Patent Application
20180193333
The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of buprenorphine, a method of treating pain using said TTS, and a process of manufacturing said TTS.
The active ingredient buprenorphine (5R,6R,7R,9R,13S,145)-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. Thus the overall efficacy of the pain medicament is enhanced. However, 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. Also, 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.
It is therefore desirable to reduce the overall size (i.e., area of release) of the TTS as well as to reduce the total amount of buprenorphine in the TTS before administration and the amount remaining in the TTS after proper use (the residual amount). Thereby, the amount of drug available for illicit use (before and after proper use), and the amount to be wasted after proper use are both reduced. US Patent Application No. 2010/0119585 describes a certain TTS size and amount of drug reduction in comparison with the commercial TTS product Transtec® approved for an up-to-4 days administration regimen. Thus, the TTS needs to be replaced after 4 days at the latest. It is recommended to change Transtec® twice a week always on the same days at specific times, e.g. Monday mornings and Thursday evenings.
For convenience reasons it is, however, desirable to maintain the once weekly exchange mode (7 day dosing regimen) as, e.g., provided by the commercial product Norspan® instead of the every three to four days exchange mode as provided by, e.g., Transtec®.
All references and publications cited herein are hereby incorporated by reference in their enteritis for all purposes.
It is an object of certain embodiments of the present invention to provide a method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small amount of buprenorphine (e.g., buprenorphine base) contained therein.
It is an object of certain embodiments of the present invention to provide a method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small area of release.
It is an object of certain embodiments of the present invention to provide a method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small amount of buprenorphine (e.g., buprenorphine base) contained therein and optionally a relatively small area of release, and provides a release suitable for providing pain relief for 7 days (corresponding to about 168 hours or one week).
These objects and others are accomplished by the present invention, which according to one aspect relates to a method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine for 7 days on the skin of a patient, said transdermal therapeutic system comprising a buprenorphine-containing self-adhesive layer structure comprising
According to one aspect, the invention relates to a method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine base for 7 days on the skin of a patient, said transdermal therapeutic system comprising a buprenorphine base-containing self-adhesive layer structure comprising
According to one aspect, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing self-adhesive layer structure comprising
According to one aspect, 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
According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a mean AUCt of more than 7,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a mean AUCt of more than 14,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a mean AUCt of more than 28,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a mean AUCt of more than 42,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a mean AUCt of more than 62,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population, in particular containing buprenorphine in the area of release in an amount of less than 0.8 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a nominal mean release rate of about 5 μg/hr over about 168 hours of administration; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a nominal mean release rate of about 10 μg/hr over about 168 hours of administration; and
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a nominal mean release rate of about 20 μg/hr over about 168 hours of administration; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a nominal mean release rate of about 30 μg/hr over about 168 hours of administration; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a nominal mean release rate of about 40 μg/hr over about 168 hours of administration, in particular containing buprenorphine in the area of release in an amount of less than 0.8 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.
According to one aspect, 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 system as described in the previous paragraphs.
According to one aspect, 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 paragraphs and subsequently applying said selected transdermal therapeutic system on the skin of said patient for 7 days.
According to one aspect, the invention relates to a set of two to five different transdermal therapeutic systems for the transdermal administration of buprenorphine selected from five different transdermal therapeutic systems, 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
According to one aspect, the invention relates to a method of treating pain in a patient by selecting for said patient the appropriate transdermal therapeutic system from the set of different transdermal therapeutic systems as described in the previous paragraph and subsequently applying said selected transdermal therapeutic system on the skin of said patient for 7 days.
According to one aspect, the invention relates to a transdermal therapeutic system selected from a set as described in the previous paragraphs for use in a method of treating pain in a patient by applying said selected transdermal therapeutic system for 7 days on the skin of the patient.
Within the meaning of this invention, the term “transdermal therapeutic system” (or 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 agent-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. During storage, such a TTS is normally located on a redetachable protective layer from which it is removed immediately before application to the surface of the patient's skin. A TTS protected this way may be stored in a blister pack or a side sealed bag.
Within the meaning of this invention, the term “buprenorphine-containing self-adhesive layer structure” refers to the active agent-containing structure.
Within the meaning of this invention, the term “additional larger active agent-free self-adhesive layer structure” refers to a self-adhesive layer structure that is free of active agent and larger 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.
Within the meaning of this invention, the term “buprenorphine-containing matrix layer” refers to the layer containing the active in a matrix-type structure of active in polymer or polymer-based adhesive, and providing the area of release of the active agent. During the storage of the TTS some of the active buprenorphine or some of the carboxylic acid may migrate from the buprenorphine-containing matrix layer into the skin contact layer. Thus the composition of the buprenorphine-containing matrix layer may change during storage. The “initial composition” refers to the composition before storage and thus before migration.
Within the meaning of this invention, the term “polymer base” refers to a composition containing from 75% to 100% of polymer based on the dry weight of the composition. The polymer base may contain 75% to 100% of one or more polymers. According to certain embodiments the polymer base is a polymer-based pressure-sensitive adhesive.
Within the meaning of this invention, “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. According to certain embodiments 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. Such polymer-based pressure-sensitive adhesives may e.g., comprise polysiloxane, polyacrylate or polyisobutylene. Polymer-based pressure-sensitive adhesives comprising polysiloxane or polyacrylate are preferred. Examples of useful pressure-sensitive adhesives comprising 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), the Soft Skin Adhesives series (7-9800) and the Bio-PSA Hot Melt Adhesive manufactured by Dow Corning. Preferred pressure-sensitive adhesives comprising polysiloxane are heptane-solvated pressure-sensitive adhesives including BIO-PSA 7-4201, BIO-PSA 7-4301. A useful pressure-sensitive adhesive comprising polyacrylate which is commercially available is Duro Tak® 387 2051 from Henkel.
Within the meaning of this invention, the term “deposit” refers to a distinguishable, e.g., visually distinguishable, area within the polymer base, e.g., the polymer-based pressure-sensitive adhesive. Such deposits are e.g., droplets. Deposits that are visually distinguishable may be identified by use of a microscope.
Within the meaning of this invention, the term “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 the buprenorphine-containing self-adhesive layer structure on top of the buprenorphine containing matrix layer. The sizes of the skin contact layer, the buprenorphine-containing matrix layer and the buprenorphine-containing self-adhesive layer structure are co-extensive and correspond to the area of release.
Within the meaning of this invention, the parameter “mean cumulative skin permeation rate” is provided in μg/cm2-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 μg/cm2 divided by the hours corresponding to said total time period of release, e.g., 168 hours.
Within the meaning of this invention, the parameter “mean non-cumulative skin permeation rate” is provided in μg/cm2-hr and is calculated from the non-cumulative release of a certain sample interval as measured in a Franz diffusion cell in μg/cm2 divided by the hours of said sample interval.
Within the meaning of this invention, the parameter “cumulative release” is provided in μg/cm2 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.
Within the meaning of this invention, the parameter “non-cumulative release” is provided in μg/cm2 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.
Within the meaning of this invention, the parameter “mean release rate” refers to the mean release rate in μg/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.
Within the meaning of this invention, 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 cm2 area of release BuTrans® reference TTS containing 20 mg buprenorphine is 20 μg/hr. The mean release rate is proportional to the size of the area of release of a TTS and may be used to distinguish TTSs by the dosage strength. The BuTrans® TTS with half the size (i.e. 12.5 cm2 area of release) and containing 10 mg of buprenorphine provides the known nominal mean release rate of 10 μg/hr. The BuTrans® TTS with a size of 6.25 cm2 area of release and containing 5 mg of buprenorphine provides the known nominal mean release rate of 5 μg/hr. Accordingly, it can be assumed that a corresponding TTS with a size of 50 cm2 area of release and containing 40 mg of buprenorphine provides a nominal mean release rate of 40 μg/hr, and a corresponding TTS with a size of 37.5 cm2 area of release and containing 30 mg of buprenorphine provides a nominal mean release rate of 30 μg/hr. The nominal mean release rates are assigned to the TTSs in accordance with the invention based on bioequivalence considerations by at least comparing the mean AUCt of the reference TTS BuTrans® with the mean AUCt of the TTSs in accordance with the invention obtained in the same clinical study.
Within the meaning of this invention, the meaning of “by applying the TTS for 7 days on the skin of said patient” corresponds to “by applying the TTS for about 168 hours on the skin of said patient” and refers to a once a week exchange mode or dosing regimen. Likewise, 4 days correspond to about 96 hours, 5 days correspond to about 120 hours and 6 days correspond to about 144 hours. The term “applying on the skin of a patient for a certain period of time” has the same meaning as “administration for a certain period of time”.
Within the meaning of this invention, 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.
If not indicated otherwise “%” refers to weight-%.
Within the meaning of this invention, 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.
Within the meaning of this invention, values and ranges specifying the area of release and the amount of buprenorphine contained in the transdermal therapeutic system are mean values of at least 3 measurements.
Within the meaning of this invention the term “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 parameters of the individual subjects are summarized 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). In the context of the present invention, 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. To allow a comparison of absolute mean values between studies, 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.
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.
Within the meaning of this invention, 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 (BMI) 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.
Within the meaning of this invention, the term “subject population” refers to at least ten individual healthy human subjects.
Within the meaning of this invention, the term “geometric mean” refers to the mean of the log transformed data backtransformed to the original scale.
Within the meaning of this invention, the term “arithmetic mean” refers to the sum of all values of observation divided by the total number of observations.
Within the meaning of this invention, 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.
Within the meaning of this invention, 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.
Within the meaning of this invention, the parameter “mean AUCt per area of release” is provided in pg·hr/ml-cm2 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.
Within the meaning of this invention, the parameter “AUCINF” is provided in pg·hr/ml and relates to the area under the plasma concentration-time curve extrapolated to infinity and is calculated using the formula:
where CLast is the last measurable plasma concentration and LambdaZ is the apparent terminal phase rate constant.
Within the meaning of this invention, the parameter “Cmax” is provided in pg/ml and and relates to the maximum observed blood plasma concentration of the active agent.
Within the meaning of this invention, the parameter “tmax” is provided in hr and relates to the time point at which the Cmax value is reached. In other words, tmax is the time point of the maximum observed plasma concentration.
Within the meaning of this invention, 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.
Within the meaning of this invention, the parameter “t½Z” is provided in hr and relates to the apparent plasma terminal phase half-life and is commonly determined as t½Z=(ln 2)/LambdaZ.
Within the meaning of this invention, the term “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.
According to the invention wherein the structure is concerned, the TTS for the transdermal administration of buprenorphine comprises a buprenorphine-containing self-adhesive layer structure comprising
According to an aspect of the invention, the TTS for the transdermal administration of buprenorphine base comprises a buprenorphine base-containing self-adhesive layer structure comprising
According to certain embodiments of the invention, 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. The area of said second active agent agent-free self-adhesive layer structure adds to the overall size of the TTS but does not add to the area of release. Said active agent-free self-adhesive layer structure comprises also a backing layer, e.g., beige colored, and an active agent free pressure-sensitive adhesive layer of polymer-based pressure-sensitive adhesive, e.g., comprising polyacrylate, polyisobutylene or polysiloxane. Polyacrylate-based pressure-sensitive adhesives are preferred for the active agent free pressure-sensitive adhesive layer, in particular pressure-sensitive adhesives comprising 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 or only one of these solvents. 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 mm2, or of at least 20 N/25 mm2, or of at least 22 N/25 mm2.
The TTS according to the invention comprises 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. According to a preferred embodiment of the invention the active agent is buprenorphine base.
The amount of buprenorphine contained in the TTS may vary from about 1 mg to about 32 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. According to certain embodiments, the TTS contains according to five different dosage strengths from about 1 mg to about 4 mg, or about 2.5 mg, or from about 3.5 mg to about 8 mg, or about 5 mg, or from about 6.5 mg to about 16 mg, or about 10 mg, or from about 11.5 mg to about 24 mg, or about 15 mg or from about 15 mg to about 32 mg, or about 20 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof.
The amount of buprenorphine contained in the buprenorphine-containing self-adhesive layer structure may be less than 0.8 mg/cm2, or may vary from about 0.2 mg/cm2 to less than 0.8 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. According to certain embodiments, the buprenorphine-containing self-adhesive layer structure contains less than 0.7 mg/cm2, or less than 0.6 mg/cm2, or less than 0.55 mg/cm2, or less than 0.5 mg/cm2, or contains from about 0.2 mg/cm2 to about 0.7 mg/cm2, or from about 0.2 mg/cm2 to about 0.6 mg/cm2, or from about 0.2 mg/cm2 to less than 0.55 mg/cm2, or from about 0.2 mg/cm2 to about 0.5 mg/cm2, or from about 0.3 mg/cm2 to about 0.5 mg/cm2, or from about 0.4 mg/cm2 to about 0.5 mg/cm2, or about 0.45 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. Based on the dry weight of the initial composition of the buprenorphine-containing matrix layer, more than 4%, or more than 5%, or more than 6%, or more than 7%, or from about 5% to about 20%, or from about 6% to about 20%, or from about 7% to about 15%, or about 7.5% buprenorphine base or equimolar amounts of pharmaceutically acceptable salts are contained in the buprenorphine-containing self-adhesive layer structure.
In accordance with the invention, a polymer base is used to form the matrix containing the active buprenorphine. The polymer base contains from 75% to 100% of polymer. The polymer base may contain 75% to 100% of one or more polymers.
According to certain preferred embodiments, the polymer base is a pressure-sensitive adhesive. Such polymer-based pressure-sensitive adhesives may e.g., comprise polysiloxane or polyisobutylene. For the present invention polysiloxane-based pressure-sensitive adhesives are preferred for the buprenorphine-containing matrix layer. Such polysiloxane adhesives need, unlike other organic pressures-sensitive adhesives, no additives like antioxidants, stabilizers, plasticizers, catalysts or other potentially extractable ingredients. These 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 preferred pressure-sensitive adhesives comprising polysiloxane 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 1×109 Poise or from about 1×105 to about 9×108 Poise, or more preferred from about 1×105 to about 1×107 Poise, or most preferred about 5×106 Poise or alternatively more preferred from about 2×107 to about 9×108 Poise, or most preferred about 1×108 Poise.
The above described adhesives for the buprenorphine-containing matrix layer may also be used for the skin contact layer, and in this case polysiloxane-based pressure-sensitive adhesives are preferred. The adhesive strength of the polysiloxane may be sufficient for the desired skin contact. In certain embodiments of the invention a plasticizer or a tackifying agent is incorporated into the formulation to improve the adhesive characteristics of the pressure-sensitive adhesive in the skin contact 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. In preferred embodiments, the tackifying agent is a silicone oil (e.g., 360 Medical Fluid, available from Dow Corning Corporation, Midland, Mich.).
According to certain other embodiments the adhesives in the buprenorphine-containing matrix layer and the skin contact layer are different, and the adhesive in the skin contact layer is a pressure-sensitive adhesive based on polyacrylate, in particular a pressure-sensitive adhesives based on an acrylate-vinylacetate polymer prepared from 2-ethylhexyl acrylate, vinylacetate and 2-hydroxyethyl acrylate.
The pressure-sensitive adhesives are supplied and used in solvents like heptane, ethyl acetate or other volatile silicone fluids. For the pressure-sensitive adhesives comprising polysiloxane heptane is preferred and the solids content is usually between 60 and 80%. For the pressure-sensitive adhesives comprising polyacrylate ethyl acetate is preferred and the solids content is usually between 40 and 80%.
Suitable pressure-sensitive adhesives comprising polysiloxane 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. 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 1×108 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 5×106 Poise.
Suitable pressure-sensitive adhesives comprising polyacrylate may be obtained 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 or only one of these solvents. 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 mm2, or of at least 20 N/25 mm2, or of at least 22 N/25 mm2.
The adhesive in the active agent-free pressure-sensitive adhesive layer may be a pressure-sensitive adhesive comprising polysiloxane, polyacrylate or polyisobutylene, and polyacrylate based pressure-sensitive adhesives are preferred, in particular pressure-sensitive adhesives based on an acrylate-vinylacetate polymer prepared from 2-ethylhexyl acrylate, vinylacetate and 2-hydroxyethyl acrylate.
The buprenorphine-containing matrix layer of the TTS according to the invention may further comprise in addition to the above mentioned ingredients a), b) and c), namely a polymer-base, the buprenorphine 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, 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.
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 nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other 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 buprenorphine-containing matrix layer comprises a) the polymer-based pressure-sensitive adhesive, b) the buprenorphine and c) 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.
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.
In addition to the carboxylic acid selected from oleic acid, linoleic acid, linolenic acid, levulinic acid, 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 polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.
Viscosity-increasing substances are preferably used in conjunction with an active agent solution. Suitable substances for increasing the viscosity of the active agent solution are, for example, cellulose derivatives such as ethylcellulose, hydroxylpropylcellulose and high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters.
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 buprenorphine-containing self-adhesive layer structure according to the invention comprises a buprenorphine-impermeable backing layer, a buprenorphine-containing matrix layer on said backing layer, and a skin contact layer on said buprenorphine-containing matrix layer. In a preferred embodiment, the buprenorphine-containing self-adhesive layer structure consists of these three elements.
The buprenorphine-containing matrix layer may be coated at any dry weight, but is preferably coated at a dry weight of less than 8 mg/cm2 (less than 80 g/m2), but is preferably coated at a dry weight of less than 7 mg/cm2 (less than 70 g/m2), or of up to 6 mg/cm2 (up to 60 g/m2), or of less than 6 mg/cm2 (less than 60 g/m2), or ranging from about 3 mg/cm2 (about 30 g/m2) to less than 8 mg/cm2 (less than 80 g/m2), or from about 4 mg/cm2 (about 40 g/m2) to less than 8 mg/cm2 (less than 80 g/m2), or from about 5 mg/cm2 (about 50 g/m2) to about 7 mg/cm2 (about 70 g/m2), or from about 5.5 mg/cm2 (about 55 g/m2) to about 6.5 mg/cm2 (about 65 g/m2), or is specifically about 6 mg/cm2 (about 60 g/m2).
The size of the buprenorphine-containing matrix layer which provides the area of release may range from more than 4.8 cm2 to about 60 cm2. According to certain embodiments, the area of release ranges according to five different dosages from more than 4.8 cm2 to about 8 cm2, or is about 5.5 cm2, or ranges from more than 9.5 cm2 to about 15 cm2, or is about 11.25 cm2, or ranges from more than 19 cm2 to about 30 cm2, or is about 22.5 cm2, or ranges from more than 28.5 cm2 to about 45 cm2, or is about 33.75 cm2, or ranges from more than 38 cm2 to about 60 cm2, or is about 45 cm2.
The skin contact layer may be coated at any dry weight, but is preferably coated at a dry weight of less than 6 mg/cm2 (less than 60 g/m2), or of less than 5 mg/cm2 (less than 50 g/m2), or of less than 4 mg/cm2 (less than 40 g/m2), or ranging from about 1 mg/cm2 (about 10 g/m2) to less than 6 mg/cm2 (about 60 g/m2), or from about 1 mg/cm2 (about 10 g/m2) to about 5 mg/cm2 (about 50 g/m2), or from about 1 mg/cm2 (about 10 g/m2) to about 4 mg/cm2 (about 40 g/m2), or from about 1 mg/cm2 (about 10 g/m2) to about 3 mg/cm2 (about 30 g/m2), or from about 1.5 mg/cm2 (about 15 g/m2) to about 2.5 mg/cm2 (about 25 g/m2), or is specifically about 2 mg/cm2 (about 20 g/m2).
The buprenorphine-containing self-adhesive layer structure preferably contains buprenorphine base, but may contain equimolar amounts of pharmaceutically acceptable salts. According to the invention preferably more than 4%, or more than 5%, or more than 6%, or more than 7%, or from about 5% to about 20%, or from about 6% to about 20%, or from about 7% to about 15% buprenorphine base or equimolar amounts of pharmaceutically acceptable salts based on the dry weight of the initial composition of the buprenorphine-containing matrix layer are contained in the buprenorphine-containing self-adhesive layer structure. In a specific embodiment, about 7.5% buprenorphine base is contained in the buprenorphine-containing self-adhesive layer structure.
The buprenorphine-containing self-adhesive layer structure in particular contains less than 0.8 mg/cm2, or less than 0.7 mg/cm2, or less than 0.6 mg/cm2, or less than 0.55 mg/cm2, or less than 0.5 mg/cm2, or from about 0.2 mg/cm2 to less than 0.8 mg/cm2, or from about 0.2 mg/cm2 to about 0.7 mg/cm2, or from about 0.2 mg/cm2 to about 0.6 mg/cm2, or from about 0.2 mg/cm2 to less than 0.55 mg/cm2, or from about 0.2 mg/cm2 to about 0.5 mg/cm2, or from about 0.3 mg/cm2 to about 0.5 mg/cm2, or from about 0.4 mg/cm2 to about 0.5 mg/cm2 buprenorphine base or contains about 0.45 mg/cm2 buprenorphine base. The TTS may also contain equimolar amounts of pharmaceutically acceptable salts.
In order to provide the desired delivery rate of buprenorphine, a carboxyclic acid is present. The carboxylic acid may be selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, wherein levulinic acid is preferred. 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. Buprenorphine, with its known physicochemical properties, namely its poor solubility, its comparatively high melting point of 216° C., and its high molecular weight, tends readily towards crystallization. For this reason, 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 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 deposit, e.g., droplet, size (diameter) itself ought preferably not to exceed about 150 μm, or ranges from about 1 to about 150 μm, preferably from about 1 to about 50 μm, or from about 5 to about 50 μm, or from about 1 to about 25 μm or from about 5 to about 25 μm. The preferred size is dependent, furthermore, on the thickness of the matrix layer.
Since the carboxylic acid, e.g., the levulinic acid, can likewise be absorbed through the skin, the amount in the TTS becomes less as the time of application elapses, and leads to a reduction of the solubility of buprenorphine. As a result, the decrease in the thermodynamic activity of buprenorphine due to depletion is compensated by the reduced drug solubility in the buprenorphine/levulinic acid deposits.
According to the invention the buprenorphine-containing self-adhesive layer structure contains more than 4%, or more than 5%, or more than 6%, or more than 7%, or more than 8%, or 9% or more, or more than 9%, or from about 5% to about 20%, or from about 6% to about 20%, or from about 7% to about 15%, or from about 8% to about 15%, or from about 9% to about 15% carboxylic acid, or about 9%, or about 10% carboxylic acid e.g., levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer. In a specific embodiment the buprenorphine-containing self-adhesive layer structure contains from about 5% to about 20% levulinic acid, or from about 6% to about 20%, or from about 7% to about 15%, or from about 8% to about 15%, or from about 9% to about 15% levulinic acid, or about 9%, or about 10% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer. According to a specific embodiment the buprenorphine-containing self-adhesive layer structure contains the same %-amount of levulinic acid and buprenorphine base or equimolar amounts of pharmaceutically acceptable salts. According to another specific embodiment, the buprenorphine-containing self-adhesive layer structure contains less %-amount of buprenorphine base or equimolar amounts of pharmaceutically acceptable salts than it contains %-amount of levulinic acid.
According to a specific embodiment, the buprenorphine-containing self-adhesive layer structure contains from about 5% to about 20% buprenorphine base and from about 5% to about 20% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer, or from about 7% to about 15% buprenorphine base and from about 9% to about 15% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer.
According to a certain embodiment, the buprenorphine-containing matrix layer is coated at a dry weight of from about 5 mg/cm2 (about 50 g/m2) to about 7 mg/cm2 (about 70 g/m2), or from about 5.5 mg/cm2 (about 55 g/m2) to about 6.5 mg/cm2 (about 65 g/m2), or is about 6 mg/cm2 (about 60 g/m2), and the buprenorphine-containing self-adhesive layer structure contains from about 6% to about 20%, or from about 7% to about 15%, or about 7.5% buprenorphine base and from about 7% to about 15%, or from about 8% to about 15%, or about 9% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer. In a specific embodiment the buprenorphine-containing matrix layer is coated at a dry weight of about 6 mg/cm2 and the buprenorphine-containing self-adhesive layer structure contains about 7.5% buprenorphine base and about 9% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer.
According to a certain other embodiment, the buprenorphine-containing matrix layer being coated at a dry weight of from about 5 mg/cm2 (about 50 g/m2) to about 7 mg/cm2 (about 70 g/m2), or from about 5.5 mg/cm2 (about 55 g/m2) to about 6.5 mg/cm2 (about 65 g/m2), or is about 6 mg/cm2 (about 60 g/m2), and the buprenorphine-containing self-adhesive layer structure contains from about 6% to about 20%, or from about 7% to about 15%, or about 7.5% buprenorphine base and from about 8% to about 15%, or from about 9% to about 15%, or about 10% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer. In a specific embodiment the buprenorphine-containing matrix layer is coated at a dry weight of about 6 mg/cm2 and the buprenorphine-containing self-adhesive layer structure contains about 7.5% buprenorphine base and about 10% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer.
According to a certain embodiment of the invention, the polymer base in the buprenorphine-containing matrix layer is a polymer-based pressure-sensitive adhesive comprising polysiloxane or polyisobutylene. According to a specific embodiment the adhesive in the buprenorphine-containing matrix layer is an amine-resistant pressure-sensitive adhesive comprising polysiloxane wherein 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. and about 60% solids content in heptanes of about 500 mPa s or of about 450 mPa s, and the buprenorphine-containing matrix layer is coated at a dry weight of about 6 mg/cm2 and the buprenorphine-containing self-adhesive layer structure contains about 7.5% buprenorphine base and about 9% or 10% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer. The buprenorphine-containing matrix layer and the skin contact layer may contain the same or different pressure-sensitive adhesives.
According to a certain embodiment of the invention, the adhesive in the buprenorphine-containing matrix layer and the adhesive in the skin contact layer are different, and the adhesive in the skin contact layer is a pressure-sensitive adhesive comprising polyacrylate. According to a specific embodiment the adhesive in the skin contact layer is a pressure-sensitive adhesive comprising polyacrylate and the buprenorphine-containing matrix layer is a polymer-based pressure-sensitive adhesive comprising polysiloxane and is coated at a dry weight of about 6 mg/cm2 and the buprenorphine-containing self-adhesive layer structure contains preferably about 7.5% buprenorphine base and about 9% or 10% levulinic acid based on the dry weight of the initial composition of the buprenorphine-containing matrix layer.
According to certain embodiments, the TTS contains from about 1 mg to about 32 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. Considering five different increasing dosage strengths, the TTS in specific cases preferably contains
Correspondingly the area of release ranges from more than 4.8 cm2 to about 60 cm2 and with respect to the five specific preferred dosage strengths a) to e)
In such embodiments the buprenorphine-containing matrix layer preferably comprises a pressure-sensitive adhesive comprising polysiloxane and is coated preferably at a dry weight of about 6 mg/cm2, the skin contact layer preferably comprises a pressure-sensitive adhesive comprising polyacrylate, and the buprenorphine-containing self-adhesive layer structure preferably contains about 7.5% buprenorphine base based on the dry weight of the initial composition of the buprenorphine-containing matrix layer.
According to certain preferred embodiments, 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:
For the treatment of pain a patient needs to be titrated to the individual dose of buprenorphine to adequately control the pain. In order to meet the individual requirements, five different dosage strengths are provided in accordance with the invention.
According to one aspect, 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 for the transdermal administration of buprenorphine for 7 days selected from:
a first transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 4.8 cm2 to about 8 cm2;
a second transdermal therapeutic system providing the area of release ranging from more than 9.5 cm2 to about 15 cm2; and
a third transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 19 cm2 to about 30 cm2; and
a fourth transdermal therapeutic system providing the area of release ranging from more than 28.5 cm2 to about 45 cm2; and
a fifth transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 38 cm2 to about 60 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release from the first to the fifth transdermal therapeutic system.
According to a certain embodiment of the invention, the set of different transdermal therapeutic systems described in the previous paragraph comprises:
the first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 4.8 cm2 to about 8 cm2;
the second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 9.5 cm2 to about 15 cm2; and
the third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 19 cm2 to about 30 cm2; and
the fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 28.5 cm2 to about 45 cm2; and
the fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 38 cm2 to about 60 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release and increasing amounts of buprenorphine from the first to the fifth transdermal therapeutic system.
According to a certain embodiment of the invention, the set of different transdermal therapeutic systems described in the previous paragraph comprises:
the first transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 7 cm2;
the second transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 13 cm2; and
the third transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 26 cm2; and
the fourth transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 39 cm2; and
the fifth transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 52 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release from the first to the fifth transdermal therapeutic system.
According to a certain embodiment of the invention, the set of different transdermal therapeutic systems described in the previous paragraph comprises:
the first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 7 cm2;
the second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 13 cm2; and
the third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 26 cm2; and
the fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 39 cm2; and
the fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 52 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release and increasing amounts of buprenorphine from the first to the fifth transdermal therapeutic system.
According to a certain embodiment of the invention, the set of different transdermal therapeutic systems comprises:
the first transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 6 cm2;
the second transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 12; and
the third transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 24 cm2; and
the fourth transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 36 cm2; and
the fifth transdermal therapeutic system providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 48 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release from the first to the fifth transdermal therapeutic system.
According to a certain embodiment of the invention, the set of different transdermal therapeutic systems comprises:
the first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 6 cm2;
the second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 12 cm2; and
the third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 24 cm2; and
the fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 12.5 mg to about 18 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 36 cm2; and
the fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 18.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 48 cm2, wherein the five different transdermal therapeutic systems have increasing areas of release and increasing amounts of buprenorphine from the first to the fifth transdermal therapeutic system.
According to the invention, the set as described in the previous paragraphs provides from the first to the fifth transdermal therapeutic system increasing amounts of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and increasing sizes of said buprenorphine-containing matrix layer providing the area of release.
According to one aspect, the invention relates to a set as described in the previous paragraphs for use in a method of treating pain.
According to the invention, the method of treating pain by applying the transdermal therapeutic system for the transdermal administration of buprenorphine as described above in detail comprises in particular the application of the TTS for about 7 days (corresponding to about 168 hours) on the skin of a patient referring to a once a week exchange mode or dosing regimen. According to other methods in accordance with the invention the TTS can be applied for more than 4 days corresponding to more than 96 hours, or about 5 days corresponding to about 120 hours and about 6 days corresponding to about 144 hours. The application for about 168 hours is preferred.
According to one aspect, 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, wherein:
the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 4.8 cm2 to about 8 cm2 and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system contains an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 9.5 cm2 to about 15 cm2 and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 19 cm2 to about 30 cm2 and provides a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 28.5 cm2 to about 45 cm2 and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 38 cm2 to about 60 cm2 and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.
The invention relates also to a method of treating pain in accordance with the previous paragraph wherein the set of five different transdermal therapeutic systems comprises
the first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 7 cm2 and providing a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 13 cm2 and providing a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 26 cm2 and providing a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 39 cm2 and providing a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 52 cm2 and providing a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.
The invention relates also to a method of treatment in accordance with the previous paragraphs wherein the set of five different transdermal therapeutic systems comprises
the first transdermal therapeutic system containing an amount of said buprenorphine ranging from about about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 6 cm2 and providing a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration;
the second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 12 cm2 and providing a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 24 cm2 and providing a mean release rate of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 12.5 mg to about 18 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 36 cm2 and providing a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 18.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 48 cm2 and providing a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or providing a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.
The invention relates also to a method of treating pain in a patient by applying a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine for 7 days on the skin of a patient, wherein the transdermal therapeutic system is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population.
The invention relates also to a method of treating pain in a patient by applying a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine for 7 days on the skin of a patient, wherein said transdermal therapeutic system is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 5 cm2 to about 7 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 10 cm2 to about 13 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 20 cm2 to about 26 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 30 cm2 to about 39 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 40 cm2 to about 52 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population.
The invention relates also to a method of treating pain in a patient by applying a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine for 7 days on the skin of a patient, wherein the said transdermal therapeutic system is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 5 cm2 to about 6 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 10 cm2 to about 12 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 20 cm2 to about 24 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 12.5 mg to about 18 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 30 cm2 to about 36 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 18.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 40 cm2 to about 48 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population.
According to one aspect, the invention relates to a method of treatment as described in the previous paragraphs, wherein the transdermal therapeutic system provides an arithmetic mean tmax from about 72 hr to about 132 hr, preferably from about 78 hr to about 126 hr, or from about 84 hr to about 120 hr after a single dose administration to a subject population.
According to the invention, the transdermal therapeutic system as described above in detail is for use in a method of treating pain comprising in particular the application of the TTS for about 7 days (corresponding to about 168 hours) on the skin of a patient which refers to a once a week exchange mode or dosing regimen. According to other methods in accordance with the invention the TTS can be applied for more than 4 days corresponding to more than 96 hours, or about 5 days corresponding to about 120 hours and about 6 days corresponding to about 144 hours. The application for about 168 hours is preferred.
According to one aspect, the invention relates to a transdermal therapeutic system for use in 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), four (first to fourth or second to fifth TTS) or five (first to fifth TTS) different transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean relase rates and/or mean release rates over about 168 hours of administration, wherein: the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 4.8 cm2 to about 8 cm2 and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system contains an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 9.5 cm2 to about 15 cm2 and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 19 cm2 to about 30 cm2 and provides a mean release rate of buprenorphine of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 28.5 cm2 to about 45 cm2 and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 38 cm2 to about 60 cm2 and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in accordance with the previous paragraph, wherein: the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 7 cm2 and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration; and
the second transdermal therapeutic system contains an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 10 cm2 to about 13 cm2 and provides a mean release rate of buprenorphine of at least about 6 μg/hr, or of from about 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 μg/hr over about 168 hours of administration; and
the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 20 cm2 to about 26 cm2 and provides a mean release rate of buprenorphine of buprenorphine of at least about 11 μg/hr, or of from about 15 to about 25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 μg/hr over about 168 hours of administration; and
the fourth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 30 cm2 to about 39 cm2 and provides a mean release rate of buprenorphine of at least about 21 μg/hr, or of from about 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 μg/hr over about 168 hours of administration; and
the fifth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 40 cm2 to about 52 cm2 and provides a mean release rate of buprenorphine of at least about 31 μg/hr, or of from about 36 to about 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 μg/hr over about 168 hours of administration.
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in accordance with the previous paragraphs, wherein: the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from about 5 cm2 to about 6 cm2 and provides a mean release rate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 μg/hr over about 168 hours of administration;
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in a patient by applying one appropriately selected transdermal therapeutic system comprising buprenorphine on the skin of said patient for 7 days, wherein said TTS is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population.
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in a patient by applying one appropriately selected transdermal therapeutic system comprising buprenorphine on the skin of said patient for 7 days, wherein said TTS is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 5 cm2 to about 7 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 10 cm2 to about 13 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 20 cm2 to about 26 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 30 cm2 to about 39 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 40 cm2 to about 52 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population for use in a method of treating pain in a patient by applying one of said transdermal therapeutic systems for 7 days on the skin of a patient.
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in a patient by applying one appropriately selected transdermal therapeutic system comprising buprenorphine on the skin of said patient for 7 days, wherein said TTS is selected from:
a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 5 cm2 to about 6 cm2 and providing a nominal mean release rate of about 5 μg/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; and
a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 10 cm2 to about 12 cm2 and providing a nominal mean release rate of about 10 μg/hr and/or providing 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
a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 20 cm2 to about 24 cm2 and providing a nominal mean release rate of about 20 μg/hr and/or providing a mean AUCt of more than 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 12.5 mg to about 18 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 30 cm2 to about 36 cm2 and providing a nominal mean release rate of about 30 μg/hr and/or providing a mean AUCt of more than 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and
a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 18.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from about 40 cm2 to about 48 cm2 and providing a nominal mean release rate of about 40 μg/hr and/or providing a mean AUCt of more than 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population for use in a method of treating pain in a patient by applying one of said transdermal therapeutic systems for 7 days on the skin of a patient.
The invention relates also to a transdermal therapeutic system for use in a method of treating pain in accordance with the previous paragraphs wherein the transdermal therapeutic system provides an arithmethic mean tmax of from about 72 hr to about 132 hr, preferably of about 48 hr to about 132 hr, or more preferably of about 60 hr to about 120 hr after a single dose administration to a subject population.
In accordance with the invention, 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 dermatome is used to prepare skin to a thickness of 800 μm, with an intact epidermis, in accordance with the OECD Guideline (adopted Apr. 13, 2004). Due to the prolonged test (168 hours) 800 μm skin is used instead of the recommended 200 to 400 μm 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° C. Example formulations with an area of 1.163 cm2 are punched from laminates, and in the present examples are each tested against 1.163 cm2 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 1.1 μg/cm2-hr, or more than 1.2 μg/cm2-hr, or more than 1.3 μg/cm2-hr over a 168 hours test, or of more than 1.4 μg/cm2-hr over a 168 hours test, or of 1.5 μg/cm2-hr or more over a 168 hours test, or from about 1.2 μg/cm2-hr to about 4 μg/cm2-hr, or from about 1.3 μg/cm2-hr to about 4 μg/cm2-hr, or from about 1.4 μg/cm2-hr to about 4 μg/cm2-hr, or from about 1.5 μg/cm2-hr to about 2 μg/cm2-hr over a 168 hours test. The commercial product Norspan® provides a mean cumulative skin permeation rate of about 1 μg/cm2-hr over a 168 hours test in said test.
According to certain embodiments, the TTS provides a cumulative release as measured in a Franz diffusion cell as mentioned above of more than 185 μg/cm2, or more than 200 μg/cm2, or more than 220 μg/cm2 over a time period of 168 hours, or of more than 235 μg/cm2, or more than 250 μg/cm2 over a time period of 168 hours, or from about 200 μg/cm2 to about 400 μg/cm2 over a time period of 168 hours, or from about 220 μg/cm2 to about 350 μg/cm2, or from about 235 μg/cm2 to about 300 μg/cm2, or from about 250 μg/cm2 to about 300 μg/cm2 over a time period of 168 hours. The commercial product Norspan® provides a cumulative release of about 175 μg/cm2 in said test. As can be seen from
According to certain embodiments, the TTS provides a non-cumulative skin permeation rate of buprenorphine base as measured in a Franz diffusion cell of
1 μg/cm2 to 10 μg/cm2 in the first 8 hours,
10 μg/cm2 to 60 μg/cm2 from hour 8 to hour 24,
10 μg/cm2 to 60 μg/cm2 from hour 24 to hour 32,
30 μg/cm2 to 100 μg/cm2 from hour 32 to hour 48,
40 μg/cm2 to 120 μg/cm2 from hour 48 to hour 72,
50 μg/cm2 to 150 μg/cm2 from hour 72 to hour 144, and
10 μg/cm2 to 50 μg/cm2 from hour 144 to hour 168.
According to certain embodiments, the TTS provides a non-cumulative skin permeation rate of buprenorphine base as measured in a Franz diffusion cell of
1 μg/cm2 to 6 μg/cm in the first 8 hours,
15 μg/cm2 to 50 μg/cm2 from hour 8 to hour 24,
15 μg/cm2 to 50 μg/cm2 from hour 24 to hour 32,
40 μg/cm2 to 80 μg/cm2 from hour 32 to hour 48,
50 μg/cm2 to 100 μg/cm2 from hour 48 to hour 72,
60 μg/cm2 to 120 μg/cm2 from hour 72 to hour 144, and
15 μg/cm2 to 40 μg/cm2 from hour 144 to hour 168.
According to certain embodiments, the TTS provides a non-cumulative skin permeation rate of buprenorphine base as measured in a Franz diffusion cell of
1 μg/cm2 to 4 μg/cm in the first 8 hours,
20 μg/cm2 to 40 μg/cm2 from hour 8 to hour 24,
20 μg/cm2 to 40 μg/cm2 from hour 24 to hour 32,
40 μg/cm2 to 60 μg/cm2 from hour 32 to hour 48,
50 μg/cm2 to 80 μg/cm2 from hour 48 to hour 72,
60 μg/cm2 to 100 μg/cm2 from hour 72 to hour 144, and
15 μg/cm2 to 30 μg/cm2 from hour 144 to hour 168.
The commercial product Norspan® provides a non-cumulative skin permeation rate of buprenorphine base as measured in a Franz diffusion cell in the same setting of
3.19 μg/cm2 in the first 8 hours,
22.40 μg/cm2 from hour 8 to hour 24,
13.83 μg/cm2 from hour 24 to hour 32,
26.17 μg/cm2 from hour 32 to hour 48,
32.43 μg/cm2 from hour 48 to hour 72,
60.10 μg/cm2 from hour 72 to hour 144, and
17.17 μg/cm2 from hour 144 to hour 168.
According to one further aspect, the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising the steps of
In step 1 of said method of manufacture, preferably buprenorphine base and levulinic acid are used and are suspended in ethanol and subsequently combined with the polymer, preferably with polysiloxane in heptane to provide the buprenorphine-containing composition.
The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention.
The composition of the buprenorphine base-containing adhesive solution is summarized in Table 1a below and the composition of the active-agent-free skin contact layer is summarized in Table 1b below.
In a stainless steel vessel, 0.42 kg of buprenorphine were suspended in 0.56 kg of levulinic acid and 0.28 kg of ethanol. With stirring, 6.25 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 74% by weight and 0.49 kg of heptane were added. The mixture was stirred until the buprenorphine base was fully dissolved, to give 8.00 kg of a buprenorphine-containing adhesive solution with 5.25% of buprenorphine, with a solids content of 70% (buprenorphine base-containing adhesive solution).
For the skin contact layer, a polyacrylate adhesive prepared from 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate were used. 3.69 kg of a solution of this adhesive, with a solids content of 50.5% by weight, was admixed with 1.64 kg of ethyl acetate, following homogenization resulting in 5.33 kg of active-agent-free polyacrylate solution with a solids content of 35% (buprenorphine base-free adhesive solution)
The buprenorphine base-containing adhesive solution was coated on an adhesive polyethylene terephthalate film (e.g., Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying at approximately 50° C. for about 10 minutes to provide the buprenorphine base-containing matrix layer. The coating thickness was chosen such that removal of the solvents results in a coating weight of the buprenorphine base-containing matrix layer of 60 g/m2. This results in the 7.5% by weight of buprenorphine base and 10% by weight of levulinic acid in this buprenorphine base-containing matrix layer. The dried film was laminated with the backing layer (e.g Scotchpak from 3M).
The active-agent-free polyacrylate adhesive solution was likewise coated onto an adhesively treated film (the later protective film to be removed before the systems are used) and the organic solvents were removed to produce the skin contact layer. The coating thickness of the resulting skin contact layer ought to amount, following removal of the solvents, to approximately 20 g/m2. The adhesively treated film was then removed from the buprenorphine base-containing matrix layer produced first, and the buprenorphine base-containing matrix layer was laminated onto the skin contact layer.
The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure. In specific embodiments 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 plasters are then punched out and sealed into pouches of the primary packaging material.
The composition of the buprenorphine base-containing adhesive solution is summarized in Table 2a below and the composition of the active-agent-free skin contact layer is summarized in Table 2b below.
The process of manufacture was as described for Example 1. The coating thickness was also chosen such that removal of the solvents results in a coating weight of the matrix layer of 60 g/m2 and thus resulted in 7.5% by weight buprenorphine base and 10% by weight levulinic acid in this buprenorphine base-containing matrix layer.
The composition of the buprenorphine base-containing adhesive solution is summarized in Table 3a below and the composition of the active-agent-free skin contact layer is summarized in Table 3b below.
The process of manufacture was as described for Example 1. The coating thickness was also chosen such that removal of the solvents results in a coating weight of the matrix layer of 60 g/m2 and thus resulted in 7.5% by weight buprenorphine base and 9% by weight levulinic acid in this buprenorphine base-containing matrix layer.
In Example 4 the in-vitro releases and the corresponding skin permeation rates of Examples 1 to 3 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 1989) was used. A dermatome was used to prepare skin to a thickness of 800 μm, with an intact epidermis for all examples 1 to 3 and the commercial product Norspan®. Diecuts with an area of 1.163 cm2 were punched from examples 1 to 3, 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 4.1 to 4.5 and
In Example 5, a pharmacokinetic study in healthy adult male and female subjects was conducted as part of a 2 stage, randomised, open-label, single-dose, 4-part crossover design pharmacokinetic study to assess the pharmacokinetics and potential of Example 1 TTS formulations for equivalence to the existing commercial formulation BuTrans®, also known as Norspan®.
The study treatments were as follows:
Test treatment: Example 1 TTS (the amount of buprenorphine base being 6.75 mg; the area of release being 15 cm2)—applied for 7 consecutive days.
Reference treatment: BuTrans® 20 μg/hr (the amount of buprenorphine base being 20 mg; the area of release being 25 cm2)—applied for 7 consecutive days.
Further study treatments were administered in the 2 stage study but are not described herein.
The treatments were each worn over a 7-day period. Each subject was randomised to both the order, and TTS site of the treatments to be delivered over the study periods.
As this study was conducted in healthy human subjects, the opioid antagonist naltrexone was co-administered to reduce opioid-related adverse events. 50 mg naltrexone were administered with 100 ml of water every 12 hours beginning −13 hours prior to TTS application and continuing until 215 hours post-TTS application.
It was anticipated that approximately 32 subjects would be randomized into stage 1 of the study, with 26 subjects targeted to complete stage 1 of the study. An adequate number of subjects were screened in the pre-treatment phase, i.e. within 21 days prior to the treatment phase to achieve this sample size.
Screening procedures were performed for all potential subjects at a screening visit conducted within 21 days prior to the treatment phase, i.e. prior to Day −1 of study period 1. The following evaluations were performed after the subject has signed the study specific consent form:
Subjects who met the following criteria were included in the study.
The following criteria excluded potential subjects from the study.
Subjects meeting all the inclusion criteria and none of the exclusion criteria were randomized into the study.
Randomisation was completed once all inclusion and exclusion criteria are verified. Randomisation order was determined on a central randomisation list held at site (one list per site).
Subjects were randomised to the order of the treatments and the skin TTS application sites.
There are 4 possible TTS application sites:
On each day prior to treatment (e.g. Day −1 or Day 17), subjects were checked in to the study unit. The following procedures were undertaken:
The treatment phase included study periods with a single dose application. The following procedures were undertaken in each period:
Where more than one procedure was scheduled at the same time-point, the following order of procedures was ideally followed:
Throughout the Study Period when subjects had the TTS applied, they were allowed to have a shower (not bath) but they had to refrain from washing, or rubbing the site of TTS application. The subjects should also refrain from showering until the day after TTS application. The TTS was removed on the eighth day of the Study Period following the blood draw at 168 hours after TTS application.
There was a minimum 10 day washout period between removal of one TTS and application of another.
Subjects were confined to the study unit from Check-In on the day before study drug administration until the time that the 192 hour post-TTS application procedures were completed. Subjects returned to the unit for the 216, 240, 264 and 288 hours post-study procedures and the Post-Study Medical. During confinement in the unit, subjects will receive standardised meals.
Blood samples for pharmacokinetic assessments were obtained for each subject at predose and at 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 169, 172, 176, 180, 192, 216, 240, 264 and 288 hours post-TTS application.
For each sample, 4 ml of blood were drawn into 4 ml tubes containing K2EDTA solution, an anticoagulant. Samples were centrifuged within 30 minutes of collection. Following centrifugation (1500 G, 4° C., 15 minutes), the plasma was transferred, via pipette, into 2 labelled 3 ml polypropylene tubes, and stored at −20° C. within 1 hour of collection.
Plasma concentrations of analytes were quantified by liquid chromatography—tandem mass spectrometric methodology (LC-MS/MS) using a previously validated assay.
For each subject, the following pharmacokinetic parameters were calculated based on the plasma concentrations of buprenorphine:
Plasma concentration values below the level of quantitation were set to equal zero for the analysis.
AUC values were calculated using the linear trapezoidal method. After removal of the BTDS, where possible, LambdaZ values were estimated using those points determined to be in the terminal log-linear phase. t½Z was determined from the ratio of ln 2 to LambdaZ.
Subjects who met one or more of the following stopping criteria were discontinued from the study:
As per the inclusion/exclusion criteria, subjects had to be willing to eat all the food supplied throughout the study. Menus were standardised while subjects are in the study unit. The menus were the same for each study period. However, the menus for each day needed not be identical. Subjects had to consume only the food given to them while in the unit. Food and water will be restricted as follows:
Subjects had to abstain from smoking within 45 days of study drug administration and during the entire study. Subjects had to abstain from alcohol from 48 hours before the first study drug administration until 72 hours after the last naltrexone dose of the last study period. Caffeine or xanthine containing food or beverages were not permitted during the study from check-in before treatment, until after the last study pharmacokinetic sample has been taken.
Subjects that completed the treatment phase or who discontinued treatment early were followed up within 7 to 10 days after the Subject's last visit/dose of study medication.
Study Completion Procedures
Subjects that completed the Treatment Phase carried out the following Completion/Discontinuation Visit procedures:
The results of this study are shown in
an = number of subjects with data available (non-zero values).
bMean = arithmetic mean; the sum of all the values of observations divided by the total number of observations.
cSD = standard deviation.
dSE = standard error.
eGeoMean = geometric mean; the mean of the log transformed data backtransformed to the original scale.
flog SD = standard deviation of the log transformed data.
glog SE = standard error of the log transformed data.
hMin = minimum value.
iMedian = middle value when the list of values is ranked.
kMax = maximum value.
lNA = not applicable.
aData analysed using a mixed effects linear model with treatment, actual sequence and period as fixed effects and subject within sequence as random effect. The analyses only consider subjects who completed both periods of the respective treatment comparison.
bLeast square mean; back-transformed from log scale to linear scale.
cLeast square mean; back-transformed from difference on log scale to ratio on linear scale.
dNumber of subjects with data for both Example 1 TTS and BuTrans ® available.
eequivalent to relative Cmax ratio.
fequivalent to relative bioavailability.
aData analysed using a mixed effects linear model with treatment, actual sequence and period as fixed effects and subject within sequence as random effect. The analyses only consider subjects who completed both periods of the respective treatment comparison.
bLeast square mean.
cNumber of subjects with data for both Example 1 TTS and BuTrans ® available.
aCalculated based on the individual subject data of Example 1 TTS (6.75 mg).
The invention relates in particular to the following further items:
1. Transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising
| Number | Date | Country | |
|---|---|---|---|
| 61736342 | Dec 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14650451 | Jun 2015 | US |
| Child | 15915369 | US |
