A crystalline form-stable donepezil hydrochloride orally disintegrating film and its preparation method

Abstract

The present invention discloses a stable crystalline form of donepezil hydrochloride orally disintegrating film and a preparation method thereof, comprising: a drug-loading layer and a film-coating layer; the raw materials of the drug-loading layer include: crystalline donepezil hydrochloride and a first film-forming substance; wherein, the raw materials of the drug-loading layer are mixed evenly with a first organic solvent to obtain a drug-loading layer solution, and a film is formed to obtain the drug-loading layer; the water content of the first organic solvent is ≤ 0.5%. The preparation method of the orally disintegrating film comprises the following steps: mixing the raw materials of the drug-loading layer with a first organic solvent to obtain a drug-loading layer solution; coating the drug-loading layer solution on the surface of the film-coating layer and drying to obtain the donepezil hydrochloride orally disintegrating film. The present invention can maintain the stability of the crystalline form of donepezil hydrochloride, without the problem of crystal transformation, while improving the stability of the orally disintegrating film; and has a good taste and bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an orally dissolving film of donepezil hydrochloride with stable crystal form and a preparation method thereof. Background Art

[0002] Donepezil hydrochloride is a new drug for the symptomatic treatment of mild and moderate AD. It is a second-generation cholinesterase inhibitor (ACheⅠ) for the treatment of Alzheimer's disease, with strong selectivity for neuronal acetylcholinesterase. It increases the content of acetylcholine in the animal brain by inhibiting acetylcholinesterase, increases the content of acetylcholine between synapses directly involved in nerve transmission, and produces therapeutic effects, which can improve learning disorders. Donepezil has strong selectivity, almost no inhibitory effect on acetylcholinesterase in the heart and intestine, a long action time, small side effects, and no hepatotoxicity. It is an ideal drug for the treatment of early Alzheimer's disease. Donepezil has the advantages of small dosage, low toxicity, and low cost, and is the first choice drug for the treatment of mild and moderate AD. In addition, it can also treat memory dysfunction, reduce memory loss, dry mouth, and constipation in patients with non-senile affective disorders; it can also be used for the treatment of purpuric rash, vascular dementia, sleep behavior disorders during rapid eye movement (REM) sleep, and Huntington's disease.

[0003] At present, the best-selling dosage form of donepezil hydrochloride in the domestic market is mainly ordinary tablets. Compared with traditional ordinary dosage forms, the oral film is a new drug delivery system that can dissolve rapidly in the mouth, does not need to be taken with water, and has good medication compliance, which is superior to most ordinary oral solid preparations, especially suitable for patient populations such as those with difficulty swallowing, the elderly, and children. In recent years, oral films have developed rapidly due to their beautiful appearance, small size, light weight, easy to carry, rapid dissolution in the mouth, and the ability to effectively improve the bioavailability of drugs.

[0004] Donepezil hydrochloride has 6 crystal forms and one amorphous form. The 6 crystal forms include 2 hydrates (Form I, FormIV) and 4 anhydrates (Form II, Form III, Form V, and Form VI). Different crystal forms of donepezil hydrochloride have different solubilities, dissolution rates, melting points, and powder properties, etc., thus affecting the bioavailability of the drug. In addition, there are problems such as low crystal form purity and poor crystal form stability in donepezil hydrochloride.

[0005] CN 116712415A discloses a donepezil orally dissolving film and a preparation method thereof. The oral dissolving film is a double-layer film structure, including a drug-loading layer containing 45-75% w / w donepezil hydrochloride and a backing layer without donepezil hydrochloride. Although it can ensure the stability of the film, the crystalline donepezil in it contains multiple crystal forms, the crystal form purity is not high, and there is still a problem of crystal form transformation, which is not conducive to the long-term stability of the film and the change of bioavailability. Summary of the Invention

[0006] Based on the technical problems existing in the background art, the present invention provides a crystalline form-stable donepezil hydrochloride orally disintegrating film and a preparation method thereof. The present invention can maintain the stability of the crystalline form of donepezil hydrochloride, without the problem of crystal transformation, while improving the stability of the orally disintegrating film; and it has good taste, bioequivalence and dissolution rate. The orally disintegrating film prepared by the present invention will not undergo crystal transformation during long-term storage, ensuring that the bioavailability of the product after listing does not decrease during the shelf life. In addition, compared with the commercially available donepezil hydrochloride orally disintegrating film, the process of the present invention is simple and the production cost is saved.

[0007] The present invention provides a crystalline form-stable donepezil hydrochloride orally disintegrating film, comprising: a drug-loading layer and a film-coating layer; the raw materials of the drug-loading layer include: crystalline donepezil hydrochloride and a first film-forming substance;

[0008] Among them, the raw materials of the drug-loading layer are mixed with a first organic solvent to obtain a drug-loading layer solution, and a film is formed to obtain the drug-loading layer; the water content of the first organic solvent is ≤ 0.5%.

[0009] Preferably, the first organic solvent is at least one of absolute ethanol, methanol, acetone, and ethyl acetate.

[0010] Preferably, the weight ratio of crystalline donepezil hydrochloride to the first organic solvent is 1:8 - 12.

[0011] The crystalline form of the above-mentioned crystalline donepezil hydrochloride can be hydrate Form I crystalline form, hydrate Form IV crystalline form, anhydrous Form II crystalline form, anhydrous Form III crystalline form, anhydrous Form V crystalline form, anhydrous Form VI crystalline form; more preferably anhydrous Form III crystalline form.

[0012] Since the influence of the solvent on the crystalline form is a complex problem, different solvent types, ratios and temperatures and other factors will all affect the formation and stability of the crystalline form. Different solvents have different effects on the crystalline form. Some solvents will promote the formation of crystals, while some solvents will inhibit the formation of crystals. The solvent ratio also has an impact on the formation and stability of the crystalline form. When the solvent ratio is appropriate, it can promote crystal formation and stability, but if the solvent ratio is inappropriate, it may inhibit crystal formation or cause crystal instability.

[0013] Donepezil hydrochloride has 6 crystalline forms and one amorphous form. Different crystalline forms of donepezil hydrochloride have different solubilities, dissolution rates, melting points, powder properties, stabilities, etc., thus affecting the bioavailability of the drug; during the production of the preparation, solvents will inevitably be used. If the solvent is not selected appropriately, it will directly affect the final state and stability of donepezil hydrochloride in the preparation.

[0014] Through multiple studies, the present invention surprisingly discovers that when water or a solvent containing water is mixed with crystalline donepezil hydrochloride and then dried, donepezil hydrochloride contains multiple crystal forms with low crystal form purity, and the crystalline donepezil hydrochloride will undergo a crystal transformation problem, transforming from the crystalline state to the amorphous state, which is not conducive to the long-term stability of the preparation and the stability of the drug efficacy.

[0015] Through multiple studies, the present invention discovers that by using an anhydrous organic solvent with a water content ≤ 0.5% and mixing it with crystalline donepezil hydrochloride and then drying, the stability of the crystal form types can be maintained, and the crystal transformation problem will not occur, thereby improving the stability of the crystal form of the preparation.

[0016] Preferably, the first film-forming substance is selected from at least one of polyvinyl alcohol, polyvinylpyrrolidone, ethylene-vinyl acetate copolymer, methyl polypropylene, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, and natural polymer materials.

[0017] The above-mentioned natural polymer materials can be gelatin, bletilla striata gum, corn gum, sodium alginate, etc.

[0018] Preferably, the first film-forming substance is selected from at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0019] Preferably, the first film-forming substance is hydroxypropyl cellulose; more preferably, it is hydroxypropyl cellulose HPC-L.

[0020] Preferably, the weight ratio of crystalline donepezil hydrochloride to the first film-forming substance is 1-12:8-12.

[0021] Preferably, the raw materials of the drug-loading layer further include: a first plasticizer and a first taste masking agent.

[0022] Preferably, the first plasticizer is selected from at least one of polyethylene glycol, ethylene glycol, glycerol, and glyceryl triacetate.

[0023] Preferably, the first plasticizer is polyethylene glycol 400.

[0024] Preferably, the first taste masking agent is selected from at least one of small molecule sweeteners, polyclinicrin and its potassium salt resin, acrylic resin, and cyclodextrin clathrates.

[0025] Preferably, the first taste masking agent is acrylic resin.

[0026] Preferably, the first taste masking agent is acrylic resin Kyron T-134.

[0027] Preferably, the weight ratio of the first film-forming substance, the first plasticizer, and the first taste masking agent is 8-12:0.8-1.2:0-1.

[0028] Preferably, the raw materials of the film coating layer include: a second film-forming substance, a second plasticizer, a second taste masking agent, and other excipients.

[0029] Preferably, the weight ratio of the second film-forming substance, the second plasticizer, the second taste masking agent, and other excipients is 8-12:0.8-1.2:0.8-1.2:0-1.5.

[0030] Preferably, the second film-forming substance is selected from at least one of polyvinyl alcohol, polyvinylpyrrolidone, ethylene-vinyl acetate copolymer, methyl polypropylene, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, and natural polymer materials.

[0031] Preferably, the second film-forming substance is selected from at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0032] Preferably, the second film-forming substance is hydroxypropyl methylcellulose; more preferably, it is hydroxypropyl methylcellulose 615.

[0033] Preferably, the second plasticizer is selected from at least one of polyethylene glycol, ethylene glycol, glycerol, and glyceryl triacetate.

[0034] Preferably, the second plasticizer is polyethylene glycol 400.

[0035] Preferably, the second taste masking agent is selected from at least one of small molecule sweeteners, polyclinicrin and its potassium salt resin, acrylic resin, and cyclodextrin inclusion compounds.

[0036] Preferably, the second taste masking agent is a small molecule sweetener.

[0037] The above-mentioned small molecule sweeteners can be sucralose, aspartame, stevioside, glycyrrhizin, sodium saccharin, menthol, etc.

[0038] Preferably, the second taste masking agent is sucralose and menthol; preferably, the weight ratio of sucralose and menthol is 1:0.8-1.2.

[0039] Preferably, the other excipient is a colorant.

[0040] Preferably, the colorant is selected from at least one of iron oxide red and calcium carbonate; preferably, the colorant is iron oxide red and calcium carbonate; more preferably, the weight ratio of iron oxide red and calcium carbonate is 0.4-0.6:1.

[0041] Preferably, the thickness of the drug-loading layer is 20-30 μm; the thickness of the film coating layer is 8-18 μm.

[0042] The present invention adopts a double-layer film structure and selects a water-soluble polymer material as the film-forming substance, which can ensure that the orally disintegrating film can quickly dissolve and release drugs in the oral cavity, and has good demolding properties, improving the preparation yield; the film-forming substance is non-toxic, non-irritating, stable in nature, and does not react with donepezil hydrochloride; and in combination with a suitable plasticizer, the orally disintegrating film has good mechanical properties and toughness.

[0043] The present invention selects a suitable taste masking agent to well mask the bitterness and numbness of the orally disintegrating film of donepezil hydrochloride in the oral cavity, improving its palatability.

[0044] The present invention also provides a preparation method of the above-mentioned orally disintegrating film of donepezil hydrochloride with stable crystal form, which includes the following steps: mixing the raw materials of the drug-loading layer with a first organic solvent to obtain a drug-loading layer solution; coating the drug-loading layer solution on the surface of the film-coating layer, and drying to obtain the orally disintegrating film of donepezil hydrochloride.

[0045] Preferably, mixing the raw materials of the film-coating layer with a mixed solution to obtain a film-coating layer solution, and making a film to obtain the film-coating layer.

[0046] The above-mentioned drug-loading layer solution and film-coating layer solution are both degassed before coating.

[0047] The specific mixing method of the above-mentioned drug-loading layer solution is: mixing donepezil hydrochloride with a first organic solvent, then adding a first film-forming substance, a first plasticizer and a first taste masking agent, and stirring for 10-12 h to mix evenly to obtain the drug-loading layer solution.

[0048] The specific mixing method of the above-mentioned film-coating layer solution is: mixing a second taste masking agent, other excipients with a mixed solution, then adding a second film-forming substance and a second plasticizer, and stirring for 10-12 h to mix evenly to obtain the film-coating layer solution.

[0049] Preferably, the mixed solution is a mixed solution of a second organic solvent and water; more preferably, the volume fraction of the second organic solvent in the mixed solution is 40-80%.

[0050] Preferably, the second organic solvent is at least one of methanol, absolute ethanol, acetone, and ethyl acetate.

[0051] Preferably, the weight ratio of the second film-forming substance to the mixed solution is 1:2.5-5.

[0052] Preferably, the drying temperature is 30-60 °C.

[0053] The present invention adopts a first organic solvent with a water content ≤0.5%, which is mixed with crystalline donepezil hydrochloride and then dried, so that the crystal form type can be kept stable and no crystal transformation problem will occur, thereby improving the stability of the preparation and the stability of bioavailability.

[0054] The present invention selects a suitable taste masking agent, which can well mask the bitter taste and numbness of the tongue in the mouth of the donepezil hydrochloride orally disintegrating film, and improve its palatability.

[0055] By selecting appropriate excipients and ratios, on the one hand, the donepezil hydrochloride orally disintegrating film of the present invention has a uniform and smooth appearance, good mechanical properties and good taste, and on the other hand, the donepezil hydrochloride orally disintegrating film has a relatively fast dissolution rate, with a disintegration time in water at 37 °C less than 60 s, can be quickly dissolved and dispersed in the mouth, release the drug, and maintain good bioavailability stability. Description of the Drawings

[0056] Figure 1 It is the XRD powder diffraction pattern of the crystalline donepezil hydrochloride raw material.

[0057] Figures 2-8 They are the XRD powder diffraction patterns of the dried donepezil hydrochloride in Examples 1-7 in sequence.

[0058] Figure 9 They are the infrared spectra of the donepezil hydrochloride raw material, the newly prepared sample in Example 9 and the raw material in its 6-month accelerated sample.

[0059] Figure 10 They are the infrared spectra of the donepezil hydrochloride raw material, the newly prepared sample in Example 10 and the raw material in its 6-month accelerated sample.

[0060] Figure 11 They are the infrared spectra of the donepezil hydrochloride raw material, the newly prepared sample in Example 16 and the raw material in its 6-month accelerated sample. Detailed Description of the Invention

[0061] Next, the technical solutions of the present invention will be described in detail through specific examples, but it should be clearly stated that these examples are for illustrative purposes only and are not construed as limiting the scope of the present invention.

[0062] In the following examples, the water content of absolute ethanol ≤ 0.5%, the water content of acetone and ethyl acetate ≤ 0.1%, and the water content of methanol ≤ 0.005%.

[0063] In the following examples, hypromellose 615 is purchased from Shin-Etsu Chemical, with a molecular weight of 60,000 - 100,000 and a viscosity of 15 mPa·s; hydroxypropyl cellulose HPC-L is purchased from Nippon Soda Co., Ltd., with a molecular weight of 140,000 and a viscosity of 6 - 10 mPa·s.

[0064] In the following examples, the crystal form of the crystalline donepezil hydrochloride raw material is anhydrous Form III crystal form, and its crystal form diagram is as Figure 1 shown.

[0065] Examples 1 - 7

[0066] Take the crystalline donepezil hydrochloride raw material, mix it with different solvents respectively according to the same method, then dry it at 45 °C, and detect the crystal forms of each group. The results are shown in Table 1 and Figures 2-7 as follows.

[0067] Figures 2-8 They are the XRD powder diffraction patterns of donepezil hydrochloride after drying in Examples 1-7 in sequence.

[0068]

[0069] From Table 1 and Figures 1-8 it can be seen that: when the solvent is water, the crystal form of donepezil hydrochloride changes to the amorphous state; when the solvent is an ethanol aqueous solution, the crystal form of donepezil hydrochloride changes, and for solvents with different water contents, the crystal form changes are also different, and after crystal form transformation, it is not a single crystal form but a mixed crystal form; while in the pure organic phase, the crystal form of donepezil hydrochloride after drying is stable and no crystal form transformation occurs.

[0070] Examples 8-11

[0071] According to the formula in Table 2, use different solvents to prepare donepezil hydrochloride single-layer films respectively

[0072]

[0073] The preparation methods of Examples 8-11 are the same, including the following steps: Take the crystalline donepezil hydrochloride raw material, calcium carbonate, red iron oxide, menthol and sucralose and add them to the solvent in sequence, stir and disperse evenly at 25 °C, then add hypromellose 615, hypromellose HPC-L and polyethylene glycol 400 and continue to stir for 10 h to disperse evenly; degas by ultrasonic for 0.5 h, then coat evenly on a glass plate, heat and dry to form a film at 45 °C, with a film thickness of 35 μm; cut into small pieces of 14×20 mm to obtain the donepezil hydrochloride orally disintegrating film agent.

[0074] It was found during the preparation process that: the film-forming effect of Examples 8-10 is good, and the appearance of the orally disintegrating film agent is uniform and smooth; while in Example 11, anhydrous ethanol is used to prepare the orally disintegrating film agent, and the film-forming performance is poor, and it is difficult to peel off after film formation.

[0075] Take the donepezil hydrochloride orally disintegrating film agents prepared in Examples 8-10 for detection, and the results are shown in Table 3.

[0076]

[0077] As can be seen from Table 3: Although the film-forming effect of Examples 8-10 is good, and the appearance of the orally disintegrating film is uniform and smooth; however, the stability is poor, and the related substances increase in the stress test and the accelerated 6-month test. It can be known that the orally disintegrating film of donepezil hydrochloride adopts a single-layer film form, and its preparation stability is not good.

[0078] The relative bioavailability of the donepezil hydrochloride orally disintegrating film prepared in Examples 8-10 was detected, using donepezil hydrochloride tablets ARICEPT ® 10 mg / tablet (purchased from Eisai Suzhou Branch, Japan, specification: 10 mg / tablet) as the reference preparation; the specific experimental process is as follows:

[0079] Eight healthy Beagle dogs were used and randomly divided into two groups, with 4 dogs in each group. According to the design method of two preparations, single-dose administration, two cycles, and double-cross test, using donepezil hydrochloride tablets as the reference preparation, a bioequivalence test study of the test preparation, donepezil hydrochloride orally disintegrating film, was carried out. The test preparation, donepezil hydrochloride orally disintegrating film, and the reference preparation, donepezil hydrochloride tablets, were cross-administered respectively. The washout period was 1 week. After one week, cross-administration was carried out.

[0080] At 0 h, 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration, a total of 16 time points, venous blood was collected into a vacuum blood collection tube anticoagulated with EDTA-K2, centrifuged, the blood sample was separated, and stored frozen at -80 °C for later measurement.

[0081] Using Phoenix WinNonlin software, pharmacokinetic parameters were calculated by the non-compartmental model. The pharmacokinetic behaviors of the two preparations in Beagle dogs were compared to evaluate the bioequivalence of the two preparations. The relative bioavailability of the donepezil hydrochloride orally disintegrating film was calculated, and the bioequivalence of the donepezil hydrochloride orally disintegrating film of Examples 8-10 and donepezil hydrochloride tablets was evaluated. The results are shown in Table 4.

[0082]

[0083] As can be seen from Table 4: The bioavailability of the donepezil hydrochloride orally disintegrating film of Examples 8-10 is relatively low, indicating that the crystal transformation of the raw material affects the bioavailability of the preparation. It can be known that the orally disintegrating film of donepezil hydrochloride adopts a single-layer film form, and its preparation stability is not good and the bioavailability is low.

[0084] Examples 12-15

[0085] According to the formula in Table 5, double-layer films of donepezil hydrochloride were prepared using different solvents

[0086]

[0087] The preparation methods of Examples 12 - 15 are the same and include the following steps:

[0088] Take the crystalline donepezil hydrochloride raw material and add it to a solvent. Stir and disperse evenly at 25°C, then add hydroxypropyl cellulose HPC-L and polyethylene glycol 400 and continue to stir for 10 h to disperse evenly. Degas by ultrasonic treatment for 0.5 h to obtain the drug-loading layer solution;

[0089] Take calcium carbonate, red iron oxide, menthol, and sucralose and add them to an aqueous 60% ethanol solution in sequence. Stir and disperse evenly at 25°C, then add hypromellose 615 and polyethylene glycol 400 and continue to stir for 10 h to disperse evenly. Degas by ultrasonic treatment for 0.5 h to obtain the film-coating layer solution;

[0090] Then, first coat the film-coating layer solution evenly on a glass plate, heat and dry to form a film at 45°C, with a film thickness of about 13 μm. Then, evenly coat the drug-loading layer solution on the surface of the film-coating layer, heat and dry to form a film at 45°C, with a film thickness of about 25 μm; cut into small pieces of 14×20 mm to obtain the donepezil hydrochloride orally disintegrating film with a bilayer structure.

[0091] Take the donepezil hydrochloride orally disintegrating films prepared in Examples 12 - 15 and conduct the stability investigation and detection of related substances. The results are shown in Table 6.

[0092]

[0093] It can be seen from Table 6 that the quality of the donepezil hydrochloride orally disintegrating films in Examples 12 - 15 is stable.

[0094] Examples 16 - 20

[0095] According to the formula in Table 7, use taste-masking agents to prepare the donepezil hydrochloride bilayer films respectively

[0096]

[0097] The preparation methods of Examples 16 - 20 are the same and include the following steps: Take the crystalline donepezil hydrochloride raw material and add it to methanol. Stir and disperse evenly at 25°C, then add the taste-masking agent, hydroxypropyl cellulose HPC-L, and polyethylene glycol 400 and continue to stir for 10 h to disperse evenly. Degas by ultrasonic treatment for 0.5 h to obtain the drug-loading layer solution; the rest is the same as in Example 12 to obtain the donepezil hydrochloride orally disintegrating film.

[0098] Take the donepezil hydrochloride orally disintegrating films prepared in Examples 12, 16 - 20 and conduct detection. The results are shown in Table 8.

[0099]

[0100] As can be seen from Table 8, the pH value of human saliva is between 6.6 and 7.1, while Kyron T-134 is relatively stable under the conditions of pH 4-7. As a taste-masking agent, it can make the drug hardly dissolve in the mouth, can well mask the bitterness, improve the taste, and enhance the compliance of patients in taking medicine. Compared with traditional taste-masking agents such as β-cyclodextrin and hydroxypropyl-β-cyclodextrin, Kyron T-134 has a better taste-masking effect and does not change the dissolution rate of the film agent.

[0101] Take the newly prepared samples of donepezil hydrochloride oral soluble films prepared in Examples 9-10 and 16, the samples after 6 months of acceleration (40°C / 75%RH), and donepezil hydrochloride raw material drug for infrared scanning. The specific results are shown in Table 9.

[0102]

[0103] As can be seen from Table 1 and Figures 1-8 it can be seen that when the solvent is water, the crystal form of donepezil hydrochloride transforms into an amorphous state; when the solvent is an ethanol aqueous solution, the crystal form of donepezil hydrochloride changes, and for solvents with different water contents, there are also differences in its crystal form changes, and the crystal form after crystal transformation is not a single crystal form but a mixed crystal form; while under a pure organic phase, the crystal form of donepezil hydrochloride is stable after drying and no crystal transformation occurs.

[0104] Furthermore, from Table 9 and Figures 9-11 it can be seen that using a water-containing solvent will cause the raw material drug in the preparation to undergo crystal transformation, and during the accelerated storage process of the preparation, the crystal form of the raw material drug is also gradually changing; while for the bilayer donepezil hydrochloride oral soluble film prepared using an organic solvent, the raw material drug in the preparation will not undergo crystal transformation, and during the accelerated storage process, the raw material drug in the preparation will not undergo crystal transformation either.

[0105] Detect the relative bioavailability of the donepezil hydrochloride oral soluble films prepared in Example 10 and Example 16 and those after 6 months of accelerated storage (40°C / 75%RH), using donepezil hydrochloride tablets ARICEPT ® 10 mg / tablet (purchased from Eisai Suzhou Branch, specification: 10 mg / tablet) as the reference preparation, and the method is the same as before. The specific results are shown in Table 10.

[0106]

[0107] As can be seen from Table 10, due to the problem of crystal transformation of the raw material drug in the donepezil hydrochloride oral soluble film of Example 10, its bioavailability decreases, and during the storage process, the crystal form gradually changes, resulting in a lower bioavailability of the film agent after 6 months of acceleration;

[0108] The donepezil hydrochloride orally disintegrating film of Example 16 has high bioavailability, is equivalent to the imported donepezil hydrochloride tablets, and has obvious advantages in the film. On the premise of maintaining the crystal form unchanged, it improves the stability and drug release rate of the drug; the use of the taste masking agent acrylic resin Kyron solves the problems of bitter and numb tongue of the raw material drug and improves the taste. In Example 16, since the crystal form of the raw material drug in the preparation does not change and the crystal form is stable during storage, after accelerating the storage for 6 months, the bioavailability of the preparation is equivalent to that of the reference preparation, ensuring that the bioavailability of the product after listing does not decrease during the shelf life.

[0109] Take the donepezil hydrochloride orally disintegrating film of Example 16 for the accelerated test (40°C / 75%RH), and the results are shown in Table 11.

[0110]

[0111] It can be seen from Table 11 that the donepezil hydrochloride orally disintegrating film prepared by the present invention has good stability. Compared with Examples 8 and 13 of CN116712415A, it still has good stability without adding hydrophobic materials (titanium dioxide, magnesium aluminum silicate).

[0112] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. An orally disintegrating film of donepezil hydrochloride with stable crystal form, characterized in that, Comprising: A drug-loading layer and a film-coating layer; The raw materials of the drug-loading layer include: crystalline donepezil hydrochloride, a first film-forming substance; Among them, the raw materials of the drug-loading layer are mixed with a first organic solvent to obtain a drug-loading layer solution, and a film is formed to obtain the drug-loading layer; the water content of the first organic solvent is ≤0.5%; The first organic solvent is at least one of absolute ethanol, methanol, acetone, and ethyl acetate; The first film-forming substance is hydroxypropyl cellulose with a viscosity of 6-10 mPa·s; In the orally disintegrating film agent of crystalline donepezil hydrochloride with stable crystal form, hydrophobic materials such as titanium dioxide and magnesium aluminum silicate are not added.

2. The orally disintegrating film of donepezil hydrochloride with stable crystal form according to claim 1, wherein The weight ratio of crystalline donepezil hydrochloride to the first film-forming substance is 1-12:8-12.

3. The orally dissolving film of donepezil hydrochloride with stable crystal form according to claim 1, characterized in that, The raw materials of the drug-loading layer further include: a first plasticizer, a first taste-masking agent.

4. The orally disintegrating film of donepezil hydrochloride with stable crystal form according to claim 3, wherein The weight ratio of the first film-forming substance, the first plasticizer, and the first taste-masking agent is 8-12: 0.8-1.2:0-1。 5. The orally disintegrating film of donepezil hydrochloride with stable crystal form according to claim 1, wherein The raw materials of the film-coating layer include: a second film-forming substance, a second plasticizer, a second taste-masking agent, and other excipients.

6. A preparation method of the crystalline form-stable donepezil hydrochloride orally disintegrating film according to any one of claims 1-5, characterized in that, Including the following steps: mixing the raw materials of the drug-loading layer with a first organic solvent to obtain a drug-loading layer solution; coating the drug-loading layer solution on the surface of the film-coating layer and drying to obtain the orally disintegrating film agent of donepezil hydrochloride.

7. The preparation method of the crystalline form-stable donepezil hydrochloride orally disintegrating film according to claim 6, wherein Mixing the raw materials of the film-coating layer with a mixed solution to obtain a film-coating layer solution, and forming a film to obtain the film-coating layer.

8. The preparation method of the crystalline form-stable donepezil hydrochloride orally disintegrating film according to claim 6, wherein, The drying temperature is 30-60°C.

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