Oral thin film

Abstract

The present invention relates to an oral thin film comprising a polymer matrix in the form of a solidified foam having cavities, the polymer matrix containing at least one pharma- ceutical active ingredient, at least one first polymer comprising a water-soluble polymer, and at least one second polymer comprising a mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol; a method for producing the oral thin film; and the use of this type of oral thin film as a medicament.

Description

[Technical Field]

[0001] The present invention relates to oral thin films, methods for their preparation, and pharmaceutical uses of such oral thin films. [Background technology]

[0002] Oral thin films are thin films containing at least one active pharmaceutical ingredient that are placed in the oral cavity or directly against the oral mucosa, where they dissolve or soften, thereby delivering the active ingredient. These films are particularly thin, single-layered, or multi-layered polymer-based films containing an active ingredient that can deliver the active ingredient directly to the mucosa, especially the oral mucosa, when applied to the mucosa. The excellent blood supply to the oral mucosa ensures the active ingredient's rapid transfer into the bloodstream. This administration system has the advantage that the active ingredient is mostly absorbed by the mucosa, avoiding the first-pass effect that occurs with active ingredients in traditional tablet dosage forms. The active ingredient can be dissolved, emulsified, or dispersed in the film.

[0003] Oral thin films in the form of foams can, in principle, have high loadings of active pharmaceutical ingredients. These high-load oral thin films in the form of foams generally exhibit very fast disintegration times, which is advantageous for many applications.

[0004] However, in other cases, it is desirable for an oral thin film in the form of a high-load foam to remain in the oral cavity longer, for example, to provide a longer delivery of its active pharmaceutical ingredient for transmucosal absorption.

[0005] A typical challenge in preparing slow-release oral thin films of active pharmaceutical ingredients is that the polymers typically used for this purpose form highly viscous aqueous solutions, thereby reducing the solids fraction of the active ingredient solution, which, among other things, significantly increases drying times. Summary of the Invention [Problem to be solved by the invention]

[0006] The problem addressed by the present invention was to form an oral thin film comprising a polymer matrix in the form of a solidified foam with voids, the disintegration time of which can be adjusted as widely as possible. Furthermore, one goal is to make the oral thin film as easy and fast as possible to manufacture. In particular, one objective is to avoid highly viscous solutions and long drying times. [Means for solving the problem]

[0007] This goal is surprisingly addressed by the oral thin film according to claim 1. Such oral thin film is characterized in that it comprises a polymer matrix in the form of a solidified foam having voids, the polymer matrix containing at least one active pharmaceutical ingredient, at least one first polymer comprising a water-soluble polymer, and at least one second polymer comprising a mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol.

[0008] The addition of a mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol can result in a foam formulation with a longer residence time in the oral cavity. Furthermore, the addition of a mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol can enhance mucoadhesion, resulting in a foam that better adheres to the mucous membrane and the active ingredient, retaining the active ingredient at the absorption site.

[0009] Oral thin films can in principle be produced similarly to previously known oral thin films, since the added mucoadhesive polymer with a number-average molecular weight equal to or greater than 100,000 g / mol has only a small effect on the physical behavior during slurrying and drying. The potential addition of active ingredients is hardly affected, since even very small amounts of mucoadhesive polymer with a number-average molecular weight equal to or greater than 100,000 g / mol can result in a delay in dissolution time. DETAILED DESCRIPTION OF THE INVENTION

[0010] In this document, the word "comprises" can also mean "consisting of."

[0011] Water-soluble polymers include chemically very different natural or synthetic polymers, the common feature of which is their solubility in water or aqueous media. As a prerequisite, these polymers have a sufficient number of hydrophilic groups to be water-soluble and are not crosslinked. The hydrophilic groups can be nonionic, anionic, cationic, and / or zwitterionic.

[0012] Water soluble is preferably understood to mean a solubility in water of more than 100 g / L at 25°C.

[0013] The mucoadhesion process is mainly influenced by the properties of the polymer used, such as the degree of cross-linking, chain length, and different functional groups in the polymer structure. Mucoadhesive systems have been used in many mucosally covered organelles to deliver active ingredients with local or systemic effects.

[0014] Mucoadhesion may be defined as the phenomenon of attractive intermolecular forces at the interface between the surface of the mucosa, here the oral mucosa, and the mucoadhesive polymer, allowing the polymer to adhere to the mucosa for a longer period of time.

[0015] The second polymer, comprising at least one mucoadhesive polymer, has a number average molecular weight equal to or greater than 100,000 g / mol, preferably greater than 200,000 g / mol, greater than 300,000 g / mol, greater than 400,000 g / mol, greater than 500,000 g / mol, greater than 600,000 g / mol, greater than 700,000 g / mol, greater than 800,000 g / mol, or greater than 900,000 g / mol.

[0016] Also particularly preferred are mucoadhesive polymers having a number average molecular weight of equal to or greater than 1,000,000 g / mol, 2,000,000 g / mol, 3,000,000 g / mol, 4,000,000 g / mol, 5,000,000 g / mol, 6,000,000 g / mol, or 7,000,000 g / mol.

[0017] Molecular weight is determined by methods known to those skilled in the art such as gel permeation chromatography.

[0018] The second polymer, which comprises at least one mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol, is preferably a water-soluble polymer as defined above.

[0019] Oral thin films according to the present invention are also preferably characterized in that the first polymer comprises a polymer having a number average molecular weight below 100,000 g / mol, preferably below 80,000 or below 60,000.

[0020] Molecular weight is determined by methods known to those skilled in the art such as gel permeation chromatography.

[0021] The first polymer, including water-soluble polymers, is preferably selected from the group comprising starch and starch derivatives, dextran, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethylcellulose, or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gums, with polyvinyl alcohol being particularly preferred.

[0022] The oral thin film according to the invention is also preferably characterized in that the second polymer comprising a mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol is selected from the group consisting of polyethylene oxide polymers, starch derivatives, polyacrylic acid, amylopectin, and / or polyvinyl alcohol, in particular polyacrylates or mixtures of polyacrylic acid and amylopectin.

[0023] Suitable second polymers are, for example, polyethylene oxide polymers such as polyethylene glycol having a number average molecular weight of about 1,000,000 g / mol or about 7,000,000 g / mol, which are available, for example, under the trade names "Polyox WSR N12" or "Polyox WSR 303."

[0024] Another suitable second polymer is a polyacrylate or a mixture of polyacrylic acid and amylopectin, available under the trade name "Proloc 15."

[0025] Long-chain polyvinyl alcohols are also suitable as second polymers. For example, polyvinyl alcohols having a number average molecular weight of about 200,000 g / mol are available under the trade name "PVA40-88."

[0026] The oral thin film according to the present invention is preferably characterized in that the first polymer is contained in the oral thin film in an amount of 40 to 95 wt %, preferably 45 to 85, and particularly preferably 48 to 80, based on the total weight of the oral thin film.

[0027] The second polymer is present in the oral thin film in an amount of 0.1 to 20 wt %, preferably 2 to 18, and particularly preferably 5 to 15, based on the total weight of the oral thin film.

[0028] The at least one active pharmaceutical ingredient is preferably selected from, in principle without any limitation, all active pharmaceutical ingredients suitable for oral and / or transmucosal application.

[0029] Preferred active ingredients are selected from the group comprising the following active ingredient classes: analgesics, hormonal drugs, hypnotics, sedatives, antiepileptics, central nervous system stimulants, psychotropic drugs, neuromuscular blocking drugs, antispasmodics, antihistamines, antiallergic drugs, cardiotonics, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasopressors, antidepressants, antitussives, expectorants, thyroid hormone drugs, sex hormone drugs, antidiabetic drugs, antitumor active ingredients, antibacterial drugs, chemotherapeutic drugs, and narcotics, but this group is not exhaustive.

[0030] The at least one active pharmaceutical ingredient is particularly preferably ketamine.

[0031] Ketamine is understood to mean (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, and its racemic form (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0032] (S)-ketamine is particularly preferably present as the single stereoisomer of ketamine, as the analgesic and anesthetic potency of (S)-ketamine is approximately three times greater than that of the (R) form of ketamine.

[0033] The content of the active ingredient in the oral thin film can vary within relatively wide limits. A range of 10 to 60 wt% based on the total weight (total dry weight) of the oral thin film is considered appropriate. In one embodiment, for example, if the active ingredient has a strong, unpleasant taste that needs to be compensated for with a larger amount of a taste-masking agent, the proportion of the active ingredient in the oral thin film is in a somewhat lower range. In this case, a range of 10 to 40 wt% is considered to be an appropriate active ingredient fraction. In another embodiment, the proportion of the active ingredient in the dosage form according to the present invention is in a somewhat higher range, with a content of 40 to 60 wt% and in particular a content of 45 to 55 wt% being particularly preferred.

[0034] The active ingredient content per dosage unit is preferably at most 100 mg, more preferably at most 50 mg, particularly preferably at most 40 mg, and most preferably at most 35 mg. The minimum active ingredient content per dosage unit should preferably be 5 mg, more preferably 10 mg, and most preferably 15 mg. Depending on the application, the active ingredient content may be higher than the above values, for example, in the range of 50-100 mg. A material content of 30-50 mg may also be appropriate.

[0035] The oral thin films according to the present invention are also preferably characterized in that they comprise at least one adjuvant selected from the group comprising colorants, flavoring agents, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives, and / or antioxidants.

[0036] Each of these supplements is preferably contained in an amount of 0.1 to 40 wt%, preferably 0.1 to 30 wt%, particularly preferably 0.1 to 15 wt%, and very particularly preferably 0.1 to 10 wt% or 0.1 to 5 wt%, based on the total weight of the oral thin film.

[0037] The multi-layer oral thin films according to the present invention are in principle not limited in the number of layers they contain.

[0038] For example, embodiments are contemplated in which oral thin films according to the present invention include multiple layers containing active ingredients.

[0039] The oral thin films according to the present invention are characterized in that they exist in the form of a solidified foam having voids.

[0040] An advantage of this embodiment is that despite the relatively high surface density, being formulated as a foam allows for faster drying than a comparable non-foam composition.

[0041] The oral thin film according to the invention is preferably characterized in that the voids are isolated from one another, are preferably present in the form of bubbles and are filled with air or a gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0042] According to another embodiment, it is provided that the voids are interconnected, preferably by forming a continuous channel system through the matrix.

[0043] The voids preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, relative to the total volume of the matrix layer, in which way the beneficial effect of accelerating the dissolution of the thin film is advantageously exerted.

[0044] Additionally, surfactants or surfactants may be added to the oral thin film for foam formation or to the resulting foam before or after drying to improve the stability of the foam before or after drying.

[0045] Another parameter that influences the properties of the oral thin film according to the present invention is the diameter of the voids or bubbles. The bubbles or voids are preferably created using a whisk, which allows the bubble diameter to be adjusted within a wide range, almost any desired size. Thus, the diameter of the bubbles or voids can be in the range of 0.01 to 60 μm. The diameter is particularly preferably in the range of 10 to 50 μm.

[0046] Oral thin films according to the present invention are preferably 0.5 cm 2 ~10cm 2 , particularly preferably 2 cm 2 ~8cm 2 It has an area of

[0047] The areal density of oral thin films according to the present invention is preferably at least 10 g / m 2 , more preferably at least 20 g / m 2 Or at least 30g / m 2 , most preferably at least 50 g / m 2 , or 400 g / m 2 less than or equal to, more preferably 350 g / m 2 Less than or equal to 300 g / m 2 less than or equal to, most preferably 150 g / m 2 The surface density is preferably 10 to 400 g / m 2 , more preferably 20 to 350 g / m 2 Or 30-300g / m 2 , most preferably 50 to 200 g / m 2 is.

[0048] The oral thin film preferably has a thickness of about 10 μm to about 1000 μm, particularly preferably about 20 μm to about 500 μm.

[0049] The active pharmaceutical ingredient released from the oral thin film is preferably either absorbed at the site of application, i.e., through the oral mucosa, or it is further transported and absorbed at a different site (e.g., in the gastrointestinal tract once the active ingredient released in the oral cavity is swallowed).

[0050] The residence time or disintegration time of the oral thin film according to the present invention at the application site (e.g., in the oral cavity) is preferably within the range of 10 seconds to 10 minutes, more preferably within the range of 30 seconds to 8 minutes, and most preferably within the range of 1 minute to 5 minutes.

[0051] The present invention provides a method for producing an oral thin film as described above, comprising: a) preparing a solution, dispersion, or melt comprising at least a first polymer, a second polymer, and at least one active pharmaceutical ingredient; b) foaming the solution, dispersion or melt by introducing a gas or gas mixture, either by chemical gas generation or by expanding dissolved gases, optionally after prior addition of a foam stabilizer; c) spreading the foamed solution, dispersion, or melt onto a coating substrate; and d) solidifying the spread solution, dispersion, or melt by drying and removing the solvent or by cooling. The present invention relates to a method comprising:

[0052] The term "drying" is understood to mean that the solvent, especially water, is removed from the oral thin film. Here, it is not necessary that all of the solvent, such as water, is removed from the oral thin film; instead, it is sufficient if a major proportion of the solvent is removed from the oral thin film, thereby solidifying the foam. Thus, the oral thin film may contain residual water after drying.

[0053] Upon solvent removal, the foam solidifies during drying, and the voids that form acquire a permanent structure. Oral thin films with desired surface dimensions or geometries can be obtained by pouring the foam mass into corresponding molds before drying, or by cutting individual oral thin films from larger two-dimensional pieces.

[0054] The shape, number and size of the produced voids can be influenced by different process parameters, such as the type and concentration of polymer, the viscosity of the polymer mass, adjustment of the foaming process, the choice of foam stabilizer, etc.

[0055] As an alternative to the above method, oral thin films according to the present invention can be prepared using a method in which voids within the polymer matrix are formed by introducing a hydrophobic solvent that is immiscible with the solvent used to prepare the aforementioned solution or dispersion.

[0056] Here, an emulsion is produced which contains the hydrophobic solvent in the form of finely distributed droplets.

[0057] Subsequent removal of the solvent during drying leaves droplet- or bubble-like voids in the polymer matrix.

[0058] In a further improvement of the above method, the aforementioned voids are generated by adding a gas-forming auxiliary or gas to a solution or dispersion containing the polymer and the active ingredient, thereby foaming the mass. This foaming can occur either during the production of the polymer mass, during the coating of this mass on a substrate, or only during the subsequent drying process, due to gas generation. Substances or mixtures of substances suitable for gas formation are known to those skilled in the art. Foaming can also be caused by the expansion of a pre-dissolved gas. In particular, inert gases such as nitrogen, carbon dioxide, or helium, or mixtures thereof, can be used as the gas.

[0059] Alternatively, a melt of the matrix polymer or polymer mixture can also be used as a starting point when producing oral thin films according to the invention. Processing is carried out in principle similarly to the methods for hot-melt compounds known from the prior art.

[0060] A gas or gas mixture is introduced into the melt by one of the above methods to foam the polymer melt.The melt is then spread onto a suitable substrate, or extruded or poured into a mold, and then allowed to cool or solidify.If the intended active ingredient is unstable or volatile at the melting temperature of the polymer melt, processing from the melt is not an option.If necessary, an auxiliary agent can be added to the polymer melt to lower the melting point.

[0061] According to a further refinement of the above manufacturing method, the polymer matrix is ​​initially produced in the form of a block, from which the desired dosage forms are separated, i.e. after drying or solidification, by subsequent cutting.

[0062] This means that in this embodiment, the above steps c) and d) are replaced by the following steps c2) and d2): c2) starting from a solution, dispersion or melt to produce a block; d2) cutting the solidified block to obtain a flat form is intended to be replaced by

[0063] The present invention also relates to oral thin films obtainable by the above method.

[0064] Additionally, the present invention relates to an oral thin film as described above or obtainable by the method described above as a medicament.

[0065] The present invention further relates to an oral thin film as described above or obtainable by the method described above, wherein ketamine, preferably (S)-ketamine or a pharmaceutically acceptable salt thereof, is used as the active pharmaceutical ingredient for use in the treatment of pain and / or in the treatment of depression, in particular, to reduce the risk of suicide, and / or preferably as a general anesthetic for initiating or performing general anesthesia or as an adjuvant in the case of local anesthesia, and / or as an analgesic.

[0066] The above preferred embodiments relating to the multi-layer oral thin film are also applicable to the method according to the invention, the multi-layer oral thin film obtainable by this method and its use as a medicament.

[0067] The invention will be explained in more detail below on the basis of non-limiting examples. [Example]

[0068] The following polymers were used in the examples below: PVA4-88: Polyvinyl alcohol (MW<100,000) PVA40-88: Polyvinyl alcohol (MW>100,000) Polyox WSR N12: Polyethylene oxide polymer (MW approximately 1,000,000) Polyox WSR 303: Poly(ethylene) oxide polymer (MW approximately 7,000,000) Proloc 15: A mixture of polyacrylate and amylopectin (MW>100,000) [Example]

[0069] Foamed oral thin films having the compositions set forth in Tables 1-5 and containing no active pharmaceutical ingredient were prepared as follows.

[0070] Each oral thin film was produced by mass production techniques known to those skilled in the art, such as stirring / mixing the contained ingredients using a stirring motor and suitable stirring equipment. Gas was introduced into the resulting mass, for example, by stirring with a whisk. This foam mass was coated onto a coating substrate in a consistent layer thickness using a suitable device (roller applicator, squeegee, coating box, etc.). Any temperature-stable web-like material that allows the dried film to be peeled off again can serve as the coating substrate. This can be ensured by the selection of the coating substrate material (different interfacial tension between the foam mass and the substrate) or by suitable release coating of the coating substrate, for example, with silicone or fluoropolymer. The processing solvent or contained solvent, usually water or a mixture of water and an organic water-miscible solvent, is removed by drying. The oral thin film is obtained by cutting or die-cutting the solid foam layer into a suitable size.

[0071] [Table 1]

[0072] [Table 2]

[0073] [Table 3]

[0074] [Table 4]

[0075] [Table 5]

[0076] Oral thin films having the compositions described in Tables 1-6 had much longer disintegration times than compositions that did not contain polymers with MW greater than 100,000 g / mol. [Example]

[0077] Foamed oral thin films having the compositions set forth in Tables 6 and 7, containing (S)-ketamine HCl as the active pharmaceutical ingredient, were prepared as described above.

[0078] [Table 6]

[0079] [Table 7]

[0080] Oral thin films having the compositions set forth in Table 6 had much longer disintegration times than oral thin films having the compositions set forth in Table 7, which did not contain a polymer with a MW greater than 100,000 g / mol.

[0081] Additionally, the release rate of the active ingredient from foamed oral thin films having the compositions set forth in Table 6 was measured.

[0082] Emission Measurement: S-ketamine was released from S-ketamine HCl oral thin films (OTF) and measured by in vitro release. The active ingredient was released into phosphate buffer pH 6.8 USP and then measured by a gradient reverse-phase HPLC method. Quantitation was performed against an external standard. USP <711> The release was carried out using the dissolution apparatus 2- (paddle over sinker) described in .

[0083] [Table 8]

[0084] The measured release rates are summarized in Table 9.

[0085] [Table 9]

[0086] The active ingredient release from oral thin films listed in Table 7 (fast release) was compared with the active ingredient release from oral thin films, which were distinguished in particular by a slower active ingredient release (sustained release).

[0087] The composition of the oral thin film with slow active ingredient release is specified in Table 10.

[0088] [Table 10]

[0089] In addition, the release rates of the active ingredients of the foamed oral thin films having the compositions set forth in Tables 7 and 10 were measured as described above.

[0090] The measured release rates are shown in FIG. [Example]

[0091] A foamed oral thin film having the composition set forth in Table 11 containing (S)-ketamine HCl as the active ingredient was prepared as described above.

[0092] [Table 11]

[0093] Additionally, the release rate of the active ingredient for foamed oral thin films having the compositions set forth in Table 11 was measured as described above.

[0094] The measured release rates are summarized in Table 12.

[0095] [Table 12] [Brief explanation of the drawings]

[0096] [Figure 1] FIG. 1 shows the measured release rate of active ingredient for foamed oral thin films having the compositions set forth in Tables 7 and 10.

Claims

1. 1. An oral thin film comprising a polymer matrix in the form of a solidified foam having voids, the polymer matrix containing at least one active pharmaceutical ingredient, at least one first polymer comprising a water-soluble polymer and having a number average molecular weight below 100,000 g / mol, and at least one second polymer comprising a mucoadhesive polymer having a number average molecular weight of 100,000 g / mol or greater.

2. 10. The oral thin film of claim 1, wherein the at least one mucoadhesive polymer comprises a water-soluble polymer.

3. 3. The oral thin film of claim 1, wherein the first polymer is selected from the group consisting of starch, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethylcellulose, or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gum.

4. 4. The oral thin film of claim 1, wherein the second polymer is selected from the group comprising polyethylene oxide polymers, starch derivatives, polyacrylic acid, amylopectin, and / or polyvinyl alcohol, in particular polyacrylates or mixtures of polyacrylic acid and amylopectin.

5. The oral thin film according to any one of claims 1 to 4, wherein the first polymer is contained in the oral thin film in an amount of 40 to 95 wt % based on the total weight of the oral thin film.

6. The oral thin film according to any one of claims 1 to 5, wherein the second polymer is contained in the oral thin film in an amount of 0.1 to 20 wt % based on the total weight of the oral thin film.

7. The oral thin film according to any one of claims 1 to 6, wherein the at least one active pharmaceutical ingredient is contained in the oral thin film in an amount of 10 to 60 wt % based on the total weight of the oral thin film.

8. The oral thin film of any one of claims 1 to 7, wherein the voids are isolated from one another, exist in the form of bubbles, and are filled with air or gas.

9. The oral thin film of any one of claims 1 to 8, wherein the voids are interconnected to form a channel system that penetrates the polymer matrix.

10. The oral thin film according to any one of claims 1 to 9, wherein the voids occupy a volume fraction of 5 to 98% of the total volume of the oral thin film.

11. A method for producing the oral thin film of any one of claims 1 to 10, comprising: a) preparing a solution, dispersion, or melt comprising at least the first polymer, the second polymer, and at least one active pharmaceutical ingredient; b) foaming said solution, dispersion or melt by introducing a gas or gas mixture, either by chemical gas generation or by expanding dissolved gases, optionally after prior addition of a foam stabilizer; c) spreading the foamed solution, dispersion, or melt onto a coating substrate; and d) solidifying the spread solution, dispersion, or melt by drying and removing the solvent or by cooling. A method characterized by:

12. Steps c) and d) may be the following steps c2) and d2): c2) starting from said solution, dispersion or melt, producing a block; d2) Cutting the solidified block to obtain a flat form The method of claim 11, wherein

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