Orally disintegrating film formulation containing naratriptan

Abstract

The present invention relates to an orally disintegrating film preparation comprising naratriptan or a pharma- ceutically acceptable salt thereof, and more particularly to an orally disintegrating film preparation comprising naratriptan or a pharma- ceutically acceptable salt thereof and a buffering agent.

Description

[Technical Field]

[0001] The present invention relates to an orally disintegrating film formulation comprising naratriptan or a pharmaceutically acceptable salt thereof, and more particularly to an orally disintegrating film formulation comprising naratriptan or a pharmaceutically acceptable salt thereof and a buffering agent. [Background technology]

[0002] Migraine is a type of headache caused by dysfunction of the brain, cranial nerves, and cerebrovascular system. It can occur at any age, but first appears in people in their teens and twenties, and is most common in people in their forties and fifties. In Korea, it is a very common disease, affecting 9% of women and 3% of men.

[0003] Although the mechanism of migraine onset has not yet been clearly elucidated, neurotransmitters such as serotonin, dopamine, and glutamate are thought to play an important role. Therefore, triptan compounds that act specifically on serotonin receptors have attracted attention.

[0004] Triptan compounds selectively bind to serotonin 5-HT1B and 5-HT1D receptors on cranial blood vessels, causing cerebral vasoconstriction and subsequently inhibiting the release of pro-inflammatory neuropeptides.

[0005] Conventional triptan compounds are taken as oral tablets with water, but this can be difficult for patients and children to swallow. To overcome this problem, orally disintegrating tablets (ODTs) have been developed in recent years, which can be rapidly disintegrated in the oral cavity and swallowed without water (Patent Documents 1 and 2). However, although orally disintegrating tablets are easier to take than tablets, they are prone to breakage due to their low hardness, and are difficult to carry due to the increased bulk caused by excipients. Furthermore, the use of large amounts of excipients can cause a foreign body sensation in the oral cavity.

[0006] To overcome these drawbacks of orally disintegrating tablets, film-type formulations have recently been developed that reduce the bulk and volume of excipients. Orally disintegrating films (ODFs) are thin and flexible, making them easy to carry and less likely to break. Furthermore, their film-like shape with a large surface area and short disintegration time masks the foreign body sensation in the mouth and the bitter taste of the drug.

[0007] However, in the case of orally disintegrating films, the mixture of the drug, film-forming base, and other additives must maintain a certain viscosity, and to maintain viscosity, the amount of water or organic solvent is limited. Therefore, some poorly soluble or water-insoluble drugs are not suitable for orally disintegrating films. In particular, active ingredients such as triptans are unstable to temperature and humidity, making them difficult to prepare as orally disintegrating film formulations.

[0008] Therefore, the present inventors developed an excellent film preparation in which the active ingredient such as triptan is stably maintained, the active ingredient is rapidly released upon disintegration in the oral cavity, and the medicinal effect is exerted, and side effects such as precipitation do not occur even during storage of the film preparation, leading to the completion of the present invention. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Korean Patent Registration No. 10-1626873 [Patent Document 2] Korean Patent Publication No. 10-2001-0107754 Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention relates to an orally disintegrating film formulation which can be taken without water and which improves the convenience of taking medication compared to general oral administration formulations, and a further object of the present invention is to provide an orally disintegrating film formulation which has improved pharmaceutical properties such as stability and dissolution rate compared to conventionally known orally disintegrating formulations. [Means for solving the problem]

[0011] To achieve the above object, the present invention provides an orally disintegrating film formulation comprising naratriptan, sumatriptan, eletriptan, frovatriptan, almotriptan, zolmitriptan, rizatriptan, or a salt thereof as an active ingredient, and a buffering agent.

[0012] In one embodiment, the orally disintegrating film formulation may be characterized in that the active ingredient is naratriptan.

[0013] In one embodiment, the formulation may be an orally disintegrating film formulation characterized in that, during a dissolution test, 85% or more of the active ingredient is dissolved within 5 minutes, more preferably 90% or more, and most preferably 95% or more.

[0014] The buffering agent may be, but is not limited to, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, malic acid, monosodium glutamate, glycine, sodium carbonate, maleic acid, sodium lactate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, or mixtures thereof.

[0015] In one embodiment, the buffering agent may comprise a mixture of citric acid and sodium citrate, and may be present in an amount of 0.1 to 2.0% by weight based on the total weight of the film solids.

[0016] In one embodiment, the buffer may contain 0.1 to 2.0% by weight of sodium citrate and 0.01 to 0.1% by weight of citric acid relative to the total weight of the film solid content.

[0017] The "total weight of film solids" refers to the sum of the weights of solid components in the film preparation, such as surfactants, binders, plasticizers, disintegrants, sweeteners, flavoring agents, and colorants, excluding solvents.

[0018] The present invention provides an orally disintegrating film formulation that, in an accelerated stability test, has a total soft matter content of less than 3%, more preferably less than 2%, and most preferably less than 1% after 6 months.

[0019] In one embodiment, the formulation may further comprise a film-forming agent, which may be, but is not limited to, flurane, sodium alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof, preferably hydroxypropyl methylcellulose.

[0020] Furthermore, the present invention provides a method for producing an orally disintegrating film formulation containing naratriptan, sumatriptan, eletriptan, frovatriptan, almotriptan, zolmitriptan, rizatriptan, or a salt thereof as an active ingredient, the method comprising the steps of: (A) adding a buffering agent to a solvent to adjust the pH of the mixture to pH 5.4 to 7.4; (B) adding an active ingredient, a film-forming agent, and an additive to the pH-adjusted mixture and stirring the mixture to prepare a final mixture; and (C) applying heat to the final mixture to dry it, thereby producing a thin film.

[0021] In one embodiment, the solvent may be water, a C1-C6 alcohol, or a mixed solvent thereof, preferably a 30 to 90% aqueous ethanol solution, and more preferably a 50 to 80% aqueous ethanol solution, but is not limited thereto.

[0022] The orally disintegrating film formulation of the present invention can be used for the treatment or prevention of migraine.

[0023] The orally disintegrating film formulation of the present invention can be administered simultaneously with or at an interval from other formulations containing topiramate as an active ingredient.

[0024] Furthermore, when the orally disintegrating film of the present invention containing 2.5 mg of naratriptan as an active ingredient is administered to a beagle dog, the AUC may be 150 to 250 ng·hr / mL and the Cmax may be 30 to 60 ng / mL. [Effects of the Invention]

[0025] The orally disintegrating film formulation containing naratriptan of the present invention disintegrates rapidly in the oral cavity, allowing for rapid onset of medicinal efficacy and maintaining stability even in long-term (6 months or more) accelerated testing. Therefore, patients suffering from migraine can take it without water, improving convenience of administration and making it easy to carry so that it can be taken immediately when symptoms appear, making it useful for patients. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a graph showing the dissolution rate of the naratriptan film formulation of Example 1 as a function of pH. [Figure 2] FIG. 1 shows the results of an accelerated test of a control drug (Naramig tablets) and the film formulation of Example 1. [Figure 3] FIG. 1 shows the results of accelerated testing of the film preparations of Example 1 and Comparative Example 1. [Figure 4] FIG. 1 shows the results of a two-week accelerated test of the film preparations of Example 1 and Comparative Examples 4 and 5. [Figure 5] FIG. 1 shows the results of a two-month accelerated test of the film preparations of Example 1 and Comparative Examples 4 and 5. [Figure 6] FIG. 1 shows the properties of the film after drying. [Figure 7]FIG. 1 shows the properties of the film after drying. [Figure 8] FIG. 1 shows the properties of the film after drying. [Figure 9] FIG. 1 shows the properties of the film after drying. [Figure 10] FIG. 1 is a graph showing the results of an acceleration test depending on the buffer concentration. [Figure 11] FIG. 1 shows the results of animal experiments on naratriptan film. DETAILED DESCRIPTION OF THE INVENTION

[0027] Hereinafter, the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. However, since the present invention can be embodied in various forms, it is not limited to the following embodiments and examples.

[0028] Throughout this specification, when a part is said to "comprise" a certain element, this does not mean that it excludes other elements, but that it may further include other elements, unless otherwise specified.

[0029] The present invention relates to an orally disintegrating film formulation comprising naratriptan, sumatriptan, eletriptan, frovatriptan, almotriptan, zolmitriptan, rizatriptan, or a salt thereof as an active ingredient, and a buffering agent.

[0030] The active ingredients, naratriptan, sumatriptan, eletriptan, frovatriptan, almotriptan, zolmitriptan, and rizatriptan, are triptan compounds, and the scope of the present invention includes not only the triptan compounds themselves but also solvates and hydrates of triptans. Triptan compounds are selective serotonin agonists and can be used as 5-HT1B1D agonists. They are used for migraine, episodic migraine, or cluster migraine, and require a small drug dose, making them suitable for use in film formulations.

[0031] Said "salt" may be any acid addition salt or base addition salt which is non-toxic and harmless to the patient and the side effects attributable to the salt do not reduce the beneficial efficacy of the compound of the present invention. Inorganic acids which form suitable salts include hydrochloric, phosphoric, sulfuric, nitric, tartaric, hydrobromic, hydroiodic, nitrous, or phosphorous acid; organic acids which form suitable salts include, but are not limited to, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic, nicotinic, tosylic, camposulfonic, naphthoic, acetic, trifluoroacetic, oxalic, mandelic, propionic, citric, lactic, gluconic, galacturonic, glutamic, glutaric, glucuronic, aspartic, carbonic, vanillic, benzenesulfonic, p-toluenesulfonic, or methanesulfonic acid.

[0032] The "orally dissolving film (ODF)" is also called an oral disintegrating film or strip and refers to a film preparation that can be taken by disintegrating, dispersing, or dissolving in the oral cavity. Such a film preparation is placed on the tongue and allowed to dissolve, but it can also be administered by adhering to the palate, sublingually, or buccal area. The film preparation of the present invention has the advantage that it can be taken without water.

[0033] The "pharmacokinetic parameters" refer to criteria for determining the absorption, distribution, metabolism, and excretion of a drug based on changes in drug concentration in the body over time. These are graphs showing the relationship between the blood concentration of an administered drug and time, and include the area under the curve (AUC), which is the area enclosed by the drawn curve and the horizontal axis, and the maximum plasma concentration (Cmax), which is the maximum or highest concentration of a drug achieved in a specific compartment or test area in the body after administration of the drug and before a second administration.

[0034] The "buffer" is a pH adjuster and includes acids, bases, salts, etc., and examples thereof include, but are not limited to, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, malic acid, sodium glutamate, glycine, sodium carbonate, maleic acid, sodium lactate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, or mixtures thereof. A preferred buffer of the present invention may be citric acid, sodium citrate, or a mixture thereof.

[0035] In one embodiment, the buffer of the present invention may contain 0.1 to 2.0 wt % sodium citrate and 0.01 to 0.1 wt % citric acid, based on the total weight of the film solids.

[0036] The film preparation of the present invention may have a total soft matter content of less than 3%, preferably less than 2%, and more preferably less than 1% after 6 months in an accelerated stability test.

[0037] The film formulation of the present invention may further comprise a film-forming agent.

[0038] The term "film-forming agent" refers to a polymer that forms an orally disintegrating film formulation, and may be at least one selected from the group consisting of flurane, sodium alginate, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. A preferred film-forming agent of the present invention is, but is not limited to, hydroxypropyl methylcellulose.

[0039] The present invention will be described in more detail below with reference to examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0040] Example: Production of film preparation According to the compositions in Table 1 below, film preparations of Examples 1 to 6 were produced as follows.

[0041] Purified water and a buffer were placed in a preparation vessel, and the main ingredient, naratriptan hydrochloride, was added. The solution was then stirred to adjust the pH to a range of 5.4 to 7.4. The remaining additives were added to the preparation vessel and stirred until a homogeneous solution was obtained, which was then used as the film production solution.

[0042] The prepared film-making solution was poured onto an OHP film, cast using a film applicator, and then dried at a temperature of 70°C or higher. The OHP film was then separated to obtain a film containing naratriptan hydrochloride. The film was cut into single sheets and then packaged in aluminum wrapping paper.

[0043] [Table 1]

[0044] [Comparative Examples 1 to 5] Comparative Example: Preparation of Film Preparation 1 Using the same steps as in Examples 1 to 6, film preparations of Comparative Examples 1 to 5 were produced according to the compositions in Table 2 below.

[0045] [Table 2]

[0046] [Comparative Examples 6 to 8] Comparative Example: Preparation of Film Preparation 2 Using the same steps as in Examples 1 to 6, film preparations of Comparative Examples 6 to 8 were produced according to the compositions in Table 3 below.

[0047] [Table 3]

[0048] [Experimental Example 1] Dissolution test of four naratriptan film solutions A dissolution test was carried out according to the following conditions and method for the film formulation of Example 1. The specific method and conditions for measuring the dissolution rate were set as follows in accordance with the test method approved by the Ministry of Food and Drug Safety of the Republic of Korea.

[0049] (1) Preparation of test solution Using one film prepared in Example 1 and test solutions of pH 1.2, pH 4.0, and pH 6.8, and DW 900 mL, a test was conducted using a disk at 37.0±0.5°C and 50 rpm according to Method 4 of the Korean Pharmacopoeia, 11th Edition, dissolution test.

[0050] 6 mL of the eluate was taken 5, 10, 15 and 30 minutes after the start of the dissolution test, and the solution was filtered through a 0.45 μm membrane filter to prepare the test solution.

[0051] (2) Operating conditions Detector: High performance liquid chromatography (measurement wavelength: 224 nm) Column: C18 (4.6 mm x 15 cm, 5 μm) Mobile phase: Isopropyl alcohol: Solution A* (1:9) *Solution A: Dilute 0.6 mL of phosphoric acid in 900 mL of water, then add triethylamine to the solution to adjust the pH to 2.5. Flow rate: 1.0mL / min

[0052] The results of the dissolution test are shown in Table 4 below and FIG.

[0053] [Table 4]

[0054] As shown in Table 4 and Figure 1, it was confirmed that 95% or more of naratriptan was dissolved within 5 minutes. Rapid release is important for an orally disintegrating film, and it can be seen that the formulation of Example 1 has an excellent effect of satisfying this condition at all pH levels.

[0055] [Experimental Example 2] Stability comparison experiment 1 Stability tests were conducted using Naramig tablets as control drugs and the film formulations of Examples 1 and 2 according to the following method.

[0056] The soft matter generated in the sample stored in the acceleration chamber (temperature 40°C, humidity 75%, aluminum quadruple wrapping) for two months was measured. The results are shown in Table 5 and Figure 2 below. The operating conditions are as follows:

[0057] Detector: High performance liquid chromatography (measurement wavelength: 225 nm) Column: Phenyl group (4.6 mm x 15 cm, 5 μm) Mobile phase: TIFF0007733114000005.tif45152 **Solution A: Dissolve 5.75g of monobasic ammonium phosphate in water to make 1L, and add phosphoric acid to adjust the pH to 3.00±0.05. Flow rate: 1.3mL / min

[0058] [Table 5]

[0059] As shown in Table 5 and Figure 2, the initial soft matter content of the control was 0.31%, while that of the film of Example 1 was 0.07%, four times less than that of the control. Furthermore, even after a two-month accelerated experiment, the soft matter content of the films of Examples 1 and 2 was 0.2%, still less than that of the control. In conclusion, it can be seen that the film formulations of Examples 1 and 2 have significantly superior stability.

[0060] [Experimental Example 4] Stability comparison experiment 2 The stability test of the film preparation of Comparative Example 1 and the film preparation of Example 1 was carried out as follows.

[0061] The soft matter generated in the sample stored in the acceleration chamber (temperature 40°C, humidity 75%, aluminum quadruple wrapping) for one month was measured. The results are shown in Table 6 below and Figure 3. The operating conditions were the same as in Experimental Example 3.

[0062] [Table 6]

[0063] 4, the film of Comparative Example 1 had an initial soft matter content of 0.07%, while the film of Example 1 had a content of 0.30%, which was four times less than the film of Comparative Example 1. Furthermore, after a one-month accelerated experiment, the film of Comparative Example 1 had a content of 0.57%, while the film of Example 1 had a content of 0.12%, which was four to five times less than the film of Comparative Example 1.

[0064] In conclusion, it can be seen that the film formulation of Example 1 having a buffer system has significantly superior stability.

[0065] [Experimental Example 5] Stability comparison experiment 3 A 6-month accelerated test was conducted on the film of Comparative Example 2 (acidic), the film of Comparative Example 3 (basic), and the film of Example 1 (citrate buffer).

[0066] The results are shown in Table 7 below.

[0067] [Table 7]

[0068] As shown in Table 7, the film of Example 1 had a significantly lower amount of soft matter and was found to have significantly better stability than the films of Comparative Examples 2 and 3. In particular, at 6 months of accelerated testing, the film of Example 1 had a soft matter amount of 0.39%, while the films of Comparative Examples 2 and 3 had soft matter amounts of 3.58% and 4.24%, respectively, which was 10 times higher than the film of Example 1.

[0069] In conclusion, it was confirmed that the film of Example 1, which used a neutral buffer, had excellent stability.

[0070] [Experimental Example 6] Stability comparison experiment 4 Accelerated testing was performed on the films of Comparative Example 4 (sodium dihydrogen phosphate (NaH2PO4) and sodium monohydrogen phosphate (Na2HPO4)), Comparative Example 5 (potassium dihydrogen phosphate (KH2PO4) and potassium monohydrogen phosphate (K2HPO4)), and Example 2 (citrate buffer).

[0071] As a result, as shown in FIGS. 4 and 5, it was found that the film of Example 1 exhibited superior stability compared to the films of Comparative Examples 4 and 5.

[0072] [Experimental Example 7] Comparison of properties depending on buffer concentration The film formulation of Example 1 was prepared by increasing the buffer concentration by 0.5, 1, 2, 3, and 3.6 times, and then dried at 80°C and 90°C for 12 minutes, respectively, and the shape of the film was observed (1 time = 0.05M). The results are shown in Tables 8 and 9 below and Figures 6 and 7.

[0073] [Table 8]

[0074] [Table 9]

[0075] As shown in the table above, it was confirmed that crystals precipitated when the buffer concentration was doubled or more.

[0076] Furthermore, the film preparation of Example 1 was prepared with buffer concentrations of 1.25, 1.5, and 1.75 times, and then dried at 80°C and 90°C for 12 minutes, respectively, and the shape of the film was observed.

[0077] The results are shown in Tables 10 and 11 below and in Figures 8 and 9.

[0078] [Table 10]

[0079] [Table 11]

[0080] As shown in the table above, it was confirmed that crystals did not precipitate until the buffer concentration was increased to 1.25 times.

[0081] [Experimental Example 8] Stability comparison experiment based on buffer concentration The film formulation of Example 1 was prepared with buffer concentrations of 0.75, 1, and 1.25 times, and then a stability test was conducted.

[0082] As a result, as shown in FIG. 10, it was confirmed that there was no difference in stability between concentrations, and it was found that the stability was excellent up to a buffer concentration of 1.25 times.

[0083] [Experimental Example 9] Animal studies on naratriptan film Animal experiments were conducted using Naramig tablets as a control drug, Topamax tablets as concomitant drugs, and the film formulation of Example 1 according to the following method.

[0084] In G1, beagle dogs were administered one tablet of the control drug (Naramig tablet), in G2, one film of Example 1 was administered to beagle dogs, and in G3, one film of Example 1 and one Topamax tablet were administered to beagle dogs to confirm the drug interaction between naratriptan and topiramate.

[0085] Blood samples were collected from beagle dogs at 0, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, and 24 hours after the start of administration, and the plasma concentrations of the drugs were measured.

[0086] The plasma concentration of the drug was measured and the pharmacokinetic parameters were calculated, the results of which are shown in Table 12 below.

[0087] [Table 12]

[0088] As shown in Table 12, the AUC, Tmax, and Cmax of Group G1 and Group G2 were evaluated to be equivalent. Therefore, it can be seen that the drug effect onset time, maximum concentration, and bioavailability of the formulations of both the control drug and Example 1 were equivalent. Furthermore, the AUC, Tmax, and Cmax of Group G1 (Example 1) and Group G3 (Example 1 + concomitantly administered drug) were also evaluated to be equivalent. When the orally disintegrating film was co-administered, they were evaluated to be equivalent because they matched within an 80-125% confidence interval, just like when administered alone, confirming that there was no drug interaction between naratriptan and topiramate.

Claims

1. a) naratriptan, or a salt thereof, as an active ingredient; b) a buffering agent; the buffer comprises a mixture of citric acid and sodium citrate; The orally disintegrating film formulation, wherein the buffering agent comprises 0.42 to 1.05 wt % of sodium citrate and 0.015 to 0.038 wt % of citric acid, based on the total weight of the film solids.

2. 2. The orally disintegrating film preparation according to claim 1, wherein 85% or more of the active ingredient is dissolved within 5 minutes during a dissolution test.

3. 3. The orally disintegrating film preparation according to claim 2, wherein 90% or more of the active ingredient is dissolved within 5 minutes during a dissolution test.

4. 10. The orally disintegrating film formulation of claim 1, wherein the formulation further comprises a film-forming agent.

5. 5. The orally disintegrating film formulation according to claim 4, wherein the film-forming agent is flurane, sodium alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof.

6. The orally disintegrating film formulation according to claim 5, wherein the film-forming agent is hydroxypropyl methylcellulose.

7. A method for producing an orally disintegrating film formulation containing naratriptan or a salt thereof as an active ingredient, comprising: (A) adding a buffer containing a mixture of citric acid and sodium citrate to the solvent to adjust the pH of the mixture to pH 5.4 to 7.4; (B) adding the active ingredient, the film-forming agent, and the additives to the pH-adjusted mixture and stirring to prepare a final mixture; (C) applying heat to the final mixture to dry it, thereby producing a thin film; The method for producing an orally disintegrating film formulation, wherein the buffer comprises 0.42 to 1.05 wt % of sodium citrate and 0.015 to 0.038 wt % of citric acid, based on the total weight of the film solids.

8. 8. The method for producing an orally disintegrating film formulation according to claim 7, wherein the solvent is water, a C1-C6 alcohol, or a mixed solvent thereof.

9. The orally disintegrating film formulation according to claim 1 , wherein the orally disintegrating film formulation is for the treatment or prevention of migraine.

10. 2. The orally disintegrating film formulation according to claim 1, which can be administered simultaneously with or at an interval from another formulation containing topiramate as an active ingredient.

11. The orally disintegrating film formulation according to claim 1, wherein when an orally disintegrating film containing 2.5 mg of naratriptan as an active ingredient is administered to a beagle dog, the AUC is 150 to 250 ng hr / mL and the Cmax is 30 to 60 ng / mL.

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