WO2007121949A1 - Systeme de liberation cutanee comprenant du sufentanil et ses analogues - Google Patents

Systeme de liberation cutanee comprenant du sufentanil et ses analogues Download PDF

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Publication number
WO2007121949A1
WO2007121949A1 PCT/EP2007/003498 EP2007003498W WO2007121949A1 WO 2007121949 A1 WO2007121949 A1 WO 2007121949A1 EP 2007003498 W EP2007003498 W EP 2007003498W WO 2007121949 A1 WO2007121949 A1 WO 2007121949A1
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WO
WIPO (PCT)
Prior art keywords
patch
sufentanil
patch system
patient
period
Prior art date
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PCT/EP2007/003498
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English (en)
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WO2007121949A8 (fr
Inventor
Armin Breitenbach
Peter Klaffenbach
Ingo Lehrke
Ulrike Vollmer
Original Assignee
LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH
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Priority claimed from DE102006019293A external-priority patent/DE102006019293A1/de
Application filed by LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH filed Critical LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH
Priority to JP2009505791A priority Critical patent/JP2009534343A/ja
Priority to EP07724434A priority patent/EP2023907A1/fr
Priority to CA002646206A priority patent/CA2646206A1/fr
Publication of WO2007121949A1 publication Critical patent/WO2007121949A1/fr
Priority to US12/255,466 priority patent/US20090130190A1/en
Publication of WO2007121949A8 publication Critical patent/WO2007121949A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene

Definitions

  • the present invention relates to methods and systems for the transdermal delivery of sufentanil and related analogs such as fentanyl.
  • the invention also relates to a sufentanil patch having a unique pharmacokinetic profile that can be used to treat persistent pain over extended periods and acute pain episodes of limited duration.
  • Sufentanil is a powerful synthetic opioid in the fentanyl family of compounds that has proven utility in human medicine.
  • the drug is chemically known as N-[4-(methoxymethyl)-l- [2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenyl-propanamide, and is characterized by the following chemical structure:
  • the drug has a number of analogs in the fentanyl family of compounds, including fentanyl, lofentanil, alfentanil, carfentanil, and remifentanil.
  • Injectable formulations of sufentanil as its citrate salt have been approved in the United States for general anesthesia under the trademark Sufenta ® .
  • a transdermal patch is a drug containing adhesive bandage which, when applied to the skin, delivers the drug through the skin of a patient at a predetermined rate.
  • the simplest type of patch is an adhesive monolith comprising a drug-containing matrix disposed on a flexible backing.
  • the matrix is typically formed from a pressure sensitive adhesive so that the matrix can be adhered directly to the skin, although the matrix can also be formed from a non- adhesive material, in which case an additional adhesive layer is formed on the skin-contacting surface of the matrix.
  • the rate at which the drug is delivered from these patches can vary due to differences in skin permeability among people and skin application sites.
  • More complex patches are multilaminate or liquid reservoir types of patches in which a drug release-rate controlling membrane is disposed between the reservoir layer and the skin-contacting adhesive. This membrane, by decreasing the in vitro release rate of drug from the patch, can reduce the effects of variations in skin permeability.
  • sufentanil has a solubility in skin of about 25-50% of fentanyl.
  • the patch suffers from a number of drawbacks, including a high lipophilicity, which results in accumulation of drug in the fatty tissue, and drug release from the fatty tissues back into the circulation in later times; a phenomenon known as the skin depot effect. In the clinic, this is significant because several applications of the patch must occur before titrating the dose upward, to ensure that maximum steady state blood concentrations have been reached before adjusting the dose.
  • transdermal opioid patches designed for periodic replacement should deliver slow and steady amounts of drug over the course of a single application of the patch, and that this slow and steady delivery over a single application was needed to ensure clinically meaningful constancy in plasma concentrations over repeated patch applications.
  • This thinking is most evident in WO 2006/047362 by Durect Corporation, which shows slow uptake of sufentanil over the first twenty-four hours of patch application, and fairly constant plasma levels of sufentanil over the next six consecutive days.
  • the patch achieves substantially zero order kinetics over the course of up to seven days from application of a single patch.
  • the examples describe a patch that contains 15.4 wt.% of a high MW polyisobutylene (Oppanol BlOO), 22 wt% of a low MW polyisobutylene (Oppanol B 12), 48.5 wt.% polybutene, 6.5 wt.% CAB-O-SiI, and 7.7 wt.% sufentanil.
  • Plasma levels from the Durect patch as reported in WO 2006/047362, are plotted in Figures 6 and 7 hereto.
  • a prior art sufentanil patch is also described in WO 02/074286 by Alza Corporation, which describes a sufentanil patch that exhibits proportionate amounts of sufentanil penetration in vitro when the concentration of sufentanil in the patch is increased, and fairly steady sufentanil flux rates over the first 36 or 72 hours of patch administration, especially at lower doses.
  • the examples describe a 2.54 cm 2 patch containing 0.25, 0.5, 0.75, 1.0 or 1.1 mg. sufentanil (corresponding to 2, 4, 6, 8 and 9 wt.% sufentanil), in a polyacrylate matrix, optionally with a permeation enhancer.
  • Figure 4 from Alza's application reports in vitro skin flux rates from the patch at the various sufentanil concentrations.
  • the sufentanil patch described therein can achieve a standardized flux rate of from about 0.1 to about 10 mcg/(cm 2 -hr), and a normalized C max (defined as C max divided by nominal in vivo flux rate), of from about 0.04 to about 10 ng/(ml-(mg/hr)).
  • the publication does not disclose how fast a sufentanil patch would reach C max , but discloses a fentanyl patch that reaches Cm, * within about 24 hours.
  • a significant concern with opioid patches is patch diversion, and the illicit use of opioid remnant after the patch is removed and discarded.
  • the present inventors have developed a patch that delivers sufentanil and its analogs for achieving clinically significant sustained pain relief — over a period of at least three days from a single patch ⁇ by achieving a high C max in a relatively short time frame, relative to the patch's average delivery rate.
  • the patch can reach plasma concentrations of at least 80% of C m2x (maximum plasma concentration) within about twelve hours of patch application, and still provide sustained pain relief for periods of at least three days.
  • these patches provide long-term and short term analgesic effect while (1) lessening the amount of active ingredient required in the patch, and (2) reducing remnant drug in the patch when it is removed and discarded.
  • these patches are characterized by a three day administration period, and a normalized Cmax (defined as Cmax divided by drug flux) over the three day period of greater than 15 or even 20 ng/(ml-(mg/hr)).
  • the patches are characterized by a standardized Cm 3x (defined as C max divided by the patch's surface area) of greater than 0.01 or even 0.03 ng/(ml-cm 2 ).
  • the patches are characterized by a Tm 3x of about 18 hours or less, or an 80% T max (i.e. time required to reach 80% C max ) of about 12 hours or less.
  • Another feature of the present invention which did not become apparent until multiple dose studies were undertaken and steady state pharmacokinetic properties were analyzed, is the relationship between mean steady state plasma concentration and steady state nominal flux.
  • theoretical calculations using intravenous infusion studies would predict that 1 mcg/hr would yield sufentanil plasma concentrations of less than 10 pg/ml (see example 9), and single dose bioavailability testing is consistent with these predictions, the inventors have discovered that at steady state the patches achieve greater than 15 pg/ml average plasma concentrations. Therefore, in another embodiment, the patches are characterized by a ratio of average plasma concentration to nominal flux of greater than 1.5*10 's hr/ml.
  • the rapid delivery of the active ingredient from the current patches can be characterized by one or more of the following pharmacokinetic parameters (preferably defined over a three day application period):
  • the patches will typically be applied to patients who are already receiving opioid therapy, as a replacement for existing intravenous or oral opioid medications.
  • a patient receiving anywhere from about 60 to about 134 mg/day of oral morphine would initially be prescribed a patch that delivered about 3.5 mcg/hr of sufentanil (averaged over a prescribed administration period).
  • the patch dose can be increased based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 1.75 mcg/hr increase in sufentanil delivery.
  • the invention relates to the use of polyisobutylene as the principle matrix component of a patch containing sufentanil or one of its analogs, in which the matrix comprises greater than 50 wt.% polyisobutylene, in which the ratio of low MW polyisobutylene to high MW polyisobutylene is preferably greater than 2: 1, 3: 1 or 4: 1, and preferably less than 20: 1.
  • the invention relates to the use of an irritation reducing agent such as calcium glycerophosphate in the formulation.
  • FIGURE l is a top plan view of an adhesive matrix patch constructed according to the present invention.
  • FIGURE 2 is a side perspective view of an adhesive matrix patch constructed according to the present invention, showing a preferred three layer construction.
  • FIGURE 4 is a graphical comparison of in vivo plasma levels over time, normalized based on 100% of C m3x for each patch, for two different patches: (1) a 2.5 cm 2 patch constructed according to the present invention containing 0.625 mg of sufentanil base, and (2) a Duragesic ® fentanyl patch having a nominal flux rate of 25 mcg/h.
  • the sufentanil patch shows a T m a x at 12 hours; the fentanyl patch at 24 hours.
  • FIGURE 5 is a graphical comparison of the coefficients of variation (CV) in C max for the two patches depicted in Figure 4.
  • the sufentanil patch is represented by the lower line; the fentanyl patch is depicted by the upper line.
  • FIGURE 6 is a graphical comparison of in vivo plasma levels over time for three different patches: (1) a 2.5 cm 2 patch constructed according to the present invention containing 0.625 mg of sufentanil base, (2) a 2.0 cm 2 patch constructed according to WO 2006/047362 containing 0.91 mg of sufentanil base, and (3) a 2.0 cm 2 patch constructed according to WO 2006/047362 containing 1.7 mg of sufentanil base.
  • FIGURE 7 is a graphical comparison of in vivo plasma levels over time for the same three patches depicted in FIGURE 6, in which the plasma levels are normalized based on the application area of the patch.
  • FIGURE 9 is a graphical depiction of the coefficient of variation for in vivo plasma levels over time for a 2.5 cm 2 patch constructed according to the present invention containing 0.625 mg of sufentanil base, in the phase I multi-dose bioavailability study depicted in FIGURE 8, wherein a fresh patch is applied every three days.
  • wt. % as used herein with reference to the final product (i.e., the patch, as opposed to the formulation used to create it), denotes the percentage of the total dry weight contributed by the subject ingredient. This theoretical value can differ from the experimental value, because in practice, the patch typically retains some of the solvent used in preparation.
  • drug refers to sufentanil and its analogs and includes sufentanil, fentanyl, lofentanil, alfentanil, carfentanil, remifentanil, and the like, and pharmaceutically acceptable salts and esters thereof.
  • a preferred drug is sufentanil, and it is preferably used as the base molecule.
  • the term "subsaturated patch” refers to a patch wherein the concentration of the drug is below its solubility limit.
  • the matrix layer typically comprises a single phase polymeric composition wherein the drug and all other components are present at concentrations no greater than, and preferably less than, their saturation concentrations in the matrix.
  • single phase polymeric composition refers to a composition in which the drug is solubilized in a polymer and is present at a concentration no greater than, and preferably less than, its saturation concentration in the matrix; wherein the active ingredient in combination with the polymer forms a single phase.
  • first sufentanil patch system refers to the first sufentanil patch system to be analyzed, and does not refer to the first sufentanil patch system ever to be administered to an individual during a sufentanil treatment regime.
  • a “first sufentanil patch system” can refer to the first, second, third etc. sequential system applied to an individual.
  • the "initial” patch system or the “first in sequence” patch system When this document intends to reference the very first sufentanil patch system applied to an individual, it will be referred to as the "initial” patch system or the "first in sequence” patch system.
  • the "first” period does not necessarily refer to the first ever period. Rather, the term “initial” or other wording of like import will be used to refer to the first period in time.
  • the present invention provides a method and patch for the transdermal delivery of sufentanil and its analogs, preferably for the treatment of pain and the provision of sustained analgesia.
  • the patch preferably delivers the drug at a rate and in an amount sufficient to induce and maintain analgesia over a period equaling or greater than two, three or four days, and up to 7 days, to a patient in need thereof.
  • the pain is acute.
  • the pain is chronic.
  • the pain is persistent moderate to severe chronic pain.
  • the patch typically comprises a protective flexible cover, an intermediate active ingredient layer having an adhesive surface opposite said protective cover, and a removable cover layer adjacent said adhesive surface.
  • active ingredient diffuses into and through the skin where it is absorbed into the bloodstream to produce a systemic analgesic effect.
  • the onset of analgesia depends on various factors such as the solubility and diffusivity of the drug in the skin, thickness of the skin, concentration of the drug within the skin application site, concentration of the drug in the matrix layer, and the like. It is preferable that a patient experience an adequate effect within eight hours of initial application. However, this is significant only on the initial application.
  • the residual drug in the application site of the patch is absorbed by the body at approximately the same rate as the drug from the new patch is absorbed into the new application area. Thus the patient should not experience any interruption of analgesia.
  • the depleted patch is removed and a fresh patch applied to a new location.
  • the patch or patch system would be sequentially removed and replaced with a fresh patch or patch system at the end of the administration period to provide sustained relief from pain.
  • absorption of the drug from the fresh patch into the new application area usually occurs at substantially the same rate as absorption by the body of the residual drug within the previous application site of the patch, blood levels will remain substantially constant. Additionally, it is contemplated that doses may be increased over time and that concurrent use of other analgesics may occur to deal with breakthrough pain.
  • the term "patch system” is used herein to refer to one or a plurality of patches applied during an administration period.
  • a "patch system” could be made from several base patches dosed simultaneously, or it could be a single larger patch having a surface area and drug delivery rate equal to a multiple of the surface area and drug delivery rate of a base patch.
  • the total surface area of the base patch could be defined as the base surface area and, because the delivery rate from transdermal patches is linearly related to the total surface area of the patch, successively larger patch systems would have surface areas of n-(base surface area), wherein n is an integer of from two to about ten.
  • the base patch system of the present invention is preferably designed to achieve mean steady state plasma concentrations greater than or equal to the minimum effective plasma concentration, or to ensure that the plasma concentration at steady state does not fall beneath the lowest effective level.
  • a base patch will typically have a base delivery rate of from about 2.0 to about 7.0 mcg/hr, or any rate in between.
  • the base patch will have a base delivery rate of from about 2.5 to about 6.0 mcg/hr, from about 4.0 to about 5.0 mcg/hr, or from about 3.0 to about 3.5 mcg/hr.
  • the patch can be described as having a base delivery rate of about 2.0 ⁇ 0.3, 2.5 ⁇ 0.3, 3.0 ⁇ 0.3, 3.5 ⁇ 0.3, 4.0 ⁇ 0.3, 4.5 ⁇ 0.3, 5.0 ⁇ 0.3, or 5.5 ⁇ 0.3, mcg/hr.
  • the patch is described as having a base delivery rate of about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5 mcg/h, optionally ⁇ 0.1, 0.2 or 0.3 mcg/hr.
  • Successively larger patch systems will have a delivery rate equal to n-(base delivery rate), wherein n is an integer of from two to about ten.
  • the patch structure comprises the patch 1 that is applied to the skin, and a removable protective layer/release liner 2 that is removed from the patch before application.
  • the patch 1 preferably comprises an adhesive layer or matrix 3 and a non-reactive cover layer 4.
  • the active ingredient is integrated within the adhesive layer or matrix, and removal of the release liner 2 exposes the adhesive layer 3 which can then be applied to the skin.
  • the patch structure including the patch 1 and removable protective layer 2 is preferably packaged in a foil package that is resistant to light and moisture.
  • Other structures that the patches can assume include those with additional layers, such as an adhesive layer between the drug matrix and release liner, or a primer between the drug matrix and the cover layer, as taught by Park et al. in U.S. Patent No. 6,190,690.
  • a base patch for the active ingredient can be any shape, but is preferably rectangular in shape, with a surface area of from about 1.0 cm 2 to about 25 cm 2 , most preferably about 1.5 cm 2 to about 5 or 10 cm 2 .
  • the thickness of the matrix layer preferably is such that from about 0.10 mg to about 2.0 mg., from about 0.15 to about 0.50 mg., or from about 0.20 to about 0.40 mg., are present in each square centimeter of the patch (most preferably about 0.25 mg/cm 2 ).
  • the thickness of the matrix layer can vary from about 5 to about 40 mil, and is preferably from about 10 to about 25 mil in thickness when applied wet during manufacture.
  • the non-reactive cover layer 4 plays an important part in the wearability of the patch. Because the transdermal system is applied to moving parts of the human body, a high degree of flexibility is necessary. It is also preferable that the cover layer 4 have good permeability to water vapor so as not to occlude the skin. Suitable materials for cover layer 4 include plastic films of polyethylene, vinyl acetate resins, ethylene/vinyl acetate copolymers, polyvinyl chloride, polyurethane, polypropylene, metal foils, woven fabrics, non-woven fabric, cloth and commercially available laminates. The backing material generally has a weight from about 2.0 to about 2.5 mg/cm 2 . A bidirectional elastic material such as, for example, a non-woven polypropylene fabric, is particularly useful.
  • Protective layer 2 is preferably a sheet-like material constructed of materials that are inert to the matrix layer, and that can be readily separated from the matrix layer.
  • the protective layer materials include polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, and the like, and combinations thereof.
  • the patches of the current invention reach Cj n a x in fairly short order, they reach a much higher C m3x than a competitive patch, and they have average plasma concentrations larger than a competitive patch, even though the patches of the current invention have a lower load of sufentanil.
  • the base 2.5 cm 2 patch containing 0.625 mg. of sufentanil which could form the basis of other patches systems, produces opioid concentrations during the first seventy-two hours that are confined predominantly between (i.e. no more than 10, 20 or 40% outside of) a minimum effective level (30 pg/ml for sufentanil) and an average effective level (60 pg/ml for sufentanil), as described in the examples hereto.
  • C m3x refers to the peak blood or plasma concentration of the drug when administered according to the methods of the present invention.
  • C max (80%) refers to a blood or plasma concentration of the drug that is reached before C max is reached, amounting to 80% of the C m3x for the drug.
  • the base sufentanil patch of the current invention can be described as having a C 013x during the first seventy two hours of the initial dose of about 45, 50, 55, 60, 65, 70, or 75 pg/ml ( ⁇ 20%).
  • the base sufentanil patch of the current invention can be described as having a C 1113x of about 55, 60, 65, 70, 75, 80, 85 or 90 pg/ml ( ⁇ 20%). Larger patch systems would typically be designed to reach a multiple of the C 1113x achieved by the base sufentanil patch, i.e. n-(C m3X .b aS e), wherein n is an integer between 2 and 10.
  • the base sufentanil patch is described as having a Cm 3x greater than about 45, 50, 55, or 60 pg/ml, and less than about 85, 80, 75 or 70 pg/ml, during the first seventy two hours of the initial dose, in any combination of mathematically possible endpoints.
  • the base sufentanil patch can be described as having a C 013x greater than about 55, 60 or 65 pg/ml, and less than about 90, 85 or 80 pg/ml, in any combination of mathematically possible endpoints.
  • the term "standardized C m3x (pg/ml-cm 2 )" refers to the C m3X (pg/ml) per unit area (cm 2 ) of the active drug delivery area of the system, e.g., the area of the matrix layer.
  • the sufentanil patch is described as having a standardized C max of 20.0, 25.0, 27.5, 30.0, 32.5, 35.0, or 40.0 pg/ml-cm 2 ( ⁇ 20%), during the initial dose or at steady state.
  • the sufentanil patch is described as having a standardized C 013x greater than about 20.0, 25.0, 27.5, 30.0, 32.5, or 35 pg/ml-cm 2 , and less than about 42.5, 40.0, 37.5 or 35.0 pg/ml-cm 2 , in any combination of mathematically possible endpoints, during the initial dose or at steady state.
  • normalized C m3x refers to the C max (pg/ml) divided by the average drug flux over a defined period of time (mcg/h).
  • the sufentanil patch is described as having a normalized C max of 10.0, 11.0, 12.5, 14.0, 15.5, 17.0, 18.5, 20.0, 21.5, 23.0, 24.5 or 26.0 pg/ml-(mcg/h) ( ⁇ 5, 10 or 20%), when the patch is applied initially or at steady state.
  • the sufentanil patch is described as having a normalized C max of greater than about 10.0, 11.0, 12.5, 14.0, 15.5, 17.0 or 18.5, 20.0 or 21.5 pg/ml-(mcg/h), and less than about 20, 25, 30 or 35 pg/ml-(mcg/h), when the patch is applied initially or at steady state, in any combination of mathematically possible endpoints.
  • the invention is characterized based upon the average plasma concentrations observed for the patch at steady state, relative to the steady state flux of drug from the patch. Whereas infusion rates would suggest that 1 mcg/hr flux would result in a steady state plasma concentration of less than 10 pg/ml, the present inventors have discovered that the steady state delivery of about 3.5 mcg/hr by the patches of the present invention results in a steady state plasma concentration of about 53.8 pg/ml. I.e. the patches of the present invention result in a ratio of mean plasma concentration to nominal (i.e. steady state) flux of greater than 1.0* 10 '5 hr/ml, 1.2*10 '5 hr/ml, 1.4*10- 5 hr/ml, or even 1.5* 10 "5 hr/ml.
  • the patches are characterized by the time it takes to reach maximum plasma concentrations, or the time it takes to reach 80% of the maximum plasma concentration.
  • the patch or patch system is described as reaching T 1113x in about 24, 21, 18 or 15 hours or less, or an 80% T n ⁇ x (i.e. time required to reach 80% Cmax) of about 22, 18, 15, or 12 hours or less.
  • a particularly important characteristic of the patches of this invention is the quick onset of plasma concentrations, and the quick decrease in plasma concentrations when the patch is removed.
  • the patches of the present invention exhibit an average plasma half life of less than 12 or 10 hours, or ranging from 8 to 11, or 9 to 10 hours.
  • 50% T max is preferably achieved in less than 10 or even 8 hours.
  • the patches are characterized by a high C 013x relative to the amount of active ingredient in the patch. Therefore, in one embodiment the patch is characterized by a loaded C 1113x (i.e. ratio of Cm 3x to amount of sufentanil in the patch) (pg/ml-mg) of from about 50 to about 200 pg/ml-mg, from about 70 to about 150 pg/ml-mg, or from about 100 to about 135 pg/ml-mg. In another embodiment, the invention is characterized by a loaded C n ⁇ x of 80, 90, 100, 110, 120, 130 or 140 pg/ml-mg ( ⁇ 20%).
  • the patches are characterized by a high C m3x relative to the amount of active ingredient that is ultimately delivered to the patient over the prescribed application period ("release load C m3x " - defined as the ratio of C max to amount of sufentanil released from the patch, as measured by the reduction in weight of the patch). Therefore, in one embodiment the patch is characterized by a release load C max (pg/ml-mg) of from about 100 to about 400 pg/ml-mg, from about 140 to about 300 pg/ml-mg, or from about 200 to about 270 pg/ml-mg. In another embodiment, the invention is characterized by a release load C 013x of 160, 180, 200, 220, 240, 260 or 280 pg/ml-mg ( ⁇ 20%).
  • the patches are characterized by a large average plasma concentration for a prescribed application period relative to the active ingredient loading in the patch.
  • the patches achieve an average plasma concentration divided by the sufentanil load in the patch of greater than 4*10 '8 , 5*10 '8 , 6*10 "8 , 7* 10 '8 , or 4*10 "8 ml "1
  • the patches can be characterized by the ratio of maximum to minimum plasma concentrations, over a prescribed administration period, wherein C n ⁇ is identified after C max has been reached.
  • the patches are characterized by a C m a x iC m i n ratio of greater than about 1.5, 1.6, 1.7, 1.8, 1.9, or even 2.0, and less than about 3.0 or 2.5, over a forty-eight hour, seventy two hour, or ninety six hour administration period for a single patch system.
  • the patches are characterized by a low coefficient of variation in maximum plasma concentrations, especially as compared to the commercial Duragesic ® product.
  • the coefficient of variation for C 13x is less than 40%, 30%, or even 25%.
  • a preferred embodiment of this invention is a patch that is bioequivalent to the patches described in the Examples of the present invention, when applied over a period of about two, three or four days.
  • the invention provides a patch that is bioequivalent to a reference patch, wherein said reference patch is a matrix patch made by a process comprising: (a) dissolving in hexane 1.0 weight parts of a high molecular weight polybutene, 5.0 weight parts of a low molecular weight polyisobutylene, and 2.0 weight parts polybutene to form an adhesive mixture; (b) dissolving 0.25 weight parts of sufentanil base in ethyl acetate to form a drug mixture; (c) mixing 0.25 weight parts of calcium glycerophosphate in said drug mixture to form a CGP mixture; (d) mixing said adhesive mixture and said CGP mixture to form a mixed liquid, and stirring said mixed liquid for one hour; (e) coating said mixed liquid onto a release liner at a
  • a standard bioequivalence study is conducted in a crossover fashion in a small number of volunteers, usually with 24 to 36 healthy normal adults.
  • Single doses of the test and reference products are administered and blood or plasma levels of the drug are measured over time.
  • Characteristics of these concentration-time curves such as the area under the blood or plasma drug concentration-time curve (AUC), the peak blood or plasma concentration (C m3x ) of the drug, and/or time to peak plasma concentration (T m ax), are examined by statistical procedures as described in greater detail hereinafter.
  • AUC area under the blood or plasma drug concentration-time curve
  • C m3x peak blood or plasma concentration
  • T m ax time to peak plasma concentration
  • the two one-sided tests are carried out at the 0.05 level of significance and the 90% confidence interval is computed.
  • the test and the reference formulation/composition are considered bioequivalent if the confidence interval around the ratio of the mean (test/reference product) value for a pharmacokinetic parameter is no less than 80% on the lower end and no more than 125% on the upper end.
  • the peak blood or plasma concentration of the drug (C max ) is standardized per unit area of the active drug delivery area of the system in order to establish bioequivalence.
  • the methods of treatment of the present invention are initiated in those patients who are opioid tolerant, and the patches are dosed based on the dose of opioid being administered daily to the patient (i.e. the opioid demand).
  • the opioid demand i.e. the opioid demand
  • the methods of the present invention are initiated in a patient that has an existing opioid demand equipotent to n-90 mg/d of oral morphine (i.e.
  • the patient is receiving opioids of a type and in an amount that is equipotent to about 90 mg/day of oral morphine, or a multiple thereof), and said first patch system delivers n-(6.0 ⁇ 0.5), n-(6.5 ⁇ 0.5), n-(5.0 ⁇ 0.5), n-(4.5 ⁇ 0.5), n-(4.0 ⁇ 0.5), n-(3.5 ⁇ 0.5), n-(3.0 ⁇ 5) or n-(2.5 ⁇ 0.5) mcg/hr of sufentanil, wherein n is an integer of from 1 to 12.
  • the patient that has an existing opioid demand equipotent to n-90 mg/d of oral morphine may be initially prescribed a patch system that delivers n-(1.0 to 8.5), n-(2.5 to 4.0), or n-(4.0 to 5.5) mcg/hr of sufentanil, wherein n is an integer of from 1 to 12.
  • a patient will not always be prescribed exactly 90 mg/d of oral morphine or a multiple thereof, in which case the conversion may be established using the following table, which is derived from the prescribing information for Duragesic ® : RECOMMENDED INITIAL SUFENTANIL PATCH DOSAGE BASED UPON DAILY ORAL MORPHINE DOSE
  • oral oxycodone is twice as potent as oral morphine
  • a patient receiving 45 mg/d of oral oxycodone would initially preferably be prescribed a patch system that delivers about 3.5 mcg/hr, which is the same dose that a patient on 90 mg/d of oral morphine would preferably receive.
  • the first patch system will most often be only the first in a series of treatments for delivering sustained analgesia over extended periods of time.
  • the invention when a second patch system is applied after the first period ends and the first patch system is removed, the invention further provides adhering a second patch system to the skin of said patient after said first period, for a second period of at least two or three days, wherein said second patch system demonstrates a second Cmax, and wherein said first and second patch systems are defined by an identical composition and size.
  • the first C max and second C m a x are preferably the same or similar, and in various embodiments the first and second C max values vary by 20%, 15%, 10% or 5 % or less. Alternatively, the first and second C max values may vary by 5%, 10%, 15% or 20% or more.
  • the dose of active ingredient is adjusted upward after the first patch administration if the patient experiences inadequate pain control during the first period of application.
  • the second patch system will have an in vivo flux rate greater than said first patch system.
  • the additional sufentanil dose can often be calculated based upon the amount of supplemental opioid taken by the patient during the first period, using the ratio of 1.75 mcg/hr sufentanil ( ⁇ 0.25 mcg/hr) for every 45 mg/d oral morphine taken by the patient during the first period, or equipotent opioid dose.
  • the methods of the present invention are characterized by a patient who experiences inadequate pain control during the first period, further comprising: (a) administering a supplemental opioid dose equipotent to n-45 mg/d oral morphine during said first period, and (b) administering a second patch system having an in vivo flux rate equal to the in vivo flux rate of said first system, plus n-(1.75 ⁇ 0.25) mcg/hr of sufentanil, wherein n is an integer of from 1 to 5.
  • the dose of active ingredient is not adjusted upward until after the initial and second or subsequent patch administration if the patient experiences inadequate pain control during the initial and second periods of application.
  • the second patch system will have a size and a composition the same as the initial patch system.
  • a third patch system may be applied having additional sufentanil.
  • the additional sufentanil dose can often be calculated based upon the amount of supplemental opioid taken by the patient during the second period, using the ratio of 1.75 mcg/hr sufentanil ( ⁇ 0.25 mcg/hr) for every 45 mg/d oral morphine taken by the patient during the second period, or equipotent opioid dose.
  • the methods of the present invention are characterized by a patient who experiences inadequate pain control during the initial period, further comprising: (a) administering a supplemental opioid dose equipotent to m-45 mg/d oral morphine during said second period, and (b) administering a third patch system having an in vivo flux rate equal to the in vivo flux rate of said first system, plus m-(1.75 ⁇ 0.25) mcg/hr of sufentanil, wherein m is an integer of from 1 to 5.
  • the matrix preferably comprises a single phase polymeric composition containing an amount of active ingredient sufficient to induce and maintain analgesia in a human for at least three days.
  • the matrix layer comprises about 0.05 to about 1.75 mg/cm 2 of sufentanil; preferably about 0.07 to about 1.50 mg/cm 2 of sufentanil; preferably about 0.08 to about 1.25 mg/cm 2 of sufentanil; more preferably about 0.09 to about 1.0 mg/cm 2 of sufentanil; more preferably about 0.1 to about 0.75 mg/cm 2 of sufentanil; more preferably about 0.12 to about 0.5 mg/cm 2 of sufentanil; and even more preferably about 0.2 to about 0.4 mg/cm 2 of sufentanil.
  • the sufentanil is preferably in a base form and it is preferably completely dissolved.
  • the matrix layer 3 is formed from a pharmaceutically acceptable pressure sensitive adhesive such as, for example, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like.
  • a pharmaceutically acceptable pressure sensitive adhesive such as, for example, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like.
  • styrenic block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene- styrene copolymer (SBS), styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogs thereof.
  • SIS styrene-isoprene-styrene block copolymer
  • SBS styrene-butadiene- styrene copolymer
  • SEBS styrene-ethylenebutene-styrene copolymers
  • Acrylic polymers may be comprised of a copolymer or terpolymer comprising at least two or more exemplary components selected from the group comprising acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups
  • Examples of monomers include, but are not limited to, vinyl acetate, acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl
  • the matrix layer of the patches is characterized by a polyisobutylene content of greater than about 40 wt.%, 50 wt.%, 60 wt.%, or even 70 wt.%.
  • the matrix layer is characterized by a polyisobutylene content of greater than 25 wt.%, 50 wt.%, 60 wt.%, or even 70 wt.%, wherein said polyisobutylene is a combination of high molecular weight and low molecular weight polyisobutylene chains, and the ratio of low MW polyisobutylene to high MW polyisobutylene is greater than 2: 1, 3: 1 or 4: 1.
  • a high MW polyisobutylene is defined as a polyisobutylene having a molecular weight greater than 250,000, 650,000, or 1,000,000 g/mol
  • a low MW polyisobutylene is defined as a polyisobutylene having a molecular weight of less than 250,000, 100,000 or 40,000 g/mol.
  • a plasticizer or tackifying agent is incorporated in the adhesive composition to improve the adhesive characteristics.
  • suitable tackifying agents include, but are not limited to, aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters; polyterpenes; hydrogenated wood resins; tackifying resins such as ESCOREZ, aliphatic hydrocarbon resins made from cationic polymerization of petrochemical feedstocks or the thermal polymerization and subsequent hydrogenation of petrochemical feedstocks, rosin ester tackifiers, and the like; mineral oil and combinations thereof.
  • a particularly preferred tackifying agent is polybutene.
  • the matrix comprises polyisobutylene and polybutene at a weight ratio of from about 1 : 1 to about 6: 1, or from about 2: 1 to about 5:1, preferably about 3: 1.
  • the matrix layer also contains the active ingredient of the patch (i.e. sufentanil or an analog thereof) solubilized in the matrix.
  • the drug can be in base, salt or ester form, though it is preferably supplied in the form of its base.
  • the matrix layer preferably comprises from about 1 to about 20 wt.%, from about 1.5 to about 10 wt.%, or from about 2 to about 5 wt.%, based on the solids content of the matrix layer.
  • the patch has an area of about 2.5 cm 2 , or a multiple thereof, and comprises about 0.25 mg of sufentanil per cm 2 ), preferably at a weight percentage of about 2.9%.
  • the patch is packaged so that the drug remains solubilized in this concentrated state, without recrystallization, for at least 6 months, one year, eighteen months or two years.
  • the patches of the present invention comprise one or more undissolved components, such as an irritation reducing agent. Surprisingly, it has been found that patches containing undissolved particles are better tolerated than patches free of undissolved particles.
  • the undissolved particles are selected from pectins (i.e. natural 1,4-glycosidic high molecular weight carbohydrates), arabinans, galactans and analogs.
  • the undissolved component is a nonsaccharide polyhydric alcohol phosphate ester, or a mono-or divalent metal ion salt thereof, such as the calcium, sodium, potassium, ammonium or magnesium salt for thereof.
  • a particularly preferred undissolved component is calcium glycerophosphate.
  • the undissolved particles are preferable present in the matrix in an amount greater than about 0.5 wt.%, 1.0 wt.%, or 3.0 wt.%, and less than about 10 wt.%.
  • Penetration enhancers can optionally be employed in the patches of the present invention.
  • Penetration enhancers are well known and are referred to in the art by terms such as skin-penetration enhancers, accelerants, adjuvants, and sorption promoters, all of which are referred to collectively herein as "penetration enhancers.”
  • Agents within this class have diverse mechanisms of action, and include agents that improve the solubility and diffusibility of a drug within the multi-monomer polymeric matrix and those which improve percutaneous adsorption, for example, by changing the ability of the stratum corneum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair- follicle openers or changing the state of the skin including the boundary layer.
  • additives and excipients may also be incorporated into the matrix including tackifying agents, binders and rheological agents (i.e., thickeners).
  • Other additives and excipients include diluents, stabilizers, fillers, clays, buffering agents, biocides, humectants, anti-irritants, antioxidants, preservatives, plasticizing agents, cross- linking agents, flavoring agents, colorants, pigments and the like.
  • the matrix also includes calcium glycerophosphate, which preferably constitutes the only undissolved component in the matrix.
  • the matrix compositions according to the present invention can be prepared by first mixing appropriate amounts of the matrix material in volatile polar and/or non-polar organic liquids. An appropriate amount of active ingredient is then added to the matrix material and the ingredients are thoroughly mixed. The active ingredient is preferably added as a solution dissolved in methanol, ethanol, 2-propanol or ethyl acetate. The mixture of the matrix composition is next formed into a film at ambient temperature, preferably by coating or casting at a controlled specified thickness onto a flexible sheet material, such as the protective layer 2, followed by evaporation of the volatile solvents at elevated temperatures (e.g., by passing through an oven). The matrix that has been coated or cast on the flexible sheet material is then laminated to another flexible sheet material, cover layer 4. Appropriate size and shape individual patches are then cut and packaged (e.g., pouched).
  • Table A summarizes the median sufentanil i.v. infusion rates, and resulting steady state plasma levels, from sufentanil infusion for intensive case applications and for sustained analgesia in post-surgical or chronic pain applications.
  • the goal is generally moderate patient sedation (somnolent but easily aroused) and effective analgesia.
  • the goal is effective pain control with minimal to moderate sedation.
  • steady-state sufentanil infusions were generally combined with additional bolus injections of sufentanil as a pre-medication and as demanded by the patient through patient controlled analgesia (PCA) pumps.
  • PCA patient controlled analgesia
  • the three analgesia studies used to derive this average were all postoperative pain studies in which intravenous sufentanil was used as the sole analgesic following major surgery. Pain was generally described as well controlled by sufentanil in these studies. TABLE A
  • Example 2 Composition of Sufentanil Patch
  • Table C sets forth an exemplary composition for the patches of the present invention.
  • Oppanol BlOO is polyisobutylene with a molecular weight of >l,000,000g/mol.
  • Oppanol BlO is polyisobutylene with a molecular weight of 40,000g/mol.
  • the required amount of the three excipients forming the PIB adhesive (Oppanol BlOO, Oppanol BlO and Parapol 920) - are weighed and dissolved in hexane under stirring. Sufentanil is dissolved in ethyl acetate. Calcium glycerol phosphate is added to the clear drug solution under stirring to yield a homogenous suspension. The adhesive solution is added slowly to the drug solution under stirring and stirred for an additional hour to yield a homogenous mixture without any air bubbles. In bench scale manufacturing this mixture is then treated with ultra-sound for 2 times 15 min (to remove bubbles if any).
  • the mixture is coated onto the release liner (the mixture has to be kept under constant stirring to avoid segregation of the dispersed calcium glycerol phosphate).
  • the coated film is dried at room temperature for 10 min followed by 20 min at 75°C.
  • the backing foil is applied and the patches are punched out of the resulting laminate, followed by primary packaging in heat sealed individual pouches.
  • Example 4 Bioavailability Testing of Sufentanil Patch
  • Figure 4 is a graphical comparison of in vivo plasma levels over time, normalized based on 100% of C nux for each patch, for two different patches: (1) a 2.5 cm 2 patch constructed according to the present invention containing 0.625 mg of sufentanil base, and (2) a Duragesic fentanyl patch having a nominal flux rate of 25 mcg/h.
  • Figure 5 is a graphical comparison of the coefficients of variation (CV) in C m3x for the two patches depicted in Figure 4.
  • the recrystallization study for determination of drug solubility in polymer was carried out by manufacturing patches having different concentrations of drug in each polymer. After manufacture the resulting laminate was free of undissolved drug. Patches were obtained from the laminate by dye cutting. The single patches were stored in four-side-sealing-pouches of composite material absolutely tight against light and humidity and stored at 25°C/60% RH or unsealed in a climate chamber of 40°C/75% RH. The patches were analysed visually and macroscopically for crystals after 1, 2 and 4 weeks of storage. The time, the amount and the size of crystals was assessed.
  • the delivery of 3.5 mcg/hr by the patches of the present invention is actually able to achieve a steady state plasma concentration of 53.8 pg/ml.

Abstract

La présente invention concerne des procédés et des systèmes de libération cutanée de sufentanil et ses analogues à partir de timbres ayant un profil pharmacodynamique unique utilisables pour traiter la douleur persistante sur des périodes prolongées et des épisodes de douleur aiguë de durée limitée.
PCT/EP2007/003498 2006-04-21 2007-04-20 Systeme de liberation cutanee comprenant du sufentanil et ses analogues WO2007121949A1 (fr)

Priority Applications (4)

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JP2009505791A JP2009534343A (ja) 2006-04-21 2007-04-20 スフェンタニル及びその類似体を含んでなる経皮送達システム
EP07724434A EP2023907A1 (fr) 2006-04-21 2007-04-20 Systeme de liberation cutanee comprenant du sufentanil et ses analogues
CA002646206A CA2646206A1 (fr) 2006-04-21 2007-04-20 Systeme de liberation cutanee comprenant du sufentanil et ses analogues
US12/255,466 US20090130190A1 (en) 2006-04-21 2008-10-21 Transdermal System for the Delivery of Sufentanil and Its Analogs

Applications Claiming Priority (4)

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DE102006019293.1 2006-04-21
DE102006019293A DE102006019293A1 (de) 2006-04-21 2006-04-21 Pflaster, enthaltend ein Fentanyl Analogum
US90350507P 2007-02-26 2007-02-26
US60/903,505 2007-02-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1986618A2 (fr) * 2006-02-13 2008-11-05 Aveva Drug Delivery Systems, Inc. Preparation adhesive comprenant du sufentanil et ses procedes d'utilisation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074286A1 (fr) * 2001-03-16 2002-09-26 Alza Corporation Administration transdermique de fentanyle et de ses analogues
DE20220982U1 (de) * 2001-03-16 2004-11-25 Alza Corp., Mountain View Transdermal-Pflaster zum Verabreichen von Fentanyl
US20050208117A1 (en) * 2001-03-16 2005-09-22 Venkatraman Subramanian S Transdermal administration of fentanyl and analogs thereof
US20050255150A1 (en) * 2004-04-26 2005-11-17 Cassel Douglas R Wound treatment patch for alleviating pain
WO2006047362A2 (fr) * 2004-10-21 2006-05-04 Durect Corporation Systemes de distribution transdermique
WO2006124749A2 (fr) * 2005-05-13 2006-11-23 Alza Corporation Systeme d'application d'agent pharmaceutique multicouche comprenant une barriere contre l'exposition a un antagoniste

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3255717B2 (ja) * 1991-08-08 2002-02-12 積水化学工業株式会社 経皮吸収製剤
JP3066515B2 (ja) * 1992-11-11 2000-07-17 久光製薬株式会社 尿失禁治療用経皮投与製剤
WO2004052378A1 (fr) * 2002-12-10 2004-06-24 Masaya Tanaka Substance pour la peau a usage externe et agent antipruritique a usage externe et instrument reduisant les rides les utilisant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074286A1 (fr) * 2001-03-16 2002-09-26 Alza Corporation Administration transdermique de fentanyle et de ses analogues
DE20220982U1 (de) * 2001-03-16 2004-11-25 Alza Corp., Mountain View Transdermal-Pflaster zum Verabreichen von Fentanyl
US20050208117A1 (en) * 2001-03-16 2005-09-22 Venkatraman Subramanian S Transdermal administration of fentanyl and analogs thereof
US20050255150A1 (en) * 2004-04-26 2005-11-17 Cassel Douglas R Wound treatment patch for alleviating pain
WO2006047362A2 (fr) * 2004-10-21 2006-05-04 Durect Corporation Systemes de distribution transdermique
WO2006124749A2 (fr) * 2005-05-13 2006-11-23 Alza Corporation Systeme d'application d'agent pharmaceutique multicouche comprenant une barriere contre l'exposition a un antagoniste

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1986618A2 (fr) * 2006-02-13 2008-11-05 Aveva Drug Delivery Systems, Inc. Preparation adhesive comprenant du sufentanil et ses procedes d'utilisation

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CA2646206A1 (fr) 2007-11-01

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