Patent ID: 12251374

DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION

The active ingredient-impermeable backing layer is constructed from a composite material and comprises a film with aluminium vapour-deposited thereon. The film is based expediently on an active ingredient-impermeable material, wherein polyesters such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphtholate, polyolefins such as polyethylene or propylene, ethylene vinyl acetate, polyvinyl chloride, polyamide (nylon) or polyurethane can be specified as suitable materials.

With regard to the matrix polymer, the transdermal therapeutic system of the present invention is not subject to any relevant limitations, with the exception of the fact that it does not contain any free carboxylic acid and/or carboxylate groups. The expression “free carboxylic acid and/or carboxylate groups” in the content of the present invention means —CO2H— and —CO2−— groups which are present in non-bonded and non-complexed form. —CO2— groups that are bonded in the form of esters or coordinate at complex-forming metals, especially transition metals such as titanium, are not considered to be free carboxylic acid and/or carboxylate groups, whereas carboxylate salts with non-coordinating metal ions, such as alkali metal ions or alkaline earth metal ions, shall be considered to be free carboxylate groups within the scope of this description.

In a preferred embodiment the matrix polymer of the reservoir layer comprises linear styrene-butadiene-styrene or styrene-isoprene-styrene block copolymer.

Further suitable matrix polymers are acrylate polymers, especially in the form of self-crosslinking acrylate copolymers of 2-ethylhexylacrylate, vinyl acetate, acrylic acid and titanium chelate ester, in which the acrylic acid bonded to the titanium forms crosslinking points, or non-self-crosslinking acrylate copolymer of 2-ethylhexylacrylate, vinyl aetate and 2-hydroxyethyl acrylate.

A polymer that likewise can be used expediently as matrix polymer is polyisobutylene, which can be used alone or in combination with polybutylene.

Polar vinyl polymers, such as polyvinyl pyrrolidone or polyvinyl alcohol, are also usable as matrix polymers.

Lastly, non-organic polymers such as polysiloxanes can also be used as matrix polymer. It is also possible to use mixtures of the aforementioned polymers as matrix polymer, however this is on the condition that the polymers are sufficiently compatible with one another, such that there is not a substantial segregation of the polymer components. Based on the higher processing effort necessary for the production of reservoir layers based on different polymers, however, it is preferred if the ITS contains only one polymer type as reservoir layer.

The matrix polymer accounts for the greatest proportion in the reservoir layer. The reservoir layer thus generally contains a proportion of matrix polymer in the range of from 70 to 99% by weight, preferably 75 to 97% by weight, and very especially preferably 80 to 95% by weight.

Besides the aforementioned constituents, the reservoir layer may also contain conventional additives. The type of potential additives is dependent on the used polymer and the active ingredient. Depending on their function, these can be divided into plasticisers, tackifiers, stabilisers, carriers, diffusion- and penetration-regulating additives, or fillers. The physiologically safe substances possible in this regard are known to a person skilled in the art. The reservoir layer has such an inherent tack that continuous contact with the skin is ensured.

Examples of suitable plasticisers are diesters of dicarboxylic acids, for example di-n-butyl adipate, and triglycerides, especially medium-chain (i.e. C6-C14) triglycerides, for example of coconut oil caprylic/capric acid.

With regard to the above-mentioned additives, it should be noted that these, similarly to the matrix polymer, should have no free carboxylic acid and/or carboxyl groups, since this would be contrary to the purpose of providing the fullest possible release of fampridine from the transdermal therapeutic system. The additives are preferably free from carboxylic acid and/or carboxyl groups.

The detachable protective layer, which is in contact with the reservoir layer and is removed prior to use, for example comprises the same materials as are used for the production of the backing layer, provided that they are made detachable, for example by a silicone treatment. Other detachable protective layers are, for example, polytetrafluoroethylene, treated paper, cellophane, polyvinylchloride, and the like. If the laminate according to the invention is divided into a format suitable for therapy (patches) before the protective layer is applied, the protective layer formats may then have a protruding end, with the aid of which they can be easily removed from the patch.

The application time for which the transdermal therapeutic system is intended is preferably at least 12 hours, more preferably at least 24 hours, and even more preferably at least 48 hours. The active ingredient amount must be coordinated with the desired application time accordingly.

The transdermal therapeutic system according to this invention is preferably configured such that a daily dose of delivered fampridine in the range of from approximately 5 to 50 mg, and preferably from 7 to 25 mg, is achieved. To this end the TTS is made in a suitable size, for example in the range of from 5 to 20 cm2.

The transdermal therapeutic system according to the invention is suitable for the treatment of patients suffering from multiple sclerosis. A further aspect of the present invention therefore relates to a transdermal therapeutic system as described above for use in the treatment of multiple sclerosis.

The present invention lastly relates to a process for producing the transdermal therapeutic system according to the invention.

The process for producing an above-described transdermal therapeutic system requires at least the following steps:applying a solution comprising the matrix polymer, fampridine and at least one pharmaceutically acceptable solvent to a detachable protective layer;drying the solution so as to form a pressure-sensitive adhesive reservoir layer; andapplying an active ingredient-impermeable backing layer to the pressure-sensitive adhesive reservoir layer.

The pharmaceutically acceptable solvent comprises conventional solvents used for pharmaceutical applications, and mixtures of such solvents.

With regard to the advantages of the process for producing the above-described transdermal therapeutic system, reference is made to the description of the transdermal therapeutic system.

The invention will be explained in greater detail hereinafter on the basis of a practical example.

EXAMPLE 1: DETERMINING THE SATURATION CONCENTRATION CSOF FAMPRIDINE IN VARIOUS POLYMERS

The saturation concentration Csof fampridine was determined in various polymer matrices by the method described by Liu. (Liu, P., Gargiulo, P., Wong, J., and Novartis (1997). A Novel Method for Measuring Solubility of a Drug in an Adhesive,Pharmaceutical Research14, page 317).

In this method, known by specialists as the “sandwich” method, the saturation concentration is determined as follows:

A laminate is constructed, having the following layer sequence: protective film—donor layer with active ingredient (dissolved and undissolved)—active ingredient-permeable membrane—acceptor layer without active ingredient—protective film. The two protective films are made of identical material; the matrix material of the donor and of the acceptor layer is likewise identical.

The donor layer is produced by dissolving the active ingredient in a solution of the polymer in organic solvent. The concentration of the active ingredient must be selected to be high enough that an undissolved residue can be identified in the polymer matrix so that the saturation concentration Csin the donor layer is reliably exceeded. This solution is applied to the protective film, and the process solvent is evaporated. The adhesive surface of the donor layer is then covered with the membrane. A dialysis tube made of regenerated cellulose (ZelluTrans®, from Roth, 46 mm flat width) that has been cut to size in the longitudinal direction is used as membrane. The acceptor layer is produced without active ingredient, similarly to the donor layer, and the membrane is applied to the other side.

The laminates thus produced are then stored for 7 days at room temperature, during which time the active ingredient diffuses through the membrane into the acceptor layer. The active ingredient concentration in the donor layer is then determined. To this end, aliquots of approximately 1 cm2are punched out using a punching tool of standardised area. The membrane is then removed, the punched blanks without membrane are weighed, and their weight is recorded (m1). The punched blanks are then placed in organic solvent so as to remove the matrices. The backing layers are removed, washed, and dried, and their weight (m2) is determined. The two measured values give the weight of the polymer proportion of the acceptor layer m3as follows:
m3=m1−m2

The concentration of fampridine in the solution is then calculated using an HPLC method, and its concentration in the donor layer is calculated. The saturation concentrations of fampridine in different polymer matrices determined on the basis of this test approach are summarised in Table 1:

TABLE 1Csof fampridine in different polymer matricesSolvent used toCsofdissolve thePolymerfampridine [%]polymerPolyisobutylene2.2TolueneStyrene-isoprene-2.7Toluenestyrene blockcopolymerAcrylate copolymer3.3Ethyl acetateof 2-ethylhexylacrylate,vinyl acetate and2-hydroxyethylacrylatePolysiloxane0.3Ethyl acetateAcrylate copolymer7.4Ethyl acetateof 2-ethylhexylacrylate,butyl acrylate,vinyl acetate,acrylic acid

It is clear from Table 1 that the saturation concentration Csof fampridine in neutral polymers is approximately 3%, whereas saturation concentrations approximately 3 times higher were determined in acidic polymers. An especially low Csof fampridine was measured in polysiloxane.

EXAMPLE 2: PRODUCTION OF FAMPRIDINE TTS

Transdermal therapeutic systems based on different base polymers were produced:

a) TTS with Polyisobutylene (PIB)

Production of Polyisobutylene Solution

50 g each of OPPANOL® B 10 and of OPPANOL® B 100 were dissolved in 250 g toluene with stirring over several days. 350 g of solution with 28.6% solids were obtained.

Production of Samples 1, 2 and 3

0.6 g, 0.9 g and 1.2 g fampridine base were scattered into 100 g each of the produced polyisobutylene solution, and several hours passed before the solids had fully dissolved. These three solutions were applied to a 100 μm siliconised. PET film (Mitsubishi RN 100) using an Erikson doctor blade.

Once the toluene had evaporated, the weight per unit area was approximately 90 g/m2. The fampridine concentration in sample 1 was 2%, that in sample 2 was approximately 3%, and that in sample 3 was approximately 4%.

b) TTS with Styrene-Isoprene-Styrene (SIS)

Production of Styrene-Isoprene-Styrene Block Copolymer Solution

95 g styrene-isoprene-styrene block copolymer and 5 g abietyl alcohol were dissolved by stirring in 250 g toluene over several days. 350 g of a solution with 28.6% solids were obtained. Since styrene-isoprene-styrene block copolymer is not a pressure-sensitive adhesive, abietyl alcohol was added as tackifying resin.

Production of Samples 4, 5 and 6

0.8 g, 1.2 g and 1.5 g fampridine base were scattered into 1.00 g each of the produced styrene-isoprene-styrene block copolymer solution, and several hours passed before the solids had fully dissolved. These three solutions were applied to a 100 μm siliconised PET film (Mitsubishi RN 100) using an Erikson doctor blade. Once the toluene had evaporated, the weight per unit area was approximately 90 g/m2. The fampridine concentration in sample 4 was 2.7%, that in sample 5 was approximately 4%, and that in sample 6 was approximately 5%.

c) TTS with Polyacrylates

Polyacrylates which can be used as medical pressure-sensitive adhesive can be procured commercially as solutions in organic solvents. For samples 7-9, the following trade products from Henkel: DUROTAK® 87-4287—a natural acrylate copolymer of 2-ethylhexylacrylate, vinyl acetate and 2-hydroxyethyl acrylate in ethyl acetate (39% solids content)—and DUROTAK® 387-2051, an acidic acrylate copolymer of 2-ethylhexylacrylate, butyl acrylate, vinyl acetate, and acrylic acid in ethyl acetate/n-heptane (51.5% solids content), were used as reference.

TTS in Neutral Polyacrylate Samples 7, 8 and 9

0.8 g, 1.3 g and 1.6 g fampridine base were scattered into 100 g each of DUROTAK® 87 4287, and several hours passed before the solids had fully dissolved. These three solutions were applied to a 100 μm siliconised PET film (Mitsubishi RN 100) using an Erikson doctor blade. Once the toluene had evaporated, the weight per unit area was approximately 135 g/m2. The fampridine concentration in sample 7 was 2%, that in sample 8 was approximately 3.3%, and that in sample 9 was approximately 3.95%.

TTS in Acid Polyacrylate (Reference) Samples 10, 11 and 12

4 g, 6 g and 7 g fampridine base were scattered into 100 g each of DUROTAK® 387 2051, and several hours passed before the solids had fully dissolved. These three solutions were applied to a 100 μm siliconised PET film (Mitsubishi RN 100) using an Erikson doctor blade. Once the solvent had evaporated, the weight per unit area was approximately 90 g/m2. The fampridine concentration in sample 1.0 was 7.2%, that in sample 11 was approximately 10.4%, and that in sample 12 was approximately 12%.

d) TTS in Polysiloxane

Production of the Solution of Polysiloxane in Toluene

Fampridine base is sufficiently soluble in aromatic hydrocarbons, but not in n-heptane. Since toluene polysiloxane solution is not commercially obtainable, BIO PSA 4201 from Dow Chemicals (polysiloxane in n-heptane) was used as starting material. The solvent was evaporated and the rubber-like polymer residue was dissolved with so much toluene that a solution with approximately 75% solids was obtained.

Production of Samples 13, 14 and 15

0.25 g, 0.5 g and 1 g fampridine base were scattered into 100 g each of the produced toluene polysiloxane solution, and several hours passed before the solids had fully dissolved. These three solutions were applied to a 100 μm siliconised PET film (Mitsubishi RN 100) using an Erikson doctor blade. Once the toluene had evaporated, the weight per unit area was approximately 90 g/m2. The fampridine concentration in sample 13 was 0.33%, that in sample 14 was approximately 0.66%, and that in sample 15 was approximately 1.3%.

The active ingredient crystallised in samples 14 and 15.

Permeation Results

Permeation experiments were performed with samples 1-15 in a Franz cell with human skin. The test parameters are summarised in Table 2.

TABLE 2Test parameters for in vitro permeationPermeationPuncheddurationPermeationblankAcceptorWater bathThicknessareaareamediumtemperatureof the skinApprox.1.1610 ml32° C.24 hours/1.6 cm2physiologicalapprox. 500salineμmsolution

The results of the permeation studies, the absolute contents of fampridine, and the active ingredient utilisation are specified in Table 3.

TABLE 3mean (x from n = 6) fampridine flux measured onhuman skin 500 μm in Franz cells over 24 hoursContent ofActivefampridineCumulativeingredientSample no./[mg/1.16flux in 24 hutilisationpolymercm2][mg/24][%]1* PIB0.210.08741.42 PIB0.310.177573 PIB0.420.264634 *SIS0.280.08329.65 SIS0.420.19145.56 SIS0.520.2242.37* neutr. PA0.310.08226.48 neutr. PA0.520.16331.39 neutr. PA0.620.27842.810* acidic PA0.750.0810.611 acidic PA1.090.15414.112 acidic PA1.260.2318.313* polysiloxane0.040.01742.514 polysiloxane0.070.0457.115 polysiloxane0.130.04736.2*Fampridine concentration close to the saturation concentration Cs

It can be seen from Table 3 that the use of neutral polymer TTS with active areas <40 cm2with use of 1-2 TTS/day makes fampridine available transdermally in daily doses that correspond to the oral daily doses. Samples 3 and 9 are especially suitable.