Film agent for treating spinal muscular atrophy

Abstract

The invention provides a film agent for treating spinal muscular atrophy, the film agent at least comprises lisethopram, a film-forming material, a stabilizing agent, and one or more of a pH regulator, a sweetening agent and essence, and the stabilizing agent is silicon dioxide. According to the invention, during the preparation of the lisethoprim film agent, the pH regulator is added to increase the solubility of the raw material medicines and ensure that the raw material medicines are quickly dissolved in the oral cavity, so that the medicine can be absorbed at the oral mucosa part, the bioavailability is improved, and the effect is quickly achieved. Meanwhile, silicon dioxide is added, so that the problem that crystals are easy to separate out of the pH regulator is solved, the stability of the lisethopram and the pH regulator can be kept, the crystals cannot be separated out, the stable curative effect is ensured, and the storage is convenient. According to the present invention, the medication convenience is significantly improved, the dose accuracy is optimized, the oral liquid is suitable for patients with dysphagia (such as infants and severe SMA patients), the bucking or vomiting risk is reduced, and the medication compliance and the market accessibility are effectively improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a film agent for treating spinal muscular atrophy. Background Art

[0002] Risdiplam is an oral therapeutic drug for spinal muscular atrophy (SMA) developed by Chugai Pharmaceutical Co., Ltd. It is a prescription drug that promotes the production of functional SMN protein by regulating the splicing process of SMN2 gene pre-mRNA. It is applicable to SMA patients predicted to develop through genetic testing and infants under 2 months old. The drug was approved in Japan in June 2021 and launched in August 2021. It is taken orally once a day after meals, and the dose needs to be adjusted according to age and weight (for example, the initial dose for infants under 2 months old is 0.15 mg / kg). Clinical data show that it significantly improves the motor function indicators of type I, II / III, and non-onset patients. For example, the unsupported sitting rate at 12 months reaches 29%, and at the same time, the SMN protein level is increased to 1.5 - 2 times the baseline. The main side effects include rash (16.4%), upper respiratory tract infection (13.7%), and skin discoloration (9.6%). Potential risks such as retinal toxicity and embryotoxicity need to be noted. When using, the powder needs to be dissolved into a 0.75 mg / mL solution and stored refrigerated, and used up within 64 days. Sub-packaging and transferring containers are prohibited.

[0003] The usage method of risdiplam is complex and has strict storage requirements. The drug needs to be strictly stored refrigerated (2 - 8°C). The prepared solution is only valid for 64 days. Expired or unrefrigerated storage may lead to reduced drug efficacy, and it has photodegradability and needs to be stored away from light. The preparation process is complex and must be operated by professional medical staff. Patients or caregivers cannot open the medicine bottle by themselves. After dissolution, it needs to be taken immediately (within 5 minutes), otherwise it needs to be discarded and re-prepared. Improper operation is likely to cause dosing errors.

[0004] Patent CN114028351A describes a risdiplam freeze-dried orally disintegrating tablet and its preparation method. The product features that the freeze-dried tablet uses a single-dose specification as the dosing unit and does not require water for administration. After directly putting it into the mouth, the freeze-dried tablet quickly dissolves when it comes into contact with oral saliva and disperses in the saliva. However, the mechanical strength of the freeze-dried orally disintegrating tablet is low, and its structure is loose and porous. Infants may choke or aspirate when taking it. In addition, the density of the freeze-dried tablet is low, and the overall tablet is relatively large, making it difficult for infants to take.

[0005] In summary, the existing marketed solution has a complex usage method, resulting in inaccurate dosing, and has strict storage requirements. Exceeding the limit may lead to excessive impurities and cause additional side effects. The disclosed freeze-dried tablets have low mechanical strength, a loose and porous structure, and infants may choke or aspirate when taking them. The overall tablet is relatively large, making it difficult for infants to take.

[0006] Based on this, the development of orally disintegrating films will be conducive to significantly improving the convenience of drug use and optimizing dose accuracy and stability. The rapid oral dissolution property is suitable for patients with swallowing difficulties (such as infants and young children, severe SMA patients), reducing the risk of choking or vomiting. The solubility of risdiplam is pH-sensitive, and within the range of pH 3.0 - 4.5, the solubility can be balanced with the taste requirements of the orally disintegrating film. However, adding pH regulators (such as citric acid, tartaric acid, etc.) may cause problems such as hygroscopicity or precipitation, which poses technical challenges to the development of orally disintegrating film agents. Summary of the Invention

[0007] In order to solve the above technical problems, the object of the present invention is to provide a film agent for treating spinal muscular atrophy that is easy to use, has precise dose control, is suitable for infant patients, has good stability, and is convenient for storage.

[0008] To achieve the above object of the present invention, the following technical solutions are adopted: A film agent for treating spinal muscular atrophy, the film agent at least includes risdiplam, a film-forming material, a stabilizer, and one or more of a pH regulator, a sweetener, and a flavoring agent, and the stabilizer is silicon dioxide.

[0009] In the film agent, calculated by weight, it at least includes 1 - 20 parts by weight of risdiplam, 3 - 20 parts by weight of a pH regulator, 53 - 95 parts by weight of a film-forming material, 0.5 - 2 parts by weight of a sweetener, and 0.5 - 5 parts by weight of a stabilizer.

[0010] Preferably, in the film agent, calculated by weight, it at least includes 1 - 20 parts by weight of risdiplam, 3 - 10 parts by weight of a pH regulator, 63 - 95 parts by weight of a film-forming material, 0.5 - 2 parts by weight of a sweetener, and 0.5 - 5 parts by weight of a stabilizer.

[0011] Preferably, in the film agent, the pH regulator is tartaric acid.

[0012] Preferably, in the film agent, the film-forming material is one or more of polyvinyl alcohol, polyethylene oxide, and copovidone.

[0013] Preferably, in the film agent, the sweetener is sucralose and the flavoring agent is strawberry flavor.

[0014] For the film agent, each dose (20 - 200 mg) is dissolved in 2 ml of water, and pH < 4.5.

[0015] The preparation method of the film agent is hot melt extrusion.

[0016] The preparation method at least includes the following steps: (1) Weigh risdiplam, film-forming materials, stabilizers, as well as pH regulators, sweeteners, and flavors, and then add them to a mixer for mixing; (2) Add the mixture to a hot melt extrusion device at a rate of 0.01 - 100 kg / h, and after extrusion, stretch it into a film; (3) Cut the prepared film into film agents of different sizes and shapes through a film cutting machine.

[0017] In the described preparation method, the die temperature of hot melt extrusion is 135°C to 155°C.

[0018] The solubility of risdiplam is sensitive to pH. For risdiplam film agents without added pH regulators, the active pharmaceutical ingredient cannot dissolve in water and can only form a suspension, making it impossible to be absorbed in the oral cavity. After adding a certain proportion of pH regulators, risdiplam can be smoothly dissolved in 2 ml of water, and the pH is maintained within the range of 3.0 - 4.5. At the same time, it can balance the solubility and the taste requirements of the orally disintegrating film. However, adding pH regulators (such as citric acid, tartaric acid, etc.) may cause hygroscopic or precipitation problems.

[0019] During the stability storage process, we found that crystallization occurred in the risdiplam film agents containing pH regulators. It is very difficult to reduce the crystallization risk and maintain the stability of the drug during the hot melt extrusion preparation process and subsequent storage process. After many experiments, we unexpectedly found that after adding silicon dioxide as a stabilizer, no crystallization occurred in the risdiplam film agents during the stability storage process.

[0020] The beneficial effects of the present invention are as follows: (1) When preparing the risdiplam film agent of the present invention, by adding a pH regulator and controlling the proportion, the drug can be quickly dissolved and has a good taste, which helps the drug to be absorbed through the oral mucosa, accelerates the drug release, and increases the bioavailability; (2) When preparing the risdiplam film agent of the present invention, adding silicon dioxide as a stabilizer enables the risdiplam film agent to maintain stability, will not precipitate crystals, ensures the stability of the curative effect, and is convenient for storage; (3) The risdiplam film agent of the present invention significantly improves the medication convenience, optimizes the dosage accuracy, is suitable for patients with swallowing difficulties (such as infants and young children, severe SMA patients), reduces the risk of choking or vomiting, and effectively improves the medication compliance and market accessibility. Specific Embodiments

[0021] Comparative Example 1 Other stabilizer ratio prescriptions The risdiplam prescription is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight percentage (w / w; %) of each component are:

[0022] Process: Mixing: After weighing the raw and auxiliary materials, add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder, conduct tests using the hot melt extruder to prepare the film agent, set the extrusion temperatures at 100, 130, 160, 160, 160, 160, 160, 160 °C, and the screw speed at 100 rpm.

[0023] Film forming: Stretch the extruded material to a thickness of 80 µm.

[0024] Film cutting: Cut the film agent to the film weight.

[0025] Testing: Tensile strength and disintegration time limit test Disintegration time limit: Determined by the disintegration time limit inspection method in Appendix 0921 of the Chinese Pharmacopoeia 2020 Edition; Tensile strength: Use a medical packaging performance tester to conduct tensile tests on film agents of different batches. Cut 5 cm long samples from each batch, set the clamp spacing at 20 mm, the test speed at 5 mm / min, test 3 samples for each batch, and record the average tensile strength.

[0026] Dissolution curve: Refer to the second method (paddle method) in General Rules 0931 for dissolution and release determination in Part IV of the Chinese Pharmacopoeia 2020 Edition to determine the film agent prepared from the prescription. The water bath temperature is 37 ± 0.1 °C, the rotation speed is 75 r / min, use an aqueous solution as the dissolution medium, take 5 ml of liquid at 5, 10, 15, 30, 45 min respectively and supplement the same volume and temperature of the dissolution medium. Filter the taken liquid through a 0.45 µm filter membrane and use high performance liquid chromatography to determine the dissolution.

[0027]

[0028] Dissolution curve results

[0029] Comparative example 2 Prescription of other acids (citric acid, fumaric acid, malic acid) The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and the proportion of each component in the total weight (w / w; %) are:

[0030] Process: Mixing: After weighing the raw and auxiliary materials, add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare film agents. Set the extrusion temperatures at 100, 120, 145, 145, 145, 145, 145, 145 °C and the screw rotation speed at 50 rpm.

[0031] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0032] Film cutting: Cut the film agent to the film weight.

[0033] Detection: pH measurement: Take 2 tablets of the film agent and place them in 4 mL of ultrapure water (at a constant temperature of 25 °C), shake until completely dissolved or completely dispersed to form a homogeneous solution. Measure using a pH meter. Immerse the calibrated electrode below the liquid surface to ensure that the glass membrane bulb is completely covered, and measure the pH value.

[0034] Related substances: Use HPLC method to determine related substances at 0 d and 10 d (40 °C, 75%).

[0035]

[0036] Conclusion: The film agents prepared with citric acid and fumaric acid as pH regulators do not meet the requirements in terms of their properties. The film agents prepared with malic acid as the pH regulator produce more impurities during stability storage and do not meet the requirements.

[0037] Example 1 Proportion of different APIs The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight percentage (w / w; %) of each component are:

[0038] Process flow: Mixing: Weigh risdiplam, polyvinyl alcohol, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare film agents. Set the extrusion temperatures at 100, 120, 145, 145, 145, 145, 145, 145 °C and the screw rotation speed at 50 rpm.

[0039] Film formation: Stretch the extruded material to a thickness of 80 µm.

[0040] Film cutting: Cut the film agent to the film weight.

[0041] Detection: Tensile strength and disintegration time limit test Disintegration time limit: Determined by the disintegration time limit inspection method in Appendix 0921 of the Chinese Pharmacopoeia 2020 Edition; Tensile strength: Using a medical packaging performance tester, conduct tensile tests on film agents of different batches. Cut samples of each batch to a length of 5 cm, set the clamp spacing to 20 mm, the test speed to 5 mm / min, test 3 samples for each batch, and record the average tensile strength.

[0042] Dissolution curve: Refer to the second method (paddle method) of the general chapter 0931, Dissolution and Release Determination Methods, in the fourth volume of the Chinese Pharmacopoeia 2020 edition to determine the film agents prepared according to the prescription. The water bath temperature is 37 ± 0.1 °C, the rotation speed is 75 r / min, using an aqueous solution as the dissolution medium. Take 5 ml of liquid at 5, 10, 15, 30, and 45 min respectively and supplement the same volume and temperature of the dissolution medium. Filter the taken liquid through a 0.45 μm filter membrane and use high performance liquid chromatography to determine the dissolution.

[0043]

[0044] Dissolution curve results

[0045] Example 2 The proportion of silicon dioxide has an impact on stability (see Example 6 for the stability experiment). The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight percentage (w / w; %) of each component are:

[0046] Process flow: The same as in Example 1.

[0047] Detection: The method is as shown in Example 1.

[0048] Dissolution curve results

[0049] Example 3 Different proportions of acid The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight percentage (w / w; %) of each component are:

[0050] Process: The same as in Example 1 Detection: The method is as shown in Example 1. Other detections: pH Measurement: Take 2 tablets of the film agent and place them in 4 mL of ultrapure water (at a constant temperature of 25 °C). Oscillate until completely dissolved or completely dispersed to form a homogeneous solution. Measure using a pH meter. Immerse the calibrated electrode below the liquid surface to ensure that the glass membrane bulb is completely covered, and measure the pH value.

[0051] Related Substances: The related substances were determined by HPLC at 0 d and 10 d (40 °C, 75%).

[0052]

[0053] Dissolution Curve Results

[0054] Conclusion: When the proportion of acid is between 3% and 20%, the film agent dissolves in water, with pH < 4.5. The active pharmaceutical ingredient can completely dissolve in water, and the properties and purity meet the expectations. When no acid is added, the film agent disperses in water, with a pH of 7.2, and the active pharmaceutical ingredient cannot dissolve in water, and the solution is in a suspension state. When the acid proportion is 30%, a small amount of crystal particles can be seen on the surface of the prepared film agent, which does not meet the requirements. Therefore, an acid proportion of 3% - 20% can meet the expectations of this product.

[0055] Example 4 Sweetener Proportion The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight ratio (w / w; %) of each component are as follows:

[0056] Process: Same as Example 1 Detection: The method is as shown in Example 1

[0057] Dissolution Curve Results

[0058] Example 5 The prescription of risdiplam is shown in the following table. Calculated based on a batch of 1000 tablets, the weight and total weight ratio (w / w; %) of each component are as follows:

[0059] Process Flow - Prescription 5 - 1a Mixing: Weigh risdiplam, polyethylene oxide, copovidone, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare a film agent. Set the extrusion temperature at 100, 120, 145, 145, 145, 145, 145, 145 °C (die orifice), and the screw speed at 200 rpm.

[0060] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0061] Film cutting: Cut the film agent to the film weight.

[0062] Process flow - Prescription 5 - 1b Mixing: Weigh risdiplam, polyethylene oxide, copovidone, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare a film agent. Set the extrusion temperature at 100, 125, 155, 155, 155, 155, 155, 155 °C (die orifice), and the screw speed at 200 rpm.

[0063] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0064] Film cutting: Cut the film agent to the film weight Process flow - Prescription 5 - 1c Mixing: Weigh risdiplam, polyethylene oxide, copovidone, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare a film agent. Set the extrusion temperature at 100, 120, 135, 135, 135, 135, 135, 135 °C (die orifice), and the screw speed at 200 rpm.

[0065] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0066] Film cutting: Cut the film agent to the film weight Process flow - Prescription 5 - 1d Mixing: Weigh risdiplam, polyethylene oxide, copovidone, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare a film agent. Set the extrusion temperature at 100, 130, 165, 200, 200, 200, 200, 200 (die orifice), and the screw speed at 200 rpm.

[0067] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0068] Film cutting: Cut the film agent to the film weight Process Flow - Prescription 5 - 1e Mixing: Weigh risdiplam, polyethylene oxide, copovidone, polyethylene glycol, sucralose, and silicon dioxide and add them to a mixer for mixing; Hot melt extrusion: Place the powder in a hot melt extruder and conduct tests using the hot melt extruder to prepare a film agent. Set the extrusion temperature at 90, 115, 130, 130, 130, 130, 130, 130 °C (die orifice), and the screw speed at 200 rpm.

[0069] Film formation: Stretch the extruded material to a thickness of 100 µm.

[0070] Film cutting: Cut the film agent to the film weight Detection: The method is as shown in Example 1

[0071] Example 6 Stability test After the samples are placed at 40 °C and 75% humidity for 1 month and 3 months, check under a microscope whether there is crystal precipitation in the appearance.

[0072]

[0073] The results show that: When preparing the risdiplam film agent of the present invention, a pH regulator is added to increase the solubility of the active pharmaceutical ingredient, so that the drug can be dissolved in the oral cavity and absorbed through the oral mucosa. At the same time, silicon dioxide is added as a stabilizer, so that risdiplam can maintain stability, will not precipitate crystals, ensure the stability of the efficacy, and is convenient for storage.

[0074] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention are all included in the protection scope of the present invention.

Claims

1. A membranous preparation for treating spinal muscular atrophy, characterized in that, The film agent at least comprises risdiplam, a film-forming material, a stabilizer, and one or more of a pH regulator, a sweetener, and a flavoring agent, and the stabilizer is silicon dioxide.

2. The film agent according to claim 1, characterized in that, Calculated by weight, it at least comprises 1-20 parts by weight of risdiplam, 3-20 parts by weight of the pH regulator, 53-95 parts by weight of the film-forming material, 0.5-2 parts by weight of the sweetener, and 0.5-5 parts by weight of the stabilizer.

3. The film agent according to claim 1, characterized in that, Calculated by weight, it at least comprises 1-20 parts by weight of risdiplam, 3-10 parts by weight of the pH regulator, 63-95 parts by weight of the film-forming material, 0.5-2 parts by weight of the sweetener, and 0.5-5 parts by weight of the stabilizer.

4. The film agent according to claim 1, characterized in that The pH regulator is tartaric acid.

5. The film agent according to claim 1, characterized in that The film-forming material is one or more of polyvinyl alcohol, polyethylene oxide, and copovidone.

6. The film agent according to claim 1, characterized in that The sweetener is sucralose, and the flavoring agent is strawberry flavor.

7. The film agent according to claim 1, characterized in that Each dose (20~200mg) is dissolved in 2 ml of water, and the pH < 4.

5.

8. The preparation method of the film agent according to any one of claims 1 to 7, characterized in that The preparation method is hot melt extrusion.

9. The preparation method according to claim 8, wherein It at least comprises the following steps: (1) Weigh risdiplam, the film-forming material, the stabilizer, and the pH regulator, the sweetener, and the flavoring agent, and then add them to a mixer for mixing; (2) Add the mixture to a hot melt extrusion device at a speed of 0.01-100 kg / h, and after extrusion, stretch it into a film; (3) Cut the prepared film into film agents of different sizes and shapes through a film cutting machine.

10. The preparation method according to claim 9, wherein, The die temperature of the hot melt extrusion is 135°C to 155°C.

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