DE10237056A1 - Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential - Google Patents

Abstract

A trandermal therapeutic system (TTS) containing buprenorphine (I) (in base or salt form) additionally contains at least one mu-, kappa- or delta-opioid receptor antagonist (II) (optionally in the form of racemate, pure stereoisomers (especially enantiomers or diastereomers) or their mixtures in all proportions, base, acid, salt or solvate (specifically hydrate)).

Description

The invention relates to opioid receptor antagonists, such as naloxone, in transdermal application forms with at least buprenorphine as an active ingredient.

Narcotics and especially opioids Products basically include the risk of abuse, the level of this risk of abuse generally depends on having what effort the potentially abusing the desired can achieve euphoric effect. Because of the poor oral Availability Most opioids are usually a prerequisite for achieving one such euphoric effect, the parenteral application of an opioid Solution. In the event of abuse, an attempt is made to use a parenterally To win drug form, even if the drug misused in one for that primary unsuitable dosage form. The easiest is the abuse Naturally with solutions or Dosage forms that are complete disbanded can be. Properly made parenteral solutions are clear, isotonic, isohydric, sterile, pyrogen-free and contain no unsolved Ingredients. It is abusive to meet all of these requirements Production practically impossible; that in addition existing health risk is accepted. transdermal Systems that are the focus of this invention are of construction rather unsuitable for Abuse purposes. Nevertheless, of course, is in principle with plasters containing opioids because of the attractiveness of the active substance potentially cannot rule out a risk of misuse. In this case, then the narcotic detached from the matrix be, where - provided this at all succeeds - which inevitably also with eluted excipients the solution continue to contaminate, and thus a parenteral application form thus obtained is unattractive.

This means that transdermally appear Systems for the abuse not suitable. Correspondingly, there are also in the prior art no further barriers to abuse in transdermal systems. Indeed should be considered as a precautionary measure that potentially abusers possibilities might discover the difficulties inherent in the transdermal system for abuse to overcome.

Accordingly, it was the task of the present one Invention, one way to find the risk of abuse with opioid, especially buprenorphine-containing, transdermal Systems further down. The subject of the invention is accordingly Containing transdermal system or trandermal therapeutic system as active ingredient at least buprenorphine in the form of the base or a salt, characterized in that it has at least one μ, κ or δ opioid receptor antagonist; possibly in the form of its racemates, the pure stereoisomers, in particular Enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, especially the enantiomers or diastereomers, in any Mixing ratio; in the form of acids or bases or in the form of the salts, especially the physiological acceptable Salts, or in the form of solvates, especially hydrates; contains.

It has now been found that the abuse so additionally made difficult or impossible becomes. The transdermal system becomes parenteral at the same time effective opioid antagonist added or the buprenorphine-containing patch with an opioid antagonist solution additionally coated. This will result in an attempt to remove the buprenorphine from the To remove the plaster, the antagonist is also released. With parenteral administration of such a solution occupies the antagonist due to its great affinity, for example to the μ-opioid receptor the receptors immediately and thereby prevents the euphoric effect, since buprenorphine does not bind as an agonist more is possible is.

The term salt is general to understand any form of an active ingredient according to the invention, in which it assumes an ionic form or is charged and with is coupled to a counterion (a cation or anion) in solution located. This includes complexes of the active ingredient with others molecules and understand ions, especially complexes that are ionic Interactions are complex.

Under the concept of (physiologically acceptable) Salt, especially with acids one understands in the sense of this invention salts at least one of the Compounds according to the invention - mostly, for example on a nitrogen, protonated - as a cation with at least an anion that is physiologically - in particular when used in or on humans and / or mammals - are compatible. Understands in particular one includes in the sense of this invention that with a physiological tolerated acid formed Salt, namely Salts of the respective active ingredient with inorganic or organic acids, the physiologically - especially when used in humans and / or mammals - are compatible. Examples of physiological compatible Salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxa acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1b6-benzo [d] isothiazole- 3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, Hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl, a-lipoic acid, Acetylglycine, acetylsalicylic acid, Hippuric acid and / or Aspartic acid. The hydrochloride, hydrobromide salt and the hydrogen citrate.

It is particularly preferred if that in the transdermal invention System contained μ, κ or δ opioid receptor antagonist a μ opioid receptor antagonist or morphine antagonist, preferably levallorphan, naltrexone, Nalorphine or naloxone, especially naloxone.

This embodiment is particularly preferred if the contained in the medicament according to the invention Levallorphan, naltrexone, nalorphine or naloxone in the form of its base or in the form of the salts, especially the physiologically acceptable ones Salts, preferably those formed with inorganic or organic acids Salts, especially as chloride, bromide or hydrogen citrate salt; is present.

It is particularly preferred if that in the transdermal invention System contained buprenorphine is present as a base.

Under a transdermal therapeutic system (TTS) or transdermal system, according to Zafaroni “is a drug-containing Device or a dosage form that a drug or several at a predetermined rate continuously over a fixed period to a specified place of application "(quoted from Heilmann, therapeutic systems - concept and implementation of programmed drug administration, 4th edition, Ferdinand Enke-Verlag Stuttgart 1984, page 26) can be understood, in which case the application site is the skin.

The structure of transdermal systems is known to the person skilled in the art. Industrial property rights, in which the basic structure is described, are, for example DE 3315272 . DE 3843239 . US 3,598,122 , The content of these patents and applications is fully part of this description.

Becomes a transdermal therapeutic System applied to the skin of a patient, the drug are delivered to be topically or systemically effective in the patient to become. Dosage forms of this type are already becoming therapeutic used. They are usually layered constructed and in the simplest case consist of a backing layer, a self-adhesive drug reservoir and a removable protective layer, which has to be removed before the application.

Transdermal systems such as those in WO 98/36728, WO 96/19975 or US are particularly preferred EP 430 019 A2 are described, the entire content of these publications and the content of the literature cited therein being part of the disclosure of this invention. According to the invention, only at least one μ, κ or δ opioid antagonist is added to the transdermal systems.

• a) über eine Beschichtung der bei therapeutischer Nutzung der Haut zugewandten Fläche des Transdermalen Systems mit mindestens einem μ, κ oder δ Opioid-Antagonisten,
• b) über eine Beimengung mindestens eines μ, κ oder δ Opioid-Antagonisten zum Wirkstoff,
• c) über eine Zugabe mindestens eines μ, κ oder δ Opioid-Antagonisten in die Wirkstoffreservoirschicht bzw. Reservoirschicht,
• d) über eine wirkstoffreservoirschicht- bzw. reservoirschicht-seitige Beschichtung der wirkstoffundurchlässigen Rückschicht mit mindestens einem μ, κ oder δ Opioid-Antagonisten oder e) über eine wirkstoffreservoirschicht- bzw. reservoirschicht-abgewandte Beschichtung der wirkstoffundurchlässigen Rückschicht mindestens einem μ, κ oder δ Opioid-Antagonisten

erfolgen. Dabei wird die Nomenklatur und Definition der EP 430 019 verwendet, deren Inhalt Teil dieser Beschreibung ist.The addition of the μ, κ or δ opioid antagonist

• a) by coating the surface of the transdermal system facing the skin with therapeutic use with at least one μ, κ or δ opioid antagonist,
• b) by adding at least one μ, κ or δ opioid antagonist to the active substance,
• c) by adding at least one μ, κ or δ opioid antagonist into the active substance reservoir layer or reservoir layer,
• d) via an active substance reservoir layer or reservoir layer side coating of the active substance-impermeable back layer with at least one μ, κ or δ opioid antagonist or e) via a coating of the active substance impermeable reservoir layer or reservoir layer away from the active substance impermeable back layer at least one μ, κ or δ opioid antagonists

respectively. The nomenclature and definition of the EP 430 019 used, the content of which is part of this description.

That is very particularly preferred Combination of buprenorphine base with naloxone salt.

In a particularly preferred embodiment of the transdermal system according to the invention is the weight ratio of the amount of the in / on μ, κ or δ opioid antagonists used in the drug Amount of μ, κ or δ opioid agonists used in the drug between 1 : 100 and 100: 1, preferably between 1:20 and 10: 1, in particular between 1:10 and 1: 1, particularly preferably between 1:10 and 3:10.

In another preferred embodiment, provided that the transdermal system remains in contact with the skin for at least 5 days, it has an average release rate of about 3 µg / h to about 86 µg / h and an increase in the plasma level of the Maintains first order opiod agonists, especially buprenorphine, from the beginning of the dosing interval to approximately 72 hours after initiation of the dosing interval; and there is an average release rate of about 0.3 µg / h to about 9 µg / h and an increase in the plasma level of the opioid agonist, especially buprenorphine, of basically zero order from about 72 hours after the start of the dosing interval to the end of the At least 5-day dosing intervals are maintained so that the following average plasma concentrations are achieved:
an average plasma concentration of about 0.3 to about 113 pg / ml about 6 hours after the start of the dosing interval;
an average plasma concentration of about 3 to about 226 pg / ml about 12 hours after the start of the dosing interval;
an average plasma concentration of about 7 to about 644 pg / ml about 24 hours after the start of the dosing interval;
an average plasma concentration of about 13 to about 753 pg / ml about 36 hours after the start of the dosing interval;
an average plasma concentration of about 13 to about 753 pg / ml by about 36 hours after loading start of the dosing interval;
an average plasma concentration of about 16 to about 984 pg / ml about 48 hours after the start of the dosing interval;
an average plasma concentration of about 20 to about 984 pg / ml about 60 hours after the start of the dosing interval;
an average plasma concentration of about 21 to about 1052 pg / ml about 72 hours after the start of the dosing interval; and
an average plasma concentration of approx. 19 to approx. 1052 pg / ml by approx. 24 hours over less than the next 48 hours.

Another object of the invention is the use of a transdermal system according to the invention Manufacture of a medicament for the treatment of pain, in particular acute, chronic, visceral, neuropathic or inflammatory pain, or to treat increased urge to urinate or urinary incontinence.

The abuse will be implemented made the invention described here more difficult to impossible. Overall, the plaster containing buprenorphine is simultaneously a parenterally active opioid antagonist added or the opioid-containing patch additionally coated with an opioid-antagonist solution. This will result in an attempt to remove the buprenorphine from the patch Antagonist also removed. With parenteral administration of such a solution the antagonist due to its high affinity, for example to the μ-opioid receptor the receptors immediately and thereby prevents the euphoric effect, since a receptor binding of the opioid as an agonist is then no longer possible possible is.

Everyone comes as opioid antagonists suitable μ-receptor or μ- and k receptor antagonists in question such as Nalorphine or naloxone in the form of their bases or salts with inorganic (e.g. chloride) or organic acids (e.g. hydrogen citrate). The opioid antagonist is preferred in the form a practically not transdermally available, but readily soluble Connection used. This is the aim of the invention achieved that buprenorphine act as an analgesic transdermally may, but when trying to remove the buprenorphine, the Antagonist with detached and this is abusive parenteral application of the solution prevents the buprenorphine from working.

The amount of opioid antagonist added is based on the total amount contained in the product Opioid agonists or buprenorphins. The ratio of opioid agonist to buprenorphine is preferably 10: 1 to 1:10.

Examples

The examples are for illustration of the present invention and preferred embodiments, but are intended to be their Do not limit the scope of protection.

example 1

Incorporation of naloxone hydrochloride into the active substance matrix:

1125 g of a 48% by weight polyacrylate solution self-crosslinking acrylate copolymers from 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (Solvent: Ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in the ratio of 37: 26: 26: 4: 1), 100 g levulinic acid, 150 g of olefin acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, 100 g of buprenorphine base and 20 g of naloxone hydrochloride are homogenized. You stir about two hours and visually checks that all solids are dissolved. The loss of evaporation is controlled by weighing back and added possibly the loss of solvent by ethyl acetate.

The mixture is then applied to a 420 mm wide, transparent polyester film in such a way that the weight per unit area of the dried adhesive layer is 80 g / m ² . A polyester film that can be removed again by silicone treatment serves as a protective layer.

The solvents are removed by drying with heated Air over the wet web is conducted. The solvents evaporate due to the heat treatment. Subsequently cover the adhesive film with a 15 μm polyester film. With suitable cutting tools you punch one of the intended amount of active ingredient corresponding area and removes those that have remained between the individual systems Edges.

The plaster thus produced is based on Example 1 of WO 96/19975 or EP 430 019 A2 The entire content of these publications and the literature cited therein form part of the disclosure of this invention.

Example 2:

coating the active ingredient matrix with naloxone hydrochloride

1139 g of a 48% by weight polyacrylate solution self-crosslinking acrylate copolymers from 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (Solvent: Ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in the ratio of 37: 26: 26: 4: 1), 100 g levulinic acid, 150 g of Oley acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base are homogenized. You stir about two hours and visually checks whether all solids are dissolved. The loss of evaporation is controlled by weighing back and added possibly the loss of solvent by ethyl acetate.

Then the mixture is so on a 420 mm wide, transparent polyester film applied that the basis weight of the dried adhesive layer is 80 g / m ² . A polyester film that can be removed again by silicone treatment serves as a protective layer.

The solvents are removed by drying with heated air which is passed over the moist web. The solvents evaporate due to the heat treatment. The matrix per m ² is then coated with a solution of 800 mg of naloxone hydrochloride in 120 ml of methanol, for example by homogeneous spraying, spraying or trickling, and the solvent is removed by drying again.

Then you cover the adhesive film with a 15 μm polyester film from. Use suitable cutting tools to punch one of the intended amounts of active ingredient corresponding area and removes those that have remained between the individual systems Edges.

The plaster thus produced is based on Example 1 of WO 96/19975 or EP 430 019 A2 The entire content of these publications and the literature cited therein form part of the disclosure of this invention.

Example 3:

Coating the polyester film with naloxone hydrochloride on the active ingredient matrix Page.

1139 g of a 48% by weight polyacrylate solution self-crosslinking acrylate copolymers from 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (Solvent: Ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in the ratio of 37: 26: 26: 4: 1), 100 g levulinic acid, 150 g of Oley acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base are homogenized. You stir about two hours and visually checks whether all solids are dissolved. The loss of evaporation is controlled by weighing back and added possibly the loss of solvent by ethyl acetate.

A 420 mm wide, transparent polyester film is coated per m ² with a solution of 800 mg naloxone hydrochloride in 120 ml methanol and the solvent is removed by drying. The mixture described above is then applied to the coated side of the coated polyester film in such a way that the weight per unit area of the dried adhesive layer is 80 g / m ² . A polyester film that can be removed again by silicone treatment serves as a protective layer.

The solvents are removed by drying with heated Air over the wet web is conducted. The solvents evaporate due to the heat treatment.

Then you cover the adhesive film with a 15 μm thick polyester film. Punch with suitable cutting tools an area corresponding to the intended amount of active ingredient is obtained and removes the edges that have remained between the individual systems.

The plaster thus produced is based on Example 1 of WO 96/19975 or EP 430 019 A2 The entire content of these publications and the literature cited therein form part of the disclosure of this invention.

Example 4:

Coating the polyester film with naloxone hydrochloride on that facing away from the active substance matrix Page.

1139 g of a 48% by weight polyacrylate solution self-crosslinking acrylate copolymers from 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (Solvent: Ethyl acetate: heptane: isopropanol: toluene: acetylacetonate in the ratio of 37: 26: 26: 4: 1), 100 g levulinic acid, 150 g of Oley acetate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base are homogenized. You stir about two hours and visually checks whether all solids are dissolved. The loss of evaporation is controlled by weighing back and added possibly the loss of solvent by ethyl acetate.

A 420 mm wide, transparent polyester film is coated per m ² with a solution of 800 mg naloxone hydrochloride in 120 ml methanol and the solvent is removed by drying. Then the film is turned over so that the uncoated side is facing up. The mixture described above is then applied to the uncoated side of the coated polyester film in such a way that the weight per unit area of the dried adhesive layer is 80 g / m ² . A polyester film that can be removed again by silicone treatment serves as a protective layer.

The solvents are removed by drying with heated Air over the wet web is conducted. The solvents evaporate due to the heat treatment.

Then you cover the adhesive film with a 15 μm thick polyester film. Punch with suitable cutting tools an area corresponding to the intended amount of active ingredient is obtained and removes the edges that have remained between the individual systems.

The plaster thus produced is based on Example 1 of WO 96/19975 or EP 430 019 A2 The entire content of these publications and the literature cited therein form part of the disclosure of this invention.

Example 5:

permeation by stratum corneum

Permeation of naloxone HCl in addition to buprenorphine (base) from a transdermal system prepared according to Examples 1 to 4.

1. Structure of penetration model:

Franz cell with approx. 100 ml acceptor volume.

First, a suitable magnetic fish given in the acceptor room. The contact areas for fixing the permeation barrier (here: stratum corneum) are coated with silicone paste (grease) and on the acceptor side as support a polycarbonate filter with 5μm pore size applied in the middle (Millipore TMTP025). On this support membrane the punched out, undamaged and watered before use Piece of stratum laid on corneum and and above the thing to be checked paving piece applied as a donor. After that, the top of the Franz cell put on and secured to the lower part with a clip.

Then the degassed, approx. 34 ° C warm Acceptor medium free of bubbles filled the riser pipe. The filling quantity at acceptor is chosen so that complete contact of the acceptor is guaranteed with the permeation barrier. The liquid level is always in the riser the level of the permeation barrier.

The weighting of the donor side An HPLC vial is placed on the plaster and the donor side Sockets closed with parafilm or another locking system.

At the start of the experiment, the prepared Franz cell in a water bath thermostatted to 34 ° C hanged, that the bath liquid practically complete reaches the acceptor medium, but there is no risk that it will reaches the Franz cell at the donor / acceptor area separation point.

The bathroom with the Franz cell will so on a magnetic stirrer placed that permanent both bath liquid and acceptor medium via magnetic fish touched become.

2. Donor

This serves as a donor accordingly tailored plasters

3. Acceptor

An isotonic phosphate buffer solution, which contains the following salts dissolved in 1 l aqueous solution, serves as the acceptor:
1.225 g of potassium dihydrogen phosphate, anhydrous
4.26 g disodium hydrogen phosphate, anhydrous
6.00 g sodium chloride

Sampling for analytical purposes: approx. 10 ml

4. Permeation barrier:

This serves as a permeation barrier Stratum corneum (S.c.).

Storage in the desiccator since 9.4.2002 with desiccant at RT.

Before using the S.c. microscopic examined, appropriate areas selected as a barrier and cut out.

5. Sampling

Sampling quantities:
2 × 200 μl are taken with the Varipette at each sampling time and the amount withdrawn is replaced by isotonic phosphate buffer solution.

Sampling takes place with the Varipette at every sampling time and with every addition of buffer solution a new pipette tip is used.

The Varipette is set to a level required to deliver an average of 200 μl (203 µl).

All samples taken are also weighed and documented. The samples taken are filled into HPLC vials, crimped, labeled and frozen.

6. Sampling times:

After each series, after 0.5; 1.0; 1.5; 2; 4; 6; 24; 48 samples of 200 μl each were taken for 48 hours.

Claims (8)

Transdermal system or trandermal therapeutic system containing as active ingredient at least buprenorphine in the form of the base or a salt, characterized in that it contains at least one μ, κ or δ opioid receptor antagonist; optionally in the form of its racemates, the pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form of the acids or bases or in the form of the salts, in particular the physiologically tolerable salts, or in the form of the solvates, in particular the hydrates; contains. Transdermal system according to claim 1, characterized in that the μ, κ or δ opioid receptor antagonist is a μ opioid receptor antagonist or morphine antagonist, preferably levallorphan, naltrexone, Nalorphine or naloxone, especially naloxone. Transdermal system according to claim 2, characterized in that levallorphan, naltrexone, nalorphine or naloxone in the form of their bases or in the form of their salts, in particular the physiologically compatible salts, preferably those with salts formed organic or organic acids, in particular as chloride, bromide or hydrogen citrate salt. Transdermal system according to one of claims 1 to 3, characterized in that the buprenorphine as the base is present. Transdermal system according to one of claims 1 to 4, characterized in that the μ, κ or δ opioid antagonist a) about a Coating of the skin facing therapeutic use area the transdermal system with at least one μ, κ or δ opioid antagonist, b) about a Addition of at least one μ, κ or δ opioid antagonist to the agent c) about adding at least one μ, κ or δ opioid antagonist to the Drug reservoir layer or reservoir layer, d) about one active substance reservoir layer or reservoir layer coating the drug-impermeable backing with at least one μ, κ or δ opioid antagonist and / or e) about a Coating facing away from the active substance reservoir or layer facing the reservoir layer the drug-impermeable backing at least one μ, κ or δ opioid antagonist added becomes. Transdermal system according to one of claims 1 to 5, characterized in that the on Weight related ratio the amount of μ, κ or δ opioid antagonists used in / on the drug the amount of buprenorphine between 1: 100 and 10: 1, preferably between 1:20 and 5: 1, especially between 1:10 and 1: 1, especially is preferably between 1:10 and 3:10. Transdermal system according to one of claims 1 to 6, characterized in that under the condition that the transdermal system in contact with the skin for at least 5 days remains, there is an average release rate of approximately 3 µg / h up to approx. 86 µg / h and an increase in the plasma level of buprenorphine, principally first order from the beginning of the dosing interval to maintained approximately 72 hours after initiation of the dosing interval; and it has an average release rate of approximately 0.3 µg / h approx. 9 µg / h and an increase in the plasma level of the opiod agonist, in particular Buprenorphine, principally zero order after about 72 hours Beginning of the dosing interval until the end of the at least 5-day dosing interval maintains, so that the following average plasma concentrations are reached become: an average plasma concentration of approx. 0.3 to about 113 pg / ml by about 6 hours after the start of the dosing interval; a average plasma concentrations from approx. 3 to approx. 226 pg / ml by approximately 12 hours after the start of the dosing interval; a average plasma concentrations from approx. 7 to approx. 644 pg / ml around 24 hours after the start of the dosing interval; a average plasma concentrations from approx. 13 to approx. 753 pg / ml by approximately 36 hours after the start of the dosing interval; a average plasma concentrations from approx. 13 to approx. 753 pg / ml by approximately 36 hours after the start of the dosing interval; a average plasma concentrations from approx. 16 to approx. 984 pg / ml by approximately 48 hours after the start of the dosing interval; a average plasma concentrations from approx. 20 to approx. 984 pg / ml around 60 hours after the start of the dosing interval; a average plasma concentrations from approx. 21 to approx. 1052 pg / ml by approximately 72 hours after the start of the dosing interval; and a average plasma concentrations from approx. 19 to approx. 1052 pg / ml by about 24 hours least the next 48 hours. Use of a transdermal system according to one of claims 1 to 9 for the manufacture of a medicament for the treatment of pain, in particular acute, chronic, visceral, neuropathic or inflammatory pain, or to treat increased urge to urinate or urinary incontinence.