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WO2003097008A2 - Dispositif transdermique pour l'administration de fentanyle - Google Patents

Dispositif transdermique pour l'administration de fentanyle Download PDF

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Publication number
WO2003097008A2
WO2003097008A2 PCT/GB2003/002120 GB0302120W WO03097008A2 WO 2003097008 A2 WO2003097008 A2 WO 2003097008A2 GB 0302120 W GB0302120 W GB 0302120W WO 03097008 A2 WO03097008 A2 WO 03097008A2
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WO
WIPO (PCT)
Prior art keywords
fentanyl
ofthe
adhesive
matrix
permeation
Prior art date
Application number
PCT/GB2003/002120
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English (en)
Other versions
WO2003097008A3 (fr
Inventor
Francisco Jose Evaristo Stefano
Alejandro Fabio Scasso
Original Assignee
Thalas Group Incorporated
Paget, Hugh, Charles, Edward
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from ARP020101791A external-priority patent/AR033748A1/es
Priority claimed from GB0229836A external-priority patent/GB0229836D0/en
Application filed by Thalas Group Incorporated, Paget, Hugh, Charles, Edward filed Critical Thalas Group Incorporated
Priority to AU2003230034A priority Critical patent/AU2003230034A1/en
Publication of WO2003097008A2 publication Critical patent/WO2003097008A2/fr
Publication of WO2003097008A3 publication Critical patent/WO2003097008A3/fr

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Classifications

    • 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
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl

Definitions

  • This invention relates to transdermal administration devices, and more particularly, to transdermal administration devices for the systemic administration of fentanyl.
  • morphine to alleviate pain drove industry interest to obtain synthetic opioids that could present some advantage over the natural alkaloid.
  • Levorphanol, heroin, oxymorphone, meperidine, buprenorphine, pentazocine and fentanyl can be named as examples. From this group fentanyl can be selected as one ofthe most potent agents with a relative short half-life of elimination and a rapid onset of action.
  • Fentanyl is chemically different to the natural morphine. Its structural formula is related to the phenylpiperidines and it has a simpler structure than that of morphine which belongs to the morphinan group of molecules. Its potency is almost 100 times greater than that of morphine and produces shorter respiratory depression than another synthetic analogue, meperidine.
  • the use of fentanyl has gained wide acceptance in its use by anaesthesiologists because it can be safely combined with neuroleptic agents such as droperidol. This combination is used as an intravenous anaesthetic without potentiation ofthe side effects.
  • the low dose of this compound makes it suitable for its use in a transdermal device and the medical profession is currently using such a device for the management of severe pain.
  • opioids antagonists such as naloxone or naltrexone can reverse these toxic effects, if the drug has been injected or administered per os, absorption will continue maintaining dangerous levels ofthe opioids till the elimination rate surpass the absorption rate and the drug is eliminated through metabolism.
  • opioids antagonists such as naloxone or naltrexone
  • the drug to be absorbed is maintained outside the body and if undesirable side effects occur, removal ofthe system will terminate the absorption phase and the decline of plasma levels will depend only on the metabolism rate.
  • the transdermal route is more convenient in some cases than the more classical routes of administration for opioids.
  • Gels or ointments are devoid ofthe advantages of transdermal devices since dosification is less precise (absorption will be extremely dependent on the size ofthe application area and the thickness ofthe layer applied). Moreover in the case that it could be helpful to remove the applied dosage either rubbing or alcohol application will rather increase the rate of absorption.
  • transdermal devices nowadays, there are different types of transdermal devices. These devices could be mainly grouped in two broad categories: reservoir-type devices and matrix- type devices. In the literature other types of devices have been described, but all of them could be considered as extension of one of these types or as a combination thereof.
  • the transdermal reservoir-type devices are characterized by a reservoir that contains the active pharmaceutical ingredient (API), a rate controlling membrane, a contact adhesive, a protective liner and a backing layer. From the reservoir, the API diffuses through the controlling membrane to the site of absorption.
  • the controlling membrane may be microporous or continuous.
  • the main advantage of this type of device is that the rate of drug delivery is maintained practically constant for long periods of time. Nevertheless, these devices are usually bulky, they have a total surface area that is bigger than the active surface and, besides, they have the disadvantage that damage ofthe controlling membrane or the reservoir sachet could produce a release higher than desired.
  • the matrix-type transdermal delivery devices comprise, generally, a nonpermeable backing liner, a polymeric adhesive matrix in which the pharmaceutical ingredient or ingredients are dissolved or dispersed and a release liner. They have a total surface area that is the same as that ofthe active surface. Generally, this type of device has had greater acceptance by patients than the reservoir-type patches.
  • the matrix-type device is that, with some active substances, it is difficult to maintain a constant dose for extended periods of time. Generally, in this type of device, the delivery rate decreases during the wearing period as a consequence ofthe depletion ofthe API in the matrix.
  • the transdermal delivery device has enough adhesiveness to be able to remain on the application site assuring the suitable drug delivery during the necessary period of time, while having, at the same time, a painless removal, which is not easy to obtain.
  • US 6174545 discloses a heat equilibration process for the manufacture of a multilaminated drug delivery device that includes fentanyl.
  • the described end products have drug in excess of saturation in layers other than the drug reservoir, such as the contact adhesive.
  • the disadvantages ofthe described devices are the amount of steps in the manufacture procedure because ofthe presence of different layers and for the heat equilibration process, and also the possibility of physical instability ofthe devices in excess of saturation.
  • 0187276 refers to an hydrogel composition for transdermal drug delivery comprising a hydrophilic polymer base.
  • lauryl alcohol is mentioned as one ofthe useful skin penetration enhancers, there is no example of its specific combination with fentanyl.
  • a matrix type patch formulation which comprises an adhesive layer containing a physiologically active substance, an organic acid, a hydrophobic high molecular material, a tackifying resin, a plasticizer and an absorption enhancer, in which the active drug forms ion-pair with the organic acid, is disclosed.
  • lauryl alcohol is one ofthe mentioned enhancers.
  • fentanyl is mentioned as one ofthe suitable active drugs, the formation of the ion-pair described would not be possible using fentanyl base because it is not stable in acidic media. Neither an example containing this drug in its base form, nor the specific combination of any form ofthe fentanyl molecule with lauryl alcohol are present in the examples. Finally, in US 4626539, liquid or gelled compositions for topical administration of opioids are described. Several enhancers are mentioned, most of which were found incompatible (or chemically unstable) with fentanyl in our experiments. Moreover, there are no examples including fentanyl and there are no descriptions of matrix type devices disclosed in this document.
  • WO 02/26217 and WO 02/074286 disclose monolithic, subsaturated patches or compositions that can be incorporated in a patch for transdermal administration of fentanyl.
  • the content of fentanyl in the device is very high, 8-30%, which makes the finished product very expensive.
  • the amount of enhancer used is also very high, 14.9-35 %, which is not recommendable for the irritation ofthe skin and the performance ofthe adhesive properties.
  • the thickness ofthe devices described makes necessary, in some cases, a manufacturing process of at least two coating/drying steps to obtain the desired device.
  • the concentration of fentanyl in all examples is also high (2.8% or higher in the adhesive solution that yields about 5.5% or more by weight of total content excluding adhesive solvents).
  • the adhesives used in all examples have amonomeric composition identical to one ofthe adhesives described below (GELNA 788), with an -OH functionality. We have found that the chemical stability of fentanyl is diminished when adhesives with -OH functionality are used.
  • the present invention has as its object to provide a simple, non-irritant and chemically stable transdermal delivery device for the systemic administration of fentanyl.
  • transdermal device for the delivery of fentanyl, complex formulation and cumbersome procedures have been proposed.
  • a matrix-type transdermal delivery device having a) a pressure sensitive acrylic adhesive matrix formed by one or more nonfunctional copolymers in which the fentanyl is incorporated, b) a backing layer, and c) a release liner wherein said matrix includes lauryl alcohol as enhancer of percutaneous permeation.
  • the device is ofthe matrix type, i.e. having a body of adhesive which contains the fentanyl to be delivered and is applied directly to the skin in use.
  • the simple device ofthe invention with a fentanyl load of 2-5% and an enhancer load lower than 15% has a performance comparable to Duragesic®.
  • the load concentration for fentanyl is between 2-4.5%, more preferably 3.5-4.5% and for lauryl alcohol is between 5-12%, more preferably 5-10 %.
  • the device ofthe present invention also has good adhesive properties and it is non-irritant.
  • the specific combination of a particular pressure sensitive acrylic adhesive without functional groups and lauryl alcohol as permeation enhancer with fentanyl can provide a device for the transdermal administration of fentanyl that delivers a sustained and controlled amount of fentanyl capable to offer suitable therapeutic plasma levels ofthe active drug for at least three days, using lower loading of fentanyl than devices previously described. Additionally, the device with this specific combination has an excellent chemical and physical stability as well as good adhesive performance without irritation ofthe application site.
  • the performance mentioned can be achieved with a final matrix thickness less than 100 ⁇ m. Preferably, it should be less than 80 ⁇ m. This thickness allows manufacture ofthe device through a simple coating/drying process.
  • Figure 1 is a schematic view of a transdermal delivery device according the present invention.
  • Figure 2 shows the dissolution profile of fentanyl from several adhesive matrixes in Example 1.
  • Figure 3 shows the in vitro permeation of fentanyl from different adhesive matrixes in Example 1.
  • Figure 4 shows the in vitro permeation of fentanyl from matrixes with lauryl alcohol or 1-decanol as permeation enhancer in Example 4.
  • Figure 5 shows the in vitro permeation of fentanyl from matrixes containing lauryl alcohol and methyl laurate as permeation enhancers in Example 5.
  • Figure 6 shows the in vitro permeation of fentanyl from matrixes with different drug load in Example 6.
  • Figure 7 shows the in vitro permeation of fentanyl from matrixes with lauryl alcohol and/or myristyl alcohol as permeation enhancers in Example 7.
  • Figure 8 shows fentanyl plasma levels in rabbits in Example 9.
  • Figure 9 shows fentanyl plasma levels in healthy volunteers in Example 10.
  • fentanyl is the active drug, which is dissolved and incorporated homogeneously in the selected adhesive polymeric matrix.
  • Adhesive matrixes were prepared with different content of fentanyl using acrylic adhesives as well as polyisobutylene. We have found that its physical stability is greater in acrylic adhesives than in polyisobutylene. Within the acrylic adhesives, copolymers with -OH functional groups, -COOH functional groups and nonfunctional groups were tested. Fentanyl showed good physical stability in all of them, but we have found that the chemical stability is optimal if copolymers with -OH functional groups are avoided.
  • dissolution experiments were performed with the mentioned acrylic adhesives, showing that the drug delivery rate from acrylic copolymer with -COOH functional group was too low to provide an adequate permeation rate.
  • the best pressure sensitive adhesive for a transdermal delivery device of fentanyl taking into account both physical and chemical stability as well as drug delivery rate, is an acrylic adhesive substantially without functional groups in the polymeric molecules present.
  • acrylic adhesives with -OH and -COOH functional groups are excluded from use in our invention for the reasons explained above.
  • amine (primary, secondary and tertiary), keto and silanol groups should preferably be excluded because they can, potentially, interact with the active drug.
  • the presence of a small amount of acrylic pressure sensitive adhesives containing a functional group can be allowed only if the total number of monomeric units carrying a functional group is less than 1% by weight of total content of adhesive, excluding adhesive solvents, in the final product.
  • acrylic pressure sensitive adhesives without functional groups an acrylic based polymer which has no or substantially no functional free reactive moieties present in its polymeric chain.
  • These non-functional acrylate copolymer adhesives are generally copolymers consisting of or containing acrylic acid esters or methacrylic acid esters as monomers.
  • Typical alkyl acrylate and alkyl methacrylate monomers in such adhesives are those having 4 to 12 carbon atoms in the alkyl group.
  • Such a monomer or monomers may be copolymerised with another monomer or monomers which do " not have functional groups, such as vinyl acetate (for example DuroTak 87-4098 obtainable from National Starch and Chemical Co.).
  • a preferred matrix is a copolymer of 2-ethylhexyl acrylate and vinyl acetate.
  • a mixture ofthe non-functional copolymers may be employed to form the matrix.
  • the permeation enhancers that show the least chemical interaction with the drug are saturated fatty alcohols.
  • Particularly 1-decanol, lauryl alcohol and myristyl alcohol are the least aggressive to the pharmaceutical moiety.
  • Fentanyl showed better chemical stability in mixtures with those saturated fatty alcohols than in mixtures with compounds having acidic groups, oleyl groups, polyols and unsaturated fatty acid esters. So, enhancers such as fatty acids, fatty acid esters and glyceryl fatty acid esters should be avoided.
  • lauryl alcohol has the best performance in drug delivery rates and adhesive properties. Also, the use of lauryl alcohol allows us to obtain a device in which the drug load is between 2-5% and the enhancer load is between 5-15% with a performance similar to Duragesic®. This low concentration for both components yields a device that is non-irritant, has good adhesive properties and can be cheaper than other proposed matrix type fentanyl devices. Lauryl alcohol is thus preferably the sole permeation enhancer present.
  • permeation enhancer or enhancers may be present, e.g. up to 10% by weight of total permeation enhancers.
  • antioxidants and stabilising agents as butylhydroxytoluene, butylhydroxyanisol, tocopherols, lecitin, polyvinyl pyrrolidone, gum guar or carboxymethylcellulose, carbomers, ethylcelluloses and other well known excipients may be included.
  • FIG. 1 A schematic view of a matrix-type transdermal delivery device for the administration of fentanyl that contains a single adhesive layer embodying the present invention is shown in Figure 1.
  • the device comprises a backing layer 1 that acts as a protective layer for the adhesive matrix 2 composed of a pressure sensitive adhesive containing the permeation enhancer and the active drug dissolved in it and a release liner 3 that is detached before the application ofthe device onto the skin.
  • Materials suitable for the backing layer are cellulose xanthate film, polyvinylidene chloride film, polyvinyl chloride, polyethylene, polypropylene, polyurethane, polyesters such as polyethylene terephthalate including binary structures such as aluminium-polyethylene coatings, etc.
  • any ofthe above mentioned materials can be used, preferably polyesters, such as polyethylene terephthalate, etc. covered with a silicone to prevent sticking ofthe adhesive.
  • the devices of this invention are preferably applied on those regions ofthe body far from mucosa or excessively keratinizated sites (such as palm of hand or sole ofthe foot).
  • EXAMPLE 1 Fentanyl performance in different adhesive matrixes.
  • the coating is performed onto siliconised polyester (1-5 PESTR Clear 6200 (P2)), supplied by DCP Lohja, which acts as release liner.
  • the dry adhesive matrix is laminated onto a polyester/EVA laminate (Scotchpack 1012), supplied by 3M, as backing layer.
  • the bulk laminate obtained is die cut to 4-cm length pieces to obtain an active surface of 20 cm 2 (approximately). 5.
  • the resulting patches are stored in aluminium pouches under the following conditions:
  • DT 87-4098 is available from National Starch and is a copolymer comprising 2-ethylhexyl acrylate and vinyl acetate.
  • DT 87-2353 is available from National Starch and is an acrylic copolymer.
  • Gelva 788 is available from Solutia Inc. and is a copolymer comprising glycidyl methacrylate, 2-ethylhexyl acrylate, vinyl acetate and 2- hydroxyethylacrylate.
  • L100:4H (45:55) is a mixture of polyisobutylene L-100 (mol. weight 1,000,000), available from Exxon and polyisobutylene 4H (mol. weight 40,000), available from Rit-Chem Co. in a ratio of 45:55.
  • Table 3 Storage Condition:40 °C / 75 % R.H.
  • Fentanyl is physically stable in all the acrylic adhesives matrixes tested, while it is unstable in matrixes made of polyisobutylene for a load of fentanyl higher than 2%.
  • Part b Chemical stability
  • Part c Dissolution profile of fentanyl from different adhesive matrixes.
  • the experiment was performed using a "Hanson Research SR8" Dissolutor according to the following procedure: 1. Arrange the dissolutor devices placing one patch per vessel (8 vessels).
  • Multishaker A suitable HPLC method to assay Fentanyl base from the receptive solution
  • the human skin block received is freed from the fat layer. Circular pieces of 2 cm diameter are cut. Each one of these pieces is sliced into 300 ⁇ thin films by means ofthe Skin Sheer. These thin slices keep the skin structure: stratum corneum - epidermis - dermis. 2. Cut the Duragesic® patches into three similar slices using a hand-operated thermosealing machine to assure the hermetic condition of each slice.
  • Figure 3 shows that formulations with -OH acrylic adhesives or with non- functional acrylic show higher permeation profiles than with -COOH functional groups. Taking into account that the formulations tested do not have any permeation enhancer, the permeation rates obtained were close to that seen with Duragesic®.
  • EXAMPLE 2 Interaction of fentanyl with enhancers. Twelve mixtures of fentanyl with different permeation enhancers were prepared according to the following procedure. Their chemical stability and the development of colours were analysed.
  • Procedure of preparation 1- Weigh 25 g of each enhancer listed in table 8 in individual glass flasks.
  • Placebo patches with the addition of 10 % of different enhancers were prepared according to general methodology previously described (see Example 1) and assessed for their adhesive properties. Shear resistance, peel and tack were evaluated.
  • the equipment and used was a Shear Test Bank (according to PSTC-7) and a Rolling
  • Shear Resistance, Peel and Tack were measured in a controlled room with temperature set to 25°C +1-2 and humidity set to 60% +/- 5, with the following parameters for the tests:
  • EXAMPLE 4 Combination of fatty alcohols enhancers with non-functional acrylic adhesive.
  • Laminate with Backing Scotch Pack 1012 with its brilliant side towards the adhesive matrix 6.
  • the laminates thus obtained are cut in 4 cm length pieces, obtaining patches of approximately 20 cm 2 area.
  • Table 12 Storage Conditions:40 °C / 75 % R.H.
  • NSC - 'TSTon-significant change
  • Table 15 Storage Conditions:40°C / 75% RH.
  • Chemical stability is good in both types of formulations, i.e. those containing lauryl alcohol and the ones containing 1-decanol.
  • Results in figure 4 show a marked difference between 1-decanol and lauryl alcohol as permeation enhancers for fentanyl.
  • the patch formulated with 10% of lauryl alcohol shows the major ratio of enhancement.
  • the increment ofthe permeation rate reaches 60 % over the value obtained for the formulation used as internal control (Lot 006).
  • EXAMPLE 5 Comparative permeation profile of formulations with lauryl alcohol and methyl laurate as enhancer.
  • results in figure 5 show that lauryl alcohol has a better in vitro performance than methyl laurate as permeation enhancer in the selected adhesive.
  • the formulation containing lauryl alcohol is capable to permeate 20 % more of the drug than the formulation containing methyl laurate within the same period of time.
  • EXAMPLE 6 Comparative permeation profile between formulations with lauryl alcohol as enhancer and Duragesic®.
  • the average flux between 24 to 72 hours was 1.55 ⁇ g/cm 2 /h fo D ⁇ r lloott 004488,, 22..0044 ⁇ gg//ccmm 22 //hh ffoorr lloott 004419, 3.24 ⁇ g/cm 2 /h for lot 050 and 2.62 ⁇ g/cm7h for the reference product DuragesictJ
  • EXAMPLE 7 Use of myristyl alcohol as co-enhancer.
  • the laminates thus obtained are cut in 40 mm length pieces, obtaining patches of approximately 20 cm 2 area.
  • Table 22 Storage Conditions:40 °C / 75 % R.H.
  • NSC Non-significant change
  • the formulations with the best adhesive performance are those containing 10% of lauryl alcohol without myristyl alcohol and regardless ofthe percentage of fentanyl.
  • EXAMPLE 8 Wearing Test of Placebo TDS on Humans.
  • a placebo patch containing lauryl alcohol as permeation enhancer was tested on 7 healthy volunteers, with evaluations at 24 h, 48 h and 72 h after patch application. The degree of adhesion, glue residue and skin reaction of placebo patches were evaluated on an open label 3-day study. Subjects were applied one placebo patch in the external side ofthe right arm, avoiding hairy zones.
  • NAS visual analogue scales
  • the irritation observed was classified according to the following scoring system:
  • the numbers in table 30 are percentage of the patch adhered to the skin at each evaluation.
  • Table 31 The data in table 31 was organized as follows: extent of cold flow, colour and % of area involved. Table 31 : Cold Flow observed in the wearing test
  • the 0.5 score was assigned to equivocal reactions observed through the patch.
  • the grade of discomfort induced by patch removal was low, obtaining 26.3 ⁇ 5.8 mm in a scale ranging from 0 (painless) to 100 mm (extremely painful).
  • EXAMPLE 9 Fentanyl plasma levels and irritation potential in rabbits.
  • Fentanyl plasma levels and irritation potential in rabbits were tested using a patch according to the present invention (Lot 114) against the reference product Duragesic® 25. Also, the estimation ofthe fentanyl delivered was calculated by the analysis of fentanyl remnants in the used patches.
  • Lot 114 has the same formulation composition and was manufactured using the same methodology employed for lot 050.
  • the patches according to the present invention used in this experiment had 10 cm 2 of active area while Duragesic® 25 had 10 cm 2 of active area in a 20 cm 2 of total area of device.
  • Plasma fentanyl levels were determined in the individual samples collected, except for those obtained with significant patch lifting (more than 30%) and/or significant hair growth below the TDS (17%> of samples for lot 114 and 35% of samples for Duragesic® 25). Plasma fentanyl levels were assessed in individual samples using g GC-MS. Evaluation of skin was performed at 24, 72 and 96 (post-removal) hours.
  • the indexes of dermal irritation (DII) Pre-Removal of TDS and Post-Removal of TDS were calculated for each patch.
  • the recovered patches were returned to their individual primary containers and kept at -20°C until analysis with intact units of both lot 114 and Duragesic® 25.
  • the fentanyl remnants in used patches were assessed by an HPLC method, using the intact patch units as reference controls.
  • Fentanyl release rate mg fentanyl in intact TDS - mg fentanyl in used TDS
  • the individual fentanyl plasma levels obtained with the lot 114 10 cm 2 patch are similar to those obtained with Duragesic® 25 in all sampling times.
  • the dispersion ofthe data of both patches was similar at 3h, 6 h and 72h, and somewhat lower for lot 114 at 24h and for Duragesic® 25 at 48 h.
  • the fentanyl data obtained in this trial enabled the estimation ofthe area under the concentration-time curve (mean AUC), maximum concentration of fentanyl (mean Cmax) and time to peak (mean Tmax) using the mean fentanyl profile calculated for each TDS.
  • TDS that were less than 30% detached during use and without hair growth development between the patch and the skin.
  • the fentanyl release rate of Lot 114 10 cm 2 was close similar to that of Duragesic® 25.
  • fentanyl plasma levels in humans produced by a patch according to the present invention were compared against the reference product Duragesic® 25
  • the estimation of fentanyl delivered by the patches was calculated by the analysis of fentanyl remnants in the used patches. Irritation potential, adhesiveness and vital signs were recorded.
  • Lot 20801 has the same formulation composition and was manufactured using the same methodology employed for Lot 050.
  • the patches according to the present invention used in this experiment had 10.6 cm 2 of active area while Duragesic® 25 (Lot 0017102) had 10 cm 2 of active area in a 20 cm 2 of total area device.
  • the design ofthe experiment was the following: Open label, single dose, randomised, active controlled, two period crossover pilot pharmacokinetics study.
  • a blood sample was obtained immediately before patch application (0 h for fentanyl assays). Each patch remained applied for 72 h. During patch use, blood samples were obtained at 2-4 h intervals during the first 24 h, and at 6 h intervals from 30 h to 72 h. Then, the patch was removed from the skin and additional blood samples were drawn at 4, 8, 12, 24, 48 and 72 h, to characterise drug decay after each system use. Results: Only five volunteers completed the study, the sixth participant refused to participate in the second period ofthe study alleging reasons not related to the medication received but to the hospital stay.
  • Figure 9 shows the mean values ( ⁇ SEM) obtained.
  • the patch according to the invention gave steady values from the 16 th hour onwards.
  • the reference patch gave a similar profile although somewhat higher. This difference in the amount delivered was not statistically significant.

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Abstract

L'invention concerne un dispositif transdermique simple, non irritant et chimiquement stable pour l'administration de fentanyle, lequel comprend une matrice adhésive acrylique sensible à la pression constituée d'un copolymère non fonctionnel contenant 2-5 % en poids de fentanyle et du dodécan-1-ol en tant qu'agent améliorant la pénétration.
PCT/GB2003/002120 2002-05-15 2003-05-15 Dispositif transdermique pour l'administration de fentanyle WO2003097008A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003230034A AU2003230034A1 (en) 2002-05-15 2003-05-15 Transdermal delivery device for the administration of fentanyl

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ARP020101791A AR033748A1 (es) 2002-05-15 2002-05-15 Un dispositivo para la administracion transdermica de sustancias farmacologicamente activas que comprende dos capas adhesivas superpuestas y un procedimiento para prepararlo
AR020101791 2002-05-15
GB0229836.2 2002-12-20
GB0229836A GB0229836D0 (en) 2002-12-20 2002-12-20 Transdermal delivery device for the administration of fentanyl

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WO2003097008A3 WO2003097008A3 (fr) 2004-03-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016100708A1 (fr) 2014-12-19 2016-06-23 3M Innovative Properties Company Dispositif d'administration transdermique de médicament, comprenant du fentanyl
WO2022107182A1 (fr) * 2020-11-18 2022-05-27 University Of Petra Composition de fentanyl et d'acides gras, et son procédé de préparation

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TW411277B (en) * 1996-05-13 2000-11-11 Hisamitsu Pharmaceutical Co Percutaneous tape preparation containing fentanyl
KR20010036685A (ko) * 1999-10-11 2001-05-07 김윤 펜타닐을 함유하는 매트릭스형 경피투여제

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WO2016100708A1 (fr) 2014-12-19 2016-06-23 3M Innovative Properties Company Dispositif d'administration transdermique de médicament, comprenant du fentanyl
JP2017538735A (ja) * 2014-12-19 2017-12-28 スリーエム イノベイティブ プロパティズ カンパニー フェンタニルを含む経皮薬物送達デバイス
WO2022107182A1 (fr) * 2020-11-18 2022-05-27 University Of Petra Composition de fentanyl et d'acides gras, et son procédé de préparation

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