Diclofenac-containing TTS with dimethylpropylene urea

Abstract

The present invention relates to a transdermal therapeutic system for administering diclofenac, comprising a support layer and a matrix layer, characterized in that the matrix layer comprises diclofenac, at least one occlusive adhesive component and at least one solvent, the at least one solvent comprising dimethylpropyleneurea.The present invention also relates to its use as a medicament.

Description

[Technical Field]

[0001] The present invention relates to a transdermal therapeutic system for administering diclofenac (2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid), or to a transdermal patch containing the active ingredient. The present invention further relates to such a system used as a pharmaceutical, more particularly to a system used for pain or inflammatory conditions. [Background technology]

[0002] Transdermal therapy systems are dosage forms that administer drugs in the form of patches. These systems offer certain advantages over conventional dosage forms. When a patch containing an active ingredient is applied to the skin, the active ingredient is absorbed precisely and in the precise dose at the corresponding site of the body via the skin, without being prematurely broken down in the gastrointestinal tract or liver. In addition, this dosage form can release the active ingredient at a constant rate over a long period of time.

[0003] In many cases, transdermal administration of active ingredients is hindered by low skin permeability. Therefore, increasing skin permeability has been important for efficient absorption of active ingredients. One possible way to achieve this is through the effect of sealing, which is understood to mean that the skin area is covered or sealed as much as possible, allowing water vapor to accumulate in the upper layers of the skin, and as a result, increasing skin permeability to the active ingredient.

[0004] However, these well-known adhesive patches generally have the drawback of being inelastic and rigid, resulting in a poor fit, which restricts the wearer's mobility and causes the patch to frequently come off unintentionally.

[0005] According to Patent Document 1, sealing of the adhesive patch is achieved by using a support layer that is impermeable to water vapor, such as a thin plastic film, preferably a polyethylene terephthalate (PET) film.

[0006] Another possibility for increasing skin permeability to facilitate the absorption of active ingredients is the use of permeability enhancers.

[0007] Patent Document 2 discloses a topically released analgesic and anti-inflammatory patch ("Dojin Patch") containing diclofenac. This system contains N-methyl-2-pyrrolidone as a solvent, which reliably increases the permeability of the active ingredient through the skin. The drawback of this system is that this solvent is a substance of concern regarding its effects on human health, and according to ICH guideline Q3C (dated February 4, 2011), the intake of N-methyl-2-pyrrolidone should not exceed 5.3 mg per day. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] DE10103860A1 [Patent Document 2] EP1312360A1 [Overview of the project] [Problems that the invention aims to solve]

[0009] The objective of the present invention is to eliminate the aforementioned drawbacks of the prior art. More specifically, the objective of the present invention is to provide a transdermal treatment system that enables optimal absorption of the active ingredient through the skin while eliminating the need for the harmful solvent N-methyl-2-pyrrolidone. Furthermore, the system must be airtight while providing a high level of comfort and adhesion, even in flexible areas of the body such as joints. [Means for solving the problem]

[0010] The above objective is achieved by a transdermal treatment system according to claim 1, comprising a support layer and a matrix layer, wherein the matrix layer comprises diclofenac, at least one sealing adhesive component and at least one solvent, and the at least one solvent comprises dimethylpropylene urea. [Modes for carrying out the invention]

[0011] When describing the percutaneous treatment system according to the present invention, the term "includes" may mean "consisting of".

[0012] The transdermal treatment system according to the present invention is more preferably characterized in that the entire matrix layer is airtight.

[0013] Generally, the matrix layer can be formed as a single layer; that is, the sealing adhesive component is contained within this single-layer matrix, ensuring the overall sealing performance of the system.

[0014] Sealing refers to covering or sealing a skin area as much as possible, with the material being impermeable to water vapor. As a result, insensible perspiration (the release of water or water vapor from human skin at rest) is impaired, moisture is accumulated, and thus the stratum corneum (the outermost layer of the epidermis) is hydrated. Under shielding conditions, the moisture content of the stratum corneum increases by up to 25% (m / m), preferably up to 50% (m / m). The surface temperature of the skin can also rise up to 37°C. Preferably, the amount of water vapor released is 500 cm³ within 24 hours, measured according to DIN EN 13726-2:2002 at a temperature of 37°C and a relative humidity of 30%. 2 Less than 200 cm, especially preferably 200 cm 2 It is less than.

[0015] Adhesive components are understood as substances that are adhesives themselves, preferably pressure-sensitive adhesives, that is, substances that are sticky on their own or that produce adhesives when mixed with other substances. An adhesive is a non-metallic substance that can join parts by surface bonding (adhesion) and adequate internal strength (tightness), as defined in DIN EN 923 (June 2008). A substance or mixture of substances is described as sticky if it can be used as an adhesive on its own, or more specifically as a pressure-sensitive adhesive. A pressure-sensitive adhesive is an adhesive that, after being applied to a carrier material, maintains high viscosity and permanent tackiness, and can then be applied to a substrate by applying light pressure to maintain its tackiness. A pressure-sensitive adhesive, as defined in DIN EN 923 (June 2008), is also characterized in that the set, dried film is permanently sticky at room temperature and maintains its tackiness, as defined in DIN EN 923 (June 2008). Adhesives made with pressure-sensitive adhesives can usually be peeled off without damaging the bonded substrate.

[0016] At least one sealing adhesive component preferably contains a pressure-sensitive adhesive or is mixed with other substances to create a pressure-sensitive adhesive.

[0017] Therefore, at least one sealing adhesive component is understood to be a component that greatly prevents insensible evaporation, i.e., the loss of water vapor from the skin, and thus leads to the accumulation of moisture in the stratum corneum. Preferably, at least one sealing adhesive component is a sealing adhesive component that is already inherently sticky.

[0018] Permeability refers to the ability of a solid (including porous solids), particularly a thin barrier, to allow a specific substance (gas, liquid, dissolved molecules, ions, or atoms) to pass through. In this case, it refers to the ability of human or animal skin to allow small molecules, more specifically, active pharmaceutical ingredients (APIs), to pass through. In technical terms, permeability is understood as the way in which one substance passes through or penetrates another. This term is often used in the context of the permeability of cosmetics or APIs into or through the skin.

[0019] Therefore, a permeation enhancer is understood to be a compound that promotes the permeation of one substance into another, i.e., increases the permeation rate or generally increases the efficiency of permeation.

[0020] In addition, at least one permeation enhancer is preferably a compound that stabilizes the form of the active ingredient and ensures a relatively high and stable absorption of the active ingredient through the skin over a long period of time.

[0021] Various mechanisms for enhancing permeability are known, such as lowering the melting point of the drug substance and / or lowering the skin barrier, for example, by opening the tight junctions of the skin.

[0022] The permeation enhancer preferably has at least one of the following characteristics.

[0023] Ideally, the effect of the permeation enhancer should be rapid, and both the activity and duration of its effect should be predictable and reproducible.

[0024] The permeation enhancer should not have any pharmacological activity in the body, i.e., it should not bind to any receptor sites, for example.

[0025] The permeation enhancer should preferably act unidirectionally, i.e., while allowing the therapeutic active ingredient to permeate into the body, it should prevent the loss of endogenous substances from the body.

[0026] When the permeation enhancer is removed from the skin, the barrier properties should return rapidly and completely.

[0027] The permeation enhancer should be suitable for formulation into different dosage forms, i.e., it should be compatible with both excipients and drugs.

[0028] The permeation enhancer should be cosmetically acceptable, have a good feel on the skin, be non-toxic, non-irritating, and non-allergenic.

[0029] The functions and properties of penetration enhancers are described, for example, in Williams et al.'s publication "Penetration Enhancers," Advanced Drug Delivery Reviews, 56 (2004), pp. 603-618, or in Amjadi et al.'s publication "Recent advances in skin penetration enhancers for transdermal gene and drug delivery," Current Gene Therapy 17(2), 2017, or in Gupta et al.'s publication "Effect of chemical penetration enhancers on skin permeability: In silico screening using molecular dynamics simulations," Scientific Reports, 9_1456 (2019), and their contents are fully incorporated herein.

[0030] A solvent is a substance that dissolves the active ingredient. A crucial requirement for a solvent's suitability is that neither the substance being dissolved nor the substance being dissolved undergoes any chemical change during the dissolution process. In contrast to permeation enhancers, the solvent itself does not necessarily need to increase the permeability of the active ingredient through the patient's skin by reducing the patient's skin barrier.

[0031] The transdermal treatment system according to the present invention is preferably characterized in that the support layer comprises an elastic woven, knitted, or nonwoven fabric. The fabric is preferably stretchable in at least one direction, more preferably in two directions. This refers to stretchability or elasticity in the longitudinal and / or transverse directions, rather than in the thickness direction of the woven, knitted, or nonwoven fabric.

[0032] It is particularly preferable to use a non-sealable, stretchable woven, knitted, or nonwoven fabric in the longitudinal and / or transverse directions as the support layer.

[0033] To be elastic or stretchable in at least one direction, preferably two directions (longitudinal and / or transverse), as used herein, means the ability of a transdermal treatment system to stretch in at least one direction, preferably two different directions, preferably longitudinal and transverse, relative to the initial state of the material, without losing its original shape, rather than in the thickness direction. No permanent deformation of the stretchable material occurs. Elasticity is evaluated by elongation and specified as a dimensionless number or as a percentage value when multiplied by 100. In transdermal treatment systems according to this specification, elongation is preferably 1 to 100%, particularly preferably 10 to 50%, and most preferably 15 to 30%, relative to the original dimensions of the transdermal treatment system. Elasticity is determined according to ISO 13934-1 of April 10, 2013.

[0034] The use of such stretchable woven, knitted, or nonwoven fabrics has the advantage that the transdermal treatment system or active ingredient-containing patch according to the present invention is very comfortable to wear, does not restrict mobility, has high adhesion to the skin, and therefore prevents unintended peeling, even in large specific examples or when applied to easily bendable parts of the body such as the joints of the limbs.

[0035] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer is formed as a single layer. In this case, diclofenac, a sealing adhesive component, and at least one solvent, dimethylpropylene urea, are present as a mixture in one same layer.

[0036] Since the sealing adhesive component is preferably a hydrophobic adhesive component, a two-phase matrix layer is preferably formed, comprising an outer nonpolar phase and an inner polar phase, the outer nonpolar phase comprising at least one sealing adhesive component, and the inner polar phase comprising diclofenac and at least one solvent, dimethylpropylene urea.

[0037] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer further preferably contains a weak acid with a pk of 5 or less.

[0038] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer further comprises citric acid and / or dilute hydrochloric acid, or another organic acid such as acetic acid, uric acid and / or lactic acid.

[0039] Here, citric acid functions as a proton donor, and diclofenac has the effect of being present as a free base in the transdermal treatment system according to the present invention.

[0040] The transdermal treatment system according to the present invention is characterized in that dimethylpropylene urea, which is a solvent, is present in the matrix layer in an amount of 0.5 to 20% by weight, particularly preferably 2 to 15% by weight, and most preferably 5 to 10% by weight, relative to the total weight of the matrix layer.

[0041] Dimethylpropylene urea can be used alone or in combination with permeability enhancers.

[0042] The transdermal treatment system according to the present invention is preferably further characterized in that at least one permeability enhancer is contained in the matrix layer.

[0043] Suitable permeability enhancers include fatty acids and / or fatty acid esters such as pentanoic acid, hexanoic acid, octanoic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, isovaleric acid, neoheptonic acid, neononanoic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, vaccenic acid, petroseric acid, elaidic acid, oleic acid, arachidonic acid, gadolic acid, erucic acid, ethyl acetate, methyl propylate, butyl acetate, methyl valerate, diethyl sebacate, methyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate (isopropyl myristate ester), isopropyl palmitate and / or isopropyl oleate.

[0044] Other suitable permeability enhancers include polyhydric alcohols such as propylene glycol or dipropylene glycol.

[0045] Preferably, the transdermal treatment system according to the present invention contains dimethylpropylene urea as a solvent and a polyhydric alcohol such as propylene glycol or dipropylene glycol as a permeation enhancer.

[0046] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer contains at least one permeability enhancer in an amount of 0.5 to 20% by weight, particularly preferably 2 to 15% by weight, and most preferably 5 to 10% by weight, relative to the total weight of the matrix layer.

[0047] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer contains propylene urea in an amount of 0.5 to 20% by weight, particularly preferably 2 to 15% by weight, and most preferably 5 to 10% by weight, based on the total weight of the matrix layer. Propylene urea functions as a preferred solvent in this specification.

[0048] Furthermore, the transdermal therapy system according to the present invention is characterized in that it does not contain permeation enhancers from the class of pyrrolidone, more particularly N-methyl-2-pyrrolidone, sulfoxide, more particularly dimethyl sulfoxide (DMSO), formamide, more particularly dimethylformamide (DMF), and / or 1-dodecyl azacycloheptan-2-one or laurocapram (azon) and / or derivatives.

[0049] The transdermal treatment system according to the present invention is characterized in that citrate is preferably present in the matrix layer in an amount of 0.1 to 10 moles, preferably 0.3 to 5 moles, and particularly preferably 0.3 to 2 moles per mole of diclofenac.

[0050] Particularly preferred is that the sealing adhesive component is a non-polar polymer.

[0051] The transdermal treatment system according to the present invention is preferably characterized in that the sealing adhesive component comprises a polyisobutylene adhesive, preferably a polyisobutylene adhesive based on low molecular weight polyisobutylene and high molecular weight polyisobutylene, and / or a styrene-isoprene-styrene block copolymer.

[0052] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer contains low molecular weight polyisobutylene as a sealing adhesive component in an amount of 30 to 80% by weight, preferably 45 to 60% by weight, relative to the weight of the matrix layer.

[0053] The transdermal treatment system according to the present invention is preferably characterized in that the matrix layer contains high molecular weight polyisobutylene as a sealing adhesive component in an amount of 10 to 30% by weight, preferably 15 to 25% by weight, relative to the weight of the matrix layer.

[0054] The transdermal treatment system according to the present invention is characterized in that the matrix layer preferably contains a total amount of polyisobutylene as a sealing adhesive component in an amount of 45 to 95% by weight, preferably 55 to 85% by weight, particularly preferably 65 to 75% by weight, and more specifically 68 to 72% by weight relative to the weight of the matrix layer.

[0055] The transdermal treatment system according to the present invention is preferably characterized in that the sealing adhesive component contains a polyisobutylene adhesive based on a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene in a ratio of 50:50 to 95:5.

[0056] The low molecular weight polyisobutylene described above is preferably a polyisobutylene having an average molecular weight of 20,000 to 60,000 g / mol (determined by viscosity measurement), and more specifically, 40,000 g / mol (determined, for example, by gel permeation chromatography).

[0057] The low molecular weight polyisobutylene described above is preferably 27.5 to 31.2 cm². 3 This is a polyisobutylene with an intrinsic viscosity of / g.

[0058] A suitable commercially available low molecular weight polyisobutylene is available from BASF under the trade name Oppanol B10.

[0059] The high molecular weight polyisobutylene described above is preferably polyisobutylene having an average molecular weight of 1,000,000 to 1,200,000 g / mol (determined by viscosity measurement), and more specifically, 1,110,000 g / mol (determined, for example, by gel permeation chromatography).

[0060] The molecular weight as described above is preferably about 416 to 479 cm³. 3 This is a polyisobutylene with an intrinsic viscosity of / g.

[0061] A suitable commercially available high molecular weight polyisobutylene is available from BASF under the trade name Oppanol B100, also known as Oppanol N100.

[0062] Preferably, the sealing adhesive component contains, in addition to low molecular weight and / or high molecular weight polyisobutylene, at least one styrene-isoprene-styrene block copolymer in an amount of 0 to 15% by weight (value 0 is simply excluded), preferably 3 to 8% by weight.

[0063] The transdermal treatment system according to the present invention is preferably characterized in that diclofenac is contained in the matrix layer in an amount of 0.5 to 10% by weight, preferably 2 to 5% by weight, relative to the weight of the matrix layer.

[0064] The transdermal treatment system according to the present invention is preferably characterized in that only dimethylpropylene urea is present as the solvent.

[0065] Most preferably, dimethylpropylurea is present in the matrix layer as the sole solvent, in combination with citric acid and / or hydrochloric acid.

[0066] Combinations of dimethylenepropylurea as a solvent and polyhydric alcohols such as propylene glycol as a permeability enhancer, in or out of the presence of citric acid and / or hydrochloric acid, are also very suitable.

[0067] In another embodiment, a transdermal therapeutic system for administering diclofenac preferably comprises a support layer and a matrix layer, wherein the matrix layer comprises diclofenac, at least one occlusive adhesive component and at least one permeation enhancer, and the at least one permeation enhancer comprises a polyhydric alcohol such as propylene glycol. In this case, it does not contain a solvent such as dimethylenepropylurea. Otherwise, all definitions above and below apply to this alternative embodiment.

[0068] In principle, all pharmaceutically acceptable salts and solvates of diclofenac can be used.

[0069] However, the transdermal treatment system according to the present invention is preferably characterized in that diclofenac exists as diclofenac sodium salt.

[0070] In another preferred embodiment, the transdermal treatment system according to the present invention preferably contains at least one antioxidant in the matrix layer. The at least one antioxidant is preferably selected from α-tocopherol, ascorbyl palmitate, and butylhydroxytoluene. The at least one antioxidant is preferably present in the matrix layer in an amount of 0.05 to 1.5% by weight, preferably 0.2 to 1% by weight, relative to the total weight of the matrix layer.

[0071] The use of antioxidants has the advantage that the transdermal treatment system according to the present invention remains stable under various external conditions over a long period of time.

[0072] The transdermal therapeutic system according to the present invention preferably further has a basis weight of the matrix layer of 50 to 400 g / m² 2 , preferably 70 to 150 g / m² 2 , particularly preferably 90 to 120 g / m² 2 .

[0073] In another preferred embodiment, the transdermal therapeutic system according to the present invention has a surface area of about 20 to 250 cm² 2 , preferably about 50 to about 150 cm² 2 .

[0074] Furthermore, in another preferred embodiment, the transdermal therapeutic system according to the present invention includes a removable protective layer, preferably a silicone-coated polyethylene terephthalate film, which is adhered to the side of the matrix layer that is not the support layer. This removable protective layer (by silicone coating on the side where the protective layer contacts the matrix) facilitates the packaging and transportation of the transdermal therapeutic system according to the present invention.

[0075] The present invention further relates to a transdermal therapeutic system as described above for use as a medicament.

[0076] Furthermore, the present invention relates to a transdermal therapeutic system as described above for use as a medicament in the treatment of inflammatory rheumatic diseases such as chronic polyarthritis, fibromyalgia, or osteoarthritis; acute gout attacks; joint injuries during sports; postoperative pain and swelling; lumbar disc herniation; and pain and inflammatory conditions such as venous disorders.

[0077] Hereinafter, the present invention will be described with reference to non-limiting examples.

Examples

[0078] The following transdermal therapeutic systems were manufactured according to standard procedures. The systems tested had the compositions according to Table 1 below. The amounts are to be understood as % by weight relative to the total weight of the matrix layer.

[0079] [Table 1]

[0080] A transdermal treatment system (Dojin patch) containing 1.00% by weight of diclofenac sodium, as disclosed in EP1312360A1, was used for comparison.

[0081] The names Dojin001, Dojin002, and Dojin003 refer to three different batches of Dojin patches.

[0082] For further comparison, the following system (G) was used. The quantity should be understood as a weight percentage relative to the total weight of the matrix layer.

[0083] [Table 2]

[0084] The in vitro human skin permeability of the systems listed in Tables 1 and 2, as well as Dojin patch 1 and 2, was measured using Franz cells. The donor compartment contains the substance or formulation (e.g., gel, ointment, solution, patch). The acceptor compartment is filled with buffer or other solution. By frequently taking samples from the acceptor compartment, the permeation of the substance from the skin can be monitored over a selected period. The effect of permeation enhancers on the permeation of the substance can also be tested using this system. Using Franz cells as a diffusion model is particularly suitable for predicting the transport (=permeation) of drugs through human skin, corresponding to systemic availability. However, it is important to note that there is no correlation between in vitro and in vivo results. In this specification, Franz cells were loaded with surgically obtained human abdominal skin. Here, the diffusion area was 1.172 cm². 2500 μm of skin samples were incubated with a topical treatment system. 10 mL of phosphate buffer + 0.1% NaN3 (pH=5.5) was used as the acceptor medium. Permeability measurements were performed at 32°C. The measurement results are shown in Figures 1 and 2. [Brief explanation of the drawing]

[0085] [Figure 1] This figure shows the results of the transmission measurement. [Figure 2] This figure shows the results of the transmission measurement.

Claims

1. A transdermal therapy system for administering diclofenac, comprising a support layer and a matrix layer, wherein the matrix layer comprises diclofenac, at least one sealing adhesive component and at least one solvent, the at least one solvent comprising dimethylpropylene urea, and the matrix layer is formed as a monolayer.

2. The transdermal treatment system according to claim 1, characterized in that the support layer includes an elastic woven fabric, knitted fabric, or nonwoven fabric.

3. The transdermal treatment system according to claim 1 or 2, further characterized in that at least one permeability enhancer, preferably a polyhydric alcohol, is contained in the matrix layer.

4. The transdermal treatment system according to any one of claims 1 to 3, characterized in that the matrix layer contains citric acid and / or hydrochloric acid.

5. The transdermal treatment system according to any one of claims 1 to 4, characterized in that dimethylpropylene urea is contained in the matrix layer in an amount of 0.5 to 20% by weight relative to the total weight of the matrix layer.

6. The transdermal treatment system according to any one of claims 1 to 5, characterized in that citric acid and / or hydrochloric acid are present in the matrix layer in an amount of 0.1 to 10 mol, preferably 0.3 to 5 mol, and particularly preferably 0.3 to 2 mol per mol of diclofenac.

7. The transdermal treatment system according to any one of claims 1 to 6, characterized in that the sealing adhesive component comprises a polyisobutylene adhesive, preferably a polyisobutylene adhesive based on low molecular weight polyisobutylene and high molecular weight polyisobutylene, and / or a styrene-isoprene-styrene block copolymer.

8. The matrix layer contains low molecular weight polyisobutylene as a sealing adhesive component in an amount of 30 to 80% by weight, preferably 45 to 60% by weight, relative to the weight of the matrix layer. A transdermal treatment system characterized by any one of claims 1 to 7.

9. The transdermal treatment system according to any one of claims 1 to 8, characterized in that the matrix layer contains high molecular weight polyisobutylene as a sealing adhesive component in an amount of 10 to 30% by weight, preferably 15 to 25% by weight, relative to the weight of the matrix layer.

10. The transdermal treatment system according to any one of claims 1 to 9, characterized in that the sealing adhesive component contains a polyisobutylene adhesive based on a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene in a ratio of 50:50 to 95:

5.

11. The transdermal treatment system according to any one of claims 1 to 10, characterized in that diclofenac is present in the matrix layer in an amount of 0.5 to 10% by weight relative to the weight of the matrix layer.

12. The transdermal treatment system according to any one of claims 1 to 11, characterized in that diclofenac exists as diclofenac sodium salt.

13. A transdermal treatment system according to any one of claims 1 to 12, characterized in that only dimethylpropylene urea is present as a solvent, and more specifically in combination with citric acid, in the matrix layer.

14. A transdermal treatment system according to any one of claims 1 to 13 for use as a pharmaceutical product.

15. A transdermal treatment system according to any one of claims 1 to 13, for use as a pharmaceutical for the treatment of pain and inflammatory conditions.

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