Sublingual formulation of an anticancer compound for the treatment of autoimmune neurodegenerative diseases

Abstract

The present invention discloses a transmucosal delivery composition in the form of a sublingual intraoral dispersible film containing cladribine as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a sublingual pharmaceutical composition comprising the active ingredient cladribine, preferably cladribine incorporated into a 2-hydroxypropyl-β-cyclodextrin (HPβCD) complex. This active ingredient is uniformly dispersed within a polymer matrix containing at least one hydrophilic polymer within an orally disintegrating film. This film delivery system, particularly for sublingual delivery of the active ingredient cladribine, can be formed during manufacture in the form of film pieces or sheets and can then be cut into uniform dosage units (orally disintegrating films), where each dosage unit has a uniform content.

[0002] The pharmaceutical composition can be used as a novel medicine, particularly in the treatment of multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD).

Background Art

[0003] Cladribine (2-CdA), chemically 2-chloro-2'-deoxyadenosine (Formula 1), is an antineoplastic agent used in the treatment of several types of leukemia, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (CLL).

[0004]

Chem.

[0005] Cladribine shows sustained efficacy in reducing the frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis (RRMS). Cladribine is very effective in treating relapsing forms of multiple sclerosis (MS).

[0006] Cladribine is a lymphocyte depleting agent that includes synthetic deoxyadenosine analogs with a hydrogen atom replaced by chlorine at the 2-position of the purine ring. This substitution renders the nucleoside analog resistant to degradation by adenosine deaminase (ADA), an enzyme that metabolizes and removes naturally occurring deoxynucleosides.

[0007] Cladribine enters cells via nucleoside transport proteins. Inside the cell, cladribine is activated via three consecutive phosphorylations, the first of which is catalyzed by the enzyme deoxycytidine kinase (DCK). Activated cladribine can be inactivated by dephosphorylation by the enzyme 5'-nucleotidase (5'-NT). Compared to other cells, lymphocytes have high levels of DCK and low levels of 5'-NT, and thus accumulate higher concentrations of phosphorylated molecules, which results in the preferential accumulation of trapped, phosphorylated, or activated cladribine within the cell.

[0008] Treatment with cladribine results in a preferential and sustained decrease in lymphocytes and monocytes, and a long-term depletion of CD4+ T cells, CD8+ T cells, and CD19+ B cells, which are involved in the development of MS lesions. The key to selectivity (the preferential activation of cladribine to deplete lymphocytes) lies in the high ratio of DCK / 5'-NT activity that is specific to lymphocytes.

[0009] To date, cladribine has been available only in injectable and oral forms. Until 2017, cladribine was marketed as a final formulation administered only by intravenous injection of saline containing 2 mg / ml of cladribine. Also, off-label subcutaneous administration of cladribine in MS has shown efficacy. Subcutaneous injection of cladribine has been described as effective in neuromyelitis optica spectrum disorder (NMOSD) (Rejdak et al., Eur J of Neurology, 2021, 28(9), 3167-3172) and in myasthenia gravis (MG) (Rejdak et al., Eur J of Neurology, 2020, 27(3), 586-589).

[0010] Off-label cladribine injection presents two problems upon subcutaneous injection. First, cladribine is slightly soluble in water and requires injection of large amounts of material to achieve the required dose. For example, Rejdak (U.S. Patent No. 10,350,231 B2) applied a 2 mg / mL concentrate for subcutaneous intravenous injection of 20 mg (10 mL of solution) over 5 days. Eight subcutaneous sites were used, with 2.5 ml injected into each site. Such an approach is not acceptable in routine clinical practice.

[0011] Second, cladribine has limited stability as a saline solution. Instability in an acidic environment is an inherent property of cladribine. At physiological temperature 37°C, the t 1 / 2 value of cladribine has been measured to be 1.6 hours in a pH 2.0 solution and 0.37 hours in a pH 1.0 solution.

[0012] To address the administration problem, Thomas W Schultz (U.S. Patent No. 6,194,395 B1) teaches preparing a complex of different types of cyclodextrin (preferably 2-hydroxypropyl-β-cyclodextrin) and cladribine to achieve a stable injectable formulation and better solubility. It is noted that using the cyclodextrin liquid formulation according to the present invention in U.S. Patent No. 6,194,395 B1 can significantly increase the solubility of cladribine. Therefore, the injection volume can be reduced to less than 1 ml (10 mg / ml) per injection. The irritation and pain caused by the high osmotic pressure or large injection volume are reduced.

[0013] In addition, Schultz states that cladribine is significantly more stable at a lower pH when combined with a cyclodextrin such as HPβCD. According to the patented invention, cyclodextrin significantly contributes to the stability of cladribine in a solution at pH 1.4, maintaining more than 80% of the active substance for nearly 5 hours and about 70% of the active substance for 8 hours, i.e., throughout the experiment. On the other hand, cladribine dissolved in solution in the absence of cyclodextrin lost about 50% of the active substance after about 3 hours, and only 15% of the active substance remained in the solution after 8 hours. Based on the results obtained, the authors proposed using the complex of cyclodextrin and cladribine not only to prepare a stable liquid but also to prepare a solid dosage form of cladribine.

[0014] WO2015 / 023889A1 discloses a rapidly soluble thin film formulation of a water-soluble digitalis glycoside for treating congestive heart failure. US Patent Application Publication No. 2020 / 390837 A1 discloses a mucoadhesive film comprising an emulsion of a cannabis extract, pullulan, hydroxypropyl methylcellulose acetate succinate, and a flavor or taste masking agent. US Patent Application Publication No. 2021 / 267934 A1 discloses an orally dispersible film composition in which an active ingredient having an average particle size of 1 to 20 μm is dispersed in the film. WO2022 / 053608A1 discloses a method for treating an autoimmune disorder in a patient, namely, a method by optionally orally administering cladribine to the patient. CA2520523A1 (WO2004 / 087101A2) discloses an oral composition of cladribine and cyclodextrin.

[0015] Mavenclad (the solid oral dosage form of cladribine) has shown sustained clinical efficacy for up to 4 years with an oral treatment over 2 years for up to 20 days to treat the relapsing form of multiple sclerosis (MS) including relapsing-remitting disease and active secondary progressive disease.

[0016] Nicholas S. Bodor discloses methods for oral formulations of cladribine in US Patent Nos. 7888328B2 and 8,785,415B2. The development of oral cladribine faced the same problems as described above associated with low solubility in water and stability at low pH. As described above, instability in an acidic environment is an inherent property of cladribine. Since the main absorption site of orally administered drugs is the gastric environment with low pH, it is difficult to achieve high absorption of acid-sensitive drugs such as cladribine.

[0017] Bodor is guided that an approach to an oral cladribine formulation using a preparation of a so-called cladribine-cyclodextrin inclusion-non-inclusion complex is described in Example 2 of U.S. Patent No. 7,888,328B2. Here, a cladribine-cyclodextrin complex is provided, which is a tight amorphous mixture of an amorphous inclusion complex of cladribine and amorphous cyclodextrin, and amorphous free cladribine associated with amorphous cyclodextrin as a non-inclusion complex. The pharmaceutical composition contains the complex and is formulated into a solid oral dosage form in tablet form. The cyclodextrin itself is amorphous, the inclusion complex with cladribine is amorphous (preferably saturated with cladribine), and the free cladribine forming the non-inclusion complex is amorphous.

[0018] Bodor states that the inclusion complex is a complex in which cladribine is inserted into the hydrophobic cavity of a selected amorphous cyclodextrin, while the non-inclusion / H-bond complex is amorphous free cladribine loosely hydrogen-bonded to cyclodextrin. When the product is obtained as exemplified below (17% HPβCD solution, complexation temperature of 45 - 50 °C for about 9 hours), it is estimated that about two-thirds (60 - 70%) of the cladribine is in the non-inclusion complex and the remaining one-third (30 - 40%) is in the inclusion complex. By increasing the percentage of cyclodextrin used and / or manipulating the temperature, a product in which a much larger proportion of the amorphous mixture is in the form of the inclusion complex can be easily obtained. In the case of hydroxypropyl-β-cyclodextrin (HPβCD), a typical amorphous cyclodextrin, a weight ratio of cladribine:cyclodextrin of about 1:10 to about 1:16 is suitable for the exemplified conditions, and this ratio is predicted to be the same for hydroxypropyl-γ-cyclodextrin under these conditions. The resulting material is characterized by the rapid dissolution of cladribine in an aqueous medium.

[0019] Generally, U.S. Patent No. 7,888,328 addresses the problem of the low bioavailability of oral cladribine.

[0020] Bioavailability studies are summarized in the EPAR of Mavenclad (EMEA / H / C / 004230) including its annex and in Hermann et al., Clinical Pharmacokinetics 2019, 58, 283 - 297. The absolute oral bioavailability in MS subjects is approximately 40%, which is mainly limited by incomplete absorption due to transporter - mediated efflux. In the IXR - 109 - 09 - 186 study, the absolute bioavailability determined using the oral / intravenous dose ratio of AUCinf was 39.1% for a 10 mg oral dose. The inter - patient variability expressed as CV% was 43.0% at Cmax, 29.2% at AUCinf, and 29.8% at AUCt. In study 25803, the absolute bioavailability was 42.9%. In the 93 - 220 study, the mean (SD) bioavailability of the oral formulation compared to the intravenous solution was 36.7%.

[0021] Examples of factors that affect drug absorption are gastrointestinal motility, gastric emptying rate, and the presence of food in the gastrointestinal tract.

[0022] The within - subject variability estimated by population PK analysis depends on the endpoint (urinary concentration vs. plasma concentration) and the study conditions (e.g., intravenous vs. oral). In the CLARITY clinical trial, it was estimated to be about 35%. The variability of AUC ranges from 30% to 35% for HPβCD tablets.

[0023] Cladribine administered as an oral solution without HPβCD was also rapidly absorbed, and the bioavailability after oral administration of cladribine was 35.3%, which is interestingly relatively close to the bioavailability of HPβCD cladribine tablets (Lindemalm et al., BMC Pharmacology 2005, 5(1), 4).

[0024] The low bioavailability can be partially explained by the fact that cladribine is a substrate of the BCRP (ABCG2) transporter protein, which is abundantly expressed in the small intestine.

[0025] In the distribution of breast cancer resistance protein, BCRP mRNA expression was highest in the duodenum and decreased continuously to the rectum (93.7% in the terminal ileum, 75.8% in the ascending colon, 66.6% in the transverse colon, 62.8% in the descending colon, and 50.1% in the sigmoid colon, respectively, compared to the duodenum), which could have a dramatic impact on cladribine absorption in the upper gastrointestinal tract. This conclusion was previously confirmed in 2008 by Cornelia de Wolf et al. They showed that ABCG2 transports not only the nucleoside monophosphate metabolite of cladribine but also cladribine itself, similar to other ABC transporters that can cause resistance to nucleobase and nucleoside analogs (de Wolf et al., Mol Cancer Ther. 2008, 7 (9), 3092-3102).

[0026] Mavenclad can also be degraded by the intestinal microbiota enzymes PNP (purine nucleoside phosphorylase) and UP (uridine phosphorylase). To evaluate the microbiota that can affect the availability of cladribine, the in vitro stability of cladribine in bacterial cultures has been tested. Clostridium perfringens, Escherichia coli, and whole feces rapidly deglycosylated cladribine to chloroadenine, while Bacteroides fragilis, Enterococcus faecalis, and saliva showed slow or no degradation of cladribine. Due to the deglycosylation of cladribine by the colonic microbiota, the bioavailability was only 21% when administered rectally.

[0027] Low bioavailability and inter-patient variability are not problems associated only with oral administration of cladribine. Oral formulations such as Mavenclad can only be used in patients who are able to swallow. Dysphagia is a significant problem in multiple sclerosis. Dysphagia is the medical term for having difficulty or trouble swallowing food or beverages. According to the National Multiple Sclerosis (MS) Society, dysphagia can occur frequently in people with MS because the disease impairs the nerve control of the muscles of the jaw, tongue, and throat involved in chewing and swallowing. The effects of the disease on the brain can cause weakness and coordination problems.

[0028] In the study by Levinthal et al., the prevalence of dysphagia was 21.1% in 218 MS patients in the United States (Levinthal et al., Mult. Scler. Int. 2013: 319201).

[0029] In a multi-center study of 1,875 Italian MS patients, 31.3% were found to have dysphagia. Similarly, patients with dysphagia had a longer disease duration and higher EDSS scores than other patients. A recent study found that the prevalence of dysphagia in Turkish MS patients was 45.3% (Tenekeci et al., Arch. Neuropsychiatr. 55 (2018), 243-247). A further study in 2018 estimated that the general prevalence of dysphagia in people living with MS was approximately 43% (Aghaz et al., Iran J Neurol. 2018; 17(4), 180-188). In the study by Alfonsi et al., the rate of dysphagia in Italian MS patients had increased up to 76.9% (!) (Alfonsi et al., Clin. Neurophysiol. 12 (2013)4, 1638-164).

[0030] In the studies by Sales et al. and Fernandes et al., dysphagia was found in 58% (Sales et al., Springerplus, 2 (2013), 332) and 90% (!) (Fernandes et al., Braz. J. Otorhinolaryngol 79 (2013), 460 - 465) of Brazilian MS patients, respectively.

[0031] Mavenclad is designed to be swallowed whole and there is no option to crush or chew it. Dysphagia can make it difficult to take tablets such as Mavenclad. Oral formulations are also inappropriate for patients who are vomiting.

[0032] Mavenclad is presumed to be a substrate for first - pass metabolism. The metabolism of cladribine in isolated perfused rat liver has been studied. The amount of 2 - chloroadenine (CAde), the main metabolite of cladribine, increased proportionally with time and dose. The first - pass effect was approximately 50% (F. Albertioni et al. Eur J Drug Metab Pharmacokinet. Jul - Sep 1995). These data conflict with the description in the EPAR for Mavenclad (EMEA / H / C / 004230) that any contribution of the first - pass effect to the intermediate bioavailability of cladribine can be ignored.

[0033] The main drawbacks associated with oral cladribine formulations are the narrow absorption window in the upper small intestine where cladribine is a substrate for the BCRP (ABCG2) transporter protein, combined with the low pH in the stomach and secondary degradation by specific enzymes produced by the microbiota such as PNP and UP.

[0034] Therefore, in order to overcome the above-mentioned drawbacks, increase the bioavailability of cladribine, and potentially reduce the therapeutic dose per day and throughout the treatment process, it is necessary to develop a new and advanced formulation of cladribine.

Summary of the Invention

Problems to be Solved by the Invention

[0035] Therefore, the present invention provides a transmucosal delivery composition in the form of a sublingual intraoral dispersible film containing cladribine as an active ingredient.

Means for Solving the Problems

[0036] More specifically, the present invention provides a transmucosal delivery composition in the form of a sublingual intraoral dispersible film containing cladribine as an active ingredient, wherein cladribine is preferably contained in the composition as a cladribine-cyclodextrin complex, and the composition contains at least two hydrophilic polymers, and the at least two hydrophilic polymers account for at least 30% (w / w) of the whole composition. According to a preferred embodiment, in the composition according to the present invention, the at least two hydrophilic polymers include one or more structure-forming polymers and one or more binding polymers and / or intercalating polymers. For both categories, the hydrophilic polymer can be either a natural polymer or a synthetic polymer.

Brief Description of the Drawings

[0037]

Figure 1

Embodiments for Carrying Out the Invention

[0038] Regarding the present invention, the term "hydrophilic polymer" refers to a polymer containing polar or charged functional groups that render the polymer soluble or swellable in water or aqueous solutions, colloids, and suspensions. Hydrophilic polymers can be natural, semi-synthetic, and synthetic hydrophilic polymers. Preferred examples of hydrophilic polymers in the compositions according to the present invention are disclosed below.

[0039] As used herein, the term "hydrophilic" refers to the ability of a chemical compound to dissolve in water due to its attractive supramolecular interactions (e.g., hydrogen bonding, dipole-dipole interactions) with water molecules. Hydrophilicity can be paraphrased as "water-loving" or "water-liking", and the axiom "like dissolves like" generally applies. Thus, hydrophilic substances tend to dissolve in water or other hydrophilic solvents. The hydrophilicity of a polymer can be estimated by the solubility of the substance in water.

[0040] In addition, the hydrophilicity of the hydrophilic polymers used in the present invention is defined by their solubility in water. Also, the hydrophilic polymers used in the present invention have a solubility in water of 0.033 g / ml or more, as defined in Chapter 5.11 Characters Section in Monographs - Solubility of the European Pharmacopoeia (for example, the disclosure on page 805 of the 11.0th edition of the European Pharmacopoeia). According to the definition of the European Pharmacopoeia, such polymers are slightly soluble (solubility: 0.033 - 0.1 g / mL), soluble (solubility: 0.1 - 1 g / mL), or very soluble (solubility: > 1 g / mL).

[0041] The solubility parameter in water and the method for measuring solubility described in Chapter 5.11 Characters Section in Monographs - Solubility of the European Pharmacopoeia are as follows.

[0042] Solubility Keywords >1 g / mL Very soluble Easily soluble at 0.1~1 g / mL Slightly soluble at 0.033~0.1 g / mL Slightly difficult to dissolve at 0.01~0.033 g / mL Difficult to dissolve at 0.001~0.01 g / mL Extremely difficult to dissolve at 0.0001~0.001 g / mL Hardly soluble at <0.0001 g / mL

[0043] The method for determining the solubility of a given polymer disclosed in the European Pharmacopoeia is as follows.

[0044] Weigh 100 mg of the fine powder substance (90) (2.9.12) into a screw-capped test tube (inner diameter 16 mm, length 160 mm), add 0.1 mL of the solvent, and follow the following procedure.

[0045] Dissolution operation [Dissolution operation: Vigorously shake for 1 minute, place in a thermostat, hold at 25.0 ± 0.5 °C for 15 minutes, and if it does not dissolve completely, shake for 1 minute and place in the thermostat for 15 minutes]. If it dissolves completely, it is "extremely easily soluble".

[0046] If it is not completely dissolved, add 0.9 mL of the solvent and follow the dissolution procedure. If it dissolves completely here, it is "easily soluble". If it is not completely dissolved, add 2.0 mL of the solvent and follow the dissolution procedure. If it dissolves completely here, it is "slightly easily soluble".

[0047] If it is not completely dissolved, add 7.0 mL of the solvent and follow the dissolution procedure. If it dissolves completely here, it is "slightly difficult to dissolve".

[0048] If it does not dissolve completely, weigh 10 mg of the finely divided substance (90) (also defined in the European Pharmacopoeia) into a stoppered test tube, add 10.0 mL of the solvent, and follow the dissolution procedure. If it dissolves completely here, it is "difficult to dissolve". If it does not dissolve completely, weigh 1 mg of the finely divided substance (90) into a stoppered test tube, add 10.0 mL of the solvent, and follow the elution procedure. If it dissolves completely here, it is "extremely difficult to dissolve".

[0049] The structure-forming polymer forms the polymer matrix of the thin film and prescribes in advance the physical and chemical properties of the polymer matrix. The structure-forming polymer is preferably a non-linear polymer, for example, a branched polymer or a cross-linked polymer, and has a high degree of polymerization.

[0050] The structure-forming polymer is selected from the group comprising starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginates, cellulose and cellulose derivatives, and mixtures or combinations thereof. Derivatives of the polymers used in the present invention can be derived from compounds in which the basic structure or chemical reactions or substitutions of functional groups have been made. Thus, as is commonly referred to in polymer chemistry, a derivative of a given polymer is a polymer having a polymer backbone of the same structure as the given polymer (e.g., in the case of cellulose, glucose units linked by 1,4-glycosidic bonds), but the functional groups of the individual units may be modified, for example, by substitution (e.g., the hydroxyl group may be replaced by methoxy, ethoxy, isopropyloxy, etc.). Thus, cellulose derivatives are preferably selected from the group comprising methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethyl, hydroxypropylmethyl, hydroxypropylcellulose, cellulose acetate succinate, sodium carboxymethylcellulose, and mixtures or combinations thereof.

[0051] The binding and / or intercalating polymer interacts with the structure-forming polymer and stabilizes and strengthens the matrix formed by the structure-forming polymer. The binding / intercalating polymer is preferably a relatively small linear polymer with a low degree of polymerization.

[0052] The binding and / or intercalating polymer is selected from the group comprising pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), and mixtures or combinations thereof.

[0053] The following synthetic polymers, due to their high diversity in the manufacturing process, can be applied not only as binding polymers / insertion polymers but also as structure-forming polymers depending on the average molecular weight of the polymer. These polymers are selected from the group of polyethylene oxide, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), vinyl phthalate acetate, and copolymers or block copolymers of these polymers. Although there may be some exceptions due to the specific properties of some polymers, these polymers with a high average molecular weight (MW > 100,000 g / mol) are typically classified as structure-forming polymers. These polymers with a lower molecular weight (MW ≤ 100,000 g / mol) are typically in the category of insertion polymers / binding polymers.

[0054] A combination of at least one of the above-mentioned structure-forming polymers and at least one of the above-mentioned binding / insertion polymers is essential for the present invention. The structure-forming polymer prescribes the properties of the ODF in advance, and the addition of the binding / insertion polymer improves the properties of the thin film, particularly the mechanical properties such as disintegration and elasticity.

[0055] However, when a hydrophilic polymer that can be either structure-forming or binding / intercalating depending on the molecular weight is used (see the above description), the polymers can be derived from the same functional group. For example, polyethylene oxide having MW > 100,000 g / mol can, inter alia, be combined within the scope of the present invention with polyethylene oxide having MW ≤ 100,000 g / mol, because these two types of polymers are classified into different categories as described above. When two types belonging to the same polymer category are used as at least one structure-forming polymer and at least one binding and / or intercalating polymer according to the present invention, the difference in the molecular weights of the two types of polymers should be 20% or more, preferably 50% or more, particularly 100% or more based on the binding / intercalating polymer species, i.e. the species with the lower MW (as defined from the binding / intercalating polymer species, i.e. the species with the lower MW). When referring to the MW of a polymer in this specification, the number average molecular weight, i.e. the total weight of the polymer divided by the total number of molecules, is used to define this MW (if in doubt).

[0056] As the structure-forming polymer, hydroxypropyl starch and / or hydroxypropyl methylcellulose (HPMC) are preferred.

[0057] As the binding / intercalating polymer, pullulan and / or polyethylene oxide (MW ≤ 100,000 g / mol) are preferred.

[0058] A combination of hydroxypropyl starch (as the structure-forming polymer) and pullulan (as the binding / intercalating polymer) is preferred.

[0059] According to a preferred embodiment, the at least two hydrophilic polymers are used in a ratio of a first hydrophilic polymer to a second hydrophilic polymer of 95:5 to 5:95 by weight, preferably 80:20 to 50:50 by weight, more preferably 70:30 to 60:40 by weight, where in particular, the first hydrophilic polymer is a structure-forming polymer and the second hydrophilic polymer is a binding and / or inserting polymer.

[0060] According to a preferred embodiment, cladribine is incorporated into the composition of the invention in 2-hydroxypropyl-β-cyclodextrin complex, hydroxypropyl pea starch, pullulan, glycerol, and optionally, soybean lecithin containing at least 70% phosphatidylcholine, such as Lipoid S75.

[0061] According to a preferred embodiment, cladribine is present in the composition according to the invention in an amount of 0.01% to 50% by weight, preferably 0.1% to 20% by weight, more preferably 1% to 10% by weight of the total composition.

[0062] Preferably, the orally disintegrating film composition according to the invention has a disintegration time of 300 seconds or less, preferably 180 seconds or less, preferably 120 seconds or less, particularly 60 seconds or less. The disintegration time of the thin film can be measured in vitro in a solution of phosphate buffered saline (pH = 6.8) at 25 °C to mimic the oral cavity. For the preparation of the eluate, 8 g of sodium chloride, 0.2 g of potassium dihydrogen orthophosphate and 2.66 g of disodium hydrogen phosphate dihydrate are dissolved in 1000 mL of deionized water, and orthophosphoric acid (85%) is added to adjust the pH to 6.8. 25 mL of the buffer solution is filled into a Petri dish and placed on an orbital shaker. Using forceps, the oral thin film is placed into the Petri dish, and the sample is swirled at a specific speed (75 rpm) to stimulate movement in the solution. The time until complete disintegration is recorded three times for each oral thin film sample.

[0063] The present invention also relates to a transmucosal delivery composition in the form of a sublingual intraoral dispersible film containing cladribine as an active ingredient, wherein cladribine is contained in the composition as a cladribine-cyclodextrin complex, the composition contains at least two hydrophilic polymers, and the at least hydrophilic polymers account for 20% (w / w) or more, preferably 25% (w / w) or more of the whole composition.

[0064] According to a preferred embodiment, the composition according to the invention contains cladribine as the sole active ingredient (i.e., only additional ingredients that have no therapeutic effect on the patient to whom the composition is administered, in particular no therapeutic effect for the treatment of MS, MG or NMOSD, are present in the composition).

[0065] As shown by the present invention, transmucosal cladribine delivery has proven to be a very good solution that solves most of the drawbacks associated with oral administration.

[0066] Intraoral disintegrating / dispersible film (ODF) technology Transmucosal administration of pharmaceuticals and therapeutic agents that occurs by absorption through the oral mucosa or sublingual mucosa can improve absorption in the gastrointestinal tract and bypass degradation, so it is an attractive alternative to standard oral administration by ingestion into the gastrointestinal tract. A fast-dissolving drug delivery system, such as the novel approach of intraoral disintegrating film (also called intraoral dispersible film, ODF), can achieve mucosal administration of beneficial drugs, resulting in a higher degree of control of the actual dose of the active ingredient and an improvement in patient compliance, especially in geriatrics. ODFs are typically the size of a regular postage stamp and disintegrate on the patient's tongue in a few seconds to rapidly release one or more active ingredients. Oral films rapidly disintegrate within seconds upon contact with saliva without the need for water.

[0067] The composition of the soluble film is usually facilitated by an aqueous polymer matrix that spans a wide molecular weight (MW) range, enabling the active pharmaceutical agent to dissolve rapidly and be released rapidly upon immediate hydration by saliva in the oral cavity, thereby providing the flexibility to achieve certain physical properties.

[0068] Compared to other oral dosage forms, orally disintegrating films have several special advantages such as improved onset of action due to a relatively large surface area and rapid disintegration and dissolution in the oral cavity, reduced dosage, enhanced efficacy and safety profiles of the drug, etc. Since the oral mucosa or buccal mucosa is highly vascularized, the drug can be directly absorbed and enter the systemic circulation without undergoing first-pass hepatic metabolism, enabling reduction of the dose of the active ingredient while minimizing the accompanying side effects. This feature of orally disintegrating films can be utilized in preparing products with improved oral bioavailability of the active ingredient.

[0069] The sublingual orodispersible film according to the present invention is provided and manufactured for sublingual administration. This sublingual administration route according to the present invention should be distinguished from (standard) oral administration. Standard oral administration is performed by applying the API through the mouth by swallowing substances such as tablets, capsules, powders and liquids. The API is then absorbed through the gastrointestinal tract (enterally), and in many cases, the bioavailability is lower. Sublingual administration is a form of transmucosal administration. The API is absorbed directly into the blood through the mucosa (non-gastrointestinal tract (=parenterally)), and thus, usually, the bioavailability is better. In contrast to such oral administration forms, the film according to the present invention that can be administered sublingually is called an orodispersible = orally dispersible = orally disintegrating film. In the European Pharmacopoeia (Chapter - Oral Mucosal Preparations), these dosage forms are defined, in accordance with the use of the terms according to the present invention, as "orodispersible films are solid oral mucosal preparations intended for oral administration and rapidly disperse to deliver the active substance for local or systemic effects. They consist of a single sheet or multiple sheets made of suitable materials".

[0070] Furthermore, the dosage of the orally disintegrating film is precisely controlled through the size of the film piece because the active ingredient is uniformly distributed in the polymer matrix of the film. Furthermore, the orally disintegrating film is easy to transport and store and is not as fragile as, for example, orally disintegrating tablets.

[0071] Furthermore, the orally disintegrating film dosage form is very useful for elderly and pediatric patients, and patients suffering from dysphagia, recurrent vomiting, motion sickness, and mental disorders are very favorable for such patients because they cannot swallow a large amount of water. Therefore, another practical use for administration by orally disintegrating film includes emergency medical situations where rapid administration of drugs by unskilled personnel can save lives; unconscious patients who may have experienced overdose or seizures; and elderly dementia patients with dysphagia. The above characteristics of the orally disintegrating film composition are also very beneficial for applying drugs safely and preventing abuse.

[0072] In summary, the application of cladribine using the orally disintegrating film described in the present invention is highly desirable and offers numerous advantages compared to oral applications in the prior art.

[0073] The ODF formulation of cladribine enables accurate dosage control. Also, since cladribine is a highly active pharmaceutical ingredient, the single - treatment dosage does not exceed 10 mg, which can be reasonably incorporated into the ODF. Furthermore, since cladribine is absorbed through sublingual mucosal absorption and dissolved into the bloodstream, the bioavailability of cladribine is strongly increased by sublingual administration. In this regard, sublingual administration results in a reduction of side effects and dosage because cladribine is directly absorbed from the sublingual mucosa, avoiding first - pass metabolism and entering the systemic circulation. Since the BCRP (ABCG2) transporter protein is not present in oral mucosal epithelial cells, the mucosal absorption of cladribine is further increased. Therefore, compared to prior - art cladribine formulations, the required daily dosage and total cumulative dosage are lower, leading to an improvement in patient compliance.

[0074] Furthermore, since the normal pH range of saliva is 6.2 - 7.6 and the average pH is 6.7, the risk of acid degradation and cladribine degradation caused by specific salivary microbiota is reduced by sublingual administration compared to oral gastric administration. The resting pH of the oral cavity does not fall below 6.3. In the oral cavity, the pH is maintained near neutral (6.7 - 7.3) by saliva.

[0075] Finally, since the fast - dissolving film rapidly disintegrates without the need for water when placed under the tongue, cladribine ODF is more acceptable in patients with dysphagia without the risk of choking. This effect particularly increases patient compliance for treating MS patients, who are often affected by dysphagia.

[0076] Cladribine formulations for improved oral and transmucosal delivery (Nicolas S Bodor, assignee Ares Trading SA (part of the Merck - Serono group)) are described in U.S. Patent No. 8623408 B2 and European Patent No. 1608343 B1, which disclose a composition comprising a cladribine - cyclodextrin complex formulated in a solid oral dosage form or a transmucosal dosage form, and a method for enhancing the oral and transmucosal bioavailability of cladribine.

[0077] Excess cyclodextrin inhibits the absorption of cladribine from a solid oral dosage form or a transmucosal dosage form comprising a cladribine - cyclodextrin complex, and a solid oral dosage form or a transmucosal dosage form of a saturated cladribine - cyclodextrin complex has been found to improve oral and / or transmucosal bioavailability and / or reduce inter - and / or intra - patient variability of the drug.

[0078] U.S. Patent No. 6,194,395 B1 discloses, in specific examples, cladribine, cyclodextrin, and an oral composition containing two hydrophilic polymers (microcrystalline cellulose and crospovidone) for use in the treatment of leukemia, such as hairy cell leukemia and chronic myelogenous leukemia, and disease states and autoimmune disorders such as multiple sclerosis, autoimmune hemolytic anemia, inflammatory bowel disease, rheumatoid arthritis, and malignant astrocytoma. The composition is either a solution of cladribine or any of the solid pharmaceutical oral dosage forms such as tablets, caplets, gel capsules, capsules, chewable tablets, lozenges, or fast-dissolving wafers. In the specific example of U.S. Patent No. 6,194,395 B1 where crospovidone and microcrystalline cellulose are contained in the crushed extrudate, crospovidone and microcrystalline cellulose are used as excipients, i.e., as binders, and caramelized pellets are prepared as intermediate products for the solid dosage form of cladribine in the hot melt - extrusion approach, thus using a manufacturing technique completely different from that in the case of transmucosal / sublingual formulations. The present orally dispersible film avoids all the drawbacks inherent in the oral route of cladribine administration, which is only usable when the patient is conscious and swallowable (this is a challenge considering the fact that the general prevalence of swallowing disorders in patients living with MS is about 43%). Furthermore, as disclosed in U.S. Patent No. 6,194,395 B1, cladribine is degraded by gastric acid or PNP and UP enzymes of the gut microbiota, which significantly reduces the efficiency of oral administration via solid compositions such as tablets and solution compositions. Cladribine is also a target of the BCRP (ABCG2) transporter protein expressed in the upper part of the intestine. Thus, the absorption of cladribine can vary, and it can also depend on various factors affecting drug absorption such as gastrointestinal motility, gastric emptying rate, and the presence of food in the gastrointestinal tract.In contrast, sublingual administration is characterized by rapid disintegration, improved drug absorption, not being decomposed at the physiological pH in saliva, better acceptance in patients with swallowing disorders, no risk of choking, and accurate dosing and great precision. The advantages of sublingual administration are in principle known in the art, but the provision of suitable means, structures, and manufacturing methods for realizing a sublingual (thin film) film containing cladribine-cyclodextrin complex that enables effective treatment of patients, particularly patients with MS, MG, or NMOSD, has not been achieved.

[0079] Importantly, the use of the defined cladribine-cyclodextrin complex, which is not obvious, to provide a final sublingual formulation that requires specific manufacturing techniques is not disclosed in U.S. Patent No. 6,194,395 B1, particularly in the extrudates in its examples. Also, the technology is significantly different from the method disclosed in U.S. Patent No. 7,888,328 B2 where the cladribine-cyclodextrin complex has to be isolated first. In contrast to the formulations disclosed in U.S. Patent No. 6,194,395 B1, the present invention enables the production of a novel sublingual dosage form of cladribine with high precision and patient compliance through the incorporation and uniform distribution of the cladribine-cyclodextrin complex into the thin film.

[0080] Therefore, the film according to the present invention has different mechanical properties such as flexibility or elasticity from orally administered products such as tablets, capsules, or wafers. Therefore, the characteristic mechanical parameter of the film according to the present invention is the folding durability. Therefore, the folding resistance value of the orally dispersible film according to the present invention should be 10 or more, preferably 50, preferably 100, more preferably 300.

[0081] The flexibility and elasticity of the film can be determined by the folding durability value. Examining the number of folds gives an indication of ODF brittleness and is important for its storage stability without breakage and for administration, and thus for patient compliance with the product. The flexibility and elasticity of the ODF can be determined by the fold resistance of the film. For the folding durability test, either an ODF or a film sample in the shape of a rectangle with an area of 10 cm 2 (e.g., 2×5 cm) is investigated. The sample is manually repeatedly folded at a 180° angle with the same folded edge until the film breaks. The number of folds until the film breaks is the folding durability value. This method for determining folding durability is also disclosed in Mahesh et al. (Curr. Drug. Deliv. 7 (2010), 21-27) and Takeuchi et al. (Int. J. Pharmac. 589 (2020), 119876). Generally, when the number of folds per film exceeds 300, it is said to have excellent flexibility.

[0082] U.S. Patent No. 8,623,408 claims a pharmaceutical composition comprising a saturated cladribine-cyclodextrin complex formulated in a solid oral dosage form, substantially free of cyclodextrin in excess of the minimum necessary amount to maximize the amount of cladribine in the complex or to maintain substantially all of the cladribine in the complex, wherein the cyclodextrin is γ-cyclodextrin and the weight ratio of cladribine to γ-cyclodextrin is from about 1:35 to about 1:50, and the complex comprises the cladribine:γ-cyclodextrin complex in a molar ratio of 1:2.

[0083] In U.S. Patent No. 8,623,408, Nicolas S. Bodor clearly differentiates between transmucosal delivery methods and dosage forms and oral dosage forms, and teaches that a transmucosal dosage form for oral use, which is intended to be swallowed and is simply called an oral dosage form, does not include the said method and the said dosage form.

[0084] According to Bodor, for transmucosal dosage forms, when in liquid form, the saturated complex can be obtained by dissolving, for example, 500 mg of the saturated complex with HPβCD in 0.5 ml of water (50% w / w solution), or 500 mg of the saturated γCD complex in 1.0 ml of water.

[0085] A few drops of such a solution can be inserted into the buccal cavity and held there for about 2 minutes to allow absorption through the buccal mucosa. Although Bodor states that solid transmucosal dosage forms are generally preferred over liquid forms, no experimental data related to solid transmucosal compositions are provided.

[0086] Instead, oral absorption or mucosal absorption can be further enhanced by the addition of various excipients and additives to increase solubility or enhance penetration, for example, by modifying the microenvironment, or by adding mucoadhesive excipients to improve contact between the delivery system and mucosal tissue.

[0087] According to the present invention, a wide range of cyclodextrins including γ-cyclodextrin; β-cyclodextrin derivatives and γ-cyclodextrin derivatives of hydroxyalkyl such as hydroxyethyl or hydroxypropyl; β-cyclodextrin derivatives and γ-cyclodextrin derivatives of carboxyalkyl such as carboxymethyl or carboxyethyl; β-cyclodextrin sulfobutyl ether; dimethyl-β-cyclodextrin; and randomly methylated β-cyclodextrin can be used for cladribine complexation, but the experimental data are limited to those related to γ-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin (HPβCD) complexes.

[0088] Bodor also provides a long list of various carriers that can be used for the preparation of so-called "buccal dosage units", but does not provide a qualitative or quantitative composition of the buccal cladribine formulation.

[0089] Examples of polymer carriers provided include acrylic acid polymers and copolymers such as those known as "carbomers", such as Carbopol®. Other suitable polymers include hydrolyzed polyvinyl alcohol, polyethylene oxide (e.g., Sentry Polyox®), polyacrylate (e.g., Gantrez®), vinyl polymers and vinyl copolymers, polyvinylpyrrolidone, dextran, guar gum, pectin, starch, and cellulose polymers such as hydroxypropylmethylcellulose (e.g., Methocel®), hydroxypropylcellulose (e.g., Klucel®), hydroxypropylcellulose ether, hydroxyethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate butyrate.

[0090] Bodor also states that any polymer carrier that is pharmaceutically acceptable, provides both appropriate adhesiveness and the desired drug release profile, and has an affinity for cladribine and any other components that may be present in the oral dosage unit being administered may be used.

[0091] It is also stated that the buccal carrier may contain a polymer having sufficient adhesiveness to ensure that the dosage unit adheres to the buccal mucosa for the required period, i.e., the period during which cladribine is delivered to the buccal mucosa. Bodor summarizes that generally the polymer carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the moist surface of the buccal mucosa.

[0092] From the detailed description of U.S. Patent No. 8,623,408, it can be understood that all carriers provided in combination with cladribine-cyclodextrin complexes are applicable to the preparation of orally adhesive solid preparations.

[0093] U.S. Patent No. 8,623,408 or U.S. Patent No. 6,194,395 B1 provides no information regarding sublingual preparations, or in particular, regarding sublingual administration by thin orally dispersible films.

[0094] In contrast, the present invention describes a sublingual pharmaceutical composition in the form of an orally dispersible film comprising the active ingredient cladribine, preferably cladribine incorporated into a 2-hydroxypropyl-β-cyclodextrin (HPβCD) complex. This active ingredient is uniformly dispersed within a polymer matrix comprising at least one bioedible water-soluble polymer within the orally dispersible film. Incorporation of the active ingredient into the polymer matrix of the orally disintegrating film is a requirement for safe and controlled sublingual administration of cladribine. The pharmaceutical composition can be used as a medicine, particularly in the treatment of multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD). Accordingly, the present invention also relates to the use of the composition according to the invention for the manufacture of a medicament for treating MS, MG, or NMOSD. The present invention also relates to a method of treating a patient suffering from multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering an effective amount of the composition according to the invention to a patient in need thereof.

[0095] The formulation of cladribine as an ODF according to the present invention offers several advantages such as high bioavailability, lower dosage, improved patient compliance, and reduced side effects.

[0096] The present invention is not limited to the specific embodiments described in this application, and these embodiments are only intended as examples of various aspects. As will be apparent to those skilled in the art, many modifications and changes can be made without departing from the scope of the present invention. In addition to those listed herein, functionally equivalent methods within the scope of the present invention will be apparent to those skilled in the art from the following description. Such modifications and changes are intended to fall within the scope of the appended claims. Similarly, it should be understood that the terms used herein are for the purpose of describing only specific embodiments and are not limiting.

[0097] As will be understood by those skilled in the art, for any purpose, such as providing a written description, all ranges disclosed herein include any and all possible sub-ranges and combinations of those sub-ranges. Any recited range can be readily recognized as fully describing and enabling the same range to be decomposed into at least equal halves, thirds, fourths, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. Also, as will be understood by those skilled in the art, all language such as "up to" and "at least" includes the recited number and refers to ranges that can be subsequently broken down into the sub-ranges discussed above. Finally, as will be understood by those skilled in the art, ranges include each individual member. Thus, for example, a group having 1 to 3 units refers to a group having 1, 2, or 3 units.

[0098] As used herein, the terms "orally disintegrating film", "orodispersible film", "orally dispersible film", "oral film", "orally disintegrating film strip", "film strip", "thin-film", and "film" refer to a variable-dimension sheet that includes a polymeric carrier matrix and has an arbitrary shape including rectangular, square, hexagonal, circular, or other desired shapes. The films described herein are typically thin films having a thickness that can range from 10 micrometers to 800 micrometers, preferably 80 to 600 micrometers, more preferably 100 to 300 micrometers, although any desired thickness and size may be used as long as it can be comfortably placed in the user's oral cavity. The film is a single layer and is typically essentially flexible to allow for rapid dissolution in the mouth, permeation through the oral mucosa, and entry into the bloodstream via capillaries.

[0099] Components of ODF Generally, the present invention relates to an orally disintegrating film having an active agent (cladribine) dispersed within a polymer matrix, which comprises a hydrophilic film-forming polymer or a combination of two or more film-forming polymers. Cladribine is preferably in the form of a cladribine-cyclodextrin complex in the formulation. Additionally, surfactants, plasticizers, and / or other additives known in the art can be used in the manufacturing process to achieve an orally disintegrating film with desired properties.

[0100] Active Agent According to the Present Invention cladribine is used as an active ingredient in the present invention. The chemical structure of cladribine, chemically 2-chloro-2'-deoxyadenosine, is shown in Formula 1. Cladribine may be used either as a crystalline solid or an amorphous solid, or as a complex. Since cladribine has very low solubility and low stability in an aqueous medium, cladribine is preferably applied as a cladribine complex with cyclodextrin.

[0101] Cyclodextrins within the scope of the present invention are amorphous derivatives of the natural cyclodextrins α-, β- or γ-cyclodextrin, where one or more of the hydroxy groups are substituted, for example, by an alkyl group, a hydroxyalkyl group, a carboxyalkyl group, an alkylcarbonyl group, a carboxyalkoxyalkyl group, an alkylcarbonyloxyalkyl group, an alkoxycarbonylalkyl group, or a hydroxy-(monoalkoxy or polyalkoxy)alkyl group, where each alkyl or alkylene moiety preferably contains up to 6 carbon atoms. Although generally referred to as a single entity, amorphous cyclodextrins are actually a mixture of many different entities since the substituents can be located on various hydroxyls of the basic cyclodextrin structure. As a result, the amorphous nature of these cyclodextrins occurs, which is actually well known. Furthermore, these cyclodextrins can be obtained with various degrees of substitution, for example 1 to 14, preferably 4 to 7, where the degree of substitution is the approximate average number of substituents on the cyclodextrin molecule, for example, in the case of a hydroxypropyl-β-cyclodextrin molecule, the approximate number of hydroxypropyl groups, and all such variations are within the scope of the present invention. Substituted amorphous cyclodextrins that can be used in the present invention include polyethers. Other cyclodextrins contemplated for use herein include glucosyl-β-cyclodextrin and maltosyl-β-cyclodextrin. Particular useful ones for complexation are dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin and polyethers, such as hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, and hydroxyethyl-γ-cyclodextrin, carboxymethyl-β-cyclodextrin, and sulfobutyl ether, especially sulfobutyl-β-cyclodextrin.In addition to simple cyclodextrins, branched cyclodextrins and cyclodextrin polymers can also be used.

[0102] Preferably, 2-hydroxypropyl-β-cyclodextrin (HPβCD) is used for complex formation of the active ingredient to form a cladribine-2-hydroxypropyl-β-cyclodextrin (HPβCD) complex.

[0103] Each cladribine complex can be prepared according to procedures known in the literature (e.g., U.S. Patent No. 8,623,408 B2 / EP 1,608,343 B1). The complex can be prepared by using either a selected amorphous cyclodextrin, such as hydroxypropyl-β-cyclodextrin (HPβCD) or hydroxypropyl-cyclodextrin, or cladribine as a fixed variable and adding other things thereto. Typically, cladribine is added to an aqueous solution having a known concentration of amorphous cyclodextrin under known conditions to promote complex formation. Generally, complex formation is carried out while heating, for example, at 30 to 60 °C for a significant period of time, such as at least 1 to 24 hours, preferably 1 to 6 hours. Then, the excess precipitated cladribine can be removed, and subsequently the cladribine concentration can be measured. The complex may be used directly for further formulation, which is preferably a one-pot reaction, or the suspension of the complex may be transferred to another reaction vessel, or it may be isolated for further use. Then, the complex is uniformly distributed within the polymer matrix to ensure uniform distribution of the active agent within the orally disintegrating film.

[0104] The active ingredient is applied for the treatment of any cladribine-responsive disease. Some disease states responsive to cladribine are well documented in the literature (see also the use of the following thin films). For any target disease state, an effective amount of an optimized cladribine-cyclodextrin complex is used (e.g., an amount effective for the treatment of multiple sclerosis, rheumatoid arthritis, or leukemia, etc.).

[0105] According to a preferred embodiment, the composition according to the invention contains cladribine as the single effective ingredient. The term "effective ingredient" relates to any specifically effective drug for which there is market approval, particularly in the European Union or the United States. This means that the composition of the invention does not contain further effective ingredients, in particular those that are approved for administration for the treatment of MS, MG or NMOSD. The expression "single effective ingredient" does not exclude the use of substances that are stabilizers, (co-)surfactants, film-forming components, plasticizers or further additives in this preferred composition, even if these substances may have a beneficial effect on health (for example, antioxidants or vitamins).

[0106] Dosage of the active ingredient The desired dosage of the active ingredient in the ODF is determined by the active dosage required for the treatment of a particular disease. The amount of active substance per unit area is determined by the uniform distribution of the film. For example, if the film is cut into individual dosage forms, the amount of active substance in the dosage form can be known very precisely. This is achieved because the amount of active substance in a given area is substantially the same as the amount of active substance in an area of the same dimensions in another part of the film. The accuracy of the dosage is particularly advantageous when the active substance is a medicament, i.e., a drug.

[0107] The drug loading of the film can be up to about 50% by weight of the film, often up to 1 - 10% dry weight. The amount of drug in each film can be calculated before or after shaping the individual film or ingestible unit into the size and shape of the dosage form. The amount of drug lost during processing can also be taken into account in order to design the ingestible unit and select the appropriate number of tablets to reach a predetermined dosage. The film can provide an accurate dosage (determined by the size of the film and the concentration of the active substance in the original polymer / water combination), regardless of whether the required dosage is large or extremely small.

[0108] Film-forming polymer The polymer matrix of the orally disintegrating film composition is formed by a combination of at least two hydrophilic polymers known in the art. Preferred film-forming polymers include starch-based polymers (processed or unprocessed), pullulan, cellulose-based polymers (e.g., HPMC), or polyethylene oxide

[0109] The film-forming polymer can be selected from the group consisting of starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginate, cellulose and cellulose derivatives (processed or unprocessed), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethyl, hydroxypropylcellulose, cellulose acetate succinate, sodium carboxymethylcellulose, pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and mixtures or combinations thereof, preferably modified starch and pullulan

[0110] When the film-forming polymer is selected from the group of starches, the source of starch can be various and can include acorns, kudzu, araca, banana, barley, beans, breadnut, buckwheat, arrowroot, cassava, chestnut, chickpea, corn, fava beans, katakuri, kudzu, lentils, taro, millet, oca, edamame, potato, rice, rye, sago palm, sorghum, sweet potato, taro, tapioca, white turnip, wheat, yam, and combinations thereof. These starches may be gelatinized, and may be raw starch, processed starch, or chemically and synthetically processed starch, including, for example, dextrin, acid-treated starch, alkali-treated starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate, phosphated distarch phosphate, acetylated distarch phosphate, acetate starch, acetylated distarch adipate, hydroxyethyl starch, hydroxypropyl starch, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, and oxidized starch, and are selected from the group thereof.

[0111] According to a particularly preferred embodiment, the orally disintegrating film composition according to the present invention contains hydroxypropyl pea starch and pullulan as film-forming polymers.

[0112] Surfactant For a uniform distribution of the active ingredient, at least one surfactant and / or cosurfactant can be used. Surfactants include sodium dodecyl sulfate (SDS), sodium lauryl sulfate (SLS), benzalkonium chloride, benzethonium chloride, benzyl dimethyl dodecyl ammonium bromide (BDDAB), and nonionic surfactants such as polysorbate 80, sorbitan monooleate, lecithin, glycolipids, fatty acids, esters of aliphatic alcohols and fatty acids, sorbitan esters, polyols such as polysorbates, sorbitan, for example stearic acid, lauric acid, linoleic acid, PEG-40 hydrogenated castor oil, sodium deoxycholate, poloxamer, long-chain fatty acids that are saturated or unsaturated and have more than 6 carbon atoms, bile salts such as sodium taurocholate, phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, polyglycolized glycerides, polyoxyethylene glycerides, polyethylene glycol-fatty acid esters, polyethylene glycol-glycerol-fatty acid esters, transesterification products of oils and alcohols, polyglycerized fatty acids, glycerol fatty acid esters, polyglycerol fatty acid esters, propylene glycol fatty acid esters, propylene glycol fatty acid esters, mono- and di-glycerides, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycol sorbitan fatty acid esters, their sorbitan fatty acid ester derivatives, and combinations thereof. Other suitable surfactants can also be used, and preferably, low molecular weight surfactants are advantageous.

[0113] The amount of such surfactant used ranges from 0.1 wt% to 20 wt%, more preferably from 0.5 wt% to 5 wt%. For example, it can be 1 wt% in total, but it is also possible to use surfactants outside this range.

[0114] Plasticizer Plasticizers can be used in the formulation of oral disintegrating film strips. Plasticizers are food-grade or pharmaceutical-grade compounds, such as low molecular weight polyols like glycerol, propylene glycol, polyethylene glycol, xylitol, erythritol, mannitol, sorbitol, etc.; monosaccharides; disaccharides such as sucrose, lactose, and maltose; oligosaccharides like glycogen and inulin; dextrins such as maltodextrin and similar compounds; citric acid, citrate, tributyl citrate, triethyl citrate, acetyl citrate, citrate esters, triacetin, castor oil, medium-chain triglycerides (MCT) of fatty acids (also known as MCT oil), and various low-viscosity vegetable oils such as soybean oil, rapeseed oil, corn oil and similar oils, mineral oil, miglyol, their derivatives and combinations of one or more of them. The amount of such plasticizer used can range from 0.5 wt% to 25 wt%, more preferably from 5 wt% to 20 wt%, for example from 15 wt% to 20 wt%, but it is also possible to use plasticizers outside this range.

[0115] Colorant / flavoring agent / sweetening agent / taste masking agent / stabilizer and thickener Colorants may also be present in the oral disintegrating film, including titanium dioxide, food-appropriate dyes such as those known as F.D.&C dyes, and natural colorants such as grape skin pigment, beet red powder, beta-carotene, annatto, carmine, turmeric, paprika, etc. When colorants are present in the film, they can range from 0 to 5% by weight of the total composition, for example 1% by weight of the total composition.

[0116] The flavoring agent may also be present in the orally disintegrating film and may include synthetic flavor oils and flavor aromatics and / or extracts from natural oils, plants, leaves, flowers, fruits, etc., and combinations thereof. These may include cinnamon oil, wintergreen oil, peppermint oil, clove oil, star anise oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cassia oil. Flavoring agents may also include vanilla, citrus oils such as lemon, orange, grape, lime, and grapefruit, and fruit essences such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Other flavorings used in the art include commercially available orange, grape, cherry, and bubble gum flavorings and mixtures thereof. Flavor acids such as citric acid, malic acid, tartaric acid, lactic acid, and ascorbic acid may also be used to provide acidity. The flavoring agent may be present in an amount in the range of 0.5% to 10.0% by weight based on the weight of the composition.

[0117] A sweetening agent or taste masking agent may also be present in the orally disintegrating film and may include natural sweeteners such as sucrose, stevia, corn syrup, honey, maple syrup, erythritol, maltitol, mannitol, dextrose, fructose, glucose, xylitol, sorbitol, isomalt, etc., or combinations thereof; and artificial sweeteners such as aspartame, sucralose, acesulfame potassium, saccharin, saccharin cyclamate, cyclodextrin derivatives, etc., or combinations thereof. The amount of one or more sweetening agents may be in the range of 0 to 2.5% by weight based on the total weight of the composition, for example, about 1% by weight.

[0118] The orally disintegrating film piece may also contain one or more of a permeation or permeability enhancer, a bitterness blocker, a filler, a foaming agent, an antioxidant, a disintegrant, a pH adjuster, a buffer, a complexing agent, a bioadhesive, a sheet adhesive, an emulsifier, a crystallization inhibitor, a preservative, a unique identifying agent such as a UV-active fluorophore, and an antibacterial agent.

[0119] Particularly when the active substance is sensitive to oxygen or light, an antioxidant may be added to the film to prevent decomposition of the active substance.

[0120] Method for preparing ODF First, a complex of cladribine and cyclodextrin is formed. The complex of cladribine and cyclodextrin is much more soluble in water and has increased stability in an aqueous medium compared to uncomplexed cladribine, so the formation of the complex is very beneficial.

[0121] For the preparation of the cladribine-cyclodextrin complex, cladribine is mixed with cyclodextrin, preferably 2-hydroxypropyl-β-cyclodextrin (Clerphed HPB), in water by stirring at a temperature of 20-60°C, preferably 40-50°C, at 100-1000 rpm, for example 300 rpm. The target mixing time is 1-24 hours, preferably 2-4 hours, to ensure complex formation and uniform distribution. The molar ratio of cladribine to cyclodextrin is in the range of 10:1 to 1:10, preferably 1:0.5 to 1:9, more preferably 1:1 to 1:9, particularly 1:1 to 1:3, and depends on the cyclodextrin used. In the case of 2-hydroxypropyl-β-cyclodextrin, the molar ratio of cladribine and cyclodextrin is preferably 1:1 to 1:3. This molar ratio follows the weight ratio of 1:5 to 1:15 of the components cladribine and HPβCD.

[0122] Accordingly, the present invention also relates to a method for producing an orally disintegrating film composition and / or a transmucosal delivery composition in the form of a sublingual intraoral dispersible film according to the present invention, wherein cladribine or a cladribine-cyclodextrin complex is mixed with a film-forming polymer by stirring at a temperature of 30°C or higher at 100 rpm or higher for 10 minutes or longer.

[0123] Preferably, after mixing, the mixture is degassed for at least 1 hour, preferably at least 6 hours. According to a preferred embodiment of the method, the mixture is cast and dried at a temperature of at least 60°C, preferably at a temperature of 65°C to 100°C. Preferably, the mixture is cast and dried into a film having a thickness of 10 to 800 μm, more preferably 50 to 500 μm, particularly 100 to 200 μm.

[0124] The cladribine-cyclodextrin complex can be produced and isolated before further use, but by directly mixing the sublingual film composition containing the cladribine-cyclodextrin complex according to the present invention with other components of the ODF in a one-pot method after preparation, except for intermediate isolation, since the active components are uniformly distributed within the polymer matrix, it is preferable to provide a very uniform distribution of the efficacy of the active components across the film surface. Accordingly, the thin film according to the present invention has a small relative standard deviation (RSD) of the concentration of the active ingredient. The RSD of the assay of the active ingredient should be less than 5%, preferably less than 2%, more preferably less than 1%.

[0125] This feature of the ODF results in more accurate dosing compared to methods of solid formulations of cladribine designed for oral administration such as tablets, capsules, or fast-dissolving wafers, thereby resulting in more consistent therapeutic efficacy.

[0126] In a separate reaction vessel, a surfactant, a plasticizer, and all other water-soluble excipients and additives (e.g., flavoring or coloring agents, preservatives, etc.) were mixed in water (at 20 - 60 °C) until all the components were uniformly dispersed to form a hydrophilic phase. These two reaction mixtures were combined and homogenized at 20 - 60 °C by applying agitation or mechanical stirring at high shear rates, for example, by using an Ultra-Turrax®. Subsequently, a hydrophilic polymer or a mixture of different hydrophilic polymers (e.g., modified starch and pullulan in their respective ratios) was added and the mixture was homogenized by stirring at 20 - 60 °C or by applying mechanical stirring at high shear rates, for example, by using an Ultra-Turrax®.

[0127] As another method for preparing the coating mass, a one-pot method can be applied for the formation of complexes of the active ingredients and the mixing of the components.

[0128] The resulting dispersion is optionally degassed by stirring at room temperature or at 30 - 50 °C for 1 - 24 hours or by stirring briefly under reduced pressure. Subsequently, an amount of water sufficient to accurately adjust the desired solids content (10 - 80 wt% w / w) and viscosity (100 - 10,000 cP) of the final coating mass is added.

[0129] Next, a stable dispersion was preferably cast to form an orally disintegrating film. The orally disintegrating film was formed by placing the stable dispersion on a clean receiving substrate or the like. The stable dispersion can be dispensed onto the receiving substrate from a suitable apparatus (e.g., a dispensing apparatus) equipped with a doctor blade as known in the art. The stable dispersion can also be poured, injected, or deposited on the receiving surface by any suitable process or means. The receiving surface can be of any suitable type, such as a tray on a conveyor belt or the conveyor belt itself. Alternatively, the release liner itself may be continuously moved by a driving roller during the casting process to ensure its continuous movement.

[0130] To form the orally disintegrating film, the cast stable dispersion was preferably dried by an infrared heater system or by applying heat or hot air. The apparatus may, for example, move the receiving surface through a conventional oven, or drying may be performed in a batch process. For example, drying can be carried out at a substrate temperature set to 40 - 110°C, for example about 80°C, using an infrared heater system. Preferably, the mixture is cast and dried at a temperature of at least 60°C, preferably 65°C - 100°C. In a typical embodiment, drying was carried out for 1 - 15 minutes. The orally disintegrating film after drying can have a uniform thickness in the range of 20 - 800 micrometers. According to a preferred embodiment, the mixture is cast and dried to form a film having a thickness of 10 - 800 μm, preferably 200 - 700 μm, particularly 100 - 300 μm.

[0131] The film can be cut into any desired shape and size, for example, by a knife / scalpel or by a LASER cutting process. Alternatively, the stable dispersion can be cast in the form of a desired size and shape, thereby eliminating the cutting step.

[0132] Those skilled in the art will understand that for this process and other processes and methods disclosed herein, the functions performed in the processes and methods can be implemented in different orders. Further, the steps and operations outlined are provided by way of example only, and some of the steps and operations are optional, can be combined into fewer steps and operations, or can be extended to additional steps and operations without impairing the essence of the disclosed embodiments.

[0133] Use of thin films The orally disintegrating film pieces can also be used for treating relapsing forms of multiple sclerosis, including not only primary progressive multiple sclerosis but also relapsing-remitting diseases and active secondary progressive diseases. The ODF can be used for treating other neurodegenerative diseases with autoimmunity, such as myasthenia gravis and neuromyelitis optica spectrum disorder (NMOSD).

[0134] Cradribine ODF can also be used in the treatment of symptomatic hairy cell leukemia and B-cell chronic lymphocytic leukemia, as well as in tumor pathology including cutaneous T-cell lymphoma, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), autoimmune hemolytic anemia, mycosis fungoides, and Sézary syndrome.

[0135] Sublingual administration of cladribine using ODF technology increases bioavailability by avoiding gastric degradation and absorption constraints in the intestine, and offers the possibility of reducing the applied drug dosage. Thus, the actual dosage of cladribine in the orally dispersible film can be less than the dosage applied in conventional oral formulations.

[0136] According to another aspect, the present invention also relates to a transmucosal delivery composition in the form of a sublingual orally dispersible film comprising cladribine as an active ingredient for the treatment of neurodegenerative diseases of autoimmune origin, preferably multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD).

[0137] Preferably, cladribine is contained in the composition as a cladribine-cyclodextrin complex. According to a preferred embodiment, this cladribine-cyclodextrin complex is present in the composition in a form mixed with at least two hydrophilic polymers corresponding to at least 20% (w / w), more preferably at least 25% (w / w), particularly at least 30% (w / w) of the whole composition.

[0138] As demonstrated also in the examples, a composition of a cladribine-cyclodextrin complex mixed with at least two hydrophilic polymers of at least 20% (w / w), preferably at least 21% (w / w) provides good result uniformity of the film and shows a very good disintegration time. In certain even more preferred embodiments, the at least two hydrophilic polymers for obtaining a film preparation further improved with respect to uniformity and disintegration time are predicted to be at least 22% (w / w), preferably at least 23% (w / w), particularly at least 25% (w / w) in the whole composition.

[0139] According to a preferred embodiment, the at least two hydrophilic polymers include at least one structure-forming polymer and at least one binding and / or inserting polymer. According to a preferred embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. According to a preferred embodiment, the cladribine-cyclodextrin complex contains cladribine and cyclodextrin in a molar ratio of 1:1 to 1:9, preferably 1:1 to 1:3.

[0140] The present invention will be further described by the following examples and drawings, but the present invention is not limited thereto.

Examples

[0141] General procedure for preparing an orally disintegrating film A general procedure for the manufacture of an orally disintegrating film composition is schematically shown in FIG. 1. First, a cladribine-2-hydroxypropyl-β-cyclodextrin complex, which is cladribine with β-cyclodextrin in water, is formed by mixing in a reaction vessel equipped with an overhead stirrer. The mixture is stirred at room temperature or high temperature until the active ingredient is homogeneously suspended. In another reaction vessel equipped with an overhead stirrer, a surfactant (for example, soy lecithin with 70% or more phosphatidylcholine such as Lipoid S75), a plasticizer (for example, glycerol and / or triacetin), and a water-soluble additive are mixed in water at at least 30° C. until all components are uniformly dispersed. A previously prepared suspension containing the complex of cladribine and creptose HPB is added, and the mixture is stirred at at least 30° C. for at least 15 minutes at 200 to 1500 rpm. Then, a hydrophilic polymer or a mixture of multiple hydrophilic polymers (for example, modified starch and pullulan in respective ratios) is added, and the mixture is homogenized by stirring at at least 30° C. for at least 15 minutes at 200 to 1000 rpm. The resulting dispersion is optionally degassed by stirring at room temperature or at 25 to 50° C. for 1 to 24 hours, or by stirring under reduced pressure for a short time.

[0142] Thereafter, an amount of water sufficient to accurately adjust the desired solids content (20 - 80% w / w) and viscosity (100 - 10,000 cP) of the final coating mass is added. Using a mechanical casting apparatus equipped with a doctor blade assembly, a stable coating mass is cast onto a substrate at a constant gap width at a speed of 0.05 - 1.5 m / min, and then dried at 40 - 100 °C using a conventional heating system or an IR drying apparatus. In this drying process, a sufficient amount of water in the composition is removed to produce a uniform thin film with an approximate thickness in the range of 20 - 500 micrometers. Subsequently, the film is cut into film pieces of the desired size and shape by carefully cutting the laminate with a knife / scalpel, or by using a punching machine, or by using a LASER cutting process.

[0143] Using the above manufacturing method, an oral disintegrating thin film containing cladribine in a cladribine - 2 - hydroxypropyl - β - cyclodextrin complex is manufactured. The active ingredient is uniformly distributed, and the mechanical properties (solubility, disintegration, elasticity, etc.) of the film can be adjusted by the composition and the manufacturing process. In this general manufacturing procedure, since the active ingredient is uniformly distributed within the polymer matrix, it is ensured that the efficacy of the active ingredient is very uniformly distributed over the entire film surface. Therefore, the thin film has a low relative standard deviation (RSD) of the concentration of the active ingredient, resulting in a more accurate dosage compared to film pieces of the prior art, thereby providing a more consistent therapeutic efficacy.

[0144] Example 1: Composition and Manufacturing Method of an Oral Disintegrating Film Containing Cladribine In a 100 mL reaction vessel equipped with an overhead stirrer, 15.38 g of kleptose HPB was suspended in 23.08 g of deionized water at room temperature at 300 rpm. Thereafter, 1.00 g of cladribine was added, and the mixture was stirred at 300 rpm at 50 °C for 3 hours.

[0145] In another 250 mL reaction vessel equipped with an overhead stirrer, 4.66 g of glycerol and 0.26 g of lipid S75 were suspended in 38.0 g of water. The previously prepared API suspension containing cladribine and crep tose HPB was added, and the mixture was stirred at 50 °C for 60 minutes at a speed of 500 rpm. Subsequently, 2.90 g of pullulan and 6.56 g of Lycaot NG720 were added, and the coating mass was stirred at 50 °C for 60 minutes at a speed of 500 rpm. The solids content of the coating mass was adjusted to 33.5% by adding water so that the desired viscosity of the coating mass was achieved. Thereafter, the stirring speed was reduced to 100 rpm, and the coating mass was stirred until it was coated (about 1 to 4 hours).

[0146] Using a mechanical casting device equipped with a doctor blade assembly and a convective heating chamber, a stable dispersion was cast onto a PET substrate at a speed of 0.12 m / min and a gap width of 100 - 300 μm, and then dried at 70 - 90 °C. Using this coating procedure, a thin film having a uniform thickness and a dry coating weight was produced.

[0147]

Table 1

[0148] The disintegration time of the ODF of this example determined by the above method (see page 9 of the international publication of the present application) was 120 - 180 seconds.

[0149] Example 2: Orally Disintegrating Film with Different Molar Ratios of Cladribine and β - Cyclodextrin Example 2 is a composition of an orally disintegrating film with different ratios of cladribine and β - cyclodextrin (molar ratio of cladribine: β - cyclodextrin 1:2). The composition of Example 2 is summarized in Table 2. The film is prepared according to the above general method and the method described in Example 1.

[0150]

Table 2

[0151] The disintegration time of the ODF of this example determined by the above method (see page 9 of the international publication of this application) was 120 - 180 s.

[0152] Example 3: Orally Disintegrating Film with Different Ratios of Modified Starch and Pullulan Example 3 is a composition of an orally disintegrating film having modified starch and pullulan in different ratios (50:50). The composition of Example 3 is summarized in Table 3. The film is prepared according to the above general method and the method described in Example 1.

[0153] [Table 3]

[0154] The disintegration time of the ODF of this example determined by the above method (see page 9 of the international publication of this application) was 120 - 180 s.

[0155] Example 4: Orally Disintegrating Film with a Total Amount of 23.4% of Two Hydrophilic Polymers (Exemplified by Modified Starch and Pullulan) Example 4 is a composition of an orally disintegrating film with a smaller total amount of polymers that are modified starch and pullulan. The total amount of the polymers (weight % in dry mass) is 23.4% in this example. The composition of Example 4 is summarized in Table 4. The film is prepared according to the above general method and the method described in Example 1.

[0156] The disintegration time of the ODF of this example determined by the above method (see page 9 of the international publication of this application) was less than 30 seconds.

[0157] [Table 4]

[0158] Example 5: An orally disintegrating film in which the total amount of two hydrophilic polymers (exemplified by modified starch and pullulan) is 21.3% which is less Example 5 is a composition of an orally disintegrating film in which the total amount of polymers which are modified starch and pullulan is less. The total amount of the polymers (weight % in dry mass) is 21.3% in this example. The composition of Example 5 is summarized in Table 5. The film is prepared according to the above general method and the method described in Example 1.

[0159] The disintegration time of the ODF of this example determined by the above method (see page 9 of the international publication of the present application) was less than 30 seconds.

[0160] [Table 5]

[0161] Comparative Example: An orally disintegrating film in which the total amount of the at least two hydrophilic polymers (exemplified by modified starch and pullulan) is less than 20% (w / w) The composition of 9.57% of modified starch and 9.57% of pullulan (total amount of polymers 19.1%) did not result in a film having the desired properties, especially because the flexibility of the obtained film was low. The composition of the comparative example is summarized in Table 6. The film was prepared according to the above general method and the method described in Example 1.

[0162] [Table 6]

[0163] Summary of Examples In conclusion, the study of the above examples manufactured according to the procedures described in the present invention demonstrates that cladribine in the cladribine-2-hydroxypropyl-β-cyclodextrin complex can be incorporated into and uniformly distributed in the thin film. The active ingredient (cladribine) is uniformly distributed in the polymer matrix within the thin film. Using the procedures described in the present invention, it is possible to manufacture an ODF containing cladribine as the active ingredient, and the properties of the ODF can also be modified by the composition. This enables the production of a novel sublingual dosage form of cladribine with high precision and patient compliance.

[0164] Examples 4 and 5 show that an orally disintegrating film with a total polymer amount (total amount of modified starch and pullulan) of 23.4% and 21.3% respectively can be manufactured, and these have a smaller total polymer amount compared to Examples 1, 2, and 3 (total polymer amounts of 30.75%, 31.4%, and 30.75%). The ODFs of these two examples have very good film homogeneity and very good disintegration properties. Therefore, the disintegration time of the ODFs of these two examples determined by the above method (see page 9 of the international publication of the present application) is even less than 30 s, which is much shorter compared to the disintegration times of Examples 1, 2, and 3 (disintegration time: 120 - 180 seconds).

[0165] However, even according to the above general procedure, with a composition of 9.57% modified starch and 9.57% pullulan (total polymer amount of 19.1%), it was impossible to obtain a film with the desired properties due to the low viscosity of the coating mass, low flexibility, and low homogeneity of the film (see the comparative example).

[0166] Based on the description and example sections of the present invention, the present invention discloses the following embodiments.

[0167] 1. A transmucosal delivery and / or orally disintegrating film composition in the form of a sublingual orally disintegrating film containing cladribine as the active ingredient. 2. The orally disintegrating film composition of Embodiment 1, wherein cladribine is applied as a cladribine-cyclodextrin complex. 3. The composition of Embodiment 1 or Embodiment 2, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, or sulfobutyl-β-cyclodextrin. 4. The sublingual orally dispersible film of cladribine according to any one of Embodiments 1 to 3, wherein the cladribine-cyclodextrin complex contains cladribine and cyclodextrin in a molar ratio of 1:1 to 1:9, preferably 1:1 to 1:3. 5. The orally dispersible film composition of cladribine according to any one of Embodiments 1 to 4, comprising the active ingredient, at least one film-forming polymer, at least one surfactant and / or cosurfactant, at least one plasticizer, and optionally further additives such as taste masking agents, flavoring agents, solubilizers, thickeners, colorants, antioxidants, pH adjusters, vitamins, or mixtures thereof.

[0168] 6. An orally disintegrating film composition according to any one of Embodiments 1 to 5, wherein the film-forming polymer is selected from the group consisting of starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginate, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl, hydroxypropyl cellulose, cellulose acetate succinate, sodium carboxymethyl cellulose and other celluloses and cellulose derivatives (processed or unprocessed), pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and mixtures or combinations thereof, preferably selected from modified starch and pullulan; In particular, the structure-forming polymer is · composed of starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginate, cellulose and cellulose derivatives; · polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and copolymers or block copolymers of these polymers, provided that the average molecular weight (MW) of these polymers is more than 100,000 g / mol; and · mixtures or combinations thereof selected from; the binding and / or intercalating polymer is · a group including pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate); · polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and copolymers or block copolymers of these polymers, provided that the average molecular weight (MW) of these polymers is less than 100,000 g / mol; and · their mixtures or combinations selected from; · provided that when two types belonging to the same polymer category are used as at least one type of structure-forming polymer and at least one type of binding and / or intercalating polymer, the difference in MW between the two types is 20% or more, preferably 50% or more, especially 100% or more based on the binding / intercalating polymer species, i.e., the species with the lower MW (at least 20%, preferably at least 50%, especially at least 100%, as defined from the binding / intercalating polymer species, i.e., the species with the lower MW). An orally disintegrating film composition. -

[0169] 7. The starch polymer is starch from acorn, aracaucha, barley, beans, hovenia dulcis, buckwheat, cassava, chickpea, chestnut, corn, lentil, millet, oat, pea, potato, rice, rye, sago palm, sorghum, sweet potato, tapioca, wheat, and combinations thereof, preferably pregelatinized starch, hydroxypropyl starch, or pregelatinized hydroxypropyl starch, particularly (unpregelatinized or pregelatinized) hydroxypropyl pea starch, where the starch may be pregelatinized, gelatinized, unprocessed starch, or processed starch, and is an orally disintegrating film composition according to any one of Embodiments 1 to 6, and disintegrates in the oral cavity. 8. The weight ratio of the first film-forming polymer to the second hydrophilic polymer is from 90:10 to 10:90, preferably from 80:20 to 50:50, more preferably from 60:40 to 50:50, and the combination of the polymers is used, and is an orally disintegrating film composition according to any one of Embodiments 1 to 7. 9. The surfactant and / or co-surfactant is selected from the group consisting of polyglycolated glycerides, polyoxyethylene glycerides, polyethylene glycol-fatty acid esters, polyethylene glycol, glycerol fatty acid esters, transesterification products of oils and alcohols, polyglycerized fatty acids, glycerol fatty acid esters, polyglycerol fatty acid esters, propylene glycol fatty acid esters, mono- and di-glycerides, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycol sorbitan fatty acid esters, sorbitan fatty acid esters, polysorbates, poloxamers, phospholipids, lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and mixtures thereof, and is an orally disintegrating film composition according to any one of Embodiments 1 to 8. 10. A buccally disintegrating film composition comprising cladribine, preferably cladribine incorporated into a 2-hydroxypropyl-β-cyclodextrin complex, hydroxypropyl faba bean starch, pullulan, and preferably at least one plasticizer and / or at least one emulsifier.

[0170] 11. A buccally disintegrating film composition comprising cladribine, preferably cladribine incorporated into a 2-hydroxypropyl-β-cyclodextrin complex, hydroxypropyl faba bean starch, pullulan, glycerol, and soy lecithin in which phosphatidylcholine is 70% or more, and optionally triacetin. 12. The buccally disintegrating film composition according to any one of the foregoing embodiments, wherein the film contains at least two hydrophilic polymers, and each of the hydrophilic polymers has a solubility in water of 0.033 g / mL or more, preferably 0.1 g / mL or more, particularly 1 g / mL or more, and the solubility in water is preferably determined by the method according to Chapter 5.11 of the European Pharmacopoeia (11.0th edition). 13. The buccally disintegrating film composition according to any one of the foregoing embodiments, wherein the folding durability value of the film is 10 or more, preferably 50 or more, more preferably 100 or more, particularly 300 or more. 14. The buccally disintegrating film composition according to any one of the foregoing embodiments, wherein the disintegration time of the film composition is 300 seconds or less, preferably 180 seconds or less, particularly 120 seconds or less. 15. The buccally disintegrating film composition according to any one of the foregoing embodiments, wherein cladribine is present in an amount of 0.01% to 50% by weight, preferably 0.1% to 20% by weight, more preferably 1% to 10% by weight of the whole composition.

[0171] 16. The buccally disintegrating film composition according to any one of the foregoing embodiments, which is used for the treatment of multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD). 17. A transmucosal delivery composition in the form of a sublingual intraoral dispersible film containing cladribine as an active ingredient, wherein the cladribine is contained in the composition as a cladribine-cyclodextrin complex, the composition contains at least two hydrophilic polymers, and the at least hydrophilic polymers account for 25% (w / w) or more of the whole composition. 18. The composition according to any one of Embodiments 1 to 17, wherein the at least two hydrophilic polymers include at least one structure-forming polymer and at least one binding polymer and / or inserting polymer. 19. The composition according to any one of Embodiments 1 to 18, containing at least one structure-forming polymer as a hydrophilic polymer, and the structure-forming polymer is preferably a modified starch polymer and / or a modified cellulose derivative. 20. The composition according to any one of Embodiments 1 to 19, containing at least one binding and / or inserting polymer as a hydrophilic polymer, and the binding and / or inserting polymer is preferably selected from pullulan and / or polyethylene oxide.

[0172] 21. The composition according to any one of Embodiments 1 to 20, wherein cladribine is the only active ingredient. 22. Use of the composition according to any one of the foregoing embodiments for the manufacture of a medicament for the treatment of multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD). 23. A method for producing an orally disintegrating film composition and / or a transmucosal delivery composition in the form of a sublingual intraoral dispersible film according to any one of the foregoing embodiments, wherein the cladribine or cladribine-cyclodextrin complex is mixed with the film-forming polymer by stirring at a temperature of 30 °C or higher at 100 rpm or higher for 10 minutes or longer. 24. The method of Embodiment 20, wherein the mixture is degassed after mixing for 1 hour or longer, preferably 6 hours or longer. 25. The method of embodiment 20 or embodiment 21, wherein the mixture is cast and dried at a temperature of 60 °C or higher, preferably at a temperature of 65 °C to 100 °C.

[0173] 26. The method of any one of embodiments 20 to 22, wherein the mixture is cast and dried to form a film having a thickness of 10 to 800 μm, preferably 50 to 500 μm, particularly 100 to 250 μm. 27. A transmucosal delivery composition in the form of a sublingual or buccal dispersible film, comprising cladribine as an active ingredient for the treatment of neurodegenerative diseases of autoimmune origin 28. The composition of any one of embodiments 1 to 21 and embodiment 27, wherein cladribine is contained in the composition as a cladribine-cyclodextrin complex. 29. The composition of any one of embodiments 1 to 21, embodiment 27 and embodiment 28, containing a cladribine-cyclodextrin complex in a state of being mixed with at least two hydrophilic polymers corresponding to 20% (w / w) or more, more preferably 25% (w / w) or more, particularly 30% (w / w) or more of the whole composition. 30. The composition of any one of embodiments 1 to 21 and embodiments 27 to 29, wherein the at least two hydrophilic polymers include at least one structure-forming polymer and at least one binding and / or inserting polymer.

[0174] 31. The composition of any one of embodiments 1 to 21 and embodiments 27 to 30, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. 32. A composition according to any one of Embodiments 1 to 21 and Embodiments 27 to 31, wherein the cladribine-cyclodextrin complex contains cladribine and cyclodextrin in a molar ratio of 1:0.5 to 1:9, preferably 1:1 to 1:9, particularly 1:1 to 1:3. 33. A composition according to any one of Embodiments 1 to 21 and Embodiments 27 to 32, wherein the total amount of cladribine in a single dosage form (sublingual film) is 0.1 mg to 20 mg, preferably 1 to 12 mg, more preferably 5 to 10 mg. 34. A method for treating a patient suffering from multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD), the method comprising administering an effective amount of a composition according to any one of Embodiments 1 to 21 and Embodiments 27 to 32 to a patient in need thereof.

Claims

1. A transmucosal delivery composition in the form of a sublingual intraoral dispersible film, comprising cladribine as an active ingredient and at least two hydrophilic polymers, wherein the at least two hydrophilic polymers account for 20% (w / w) or more, preferably 25% (w / w) or more of the whole composition, and cladribine is contained in the composition as a cladribine-cyclodextrin complex.

2. The composition according to claim 1, wherein the at least two hydrophilic polymers comprise at least one structuring polymer and at least one binding and / or intercalating polymer.

3. The composition according to claim 2, wherein the molecular weight of the structuring polymer is more than 100,000 g / mol, and the molecular weight of the at least one binding and / or intercalating polymer is 100,000 g / mol or less.

4. The composition according to any one of claims 1 to 3, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, carboxymethyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin.

5. The composition according to any one of claims 1 to 4, wherein the cladribine-cyclodextrin complex contains cladribine and cyclodextrin in a molar ratio of 1:1 to 1:9, preferably 1:1 to 1:

3.

6. The composition according to any one of claims 1 to 5, comprising the active ingredient, the at least two hydrophilic polymers, at least one surfactant and / or cosurfactant, and at least one plasticizer, and optionally further additives such as a taste masking agent, a flavoring agent, a solubilizing agent, a thickening agent, a coloring agent, an antioxidant, a pH adjuster, a vitamin, or a mixture thereof.

7. The hydrophilic polymer is selected from the group consisting of starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginate, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl, hydroxypropyl cellulose, cellulose acetate succinate, sodium carboxymethyl cellulose and other celluloses and cellulose derivatives (processed or unprocessed), pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and mixtures or combinations thereof, preferably selected from modified starch and pullulan, In particular, the structure-forming polymer is - consisting of starch (processed or unprocessed), dextrin, dextran, gelatin, glycogen, chitosan, xanthan gum, polymerized rosin, alginic acid and alginate, cellulose and cellulose derivatives; - polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and copolymers or block copolymers of these polymers, provided that the average molecular weight (MW) of these polymers is more than 100,000 g / mol; and - mixtures or combinations thereof selected from; The binding and / or insertable polymer is - A group comprising pullulan, maltodextrin, pectin, polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly(lactic acid-co-glycolic acid) (PLGA), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate); - Polyethylene oxide, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polyvinyl acetate phthalate, and copolymers or block copolymers of these polymers, provided that the average molecular weight (MW) of these polymers is less than 100,000 g / mol; and - Mixtures or combinations thereof selected from; - Provided that when two types belonging to the same polymer category are used as at least one structure-forming polymer and at least one binding and / or insertable polymer, the difference in MW between the two types is 20% or more, preferably 50% or more, particularly 100% or more, based on the binding / insertable polymer species with the lower MW. The composition according to any one of claims 1 to 6.

8. Comprising at least one structure-forming polymer as a hydrophilic polymer, preferably the structure-forming polymer is a starch polymer, particularly the starch polymer is selected from the starch of chestnut, aracaucha, barley, beans, breadnut, buckwheat, cassava, chickpea, chestnut, corn, lentil, millet, oat, pea, potato, rice, rye, sago palm, sorghum, sweet potato, tapioca, wheat, and combinations thereof, pregelatinized starch, hydroxypropyl starch or pregelatinized hydroxypropyl starch, hydroxypropyl pea starch, the starch may be pregelatinized, gelatinized, modified starch, or unmodified starch, the composition according to any one of claims 1 to 7.

9. Comprising at least one binding and / or inserting polymer as a hydrophilic polymer, said binding and / or inserting polymer being preferably selected from pullulan and / or polyethylene oxide, the composition according to any one of claims 1 to 8.

10. The at least two hydrophilic polymers are used in a ratio of the first hydrophilic polymer to the second hydrophilic polymer of 95:5 to 5:95 by weight, preferably 80:20 to 50:50 by weight, more preferably 70:30 to 60:40 by weight, and in particular, the first hydrophilic polymer is a structure-forming polymer and the second hydrophilic polymer is a binding and / or inserting polymer, the composition according to any one of claims 1 to 9.

11. The composition according to any one of claims 1 to 10, wherein cladribine is incorporated into 2-hydroxypropyl-β-cyclodextrin complex, hydroxypropyl pea starch, pullulan, glycerol, and optionally soy lecithin having 70% or more phosphatidylcholine and / or triacetin.

12. The composition according to any one of claims 1 to 11, wherein cladribine is present in an amount of 0.01% to 50% by weight, preferably 0.1% to 20% by weight, more preferably 1% to 10% by weight of the total composition.

13. The composition according to any one of claims 1 to 12, wherein cladribine is the only active ingredient.

14. The composition according to any one of claims 1 to 13, for use in the treatment of multiple sclerosis (MS), myasthenia gravis (MG), or neuromyelitis optica spectrum disorder (NMOSD).

15. A method for producing a transmucosal delivery composition in the form of a sublingual buccal dispersible film according to any one of claims 1 to 1 or the composition according to claim 14, wherein cladribine or a cladribine-cyclodextrin complex is mixed with a film-forming polymer by stirring at a temperature of 30 °C or higher at 100 rpm or higher for 10 minutes or longer.

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