WO2022207257A1

WO2022207257A1 - Oral thin film

Info

Publication number: WO2022207257A1
Application number: PCT/EP2022/055928
Authority: WO
Inventors: Michael Linn; Markus Müller
Original assignee: Lts Lohmann Therapie-Systeme Ag
Priority date: 2021-03-29
Filing date: 2022-03-08
Publication date: 2022-10-06
Also published as: DE102021107829A1

Abstract

The invention relates to an oral thin film, comprising ketamine or a pharmaceutically acceptable salt thereof, and at least one polymer including free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer including free carboxyl groups are present in neutralized form, as a salt. The invention further relates to a method for the production of said oral thin film and to its use as a drug.

Description

Oral Thin Film

The present invention relates to an oral thin film for the administration of ketamine, a method for its production, and the use of such an oral thin film as a medicament, in particular in the treatment of pain and/or depression.

Oral thin films are thin films containing at least one pharmaceutically active ingredient that are placed directly in the oral cavity or applied to the oral mucosa and dissolve or swell there and thereby release the active ingredient. These are, in particular, thin polymer-based films containing active substance which, when applied to a mucous membrane, in particular the oral mucosa, can release the active substance directly into the latter. The very good blood circulation in the oral mucosa ensures that the active substance enters the bloodstream quickly. This delivery system has the advantage that the active ingredient is largely absorbed through the mucous membrane, thus avoiding the "first-pass metabolism" that occurs with the conventional dosage form of an active ingredient in tablet form. The active ingredient can be dissolved, emulsified or dispersed in the film will.

Oral thin films known from the prior art for administering ketamine based on water-soluble polymers have the disadvantage that they disintegrate relatively quickly on contact with aqueous media. Thus the Active ingredient released very quickly, which can be disadvantageous depending on the treatment regimen. In the case of the known systems, this disintegration time can only be varied by laboriously varying the entire formulation.

The object of the present invention is to eliminate the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide an oral thin film for the administration of ketamine with a relatively long, preferably easily variable, disintegration time, wherein ketamine is chemically and physically stably dissolved in the oral thin film. In addition, the oral thin film should be simple and inexpensive to produce.

The above object is achieved by an oral thin film according to claim 1 comprising ketamine or a pharmaceutically acceptable salt thereof, at least one polymer comprising free carboxyl groups, wherein 10 to 100%, more preferably 15 to 100%, of the free carboxyl groups of the at least one Polymer comprising free carboxyl groups, neutralized as a salt, includes.

Preferably there is 15 to 100% or 20 to 100% or 25 to 100% or 30 to 100% or 35 to 100% or 40 to 100% or 45 to 100% or 50 to 100% or 60 to 100% or 70 to 100 % or 80 to 100% or 90 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.

Preferably there is 10 to 100% or 15 to 100% or 20 to 95% or 25 to 90% or 30 to 85% or 35 to 80% or 40 to 75% or 45 to 70% or 50 to 65% or 55 to 60 % of the free carboxyl groups of the at least one polymer comprising free carboxyl groups, neutralized as a salt.

If 0% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer is preferably insoluble. If approximately 10% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4 (in aqueous solution at 20° C.) and is therefore very slowly soluble. If approximately 15% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4.5 to 7 (in aqueous solution at 20° C.).

If more than one polymer comprising free carboxyl groups is present, the values given for the degree of neutralization of the free carboxyl groups relate to the sum of all carboxyl groups present.

In the present description of the oral thin film, "comprising" can also mean "consisting of".

The at least one polymer comprising free carboxyl groups is preferably a sparingly soluble, very sparingly soluble or practically insoluble polymer according to the table below.

Solubility in water at 15°C to 25°C:

It has been shown that the solubility of polymers containing free carboxyl groups in water can be varied by adding at least one base. Applied to the oral thin film, this means that the disintegration time of the oral thin film in the patient's mouth can also be easily varied by the presence of at least one base in the oral thin film.

The oral thin film according to the invention is further characterized in that the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by adding at least one base, preferably NaOH.

In addition to NaOH, other alkali metal or alkaline earth metal hydroxides are also suitable as bases, for example KOH.

The amount of the at least one base is preferably from 1 to 15% by weight, in particular from 0.7 to 3% by weight, based on the weight of the at least one polymer which comprises free carboxyl groups.

The amount of the at least one base added is preferably such that the equivalence ratio of the base to the free carboxyl groups of the at least one polymer comprising free carboxyl groups is 1:10 to 2:1, preferably 1:10 to 1:1.

It is clear to the person skilled in the art that the amount of base used also depends on the molecular weight of the base and on its solubility.

The at least one polymer, which comprises free carboxyl groups, preferably comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.

Very particularly preferably, the at least one polymer comprising free carboxyl groups comprises a copolymer of (meth)acrylic acid and (meth)acrylic acid esters, very particularly preferably a (meth)acrylic acid/ethyl acrylate copolymer.

Suitable polymers are available, for example, under the trade names Eudragit L (from Evonik) or Kollicoat MAE (from BASF). These polymers have the advantage that they are almost insoluble in water and this solubility can be easily varied by adding at least one base. Furthermore, these polymers are well compatible with the active ingredient ketamine.

The oral thin film of the present invention preferably further comprises at least one water-soluble polymer.

Water-soluble polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility and are not crosslinked. The hydrophilic groups can be non-ionic, anionic, cationic and/or zwitterionic.

Water-soluble polymers preferably have a solubility in water according to the table above of at least "soluble".

The at least one water-soluble polymer is preferably selected from starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers , polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.

The addition of such a water-soluble polymer has the advantage that the compatibility between the film and the drug can be improved (e.g. also to stabilize a solid solution). Furthermore, the additional polymer can serve as a filler, for example to achieve a certain weight/thickness of the oral thin film.

The oral thin film according to the invention is preferably characterized in that the at least one water-soluble polymer is present in an amount of 5 to 40% by weight, preferably 8 to 30% by weight, particularly preferably 10 to 25% by weight % by weight based on the total weight of the oral thin film is present in the oral thin film.

Ketamine and/or a pharmaceutically acceptable salt thereof, preferably ketamine-HCl, is present in the oral thin film of the present invention. Under ketamine, (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l-one, (R)-(±)-2-(2-chlorophenyl)-2-( methylamino)cyclohexan-l-one, and the racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-l-one.

However, (S)-ketamine or a pharmaceutically acceptable salt thereof, in particular (S)-ketamine-HCl, is particularly preferred as the sole stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is approximately three-fold higher than that of (R) form.

The oral thin film of the present invention is further preferably characterized in that the ketamine is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, more preferably 25 to 35% by weight based on the total weight of the oral thin film in which oral thin film is present.

In addition, the oral thin film according to the invention is preferably characterized in that the at least one polymer comprising free carboxyl groups is present in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 25 to 35% by weight % based on the total weight of the oral thin film is present in the oral thin film.

The oral thin film according to the invention is preferably characterized in that the oral thin film contains at least one excipient selected from the group comprising dyes, plasticizers (such as glycerin), flavorings, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or or antioxidants.

Each of these excipients is preferably contained in the oral thin film in an amount of about 0.1 to 10% by weight based on the total weight of the oral thin film.

The oral thin film of the present invention preferably has an area of from about 0.5 cm ² to about 10 cm ² , more preferably from about 2 cm ² to about 8 cm ² . The oral thin film of the present invention is preferably characterized in that the basis weight of the oral thin film is about 50 to 300 g/m ² , preferably about 100 to 200 g/m ² .

This preferably corresponds to a layer thickness of preferably about 20 μm to about 500 μm, particularly preferably from about 50 μm to about 300 μm.

The oral thin film of the present invention preferably dissolves in the oral cavity in a period greater than about 10 minutes, more preferably in a period greater than about 20 minutes, more preferably in a period of 20 to 40 minutes.

The present invention further relates to a method for producing the oral thin film of the present invention. The method comprises the steps a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent, such as ethanol, comprising ketamine, at least one polymer comprising free carboxyl groups, with 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups, present in neutralized form as a salt, and, if present, the other ingredients; b) spreading out and drying the solution obtained according to step a), so that the dried solution preferably has a basis weight of about 50 to about 300 g/m ² .

In a preferred embodiment of the method according to the invention, step a) is designed as follows. a) preparing a solution, preferably based on a mixture comprising water and/or at least one organic solvent such as ethanol, comprising ketamine, at least one base, preferably NaOH, and the at least one polymer comprising free carboxyl groups, and, if present, the other ingredients.

In this case, the at least one polymer, which comprises free carboxyl groups, is partially neutralized directly in the solution by adding at least one base. All preferred embodiments and definitions for the oral thin film according to the invention apply analogously to the method according to the invention.

The present invention further relates to an oral thin film obtainable by the method described above.

In addition, the present invention relates to an oral thin film as described above or obtainable by the method described above as a medicament.

The present invention also relates to an oral thin film as described above or obtainable by the method described above as a medicament for use in the treatment of pain and/or depression, in particular for reducing the risk of suicide and/or for use as a general anaesthetic, preferably for induction and administration of general anesthesia or as an adjunct to regional anesthesia and/or as an analgesic.

The preferred embodiments listed above for the thin film according to the invention also apply to the method according to the invention, the oral thin film obtained with this and for its use as a medicament.

Description of the figures

Figure 1 shows the permeation data of the formulations according to Table 1.

Figure 2 shows the in vitro release data of the formulations according to Table 1.

The invention is explained in more detail below using non-limiting examples. examples

Table 1: Formulations according to the invention

Kollidon VA 64: polyvinylpyrrolidone from BASF

Kollicoat MAE: (meth)acrylic acid/ethyl acrylate copolymer from BASF

The oral thin films of the compositions according to the table above were prepared as follows:

The solvent is introduced and the ingredients according to Table 1 are dissolved one after the other. The mass is now left to rest until it is bubble-free. The mass is applied to a siliconized liner and the resulting film is dried.

For these formulations, the permeation of the active ingredient was determined according to the following procedure.

The following series of tests with the active substances selected in each case were carried out as part of a typical in vitro permeation using multiwell plates at 37°C. At predetermined exchange times, the acceptor medium used in each case was completely replaced with a new one and the amount of permeated active ingredient in these acceptor solutions was determined by means of HPLC.

Esophageal mucosa (domestic pig) with a layer thickness of 400 μm was used as a skin model. Phosphate buffer pH 7.4 was used as the acceptor medium.

The comparison measurement was carried out against the quick-release foam formulation (140Kea0002) used, which has a composition according to the table below.

Figure 1 shows that in the formulations 140Kea0041 (1% NaOH), 140Kea0043 (2% NaOH), 140Kea0044 (2.8% NaOH) the permeation slows down significantly with increasing NaOH content until it is in the formulation 140Kea0047 (9th % NaOH) stagnates.

The disintegration time was tested in a further experiment and confirmed the results shown in the permeation. The formulation 140Kea0041 (1% NaOH) was shown to have the highest disintegration time, which correlates with the slowest release.

The disintegration time of the oral thin films was measured using the USP Method <701> Disintegration, from 2016.

Apparatus used: disintegration tester DIST 3 with disintegration basket

Number of strokes per minute: 29 - 32

Medium: water

Temperature: 37ºC ± 2ºC

Endpoint Determination: Visual

End point: total disintegration of the film

The results of the disintegration measurement are summarized in Table 2. Table 2: Decay time measurement

In an in vitro release study, it was possible to show not only the slower decay but also the slower release of the active ingredient.

The in vitro release was determined as follows:

During the in-vitro release, S-ketamine is released from the oral thin film (OTF) and determined. The drug is released in phosphate buffer pH 6.8 USP and then determined by a gradient reverse phase HPLC method. The quantification was carried out against an external standard.

Dissolution is performed with Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711>.

The in vitro release results are shown in FIG. Here again the formulation 140Kea0041 (1% NaOH) showed the slowest release.

Claims

Expectations

An oral thin film comprising ketamine or a pharmaceutically acceptable salt thereof, at least one polymer comprising free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.

2. Oral thin film according to claim 1, wherein the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by the addition of at least one base, preferably NaOH.

3. Oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups comprises a polymer based on (meth)acrylic acid and/or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.

The oral thin film of claim 3, wherein the at least one polymer comprising free carboxyl groups comprises a (meth)acrylic acid/ethyl acrylate copolymer.

5. The oral thin film according to any one of the preceding claims, wherein the oral thin film further comprises at least one water soluble polymer.

6. Oral thin film according to claim 5, wherein the at least one water-soluble polymer is selected from starch and starch derivatives,

Dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinyl pyrrolidones, vinyl pyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin , pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.

7. Oral thin film according to any one of the preceding claims, wherein the at least one base comprises a hydroxide, preferably NaOH.

8. An oral thin film according to any one of the preceding claims, wherein the ketamine comprises (S)-ketamine or a pharmaceutically acceptable salt thereof.

9. An oral thin film according to any one of the preceding claims, wherein the ketamine is present in the oral thin film in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the oral thin film.

10. Oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the oral thin film , in which oral thin film is present.

11. The oral thin film of any one of claims 2 to 10, wherein at least 10% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt of the at least one base.

12. Oral thin film according to any one of the preceding claims, characterized in that the oral thin film further contains at least one excipient selected from the group comprising colorants, flavorings, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and /or antioxidants.

13. Oral thin film according to any one of the preceding claims, characterized in that the basis weight of the oral thin film is about 50 to 300 g/m ² .

14. A method for preparing an oral thin film according to any one of claims 1 to 13, comprising the steps of: a) preparing a solution comprising ketamine, at least one base and the at least one polymer comprising free carboxyl groups; b) spreading out and drying the solution obtained in step a).

15. Use of an oral thin film according to any one of claims 1 to 13 as a medicament, preferably in the treatment of pain and/or depression.