Sublingual dispersible film for pain relief

Abstract

FIELD: pharmaceuticals.SUBSTANCE: sublingual dispersible film for pain relief. The proposed film comprises 15.0–20.0 wt.% ketorolac as an active substance, 55.0–70.0 wt.% pullulan as a water-based film-forming agent, 2.0–3.0 wt.% ondansetron or tropisetron as an antiemetic, 3.0–5.0 wt.% permeation enhancer and 10.0–12.0 wt.% sweetener or sweetener with flavoring, wherein the average particle size of ketorolac is 150–350 nm.EFFECT: increase in the effectiveness and speed of onset of the analgesic effect, as well as an increase in the duration of the analgesic effect and the absence of an irritating effect on the gastrointestinal tract.3 cl, 5 ex

Description

[0001] The invention relates to the pharmaceutical industry, in particular to medicinal products in the form of sublingual dispersible films, and can be used in medicine for the relief of acute pain of moderate and severe intensity.

[0002] Various oral medications for pain relief are available, including tablets and film-dispersible tablets. Disadvantages of oral medications in tablet form include a relatively slow onset of action (30-60 minutes), irritating effects on the gastrointestinal (GI) mucosa, and the risk of developing NSAID-induced gastropathy with long-term use.

[0003] Orally dispersible films containing various active substances, including ketorolac, are also known.

[0004] For example, an orally disintegrating film composition is known (US application No. 2024180821, published 06.06.2024, IPC A61K 9 / 00), including the following components, mass %: ketorolac as an active substance 10-20%; sucralose 0.33-4%; silicified microcrystalline cellulose 1-20%; hydroxypropyl beta-cyclodextrin 0.1-10%; ammonium glycyrrhizinate 0.33-4%; xylitol 0.33-4%; hydroxypropyl methylcellulose 10-25%; glycerin 0.1-10%; flavoring agent 2.5-10%; cooling agent flavoring agent 2.5-10%; sodium carbonate 0.05-5%; citric acid 0.05-5%; dye 0.001-0.1%; purified water - the rest up to 100%.

[0005] Or a sublingual film with ketorolac is known (CN patent No. 118903063, published on 08.11.2024, IPC A61K 31 / 407), containing the following components, by weight %: 10-50 ketorolac tromethamine; 24-75 polymer film-forming material; 1-13.2 surfactant; 3.8-24 thickener; 3-8 biological glue. In this case, the polymer film-forming material contains the main film-forming material pullulan and an auxiliary film-forming material. The mass ratio of the main film-forming material pullulan to the auxiliary film-forming material is (1:2) - (2:1), and the mass ratio of the polymer film-forming material to the biological glue is (25:1) - (3:1).

[0006] Also known is a sublingual dispersible film for pain relief (application WO No. 2016151461, published on September 29, 2016, IPC A61K 31 / 00), comprising ketorolac as an active substance and pharmaceutically acceptable excipients with a diffusion flow of about 10-1 μg / cm 2 / min. The ketorolac mass may comprise 2-10 mg of the total mass of the sublingual film. Pharmaceutically acceptable excipients may include water-soluble polymer components with at least one water-soluble polymer selected from maltodextrin, hydroxypropyl methylcellulose, and polyethylene oxide.

[0007] The disadvantages of the above-mentioned and other known sublingual films containing ketorolac as the active ingredient include the insufficient onset and effectiveness of the analgesic effect and the inability to effectively mask the strong bitter taste of ketorolac, which leads to a gag reflex and low compliance. Furthermore, known sublingual films can provide rapid, but only short-term, release and do not address the need for prolonged action.

[0008] There is a need to obtain a highly effective medicinal product (drug) that allows for quick and reliable pain relief, does not irritate the gastrointestinal tract and has a prolonged effect.

[0009] The technical result of the claimed invention is to increase the effectiveness and speed of onset of the analgesic effect of the sublingual dispersible film, as well as to increase the duration of the analgesic effect and the absence of the irritating effect of the sublingual dispersible film on the gastrointestinal tract.

[0010] The claimed technical result is achieved in that the sublingual dispersible film for pain relief includes ketorolac as an active substance, pullulan as a water-based film-forming agent, ondansetron or tropisetron as an antiemetic, a permeability enhancer and a sweetener or a sweetener with a flavoring agent as pharmaceutically acceptable excipients in the following ratio of components, mass%:

[0011] - ketorolac 15,0-20,0 - pullulan 55,0-65,0 - permeability enhancer 3,0-5,0 - sweetener or sweetener with flavoring 10,0-12,0 - ondansetron or tropisetron 2,0-3,0,

[0012] while the average particle size of ketorolac is 150-350 nm.

[0013] The permeation enhancer is sodium glycocholate or polysorbate 80.

[0014] The sweetener is mannitol or xylitol.

[0015] The proposed sublingual dispersible film is intended for the relief of shock pain syndrome, local anesthesia during dental procedures, as well as in other cases for the rapid relief of headaches, toothaches or muscle pain and other acute conditions.

[0016] Sublingual dispersible film can also be used in cases where it is difficult to take tablets or injections are not possible.

[0017] Increasing the effectiveness and speed of onset of the analgesic effect of the sublingual dispersible film (medicinal product) is achieved through the use of the nanosized state of the active substance (ketarolac) in the stated percentage ratio and ensuring increased bioavailability, including through the inclusion of a permeability enhancer in the composition of the sublicensed film - the analgesic effect of the declared product occurs in less than 2 minutes after the start of its use.

[0018] The increase in the duration of the analgesic effect of the sublingual dispersible film (more than 6 hours from the start of its use) is ensured by the prolonged effect due to the controlled release of the active substance (ketorolac).

[0019] The absence of an irritating effect of the sublingual dispersible film on the gastrointestinal tract is ensured by minimizing the overall toxicity and danger of the film, as well as the inclusion of an antiemetic in its composition, designed to suppress or reduce the gag reflex.

[0020] The sublingual dispersible film can have a total weight of 150-200mg and the dimensions are length 10-20mm, width 10-20mm, convenient for placement in the oral cavity.

[0021] The active substance used in the claimed solution is ketorolac, which belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) that have a pronounced analgesic (pain-relieving) effect, with anti-inflammatory and moderate antipyretic effects.

[0022] The ketorolac content of the sublingual dispersible film is 15.0-20.0% by weight, providing an effective therapeutic dose of analgesia with a single application. This range was chosen because using ketorolac in amounts less than 15.0% by weight does not provide a sufficient analgesic effect, while using ketorolac in amounts greater than 20.0% by weight increases the risk of gastrointestinal mucosal irritation and reduces the mechanical properties of the sublingual film (fragility).

[0023] The inclusion of ketorolac with an average particle size of 150-350 nm is due to the fact that when using ketorolac with an average particle size of less than 150 nm, the active substance enters the bloodstream so quickly that the time of the prolonged effect of the drug is reduced, and when using ketorolac with an average particle size of more than 350 nm, the particles of the active substance are released more slowly and can be washed away by saliva, which does not allow the drug to perform the main function of pain relief.

[0024] The mass of ketorolac should not exceed 30 mg of the total mass (150-200 mg) of the sublingual dispersible film.

[0025] A water-based film-forming agent (film former) is designed to form a strong and simultaneously rapidly dispersible (fast-dissolving) base. In addition, the presence of a film-forming agent improves the viscosity and stability of the film and ensures controlled release of the active substance (ketorolac). The mass fraction of a water-based film-forming agent in the sublingual dispersible film is 55.0-65.0 wt.%, which is due to the fact that at a content below 55.0 wt.%, the resulting sublingual film becomes too thin and brittle, and at a content above 65.0 wt.%, the sublingual film is too dense and dissolves slowly during use.

[0026] Natural water-soluble polysaccharides such as pullulan can be used as a water-based film-forming agent, which has the ability to form a film, retain moisture, provide antioxidant protection and serve as a thickener.

[0027] A mixture of pullulan (the primary film-forming agent) and methacrylic acid copolymer (an auxiliary film-forming agent) can also be used as a water-based film-forming agent. This improves the viscosity, stability of the sublingual film, and controllability of the active substance (ketorolac) release. To ensure optimal physicochemical parameters of the film-forming agent, the ratio of these components is: pullulan 40.0-52.0 wt.% and methacrylic acid copolymer 13.0-15.0 wt.%.

[0028] The percentage ratio of ketorolac to the water-based film-forming agent is 21.5-36.4% by weight and is due to the fact that when the ratio of these components is less than 21.5% by weight, the release of particles on the gastrointestinal mucosa is slow and does not achieve the desired result, the analgesic effect of the sublingual dispersible film is reduced, and more than 36.4% by weight - an increased concentration of released particles can cause irritation of the gastrointestinal mucosa, and also contribute to an increase in the gag reflex.

[0029] The presence of a permeation enhancer in the sublingual dispersible film increases the permeability of the active substance (ketorolac) through the gastrointestinal mucosa, contributing, among other things, to improved bioavailability of the sublingual film. The permeation enhancer content in the sublingual dispersible film is 3.0-5.0% by weight, as its content below 3.0% by weight reduces the permeability of the active substance, while its content above 5.0% by weight may cause irritation of the gastrointestinal mucosa and alter the organoleptic properties of the sublingual film.

[0030] Surfactants such as sodium glycocholate or polysorbate 80 can be used as a permeation enhancer.

[0031] The inclusion of a sweetener or a sweetener together with a flavoring agent in the sublingual dispersible film allows for complete masking of the bitter taste of ketorolac, improves the plasticity and solubility of the sublingual film, and gives it the desired aromatic taste.

[0032] The mass fraction of the sweetener or sweetener with flavoring in the sublingual dispersible film is 10.0-12.0 wt.%. When using a sweetener or sweetener with flavoring in the composition of the proposed product in an amount of less than 10 wt.%, complete masking of the bitter taste of ketorolac is not ensured, and the resulting sublingual film becomes hard and brittle, and when using more than 12 wt.%, the sublingual film may have a cloying taste, and it turns out sticky or too soft.

[0033] A natural sweetener such as mannitol or xylitol can be used as a sweetener.

[0034] For example, natural flavoring based on concentrated juice can be used as a flavoring agent.

[0035] A combination of these two components in various combinations can be used as a sweetener with flavoring.

[0036] The presence of an antiemetic in the sublingual dispersible film prevents the occurrence of emesis. The mass fraction of antiemetic in the sublingual dispersible film is 2.0-3.0% by weight. If the antiemetic content is less than 2.0% by weight, the antiemetic effect is insufficient, and if it is above 3.0% by weight, there is a risk of side effects and the solubility of the sublingual film is impaired.

[0037] Ondansetron or tropisetron can be used as an antiemetic.

[0038] The method for producing the claimed sublingual dispersible film for pain relief is carried out as follows.

[0039] In the first step, pharmaceutical excipients - aqueous film-forming agent (water-soluble polymer, such as pullulan), permeation enhancer (such as sodium glycocholate), sweetener (such as mannitol) or sweetener with flavoring and antiemetic (such as ondansetron) - are thoroughly mixed using ultrasonic dispersion method or by high-speed mixing until a homogeneous mixture is obtained, which is necessary to ensure uniform distribution of the active substance (ketorolac) in the next step and increase its solubility.

[0040] In the second step, the active substance (ketorolac) is added to the resulting homogeneous mixture and mixed again using ultrasonic dispersion at room temperature (20-25°C). Temperature and mixing parameters are controlled (frequency 20 kHz, amplitude 60%, time 10-20 minutes). This allows the agglomerates to be reduced to the nanoscale without further fragmentation and prevents polymer (pullulan) denaturation. Humidity in the mixing room is maintained at 40-60%.

[0041] In the third stage, the resulting mixture is poured into a suitable mold to form the film blank and dried in a drying chamber at a temperature of 40-50°C. Low relative humidity is maintained in the drying chamber—approximately 20-30%—to ensure effective moisture removal. Drying time is up to 6 hours or more, depending on the required film blank thickness. For example, to produce a film blank up to 100 microns thick, the drying time is 2 to 3 hours.

[0042] In the fourth step, the film blank is cut into sections using laser cutting or mechanical cutters to produce finished sublingual dispersible films, each corresponding to a single dose (e.g., 200 mg sublingual films containing 30 mg ketorol). The film blank cutting process is controlled to ensure uniformly cut sections corresponding to each single dose of the drug.

[0043] In the fifth step, the finished sublingual dispersible films are placed in a sealed package, for example, in aluminum foil laminated with plastic (PVC / PVDC / aluminum), to prevent exposure to moisture and light, which can negatively affect the stability of the resulting drug.

[0044] Below are examples of obtaining a sublingual dispersible film for pain relief with different ratios of its components in the composition.

[0045] Example 1

[0046] The sublingual dispersible film for pain relief was prepared by the above method to obtain the following component ratio, mass %:

[0047] - ketorolac 16,0 - water-based film-forming agent 73,0 - permeability enhancer 3,0 - sweetener or sweetener with flavoring 5,0 - antiemetic 3,0

[0048] The average particle size of ketorolac is 250 nm.

[0049] The percentage of ketorolac to water-based film-forming agent is 21.9%.

[0050] The total mass of the sublingual dispersible film sample is 150mg.

[0051] As a result of the studies of the obtained sample of sublingual dispersible film, an increase in the time of onset of the therapeutic effect (analgesic effect) was revealed.

[0052] Example 2

[0053] The sublingual dispersible film for pain relief was prepared by the above method to obtain the following component ratio, mass %:

[0054] - ketorolac 13,0 - water-based film-forming agent 68,0 - permeability enhancer 4,0 - sweetener or sweetener with flavoring 12,0 - antiemetic 3,0

[0055] The average particle size of ketorolac is 300nm.

[0056] The percentage of ketorolac to water-based film-forming agent is 19.1%.

[0057] The total mass of the sublingual dispersible film sample is 200 mg.

[0058] As a result of the studies of the obtained sample of sublingual dispersible film, the ineffectiveness of the analgesic effect was revealed, which will lead to the absence of the desired analgesic effect when using such a film and can be critical when providing emergency care to a person.

[0059] Example 3

[0060] The sublingual dispersible film for pain relief was prepared by the above method to obtain the following component ratio, mass %:

[0061] - ketorolac 14 - water-based film-forming agent 69,0 - permeability enhancer 4,0 - sweetener or sweetener with flavoring 10,0 - antiemetic 3,0

[0062] The average particle size of ketorolac is 380nm.

[0063] The percentage of ketorolac to water-based film-forming agent is 20.3%.

[0064] The total mass of the sublingual dispersible film sample is 190 mg.

[0065] As a result of the studies of the obtained sample of sublingual dispersible film, it was found that the release of ketorolac particles on the mucous membrane occurs slowly and the likelihood of the active substance entering the gastrointestinal tract increases (before the onset of the analgesic effect).

[0066] Example 4

[0067] The sublingual dispersible film for pain relief was prepared by the above method to obtain the following component ratio, mass %:

[0068] - ketorolac 9,0 - water-based film-forming agent 74,0 - permeability enhancer 3,0 - sweetener or sweetener with flavoring 10,0 - antiemetic 3,0

[0069] The average particle size of ketorolac is 200 nm.

[0070] The percentage of ketorolac to water-based film-forming agent is 12.2%.

[0071] The total mass of the sublingual dispersible film sample is 150 mg.

[0072] As a result of the studies of the obtained sample of sublingual dispersible film, it was found that the analgesic effect was not achieved.

[0073] Example 5

[0074] The sublingual dispersible film for pain relief was manufactured by the above method to obtain the following ratio of the declared components, mass %:

[0075] - ketorolac 20,0 - water-based film-forming agent 65,0 - permeability enhancer 3,0 - sweetener or sweetener with flavoring 10,0 - antiemetic 2,0

[0076] The average particle size of ketorolac is 250nm.

[0077] The percentage of ketorolac to water-based film-forming agent is 30.7%.

[0078] The total mass of the sublingual dispersible film sample is 150 mg.

[0079] As a result of the studies of the obtained sample of sublingual dispersible film, it was found that this film has good mechanical strength and flexibility, has a fast, effective and long-lasting analgesic effect, while not having an irritating effect on the gastrointestinal tract.

[0080] From the above examples, it follows that only the use of the stated ratio of components allows one to obtain a sublingual dispersible film with the required physicochemical properties and taste qualities, easy to use and with an effective analgesic effect.

[0081] Thus, it can be concluded that the declared sublingual dispersible film allows for quick and reliable pain relief, does not irritate the gastrointestinal tract and has a prolonged effect.

Claims

1. A sublingual dispersible film for pain relief, comprising ketorolac as an active substance, pullulan as a water-based film-forming agent, ondansetron or tropisetron as an antiemetic, a permeation enhancer and a sweetener or a sweetener with a flavoring agent as pharmaceutically acceptable excipients in the following ratio of components, wt.%: - ketorolac 15,0-20,0 - pullulan 55,0-70,0 - permeability enhancer 3,0-5,0 - sweetener or sweetener with flavoring 10,0-12,0 - ondansetron or tropisetron 2,0-3,0, The average particle size of ketorolac is 150-350 nm.

2. A sublingual dispersible film according to claim 1, characterized in that the permeation enhancer is sodium glycocholate or polysorbate 80.

3. A sublingual dispersible film according to claim 1, characterized in that the sweetener is mannitol or xylitol.