US20160008294A1 - Transdermal delivery system - Google Patents

Transdermal delivery system Download PDF

Info

Publication number
US20160008294A1
US20160008294A1 US14/772,474 US201414772474A US2016008294A1 US 20160008294 A1 US20160008294 A1 US 20160008294A1 US 201414772474 A US201414772474 A US 201414772474A US 2016008294 A1 US2016008294 A1 US 2016008294A1
Authority
US
United States
Prior art keywords
buprenorphine
transdermal therapeutic
adhesive layer
therapeutic system
sensitive adhesive
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US14/772,474
Other languages
English (en)
Inventor
Thomas Hille
Gabriel Wauer
Frank Seibertz
Shu-Lun Weinheimer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LTS Lohmann Therapie Systeme AG
Original Assignee
Purdue Pharma LP
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51022809&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20160008294(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Purdue Pharma LP filed Critical Purdue Pharma LP
Priority to US14/772,474 priority Critical patent/US20160008294A1/en
Assigned to LTS LOHMANN THERAPIE-SYSTEME AG reassignment LTS LOHMANN THERAPIE-SYSTEME AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HILLE, THOMAS, SEIBERTZ, FRANK, WAUER, Gabriel
Assigned to PURDUE PHARMA L.P. reassignment PURDUE PHARMA L.P. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Weinheimer, Shu-Lun
Assigned to LTS LOHMANN THERAPIE-SYSTEME AG reassignment LTS LOHMANN THERAPIE-SYSTEME AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PURDUE PHARMA L.P.
Assigned to PURDUE PHARMA L.P. reassignment PURDUE PHARMA L.P. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LTS LOHMANN THERAPIE-SYSTEME AG
Publication of US20160008294A1 publication Critical patent/US20160008294A1/en
Assigned to LTS LOHMANN THERAPIE-SYSTEME AG reassignment LTS LOHMANN THERAPIE-SYSTEME AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PURDUE PHARMA L.P.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive plasters or dressings
    • A61F13/0246—Adhesive plasters or dressings characterised by the skin adhering layer
    • A61F13/0256—Adhesive plasters or dressings characterised by the skin adhering layer characterized by the parametric properties of the adhesive
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of buprenorphine, and processes of manufacture, uses thereof, and corresponding methods of treatment therewith.
  • TTS transdermal therapeutic system
  • buprenorphine (5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol) is a partially synthetic opiate with high potency. Cancer patients may be treated with daily doses of around 1 mg. Despite its rather high molecular weight of 467.64 daltons, it is currently used for transdermal administration.
  • the commercial TTS product Norspan® also known as BuTrans®, delivers buprenorphine to the skin sufficiently to treat patients in pain for a time period of 7 days (about 168 hours) and allows therefore a use of the TTS over a time period of 7 days and allows in a fixed dosing regimen a once-weekly TTS exchange.
  • This is specifically beneficial in terms of convenience and patient compliance.
  • the overall efficacy of the pain medicament is enhanced.
  • the long administration periods may cause problems with skin irritation, which in combination with the considerable size (i.e., area of release) of the TTS may be problematic.
  • the large amount of excess drug in the TTS necessary to sustain enough driving force for sustaining the appropriate drug delivery over the long period of time is costly and has the potential to be subject to illicit use.
  • the maintenance of sufficient release rates during a seven-day administration period is in particular challenging since the system is particularly sensitive to variability in the drug release.
  • the tolerance for higher drug delivery at the beginning of the dosing period (also know as “drug burst”) is very limited since the loss of drug at the beginning will lead to a loss of driving force later in the dosing period, in particular after three to four days of delivery.
  • a microreservoir system including deposits of buprenorphine and a carboxylic acid dispersed in a hydrophobic pressure sensitive adhesive layer provides high overall release rates during a seven-day administration period allowing a reduction of size and drug content in comparison to the commercial product Norspan®.
  • These systems provide high performance but are biphasic due to the dispersed deposits (1. phase) in the adhesive (2. phase).
  • the size and size distribution of the deposits influences the drug delivery. Large deposits release the drug too fast and provide for an undesired burst in the beginning of the dosing period and a failure of the system after three to four days. There is thus a need to sufficiently control the size and size distribution of the deposits.
  • buprenorphine e.g., buprenorphine base
  • buprenorphine base e.g., buprenorphine base
  • buprenorphine e.g., buprenorphine base
  • buprenorphine base e.g., buprenorphine base
  • a transdermal therapeutic system for the transdermal administration of buprenorphine e.g., buprenorphine base
  • buprenorphine e.g., buprenorphine base
  • a buprenorphine e.g., buprenorphine base
  • self-adhesive layer structure comprising
  • the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising
  • the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure comprising
  • the invention relates to a method of treating pain in a patient by applying a transdermal therapeutic system in accordance with the invention to the skin of a patient, in particular to a method of treating pain in a patient by applying a transdermal therapeutic system in accordance with the invention to the skin of said patient for more than about 96 hours (or for more than 4 days), or for about 120 hours (or for 5 days), or for about 144 hours (or for 6 days) or for about 168 hours (or for 7 days or for one week).
  • the invention relates to a method of treating pain in a patient by applying to the skin of said patient for about 168 hours (or for 7 days or for one week) a transdermal therapeutic system, comprising a buprenorphine (e.g., buprenorphine base) containing self-adhesive layer structure comprising
  • a buprenorphine e.g., buprenorphine base
  • self-adhesive layer structure comprising
  • the invention relates to a method of treating pain in a patient by applying for about 168 hours on the skin of a patient a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising
  • the invention relates to a method of treating pain in a patient by applying to the skin of said patient for about 168 hours a transdermal therapeutic system, comprising a buprenorphine base-containing self-adhesive layer structure comprising
  • the invention relates to a set of two to five different transdermal therapeutic systems for the transdermal administration of buprenorphine base selected from five different transdermal therapeutic systems, i.e., a first, a second, a third, a forth and a fifth transdermal therapeutic system, each of the five different transdermal therapeutic systems comprising a buprenorphine-containing self-adhesive layer structure comprising
  • the invention relates to a set of transdermal therapeutic systems including at least two transdermal therapeutic systems selected from the first, second, third, fourth and fifth transdermal therapeutic systems as described in the previous paragraphs.
  • the at least two transdermal therapeutic systems can be selected from the first, second, third, fourth and fifth transdermal therapeutic system as described in the previous paragraphs, and the further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 14 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base.
  • the invention relates to a method of treating pain in a patient by selecting for said patient the appropriate transdermal therapeutic system from the first, second, third, fourth and fifth transdermal therapeutic system as described in the previous two paragraphs, and subsequently applying said selected transdermal therapeutic system on the skin of said patient for about 168 hours.
  • the invention relates to a method of treating pain in a patient by selecting for said patient the appropriate transdermal therapeutic system from the first, second, third, fourth and fifth, and the further transdermal therapeutic system as described in the previous two paragraphs, and subsequently applying said selected transdermal therapeutic system on the skin of said patient for about 168 hours.
  • the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of
  • the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of
  • the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine in accordance with the invention, comprising the steps of
  • Useful solvents for dissolving buprenorphine, carboxylic acid and the viscosity-increasing substance are alcohols (e.g. ethanol), acetone and methyl ethyl ketone, ethanol is preferred.
  • the polymer-based pressure-sensitive adhesive may be dissolved in heptanes, hexanes, toluene, or ethylacetate, preferably in heptane.
  • the solvent for buprenorphine has preferably only limited or no capability of dissolving the polymer-based pressure-sensitive adhesive and the solvent for the polymer-based pressure-sensitive adhesive has preferably only limited or no capability of dissolving buprenorphine.
  • the invention relates to the use of polyvinylpyrrolidone in the manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine which system includes deposits of a mixture including buprenorphine base and a carboxylic acid dispersed in a pressure-sensitive adhesive based on polysiloxane to control the size of the deposits during the manufacture.
  • the term “transdermal therapeutic system” refers to the entire individual unit that is applied to the skin of a patient, and which comprises the buprenorphine-containing self-adhesive layer structure and optionally an additional larger active-free self-adhesive layer structure on top of the buprenorphine-containing self-adhesive layer structure, which TTS provides the percutaneous delivery of the active buprenorphine to the patient.
  • TTS transdermal therapeutic system”
  • TTS refers to the entire individual unit that is applied to the skin of a patient, and which comprises the buprenorphine-containing self-adhesive layer structure and optionally an additional larger active-free self-adhesive layer structure on top of the buprenorphine-containing self-adhesive layer structure, which TTS provides the percutaneous delivery of the active buprenorphine to the patient.
  • TTS is normally located on a redetachable protective layer from which it is removed immediately before application to the surface of the patient
  • buprenorphine-containing self-adhesive layer structure refers to the active agent-containing structure providing the area of release of the active agent.
  • polymer-based pressure-sensitive adhesive refers to a pressure-sensitive adhesive containing from 75% to 100% of said polymer based on the dry weight of the pressure-sensitive adhesive, e.g., 75% to 100% of polysiloxane.
  • the pressure-sensitive adhesive contains from 80% to 100%, or from 85% to 100%, or from 90% to 100%, or from 95% to 100% of the polymer (e.g., polysiloxane) based on the dry weight of the pressure sensitive adhesive.
  • a pressure-sensitive adhesive is in particular a material that adheres with finger pressure, is permanently tacky, exerts a strong holding force and should be removable from smooth surface without leaving a residue.
  • Examples of useful pressure-sensitive adhesives based on polysiloxane which are commercially available include the standard Bio-PSA series (7-4400, 7-4500 and 7-4600 series), the amine compatible (endcapped) Bio-PSA series (7-4100, 7-4200 and 7-4300 series) and the Soft Skin Adhesives series (7-9800) manufactured by Dow Corning.
  • Preferred pressure-sensitive adhesives based on polysiloxane are heptane-solvated pressure-sensitive adhesives including BIO-PSA 7-4201, BIO-PSA 7-4301 and BIO-PSA 7-4501.
  • additional larger active agent-free self-adhesive layer structure refers to a self-adhesive layer structure that is free of active agent and larger in area than the active agent-containing structure and providing additional area adhering to the skin, but no area of release of the active agent, and enhancing thereby the overall adhesive properties of the TTS.
  • the term “buprenorphine-containing pressure-sensitive adhesive layer” and “matrix layer” have the same meaning and refer to the layer containing the active agent (the buprenorphine) in a matrix-type structure of active in-adhesive. % amount of ingredients refers to the solid contents.
  • skin contact layer refers to the part of the TTS which is in direct contact with the skin of the patient during administration and is located in/co-extensive with the buprenorphine-containing self-adhesive layer structure.
  • the sizes of the “skin contact layer” and the buprenorphine-containing self-adhesive layer structure are co-extensive and correspond to the area of release.
  • deposit refers to distinguishable, e.g., visually distinguishable, areas within the pressure-sensitive adhesive. Such deposits are e.g., droplets. Deposits that are visually distinguishable may be identified by use of a microscope.
  • viscosity-increasing substance refers to a substance which when added to the mixture of buprenorphine and carboxylic acid increases the viscosity of the mixture.
  • the K-value refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the Ph.Eur. and USP monographs for “Povidone”.
  • soluble polyvinylpyrrolidone refers to polyvinylpyrrolidone which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid.
  • soluble polyvinylpyrrolidone is supplied by BASF as Kollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 30 and Kollidon 90 F. Kollidon 90 F is used throughout the examples.
  • the size of the deposits refers to the diameter of the deposits as measured using a microscopic picture of the layers structure.
  • roll coater refers to a coater which provides a coating whereby the fluid flow in a nip between a pair of rotating rolls controls both the thickness and the uniformity of the coated film.
  • the “in-vitro dissolution” is determined using a rotating cylinder apparatus of the Ph Eur/USP using 600 ml degassed 0.9% sodium chloride solution at 32° C. and rotated at 50 rpm. At 0.5, 2, 8 (or 5) and 24 hours, 4 ml samples are removed and analyzed by a reverse phase HPLC method using a mobile phase of 55:45% v/v acetonitrile:0.05 M potassium dihydrogen phosphate (adjusted to pH 3.5) and UV detection at 220 nm.
  • the parameter “mean cumulative skin permeation rate” is provided in ⁇ g/cm 2 -hr and is calculated from the cumulative release as measured by in vitro experiments carried out with the Franz diffusion cell over the total time period of release, e.g., 168 hours, in ⁇ g/cm 2 divided by the hours corresponding to said total time period of release, e.g., 168 hours, taking into account a lag time of 24 hours.
  • the parameter “mean non-cumulative skin permeation rate” is provided in ⁇ g/cm 2 -hr and is calculated from the non-cumulative release of a certain sample interval as measured in a Franz diffusion cell in ⁇ g/cm 2 divided by the hours of said sample interval.
  • the parameter “cumulative release” is provided in ⁇ g/cm 2 and relates to the total amount released over the total time period of release, e.g., 168 hours, as measured in a Franz diffusion cell.
  • the value is a mean value of at least 3 experiments.
  • the parameter “non-cumulative release” is provided in ⁇ g/cm 2 and relates to the amount released in a sample interval at certain elapsed time within the total time period of release, e.g., hour 16 of release corresponding to a sample interval of 8 hours from hour 8 to hour 16 of release within 168 hours of total time period of release, as measured in a Franz diffusion cell.
  • the value is a mean value of at least 3 experiments.
  • the parameter “mean release rate” refers to the mean release rate in ⁇ g/hr over the period of administration (e.g., 7 days) by which the active agent permeates through the human skin into the blood system and is based on the AUC obtained over said period of administration in a clinical study.
  • the parameter “nominal mean release rate” refers to an assigned mean release rate determined by comparison with the commercial reference product BuTrans® which is applied for 7 days to the skin of the subjects and of which mean release rates are publicly available from the package insert.
  • the corresponding known nominal mean release rate of the 25 cm 2 area of release BuTrans® reference TTS containing 20 mg buprenorphine is 20 ⁇ g/hr.
  • the mean release rate is proportional to the size of the area of release of a TTS and may be used to distinguish TTS's by the dosage strength.
  • the BuTrans® TTS with half the size (i.e. 12.5 cm 2 area of release) and containing 10 mg of buprenorphine provides the known nominal mean release rate of 10 ⁇ g/hr.
  • the BuTrans® TTS with a size of 6.25 cm 2 area of release and containing 5 mg of buprenorphine provides the known nominal mean release rate of 5 ⁇ g/hr. Accordingly, it can be assumed that a corresponding TTS with a size of 50 cm 2 area of release and containing 40 mg of buprenorphine provides a nominal mean release rate of 40 ⁇ g/hr, and a corresponding TTS with a size of 37.5 cm 2 area of release and containing 30 mg of buprenorphine provides a nominal mean release rate of 30 ⁇ g/hr, and a corresponding TTS with a size of 18.75 cm 2 area of release and containing 15 mg of buprenorphine provides a nominal mean release rate of 15 ⁇ g/hr.
  • the nominal mean release rates are assigned to the TTSs in accordance with the invention by comparing the Franz diffusion cell skin permeation rates of the reference TTS BuTrans® with the Franz diffusion cell skin permeation rates of the TTS's in accordance with the
  • the meaning of “by applying to the skin of said patient for about 168 hours” corresponds to “by applying to the skin of said patient for about 7 days or for one week” and refers to a once a week exchange mode or dosing regimen.
  • about 96 hours correspond to 4 days
  • about 120 hours correspond to 5 days
  • about 144 hours correspond to 6 days.
  • applying to the skin of a patient for a certain period of time has the same meaning as “administration for a certain period of time”.
  • the term “patient” refers to a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
  • the term “active”, “active agent”, and the like, as well as the term “buprenorphine” refers to buprenorphine base or a pharmaceutically acceptable salt thereof. Unless otherwise indicated the amounts of buprenorphine in the TTS relate to the amount of buprenorphine before administration of the TTS. The amounts of buprenorphine in the TTS after administration are referred to as residual amounts.
  • values and ranges specifying the size of the area of release and the amount of buprenorphine contained in the transdermal therapeutic system are mean values of at least 3 measurements.
  • pharmacokinetic parameters refers to parameters describing the blood plasma curve, e.g. Cmax, AUCt and AUCINF obtained in a clinical study, e.g. by single-dose administration of the active agent TTS, e.g. the buprenorphine base TTS to healthy human subjects.
  • the pharmacokinetic performance of the TTSs in accordance with the invention can be deduced from the performance of the buprenorphine-containing microreservoir systems disclosed in the international application PCT/IB2012/002973 (see e.g. pages 69 to 100 of PCT/IB2012/002973).
  • pharmacokinetic parameters of the individual subjects are summarized in PCT/IB2012/002973 using arithmetic and geometric means, e.g. a mean Cmax, a mean AUCt and a mean AUCINF, and additional statistics such as the respective standard deviations and standard errors, the minimum value, the maximum value, and the middle value when the list of values is ranked (Median).
  • pharmacokinetic parameters e.g. the mean Cmax, the mean AUCt and the mean AUCINF refer to geometric mean values if not indicated otherwise. It cannot be precluded that the absolute mean values obtained for a certain TTS in a clinical study vary to a certain extend from study to study.
  • a reference formulation e.g. the commercial reference product BuTrans® or in the future any product based on the invention, may be used as internal standard.
  • a comparison of the AUC per area of release e.g. the mean AUCt per area of release of the respective reference product in the earlier and later study can be used to obtain a correction factor to take into account differences from study to study.
  • the commercial reference product BuTrans® provides an AUCt per area of release of 1624.53 pg ⁇ hr/ml-cm 2 .
  • microreservoir systems including deposits of buprenorphine and a carboxylic acid dispersed in a hydrophobic pressure sensitive adhesive layer provide a better performance in terms of the AUCt per area of release compared with the commercial product BuTrans®, i.e., Examples 1 and 2 of PCT/IB2012/002973 provide an AUCt per area of release of 2690.49 pg ⁇ hr/ml-cm 2 and 2746.86 pg ⁇ hr/ml-cm 2 , respectively.
  • the microreservoir systems thus provide an about 1.7-fold better performance than the commercial product BuTrans® in the same study.
  • Clinical studies according to the present invention refer to studies performed in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.
  • ICH International Conference for Harmonization of Clinical Trials
  • GCP global Good Clinical Practices
  • the term “healthy human subject” refers to a male or female subject with a body weight ranging from 55 kg to 100 kg and a body mass index (BM) ranging from 18 to 29 and normal physiological parameters, such as blood pressure, etc. Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria which are based on and in accordance with recommendations of the ICH.
  • BM body mass index
  • subject population refers to at least ten individual healthy human subjects.
  • geometric mean refers to the mean of the log transformed data backtransformed to the original scale.
  • the term “arithmetic mean” refers to the sum of all values of observation divided by the total number of observations.
  • the parameter “AUC” corresponds to the area under the plasma concentration-time curve.
  • the AUC value is proportional to the amount of active agent absorbed into the blood circulation in total and is hence a measure for the bioavailability.
  • the parameter “AUCt” is provided in pg ⁇ hr/ml and relates to the area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration and is calculated by the linear trapezoidal method.
  • the parameter “mean AUCt per area of release” is provided in pg ⁇ hr/ml-cm 2 and is calculated from the geometric mean AUCt as determined for a certain TTS in pg ⁇ hr/ml divided by the area of release of said TTS.
  • AUCINF AUCINF
  • the parameter “Cmax” is provided in pg/ml and and relates to the maximum observed blood plasma concentration of the active agent.
  • tmax is provided in hr and relates to the time point at which the Cmax value is reached.
  • tmax is the time point of the maximum observed plasma concentration.
  • the parameter “LambdaZ” is provided in 1/hr and relates to the apparent terminal phase rate constant, where LambdaZ is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase.
  • mean plasma concentration is provided in pg/ml and is a mean of the individual plasma concentrations of active agent, e.g. buprenorphine base, at each point in time.
  • bioequivalent is defined to refer to a TTS that provides geometric mean values of Cmax, AUCt, and AUCINF for buprenorphine, wherein the 90% confidence intervals estimated for the ratio test/reference fall within the range of 80.00% to 125.00%.
  • FIG. 1 depicts a microsopic picture of the matrix layer of Comparative Example 1.
  • FIG. 2A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Comparative Example 2.
  • FIG. 2B depicts a microscopic picture of the matrix layer of Comparative Example 2.
  • FIG. 3A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 3.
  • FIG. 3B depicts a microsopic picture of the matrix layer of Example 3.
  • FIG. 4A depicts a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 4.
  • FIG. 4B depicts a microscopic picture of the matrix layer of Example 4.
  • FIG. 5 depicts the mean in-vitro-dissolution of Comparative Example 1.
  • FIG. 6 depicts the mean in-vitro-dissolution of Comparative Example 2.
  • FIG. 7 depicts the mean in-vitro-dissolution of Example 3.
  • FIG. 8 depicts the mean in-vitro-dissolution of Example 4.
  • FIG. 9 depicts the mean non-cumulative skin permeation rates for Comparative Examples 1 and 2 and Norspan®.
  • FIG. 10 depicts the mean non-cumulative skin permeation rates for Examples 6, 7.1, 8 and BuTrans®.
  • FIG. 11 depicts the mean non-cumulative skin permeation rates for Examples 7.1, 7.2 and BuTrans®.
  • FIG. 12 depicts the mean non-cumulative skin permeation rates for Examples 7.2, 5.2 and BuTrans®.
  • FIG. 13 depicts the mean non-cumulative skin permeation rate of the of the transdermal therapeutic systems.
  • the area of release of the transdermal therapeutic system according to Example 5.2 is 14 cm 2 and the area of release for BuTrans® is 25 cm 2 .
  • the amount of buprenorphine base for Example 5.2 is 12.6 mg and the amount of buprenorphine base for BuTrans® is 20 mg.
  • a microreservoir system including deposits of buprenorphine and a carboxylic acid dispersed in a hydrophobic pressure-sensitive adhesive layer provides high overall release rates during a seven-day administration period, thereby allowing a reduction of size and drug content of the TTS in comparison to the commercial product Norspan®.
  • Such systems are described in the parallel patent application PCT/US2012/069242, corresponding to PCT/IB2012/002973, which is hereby incorporated by reference. In particular reference is made to Examples 1 to 4 in PCT/US2012/069242, corresponding to PCT/IB2012/002973. The manufacturing of several batches, however, shows a high variability in the performance. These systems provide high performance but are biphasic due to the dispersed deposits (1.
  • the production of a commercial transdermal product as disclosed herein requires a continuous coating and drying process to form the buprenorphine-containing pressure sensitive adhesive layer.
  • Such coating is usually accomplished with a sufficiently sized roller coater and attached drying compartment.
  • the buprenorphine-containing mixture to be coated is usually prepared batch wise, and is then stored for some time until the coater is ready to coat the mixture.
  • the time between the preparation of the mixture and the coating of the mixture in a normal production routine can be almost zero, if after mixing/homogenizing the mass will be transferred to the coating station and is coated directly and may be as long as several days, e.g. four to six days, to store the mixture during the time of a failure of the coater or a weekend or other reasons for a coating process interruption.
  • a microreservoir system as described herein including two phases, namely the deposits and the adhesive surrounding the deposits which may change over time due to the fusion of individual deposits forming larger deposits.
  • the deposits must be hindered in fusing during the stoning time between mixing and coating.
  • the shearing force applied to the coating mixture during coating in a roller coater is different and higher than on a laboratory scale coating technique like such as when using the Erichsen coater. But for commercial scale production, a roller coater is necessary to provide the necessary scale up and the necessary coating precision. However, the shear force in a roller coater causes additional fusion of the deposits. Thus the deposits must be hindered in fusing during the coating process using a roller coater.
  • the viscosity-increasing substance increases the viscosity of the deposits (inner phase) within the adhesive solution (outer phase) during the production and within the adhesive matrix (outer phase) during the storage of the dried buprenorphine-containing layer.
  • Useful viscosity-increasing substances may be selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, in particular soluble polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum.
  • a preferred viscosity-increasing substance is polyvinylpyrrolidone.
  • the viscosity-increasing substance is present in an amount of about 0.1% to about 7%, or in an amount of about 0.5% to about 5%, preferably in an amount of about 1% to about 4%, more preferably in an amount of about 2% to about 3% of the buprenorphine-containing pressure-sensitive adhesive layer.
  • the transdermal therapeutic system for the transdermal administration of buprenorphine comprises a buprenorphine-containing self-adhesive layer structure comprising
  • the polyvinylpyrrolidone having a K-Value of at least 5, at least 10, at least 15, at least 20, at least 50, or a K-Value of at least 80 is in particular beneficial in increasing the viscosity of the deposits (inner phase) within the adhesive solution (outer phase) during the production and within the adhesive matrix (outer phase) during the storage of the dried buprenorphine-containing layer.
  • the increase in viscosity si beneficial because the deposits are thereby hindered in fusing during the storing time between mixing and coating.
  • the buprenorphine-containing pressure-sensitive adhesive layer comprises an additional skin contact layer.
  • the TTS comprises in addition to the buprenorphine-containing self-adhesive layer structure attached thereto a larger active agent-free self-adhesive layer structure, e.g., a peripheral adhesive or overlying adhesive, for enhancing the adhesive properties of the overall transdermal therapeutic system.
  • Said active agent-free self-adhesive layer structure comprises also a backing layer. In certain embodiments, this additional layer is beige colored.
  • the active agent-free pressure-sensitive adhesive layer of polymer-based pressure-sensitive adhesive is e.g., based on polyacrylates or polysiloxanes.
  • the area of said second active agent-free self-adhesive layer structure adds to the overall size of the TTS but does not add to the area of release.
  • the pressure-sensitive adhesive in the active agent-containing and the active agent-free self-adhesive layer structures may be the same or different.
  • pressure-sensitive adhesives selected from the group of polyacrylate-based or polyisobutylene-based pressure-sensitive adhesives can be used, and polyacrylate based pressure-sensitive adhesives are preferred, in particular pressure-sensitive adhesives based on an acrylate-vinylacetate polymer, e.g., such as those available from Henkel under the tradename Duro Tak®, e.g., Duro Tak® 387 2051.
  • Such pressure-sensitive adhesives are provided in an organic solution of ethyl acetate and heptane.
  • Such pressure-sensitive adhesives provide a 180° Peel at 20 minutes of at least about 20 N/25 mm, and at 24 minutes of at least about 25 N/25 cm, and at one week of at least about 30 N/25 mm and a Loop tack of at least 15 N/25 mm 2 , or of at least 20 N/25 mm 2 , or of at least 22 N/25 mm 2 .
  • the TTS according to the invention comprises an analgesically effective amount of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts may be selected from those known in the art, such as the hydrochloride, sulphate, phosphate, tartrate, maleinate, oxalate, acetate and lactate salts.
  • the active agent is included in the form of buprenorphine base.
  • buprenorphine base does not exclude interactions, including complexation between the buprenorphine base and other ingredients of the buprenorphine-containing layer e.g. levulinic acid.
  • An analgesically effective amount may vary from about 1 mg to about 50 mg, in particular from about 2 mg to about 30 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt, or from about 2 mg to about 25 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
  • the TTS contains according to five different dosages from about 1 mg to about 4 mg, or from about 3.5 mg to about 8 mg, or from about 6.5 mg to about 16 mg, or from about 11.5 mg to about 24 mg, or from about 15 mg to about 32 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof, or the TTS contains according to five different dosages from about 1 mg to about 4.5 mg, or about 3 mg, or from about 4 mg to about 9 mg, or about 6 mg, or from about 8 mg to about 14 mg, or about 12 mg, or from about 15 mg to about 20 mg, or about 18 mg or from about 20 mg to about 28 mg, or about 24 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof.
  • Further dosages are provided by transdermal therapeutic systems containing smaller or greater amounts, e.g., from about 5.5 mg to about 13 mg of buprenorphine base or an equimolar amount of
  • the pressure-sensitive adhesives used for the present invention are polymer-based pressure-sensitive adhesives.
  • Such polymer-based pressure-sensitive adhesives may e.g., be based on polysiloxanes or polyisobutylenes.
  • polysiloxane-based pressure-sensitive adhesives are preferred.
  • Such polysiloxanes adhesives need, unlike other organic pressures-sensitive adhesives, no additives like antioxidants, stabilizers, plasticizers, catalysts or other potentially extractable ingredients.
  • pressure-sensitive adhesives provide for suitable tack for quick bonding to various skin types, including wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin of up to 7 days, a high degree of flexibility, a permeability to moisture, and compatibility to many actives and film-substrates. It is possible to provide them with sufficient amine resistance and therefore enhanced stability in the presence of amines.
  • Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin, a polysiloxane is prepared which for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups.
  • the dimethiconol content contributes to the viscous component of the visco-elastic behavior, and impacts the wetting and the spreadability properties of the adhesive.
  • the resin acts as a tackifying and reinforcing agent, and participates in the elastic component. The correct balance between dimethiconol and resin provides for the correct adhesive properties.
  • the adhesive strength of the polysiloxanes may be sufficient for the desired skin contact.
  • a plasticizer or a tackifying agent is incorporated into the formulation to improve the adhesive characteristics of the pressure-sensitive adhesive layer. It may be advantageous in an individual case to improve the tack by adding small amounts of tackifiers such as polyterpenes, rosin derivatives, or silicone oils.
  • the tackifying agent is a silicone oil (e.g., 360 Medical Fluid, available from Dow Corning Corporation, Midland, Mich.).
  • the pressure-sensitive adhesives are supplied and used in solvents like heptane, ethyl acetate or volatile silicone fluids.
  • solvents like heptane, ethyl acetate or volatile silicone fluids.
  • heptane is preferred.
  • the solids content is usually between 60 and 80%.
  • the preferred pressure-sensitive adhesives based on polysiloxanes in accordance with the invention are characterized by a solution viscosity at 25° C. and 60% solids content in heptane of more than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, in particular from about 350 mPa s to about 600 mPa s, more preferred from about 480 mPa s to about 550 mPa s, or most preferred of about 500 mPa s or alternatively from about 400 mPa s to about 480 mPa s, or most preferred of about 450 mPa s.
  • Theses may also be characterized by a complex viscosity at 0.01 rad/s at 30° C. of less than about 1 ⁇ 10 9 Poise, or from about 1 ⁇ 10 5 to about 9 ⁇ 10 8 Poise, or more preferred from about 1 ⁇ 10 5 to about 1 ⁇ 10 7 Poise, or most preferred about 5 ⁇ 10 6 Poise, or alternatively more preferred from about 2 ⁇ 10 7 to about 9 ⁇ 10 8 Poise, or most preferred about 1 ⁇ 10 8 Poise.
  • BIO-PSA 7 4301 Suitable pressure-sensitive adhesives based on polysiloxanes may be obtained from Dow Corning® BIO-PSA Standard Silicone Adhesives. Preferred are the BIO-PSA 7 4301 and BIO-PSA 7 4201 Silicone Adhesives. According to certain embodiments BIO-PSA 7 4301 is preferred and according to certain other embodiments BIO-PSA 7 4201 is preferred. To avoid excessive cold flow, BIO-PSA 7 4201 is preferred. BIO-PSA 4201 has a solution viscosity at 25° C. and about 60% solids content in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 1 ⁇ 10 8 Poise.
  • BIO-PSA 4301 has a solution viscosity at 25° C. and about 60% solids content in heptane of 500 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 5 ⁇ 10 6 Poise.
  • the pressure-sensitive adhesive layer of the TTS of the invention may further comprise in addition to the above mentioned ingredients a), b), c) and d), (i.e. the polymer-based pressure-sensitive adhesive, the buprenorphine, the viscosity-increasing substance/the polyvinylpyrrolidone and the carboxylic acid selected from the group of oleic acid, linoleic acid, linolenic acid and levulinic acid as described herein), other various excipients or additives, selected, for example, from the group of solubilizers, fillers, tackifiers, substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability, pH regulators, and preservatives.
  • the polymer-based pressure-sensitive adhesive i.e. the polymer-based pressure-sensitive adhesive, the buprenorphine, the viscosity-increasing substance/the polyvinylpyrrolidone and the carb
  • Substances which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability are known to the skilled worker and the substance appropriate for the respective active agents must—if necessary—be found by means of permeation studies.
  • Some examples are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamine, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nic
  • agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.
  • the TTS of the invention may additionally comprise according to certain embodiments (in which the pressure-sensitive adhesive layer comprises a) the polymer-based pressure-sensitive adhesive, b) the buprenorphine, c) the viscosity-increasing substance/the polyvinylpyrrolidone and d) levulinic acid or linolenic acid or mixtures of both as the carboxylic acid as described herein) oleic and linoleic acids as substances influencing the barrier properties of the stratum corneum in the sense of increasing the active agent permeability.
  • the pressure-sensitive adhesive layer comprises a) the polymer-based pressure-sensitive adhesive, b) the buprenorphine, c) the viscosity-increasing substance/the polyvinylpyrrolidone and d) levulinic acid or linolenic acid or mixtures of both as the carboxylic acid as described herein) oleic and linoleic acids as substances influencing the
  • Such substances as described in the previous paragraph may be included in a TTS and may be present in an amount of about 1% to about 10% by weight. In a preferred embodiment of the present invention such additional substances are however not necessary. According to an embodiment of the invention the TTS does not comprise such additional substances as mentioned in the previous paragraph.
  • the solubility of the drug can be further altered by the optional addition of an agent that increases the solubility of drug or inhibits drug crystallization in the transdermal composition, such as vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.
  • Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.
  • the anti-oxidant may be selected from the group consisting of tocopherol, esters thereof, e.g. ⁇ -tocopherol acetate, ascorbyl palmitate, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl gallate, preferably ascorbyl palmitate.
  • the antioxidant may be conveniently present in an amount of from about 0.01 to about 0.5%, e.g. 0.05 to 0.30, e.g. 0.18% or 0.2% of the buprenorphine-containing pressure-sensitive adhesive layer.
  • the buprenorphine-containing self-adhesive layer structure comprises a buprenorphine-impermeable backing layer, and a buprenorphine-containing pressure-sensitive adhesive layer coated thereon.
  • the buprenorphine-containing self-adhesive layer structure consists of these two elements.
  • the buprenorphine-containing pressure-sensitive adhesive layer may be coated at any dry weight, but is preferably coated at a dry weight of more than about 6 mg/cm 2 (about 60 g/m 2 ), or of more than about 8 mg/cm 2 (about 80 g/m 2 ), or ranging from about 6 mg/cm 2 (about 60 g/m 2 ) to about 14 mg/cm 2 (about 140 g/m 2 ), or from about 8 mg/cm 2 (about 80 g/m 2 ) to about 14 mg/cm 2 (about 140 g/m 2 ).
  • the dry weight is more than about 10 mg/cm 2 (about 100 g/m 2 ), or ranges from about 10 mg/cm 2 (about 100 g/m 2 ) to about 13 mg/cm 2 (about 130 g/m 2 ), or ranges from about 11.5 mg/cm 2 (about 115 g/m 2 ) to about 12.5 mg/cm 2 (about 125 g/m 2 ), or is specifically about 12 mg/cm 2 (about 120 g/m 2 ).
  • the dry buprenorphine-containing pressure-sensitive adhesive layer preferably contains buprenorphine base, but may contain an equimolar amount of a pharmaceutically acceptable salt. According to the invention, preferably more than 5%, or more than about 6%, or more than about 7%, or more than about 8%, or more than about 9%, or from about 6% to about 20%, or from about 7% to about 20%, or from about 8% to about 20%, or from about 9% to about 20%, or from about 6% to about 15%, or from about 7% to about 15%, or from about 8 to about 15%, or from about 9 to about 15% buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt based on the total dry weight of the dry buprenorphine-containing pressure-sensitive adhesive layer is contained in the dry buprenorphine-containing pressure-sensitive adhesive layer. In a specific embodiment, about 10% buprenorphine base is contained in the dry buprenorphine-containing pressure-sensitive adhesive layer.
  • the TTS contains in the pressure-sensitive adhesive layer more than about 0.55 mg/cm 2 , or more than about 0.6 mg/cm 2 , or more than about 0.7 mg/cm 2 , or more than about 0.8 mg/cm 2 , or more than about 0.9 mg/cm 2 , or more than about 1 mg/cm 2 , or more than about 1.1 mg/cm 2 , buprenorphine base, or from about 0.55 mg/cm 2 to about 2 mg/cm 2 , or from about 0.6 mg/cm 2 to about 2 mg/cm 2 , or from about 0.7 mg/cm 2 to about 2 mg/cm 2 , or from about 0.8 mg/cm 2 to about 2 mg/cm 2 , or from about 0.9 mg/cm 2 to about 2 mg/cm 2 , or from about 1 mg/cm 2 to about 2 mg/cm 2 , or from about 1.1 mg/cm 2 to about 2 mg/cm 2 buprenorphine base, or
  • a carboxylic acid is present.
  • the carboxylic acid may be selected from the group consisting of C 3 to C 24 carboxylic acids including oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, wherein levulinic acid is preferred.
  • a substance selected from the group consisting of alcohols and esters may be present.
  • the buprenorphine is in mixture with, e.g., dissolved in, the carboxylic acid, e.g., the levulinic acid, and this mixture, e.g., solution, is dispersed in the form of small deposits, e.g., droplets, in the matrix layer.
  • the carboxylic acid e.g., the levulinic acid
  • this mixture e.g., solution
  • a solubilizer with at least one acidic group is used in order to prevent the buprenorphine from crystallizing during the storage of the pharmaceutical form.
  • Buprenorphine and levulinic acid have an extremely low solubility in polysiloxanes. As a consequence of this, it is possible to solubilize buprenorphine in levulinic acid and to disperse this mixture in the form of small deposits (e.g. droplets) in a matrix layer prepared on the basis of polysiloxanes as described herein.
  • Levulinic acid is sparingly soluble in the organic solvents of the adhesives. Consequently, the liquid mixture of buprenorphine and levulinic acid can be dispersed in the solution of the adhesive, with the dispersion being retained following removal of the solvent. In a matrix layer of this kind, the solubility of the buprenorphine is dependent virtually only on the amount of the levulinic acid.
  • the amount of the dispersed mixture of buprenorphine, e.g., buprenorphine base, and the carboxylic acid, e.g., levulinic acid can be up to about 40% by weight, it being preferred not to exceed about 25% or about 20% by weight and ranges from about 15% to about 25%, or from about 15% to about 20%, or from about 17% to about 20%.
  • the size of the deposit, e.g., droplet (diameter) itself ought preferably not to exceed about 150 ⁇ m, or ranges from about 1 to about 150 ⁇ m, preferably from about 1 to about 50 ⁇ m, or from about 5 to about 50 ⁇ m, or from about 1 to about 25 ⁇ m or from about 5 to about 25 ⁇ m.
  • the preferred size is dependent, furthermore, on the thickness of the matrix layer.
  • the carboxylic acid e.g., the levulinic acid
  • the amount in the TTS becomes less as the time of application elapses, and leads to a reduction of the solubility of buprenorphine.
  • the decrease in the thermodynamic activity of buprenorphine due to depletion is compensated by the reduced drug solubility in the buprenorphine/levulinic acid deposits.
  • the dry buprenorphine-containing pressure-sensitive adhesive layer contains more than about 5%, or more than about 6%, or more than about 7%, or more than about 8%, or more than about 9%, or from about 6% to about 20%, or from about 7% to about 20%, or from about 8 to about 20%, or from about 9 to about 20%, or from about 5% to about 15%, or from about 6% to about 15%, or from about 6% to about 9%, or from about 9% to about 15% carboxylic acid, e.g., levulinic acid based on the total dry weight of the dry buprenorphine-containing pressure-sensitive adhesive layer.
  • carboxylic acid e.g., levulinic acid
  • the dry buprenorphine-containing pressure-sensitive adhesive layer contains from about 6% to about 11% levulinic acid, or from about 6% to about 9% or from about 9% to about 15% levulinic acid, or about 7% levulinic acid or about 10% levulinic acid.
  • the pressure-sensitive adhesive layer contains the same %-amount of levulinic acid and buprenorphine base or equimolar amounts of pharmaceutically acceptable salts.
  • the pressure-sensitive adhesive layer contains less %-amount of levulinic acid than it contains %-amount of buprenorphine base or equimolar amounts of pharmaceutically acceptable salts.
  • the pressure-sensitive adhesive layer contains more than about 9% to about 15% buprenorphine base and from about 6% to about 9% levulinic acid or from more than about 9% to about 15% buprenorphine base, and from about 9% to about 15% levulinic acid based on the total dry weight.
  • the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm 2 to about 14 mg/cm 2 , or from about 11.5 mg/cm 2 to about 12.5 mg/cm 2 , or is about 12 mg/cm 2 , and the dry pressure-sensitive adhesive layer contains from about 7% to about 13% or from about 8% to about 12%, or from about 9% to about 11% or about 10% buprenorphine base and from about 6% to about 8%, or about 7% levulinic acid.
  • the dry pressure-sensitive adhesive layer has a dry weight of about 12 mg/cm 2 and contains about 7% levulinic acid and about 10% buprenorphine base.
  • the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm 2 to about 14 mg/cm 2 , or from about 11.5 mg/cm 2 to about 12.5 mg/cm 2 , or is about 12 mg/cm 2 , and the dry pressure-sensitive adhesive layer contains from about 7% to about 13% or from about 8% to about 12%, or from about 9% to about 11% or about 10% buprenorphine base and from about 8 to about 12% or about 10% levulinic acid.
  • the dry pressure-sensitive adhesive layer has a dry weight of about 12 mg/cm 2 , and contains about 10% levulinic acid and about 10% buprenorphine base.
  • the TTS contains more than about 0.55 mg/cm 2 , or more than about 0.6 mg/cm 2 , or more than about 0.7 mg/cm 2 , or more than about 0.8 mg/cm 2 , or more than about 0.9 mg/cm 2 , or more than about 1 mg/cm 2 , or more than about 1.1 mg/cm 2 buprenorphine base or from about 0.6 mg/cm 2 to about 2 mg/cm 2 , or from about 0.7 mg/cm 2 to about 2 mg/cm 2 , or from about 0.8 mg/cm 2 to about 2 mg/cm 2 , or from about 0.9 mg/cm 2 to about 2 mg/cm 2 , or from about 1 mg/cm 2 to about 2 mg/cm 2 , or from about 1.1 mg/cm 2 to about 2 mg/cm 2 buprenorphine base or contains about 1.2 mg/cm 2 buprenorphine base or an equimolar amount of
  • buprenorphine base is preferred.
  • the pressure-sensitive adhesive layer contains the same amounts of levulinic acid and buprenorphine base.
  • the pressure-sensitive adhesive layer contains less levulinic acid than it contains buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof
  • the pressure-sensitive adhesives in the buprenorphine-containing layer and in the active agent-free layer are different, and the adhesive in the active agent-free layer is a pressure-sensitive adhesive based on polyacrylates.
  • the adhesive in the active agent-containing and the active agent-free layer are the same and are an amine-resistant pressure-sensitive adhesive based on polysiloxane.
  • the polysiloxane is a product of the condensation reaction of silanol endblocked polydimethylsiloxane with a silica resin and the residual silanol functionality is capped with trimethylsiloxy groups and characterized by a solution viscosity at 25° C.
  • the buprenorphine-containing pressure-sensitive adhesive layer is coated at a dry weight of about 12 mg/cm 2 and contains about 10% buprenorphine base and about 10% levulinic acid.
  • the area of release ranges from about 1 cm 2 to about 38 cm 2 , or is less than 25 cm 2 , or less than 22 cm 2 , or ranges from about 1.5 to about 25 cm 2 , or from about 1.5 to about 22 cm 2 , or from about 1.5 to about 20 cm 2 , or is about 3 cm 2 , or about 6 cm 2 , or about 10 cm 2 , or about 15 cm 2 or about 20 cm 2 .
  • the TTS contains from about 1 mg to about 32 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or from about 1 mg to about 28 mg, or from about 2 mg to about 25 mg, or from about 2 mg to about 24 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
  • the TTS in specific cases preferably contains
  • the TTS contains with respect to five dosage strengths a) to e) the following amounts of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides the following corresponding area of release ranges:
  • TTS providing the dosage strength between strength b) and c) provides from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and the area of release ranges from about 5 cm 2 to about 14 cm 2 , or from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and the area of release ranges from about 5 cm 2 to about 13.5 cm 2 .
  • the invention relates to a set of two (first and second, or second and third, or third and fourth, or fourth and fifth TTS, or any other combination of two of the five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three of the five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage strengths) or five (first to fifth TTS) different transdermal therapeutic systems in accordance with the invention, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm 2 to about 4.8 cm 2 , or from about 1.5 cm 2 to about 5.5 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 4.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm 2 to about 9.5 cm 2 , or from about 3 cm 2 to about 9 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 4 mg to about 9 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing
  • the set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 14 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.
  • the invention relates also to set of transdermal therapeutic systems, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm 2 to about 4.5 cm 2 , or from about 2 cm 2 to about 4 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 3.5 mg, or from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm 2 to about 9 cm 2 , or from about 4.5 cm 2 to about 7.5 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or from about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic
  • the set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 13.5 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.
  • the invention relates also to set of different transdermal therapeutic, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm 2 to about 4 cm 2 , or from about 2 cm 2 to about 3 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 3 mg, or from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 8 cm 2 , or from about 4.5 cm 2 to about 6 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 6 mg, or from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of
  • the set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by one or more further transdermal therapeutic system(s) which may provide smaller, greater or intermediate areas of release and amounts of buprenorphine compared with the five different transdermal therapeutic systems described above, preferably the set of two to five different transdermal therapeutic systems is expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 13.5 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, providing an intermediate transdermal therapeutic system between the second and the third transdermal therapeutic system.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by such a further transdermal therapeutic system.
  • transdermal therapeutic system selected from a set of transdermal therapeutic systems as described in the previous paragraphs is provided wherein buprenorphine is present in the form of buprenorphine base and wherein
  • the first transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 6.25 cm 2 and providing a nominal mean release rate of about 5 ⁇ g/hr over about 168 hours of administration
  • the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 12.5 cm 2 and providing a nominal mean release rate of about 10 ⁇ g/hr over about 168 hours of administration
  • the third transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 25 cm 2 and providing a nominal mean release rate of about 20 ⁇ g/hr over about 168 hours of administration
  • the fourth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 37.5 cm 2 and providing a nominal mean release rate of about 30 ⁇ g/hr over about 168 hours of administration
  • the invention relates to a transdermal therapeutic system described as first transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 6.25 cm 2 .
  • BuTrans® also known as Norspan®
  • the invention relates to a transdermal therapeutic system described as second transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 12.5 cm 2 .
  • BuTrans® also known as Norspan®
  • the invention relates to a transdermal therapeutic system described as third transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans®, also known as Norspan®, having an area of release of 25 cm 2 .
  • BuTrans® also known as Norspan®
  • the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:
  • a first transdermal therapeutic system providing a size of the area of release ranging from about 1 cm 2 to about 4.8 cm 2 and containing an amount of said buprenorphine from 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 ⁇ g/hr and/or providing a mean AUCt of more than 7,000 pg ⁇ hr/ml, preferably more than 8,000 pg ⁇ hr/ml, or of from more than 7,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml, or of from more than 8,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml over about 168 hours of administration after a single-dose administration to a subject population; a second transdermal therapeutic system providing a size of the area of release ranging from about 3 cm 2 to about 9.5 cm 2 and containing an amount of said buprenorphine from
  • the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:
  • a first transdermal therapeutic system providing a size of the area of release ranging from about 1 cm 2 to about 4.5 cm 2 and containing an amount of said buprenorphine from 1 mg to about 4 mg, or from 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 ⁇ g/hr and/or providing a mean AUCt of more than 7,000 pg ⁇ hr/ml, preferably more than 8,000 pg ⁇ hr/ml, or of from more than 7,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml, or of from more than 8,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml over about 168 hours of administration after a single-dose administration to a subject population; a second transdermal therapeutic system providing a size of the area of release ranging from about 3 cm 2 to about 9 cm 2 and containing an amount
  • the invention relates a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:
  • a first transdermal therapeutic system providing a size of the area of release ranging from about 2.5 cm 2 to about 4 cm 2 and containing an amount of said buprenorphine from 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 ⁇ g/hr and/or providing a mean AUCt of more than 7,000 pg ⁇ hr/ml, preferably more than 8,000 pg ⁇ hr/ml, or of from more than 7,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml, or of from more than 8,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml over about 168 hours of administration after a single-dose administration to a subject population; a second transdermal therapeutic system providing a size of the area of release ranging from about 5 cm 2 to about 8 cm 2 and containing an amount of said buprenorphine from about
  • the TTS is further characterized by the skin permeation rate determined by in vitro experiments carried out with the Franz diffusion cell (e.g., a 9 ml Franz diffusion cell), using human split thickness skin. Skin from cosmetic surgeries (female breast, date of birth 1989) can be used. A dermatone is used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis, in accordance with the OECD Guideline (adopted Apr. 13, 2004). Due to the prolonged test (168 hours) 800 ⁇ m skin is used instead of the recommended 200 to 400 ⁇ m skin.
  • the receptor medium used is a phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent is used at a temperature of 32 ⁇ 1°.
  • Example formulations with an area of 1.163 cm 2 are punched from laminates, and in the present examples are each tested against 1.163 cm 2 samples of the commercial product Norspan®. The concentrations of buprenorphine in the acceptor medium of the Franz cell are measured.
  • the TTS according to the invention provides a mean cumulative skin permeation rate of more than about 1.3 ⁇ g/cm 2 -hr, or more than about 1.5 ⁇ g/cm 2 -hr or more than about 1.7 ⁇ g/cm 2 -hr over a 168 hours test, or of more than about 2 ⁇ g/cm 2 -hr over a 168 hours test, or of more than about 2.5 ⁇ g/cm 2 -hr over a 168 hours test, or of more than 2.7 ⁇ g/cm 2 -hr over a 168 hours test, or of more than about 3 ⁇ g/cm 2 -hr over a 168 hours test, or from about 1.3 ⁇ g/cm 2 -hr to about 4 ⁇ g/cm 2 -hr, or from about 1.7 ⁇ g/cm 2 -hr to about 4 ⁇ g/cm 2 -hr, or from about 2 ⁇ g/cm 2 -hr to
  • the TTS provides a cumulative release as measured in a Franz diffusion cell as mentioned above of about 220 ⁇ g/cm 2 to about 640 ⁇ g/cm 2 over a time period of 168 hours, or of about 400 ⁇ g/cm 2 to about 640 ⁇ g/cm 2 , or of about 450 ⁇ g/cm 2 to about 640 ⁇ g/cm 2 , or of about 500 ⁇ g/cm 2 to about 640 ⁇ g/cm 2 , or of about 600 ⁇ g/cm 2 to about 640 ⁇ g/cm 2 over a time period of 168 hours.
  • BuTrans® provides a cumulative release of about 250.7 ⁇ g/cm 2 in said test.
  • comparable skin permeation rates are measured using the 25 cm 2 BuTrans® TTS including 20 mg buprenorphine base and a TTS of an example in accordance with the invention with an area of 14 cm 2 and including 12.6 mg buprenorphine base. This corresponds to about a 44% size reduction in area of release and a reduction of about 50% in the amount of used buprenorphine base.
  • the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of
  • the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of
  • the TTS provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell of
  • BuTrans® provides a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell in the same setting of
  • the transdermal therapeutic system in accordance with the invention and as described above in detail is for use in a method of treating pain.
  • the Method comprises in particular the application of the TTS for about 168 hours (corresponding to 7 days or one week) on the skin of a patient.
  • the TTS can be applied for more than about 96 hours corresponding to more than 4 days, or about 120 hours corresponding to 5 days and about 144 hours corresponding to 6 days.
  • the application for about 168 hours is preferred.
  • the invention relates to a method of treatment wherein a set of five different transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1.5 cm 2 to about 5.5 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 4.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm 2 to about 9 cm 2 and contains an amount of said buprenorphine from about 4 mg to about 9 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides
  • the invention relates also to set of transdermal therapeutic systems, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm 2 to about 4 cm 2 and contains an amount of said buprenorphine from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm 2 to about 7.5 cm 2 and contains an amount of said buprenorphine from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides
  • the invention relates also to set of different transdermal therapeutic, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm 2 to about 3 cm 2 and contains an amount of said buprenorphine from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm 2 to about 6 cm 2 and contains an amount of said buprenorphine from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides
  • the invention relates to a method of treating pain in a patient wherein said patient is treated with one appropriately selected TTS from a set of two (first and second, or second and third, or third and fourth, or fourth and fifth TTS, or any other combination of two of the five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three of the five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage strengths) or five (first to fifth TTS) different transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm 2 to about 4.8 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 ⁇ g/hr, or of from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm 2 to about 9.5 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equi
  • the set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 14 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 ⁇ g/hr, or of from about 12 to about 18 ⁇ g/hr or from about 13.5 to about 16.5 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 15 ⁇ g/hr over about 168 hours of administration.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system.
  • the invention relates also to a set of transdermal therapeutic systems, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm 2 to about 4.5 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 4 mg, or from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 ⁇ g/hr, or of from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm 2 to about 9 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg, or
  • the set of two to five different transdermal therapeutic systems in accordance with this paragraph can be expanded by a further transdermal therapeutic system which provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 13.5 cm 2 and contains an amount of said buprenorphine from about 5.5 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 11 ⁇ g/hr, or of from about 12 to about 18 ⁇ g/hr or from about 13.5 to about 16.5 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 15 ⁇ g/hr over about 168 hours of administration.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system.
  • one of the transdermal therapeutic systems of the set of two to five different transdermal therapeutic systems can be replaced by said transdermal therapeutic system.
  • the invention relates also to set of different transdermal therapeutic, wherein:
  • the first transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm 2 to about 4 cm 2 and contains an amount of said buprenorphine from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 ⁇ g/hr, or of from about 2.5 to about 7.5 ⁇ g/hr or from about 4 to about 6 ⁇ g/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 ⁇ g/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm 2 to about 8 cm 2 and contains an amount of said buprenorphine from about 3.5 mg to about 6 mg buprenorphine base or an equimolar
  • the invention relates to a method of treating pain in a patient wherein a patient is treated with one appropriately selected TTS from a set of different transdermal therapeutic systems as described in the previous paragraphs, wherein:
  • the first transdermal therapeutic system provides a mean AUCt of more than 7,000 pg ⁇ hr/ml, preferably more than 8,000 pg ⁇ hr/ml, or of from more than 7,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml, or of from more than 8,000 pg ⁇ hr/ml to about 16,000 pg ⁇ hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the second transdermal therapeutic system provides a mean AUCt of more than 14,000 pg ⁇ hr/ml, preferably of more than 16,000 pg ⁇ hr/ml, or of from more than 14,000 pg ⁇ hr/ml to about 32,000 pg ⁇ hr/ml, or of from more than 16,000 pg ⁇ hr/ml to about 32,000 pg ⁇ hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the third trans
  • the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system provides a mean AUCt per area of release of more than 1,700 pg ⁇ hr/ml-cm 2 , or of more than 1,900 pg ⁇ hr/ml-cm 2 , or of more than 2,300 pg ⁇ hr/ml-cm 2 over about 168 hours of administration after a single-dose administration to a subject population or provides a mean AUCt per area of release of from more than 1,700 pg ⁇ hr/ml-cm 2 to about 5,000 pg ⁇ hr/ml-cm 2 , or of from more than 1,900 pg ⁇ hr/ml-cm 2 to about 5,000 pg ⁇ hr/ml-cm 2 , or of from more than 2,300 pg ⁇ hr/ml-cm 2 to about 5,000 pg ⁇ hr/ml-cm 2 over about 168 hours of administration after
  • the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system provides an arithmetic mean tmax of from about 60 hr to about 120 hr, preferably from about 66 hr to less than 108 hr, or from about 72 hr to about 96 hr after a single-dose administration to a subject population.
  • the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising the steps of
  • step 1 of said method of manufacture preferably buprenorphine base, levulinic acid and polyvinylpyrrolidone are used and are dissolved in ethanol and subsequently suspended in a polymer-based pressure-sensitive adhesive based on polysiloxane in heptane to provide the buprenorphine-containing adhesive mixture or emulsion.
  • the homogenization provides homogeneous mixtures and helps to provide narrower deposit size distributions.
  • a viscosity-increasing substance in the deposits the size and size distribution of the deposits remains during the time between homogenization and coating and during coating.
  • the process is suitable for a commercial production skale.
  • Homogenization speeds of e.g. at least 1000 rpm can be applied with a homogenizer, e.g. with a rotor-stator homogenizer (e.g. BECOMIX RW 30 Ex).
  • a homogenizer e.g. with a rotor-stator homogenizer (e.g. BECOMIX RW 30 Ex).
  • the homogenization speed is from about 1500 rpm to about 3800 rpm, or from about 1500 rpm to about 3000 rpm.
  • the preferred homogenization speed is about 2000 rpm.
  • composition of the buprenorphine base-containing adhesive mixture is summarized in Table 1 below.
  • buprenorphine in a suitable vessel, 7.00 g of buprenorphine were dissolved in 4.90 g of levulinic acid, 3.80 g of Ethanol and 0.175 g of Ascobyl palmitate by stirring until the buprenorphine was completely dissolved forming the buprenorphine solution.
  • 79.57 g of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 4.56 g of heptane were added. The mixture was stirred to give 100.01 g of a buprenorphine-containing adhesive mixture with 7% of buprenorphine, with a solids content of 70% (buprenorphine base-containing adhesive mixture).
  • the buprenorphine base-containing adhesive mixture was coated within less than 24 h after the buprenorphine containing mixture was finished on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying at approximately 50° C. for approx. 8 minutes.
  • a polyethylene terephthalate film e.g. Scotchpak from 3M
  • the coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of approx. 120 g/m 2 . This results in the 10% by weight of buprenorphine base, and 7% by weight of levulinic acid in this matrix layer.
  • the dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 ⁇ m) to provide the buprenorphine-containing self-adhesive layer structure.
  • PET polyethylenterephthalate
  • FIG. 1 shows a microscopic picture of the matrix layer of Example 1.
  • composition of the buprenorphine base-containing adhesive mixture is summarized in Table 2 below.
  • the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate film (e.g., Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station.
  • the solvent was removed by drying at approximately 30-50° C.
  • the matrix layer remained within the drying tunnel at approx. 8 minutes.
  • the coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of 120 g/m 2 . This results in the 10% by weight of buprenorphine base and 7% by weight of levulinic acid in this matrix layer.
  • the dried film was laminated with the backing layer (e.g: polyethylenterephthalate (PET) film 19 ⁇ m) to provide the buprenorphine-containing self-adhesive layer structure.
  • PET polyethylenterephthalate
  • TTS The individual systems
  • a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape).
  • This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes).
  • the overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.
  • FIG. 2A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Comparative Example 2
  • FIG. 2B shows a microscopic picture of the matrix layer of Comparative Example 2.
  • composition of the buprenorphine base-containing adhesive mixture is summarized in Table 3 below.
  • a suitable vessel 37.86 g of polyvinylpyrrolidone and 113.57 g of ethanol were dissolved to form a 25% PVP pre-solution.
  • the prescribed amount of the PVP pre-solution, Levulinic acid and Ascorbyl palmitate were suspended with stirring and afterwards the remaining part of Ethanol and the Buprenorphine was added to form a buprenorphine containing solution by stirring until a solution is formed.
  • 82.50 g of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 1.74 g of heptane were added. The mixture was stirred to give 109.67 g of a buprenorphine-containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68% (buprenorphine base-containing adhesive mixture).
  • the buprenorphine base-containing adhesive mixture was coated within less than 24 h after the buprenorphine containing mixture was finished on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying in a first step at room temperature for approximately 10 minutes, followed by a second drying step at approximately 60° C. for approx. 10 minutes.
  • a polyethylene terephthalate film e.g. Scotchpak from 3M
  • the coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of approx. 120 g/m 2 . This results in the 10% by weight of buprenorphine base, 7% by weight of levulinic acid and 2.5% by weight of polyvinylpyrrolidone in this matrix layer.
  • the dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 ⁇ m) to provide the buprenorphine-containing self-adhesive layer structure.
  • PET polyethylenterephthalate
  • FIG. 3 shows a microscopic picture of the matrix layer of Example 3.
  • FIG. 3A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 3
  • FIG. 3B shows a microscopic picture of the matrix layer of Example 3.
  • composition of the buprenorphine base-containing adhesive mixture is summarized in Table 4 below.
  • a 10 l vessel 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanol were dissolved to form a 25% PVP pre-solution.
  • a homogenizing/mixing vessel Becomix Lab mixer RW 30 Ex, 1.368 kg of PVP pre-solution, 0.958 kg levulinic acid, 0.027 kg of Ascorbyl palmitate and the main part of 0.912 kg of Ethanol were suspended by stirring.
  • the prescribed amount of buprenorphine was weighed and added to the homogenizing/mixing vessel followed by rinsing the weighing container used for buprenorphine with the remaining part of Ethanol.
  • the mixture was kept under stirring for at least 1 h until a buprenorphine containing solution was formed.
  • 15.048 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 0.319 kg of n-heptane were added to the mixing/homogenizing vessel The mixture was stirred for at least 2 h until a buprenorphine-containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68% (buprenorphine base-containing adhesive mixture) was formed.
  • the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate foil (e.g. Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station.
  • the solvent was removed by drying at approximately 30-50° C.
  • the matrix layer remained within the drying tunnel at approx. 8 minutes.
  • the coating thickness was chosen such that removal of the solvents results in a coating weight of the matrix layer of 120 g/m 2 . This results in the 10% by weight of buprenorphine base and 7% by weight of levulinic acid and 2.5% by weight of polyvinylpyrrolidone in this matrix layer.
  • the dried film was laminated with the backing layer (e.g. polyethylenterephthalate (PET) foil 19 ⁇ m) to provide the buprenorphine-containing self-adhesive layer structure.
  • PET polyethylenterephthalate
  • TTS The individual systems
  • a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape).
  • a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape).
  • the overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.
  • FIG. 4A shows a microscopic picture of the buprenorphine base-containing adhesive mixture of Example 4
  • FIG. 4B shows a microscopic picture of the matrix layer of Example 4.
  • the composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 4. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 2000 rpm-2500 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).
  • a polyethylene terephthalate film e.g. Scotchpak from 3M.
  • Example 5 matrix layer [g/m 2 ]
  • Example 5.1 120 Example 5.2 90
  • composition of the buprenorphine base-containing adhesive mixture is summarized in Table 6 below.
  • a 10 l vessel 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanol were dissolved to form a 25% PVP pre-solution.
  • a homogenizing/mixing vessel Becomix Lab mixer RW 30 Ex, 0.716 kg of PVP pre-solution, 1.002 kg levulinic acid, 0.029 kg of Ascorbyl palmitate and the main part of 0.478 kg of Ethanol were suspended by stirring.
  • the prescribed amount of buprenorphine was weighed and added to the homogenizing/mixing vessel followed by rinsing the weighing container used for buprenorphine with the remaining part of Ethanol.
  • the mixture was kept under stirring for at least 1 h until a buprenorphine containing solution was formed.
  • 15.997 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 0.346 kg of n-heptane were added to the mixing/homogenizing vessel
  • the mixture was stirred for at least 2 h until a buprenorphine-containing adhesive mixture with 7.2% of buprenorphine, with a solids content of 72% (buprenorphine base-containing adhesive mixture) was formed.
  • the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station.
  • the solvent was removed by drying at approximately 30-50° C.
  • the matrix layer remained within the drying tunnel at approx. 8 minutes.
  • the coating thickness was chosen such that removal of the solvents results in a specific coating weight of of 120 g/m 2 .
  • TTS The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure.
  • a TTS as described above can be provided with a further self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably skin-colored backing layer. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes).
  • the overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.
  • the composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 6. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 2000 rpm-2500 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).
  • a polyethylene terephthalate film e.g. Scotchpak from 3M.
  • Example 7 TABLE 7 Coating weight of the Example 7 matrix layer [g/m 2 ] Example 7.1 120
  • the composition of the buprenorphine base-containing adhesive mixture and the process of manufacture was as described for Example 6. After the mixing step forming a buprenorphine containing mixture, the buprenorphine base-containing adhesive mixture was additionally homogenized at a homogenizing speed of 3500 rpm-4000 rpm before coated on a polyethylene terephthalate film (e.g. Scotchpak from 3M).
  • a polyethylene terephthalate film e.g. Scotchpak from 3M.
  • Example 9 the in-vitro dissolution of Comparative Examples 1 and 2, and Examples 3 and 4 were determined using the rotating cylinder apparatus of the Ph Eur/USP.
  • the back of the TTS is affixed to the cylinder element using double sided adhesive tape.
  • the cylinder is lowered into the dissolution medium (600 ml, degassed 0.9% sodium chloride solution at 32° C.) and rotated at 50 rpm.
  • Example 10 the in-vitro skin permeation rates of Comparative Examples 1 and 2 and Norspan® were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 9 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female breast, date of birth 1987) was used. A dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all examples Comparative Examples 1 and 2 and the commercial product Norspan®. Diecuts with an area of 1.163 cm 2 were punched from Comparative Examples 1 and 2, and were each tested against diecuts of the commercial product Norspan®.
  • the concentrations of buprenorphine in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32 ⁇ 1° C. were measured. The results are shown in Tables 9.1 to 9.4 and FIG. 9 .
  • Example 11 the in-vitro skin permeation rates of Examples 5 to 8 and BuTrans® were determined by in vitro experiments in accordance with the OECD Guideline (adopted Apr. 13, 2004) carried out with a 9 ml Franz diffusion cell.
  • Split thickness human skin from cosmetic surgeries female sample of abdomen region, date of birth 1983
  • a dermatome was used to prepare skin to a thickness of 800 ⁇ m, with an intact epidermis for all examples 5 to 8 and the commercial product BuTrans®. Diecuts with an area of 1.163 cm 2 were punched from examples 5 to 8, and were each tested against diecuts of the commercial product BuTrans®.
  • the concentrations of buprenorphine in the receptor medium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent) at a temperature of 32 ⁇ 1° C. were measured. The results are shown in Tables 10.1 to 10.7 and FIGS. 10 to 13 .
US14/772,474 2013-06-04 2014-06-04 Transdermal delivery system Abandoned US20160008294A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/772,474 US20160008294A1 (en) 2013-06-04 2014-06-04 Transdermal delivery system

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361830975P 2013-06-04 2013-06-04
PCT/EP2014/061567 WO2014195352A1 (en) 2013-06-04 2014-06-04 Transdermal delivery system
US14/772,474 US20160008294A1 (en) 2013-06-04 2014-06-04 Transdermal delivery system

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/061567 A-371-Of-International WO2014195352A1 (en) 2013-06-04 2014-06-04 Transdermal delivery system

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/970,641 Continuation US20160101100A1 (en) 2013-06-04 2015-12-16 Transdermal delivery system
US15/414,138 Continuation US20170128384A1 (en) 2013-06-04 2017-01-24 Buprenorphine transdermal delivery system

Publications (1)

Publication Number Publication Date
US20160008294A1 true US20160008294A1 (en) 2016-01-14

Family

ID=51022809

Family Applications (6)

Application Number Title Priority Date Filing Date
US14/772,474 Abandoned US20160008294A1 (en) 2013-06-04 2014-06-04 Transdermal delivery system
US14/970,641 Abandoned US20160101100A1 (en) 2013-06-04 2015-12-16 Transdermal delivery system
US15/414,138 Abandoned US20170128384A1 (en) 2013-06-04 2017-01-24 Buprenorphine transdermal delivery system
US15/820,978 Abandoned US20180092905A1 (en) 2013-06-04 2017-11-22 Transdermal delivery system
US16/844,767 Active US11529345B2 (en) 2013-06-04 2020-04-09 Buprenorphine transdermal delivery system
US16/905,476 Abandoned US20200316055A1 (en) 2013-06-04 2020-06-18 Transdermal delivery system

Family Applications After (5)

Application Number Title Priority Date Filing Date
US14/970,641 Abandoned US20160101100A1 (en) 2013-06-04 2015-12-16 Transdermal delivery system
US15/414,138 Abandoned US20170128384A1 (en) 2013-06-04 2017-01-24 Buprenorphine transdermal delivery system
US15/820,978 Abandoned US20180092905A1 (en) 2013-06-04 2017-11-22 Transdermal delivery system
US16/844,767 Active US11529345B2 (en) 2013-06-04 2020-04-09 Buprenorphine transdermal delivery system
US16/905,476 Abandoned US20200316055A1 (en) 2013-06-04 2020-06-18 Transdermal delivery system

Country Status (34)

Country Link
US (6) US20160008294A1 (ko)
EP (2) EP2810646B1 (ko)
JP (1) JP6559121B2 (ko)
KR (1) KR102302505B1 (ko)
CN (1) CN105377245B (ko)
AP (1) AP2015008920A0 (ko)
AR (1) AR096521A1 (ko)
AU (1) AU2014276910B2 (ko)
BR (1) BR112015029920A2 (ko)
CA (1) CA2914425C (ko)
CL (1) CL2015003377A1 (ko)
CR (1) CR20150647A (ko)
CY (1) CY1118054T1 (ko)
DE (1) DE112014002664T5 (ko)
DK (1) DK2810646T3 (ko)
EA (1) EA201592246A1 (ko)
ES (1) ES2599802T3 (ko)
GB (1) GB2529789A (ko)
HK (2) HK1204766A1 (ko)
HU (1) HUE031662T2 (ko)
LT (1) LT2810646T (ko)
MA (1) MA38698B1 (ko)
MX (1) MX362614B (ko)
NI (1) NI201500170A (ko)
PE (1) PE20160002A1 (ko)
PH (1) PH12015502550A1 (ko)
PL (1) PL2810646T3 (ko)
PT (1) PT2810646T (ko)
SG (1) SG11201509218SA (ko)
SI (1) SI2810646T1 (ko)
TN (1) TN2015000493A1 (ko)
TW (1) TW201509416A (ko)
WO (1) WO2014195352A1 (ko)
ZA (1) ZA201509309B (ko)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9549903B2 (en) 2011-12-12 2017-01-24 Purdue Pharma L.P. Transdermal delivery system comprising buprenorphine
US20180162371A1 (en) * 2016-12-14 2018-06-14 Bendix Commercial Vehicle Systems Llc Front End Motor-Generator System and Hybrid Electric Vehicle Operating Method
US20180221297A1 (en) * 2017-02-03 2018-08-09 Kirti H. Valia System and Method for Improving Adhesion of Transdermal Delivery Devices
CN113952319A (zh) * 2021-11-30 2022-01-21 烟台大学 一种含丁丙诺啡的骨架型透皮贴剂及其制备方法
US11529345B2 (en) 2013-06-04 2022-12-20 Lts Lohmann Therapie-Systeme Ag Buprenorphine transdermal delivery system

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006054731B4 (de) 2006-11-21 2013-02-28 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System zur Verabreichung des Wirkstoffs Buprenorphin und Verwendung desselben in der Schmerztherapie
TW201431570A (zh) 2012-11-22 2014-08-16 Ucb Pharma Gmbh 用於經皮投服羅替戈汀（Ｒｏｔｉｇｏｔｉｎｅ）之多天式貼片
CA2916183C (en) 2013-07-03 2022-03-29 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system with electronic component
US11426359B2 (en) 2014-05-20 2022-08-30 Lts Lohmann Therapie-Systeme Ag Method for adjusting the release of active agent in a transdermal delivery system
CN106456566B (zh) 2014-05-20 2020-06-16 Lts勒曼治疗系统股份公司 含罗替戈汀的经皮递送系统
US11752110B2 (en) 2014-05-20 2023-09-12 Lts Lohmann Therapie-Systeme Ag Transdermal delivery system including an interface mediator
MA45902A (fr) 2015-03-10 2019-06-19 Rhodes Tech Sel d'acã‰tate de bruprã‰norphine et procã‰dã‰s pour la prã‰paration de bruprã‰norphine
EP3349737A4 (en) * 2015-09-14 2019-05-15 Amneal Pharmaceuticals LLC SYSTEM FOR TRANSDERING
AR102214A1 (es) * 2015-10-08 2017-02-15 Amarin Tech S A Un dispositivo para la administración transdermal de buprenorfina
RU2764443C2 (ru) 2016-12-20 2022-01-17 Лтс Ломанн Терапи-Систем Аг Трансдермальная терапевтическая система, содержащая азенапин и полисилоксан или полиизобутилен
EP3558275A1 (en) 2016-12-20 2019-10-30 LTS Lohmann Therapie-Systeme AG Transdermal therapeutic system containing asenapine
JP2020525545A (ja) 2017-06-26 2020-08-27 エルテーエス ローマン テラピー−ジステーメ アーゲー アセナピンおよびシリコーンアクリルハイブリッドポリマーを含有する経皮治療システム
US20200246276A1 (en) 2017-09-04 2020-08-06 Lts Lohmann Therapie-Systeme Ag Transdermal delivery system including an emulsifier
WO2019064026A1 (en) 2017-09-29 2019-04-04 Orexo Ab NEW PHARMACEUTICAL COMPOSITIONS
WO2019166572A1 (en) 2018-02-28 2019-09-06 Pharming Intellectual Property B.V. Pharmaceutical system for transdermal administration of a c1 -esterase inhibitor
BR112020017484A2 (pt) * 2018-03-13 2020-12-22 Lts Lohmann Therapie-Systeme Ag Sistema terapêutico transdérmico para a administração transdérmica de buprenorfina compreendendo um polímero híbrido de acrílico e silicone
WO2019209940A1 (en) * 2018-04-25 2019-10-31 Shinkei Therapeutics Llc Tetrabenazine transdermal delivery device
KR20210022656A (ko) 2018-06-20 2021-03-03 에르테에스 로만 테라피-시스테메 아게 아세나핀을 함유하는 경피 치료 시스템
GB201904767D0 (en) 2019-04-04 2019-05-22 Orexo Ab New pharmaceutical compositions

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6365178B1 (en) * 1996-09-06 2002-04-02 Watson Pharmaceuticals, Inc. Method of making pressure sensitive adhesive matrix patches for transdermal drug delivery using hydrophilic salts of drugs and hydrophobic pressure sensitive adhesive dispersions
US20040202710A1 (en) * 1999-07-02 2004-10-14 Walter Muller Microreservoir system based on polysiloxanes and ambiphilic solvents
US20040202707A1 (en) * 2003-04-14 2004-10-14 Walter Muller Therapeutic patch
US20050232964A1 (en) * 2004-04-14 2005-10-20 Fennimore Roy R Jr Use of antioxidants to prevent oxidation and reduce drug degradation in drug eluting medical devices
US20100119585A1 (en) * 2006-11-21 2010-05-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for administering the active substance buprenorphine
US20110288112A1 (en) * 1997-02-24 2011-11-24 Reder Robert F Method of Providing Sustained Analgesia With Buprenorphine

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1136214A (en) 1965-06-15 1968-12-11 Reckitt & Sons Ltd Thebaine and oripavine derivatives
US3474101A (en) 1960-09-05 1969-10-21 Reckitt & Sons Ltd Thebaine and oripavine derivatives
US4588580B2 (en) 1984-07-23 1999-02-16 Alaz Corp Transdermal administration of fentanyl and device therefor
US4806341A (en) 1985-02-25 1989-02-21 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration
CA2002299A1 (en) 1988-11-10 1990-05-10 Eugene G. Drust Compositions for the transdermal delivery of buprenorphine salts
US5788983A (en) 1989-04-03 1998-08-04 Rutgers, The State University Of New Jersey Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes
US5240711A (en) 1989-11-29 1993-08-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system comprising as active component buprenorphine
DE3939376C1 (ko) 1989-11-29 1991-05-08 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg, 5450 Neuwied, De
US5069909A (en) 1990-06-20 1991-12-03 Cygnus Therapeutic Systems Transdermal administration of buprenorphine
DE4446600A1 (de) 1994-12-24 1996-06-27 Lohmann Therapie Syst Lts Transdermale Resorption von Wirkstoffen aus unterkühlten Schmelzen
DE19738855C2 (de) * 1997-09-05 2001-01-04 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit haftklebender Reservoirschicht und unidirektional elastischer Rückschicht
DE19922662C1 (de) 1999-05-18 2000-12-28 Sanol Arznei Schwarz Gmbh Transdermales therapeutisches System (TTS) Tolterodin enthaltend
DE19958554C2 (de) 1999-07-02 2002-06-13 Lohmann Therapie Syst Lts Mikroreservoirsystem auf Basis von Polysiloxanen und ambiphilen Lösemitteln und ihre Herstellung
MEP48308A (en) 2000-02-08 2011-05-10 Euro Celtique Sa Tamper-resistant oral opioid agonist formulations
US6682757B1 (en) 2000-11-16 2004-01-27 Euro-Celtique, S.A. Titratable dosage transdermal delivery system
JP2004525960A (ja) 2001-02-16 2004-08-26 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 尿失禁、特に切迫尿失禁の治療用経皮デリバリーディバイスの製造にブプレノルフィンを使用する方法
DE10141651B4 (de) * 2001-08-24 2007-02-15 Lts Lohmann Therapie-Systeme Ag Transdermales Therapeutisches System (TTS) mit dem Wirkstoff Fentanyl und Verfahren zu seiner Herstellung
WO2003043657A1 (en) 2001-11-19 2003-05-30 Control Delivery Systems, Inc. Topical delivery of codrugs
US20050118245A1 (en) 2002-03-27 2005-06-02 Wilsmann Klaus M. Assembled unit consisting of individually separable, transdermal, therapeutic systems
DE10213772A1 (de) 2002-03-27 2003-10-09 Gruenenthal Gmbh Zusammenhängende Einheit aus vereinzelbaren transdermalen therapeutischen Systemen
US20050191340A1 (en) 2002-08-09 2005-09-01 Gruenenthal Gmbh Opioid-receptor antagonists in transdermal systems having buprenorphine
AU2003283055A1 (en) 2002-08-09 2004-02-25 Grunenthal Gmbh Opioid-receptor antagonists in transdermal systems having buprenorphine
US7270830B2 (en) 2002-12-13 2007-09-18 Purdue Pharma L.P. Transdermal buprenorphine dosage regimen for analgesia
RU2324372C2 (ru) 2003-03-25 2008-05-20 Моринда, Инк. Селективное ингибирование продукции эстрогена и обеспечение эстрогенного действия в организме человека
US7182955B2 (en) 2003-04-30 2007-02-27 3M Innovative Properties Company Abuse-resistant transdermal dosage form
US8790689B2 (en) 2003-04-30 2014-07-29 Purdue Pharma L.P. Tamper resistant transdermal dosage form
DE102004019916A1 (de) * 2004-04-21 2005-11-17 Grünenthal GmbH Gegen Missbrauch gesichertes wirkstoffhaltiges Pflaster
DE102004045599A1 (de) 2004-09-17 2006-03-23 Grünenthal GmbH System zur sequentiellen, transdermalen Verabreichung von systemisch wirksamen Substanzen
DE102004062647A1 (de) 2004-12-21 2006-06-29 Kronotec Ag Holzfaserdämmstoffplatte bzw.- matte
DE102004062614B4 (de) 2004-12-24 2011-12-29 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System mit aktivierbarer Übersättigung und kontrollierter Permeationförderung sowie Verfahren zu dessen Herstellung
DE102006026578B4 (de) 2006-06-08 2009-01-08 Lts Lohmann Therapie-Systeme Ag Wirkstoffpartikelhaltiges Transdermales Therapeutisches System mit erhöhtem Wirkstofffluss und Verfahren zu seiner Herstellung sowie Verwendung
DE102006054732B4 (de) 2006-11-21 2010-12-30 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System mit Ionenpaar-Mikroreservoiren
JP5235384B2 (ja) 2007-11-08 2013-07-10 リンテック株式会社 貼付シート
GB0815435D0 (en) * 2008-08-22 2008-10-01 Camurus Ab Formulations
EP2366388A1 (de) * 2010-03-17 2011-09-21 Ratiopharm GmbH Nicht-okklusives transdermales therapeutisches System zur Verabreichung von Buprenorphin
CN103200944B (zh) * 2010-11-17 2016-05-04 赫克萨尔股份公司 包含丁丙诺啡的经皮治疗系统
MX352795B (es) 2011-12-12 2017-12-07 Lts Lohmann Therapie Systeme Ag Sistema de administracion transdermica que comprende buprenorfina.
US9895320B2 (en) 2012-09-28 2018-02-20 KM Transderm Ltd. Transdermal patch with different viscosity hydrocarbon oils in the drug layer and the adhesive layer
AU2013205080B2 (en) 2012-12-12 2016-07-07 Lts Lohmann Therapie-Systeme Ag Transdermal Delivery System
JP6559121B2 (ja) 2013-06-04 2019-08-14 エルテーエス ローマン テラピー−ジステーメ アーゲー 経皮送達システム

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6365178B1 (en) * 1996-09-06 2002-04-02 Watson Pharmaceuticals, Inc. Method of making pressure sensitive adhesive matrix patches for transdermal drug delivery using hydrophilic salts of drugs and hydrophobic pressure sensitive adhesive dispersions
US20110288112A1 (en) * 1997-02-24 2011-11-24 Reder Robert F Method of Providing Sustained Analgesia With Buprenorphine
US20040202710A1 (en) * 1999-07-02 2004-10-14 Walter Muller Microreservoir system based on polysiloxanes and ambiphilic solvents
US20040202707A1 (en) * 2003-04-14 2004-10-14 Walter Muller Therapeutic patch
US20050232964A1 (en) * 2004-04-14 2005-10-20 Fennimore Roy R Jr Use of antioxidants to prevent oxidation and reduce drug degradation in drug eluting medical devices
US20100119585A1 (en) * 2006-11-21 2010-05-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for administering the active substance buprenorphine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9549903B2 (en) 2011-12-12 2017-01-24 Purdue Pharma L.P. Transdermal delivery system comprising buprenorphine
US11529345B2 (en) 2013-06-04 2022-12-20 Lts Lohmann Therapie-Systeme Ag Buprenorphine transdermal delivery system
US20180162371A1 (en) * 2016-12-14 2018-06-14 Bendix Commercial Vehicle Systems Llc Front End Motor-Generator System and Hybrid Electric Vehicle Operating Method
US20180221297A1 (en) * 2017-02-03 2018-08-09 Kirti H. Valia System and Method for Improving Adhesion of Transdermal Delivery Devices
CN113952319A (zh) * 2021-11-30 2022-01-21 烟台大学 一种含丁丙诺啡的骨架型透皮贴剂及其制备方法

Also Published As

Publication number Publication date
JP6559121B2 (ja) 2019-08-14
AU2014276910B2 (en) 2017-03-09
BR112015029920A2 (pt) 2017-07-25
US20180092905A1 (en) 2018-04-05
HUE031662T2 (en) 2017-07-28
CA2914425A1 (en) 2014-12-11
ZA201509309B (en) 2017-11-29
GB201522307D0 (en) 2016-02-03
PE20160002A1 (es) 2016-01-23
KR102302505B1 (ko) 2021-09-15
CL2015003377A1 (es) 2016-06-17
JP2016520638A (ja) 2016-07-14
US20200237748A1 (en) 2020-07-30
EP2810646A1 (en) 2014-12-10
MA38698A1 (fr) 2017-02-28
PH12015502550A1 (en) 2016-02-22
AP2015008920A0 (en) 2015-12-31
DK2810646T3 (en) 2016-10-31
CN105377245B (zh) 2018-07-17
CR20150647A (es) 2016-02-19
LT2810646T (lt) 2016-10-25
EP3106153A1 (en) 2016-12-21
AU2014276910A1 (en) 2016-01-28
EA201592246A1 (ru) 2016-05-31
MA38698B1 (fr) 2017-10-31
PL2810646T3 (pl) 2017-02-28
HK1204766A1 (zh) 2015-12-04
MX362614B (es) 2019-01-28
NI201500170A (es) 2016-08-05
WO2014195352A1 (en) 2014-12-11
EP2810646B1 (en) 2016-07-27
CN105377245A (zh) 2016-03-02
DE112014002664T5 (de) 2016-04-07
SI2810646T1 (sl) 2016-11-30
MX2015016123A (es) 2016-07-21
AR096521A1 (es) 2016-01-13
ES2599802T3 (es) 2017-02-03
GB2529789A (en) 2016-03-02
CY1118054T1 (el) 2017-06-28
US20170128384A1 (en) 2017-05-11
CA2914425C (en) 2019-09-17
HK1222135A1 (zh) 2017-06-23
PT2810646T (pt) 2016-10-05
TN2015000493A1 (en) 2017-04-06
US20160101100A1 (en) 2016-04-14
KR20160014064A (ko) 2016-02-05
SG11201509218SA (en) 2015-12-30
US20200316055A1 (en) 2020-10-08
US11529345B2 (en) 2022-12-20
TW201509416A (zh) 2015-03-16

Similar Documents

Publication Publication Date Title
US11529345B2 (en) Buprenorphine transdermal delivery system
US20200306204A1 (en) Transdermal delivery system comprising buprenorphine
US20200253957A1 (en) Transdermal delivery system
US20140276478A1 (en) Compositions and methods for transdermal delivery of tertiary amine drugs
ES2900255T3 (es) Sistema de administración transdérmica que incluye un emulsionante
OA17599A (en) Transdermal delivery system
US20210251916A1 (en) Transdermal therapeutic system containing rivastigmine

Legal Events

Date Code Title Description
AS Assignment

Owner name: LTS LOHMANN THERAPIE-SYSTEME AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PURDUE PHARMA L.P.;REEL/FRAME:036489/0016

Effective date: 20140603

Owner name: LTS LOHMANN THERAPIE-SYSTEME AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HILLE, THOMAS;SEIBERTZ, FRANK;WAUER, GABRIEL;REEL/FRAME:036488/0776

Effective date: 20130801

Owner name: PURDUE PHARMA L.P., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:WEINHEIMER, SHU-LUN;REEL/FRAME:036488/0914

Effective date: 20140602

Owner name: PURDUE PHARMA L.P., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LTS LOHMANN THERAPIE-SYSTEME AG;REEL/FRAME:036541/0101

Effective date: 20150409

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: LTS LOHMANN THERAPIE-SYSTEME AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PURDUE PHARMA L.P.;REEL/FRAME:047438/0443

Effective date: 20180815