RU2635769C1 - Drug based on 5-amino-2,3-dihydrophthalazine-1,4-dione as quick-soluble film for transbuccal introduction - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: drug in the form of easily soluble biocompatible film for transbuccal application includes a therapeutically effective amount of pharmacologically active agent, such as a salt of alkaline or alkaline-earth metal 5-amino-2.3-dihydrophthalazine-1.4-dione as a waterless salt or its monohydrate or dihydrate, or their mixtures, mucoadhesive film forming polymer plasticiser and taste flavour, represented by a mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol when their mass ratio of 4:1-1:2, the content of the specified mixture in the film is 15-40 wt % of the weight of the entire film.

EFFECT: increased release speed of the pharmacologically active agent when applying the film, increased transparency, uniformity and stability in storage while retaining elasticity and strength.

16 cl, 5 tbl

Description

The invention relates to the field of the pharmaceutical industry, namely to drugs that have immunomodulatory, anti-inflammatory, antitumor and antioxidant effects, with the form of delivery in the form of buccal films.

At the present stage of development of pharmaceutical science, the introduction of innovative methods of drug delivery is relevant. One of the promising directions in solving the problem of improving the bioavailability of drugs is the creation of instant dosage forms (tablets and films), the use of which is especially important in pediatrics and in people who have difficulty swallowing.

In this regard, in the 70s of the last century, the first studies began on the creation of instant tablets and capsules, which further facilitated the transition from simple tablets to modified-release capsules and quick-release tablets, and then to instant films (PDP).

PDUs were developed on the basis of technology of transdermal therapeutic systems and are thin films 1-20 cm in size (depending on the dose and concentration of the active substance) containing one or more active and auxiliary components (film-forming polymers, plasticizers, surfactants, flavoring agents taste and / or smell, stimulators of saliva production, etc.), which are placed on the mucous membrane of the oral cavity (cheek, palate) and during the dissolution process release active components. PDPs have several advantages compared to traditionally used oral drugs [Egorova A.S. and others. Instant films - an innovative method of drug delivery / Bulletin of RUDN, Medicine series, 2013, No. 3, p. 100-104]:

- rapid dissolution in the oral cavity with a small amount of saliva;

- no additional washing down with water and chewing;

- high permeability of the oral mucosa and a large area of interaction accelerate the flow of the drug directly into the bloodstream, bypassing the aggressive environment of the stomach and liver enzyme systems;

high bioavailability provides a rapid onset of therapeutic effect;

- the possibility of minimal dosing and the almost complete absence of side effects;

- the possibility of use in cases where the intake of syrups, tablets, suspensions and other forms is impossible due to the patient’s cough, problems with swallowing, allergic edema, vomiting, diarrhea;

- the possibility of use in pediatrics;

- exact dosage in each film in comparison with syrups and suspensions;

- local and resorptive effect in diseases of the oral cavity (teething, mucosal injury, herpes, etc.).

In addition to the advantages, there are also disadvantages of instant films: the high cost of packaging and the difficulty of incorporating large doses of a medicinal substance, as well as the difficulty in achieving the desired mechanical properties that contribute to the elimination of premature damage to the films when removed from the package and use.

Currently, instant films are widely used for buccal administration of various drugs.

So, in the prior art [patent RU 2109509 C1, publ. 04/27/1998] discloses a composition for buccal administration of a drug, including agar and sugar, consisting of lactose and / or mannitol. The source indicates that various active agents can be used as a medicine, for example, analgesics, hormone hypnotics, etc. However, specific examples of this patent describe films containing famotidine or formoterol fumarate as an active agent.

As the disadvantages of the films disclosed in the indicated source, their not quite sufficient disintegration (the dissolution rate of the films) is noted. Attempts to increase the dissolution rate of these films led to an increase in their fragility, which could negatively affect their premature damage during storage, removal from packaging, and use.

From the document [patent RU 2225705 C2, publ. 03/20/2004] an adhesive adhesive film with bilateral adhesion is known for fixing removable laminar dentures, including a drug, one or more water-soluble polymers, one or more plasticizers (not more than 10% by weight of the polymer), a partially soluble polymer compatible with the main one water-soluble polymer, in an amount of not more than 30%. As a medicine, Solcoseryl and Actovegin are used.

In the document [US 8475832 B2, publ. 07/02/2013] films for buccal administration are disclosed, including in a therapeutically effective amount a combination of active agents such as buprenorphine and naloxone (or their pharmaceutically acceptable salts), a polymer matrix and a buffer to create a local pH of 3.0-3.5, in the presence of saliva.

In addition, the prior art document is known [patent RU 2492854 C2, publ. 09/20/2013], in which the problem of creating instant films comprising a large proportion of active substances (at least 60 wt.% Of the dry film mass) is solved. These films include one or more active substances, at least one water-soluble polymer selected from pullulan, hydroxypropyl methylcellulose, polyvinylpyrrolidone and mixtures thereof in an amount of 12-18 wt. % by weight of dry film, and additional ingredients. As active substances, acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofert, flurbiprofen, indomethacin, ketoprofen, naproxen are considered. These films provide a sustained release of the active (s) agent (s).

However, the physicomechanical properties of the obtained films are not investigated in these documents.

Moreover, in the source [Sakipova Z.B. et al. Development of the composition and production technology of a buccal film with acetylsalicylic acid / Bulletin of KazNMU, 2013, No. 4 (1), p. 310-317] on the example of various compositions of buccal films with acetylsalicylic acid, it is revealed that their organoleptic (uniformity, transparency, absence of cracks and / or tears, etc.) and mechanical properties (elasticity, strength, etc.) can vary significantly depending on components included in the film. The specified parameters of the films are important because they largely determine their effectiveness, consumer quality and ease of use.

Also known from the prior art are solutions for increasing the uniformity and transparency of buccal films, for example, by incorporating β-cyclodextrin or modified β-cyclodextrin into the films.

From the literature [Beta-cyclodextrins as a tool for the solubilization of insoluble APS (BCS class II and class VI) / Pharmaceutical industry, 2015, No. 2, p. 52-56; patent application WO 2011101734 A2, publ. 08/25/2011] it is known that β-cyclodextrins, such as β-cyclodextrin (or native β-cyclodextrin) and modified β-cyclodextrins (methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin, β-cyclodextrin sodium sulfobutyl ether), are cyclic oligosaccharides that have an external hydrophilic surface and an internal hydrophobic cavity. Such a unique structure makes it possible to form inclusion complexes in which lipophilic (hydrophobic) substances enter the internal cavity of β-cyclodextrin without the formation of covalent bonds. As a result of this property, β-cyclodextrins are used in pharmaceutical formulations to increase the solubility of a substance in water; increasing chemical and physical stability; reduction of local toxic effects (with oral or local use); improve delivery to and through biological membranes, as well as to mask the taste and smell of the drug, as they are also flavor and / or odor correlators.

So, in the document [patent application US 20070292479 A1, publ. December 20, 2007] transmucosal buccal films are disclosed, including an active agent, a steroid hormone, and a film-forming polymer and cyclodextrin.

In the source [Mahesh A. et al. Development of Taste Masked Fast Disintegrating Films of Levocetirizine Dihydrochloride for Oral Use / Current Drug Delivery, 2010, V. 7, pp. 21-27] contemplated are the rapidly disintegrating films of levocetirizine dihydrochloride, including cyclodextrin, a water-soluble polymer (pullulan or Kollicoat IR, sweeteners (aspartame or sucrose) and a disintegrant (pregelatinized starch).

These sources demonstrate an increase in the solubility of the active agent, as a result of which the resulting films were transparent and uniform. However, the mechanical properties of the obtained films were in most cases unsatisfactory.

Thus, the research and development of drugs in the form of instant films for buccal administration, with acceptable and desirable organoleptic and physico-mechanical properties, is an urgent task for pharmacy, which will improve the quality, stability and effectiveness of such films.

The prior art known drug is a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione, having immunomodulating, anti-inflammatory, anti-tumor and antioxidant effects [patent RU 2163122 C1, publ. 02/20/2001; Patent RU 2169139 C1, publ. 06/20/2001; patent RU2211036 C2, publ. 08/27/2003].

The prior art also discloses the creation of biocompatible polymer films comprising, as a pharmacologically active agent, the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione (Galavit) [patent RU 2185807 C1, publ. 07.27.2002] or its combination with another active agent (lincomycin) [patent RU 2185806 C1, publ. July 27, 2002].

The disadvantages include the absence in these sources of experiments to study the release rate of the active agent, as well as the lack of data on the study of the organoleptic and physico-mechanical properties of these films and their storage stability, which makes it impossible to evaluate their effectiveness and quality.

The objective of the present invention is to provide a drug based on a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of a rapidly dissolving biocompatible film for buccal application, which has high efficiency, high organoleptic, physico-mechanical parameters and high storage stability.

The technical result of the present invention is to increase the release rate of the pharmacologically active agent when using films, as well as to increase the transparency, uniformity of the films and their stability during storage, while maintaining their elasticity and strength.

As a result of numerous studies, it was found that the achievement of high quality and efficacy films for buccal application based on an alkali or alkaline earth metal salt of 5-amino-2,3-dihydrophthalazine-1,4-dione is ensured by the inclusion of a mixture of β-cyclodextrin in the film or modified β-cyclodextrin with sorbitol at a certain mass ratio (4: 1-1: 2) and the content of the specified mixture in the film of 15-40 wt. % by weight of the entire film.

Thus, the above technical result is achieved by a new drug in the form of an instant biocompatible film for buccal administration, comprising a therapeutically effective amount of a pharmacologically active agent, such as a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of an anhydrous salt or its monohydrate or dihydrate or a mixture thereof, a film-forming mucoadhesive polymer, a plasticizer and flavor flavor, which use a mixture of β-qi clodextrin or modified β-cyclodextrin with sorbitol in their mass ratio of 4: 1-1: 2, while the content of the mixture in the film is 15-40 wt. % by weight of the entire film.

The proposed drug in the form of a film based on a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione has an immunomodulating, anti-inflammatory, anti-tumor and antioxidant effect.

In one embodiment, a pharmacologically active agent, such as an alkali or alkaline earth metal salt of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of an anhydrous salt or its monohydrate or dihydrate, can be used in combination with another pharmacologically active agent .

The amount of pharmacologically active agent, such as a salt of an alkali or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione, can be 5-50 wt. % by weight of the entire film.

As an additional active agent, immunomodulators, immunostimulants, antibiotics (for example, gramicidin, tyrocidin, bacitracin, tizotricin, polymyxins, cephalosporins, aminoglycosides, tetracyclines, macrolides, aminoglycoside, lincosamide, etc. are used, for example, antimicrobial, benzene, microbial, ethylbenzetonium chloride, cetyl pyridinium chloride, cetrimide, chlorhexidine salts, imidazolidinyl urea, metronidazole, etc.), anti-inflammatory drugs (benzidamine, sodium diclofenac, indium tatsin, ketoprofen, ketorolac, metamizole sodium, piroxicam and others.).

In the films of the present invention, film-forming mucoadhesive polymers and plasticizers can be used those that are widely used in the manufacture of films for buccal administration, for example, those described in the source [Patel Priti et al. A Review on Fast Dissolving Sublingual Film / Journal of Pharmaceutical Science and Bioscientific Research (JPSBR), 2015, V. 5, No. 3, pp. 279-285].

Namely, natural and synthetic polymers selected from pullulan, gelatin, modified starch, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and alginate can be used as the film-forming mucoadhesive polymer. Preferably, the amount of film-forming mucoadhesive polymer in the film is 15-40 wt. % by weight of the entire film.

As a plasticizer, glycerol, propylene glycol, castor oil, tributyl citrate, triethyl citrate, acetyl citrate, triacetin and mixtures thereof can be used. Preferably, the amount of plasticizer in the film is 4-10 wt. % by weight of the entire film.

In addition, the film may include additional excipients, such as stimulators of the production of saliva, flavorings, dyes or mixtures thereof in an amount of not more than 4 wt. % by weight of the entire film. For example, malic acid, citric acid, lactic acid, and ascorbic acid can be used as a stimulator of saliva production.

As the modified β-cyclodextrin, methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutyl ether of the sodium salt of β-cyclodextrin can be used.

In one preferred embodiment of the invention, the film comprises a mixture of hydroxypropyl β-cyclodextrin with sorbitol.

Preferred weight ratios of β-cyclodextrin or modified β-cyclodextrin to sorbitol in the film are 2: 1 or 1: 1.

The preferred content of a mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol in the film is 20-40 wt. %, even more preferred 25-35 wt. %

In addition, it is preferable that the film thickness is not more than 150 μm.

The present invention can be illustrated by the following examples.

The general procedure for preparing films for buccal administration based on an alkaline or alkaline earth metal salt of 5-amino-2,3-dihydrophthalazine-1,4-dione as a pharmacologically active agent: a measured amount of mucoadhesive film-forming polymer and plasticizer is dissolved in the required amount of water with stirring; the resulting solution, if necessary, incubated for some time (5-20 minutes) to remove air bubbles formed with stirring; add a measured amount of a pharmacologically active agent, β-cyclodextrin and sorbitol and, if necessary, other auxiliary ingredients (excipients) to the solution with slow stirring; carry out further slow mixing until a homogeneous dispersion or solution is obtained; further, if necessary, in some cases, flavoring may be added; after stopping the stirring, the solution, if necessary, is kept for some time (5-20 minutes) to remove air bubbles formed during stirring. The resulting mixture was poured into a Teflon or glass Petri dish and dried in an oven at a temperature of 40-50 ° C for 18-24 hours to obtain a dried film. The amounts of the starting ingredients in each case, based on the knowledge of a person skilled in the art, were selected and measured depending on the desired final quantitative composition of the film.

Qualitative and quantitative compositions of the obtained final films (weighing 200 mg) according to the present invention are presented in table 1 (examples 1-4 (P1-P4)), as well as in examples 5-13 (P5-P16).

Films were also prepared according to Example 2 (Table 1), with the difference that the lithium salt of 5-amino-2,3 was used as the active agent instead of the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione -dihydrophthalazine-1,4-dione (Example 5 (P5)) or the potassium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione (Example 6 (P6)).

In addition, films were prepared according to Example 2 (Table 1) with the difference that β-cyclodextrin (Example 7 (P7)) or methyl β-cyclodextrin (Example 8 (P8)) were used instead of hydroxypropyl β-cyclodextrin.

Films were also prepared according to Example 2 (Table 1), with the difference that hydroxypropyl cellulose (Example 9 (P9)), or polyvinylpyrrolidone (Example 10 (P10)), or polyvinyl alcohol (Example 10) was used as a mucoadhesive film-forming polymer. 11 (P11)), or sodium alginate (example 12 (P12)), or a mixture of pullulan and polyvinylpyrrolidone in their mass ratio 1: 1 (example 13 (P13)).

Films were also prepared according to Example 2 (Table 1), with the difference that glycerol (Example 14 (A14)) or triethyl citrate (Example 15 (A15)) was used as a plasticizer instead of propylene glycol.

A film was also prepared that included a combination of pharmacologically active agents: 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt and sodium diclofenac. The film was prepared in accordance with example 3 (table 1) with the difference that instead of 80 mg of the 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt, 55 mg of the 5-amino-2 sodium salt was included in the film, 3-dihydrophthalazine-1,4-dione and 25 mg of diclofenac sodium (Example 16 (P16)).

We studied the rate of release of the active agent from these films, as well as the organoleptic (uniformity, transparency, etc.), physicomechanical properties (strength, elasticity) of the obtained films and their stability during storage, and compared these parameters with the properties of the film based on sodium salt 5- amino-2,3-dihydrophthalazine-1,4-dione obtained in accordance with the document [patent RU 2185807 C1, publ. 07.27.2002] - comparative example 1 (SP1).

The release rate of the active agent ("dissolution test"). The solubility profile of the films was determined by sampling a pharmacologically active agent released from the film into a solvent (purified water t = 37 ° C) at frequently repeated times, such as 10 sec, 20 sec, 30 sec, 40 sec, 50 sec, 60 sec., 90 sec., 120 sec. The drug content in the samples was evaluated by HPLC and a solubility profile was made. The analysis was carried out until the film was completely dissolved.

The film thickness was evaluated using a Mitutoyo 547-401 thickness gauge with a resolution of 0.001 mm (1 μm).

The strength and elasticity of the films was measured using a texture analyzer (HD plus, Stable Micro System, Surrey, UK).

Organoleptic properties (transparency, uniformity, taste) were evaluated visually on a 3-point scale: 3 - transparent, homogeneous (absence of microcracks, tears and bubbles), pleasant to taste; 2 - slightly cloudy, microcracks are present, neutral in taste; 1 - cloudy, tears present, taste unpleasant. The uniformity index was also evaluated after bending the film.

The data obtained are summarized in tables 2 and 3.

The data in table 1 indicate a high dissolution rate of the films of the present invention and, as a consequence, a high release rate of the pharmacologically active agent. It should be noted that in almost all cases, more than 95% of the active agent is released within 30 seconds, for comparison, the dissolution rate of the film in comparative example 1 (SP1) is less than the claimed films, and more than 90% of the active agent is released in a longer time - 120 sec

The data presented in table 2 show high strength and elasticity parameters of the films for buccal administration obtained in the present invention. Moreover, for different films P1-P16, these parameters are comparable with each other. All organoleptic characteristics of these films have the highest score ("3"), which allows us to conclude that they are of high quality and satisfactory characteristics for the consumer. It is worth noting that the films of comparative example 1 had slightly lower strength and elasticity indicators (perhaps this is due to the fact that the thickness of these films is less), but low organoleptic parameters of the film (in particular, the uniformity of the films after bending) indicate that during storage, removal from packaging and use of such a film, damage may occur, which is not satisfactory to the consumer.

Determination of the stability of the films during storage was evaluated by the content of the pharmacologically active agent, as well as the presence of impurities. The resulting films were packaged in aluminum foil blisters ('Alu-Alu') and placed in a climate chamber for 6 months under accelerated and long-term (“real-time”) tests. The content of the pharmacologically active agent (salts of 5-amino-2,3-dihydrophthalazine-1,4-dione) and any impurities was determined by HPLC using standards.

It was found that after 1-2 years of storage of the films obtained in examples 1-16 (P1-P16), these films had almost equal stability indicators and remained chemically pure (the content of the pharmacologically active agent is the salt of 5-amino-2,3-dihydrophthalazine -1,4-dione decreased by no more than 0.1%, no impurities were present). The films obtained in accordance with comparative example 1 (SP1) remained chemically pure for 1 year, then the sodium salt content of 5-amino-2,3-dihydrophthalazine-1,4-dione decreased by more than 1.0%. Thus, the films obtained in accordance with the present invention are more stable.

Further, for a more obvious demonstration of the positive technical effects of the films obtained in accordance with the present invention, films were obtained (comparative examples 2-9 (SP2-SP9)), which are not included in the scope of the claims claimed in the present invention. The qualitative and quantitative composition of these films is presented in Table 4. For the 2-9 films obtained in comparative examples, their organoleptic and physicomechanical parameters were studied and compared with the film obtained in Example 2 (in accordance with the present invention) - these indicators are summarized to table 5.

According to table 5:

- the film according to comparative example 2, in which the mass ratio of hydroxypropyl β-cyclodextrin to sorbitol was 5: 1, shows a decrease in strength, elasticity and uniformity after bending;

- the film according to comparative example 3, in which the mass ratio of hydroxypropyl β-cyclodextrin to sorbitol was 1: 3, and the film according to comparative example 7, in which hydroxypropyl β-cyclodextrin is not included in the film, showed a decrease in all physical, mechanical and organoleptic parameters ;

- a film according to comparative example 4, in which the total amount of a mixture of hydroxypropyl β-cyclodextrin and sorbitol in the film is 14 wt. % (i.e., less than 15 wt.%), is characterized by a slight decrease in strength and elasticity, but its transparency, uniformity and uniformity after bending are not satisfactory;

- a film according to comparative example 5, in which, on the contrary, the total amount of a mixture of hydroxypropyl β-cyclodextrin and sorbitol in the film is 43 wt. % (i.e., more than 40 wt.%), is characterized by a significant decrease in elasticity and small changes in strength and uniformity after bending;

- in the film according to comparative example 6, in which sorbitol is not included in the composition of the film, there was a significant decrease in strength, elasticity and uniformity after bending;

- films according to comparative examples 8 and 9, in which sucrose or aspartame were used instead of sorbitol mixed with hydroxypropyl β-cyclodextrin, showed a significant decrease in strength, elasticity and uniformity after bending.

Thus, the data given in table 5 indicate that the choice in the present invention of a mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol at a certain ratio and the choice of the amount of this mixture in the film are not random, but are based on numerous studies of the parameters of films for buccal administration based on the salt of 5-amino-2,3-dihydrophthalazine-1,4-dione, and these distinctive features affect the achievement of positive technical effects. In addition, it is worth noting that the drugs of the present invention in the form of films for buccal administration (use) based on the salt of 5-amino-2,3-dihydrophthalazine-1,4-dione have high quality and satisfactory organoleptic and mechanical parameters for consumer.

Claims (16)

1. The drug is in the form of a rapidly dissolving biocompatible film for buccal administration comprising a therapeutically effective amount of a pharmacologically active agent, such as an alkali or alkaline earth metal salt of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of an anhydrous salt or its monohydrate or a dihydrate or mixtures thereof, a film-forming mucoadhesive polymer, a plasticizer and flavor flavor, characterized in that a mixture of β-cyclodextrin or a modified flavor is used as flavor flavor β-cyclodextrin or α- or γ-cyclodextrin or other cyclodextrins with sorbitol in their mass ratio of 4: 1-1: 2, while the content of this mixture in the film is 15-40 wt. % by weight of the entire film. 2. The drug according to claim 1, characterized in that it has immunomodulatory, anti-inflammatory, antitumor and antioxidant effects. 3. The drug according to claim 1, characterized in that a pharmacologically active agent, such as a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of an anhydrous salt or its monohydrate or dihydrate, can be used in combination with another pharmacologically active agent selected from an immunomodulator, immunostimulant, immunosuppressant, antibiotic, antimicrobial agent, anti-inflammatory, antiviral, analgesic, bactericidal, antifungal, narcotic, pro ivoparazitarnogo, antitumor, anthelminthic, anti-emetic, Organotropona, hormonal, metabolic, neurotropic, vegetable agents and biologically active component, a peptide, vitamins and trace elements. 4. The drug according to any one of paragraphs. 1-3, characterized in that the amount of pharmacologically active agent, such as a salt of an alkaline or alkaline earth metal of 5-amino-2,3-dihydrophthalazine-1,4-dione, can be 5-50 wt. % by weight of the entire film. 5. The drug according to any one of paragraphs. 1-3, characterized in that the modified β-cyclodextrin is selected from methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutyl ether sodium salt of β-cyclodextrin. 6. The drug according to any one of paragraphs. 1-3, characterized in that a mixture of hydroxypropyl β-cyclodextrin with sorbitol is used. 7. The drug according to any one of paragraphs. 1-3, characterized in that as the film-forming mucoadhesive polymer can be used natural and synthetic polymers selected from pullulan, gelatin, modified starch, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinylate and polyvinylamine. 8. The drug according to any one of paragraphs. 1-3, characterized in that the amount of film-forming mucoadhesive polymer in the film is 15-40 wt. % by weight of the entire film. 9. The drug according to any one of paragraphs. 1-3, characterized in that glycerol, propylene glycol, castor oil, tributyl citrate, triethyl citrate, acetyl citrate, triacetin and mixtures thereof can be used as plasticizer. 10. The drug according to any one of paragraphs. 1-3, characterized in that the amount of plasticizer in the film is 4-10 wt. % by weight of the entire film. 11. The drug according to any one of paragraphs. 1-3, characterized in that the film may include additional auxiliary substances, such as stimulators of the production of saliva, flavorings, dyes or mixtures thereof in an amount of not more than 4 wt. % by weight of the entire film. 12. The drug according to any one of paragraphs. 1-3, characterized in that the mass ratio of β-cyclodextrin or modified β-cyclodextrin to sorbitol in the film is 2: 1. 13. The drug according to any one of paragraphs. 1-3, characterized in that the mass ratio of β-cyclodextrin or modified β-cyclodextrin to sorbitol in the film is 1: 1. 14 The drug according to any one of paragraphs. 1-3, characterized in that the content of the mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol in the film is 20-40 wt. % 15. The drug according to any one of paragraphs. 1-3, characterized in that the content of the mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol in the film is 25-35 wt. % 16. The drug according to any one of paragraphs. 1-3, characterized in that the film thickness is not more than 150 microns.