WO2014159778A1 - Système d'administration de médicament transdermique contenant du fentanyl - Google Patents

Système d'administration de médicament transdermique contenant du fentanyl Download PDF

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Publication number
WO2014159778A1
WO2014159778A1 PCT/US2014/025099 US2014025099W WO2014159778A1 WO 2014159778 A1 WO2014159778 A1 WO 2014159778A1 US 2014025099 W US2014025099 W US 2014025099W WO 2014159778 A1 WO2014159778 A1 WO 2014159778A1
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WO
WIPO (PCT)
Prior art keywords
delivery system
drug delivery
transdermal drug
acrylate
fentanyl
Prior art date
Application number
PCT/US2014/025099
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English (en)
Inventor
Je Phil Ryoo
Hoo-Kyun Choi
Original Assignee
Nal Pharmaceuticals, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nal Pharmaceuticals, Ltd. filed Critical Nal Pharmaceuticals, Ltd.
Publication of WO2014159778A1 publication Critical patent/WO2014159778A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl

Definitions

  • the present invention relates to a transdermal drug delivery system comprising fentanyl or a pharmaceutically acceptable salt thereof as an active ingredient, more specifically to a transdermal drug delivery system comprising a drug-containing matrix layer the matrix of which is formed with an acrylate-rubber hybrid adhesive having less than 60 ⁇ thickness and low contents of fentanyl.
  • Fentanyl is known to have more than about 80 times stronger than morphine, it has been used to reduce pain in patient with cancer of after surgery.
  • Fentanyl citrate is administered intravenous (i.v.) or orally or via buccal or fentanyl base is administered transdermal delivery.
  • i.v. intravenous
  • buccal or fentanyl base is administered transdermal delivery.
  • above the effective amount of the dose in the plasma can cause side effect such as respiratory depression or muscular rigidity.
  • transdermal delivery is desirable option as it can provide a sustained delivery of fentanyl by one time application for even several days.
  • concentration of fentanyl in plasma can be maintained constant to reduce or prevent side effect often caused by i.v. injection, which can cause initial high concentration of fentanyl in plasma to result in the side effects.
  • transdermal delivery is easy to apply and easy to remove to provide an advantage in any emergency situation.
  • transdermal patch containing fentanyl employs silicon adhesive.
  • U.S. Patent No. 4, 588,580 teaches a matrix type transdermal patch where fentanyl is contained in silicon or polyisobutylene class adhesives and
  • U.S. Patent No. 5, 186,939 teaches a transdermal patch comprising fentanyl dissolved in an amine-resistant
  • fentanyl has a low solubility in silicon or polyisobutylene class adhesives and high contents of fentanyl in a high concentration in these adhesives can result in a crystallization of fentanyl and eventually low permeation of fentanyl due to the crystallized fentanyl in the patch.
  • an adhesive like polyisobutylene does not have enough adhesive property to properly support the transdermal patch long enough to deliver the drug for a long period of time.
  • U.S. Patent Application Publication 2009/0238861 teaches a transdermal patch where fentanyl is suspended in solvated silicone adhesives.
  • it is not easy to suspend the solid particles evenly through the matrix manufacturing could be a problematic.
  • the permeation rate depends on the particle size, permeation of fentanyl may also experience difficulties.
  • Korean Patent 10-0895188 introduced a micro reservoir within the matrix layer to prevent overdose of fentanyl.
  • an additional process to prepare the micro reservoir can increase the production cost significantly.
  • U.S. Patent Application Publication 2011/0111013 suggests suspending the drug in a gel to resolve the problem of inconsistent solubility, irregular permeation and other problems caused by polyisobutylene class adhesives. However, the patch still contains undissolved drug and could not resolve all previous problems.
  • U.S. Patent Application Publication 2011/0038918 and Korean Patent 10-0904158 teach fentanyl containing transdermal patch using acrylate adhesives.
  • Korean Patent Application Publication 10-2009-0101579 filed by the present inventors, also teaches a fentanyl containing transdermal patch having acrylate adhesives and, optionally, an absorption enhancer such as polyethylene glycol- 12 palm kernel glyceride. Even though fentanyl' s solubility in acrylate adhesives is high, permeation of fentanyl was not satisfactory and requires a high contents of fentanyl in the transdermal patch to result in wasting the expensive fentanyl and it is very likely the undelivered fentanyl will remain in the patch.
  • the present invention provides a fentanyl containing transdermal drug delivery system having improved skin permeation and absorption which allows low contents of fentanyl in the transdermal drug delivery system and also with reduced cost of manufacturing by having simpler process for preparation.
  • the present invention provide a fentanyl containing transdermal drug delivery system having certain adhesives such as acryl-rubger hybrid adhesives in a fentanyl containing matrix, which can also provide improved skin permeation and absorption to allow low contents of fentanyl in the system but to deliver fentanyl longer time period.
  • certain adhesives such as acryl-rubger hybrid adhesives in a fentanyl containing matrix
  • the transdermal drug delivery system of the present invention has less than 60 ⁇ thickness, more preferably less than 50 ⁇ thickness, even more preferably 40 ⁇ thickness.
  • the transdermal drug delivery system of the present invention not only show high skin penetration rate but also continuously maintain a therapeutically effective blood concentration for at least 24 hours. And also, the present invention provides a transdermal drug delivery system, which can inhibit recrystallization of fentanyl and maintain skin penetration rate intact, even during the long-term storage.
  • FIG. 1 shows the results obtained by measuring skin penetration rates of the transdermal drug delivery systems according to the Examples prepared.
  • the present invention provides a transdermal drug delivery system containing back support or back film, drug-containing matrix containing fentanyl or pharmaceutical as the active ingredient and acryl-rubber hybrid as the adhesive.
  • the present invention provides a fentanyl-containing transdermal drug delivery system, both showing high skin penetration rate continuously for more than 24 hours and having an excellent stability.
  • a transdermal drug delivery system comprising a drug-containing matrix layer comprising: (a) fentanyl or a pharmaceutically acceptable salt thereof as an active ingredient; and (b) an acrylate-rubber hybrid as an adhesive.
  • the transdermal drug delivery system may consist of a backing layer, the drug-containing matrix layer, and a release layer.
  • the acrylate-rubber hybrid may be an acrylic polymer comprising a C4-C18 alkyl acrylate monomer grafted with ethylene-butylene macromers.
  • the C4-C18 alkyl acrylate monomers may contain monomers having a glass transition temperature of not more than - 30 °C. More specifically, C4-C18 alkyl acrylate monomers is one or more selected from among butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, or dodecyl acrylate, preferably 2-ethylhexyl acrylate.
  • the fentanyl or its pharmaceutically acceptable salt may be present in an amount ranging from 5 to 40% by weight, based on the total weight of the drug-containing matrix layer and the acrylate-rubber hybrid adhesive may be present in an amount ranging from 60 to 95% by weight, based on the total weight of the drug-containing matrix layer.
  • the transdermal drug delivery system according to the present invention may further comprise an acrylate polymer or a methacrylate polymer as a crystallization-inhibiting agent.
  • the crystallization-inhibiting agent may be present in an amount ranging from 1 to 10% by weight, based on the total weight of the drug-containing matrix layer.
  • the crystallization- inhibiting agent may be a copolymer of butyl methacrylate, 2-dimethylaminoethyl
  • the transdermal drug delivery system may further comprise one or more absorption enhancers selected from the group consisting of terpenes; non-ionic surfactants; polyoxyethylene alkyl ethers; polyethylene glycol glycerides; fatty alcohols; fatty acid esters; propylene glycol esters; polyglyceryl fatty acid esters; sugar esters; fatty acids; glycerols; alkyl 2-ethyl hexanates; and diethoxylethyl succinates.
  • the absorption enhancer may be present in an amount ranging from 1 to 20% by weight, based on the total weight of the drug-containing matrix layer.
  • the absorption enhancer may be one or more selected from the group consisting of polyethylene glycol palm kernel glyceride, polyoxy ethylene lauryl ether, polyglyceryl-3 oleate, lauryl alcohol, and oleyl alcohol.
  • the transdermal drug delivery system according to the present invention comprises a matrix obtained by using an acrylate-rubber hybrid as an adhesive, which can increase the diffusion rate of fentanyl from the matrix layer. Therefore, the transdermal drug delivery system according to the present invention can not only show high skin penetration rate but also continuously maintain a therapeutically effective blood concentration for at least 24 hours. And also, the transdermal drug delivery system of the present invention can inhibit recrystallization of fentanyl and maintain skin penetration rate intact, even during the long- term storage. Therefore, the transdermal drug delivery system according to the present invention can improve drug compliance of patients suffering from pain.
  • the present invention can reduce the thickness of the drug-containing matrix significantly, preferably less than 60 ⁇ and achieve high absorption and permeation through the skin consistently even at the lower contents or concentration of the drug per unit area.
  • the low contents of drug per unit area also will reduce the remaining drugs in the matrix after the treatment to reduce the waste of the drug, which can also provide benefit of reduction of drug abuse or overdose.
  • the transdermal drug delivery system comprises a matrix layer containing fentanyl or pharmaceutically effective salts thereof, which is evenly well distributed throughout the matrix layer to provide consistent delivery of fentanyl.
  • acrylate-rubber hybrid adhesive refers to an acrylic polymers containing acrylate monomers grafted with a rubber macromere such as ethylene- butylene macromers.
  • a rubber macromere such as ethylene- butylene macromers.
  • the above-mentioned 'grafting' or 'hybrid' means the above macromers are attached or conjugated at the functional groups of the alkyl acrylate monomers.
  • the 'grafting' is accomplished by dissolving alkyl acrylate or rubber macromers in ethyl acetate, hexane or mixture of both and adding an initiator such as, but not limited to, azobis(isobutyronitrile, AIBN). More detailed 'grafting' procedure is disclosed in U.S. Pat. No.
  • the acrylate-rubber hybrid adhesive in the present application is, preferably, grafted acryl polymers containing C4-C18 alkyl acrylate monomers grafted with ethylene-butylene macromers or rubber macromere, wherein the C4-C18 alkyl acrylate monomers have a glass transition temperature of not more than -30 °C.
  • the C4-C18 alkyl acrylate monomers may be one of more selected from among butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, or dodecyl acrylate and preferably 2-ethylhexyl acrylate.
  • the acrylate-rubber hybrid adhesive may be one or more selected from commercially available acrylate-rubber hybrids, i.e., Duro- TakTM 87-502A (National Starch), Duro-TakTM 87-502B (National Starch), Duro-TakTM 87- 503A (National Starch), Duro-TakTM 87-504A (National Starch), or Duro-TakTM 87-504B (National Starch). .
  • the acrylate-rubber hybrid adhesives may be one of more selected from commercially available acrylate-rubber hybrids, Duro-TakTM 87-502B (National Starch), and Duro-TakTM 87-504B (National Starch). Also, it can be further distinguished that different acrylate-rubber hybrid adhesives can be prepared by different of solvent systems. The final composition of hybrid adhesives can be quite different by the solvent used in the process. Therefore, even though the individual monomers of polymer employed for hybrid may be same but the chemical composition or structure of the final hybrid adhesive could be different to provide different properties.
  • the hybrid adhesives act as a solvent to dissolve the drug substance in the preparation of the transdermal patch.
  • the formulation for developing a transdermal patch should be modified significantly according to the hybrid adhesive or solvent compositions. Since their physical properties and the compatibility of adhesives to drug substance were changed, the formulation development of patch should be approached with totally different methods to maintain the better stability of the final formula.
  • the present invention provides a transdermal drug delivery system, which comprises a drug-containing matrix layer comprising: (a) fentanyl or a pharmaceutically acceptable salt thereof as an active ingredient; and (b) an acrylate-rubber hybrid as an adhesive.
  • the transdermal drug delivery system may consist of a backing layer, the drug-containing matrix layer, and a release layer.
  • the acrylate-rubber hybrid is used as an adhesive; and the acrylate-rubber hybrid adhesive forms a matrix in the drug-containing matrix layer. That is, fentanyl or its pharmaceutically acceptable salt is homogeneously dispersed in the acrylate-rubber hybrid adhesive, thereby forming the drug-containing matrix layer.
  • a matrix formed from the acrylate- rubber hybrid having low glass transition temperature can improve flexibility of polymer chains, thereby increasing a diffusion rate of an active ingredient (i.e., fentanyl or its pharmaceutically acceptable salt) to the skin from the matrix layer.
  • an active ingredient i.e., fentanyl or its pharmaceutically acceptable salt
  • the use of the acrylate-rubber hybrid leads to higher skin penetration rate and excellent adhesive force, in comparison with not only acrylic adhesives having no functional group (for example, Duro- TakTM 87-4098, Duro-TakTM 87-900A, Duro-TakTM 87-9301 etc.) but also other acrylic adhesives having hydroxyl or carboxyl functional group (for example, Duro-TakTM 87-2516, Duro-TakTM 87-2510, Duro-TakTM 87-2525, Duro-TakTM 87-2596, Duro-TakTM 87-2825, Duro-TakTM 87-2502, Duro-TakTM 87-2979, Duro-TakTM 87-2074 etc.).
  • acrylic adhesives having no functional group for example, Duro- TakTM 87-4098, Duro-TakTM 87-900A, Duro-TakTM 87-9301 etc.
  • other acrylic adhesives having hydroxyl or carboxyl functional group for example, Duro-TakTM
  • the acrylate-rubber hybrid adhesive may be used in an amount sufficient to form a matrix layer, for example, in an amount ranging from 60 to 95% by weight, based on the total weight of the drug-containing matrix layer.
  • the fentanyl or its pharmaceutically acceptable salt may be used in an amount sufficient to obtain a therapeutically effective blood concentration, for example, in an amount ranging from 5 to 40%) by weight, preferably from 5 to 20%> by weight, more preferably 7-16% by weight based on the total weight of the drug-containing matrix layer. If the amount of fentanyl or its pharmaceutically acceptable salt is more than 40% by weight, drug crystals may be formed in the transdermal drug delivery system, which results in reducing adhesive force or lowering absorption rate of the drug.
  • the thickness of the system can be significantly reduced to less than 60 ⁇ , preferably less than 50 ⁇ , more preferably less than 40 ⁇ , or even more preferably between 15-40 ⁇ considering the adhesiveness and duration of application. In other words, reduction of the thickness of the matrix later and high concentration of fentanyl in a unit area but still provides consistently high permeation of fentanyl.
  • the transdermal drug delivery system according to the present invention may further comprise a crystallization-inhibiting agent.
  • the crystallization-inhibiting agent may be an acrylate polymer or a methacrylate polymer, preferably a copolymer of butyl methacrylate, 2- dimethylaminoethyl methacrylate, and methyl methacrylate in a weight ratio of 1 :2: 1 (for example, EudragitTM El 00).
  • the crystallization-inhibiting agent may be present in an amount ranging from 1 to 10% by weight, based on the total weight of the drug-containing matrix layer.
  • the transdermal drug delivery system according to the present invention does not contain crystallization-inhibiting agent.
  • the transdermal drug delivery system according to the present invention may comprise a conventional absorption enhancer used in the field of a transdermal drug delivery system.
  • the absorption enhancer may be present in an amount ranging from 1 to 20% by weight, preferably from 5 to 15% by weight, based on the total weight of the drug- containing matrix layer. If the amount of an absorption enhancer is more than 20% by weight, adhesive force may be reduced; or cold flow may occur due to weaken cohesive force.
  • the absorption enhancer may be one or more selected from the group consisting of terpenes; surfactants; polyoxyethylene alkyl ethers; fatty alcohols; sugar esters; glycerols; alkyl 2-ethyl hexanates; and diethoxylethyl succinates.
  • Examples of the terpenes include cineole, limonene, etc.
  • Examples of the surfactants include isopropyl myristate, isopropyl palmitate, 2-(2- ethoxyethoxy) ethanol, oleic acid oleyl ester, caprylocaproyl macrogolglyceride, oleoyl macrogolglyceride, diisopropyl dirrerate, diisopropyl adipate, hexyl laurate, polysorbate, sorbitan oleate, etc.
  • polyoxyethylene alkyl ethers examples include polyethylene glycol palm kernel glyceride, 2-ethyl hexyl hydroxystearate, polyoxyethylene lauryl ether,
  • fatty alcohols examples include polyglyceryl-3 oleate, polyethylene glycol almond glyceride, lauryl alcohol, oleyl alcohol, etc.
  • sugar esters examples include sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, etc.
  • alkyl 2-ethyl hexanates examples include 2-ethylhexanonate, cetyl 2- ethylhexanonate, stearyl 2-ethylhexanonate, etc.
  • the polyoxyethylene alkyl ethers and/or the fatty alcohols may be preferably used.
  • the absorption enhancer may be one or more selected from the group consisting of polyethylene glycol palm kernel glyceride (for example, CrovolTM A40), polyoxyethylene lauryl ether (for example, BrijTM 30, BrijTM 52, etc.), polyglyceryl-3 oleate (for example, Plurol oleiqueTM cc497), lauryl alcohol, and oleyl alcohol.
  • polyethylene glycol palm kernel glyceride for example, CrovolTM A40
  • polyoxyethylene lauryl ether for example, BrijTM 30, BrijTM 52, etc.
  • polyglyceryl-3 oleate for example, Plurol oleiqueTM cc497
  • lauryl alcohol and oleyl alcohol.
  • polyoxyethylene lauryl ether for example, BrijTM 30
  • the transdermal drug delivery system of the present invention may be prepared by forming the drug-containing matrix layer on a release layer and then forming a backing layer thereon.
  • a release layer conventional release liners or their laminates used in the field of a transdermal drug delivery system may be used.
  • a film, a paper, or a laminates thereof which made of polyethylene, polyester, polyvinyl chloride, polyvinylidene chloride, etc. coated with silicone resin or fluoride resin.
  • drug nonabsorbable and flexible materials conventionally used in the field of a transdermal drug delivery system may be used as the backing layer (also referred to as "backing membrane").
  • transdermal drug delivery system of the present invention may be prepared, for example by dissolving fentanyl or its pharmaceutically acceptable salt and an acrylate-rubber hybrid adhesive, optionally along with an absorption enhancer and/or a crystallization-inhibiting agent, in an appropriate solvent (e.g., ethyl acetate, etc.), casting the resulting solution on a release liner coated with silicone followed by drying the mixture, and then laminating a backing layer.
  • an appropriate solvent e.g., ethyl acetate, etc.
  • the transdermal drug delivery systems were prepared according to the components and amounts shown in Tables 1-5. To a mixture of fentanyl and an acrylate -rubber hybrid adhesive, was added ethyl acetate as a solvent so as to attain to 25% of solid content. After stirring each mixture, the resulting each solution was casted on a release liner coated with silicone, followed by drying the mixture. A polyethylene film (CotranTM 9720) was laminated onto the resulting each layer to form a backing membrane, so as to prepare each fentanyl-containing transdermal drug delivery system.
  • the acrylate-rubber hybrid adhesives classified three different types (Table 1-2) according to the presence of a cross-liking agent and a tackifier. Also, it can be distinguished by two groups of solvent system (Table 1-3). The compositions of two solvent systems
  • Group A (502A, 503 A and 504B) & Group B (502B and 504B)] are described in Table 1-3.
  • the solid part of adhesive is solved in the solvents, in which the drug substance and other excipients can be dissolved in.
  • Examples 1 to 4 were applied onto hairless mouse skins and Human cadaver skin (58 year old male or 68 year old female), for determining their skin penetration rates. Specifically, skins were excised from hairless mice (6 to 8 weeks old) right before the experiment. Each transdermal drug delivery system was cut in a circular form having a size of 2 cm 2 and then attached to the isolated skins. Each resulting skin was fixed in each flow-through diffusion cell with a clamp thereof. To the receiver thereof, was added an isotonic phosphate buffer solution (pH 6.0). While the diffusion cell was maintained at 37 °C under stirring with a magnetic stirrer, samples were collected at an interval of 4 hours for 24 hours. The samples were subject to quantitative analysis using high-performance liquid chromatography under the following conditions as provided in Table 9 and the results are presented in Table 10.
  • those prepared using acryl-rubber hybrid adhesive 87-502B or 87-504B presented a better stability than those with 87-502A or 87- 504 A, respectively.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un système d'administration de médicament transdermique comprenant du fentanyl ou son sel pharmaceutiquement acceptable et un procédé de fabrication de celui-ci. La présente invention concerne un système d'administration de médicament transdermique comprenant du fentanyl ou un sel pharmaceutiquement acceptable de celui-ci comme principe actif, de façon plus spécifique un système d'administration de médicament transdermique comprenant une couche de matrice contenant un médicament, dont la matrice est formée par un adhésif hybride acrylate-caoutchouc ayant moins de 60 µm d'épaisseur et de faibles teneurs en fentanyl.
PCT/US2014/025099 2013-03-13 2014-03-12 Système d'administration de médicament transdermique contenant du fentanyl WO2014159778A1 (fr)

Applications Claiming Priority (2)

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US201361780107P 2013-03-13 2013-03-13
US61/780,107 2013-03-13

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WO2014159778A1 true WO2014159778A1 (fr) 2014-10-02

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6670417B2 (en) * 2001-03-16 2003-12-30 National Starch And Chemical Investment Holding Corporation Rubber-acrylic adhesive formulation
WO2012002640A2 (fr) * 2010-06-30 2012-01-05 엔에이엘 파마슈티칼즈 엘티디. Système transdermique d'administration de médicament contenant du donépézil
WO2012124966A2 (fr) * 2011-03-15 2012-09-20 아이큐어 주식회사 Timbre transdermique contenant du fentanyl

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6670417B2 (en) * 2001-03-16 2003-12-30 National Starch And Chemical Investment Holding Corporation Rubber-acrylic adhesive formulation
WO2012002640A2 (fr) * 2010-06-30 2012-01-05 엔에이엘 파마슈티칼즈 엘티디. Système transdermique d'administration de médicament contenant du donépézil
WO2012124966A2 (fr) * 2011-03-15 2012-09-20 아이큐어 주식회사 Timbre transdermique contenant du fentanyl

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