EP1691794A2

EP1691794A2 - Form of administration for controlling primary headaches

Info

Publication number: EP1691794A2
Application number: EP04803785A
Authority: EP
Inventors: Rasoul Sedaghat Kerdar; Maria Christina Vazquez Lantes
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2003-12-12
Filing date: 2004-12-13
Publication date: 2006-08-23
Also published as: CA2542256A1; WO2005055977A3; WO2005055977A2; JP5557416B2; US7998503B2; CA2542256C; CN1905862A; CN1905862B; US20070086955A1; DE10358749A1; JP2007513918A

Abstract

The invention relates to a nasally applied, film-shaped, bioadhesive pharmaceutical form of administration containing at least one agent-containing layer that is based on crosslinked hydrophilic polymers comprising up to 60 percent by weight of Lidocaine, the percentage being in relation to the total quantity of crosslinked hydrophilic polymers. Also disclosed is the use thereof for controlling primary headaches, preferably migraine.

Description

Dosage form to combat primary headaches

The present invention relates to a nasally applicable, film-shaped, bioadhesive, pharmaceutical dosage form containing at least one active ingredient-containing layer based on crosslinked hydrophilic polymers with up to 60% by weight, based on the total amount of crosslinked hydrophilic polymers, lidocaine and the use of the active ingredient-containing layer for the production a pharmaceutical, nasally applicable, single or multi-layer dosage form to combat primary headaches, especially migraines.

With headaches, a distinction is made between primary and secondary headaches. While secondary headache pain is just the result of another condition, primary headache is an illness in and of itself. Accordingly, fighting the headache is the real treatment goal in this case.

Primary headaches can have different causes, such as: B. have changes in the vascular system. The corresponding headache is then referred to as neurovascular pain.

Repeated, preferably unilateral neurovascular headaches are also known as migraines.

Since an immediate effect to alleviate the pain is particularly sought after in the treatment of primary headaches, dosage forms which guarantee a rapid release of active ingredient into the circulation are particularly suitable. Oral dosage forms such as tablets or capsules are not the first choice for this, but rather a nasal application that can be used to quickly alleviate primary headaches, especially migraines. If a transmucosal administration of active substances through the nasal mucosa to combat headaches is described in WO 01/43733, dosage forms with only lidocaine as the only active substance are assessed as unsuitable.

It is also known from the prior art that lidocaine after nasal administration, e.g. B. in the form of sprays leads to a quick relief from migraine pain, but this pain flares up again after a short time. The publication by Maizels et al., Journal of the American Medical Association (1996, July) 276 (4), pages 319-321 confirms that nasal lidocaine leads to a rapid relief from migraine pain. On the other hand, a relapse, i.e. a recurrence of the pain, was found shortly after the application of lidocaine.

In order to combat this recurrence of pain, in particular migraine pain, continued administration of lidocaine, in particular continued nasal application of lidocaine, is desirable.

It was therefore an object of the present invention to provide a dosage form which ensures both an accurate dosage and a continuous release of lidocaine over several hours via the nasal mucosa for combating headaches, in particular migraine pain in humans, with a - And the same dosage form both immediate pain control and the fight against flare-up, d. H. repeated or continuous pain, and a simple application of the dosage form, preferably as a singular application form, should be possible.

This object is achieved by providing a nasally applicable, film-like, bioadhesive, pharmaceutical, single- or multilayer dosage form with at least one active ingredient-based layer based on crosslinked hydrophilic polymers with up to 60% by weight lidocaine, based on the total amount of crosslinked hydrophilic polymers. The high loading of up to 60% by weight of lidocaine in at least one of the active ingredient-containing layers of the dosage form according to the invention was not to be expected, since other film-forming polymers, such as, for. B. ethyl cellulose, only a load up to about 25 wt .-% of active ingredient. An additional concentration of the active ingredient usually leads to its crystallization. Crystallization causes brittle films which do not guarantee safe handling, for example during application. The films are also cloudy, which affects patient acceptance.

The inventive selection of crosslinked hydrophilic polymers as film-forming substances for the active substance-containing layer, which are preferably crosslinked during or after loading with lidocaine, enables layers containing lidocaine with a proportion of lidocaine of up to 60% by weight, based on the To provide the total amount of crosslinked hydrophilic polymers, preferably from 20 to 55% by weight and particularly preferably from 30 to 50% by weight.

In addition, by designing the claimed dosage form as a film, it is possible to ensure reliable and accurate dosing. It can be checked at any time whether the dosage form adheres to the nasal mucosa. In addition, the dosage form without active ingredient can be removed again at the end of the therapy.

The film-forming, active ingredient-containing, hydrophilic polymers are preferably crosslinked during the layer formation, ie. H. in situ, with the aid of known crosslinkers, preferably phenolic crosslinkers and / or polyacrylic acid derivatives, particularly preferably with tannin and / or polycarbophil (homopolymers of acrylic acids crosslinked with divinyl glycol, optionally neutralized with calcium). The weight ratio of hydrophilic polymers to crosslinking agent is preferably 2: 1 to 5: 1, particularly preferably 4: 1.

The crosslinking of the film-forming polymers makes it possible, despite the high lidocaine loading, to handle the dosage form in a sufficiently safe manner, e.g. B. when removing from the packaging and inserting it into the nose, without ensuring damage to the dosage form by tearing. Through the Crosslinking according to the invention succeeds in providing dosage forms with an at least tear strength of 40 N, preferably of at least 50 N, particularly preferably of at least 60 N despite a high lidocaine concentration.

Water-soluble cellulose ethers, particularly preferably hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose, very particularly preferably hydroxypropyl methyl cellulose, are preferably used as hydrophilic polymers for the dosage form according to the invention.

The dosage forms according to the invention can have one or more layers. If the dosage forms are multi-layered, they can have more than one active substance-containing layer and / or a cover layer and / or an adhesive layer.

The release of lidocaine from the active ingredient-containing layer or the further active ingredient-containing layers can be controlled not only via the different levels of the lidocaine concentration, but also via the degree of crosslinking of the hydrophilic polymers. The release can be controlled within a lidocaine-containing layer, for example, via a concentration gradient of the lidocaine. A further possibility for influencing the release of lidocaine consists in providing several layers containing lidocaine with different lidocaine concentrations in the dosage forms according to the invention. Furthermore, there can also be active substance-free layers, optionally made of crosslinked hydrophilic polymers, between the active substance-containing layers. Thus, the active ingredient can be released quickly and in a sufficient amount for immediate pain relief from an active ingredient-containing layer, while a longer-lasting release of lidocaine is achieved from further active ingredient-containing layers in order to enable continued pain relief.

The active substance-containing layer preferably has a thickness of 30-500 μm. In order to ensure adequate adhesion of the dosage form according to the invention in nasal application, either a bioadhasive polymer can be incorporated into the lidocaine-containing layer or an additional layer can be provided as an adhesive layer in the dosage form according to the invention. An adhesive layer can consist of one or more of the known bioadhesive polymers such as polyacrylic acid derivatives. For example, the adhesive layer can consist of a mixture of optionally crosslinked hydrophilic polymers and a polyacrylic acid derivative or only of polyacrylic acid derivatives. Suitable bioadhesive polyacrylic acid derivatives are polyacrylic acids, some of which may be in the form of a calcium salt and possibly crosslinked. Polyacrylic acids partially present as calcium salt are particularly preferably crosslinked with divinylglycol. Such products are marketed as Polycarbophile®.

The adhesive layer can also consist of a mixture of one or more of the bioadhesive polymers mentioned and of one or more non-bioadhesive polymers, such as, for example, As ethyl cellulose, exist, especially if additional control of the release of the active ingredient with the help of the adhesive layer is desired.

The adhesive layer preferably has a thickness of 10 to 100 μm.

The dosage form according to the invention preferably also has a cover layer. The cover layer preferably consists of a water-insoluble polymer and is impermeable to the active ingredient, lidocaine. This ensures unidirectional drug release. With this unidirectional release, the active ingredient is only released to the nasal mucosa.

The cover layer can be built up from crosslinked hydrophilic polymers, for example from hydroxypropylmethylcellulose crosslinked with tannin.

It is also possible to make the cover layer from at least one water-insoluble cellulose ether, preferably from alkyl cellulose, particularly preferably from ethyl cellulose, or from a water-insoluble cellulose ester, preferably cellulose acetate, and / or from a water-insoluble poly (meth) acrylate a poly (C1 -4) alkyl (meth) acrylate, poly (C1 -4) dialkylamino (C1 - 4) alkyl (meth) acrylate and / or their copolymers, very particularly preferably a copolymer of ethyl acrylate / methyl methacrylate and / or a copolymer of ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride. The cellulose ethers, the cellulose esters and the poly (meth) acrylates can optionally contain plasticizers.

The cover layer preferably has a thickness of 10 to 100 μm.

In a preferred embodiment of the claimed invention, the cover layer is made of ethyl cellulose or a copolymer of ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride with a molar ratio of the respective monomers of 1: 2: 0.1, in both cases with a percentage of the plasticizer, preferably triethyl citrate, from 20 to 40 wt .-%, based on the amount of the polymer. A top layer consisting of a copolymer of ethyl acrylate / methyl methacrylate with a molar ratio of the respective monomers of 2: 1 is very particularly preferred, the addition of plasticizer not being absolutely necessary.

For protection, the dosage form according to the invention can also be applied with a protective layer, e.g. B. a plastic or aluminum foil.

The dosage form according to the invention is particularly suitable for combating primary headaches in humans because of the high loading with lidocaine.

Another object of the present invention is then the use of at least one lidocaine-containing, film-shaped layer based on crosslinked hydrophilic polymers with up to 60 wt .-% lidocaine, based on the total amount of crosslinked hydrophilic polymers, for the production of a pharmaceutical, nasally administrable dosage form for combating primary headache, preferably neurovascular headache, particularly preferred for the treatment of migraines in humans. The dosage form according to the invention is preferably produced by the active substance-containing layer or layers, preferably from an aqueous solution of the hydrophilic polymers and the lidocaine, by application with simultaneous or subsequent action of the crosslinking agent, preferably by in-situ crosslinking and preferably as an aqueous solution, and removal of the water is formed by drying.

The top layer can be applied to the dried active substance-containing layer by applying an aqueous dispersion such as a latex or pseudolatex dispersion of a water-insoluble polymer or a solution of such a polymer in a suitable organic solvent with subsequent removal of the water or organic solvent by drying and / or vacuum treatment getting produced.

If an adhesive layer is present in the dosage form according to the invention, it is preferably produced like the active ingredient-containing layers.

The dosage form according to the invention is preferably produced by building up the individual layers one above the other on a smooth surface, the film-forming polymer in each case being applied as partial layers together with the crosslinking agent which may be present and the active ingredient which may be present per layer by spraying and drying. The drying is preferably carried out simultaneously with the spraying. The partial layers preferably each have a thickness of 0.1 to 10 μm.

The spraying of the aqueous solution of the hydrophilic polymers and the aqueous solution of the crosslinking agent is preferably carried out simultaneously, the hydrophilic polymers and the crosslinking agent mixing after the spraying and then the polymer being crosslinked in situ.

If the active ingredient lidocaine is present in a layer, the loading is preferably carried out by the lidocaine already being dissolved in the aqueous solution of the hydrophilic polymers before this solution is brought together with the solution of the crosslinking agent. The great variability of this procedure allows the layer structure to be carried out in any order. In this way, the adhesive layer or first the cover layer can be formed as the basis for the subsequent layers.

An apparatus as described in DE 101 46 251 is preferably used to carry out the production process. The corresponding disclosure is considered part of the present disclosure.

This device comprises at least one spray device, a dryer and at least one plate which is cyclically moved under the spray device. The device preferably has a plurality of nozzles whose spray cones overlap

Method of determining tensile strength

A TA.XT2i texture analyzer from Winopal (Germany) is used to determine the tear strength. Pieces of the dosage form according to the invention with a length of 9.5 cm and a width of 1 cm are clamped at both ends with clamping jaws and slightly clamped so that the free clamping length is 7 cm. The clamping jaws are provided with coatings on the surface that come into contact with the pieces in order to avoid premature tearing of the pieces on the clips. If a piece tears despite the coatings on the clips, these values are not taken into account. The upper bracket pulls upwards at a constant speed of 0.5 mm / s. The force used at all times and the resulting stretch are recorded by the texture analyzer. The force, the stretch and the time are then displayed and analyzed with the help of software.

The tensile strength of a piece of film examined is the force which acts on the piece of film at the moment when the piece in question is torn. Example 1:

a) A solution of 10 g of hydroxypropylmethyl cellulose and 490 g of water and a solution of 2.5 g of tannin in 497.5 g of water were prepared to produce the cover layer. With the aid of the apparatus described in DE 101 46 251, these two solutions were sprayed onto a glass plate at the same time with nozzles, dried at 80 ° C. and the spraying process was repeated several times after the formation of the respective sub-layer until a layer thickness of 100 μm had been reached.

b) In the same manner as described in a), a solution of 10 g of hydroxypropylmethyl cellulose, 6.25 g of lidocaine and 490 g of water, and a solution of 2.5 g of tannin in 497.5 g of water were made using the same Applied by spraying several times on the top layer in partial layers until a layer thickness of 300 μm was reached. Lidocaine loading in the active ingredient-containing layer was 50% by weight.

c) A dispersion of 6 g of polyacrylic acid crosslinked with divinylglycol (Polycarbophil®) in 494 g of water was produced. This dispersion was also sprayed with the aid of the apparatus specified above, in which the partial layers were produced in each case until a layer thickness of the adhesive layer of 50 μm had been reached.

The dosage form produced in this way was flexible and easy to use.

Example 2:

A dosage form according to the invention was produced as described in Example 1, with the difference that according to a) for the preparation of the top layer a solution of 333.33 g of a 30% aqueous latex from a copolymer of ethyl acrylate / methyl methacrylate with a molar ratio of the monomers of 1: 1 in 666.67 g water was used. In contrast to the cover layer in Example 1 a), the layer thickness of the cover layer was only up to a thickness of 50 μm applied. The dosage form produced in this way was flexible and easy to use.

Example 3:

A dosage form according to the invention was produced as described in Example 1, with the difference that according to b) for the preparation of the active substance-containing ones

Layer 7.5 g of lidocaine was used. Lidocaine loading in the active ingredient

Layer was 60%.

The dosage form produced in this way was flexible and easy to use.

Example 4:

a) To prepare the active substance-containing layer with a concentration gradient of 8% by weight to 50% by weight and with a lidocaine loading of 35%, three solutions were prepared: a first solution of 0.6 g of lidocaine, 6 g of hydroxypropylmethyl cellulose and 294 g Water, a second solution of 7.5 g lidocaine, 10 g hydroxypropylmethyl cellulose and 490 g water, and a third solution 2.5 g tannin and 497.5 g water. With the aid of the apparatus described in DE 101 46 251, the first and the third solution were simultaneously sprayed onto a glass plate, the second solution being added continuously to the first solution, so that the volume of the first solution remained constant during the spraying process and the concentration continuously increased. It was dried at 80 ° C. The spraying process ended when the second and third solutions were completely used up. What remained was the first solution, which at the end of the spraying process still contained 3.77 g lidocaine and 6 g hydroxypropylmethyl cellulose. The active substance-containing layer had a layer thickness of 250 μm. b) A solution of 333.33 g of a 30% aqueous latex from a copolymer of ethyl acrylate / methyl methacrylate with a molar ratio of the monomers of 1: 1 in 666.67 g of water was used to produce the cover layer. The top layer was applied up to a thickness of 50 μm. The dosage form produced in this way was flexible and easy to use. The release of lidocaine from this dosage form is shown in FIG. 1 (the release was carried out using the apparatus described in German patent application 102 24518.5, the flow in the measuring cell being 1 ml / min).

Claims

claims:

1. Nasally administrable, film-like, bioadhesive, pharmaceutical dosage form containing up to 60% by weight, based on the total amount of cross-linked hydrophilic polymers, lidocaine in at least one active ingredient-containing layer based on cross-linked hydrophilic polymers.

2. Dosage form according to claim 1, characterized in that the amount of lidocaine 10 wt .-% to 60 wt .-%, preferably 20 wt .-% to 55 wt .-%, particularly preferably 30 wt .-% to 50 wt. -%.

3. Dosage form according to claim 1 or 2, characterized in that it has a tensile strength of at least 40 N, preferably of at least 50 N, particularly preferably of at least 60 N.

4. Dosage form according to one of claims 1 to 3, characterized in that a cellulose ether, preferably hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose was used as the hydrophilic polymer.

5. Dosage form according to one of claims 1 to 4, characterized in that the hydrophilic polymer of the active ingredient-containing layer has been crosslinked in situ.

6. Dosage form according to one of claims 1 to 5, characterized in that it has a controlled release of the lidocaine.

7. Dosage form according to one of claims 1 to 6, characterized in that it is one or more layers.

8. Dosage form according to claim 7, characterized in that it has at least one active substance-containing layer, a cover layer and / or an adhesive layer.

9. Dosage form according to claim 8, characterized in that an active substance-containing layer is the adhesive layer.

10. Dosage form according to claim 8 or 9, characterized in that the cover layer is impermeable to the active ingredient.

11. Use of a lidocaine-containing, film-like layer based on crosslinked hydrophilic polymers with up to 60% by weight lidocaine for the production of a film-like, pharmaceutical, nasally administrable, single-layer or multilayer dosage form for combating primary headaches in humans.

12. Use according to claim 11 for combating neurovascular pain.

13. Use according to claim 11 for combating migraines.