EA037769B1 - Medicinal preparation based on 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of a fast-dissolving film for transbuccal administration - Google Patents

Abstract

The invention relates to the pharmaceutical industry, and specifically to a medicinal preparation in the form of a fast-dissolving biocompatible film for transbuccal use including a therapeutically effective amount of a pharmacologically active agent, such as an alkali salt or alkali earth metal salt of 5-amino-2,3-dihydrophthalazine-1,4-dione in the form of an anhydrous salt or a monohydrate or dihydrate thereof or a mixture thereof, a film-forming mucoadhesive polymer; a plasticizer; and a flavoring, for which a mixture of -cyclodextrin or modified -cyclodextrin with sorbitol in a weight ratio of 4:1-1:2 is used, the content of said mixture in the film constituting 15-40 wt.% of the weight of the entire film. The invention provides an increase in the rate of release of the pharmacologically active agent when the films are used, as well as increased transparency and uniformity of the films and their storage stability, while maintaining their elasticity and strength.

Description

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

At the present stage of development of pharmaceutical science, it is important to introduce innovative methods of drug delivery. One of the promising directions in solving the problem of improving the bioavailability of drugs is the creation of rapidly dissolving dosage forms (tablets and films), the use of which is especially important in pediatrics and in people with 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 subsequently contributed to the transition from simple tablets to modified-release capsules and fast-disintegrating tablets, and then to instant films (PRF).

BRPs were developed on the basis of the 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, flavors taste and / or odor, stimulants of saliva production, etc.), which are placed on the mucous membrane of the oral cavity (cheeks, palate) and in the process of dissolution release active components. BRP have a number of advantages over the traditionally used oral drugs [Egorova A.S. and others. Instant films - an innovative way of drug delivery / Bulletin of RUDN, Medicine series, 2013, No. 3, p.100-104]:

rapid dissolution in the mouth with a small amount of saliva;

additional drinking with water and chewing is not required;

high permeability of the oral mucosa and a large interaction area 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 quick onset of the therapeutic effect;

the possibility of minimal dosage and 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 presence of a cough, problems with swallowing, allergic edema, vomiting, diarrhea;

the possibility of using in pediatrics;

accurate dosing in each film compared to syrups and suspensions;

local and resorptive action in diseases of the oral cavity (teething, mucosal trauma, herpes, etc.).

In addition to the advantages, there are also disadvantages of instant films: the high cost of packaging and the difficulty of including large doses of the drug, as well as the difficulty in achieving the desired mechanical properties that help eliminate premature damage to the films during removal from the package and use.

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

So, in the prior art [patent RU 2109509 C1, publ. 04/27/1998] discloses a composition for buccal drug administration, comprising 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, hypnotics, hormonal, etc. However, in specific examples of this patent, films are described containing famotidine or formoterol fumarate as an active agent.

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

From the document [patent RU 2225705 C2, publ. 20.03.2004] known adhesive elastic film with double-sided adhesion for fixing removable plate prostheses, including a drug, one or more water-soluble polymers, one or more plasticizers (not more than 10% by weight of the polymer), partially water-soluble polymer, compatible with the base water-soluble polymer, in an amount of not more than 30%. Solcoseryl and Actovegin are used as a medicine.

In the document [US 8475832 B2, publ. 07/02/2013] discloses films for buccal administration, comprising 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 equal to 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], which solves the problem of creating fast-dissolving films, including a large proportion of active

- 1,037769 substances (at least 60 wt.% Of the dry film weight). 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% based on the dry film weight, and additional ingredients. As active substances, acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofert, flurbiprofen, indomethacin, ketoprofen, naproxen are considered. These films provide sustained release of the active agent (s).

However, these documents do not investigate the physical and mechanical properties of the resulting films.

At the same time, in the source [Sakipova Z.B. and others. Development of the composition and technology for the production of buccal films 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 ruptures, etc.) and mechanical properties (elasticity, strength, etc.) can vary significantly depending on the components included in the film. The specified parameters of the films are important, since 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 including β-cyclodextrin or modified β-cyclodextrin in the films.

From the literature [Beta-cyclodextrins as a tool for the solubilization of insoluble APIs (BCS class II and class VI) / Pharmaceutical industry, 2015, No. 2, p.52-56; patent application WO 2011101734 A2, publ. 25.08.2011] 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 sulfobutyl ether of sodium salt), are cyclic oligosaccharides, which have an external hydrophilic surface and an internal hydrophobic cavity. This unique structure allows the formation of 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; improving chemical and physical stability; reduction of local toxic effects (with oral or local application); improving delivery to and through biological membranes, as well as for masking the taste and odor of the drug, since they are also taste and / or odor corrigants.

So, in the document [patent application US 20070292479 A1, publ. 12/20/2007] discloses transmucosal buccal films, 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] discusses rapidly disintegrating films of levocetirizine dihydrochloride, also including cyclodextrin, a water-soluble polymer (pullulan or Kollicoat IR, sweeteners ( aspartame or sucrose) and disintegrant (pregelatinized starch).

In these sources, an increase in the solubility of the active agent is demonstrated, as a result of which the resulting films were transparent and uniform. However, the mechanical properties of the films obtained 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 physicomechanical properties is an urgent task of pharmacy, which will improve the quality, stability and effectiveness of such films.

From the prior art, a drug is known - a salt of an alkali or alkaline earth metal 5-amino-2,3-dihydrophthalazine-1,4-dione, which has immunomodulatory, anti-inflammatory, antitumor and antioxidant effects [patent RU 2163122 C1, publ. 02/20/2001; patent RU 2169139 C1, publ. 06/20/2001; patent RU2211036 C2, publ. 27.08.2003].

The prior art also discloses the creation of biocompatible polymer films, including as a pharmacologically active agent 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. 07/27/2002].

As disadvantages, we can note the absence in the indicated sources of experiments to study the rate of release of the active agent, as well as the lack of data on the study of the organoleptic and physicomechanical properties of these films and their stability during storage, which makes it impossible to assess their effectiveness and quality.

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

The technical result of the present invention is to increase the rate of release 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 efficiency of films for buccal application based on the 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 composition or modified β-cyclodextrin with sorbitol at a certain weight ratio (4: 1-1: 2) and the content of the specified mixture in the film 15-40 wt% based on the weight of the entire film.

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

Α- or γ-cyclodextrin or other cyclodextrins can also be used as a flavoring agent.

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

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 as an anhydrous salt or a monohydrate or dihydrate thereof can be used in combination with another pharmacologically active agent.

In another embodiment of the invention, the pharmacologically active agent is an immunosuppressant, antiviral, analgesic, bactericidal, antifungal, narcotic, antiparasitic, antihelminthic, antiemetic, organotropic, hormonal, metabolic, neurotropic, herbal agent and a biologically active component, peptide, vitamins and trace elements.

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

As an additional active agent, immunomodulators, immunostimulants, antibiotics (for example, gramicidin, thyrocidin, bacitracin, tizotricin, polymyxins, cephalosporins, aminoglycosides, tetracyclines, macrolides, aminoglycosides, lincosamides, ethylbenzethonium chloride, cetylpyridinium chloride, cetrimide, chlorhexidine salts, imidazolidinyl urea, metronidazole, etc.), anti-inflammatory drugs (benzydamine, sodium diclofenac, indomethacin, ketoprofen, ketorolac, sodium pyroxicamizole, dr.

In proposed in the present invention films as 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 their mixtures, sodium alginate can be used as a film-forming mucoadhesive polymer. Preferably, the amount of the film-forming mucoadhesive polymer in the film is 15-40% by weight of the total 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% by weight of the total film.

In addition, the film may include additional excipients such as saliva production stimulants, flavors, dyes, or mixtures thereof in an amount of not more than 4 wt% based on the weight of the entire film. For example, malic, citric, lactic, ascorbic acids can be used as a stimulant for the production of saliva.

- 3 037769

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

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

The 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 the mixture of β-cyclodextrin or modified β-cyclodextrin with sorbitol in the film is 20-40 wt%, even more preferably 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 alkali 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, is kept for some time (5-20 minutes) to remove air bubbles formed during 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; further slow mixing is carried out until a homogeneous dispersion or solution is obtained; further, if necessary, in some cases, a flavoring agent can be added; after stopping stirring, the solution, if necessary, is kept for some time (5-20 min) 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 metered depending on the required final quantitative composition of the film.

The qualitative and quantitative compositions of the resulting 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 (P5P16).

Table 1

Ingredients Example 1 (A1) Example 2 (P2) Example 3 (PP) Example 4 (A4) mg wt% mg wt% mg wt% mg wt% active agent - sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione twenty 10.0 fifty 25.0 80 40.0 100 50.0 mucoadhesive film-forming polymer - pullulan 80 40.0 60 30.0 44 22.0 30.0 15.0 propylene glycol plasticizer sixteen 8.0 eight 4.0 10 5.0 10.0 5.0 hydroxypropyl βcyclodextrin 26 13.0 40 20.0 44 22.0 48.0 24.0 sorbitol fifty 25.0 40 20.0 22 11.0 12.0 6.0 saliva production stimulant - citric acid eight 4.0 2 1.0 - - - - Amount: 200 100.0 200 100.0 100.0 200 100.0

We also obtained films in accordance with Example 2 (Table 1), with the difference that the 5-amino-2 lithium salt was used as an active agent instead of the sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione, 3-dihydrophthalazine-1,4-dione (example 5 (P5)), or the calcium salt of 5-amino-2,3 dihydrophthalazine-1,4-dione (example 6 (P6)).

In addition, films were obtained in accordance with 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.

We also obtained films in accordance with example 2 (Table 1), with the difference that hydroxypropyl cellulose (example 9 (P9)), or polyvinylpyrrolidone (example 10 (P10)), or polyvinyl alcohol ( example 11 (P11)), or sodium alginate (example 12 (P12)), or a mixture of pullulan and polyvinylpyrrolidone in their mass ratio of 1: 1 (example 13 (P13)).

We also obtained films in accordance with example 2 (table. 1) with the difference that glycerol (example 14 (P14)) or triethyl citrate (example 15 (P15)) was used as a plasticizer instead of propylene glycol.

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

- 4 037769 dione and 25 mg of sodium diclofenac (example 16 (P16)).

The rate of release of the active agent from these films, as well as the organoleptic (uniformity, transparency, etc.), physical and mechanical properties (strength, elasticity) of the obtained films and their storage stability were studied, and these parameters were compared with the properties of a 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).

Release rate of the active agent (dissolution test).

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

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

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

Organoleptic properties (transparency, uniformity, taste) were assessed visually on a 3-point scale: 3 - transparent, homogeneous (no microcracks, tears and bubbles), pleasant to the taste; 2 - slightly cloudy, there are microcracks, neutral in taste; 1 - cloudy, gaps are present, unpleasant in taste. The uniformity index was also evaluated after folding the film.

The data obtained are summarized in table. 2 and 3.

table 2

Solubility profile of films versus time% release of active agent

Time, sec 10 twenty thirty 40 fifty 60 90 120 film P1 40.3 78.5 97.2 98.1 98.9 99.6 99.7 99.7 film P2 40.1 73.2 96.7 97.8 98.5 99.1 99.4 99.6 PZ film 38.3 72.1 96.0 97.3 98.2 98.8 99.1 99.5 P4 film 35.2 70.6 94.3 98.7 96.8 98.0 99.0 99.5 P5 film 40.0 72.9 96.4 97.5 98.5 99.2 99.5 99.7 P6 film 39.4 72.5 95.7 97.0 98.2 99.0 99.4 99.4 P7 film 40.3 73.5 96.8 98.0 98.6 99.3 997 99.7 P8 film 40.2 73.3 97.0 97.9 98.7 99.4 99.5 99.5 P9 film 39.4 72.4 95.4 96.0 98.1 98.7 99.5 99.6 P10 film 40.0 73.1 97.0 98.4 98.9 99.3 99.4 99.5 P11 film 42.1 76.2 95.1 98.7 99.5 99.8 99.9 99.9 film P12 35.2 69.8 91.2 94.5 96.3 97.6 98.2 98.9 P13 film 31.5 67.2 95.0 97.2 99.0 99.6 99.8 99.9 film P14 40.0 72.5 95.3 97.8 98.9 99.3 99.5 99.6 film P15 40.5 73.0 95.1 97.5 98.6 99.1 99.4 99.7 P16 film 34.2 68.4 86.1 92.3 94.2 97.1 98.6 99.1 film SP1 21.3 46.2 68.2 81.5 86.7 90.2 92.5 93.9

Given in table. 1, the data indicate a high dissolution rate of the films according to the present invention, and, as a consequence, a high rate of release 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 s, for comparison - the dissolution rate of the film according to Comparative Example 1 (SP1) is less than that of the claimed films, and more than 90% of the active agent is released over a longer time - 120 s.

- 5 037769

Table 3

Physicomechanical and organoleptic properties of the films obtained

Film no. Film thickness, microns Tensile strength, N / mm ² Elasticity,% Transparency, score Uniformity, score Uniformity (after flexion), score Taste film W -115 18.2 ± 0D 67.8 ± 0.6 3 3 3 3 film P2 - 110 21.3 ± 1.3 69.3 ± 0D 3 3 3 3 PZ film - 105 20, H1.2 69.2 ± 0.6 3 3 3 3 P4 film - 105 17D ± 0.6 62, BUT, 5 3 3 3 3 P5 film - 115 20.9 ± 1.1 69, GCD 3 3 3 3 P6 film -115 22.4 ± 1.4 69.2 ± 0D 3 3 3 3 P7 film - BY 20.9 ± 1.1 68.9 ± 0D 3 3 3 3 P8 film - 110 21, H1.1 68.7 ± 0.6 3 3 3 3 P9 film - 100 17.3 ± 0.6 69.5 ± 0D 3 3 3 3 P10 film -95 19.6 ± 0.9 67.5 ± 0.6 3 3 3 3 film PN - 100 19.3 ± 0.8 66.2 ± 0.6 3 3 3 3 P12 film - BY 17.6 ± 0D 70, GCD 3 3 3 3 P13 film - 120 22.4 ± 1.2 69.6 ± 0.6 3 3 3 3 P14 film - 115 21.4 ± 1.2 69.2 ± 0.6 3 3 3 3 P15 film - BY 21.2 ± 1.1 69.3 ± 0.6 3 3 3 3 P16 film - 120 19.6 ± 0.8 65.6 ± 0.5 3 3 3 3 film SP1 -60 13, GCD 51, BUT, 5 one 2 one 3

Given in table. 2, the data demonstrates the 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 about their high quality and satisfactory characteristics for the consumer. It should be noted that the films according to 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), however, the low indicators of the organoleptic parameters of the film (especially the uniformity of the films after folding) indicate that that during storage, removal from packaging and use of such a film, it can be damaged, which is not satisfactory for the consumer.

Determination of the stability of the films during storage was assessed by the content of the pharmacologically active agent, as well as by the presence of impurities. The resulting films were packed in aluminum foil blisters ('Alu-Alu') and placed in a climate chamber for 6 months under accelerated and long-term (real-time) testing. The content of the pharmacologically active agent (5-amino-2,3-dihydrophthalazine-1,4-dione salt) 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 practically equivalent stability indicators and remained chemically pure (the content of the pharmacologically active agent - 5-amino-2,3-dihydrophthalazine salt -1,4-dione decreased by no more than 0.1%, no impurities were present). The films obtained in accordance with Comparative Example 1 (CP1) remained chemically pure for 1 year, then the content of sodium salt of 5-amino-2,3-dihydrophthalazine-1,4-dione decreased by more than 1.0%. Thus, films obtained in accordance with the present invention are more stable.

Further, to more clearly demonstrate the positive technical effects of films obtained in accordance with the present invention, films (comparative examples 2-9 (SP2-SP9)) were obtained, which are not included in the scope of the claimed in the present invention. The qualitative and quantitative composition of these films is presented in table. 4. For the films obtained in comparative examples 2-9, their organoleptic and physicomechanical indicators were examined and compared with the indicators of the film obtained in example 2 (in accordance with the present invention) - these indicators are summarized in table. five.

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Table 4

Ingredients, wt% film P2 film SP2 SDR film film SP4 film SP5 film SPb film SP7 film SP8 film SP9 active agent 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 mucoadhesive film-forming polymer - pullulan 30.0 28.0 30.0 43.0 27.0 30.0 30.0 30.0 30.0 propylene glycol plasticizer 4.0 4.0 4.0 10.0 4.0 4.0 4.0 4.0 4.0 hydroxypropyl βcyclodextrin 20.0 35.0 10.0 10.0 23.0 40.0 - 20.0 20.0 sorbitol 20.0 7.0 30.0 4.0 20.0 - 40.0 - - saliva stimulant citric acid 1.0 1.0 1.0 4.0 1.0 1.0 1.0 1.0 1.0 flavoring agent sucrose - - - 4.0 - - - 20.0 - flavoring agent aspartame - - - - - - - 20.0 Amount: | 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Table 5

Physicomechanical and organoleptic properties of films obtained in accordance with example 2 (P2) of the present invention and in accordance with _______ with comparative examples 2-9 (SP2-SP9) _____

Film no. Film thickness, microns Tensile strength, N / mm ² Elasticity,% Transparency, score Uniformity, score Uniformity (after flexion), score Taste film P1 ~ by 21.3 ± 1.3 69.3 ± 0.7 3 3 3 3 film SP2 ~ 109 12.1 ± 0.5 41.2 ± 0.4 3 2 one 3 SDR film -93 14.3 ± 0.6 41.3 ± 0.5 one 2 2 3 film SP4 - 122 18.3 ± 1.1 65.4 ± 0.6 one one one 2 film SP5 - 116 15.2 ± 0.8 31.2 ± 0.4 3 3 2 2 film SPb - 104 11.5 ± 0.5 37.2 ± 0.4 3 2 one 3 film SP7 ~ 95 10.2 ± 0.4 38.2 ± 0.4 one one one 3 film SP8 - 104 12.5 ± 0.5 32.7 ± 0.4 3 2 one 3 film SP9 - 108 11.8 ± 0.4 33.0 ± 0.5 3 2 one 3

According to the table. 5, the film of Comparative Example 2, in which the weight ratio of hydroxypropyl β-cyclodextrin to sorbitol was 5: 1, showed a decrease in strength, elasticity and uniformity after folding;

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

the film of Comparative Example 4, in which the total amount of the 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 indicators of transparency, uniformity and uniformity after flexion is unsatisfactory;

the film of Comparative Example 5, in which, on the contrary, the total amount of the 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 folding ;

in the film of Comparative Example 6, in which sorbitol was not included in the film, there was a significant decrease in strength, elasticity and uniformity after folding;

the films of Comparative Examples 8 and 9, in which sucrose or aspartame were used instead of sorbitol in admixture with hydroxypropyl β-cyclodextrin, respectively, showed a significant decrease in strength, elasticity and uniformity after folding.

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 oriented on the basis of numerous studies of the parameters of films for buccal administration based on salts of 5-amino-2,3-dihydrophthalazine-1,4-dione, and it is these distinctive features that influence the achievement of positive technical effects. In addition, it should be noted that the drugs of the present invention in the form of films for buccal administration

- 7 037769 (applications) based on 5-amino-2,3-dihydrophthalazine-1,4-dione salt have high quality and satisfactory organoleptic and mechanical parameters for the consumer.

Claims (16)

CLAIM 1. A medicinal preparation in the form of a rapidly dissolving biocompatible film for buccal use, comprising a therapeutically effective amount of a pharmacologically active agent, which is a salt of an alkali or alkaline earth metal 5-amino-2,3 dihydrophthalazine-1,4-dione in the form of an anhydrous salt or its monohydrate or dihydrate or mixtures thereof, a film-forming mucoadhesive polymer, a plasticizer and a flavoring agent, characterized in that a mixture of β-cyclodextrin or modified β-cyclodextrin or α- or γ-cyclodextrin or other cyclodextrins with sorbitol is used as a flavoring agent at a weight ratio of 4: 1-1 : 2, while the content of the specified mixture in the film is 15-40 wt.% By weight of the entire film. 2. A medicinal preparation according to claim 1, characterized in that it has immunomodulatory, anti-inflammatory, antitumor and antioxidant effects. 3. A medicinal preparation according to claim 1, characterized in that the pharmacologically active agent, which is a salt of an alkali or alkaline earth metal 5-amino-2,3-dihydrophthalazine 1,4-dione in the form of an anhydrous salt or its monohydrate or dihydrate, is used in combination with another pharmacologically active agent selected from an immunomodulator, an immunostimulant, an immunosuppressant, an antibiotic, an antimicrobial agent, an anti-inflammatory, antiviral, analgesic, bactericidal, antifungal, narcotic, antiparasitic, antitumor, antihelminthic, antiemetic agent biologically active component, peptide, vitamins and microelements. 4. A medicinal preparation according to any one of claims 1 to 3, characterized in that the amount of a pharmacologically active agent, which is a salt of an alkali or alkaline earth metal 5amino-2,3-dihydrophthalazine-1,4-dione, is 5-50 wt% from the mass of the entire film. 5. A medicinal preparation according to any one of claims 1 to 3, characterized in that the modified β-cyclodextrin is selected from methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutyl ester of the sodium salt of β-cyclodextrin. 6. A medicinal preparation according to any one of claims 1 to 3, characterized in that a mixture of hydroxypropyl β-cyclodextrin with sorbitol is used. 7. A medicinal preparation according to any one of claims 1 to 3, characterized in that natural and synthetic polymers selected from pullulan, gelatin, modified starch, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolysis are used as a film-forming mucoadhesive polymer sodium alginate; and mixtures thereof. 8. A medicinal preparation according to any one of claims 1 to 3, characterized in that the amount of the film-forming mucoadhesive polymer in the film is 15-40 wt% based on the weight of the entire film. 9. A medicinal preparation according to any one of claims 1 to 3, characterized in that glycerol, propylene glycol, castor oil, tributyl citrate, triethyl citrate, acetyl citrate, triacetin and mixtures thereof are used as the plasticizer. 10. A medicinal preparation according to any one of claims 1 to 3, characterized in that the amount of plasticizer in the film is 4-10 wt% based on the weight of the entire film. 11. A medicinal preparation according to any one of claims 1 to 3, characterized in that the film includes additional auxiliary substances, preferably saliva production stimulants, flavors, dyes or mixtures thereof in an amount of not more than 4 wt% based on the weight of the entire film. 12. A medicinal preparation according to any one of claims 1 to 3, characterized in that the weight ratio of β-cyclodextrin or modified β-cyclodextrin to sorbitol in the film is 2: 1. 13. A medicinal preparation according to any one of claims 1 to 3, characterized in that the weight ratio of β-cyclodextrin or modified β-cyclodextrin to sorbitol in the film is 1: 1. 14. A medicinal preparation according to any one of claims 1 to 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. A medicinal preparation according to any one of claims 1 to 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. A medicinal preparation according to any one of claims 1 to 3, characterized in that the film thickness is not more than 150 microns.