic acid and hPTH (1-34) is shown. As illustrated in FIG. 8, the pH of PTH hexaacetate (molar ratio 1-6) in solution is about pH 5. At pH 5, there is a negligible amount of PTH with PTH zero net charge (PTH 0). PTH is also very soluble in water, at concentrations above 20%. During drying and subsequent storage, free acetic acid evaporates, essentially causing the formation of water insoluble PTH 0. Subsequent reconstitution in water will not allow total solubilization of PTH. Thus, the use of low volatility counterions provides a solid soluble preparation of PTH so long as the pH is maintained at least 2.5 pH units, preferably 3 pH units, below the pI of PTH. Preferably, this can be achieved by providing at least two low volatility counterions for each molecule of PTH.

Thus, in one embodiment of the invention, the coating formulation comprises a counterion or a mixture of counterions. In addition, in the preferred pH range of pH 3-pH 6, the PTH based agent has a positive charge.

In a preferred embodiment, the PTH-based agent is recombinant hPTH (1-34), synthetic hPTH (1-34), PTH (1-34), teriparatide, hPTH (1-34) salt, hPTH (1-34) HPTH (1-34), hPTH salts and analogues, including tertiary derivatives of hPTH (1-34), and simple peptides such as amides; Such as any other closely related osteogenic peptide. Synthetic hPTH (1-34) is the most preferred PTH based agent.

Examples of suitable hPTH salts include, without limitation, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate , Glucuronate, 3-hydroxyisobutyrate, tricarvalilicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpropionate , Tiglycate, Glycerate, Methacrylate, Isocrotonate, β-hydroxybutyrate, Crotonate, Angelate, Hydracrylate, Ascorbate, Aspartate, Glutamate, 2-hydroxyisobutyrate , Lactate, maleate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, Methane sulfonate, sulfate and sulfonate.

Preferably, the PTH-based agent is present in the coating formulation in the concentration range of about 1-30% by weight.

More preferably, the amount of PTH-based agent included in the biocompatible coating on the microprojection member is in the range of 1-1000 μg, more preferably in the range of 10-100 μg.

Preferably, the pH of the coating formulation is less than pH 6. More preferably, the coating formulation has a pH in the range of pH 2-pH 6. More preferably, the coating formulation has a pH in the range of about pH 3-pH 6.

In any embodiment of the present invention, the viscosity of the coating formulation is enhanced by adding low volatility counterions. In one embodiment, the PTH-based agent has a positive charge at the formulation pH and the viscosity-enhancing counterion comprises an acid having at least two acidic pKa. Suitable acids include, but are not limited to, maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramal acid, tartronic acid, citric acid, Tricarvallylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid and phosphoric acid.

Another preferred embodiment relates to a viscosity-enhancing mixture of counterions, wherein the PTH-based agent has a positive charge at the formulation pH and at least one counterion comprises an acid having at least two acidic pKa. Other counterions are acids with one or more pKa. Examples of suitable acids include, without limitation, 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, tartaric acid, fumaric acid, acetic acid, propionic acid, pentanic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramal acid, citric acid , Aspartic acid, glutamic acid, tricarvallic acid and ethylenediaminetetraacetic acid.

In the mentioned embodiments of the present invention, the amount of counterion is preferably sufficient to neutralize the charge of PTH. In this embodiment the counterion or mixture of counterions is preferably sufficient to neutralize the charge present on the drug at the pH of the formulation. In additional embodiments, excess counterions (as salts that turn into free acids) are added to the peptide to adjust pH and provide adequate buffering capacity.

In one embodiment, the medicament comprises hPTH (1-34) and the counterion comprises a viscosity-enhancing mixture of counterions selected from the group consisting of citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic acid and acetic acid. Preferably, the counterion is added to the formulation to achieve a viscosity in the range of about 20-200 cps.

In a preferred embodiment, the viscosity-enhancing counterion comprises an acid counterion, for example a low volatility weak acid. Preferably, the low volatility weak acid counterion exhibits at least one acidic pKa at P _atm and a melting point above about 50 ° C. or a boiling point above about 170 ° C. Examples of such acids include, without limitation, citric acid, succinic acid, glycolic acid. , Gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid and fumaric acid.

In other embodiments, the counterion includes a strong acid. Preferably, the strong acid exhibits a pKa of at least one less than two. Examples of such acids include, without limitation, hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid.

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

Another preferred embodiment relates to a mixture of counterions, wherein at least one of the counterions comprises a strong acid and at least one of the counterions comprises a weak acid having high volatility. Preferably, the volatile weak acid counterion exhibits at least one pKa higher than 2 at P _atm , a melting point lower than 50 ° C. or a boiling point lower than 170 ° C. Examples of such acids include, without limitation, acetic acid, propionic acid, pentanic acid, and the like.

The acidic counterion is preferably present in an amount sufficient to neutralize the positive charge present on the PTH-based drug at the pH of the formulation. In a further embodiment, excess counterions (either as free acid or as salt) are added to adjust pH and provide adequate buffering capacity.

In another embodiment of the present invention, the coating formulation comprises at least one buffer. Examples of such buffers include, but are not limited to, 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, tricarvalic acid, mal Lonic acid, adipic acid, citraconic acid, glutaric acid, itaconic acid, mesaconic acid, citramal acid, dimethylolpropionic acid, tiglylic acid, glyceric acid, methacrylic acid, isocrotonic acid, β-hydroxybutyric acid, Crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and mixtures thereof.

In one embodiment of the present invention, the coating formulation comprises at least one antioxidant, which is a metal ion inhibitor, such as sodium citrate, citric acid, EDTA (ethylene-dinitrilo-tetraacetic acid) or free radical scavin Low ascorbic acid, methionine, sodium ascorbate and the like. Presently preferred antioxidants include EDTA and methionine.

In the mentioned embodiments of the invention, the concentration of antioxidant is in the range of about 0.01-20% by weight of the coating formulation. Preferably the antioxidant is in the range of about 0.03-10% by weight of the coating formulation.

In one embodiment of the invention, the coating formulation comprises at least one surfactant, which includes, without limitation, sodium lauroampoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium Zwitterionic, amphoteric, cationic, anionic, or nonionic, other sorbitan derivatives, including polysorbates such as chloride (TMAC), benzalkonium, chloride, Tween 20 and Tween 80, eg example include sorbitan laurate, alkoxylated alcohols such as laureth-4 and polyoxyethylene castor oil derivatives, for example, Cremophor ^® EL.

In one embodiment of the invention, the concentration of surfactant is in the range of about 0.01-20% by weight of the coating formulation. Preferably the surfactant is in the range of about 0.05-1% by weight of the coating formulation.

In a further embodiment of the invention, the coating formulation comprises at least one polymeric material or polymer with amphipathic properties, which, without limitation, not only fluoronics but also cellulose derivatives, for example hydroxyethylcellulose (HEC) , Hydroxypropylmethylcellulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxy-ethylcellulose (EHEC).

In one embodiment of the present invention, the concentration of the polymer exhibiting amphiphilic properties in the coating formulation is preferably in the range of about 0.01-20 wt%, more preferably in the range of about 0.03-10 wt% of the coating formulation.

In another embodiment, the coating formulation comprises a hydrophilic polymer selected from the following groups: hydroxyethyl starch, carboxymethyl cellulose and salts, dextran, poly (vinyl alcohol), poly (ethylene oxide), poly (2-hydride Oxyethylmethacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and analogous polymers.

In a preferred embodiment, the concentration of hydrophilic polymer in the coating formulation is in the range of about 1-30 wt%, more preferably in the range of about 1-20 wt% of the coating formulation.

In another embodiment of the invention, the coating formulation comprises a biocompatible carrier, which includes, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acid, Sucrose, trehalose, melezitose, raffinose, stachiose, mannitol, and other sugar alcohols.

Preferably, the concentration of biocompatible carrier in the coating formulation is in the range of about 2-70 wt%, more preferably in the range of about 5-50 wt% of the coating formulation.

In other embodiments, the coating formulation includes a stabilizer, which may include, without limitation, non-reducing sugars, polysaccharides or reducing sugars.

Suitable non-reducing sugars for use in the methods and compositions of the present invention include, for example, sucrose, trehalose, starchiose, or raffinose.

Suitable polysaccharides for use in the methods and compositions of the present invention include, for example, dextran, soluble starch, dextrin, and insulin.

Reducing sugars suitable for use in the methods and compositions of the present invention are, for example, monosaccharides such as apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinobose , Rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; And disaccharides such as primeberose, bicyanos, lutinos, silaviose, cellobiose, genthiobiose, lactose, lactulose, maltose, melibiose, sophorose, and turanose, and the like.

Preferably, the concentration of stabilizer in the coating formulation is in a ratio of about 0.1-2.0: 1 for PTH based agents, more preferably about 0.25-1.0: 1 for PTH based agents.

In other embodiments, the coating formulation includes vasoconstrictors, which include, but are not limited to, amidefrin, capaminol, cyclopentamine, deoxyepinephrine, epinephrine, pellpressin, indazolin, metizoline, midodorin, Napazoline, nordephrine, octodrine, ornipressin, oxymethazolin, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexerine, sudophedrine, tetrahydrozoline, tramazoline, twoaminoheptane, Thimazoline, vasopressin, xylometazoline and mixtures thereof. Most preferred vasoconstrictive agents include epinephrine, napazoline, tetrahydrozoline indanazoline, methizoline, tramazoline, timozoline, oxymethazolin and xylmethazolin.

As will be appreciated by those skilled in the art, the addition of vasoconstrictors to the coating formulations and solid biocompatible coatings of the present invention prevents bleeding that may occur after application of the microprojection member or array, and reduces blood flow at the site of application. And prolonged pharmacokinetics of PTH-based drugs through a decrease in the rate of absorption from the skin site into the system circulation.

The concentration of vasoconstrictor, if used, is preferably in the range of about 0.1% to 10% by weight of the coating formulation.

In another embodiment of the present invention, the coating formulation comprises at least one "path modifier", which includes, without limitation, osmotic agents (eg sodium chloride), zwitterionic compounds (eg amino acids), and anti-inflammatory Agents such as betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate disodium salt, methylprednisolone 21 -Succinate sodium salts, paramethasone disodium phosphate and prednisolone 21-succinate sodium salts, and anticoagulants such as citric acid, citrate salts such as sodium citrate, dextrin sulfate sodium, aspirin and EDTA have.

In another embodiment of the invention, the coating formulation comprises a solubilizing / complexing agent, which is alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclo Dextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, hydroxy Ethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin. Most preferred solubilizing / complexing agents are beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether7 beta-cyclodextrin.

The concentration of the solubilizing / complexing agent is preferably in the range of about 1% to 20% by weight of the coating formulation.

In another embodiment of the invention, the coating formulation comprises at least one non-aqueous solvent such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethisulfoxide, glycerin, N, N-dimethylformamide and polyethylene Glycol 400. Preferably, the non-aqueous solvent is present in the coating formulation in the range of about 1% to 50% by weight of the coating formulation.

Other known formulation auxiliaries provided may also be added to the coating formulation which do not adversely affect the required solubility and viscosity properties of the coating formulation and the physical cohesion of the dried coating.

Preferably, the coating formulation has a viscosity of less than about 500 centipoise and greater than 3 centipoise.

In one embodiment of the present invention, the thickness of the biocompatible coating is measured from the microprojection surface and is less than 25 μm, more preferably less than 10 μm.

The desired coating thickness depends on several factors including the dosage required and the coating thickness required for dose delivery, the density of microprojections per unit area of the sheet, the viscosity and concentration of the coating composition and the coating method chosen.

According to one embodiment of the invention, a method of delivering a PTH-based agent included in a biocompatible coating on a microprojection member comprises the following steps: The coated microprojection member is initially applied to the skin of the patient via an actuator, Here microprojection punctures the stratum corneum. The coated microprojection member is preferably left on the skin for 5 seconds-24 hours continuously. After the desired wear time, the microprojection member is removed.

Preferably, the amount (ie, dosage) of the PTH-based agent included in the biocompatible coating is in the range of about 1 μg-1000 μg, more preferably in the range of about 10-200 μg per dosage unit. More preferably, the amount of PTH-based agent included in the biocompatible coating is in the range of 10-100 μg per dosage unit.

As mentioned, according to the present invention, PTH-based drugs are delivered to patients in the pulsertile fashion and thus exhibit pharmacokinetics resulting in the pulsertile concentration profile. In one embodiment of the invention, the pulsar tile concentration profile is about about microprojection members comprising an area under the curve (AUC) and nominally 30 μg PTH (1-34) in the range of about 0.014-5.24 h.ng/mL. Reflected (confirmed) by the curve of PTH-based drug concentration in the host's serum over time, with C _max in the range 0.13-0.72 ng / mL and also T _max in the range 5-15 minutes.

In a presently preferred embodiment, a 20 g mass dose of PTH-based medicament is delivered to the pulsar tile fashion with the microprojection members in place for up to 15 minutes.

The pulsartile concentration profile mentioned is preferably achieved via the PTH delivery mode in the range of 0.5 pulses per day (ie once every two days) -2, more preferably one full pulse (or dosage) per day. However, as those skilled in the art will understand, PTH can also be delivered in a variety of additional dosage forms.

In all cases, after the coating is applied, the coating formulation is dried by various means on microprojection 34. In a preferred embodiment of the invention, the coated microprojection member 30 is dried at room temperature conditions. However, various temperature and humidity levels can be used to dry the coating formulation on the microprojection. In addition, the coated member can be heated, lyophilized, and similar techniques used to cool water or remove water from the coating can be used.

This can be understood by those skilled in the art to facilitate drug delivery across the skin barrier, and the present invention is not limited in any way in this respect, as the present invention is directed to a variety of iontophoretic or electron transfer systems. Can also be used in this regard. Exemplary electron transfer drug delivery systems are disclosed in US Pat. Nos. 5,147,296, 5,080,646, 5,169,382 and 5,169,382, which are incorporated herein by reference in their entirety.

The term "electron transfer" generally means a pathway through the body surface of a beneficial agent, such as a drug or drug precursor, such as skin, mucous membranes, nails and the like. The delivery of the medicament is caused or enhanced by the application of an electric field, which results in the application of an electric current, which either conveys or enhances the delivery of the medicament, or samples a medicament for "reverse" electron transfer. Promote. Electron delivery of a medicament into or out of the human body can be accomplished in a variety of ways.

One widely used electron transfer method, iontophoresis, involves the electrically induced transfer of charged ions. Another type of electron transfer method involved in the transdermal delivery of uncharged or neutral charged molecules (eg, transdermal sampling of glucose), electroosmosis involves the movement of the solvent with the agent through the membrane under the influence of an electric field. Electroporation, still another method of electron transfer, involves the passage of a medicament through a hole formed by applying an electric pulse, a high pressure pulse to the membrane.

In many cases, one or more of the mentioned methods may occur simultaneously in different ranges. Thus, the term “electron transfer” is intended to encompass the broadest possible range, including regardless of the specific mechanism (s) to which the actual agent is delivered, including electrically induced or enhanced delivery of at least one charged or uncharged agent, or mixtures thereof. Given as an explanation.

In addition, it may be used in connection with other methods of enhancing delivery, for example sonophoresis or the invention of piezoelectric devices.

The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They are not to be understood as limiting the scope of the present invention, but are merely exemplary thereof.

Example  One

The delivery of hPTH (1-34) in the coated microprojection array in the hairless guinea pig (HGP) model was evaluated. Photo / chemical etching was used to fabricate and form the microprojection array. In the micro projection array 2cm ² area used in this study, have a projection length of 320 microprojections / cm ² and 200μm. The microprojection array was coated at 40 ± 10 μg per ² cm ² array with a 25% aqueous solution of hPTH with a solid coating limited to the first 100 μm of microprojection. Each coated microprojection array was assembled on a soft polymeric tacky backside. The resulting patch was assembled on the retainer ring and mounted on a reusable impact applicator when applied to the HGP.

Each anesthetized HGP received a patch applied under clean skin for a one hour wear time. At various time intervals after patch application, blood samples were taken. Enzyme immunoassay was used to determine plasma hPTH (1-34) levels (Peninsula Lab).

Plasma levels of HGPs receiving 40 μg of hPTH (1-34) coated microprojection array patches were compared with subcutaneous (SC) dosing of 20 μg of hPTH (1-34) (see FIG. 11).

In individual groups of five animals, intravenous infusion (IV) of 23 μg of hPTH (1-34) was performed and total uptake / delivery after SC or microneedle array dosing using the area under the curve (AUC) as reference Was calculated. The pharmacokinetic parameters following IV, SC and microneedle array dosing are shown in Table 1.

The pharmacokinetic (PK) profile of the immune response hPTH (1-34) was similar for both SC and microprojection array delivery; t _max (SC: 10 mins 20 min, C _max (SC: 4.6 ± 1.5 ng / mL vs 3.4 ± 1.0 ng / ml); AUC _{240 min} (SC: 8.2 ± 2.9 μg vs 6.6 ± 1.8 μg) (n = 10 Per group, mean ± SD).

The data indicate that hPTH (1-34) can be delivered transdermally with a PK profile similar to the profile of subcutaneous injection, and hPTH (1-34) using microprojection array technology, which can be a more convenient alternative for osteoporosis patients. Highlights the possibility of transdermal delivery.

Table 1

Example  2

Example 2 showed the use of a weak acid with the hPTH (1-34) agent to enhance viscosity. The interaction of positively charged hPTH (1-34) agents with the anions of the weak acid led to the formation of secondary bonds, for example hydrogen bonds, leading to an increase in the viscosity of the solution. The larger the number of acidic groups, the larger the number of secondary bonds formed between the anion and the hPTH (1-34) agent, and thus the higher the viscosity increase. Thus, the theoretical viscosity-promoting ability increased when comparing diacid, igi-acid, samgi-acid and fructo-acid.

In this experiment, various weak acid buffers were included in the hPTH (1-34) formulations. Control formulations were also prepared comprising PTH (1-34) acetate with sucrose. Experiments examined the physicochemical properties provided to hPTH (1-34) by various mixtures of short-, di- and tri-acids, and the stability of the solution formulations exceeded 48 hours at 2-8 ° C. PTH (1-34) formulations were buffered at pH 5.2.

Referring now to Table 2, the viscosity results of the formulations are shown here. Citric acid and malic acid buffered formulations showed the greatest viscosity enhancement compared to control formulations. Citric acid, tri-acid, yielded the formulation with the highest viscosity.

The data reflected in Table 2 shows that the counterion mixtures of citric acid / acetic acid, malic acid / acetic acid, tartaric acid / acetic acid and hydrochloric acid / acetic acid showed hPTH (1-34) for a control formulation of 20% PTH, 20% sucrose, 0.2% Tween 20. It was shown to increase the viscosity of. Based on the results reflected in Table 2, the trend of viscosity enhancement after addition of the weak acid buffer is preferably tri-acid to di-acid to di-acid.

TABLE 2

Example  3

Example 3 was shown to enhance the in vivo dissolution of hPTH-based drugs by using a mixture of a counterion and a hPTH (1-34) agent.

In the solid coating on the microprojection array, the medicament is typically present in an amount of less than about 1 mg per unit dose. With the addition of additives and counterions, the total mass of the solid coating may be present in an amount less than about 3 mg per unit dose.

The array is usually on the sticky back side which is attached to a polymeric retainer ring that can be used and discarded. Such assemblies are typically packaged individually in pouches or polymeric housings. In addition to the assembly, this package contains an atmosphere (usually inert) representing a volume of at least 3 mL. This large volume acts as a sink for any volatile component (relative to coating). For example, at 20 ° C., the amount of acetic acid is present in 3 mL of air as a result of its vapor pressure of about 0.15 mg. This amount is typically present in solid coatings when acetic acid is used as the counterion. In addition, components of the assembly, such as tack, can act as an additional sink for volatile components. As a result, during long term storage, the concentration of any volatile components present in the coating changes radically. These conditions are typical of pharmaceutical compounds in which large amounts of additives are usually present. Even with very potential biotech compounds lyophilized for use injectable, very large amounts of buffers and additives are present in the dry cake.

In solution, or in the solid state, volatilization of counter ions occurs between the interface of the solution or solid and the atmosphere. High diffusivity of the solute generally minimizes the difference in concentration between the interface and the bulk of the solution. In contrast, in the solid state, the diffusivity is very slow and the concentration gradient of volatile counterions is achieved between the interface and the bulk of the solution. Ultimately, the outer layer of the coating lacked counter ions and the bulk of the solid coating remained relatively unchanged compared to the initial dry state. If the counterion is associated with a drug that is substantially insoluble in the neutral net charge state, this situation can result in a very high insoluble outer coating. Indeed, volatilization of the counterion results in the formation of a water insoluble neutral species. This in turn jeopardizes the dissolution of the medicament from the solid coating as it is exposed to biological fluids. Thus, this experiment investigated the effect of addition of low volatility counterions to enhance coating solubility.

Several aqueous formulations containing hPTH (1-34) were prepared and shown in Table 3. These formulations included volatile counterionic acetic acid. Optional formulations included additional low volatility counterion hydrochloric acid, glycolic acid, or tartaric acid. The microprojection array (microprojection length 200 mm, 595 microprojections per array) had a skin contact area of about 2 cm ² . The tip of the microprojection was coated with the formulation mentioned by passing the array on a rotating drum carrying the PTH formulation using the methods and apparatus disclosed in US Patent Application No. 10 / 099,604, which is incorporated herein by reference in its entirety. .

At 2-8 ° C., four successive coatings were performed on each microprojection array. The amount of peptide coated on the array was measured by ultraviolet spectroscopy at a wavelength of 275 nm. Scanning electron microscopy showed that the solid coating had a very smooth surface without cracking. In addition, with a coating limited to the first 100 μm of the microprojection tip, excellent uniformity of the coating from microprojection to microprojection was observed.

Tip-coated arrays made in this way were then used for drug delivery studies in hairless guinea pigs (HGPs). HGP was anesthetized by intramuscular injection of xylazine (8 mg / kg) and ketamine HCl (44 mg / kg). A catheter was inserted through the carotid artery into the anesthetized HGP. Conduits were flushed with heparinized saline (20 IU / mL) to prevent entanglement. HGP was maintained in anesthesia via an experiment in which sodium pentobarbital (32 mg / mL) was injected directly into the catheter (0.1 mL / injection). Prior to application, blood samples were taken in heparinized vials (final concentration of heparin at 15 IU / mL), which was performed with zero or baseline samples.

Microprojection array coated on the flanks of anesthetized animals with spring-driven impact applicators of the type disclosed in US Patent Application No. 09 / 976,798, which is incorporated by reference in its entirety (total energy = 0.4 Joules, 10 milliseconds or less). Was applied. The applied system included a coated microprojection array device, adhered to the center of the LDPE backside with a tack. The patch was kept on skin for 1 hour (n = 4-5). The control group of animals (n = 5) received an intravenous infusion of 22 μg of hPTH.

Blood samples were collected through the carotid catheter at time intervals after patch application. All blood samples were immediately centrifuged for plasma collection and the latter was then stored at -80 ° C until analysis. Plasma hPTH was determined with Peninsula Lab. (San Carlos, Calif.) (EIA), a commercial enzyme immunoassay kit for hPTH. The hPTH dose delivered by the microprojection array was extrapolated based on AUC calculations compared to the UV dose of hPTH.

As shown in Table 3, different amounts of PTH were delivered from each solid formulation. Solid formulations containing only PTH acetate delivered on average less than 2 mg. The addition of low volatile counterions to PTH acetate substantially increased delivery up to 11.2 mg after addition of low volatile counter glycolic acid. Two other non-relative ions tested, namely tartaric acid and hydrochloric acid, also increased PTH delivery. In particular, the counterion mixture of glycolic acid / acetic acid, tartaric acid / acetic acid and hydrochloric acid / acetic acid increased the delivered amount of hPTH (1-34) relative to the control formulation of 21.2% PTH, 3.8% acetic acid.

TABLE 3

Example  4

Example 4 demonstrates the use of hPTH (1-34) agents and stabilizers to enhance the stability of hPTH (1-34) agents.

As shown in Table 4, ten formulations were coated on titanium and observed for chemical stability at 40 ° C. for 60 days. The pH of the formulation with the weak acid buffer was about pH 5.2, while the pH of the chloride with the formulation was about pH 5.4. Purity, oxidized PTH (1-34) product and soluble aggregates were observed as a function of time by reverse phase high pressure liquid chromatography (RPHPLC) and size exclusion chromatography. The results for each formulation are summarized in Tables 5-14.

The stability data generated suggest that the main mechanism of PTH decomposition in the solid state is through the aggregation process. In addition, stabilization data showed that addition of sucrose prevents aggregation of hPTH (1-34). 12 shows the percentage aggregation of hPTH (1-34) formulations with and without sucrose at 60 days.

Table 4

Table 5

Table 6

TABLE 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Example  5

Example 5 showed the use of antioxidants to retard the oxidation of the hPTH (1-34) agent. Table 15 lists the seven formulations prepared for stability studies.

Table 15

Table 16 highlights the results of the three month stability study. Three peaks detected by RPHPLC at relative retention times at 0.36, 0.53 and 0.68 contributed to the oxidized species of hPTH (1-34), denoted as oxides 1, 2, and 3, respectively. In all cases, three oxides were the predominant oxidation product.

Table 16

In summary, formulations without antioxidants showed the highest percentage of total oxide, and the addition of methionine or EDTA retarded oxidation. The results indicated that methionine retarded oxidation in a concentration dependent manner. However, EDTA did not exhibit this phenomenon. The addition of 0.5 mM EDTA to the formulation was as effective as 3 mM in the oxidation retardation. The results also showed that EDTA was more effective at delaying oxidation than methionine. These results are illustrated graphically in FIG. 13, which gave the sum of the oxidized species of hPTH (1-34).

Example  6

In this example, transdermal delivery of PTH-based drugs using coated microprojection members was compared to subcutaneous delivery of conventional teriparatide PTH (Forteo ^™ ). Dose-irradiation studies were performed in 10 healthy young women treated at least twice daily at a randomly assigned sequence of subcutaneous delivery of Forteo ^™ 20 μg and transdermal delivery of 30 μg of PTH-based drug of coated microprojection. It was. Bioavailability of transdermal delivery of PTH to 20 healthy young women treated at least twice daily, in a randomly assigned sequence of subcutaneous delivery of Forteo ^™ 40 μg and transdermal delivery of 30 μg of PTH-based drug of coated microprojection. Was determined.

In the dose-investigation study, two participants dropped out and eleven patients participated and eight available data were generated. After subcutaneous injection, three patients had measurable PTH plasma levels and eight patients had measurable PTH plasma levels after transdermal delivery. In the bioavailability study, 15 patients showed measurable PTH plasma levels after subcutaneous delivery and 20 patients showed measurable PTH plasma levels after transdermal delivery, thus completing 20 patients.

As shown in FIG. 14, transdermal delivery of PTH-based drugs obtained effective absorption into the bloodstream. 12 additionally reflected the preferred pulsartile concentration profile of the PTH agent, ie, rapid off-set after rapid onset and C _max reached. In addition, as shown in FIG. 15, as evidenced by increased levels of urine cAMP secretion, the biological activity of PTH after transdermal delivery was comparable to that after subcutaneous delivery.

Plasma concentrations of PTH after subcutaneous and transdermal delivery were compared in FIG. 16, which further indicated rapid absorption after transdermal delivery. FIG. 16 similarly reflected the preferred pulsartile concentration profile of the PTH based agent, ie, rapid curve after rapid onset and C _max reached.

PK / PT results of subcutaneous and transdermal delivery are additionally provided in Table 17, indicating similar bioavailability of PTH.

Table 17

* Standardized to 30µg dosage.

The safety of transdermal delivery was also evaluated during this experiment. In general, transdermal delivery through coated microprojections has been reported to favor adverse subcutaneous delivery, with similar proportions of patients with adverse events reported but not severe. Nausea and vomiting were more common in subcutaneous delivery.

As will be appreciated by those skilled in the art, the present invention provides various advantages. For example, microprojection-based devices and methods have the advantage of transdermal delivery of PTH-based drugs that exhibit a PTH-based pharmacokinetic profile similar to that observed after subcutaneous dosing. Another advantage is the transdermal delivery of PTH based agents with rapid onset of biological action. Nevertheless, another advantage is the transdermal delivery of PTH-based drugs with continuous biological action of up to 8 hours. Additionally, transdermal delivery from microprojection arrays coated with 10-100 μg doses of teriparatide (hPTH (1-34)) showed a plasma C _max of at least 50 pg / mL after one application.

Without departing from the spirit and scope of the present invention, one of ordinary skill in the art may make various changes and modifications to the present invention to suit various uses and conditions. As such, these changes and modifications may be intended to be appropriately and duly within the equivalents of the full scope of the following claims.

Claims (86)

A microprojection member having a plurality of microprojections adapted to puncture the stratum corneum of the patient; And A biocompatible coating arranged on the microprojection member, which is a coating formed from a coating formulation in which at least one PTH based agent is arranged on the coating. Device for transdermal delivery of PTH-based medicine to a patient comprising a. The device of claim 1, wherein the coating is arranged on at least one of the plurality of microprojections. The device of claim 1, wherein the microprojection member has a microprojection density of at least about 10 microprojections / cm ² . The microprojection member of claim 1, wherein the microprojection member has a microprojection density in the range of about 200-2000 microprojections / cm ² . The device of claim 1, wherein the microprojection member is comprised of a material selected from the group consisting of stainless steel, titanium and nickel titanium alloys. 6. The device of claim 5, wherein the microprojection member is coated with a non-conductive material. The device of claim 6, wherein the non-conductive material is selected from the group consisting of Parylene ^® , Teflon ^® and Silicone. The device of claim 1, wherein the microprojection member is comprised of a non-conductive material. The device of claim 1, wherein the coating formulation comprises an aqueous formulation. The device of claim 1, wherein the coating formulation comprises a non-aqueous formulation. The device of claim 1, wherein the PTH based agent is selected from the group consisting of hPTH (1-34), hPTH salts and analogs, teriparatide and associated peptides. The method of claim 11, wherein the hPTH salt is acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycol Latex, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarvalilicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethyl Allpropionate, tiglycate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, glutamate, 2- Hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, The device selected from the group consisting of methane sulfonate, sulfate and sulfonate. The device of claim 1, wherein the PTH-based agent comprises about 1-30% by weight of the coating formulation. The device of claim 1, wherein the PTH-based agent comprises about 1 μg-1000 μg range of the biocompatible coating. The device of claim 1, wherein the PTH-based agent comprises about 10 μg-100 μg of the biocompatible coating. The device of claim 1, wherein the pH of the coating formulation is lower than about pH 6. 6. The device of claim 16, wherein the pH of the coating formulation is in the range of about pH 2-pH 6. The device of claim 16, wherein the coating formulation comprises at least one low volatility counterion. 19. The device of claim 18, wherein the coating formulation comprises a plurality of low volatility counterions. 19. The device of claim 18, wherein the PTH based agent has a positive charge at the pH of the coating formulation and the viscosity-enhancing counterion comprises primary acid having at least two acidic pKa. The method of claim 20, wherein the first acid is maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramal acid, tart A device selected from the group consisting of lonic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid and phosphoric acid. The device of claim 20, wherein the PTH-based agent has a positive charge at the coating formulation pH, wherein the coating formulation comprises at least one counterion comprising a second acid having at least one pKa. The method of claim 22, wherein the second acid is 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, tartaric acid, fumaric acid, acetic acid, propionic acid, pentanic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramal acid, A device selected from the group comprising citric acid, aspartic acid, glutamic acid, tricarvallylic acid and ethylenediaminetetraacetic acid. 19. The device of claim 18, wherein the amount of low volatility counterion present in the coating formulation is sufficient to neutralize the charge of the PTH-based agent. The device of claim 1, wherein the PTH based agent comprises hPTH (1-34), wherein the coating formulation comprises at least one viscosity-enhancing counterion. 27. The device of claim 25, wherein said viscosity-enhancing counterion is selected from the group comprising citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic acid, and acetic acid. The device of claim 25, wherein the coating formulation has a viscosity in the range of about 20-200 cps. The device of claim 1, wherein the coating formulation comprises a viscosity-enhancing counterion comprising an acidic counterion. 29. The device of claim 28, wherein said acidic counterion comprises a low volatility weak acid representing at least one acidic pKa. 30. The device of claim 29, wherein the low volatility weak acid has a melting point higher than about 50 ° C. The device of claim 29, wherein the low volatility weak acid has a boiling point higher than about 170 ° C. at P _atm . 30. The device of claim 29, wherein the low volatility acid 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. 29. The device of claim 28, wherein the acidic counterion comprises a strongest acid that exhibits at least one pKa of less than about 2. 34. The device of claim 33, wherein the strongest 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. 29. The device of claim 28, further comprising a plurality of acidic counterions, wherein at least the first counterion comprises a strong acid and at least the second counterion comprises a low volatility weak acid. The method of claim 28, further comprising a plurality of acidic counterions, wherein at least the first counterion comprises a strong acid, and at least the second counterion comprises a highly volatile weak acid having at least one pKa greater than two. Device. 37. The device of claim 36, wherein the high volatility weak acid has a melting point of less than about 50 ° C. The device of claim 36, wherein the high volatility weak acid has a boiling point lower than about 170 ° C. at P _atm . 37. The device of claim 36, wherein the high volatility weak acid is selected from the group consisting of acetic acid, propionic acid and pentanoic acid. The method of claim 1, wherein the coating formulation is 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, tricarvalic acid, Malonic acid, adipic acid, citraconic acid, glutaric acid, itaconic acid, mesaconic acid, citramal acid, dimethylropropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, β-hydroxybutyric acid And at least one buffer selected from the group consisting of crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine, and mixtures thereof. The device of claim 1, wherein the coating formulation comprises at least one antioxidant selected from the group consisting of metal ion inhibitors and free radical scavengers. 42. The device of claim 41, wherein said metal ion inhibitor is selected from the group consisting of sodium citrate, citric acid, and ethylene dinitro-tetraacetic acid. 42. The device of claim 41 wherein the free radical scavenger is selected from the group comprising ascorbic acid, methionine and sodium ascorbate. 42. The device of claim 41 wherein the concentration of antioxidant is in the range of about 0.01-20% by weight of the coating formulation. 42. The device of claim 41 wherein the concentration of antioxidant is in the range of about 0.03-10% by weight of the coating formulation. The method of claim 1, wherein the coating formulation is sodium lauroampoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbate And at least one surfactant selected from the group comprising sorbitan derivatives, sorbitan lauratealkoxylated alcohols, polyoxyethylene castor oil derivatives and mixtures thereof. The device of claim 46, wherein the concentration of surfactant is in the range of about 0.01-20% by weight of the coating formulation. The device of claim 1, wherein the coating formulation comprises at least one polymeric material having amphipathic properties. 49. The device of claim 48, wherein the polymeric material comprises a cellulose derivative. 50. The method of claim 49, wherein the cellulose derivative is hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC), hydroxypropycellulose (HPC), methyl cellulose (MC), hydroxyethyl-methyl cellulose (HEMC). Or ethylhydroxy-ethylcellulose (EHEC), and pluronix. 49. The device of claim 48, wherein the concentration of polymer is in the range of about 0.01-20% by weight of the coating formulation. The method of claim 1, wherein the coating formulation is hydroxyethyl starch, carboxymethyl cellulose and salts, dextran, poly (vinyl alcohol), poly (ethylene oxide), poly (2-hydroxyethyl-methacrylate), A device comprising a hydrophilic polymer selected from the group consisting of poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof. The device of claim 52, wherein the concentration of hydrophilic polymer is in the range of about 1-30% by weight of the coating formulation. The method of claim 1, wherein the coating formulation is bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acid, sucrose, trehalose, melezitose, raffinose, stakiose A device comprising a biocompatible carrier selected from the group consisting of mannitol and similar sugar alcohols. 55. The device of claim 54, wherein the biocompatible carrier comprises about 2-70% by weight of the coating formulation. The device of claim 1, wherein the coating formulation comprises a stabilizer selected from the group consisting of non-reducing sugars, polysaccharides, and reducing sugars. 59. The device of claim 56, wherein the non-reducing sugar is selected from the group consisting of sucrose, trehalose, starchiose and raffinose. The device of claim 56, wherein the polysaccharide is selected from the group consisting of dextran, soluble starch, dextrin, and insulin. 59. The device of claim 56, wherein the reducing sugar is selected from the group consisting of monosaccharides and disaccharides. 60. The method according to claim 59, wherein the monosaccharides are apios, arabinose, lyxose, ribose, xylose, digitose source, fucose, quercitol, quinobose, rhamnose, allose, altrose, fructose, galactose , A device selected from the group consisting of gulose, hamamelose, idose, mannose and tagatose. 60. The disaccharide according to claim 59, wherein the disaccharide is selected from the group consisting of primeberose, bicyanos, lutinos, silaviose, cellobiose, genthiobiose, lactose, lactulose, maltose, melibiose, sophorose and turanose. Device. The device of claim 56, wherein the concentration of the stabilizer in the coating formulation is in a ratio of about 0.01-2.0: 1 relative to the PTH-based drug. The method of claim 1, wherein the coating formulation is amideprine, carpaminol, cyclopentamine, deoxyepinephrine, epinephrine, pellipsin, indazoline, methizoline, middorin, napazoline, nordephrine, octodrin, Ornipressin, oxymethazolin, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexerin, suedephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, thimazoline, vasopressin, xylometazoline, And at least one vasoconstrictor selected from the group consisting of mixtures thereof. 64. The device of claim 63, wherein the concentration of the vasoconstrictor is in the range of about 0.1-10% by weight of the coating formulation. The device of claim 1, wherein the coating formulation comprises at least one pathway opener selected from the group consisting of osmotic agents, zwitterionic compounds, anti-inflammatory agents, and anticoagulants. 66. The method of claim 65, wherein the anti-inflammatory agent is betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate An apparatus selected from the group consisting of disodium salt, methylprednisolone 21-succinate sodium salt, paramethasone disodium phosphate and prednisolone 21-succinate sodium salt. 66. The device of claim 65, wherein the anticoagulant is selected from the group consisting of citric acid, citrate salt, dextrin sulfate sodium, aspirin and EDTA. The method of claim 1, wherein the coating formulation is alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin, hydroxyethyl-beta-cyclodextrin, A device comprising a solubilizing / complexing agent selected from the group consisting of methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin. The device of claim 68, wherein the concentration of the solubilizing / complexing agent is in the range of about 1-20% by weight of the coating formulation. The device of claim 1, wherein the coating formulation has a viscosity in the range of about 3-500 centipose. The device of claim 1, wherein the thickness of the biocompatible coating is less than about 25 μm. A coating comprising at least one PTH based agent provides a plurality of microprojection members having a plurality of stratum corneum-perforated microprotrusions arranged thereon; Applying the microprojection member to the skin area of the patient, whereby a plurality of stratum corneum-perforated microprotrusions perforate the stratum corneum and deliver the PTH-based agent to the patient; A method of transdermal delivery of a PTH agent to a patient comprising the step of removing the microprojection member from the skin site. 73. The method of claim 72, wherein the microprojection member remains applied to the skin site for a range of 5 seconds-24 hours. The method of claim 72, wherein the PTH-based agent comprises about 1 μg-1000 μg range of the biocompatible coating. 73. The method of claim 72, wherein applying the microprojection member comprises applying the microprojection member to the skin area with an impact applicator. The method of claim 72, wherein the delivered PTH based agent provides a pharmacokinetic profile that is at least similar to the pharmacokinetic profile provided by subcutaneous administration of the PTH based agent. 73. The method of claim 72, wherein said PTH-based agent is selected from the group consisting of hPTH (1-34), hPTH salts and analogs, teriparatide and associated peptides. 78. The composition of claim 77, wherein the hPTH salt comprises acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, Gluconate, Glucuronate, 3-hydroxyisobutyrate, Tricarvalilicate, Malonate, Adipate, Citraconate, Glutarate, Itaconate, Mesaconate, Citramaleate, Dimethylol Propionate, Tiglycate, Glycerate, Methacrylate, Isocrotonate, β-hydroxybutyrate, Crotonate, Angelate, Hydracrylate, Ascorbate, Aspartate, Glutamate, 2-Hydrate Oxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene, sulfonate, Method selected from the group consisting of methane sulfonate, sulfate and sulfonate. 73. The method of claim 72, wherein said delivery of said PTH based agent indicates a rapid onset of biological action. 73. The method of claim 72, wherein said delivery of said PTH based agent exhibits a sustained biological action of up to 8 hours. 73. The method of claim 72, wherein the PTH-based agent comprises teriparatide (hPTH (1-34)), wherein the biocompatible coating comprises a dosage of the PTH-based agent in the range of about 10-100 μg. Wherein the delivery of the PTH based agent results in a plasma C _max of at least 50 pg / mL after a single application. A coating comprising at least one PTH based agent provides a plurality of microprojection members having a plurality of stratum corneum-perforated microprotrusions arranged thereon; Applying the microprojection member to the skin area of the patient, whereby a plurality of stratum corneum-perforated microprotrusions perforate the stratum corneum and deliver the PTH-based agent to the patient; Removing the microprojection member from the skin site. 83. The method of claim 82, wherein the improved pharmacokinetics comprises increased bioavailability of the PTH based agent. The method of claim 82, wherein the improved pharmacokinetics comprises increased C _max . 83. The method of claim 82, wherein the improved pharmacokinetics comprises reduced T _max . 83. The method of claim 82, wherein the improved pharmacokinetics comprises an enhanced rate of absorption of the PTH-based drug.

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