Bromide pyridostigmine sublingual immediate-release tablet and preparation method and application thereof

Abstract

The present application relates to a kind of bromine pyridostigmine sublingual immediate-release tablets, with 15-60% pyridostigmine inclusion complex, 20-75% filler, 5-25% disintegrant, 0.1-10% penetration enhancer, 0-1.5% flavoring agent, 0.4-2% lubricant and 0-5% flow aid in weight percentage, wherein the weight ratio of pyridostigmine in pyridostigmine inclusion complex: inclusion agent is 1:1.3-3.The sublingual immediate-release tablets of the present application have the advantages of rapid release, high bioavailability, good taste, low dosage, good stability, easy to take, etc., significantly improve medication compliance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a pyridostigmine sublingual immediate-release tablet, its preparation method, and its application. Background Technology

[0002] Myasthenia gravis (MG) is an autoimmune disease primarily caused by cellular and humoral immunity, involving complement and cytokines, mediated by multiple antibodies, and characterized by acquired neuromuscular junction (NMJ) transmission disorders. The typical clinical features of MG are fluctuating skeletal muscle weakness and easy fatigue, with symptoms typically worsening in the evening and improving after activity. According to the "Guidelines for the Diagnosis and Treatment of Myasthenia Gravis in China (2025 Edition)," the global prevalence of myasthenia gravis is approximately 12.4 per 100,000 people, and the prevalence has been increasing in recent decades. In my country, the incidence of myasthenia gravis is approximately 0.68 per 100,000 people, with a slightly higher incidence in women than men. Myasthenia gravis can occur at any age, with a bimodal peak around age 30 and 50. Myasthenia gravis is also common in pediatric neurology. The incidence rate of myasthenia gravis in my country is 0.68 / 100,000, with children accounting for approximately 7.7%–47.0% of the total myasthenia gravis population. Onset can occur in infancy, with an average age of diagnosis of about 6 years, and no significant gender difference. Ocular myasthenia gravis is the most common type in children, accounting for up to 86.3%. Severe cases can lead to dysphagia, choking while drinking, and even respiratory distress. According to the Myasthenia Gravis Foundation (MGFA) clinical classification, types IIb and IVb primarily affect the pharyngeal and / or respiratory muscles, resulting in dysarthria, dysphagia, choking while drinking, weakness in chewing, and even respiratory distress. There is an urgent clinical need for drug administration routes that do not require swallowing, and long-term medication is necessary to slow disease progression.

[0003] Myasthenia gravis is primarily mediated by pathogenic acetylcholine receptor (AChR) antibodies. Over 80% of childhood myasthenia gravis cases are caused by AChR antibodies, which exist in IgG1 and IgG3 subtypes. Upon binding to AChR, these antibodies activate complement to produce the membrane attack complex, disrupting postsynaptic membrane folds, reducing the number of AChRs, and decreasing their sensitivity to acetylcholine binding. Approximately 1%–4% of myasthenia gravis patients are positive for muscle-specific receptor tyrosine kinase (MuSK) antibodies; these patients primarily involve the bulbar, neck, and respiratory muscles. Some patients may also have detectable low-density lipoprotein receptor-associated protein 4 (LRP4) antibodies, which interfere with AChR aggregation and affect neuromuscular junction signaling. In my country, 80% of children with myasthenia gravis also have thymic hyperplasia, 3% have thymoma, and only 7% have a normal thymus.

[0004] The Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2025 Edition) have updated the treatment goal to achieve minimal symptom expression (MSE), i.e., an MG-ADL score of 0 or 1, and treatment-related adverse reactions ≤ grade 1. This requires extremely high adherence to long-term medication.

[0005] Pyridostigmine bromide is a reversible cholinesterase inhibitor. It works by inhibiting cholinesterase activity, leading to the accumulation of acetylcholine in the synaptic cleft. This results in the excitation of muscarinic (M) and nicotinic (N) cholinergic receptors, and also has a direct excitatory effect on N2 receptors on the motor endplate, thereby increasing muscle tone in the gastrointestinal tract, bronchial smooth muscle, and skeletal muscles throughout the body. Pyridostigmine bromide is the most widely used AChEI preparation in clinical practice. It has a longer duration of action, better tolerability, and fewer cholinergic adverse reactions. It takes effect within 15-30 minutes and lasts for 3-4 hours, relieving and improving the clinical symptoms of most MG patients. It is suitable for basic symptomatic treatment of myasthenia gravis patients (Class Ia / A) and is used as a first-line drug for treating all types of myasthenia gravis and the first-line drug for initial treatment of MG patients.

[0006] The usual adult dosage of pyridostigmine bromide is 60 mg orally 3-4 times daily, with a maximum daily dose not exceeding 480 mg. The dose can be reduced or discontinued once the treatment goal is achieved. Approximately 38.4% of children with ocular myasthenia gravis can achieve remission with AChEI treatment alone. For children and adolescents with jugular myasthenia gravis (JMG), guidelines state that "JMG treatment is primarily based on pyridostigmine bromide," with an initial dose of 0.5-1.0 mg / kg, 3-4 times daily, which can be gradually increased to 1.5 mg / kg, 5 times daily, with a maximum daily dose not exceeding 450 mg. If the treatment goal is not achieved, glucocorticoids and other non-hormonal oral immunosuppressants can be added. This means that pediatric patients need to take high doses of pyridostigmine bromide long-term, frequently, and often require combined immunosuppressive therapy, resulting in a heavy medication burden.

[0007] Pyridostigmine bromide is relatively stable chemically at room temperature (15-30℃), but high temperatures (>40℃) may accelerate its degradation, and it is sensitive to alkaline environments. Pyridostigmine bromide has an extremely bitter taste and is readily soluble in water, ethanol, and chloroform. It is highly hygroscopic, showing significant weight gain at RH>40% and complete liquefaction at RH≥60%. Pyridostigmine bromide extended-release tablets may develop spots under high temperature and humidity conditions due to its hygroscopic nature. The bioavailability of oral formulations of pyridostigmine bromide is only 11.5%–18.9%; in healthy volunteers, the time to peak concentration after oral administration of 60 mg is 1–5 hours, with a half-life of approximately 3.3 hours. It can be hydrolyzed by plasma cholinesterase and is also metabolized in the liver; it can cross the placenta but does not readily enter the central nervous system; it is primarily excreted unchanged and as metabolites in the urine, with trace amounts excreted in breast milk. Excessive doses of pyridostigmine bromide can stimulate muscarinic receptors, leading to gastrointestinal disturbances, bronchospasm, and bradycardia. It can also stimulate nicotinic receptors, potentially causing cholinergic crisis and other adverse reactions.

[0008] Currently, commonly used clinical dosage forms of pyridostigmine bromide include 60mg immediate-release tablets (sugar-coated), 180mg extended-release tablets, 12mg / mL syrup, and sterile powder for injection (1mg / vial, 5mg / vial, 10mg / vial). In long-term clinical application, existing dosage forms have the following prominent problems: First, they are difficult for patients with myasthenia gravis who have difficulty swallowing to take the medication. MG patients, especially those with type IIB and above, often experience symptoms such as pharyngeal muscle weakness, difficulty chewing, difficulty swallowing, and choking when drinking water. Commercially available immediate-release tablets are sugar-coated, which disintegrate slowly, requiring the patient to drink water to aid swallowing; extended-release tablets (180mg) must be swallowed whole and cannot be broken, chewed, or crushed, otherwise the extended-release structure will be destroyed, leading to a sudden release of the drug, which may cause serious adverse reactions such as cholinergic crisis. Both types of solid dosage forms are extremely unfriendly to patients with swallowing dysfunction; second, pyridostigmine bromide is a water-soluble drug with a strong bitter taste, and current taste-masking techniques cannot completely mask its strong bitterness. Although syrups contain flavoring agents, they still have a noticeably bitter taste when taken. For MG patients (especially children) who need long-term or even lifelong medication, the extremely bitter taste leads to medication resistance, nausea, and vomiting, resulting in very poor medication adherence. Thirdly, oral formulations have low bioavailability, requiring large single-dose and frequent administration. The bioavailability of ordinary tablets and syrups is only about 11.5%-18.9%, requiring high-dose, high-frequency dosing regimens to achieve effective therapeutic concentrations. This increases the burden on patients and their families and is more likely to cause cholinergic adverse reactions such as diarrhea, salivation, nausea, vomiting, abdominal pain, increased salivation, bradycardia, and increased sweating. Excessive doses may even induce cholinergic crisis. Fourthly, injectable formulations are not suitable for long-term, frequent administration. While pyridostigmine bromide for injection can be used for short-term replacement therapy in patients with extreme swallowing difficulties, injection is an invasive procedure and is not suitable for long-term maintenance therapy in patients with myasthenia gravis (requiring lifelong, frequent administration). Furthermore, during myasthenic crisis resuscitation, pyridostigmine bromide may increase muscarinic reactions and respiratory secretions, requiring short-term discontinuation to avoid airway management difficulties. Fifth, there are unique challenges in pediatric medication use: over 90% of chemical drug formulations in my country lack pediatric formulations, resulting in a severe shortage of pediatric-specific formulations. Clinically, adult formulations are often split for dosage forms or suspensions are prepared on-the-spot by pharmacists, leading to problems such as disrupted formulation structure, inaccurate dosage, poor stability, poor quality uniformity, and increased risk of medication errors. Pyridostigmine bromide tablets (60mg), extended-release tablets (180mg), and syrup (12mg / mL) are not pediatric-specific formulations. The tablets need to be split into smaller doses, making it difficult to achieve precise "milligram-level" dosing. The dose of the extended-release tablets far exceeds the maximum daily dose for children and cannot be split. The syrup requires precise measurement and is subject to the risk of moisture-induced deterioration. Sixth, the stability of the formulation needs to be improved: Pyridostigmine bromide is highly hygroscopic and sensitive to light, heat, and alkaline environments.Existing sugar-coated tablets and syrups pose stability risks in humid and light-exposed environments; pyridostigmine bromide extended-release tablets may develop spots under high temperature and humidity due to drug hygroscopicity, and if the structure is damaged (e.g., patients have to crush them to take them due to difficulty swallowing), it may lead to sudden drug release.

[0009] In summary, existing pyridostigmine bromide formulations have significant shortcomings in terms of ease of swallowing, bitterness masking and palatability, bioavailability, suitability for long-term administration, dosage accuracy in children, and formulation stability. These deficiencies are inconsistent with the cornerstone status established in the "Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2025 Edition)"—that pyridostigmine bromide is suitable for the basic symptomatic treatment of MG patients—and fail to meet the clinical requirement of "initiating rapid-onset therapy to achieve treatment goals (MSE) as quickly as possible." Therefore, there is an urgent need to develop a new formulation of pyridostigmine bromide that is easy for patients with swallowing difficulties to take, has good palatability, excellent stability, and is safe for long-term use, in order to improve the treatment effect and medication adherence of patients with myasthenia gravis (especially children and patients with swallowing disorders). Summary of the Invention

[0010] The purpose of this invention is to provide a pyridostigmine sublingual immediate-release tablet, which, by weight percentage, contains 15-60% pyridostigmine inclusion complex, 20-75% filler, 5-25% disintegrant, 0.1-10% penetration enhancer, 0-1.5% flavoring agent, 0.4-2% lubricant, and 0-5% flow aid, wherein the weight ratio of pyridostigmine to inclusion agent in the pyridostigmine inclusion complex is 1:1.3-3.

[0011] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 3-30 mg of pyridostigmine bromide per unit dose by weight percentage, preferably 5-25 mg, and more preferably 10-20 mg.

[0012] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 18-58% bromide pyridostigmine inclusion complex, preferably 20-56%, by weight percentage.

[0013] In a preferred embodiment of the present invention, the inclusion agent is selected from any one or a combination of sulfobutyl betacyclodextrin and hydroxypropyl betacyclodextrin.

[0014] In a preferred embodiment of the present invention, the weight ratio of pyridostigmine bromide to inclusion agent in the pyridostigmine bromide inclusion complex is 1:1.5-3, preferably 1:2-3.

[0015] In a preferred embodiment of the present invention, the filler is selected from any one or a combination of mannitol, lactose, xylitol, glucose, sucrose, and sorbitol.

[0016] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 23-73% filler, preferably 25-70%, by weight percentage.

[0017] In a preferred embodiment of the present invention, the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and chitosan.

[0018] In a preferred embodiment of the present invention, the disintegrant D 90 ≤200μm, preferably disintegrant D 90 ≤150μm, more preferably disintegrant D 90 ≤110μm, further preferred disintegrant D 90 ≤70μm.

[0019] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 6-22% disintegrant, preferably 8-19%, by weight percentage.

[0020] In a preferred embodiment of the present invention, the penetration enhancer is selected from any one or a combination of menthol, sodium deoxycholate, sodium dodecyl sulfate, polysorbate 80, sodium 8-(2-hydroxybenzamido)octanoate, and azone.

[0021] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.3-9% permeability enhancer, preferably 0.5-8%, by weight percentage.

[0022] In a preferred embodiment of the present invention, the lubricant is selected from any one or a combination of magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and sodium stearate fumarate.

[0023] In a preferred embodiment of the present invention, the immediate-release tablets contain 0.2-4% lubricant by weight, preferably 0.45-2.22%.

[0024] In a preferred embodiment of the present invention, the flow aid is any one or a combination of silica, talc.

[0025] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.2-4% (by weight), preferably 0.45-2.22% (by weight).

[0026] In a preferred embodiment of the present invention, the flavoring agent is selected from any one or a combination of aspartame, sucralose, steviol glycoside, stevioside, flavoring, and sodium glycine.

[0027] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.1-1.4% flavoring agent, preferably 0.22-1.25% by weight.

[0028] In a preferred embodiment of the present invention, the disintegration time of the sublingual immediate-release tablet is ≤5 min, preferably ≤3 min, and more preferably ≤2 min.

[0029] In a preferred embodiment of the present invention, the dissolution rate of the sublingual immediate-release tablet after being placed in water for 15 minutes is ≥80%, preferably ≥90%, and more preferably ≥95%.

[0030] In a preferred embodiment of the present invention, the preparation method of the sublingual immediate-release tablet includes the following steps:

[0031] (1) Dissolve the required amount of flavoring agent, inclusion agent and pyridostigmine bromide in water, and then dry the resulting solution to obtain the pyridostigmine bromide inclusion complex.

[0032] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of filler, disintegrant, penetration enhancer and flow aid, the required amount of lubricant is added, and after evenly mixed, it is compressed into tablets to obtain the product.

[0033] or

[0034] (1) Weigh the required amount of inclusion agent and pyridostigmine bromide, dissolve them in water, and dry the resulting solution to obtain the pyridostigmine bromide inclusion complex.

[0035] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of flavoring agent, filler, disintegrant, penetration enhancer and flow aid, the required amount of lubricant is added, and after evenly mixed, it is compressed into tablets to obtain the product.

[0036] or

[0037] (1) Weigh the required amount of flavoring agent, inclusion agent and pyridostigmine bromide, dissolve them in water, add the penetration enhancer, mix them evenly, and then dry the mixed solution to obtain the pyridostigmine bromide inclusion complex.

[0038] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of filler, disintegrant and glidant, the required amount of lubricant is added, and after even mixing, it is compressed into tablets to obtain the product.

[0039] In the preferred embodiment of the present invention, the drying loss of the bromide pyridostigmine inclusion complex in step (1) is ≤5%, preferably ≤3%.

[0040] In the preferred embodiment of the present invention, the drying in step (1) is selected from either spray drying or vacuum drying.

[0041] In the preferred embodiment of the present invention, the spray drying conditions in step (1) are: the air inlet temperature is 60-90℃ and the material temperature is controlled to be below 80℃.

[0042] In the preferred embodiment of the present invention, the stirring conditions in step (1) are: stirring speed of 30-120 rpm and stirring time of not less than 1 hour.

[0043] In the preferred embodiment of the present invention, the mixing conditions in step (2) are: 10-35 rpm * 1-10 min, preferably 10-20 rpm * 2-5 min.

[0044] In the preferred embodiment of the present invention, the tableting conditions in step (2) are: tablet hardness 10-80N.

[0045] In a preferred embodiment of the present invention, the hardness of the sublingual immediate-release tablet is 10-80N, preferably 20-70N, and more preferably 30-60N.

[0046] In a preferred embodiment of the present invention, the friability of the sublingual immediate-release tablet is ≤1%.

[0047] Another object of the present invention is to provide a method for preparing a pyridostigmine sublingual immediate-release tablet, wherein the sublingual immediate-release tablet contains 15-60% pyridostigmine inclusion complex, 20-75% filler, 5-25% disintegrant, 0.1-10% penetration enhancer, 0-1.5% flavoring agent, 0.4-2% lubricant, and 0-5% flow aid, wherein the weight ratio of pyridostigmine to inclusion agent in the pyridostigmine inclusion complex is 1:1.3-3, and the method for preparing the sublingual immediate-release tablet is to prepare the inclusion complex by spray drying and then prepare the sublingual tablet by mixing and compressing.

[0048] In a preferred embodiment of the present invention, the preparation of sublingual immediate-release tablets by spray drying and subsequent mixing and compression of the inclusion complex includes the following steps:

[0049] (1) Dissolve the required amount of flavoring agent, inclusion agent and pyridostigmine bromide in water, and then dry the resulting solution to obtain the pyridostigmine bromide inclusion complex.

[0050] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of filler, disintegrant, penetration enhancer and flow aid, the required amount of lubricant is added, and after evenly mixed, it is compressed into tablets to obtain the product.

[0051] or

[0052] (1) Weigh the required amount of inclusion agent and pyridostigmine bromide, dissolve them in water, and dry the resulting solution to obtain the pyridostigmine bromide inclusion complex.

[0053] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of flavoring agent, filler, disintegrant, penetration enhancer and flow aid, the required amount of lubricant is added, and after evenly mixed, it is compressed into tablets to obtain the product.

[0054] or

[0055] (1) Weigh the required amount of flavoring agent, inclusion agent and pyridostigmine bromide, dissolve them in water, add the penetration enhancer, mix them evenly, and then dry the mixed solution to obtain the pyridostigmine bromide inclusion complex.

[0056] (2) After the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of filler, disintegrant and glidant, the required amount of lubricant is added, and after even mixing, it is compressed into tablets to obtain the product.

[0057] In the preferred embodiment of the present invention, the drying loss of the bromide pyridostigmine inclusion complex in step (1) is ≤5%, preferably ≤3%.

[0058] In the preferred embodiment of the present invention, the spray drying conditions in step (1) are: the air inlet temperature is 60-90℃ and the material temperature is controlled to be below 80℃.

[0059] In the preferred embodiment of the present invention, the stirring conditions in step (1) are: stirring speed of 30-120 rpm and stirring time of not less than 1 hour.

[0060] In the preferred embodiment of the present invention, the mixing conditions in step (2) are: 10-35 rpm * 1-10 min, preferably 10-20 rpm * 2-5 min.

[0061] In the preferred embodiment of the present invention, the tableting conditions in step (2) are: tablet hardness 10-80N.

[0062] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 3-30 mg of pyridostigmine bromide per unit dose by weight percentage, preferably 5-25 mg, and more preferably 10-20 mg.

[0063] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 18-58% bromide pyridostigmine inclusion complex, preferably 20-56%, by weight percentage.

[0064] In a preferred embodiment of the present invention, the inclusion agent is selected from any one or a combination of sulfobutyl betacyclodextrin and hydroxypropyl betacyclodextrin.

[0065] In a preferred embodiment of the present invention, the weight ratio of pyridostigmine bromide to inclusion agent in the pyridostigmine bromide inclusion complex is 1:1.5-3, preferably 1:2-3.

[0066] In a preferred embodiment of the present invention, the filler is selected from any one or a combination of mannitol, lactose, xylitol, glucose, sucrose, and sorbitol.

[0067] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 23-73% filler, preferably 25-70%, by weight percentage.

[0068] In a preferred embodiment of the present invention, the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and chitosan.

[0069] In a preferred embodiment of the present invention, the disintegrant D 90 ≤200μm, preferably disintegrant D 90 ≤150μm, more preferably disintegrant D 90 ≤110μm, further preferred disintegrant D 90 ≤70μm.

[0070] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 6-22% disintegrant, preferably 8-19%, by weight percentage.

[0071] In a preferred embodiment of the present invention, the penetration enhancer is selected from any one or a combination of menthol, sodium deoxycholate, sodium dodecyl sulfate, polysorbate 80, sodium 8-(2-hydroxybenzamido)octanoate, and azone.

[0072] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.3-9% permeability enhancer, preferably 0.5-8%, by weight percentage.

[0073] In a preferred embodiment of the present invention, the lubricant is selected from any one or a combination of magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and sodium stearate fumarate.

[0074] In a preferred embodiment of the present invention, the immediate-release tablets contain 0.2-4% lubricant by weight, preferably 0.45-2.22%.

[0075] In a preferred embodiment of the present invention, the flow aid is any one or a combination of silica, talc.

[0076] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.2-4% (by weight), preferably 0.45-2.22% (by weight).

[0077] In a preferred embodiment of the present invention, the flavoring agent is selected from any one or a combination of aspartame, sucralose, steviol glycoside, stevioside, flavoring, and sodium glycine.

[0078] In a preferred embodiment of the present invention, the sublingual immediate-release tablet contains 0.1-1.4% flavoring agent, preferably 0.22-1.25% by weight.

[0079] In a preferred embodiment of the present invention, the disintegration time of the sublingual immediate-release tablet is ≤5 min, preferably ≤3 min, and more preferably ≤2 min.

[0080] In a preferred embodiment of the present invention, the dissolution rate of the sublingual immediate-release tablet after being placed in water for 15 minutes is ≥80%, preferably ≥90%, and more preferably ≥95%.

[0081] In a preferred embodiment of the present invention, the hardness of the sublingual immediate-release tablet is 10-80N, preferably 20-70N, and more preferably 30-60N.

[0082] In a preferred embodiment of the present invention, the friability of the sublingual immediate-release tablet is ≤1%.

[0083] Another object of the present invention is to provide a pharmaceutical composition comprising the pyridostigmine sublingual immediate-release tablet and the second drug as described in the present invention.

[0084] In a preferred embodiment of the present invention, the second drug is selected from any one or a combination of hormones (such as prednisone, methylprednisolone, etc.) and other non-hormonal immunosuppressive drugs (such as azathioprine (AZA), tacrolimus (FK-506), mycophenolate mofetil (MMF), cyclosporine, methotrexate (MTX), cyclophosphamide, etc.).

[0085] Another object of the present invention is to provide the use of the pyridostigmine bromide sublingual immediate-release tablets described herein in the preparation of a medicament for the prevention and treatment of any one of myasthenia gravis, postoperative functional flatulence, urinary retention, or their complications.

[0086] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0087] Unless otherwise stated, the present invention uses the following method for detection:

[0088] 1. This invention refers to Method II (paddle method) of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2025 Edition, to determine the dissolution rate of pyridostigmine sublingual immediate-release tablets. The dissolution medium is 900 mL of water, at 37℃±0.5℃, and the rotation speed is 50 rpm. A 10 mL sample is taken at 15 minutes, and the same volume of dissolution medium at the same temperature is immediately replenished. The filtrate is then analyzed by high performance liquid chromatography (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2025 Edition).

[0089] 2. This invention refers to the method (tablets) of General Chapter 0921 (tablets) of Part IV of the Chinese Pharmacopoeia 2025 Edition to detect the disintegration time of pyridostigmine sublingual immediate-release tablets. The ZB-1 intelligent disintegrator (Tianjin Tianda Tianfa) was used, and the dissolution medium was purified water at 37℃±0.5℃.

[0090] 3. This invention selected six healthy volunteers with no history of smoking to evaluate palatability. Before the experiment, the volunteers rinsed their mouths with saline solution. One tablet of each test substance was placed under the volunteer's tongue and held until it completely disintegrated (without a hard core). The remaining powder in the mouth was then spat out, and the volunteers rinsed their mouths again with saline solution, recording their subjective feelings. The taste grading criteria were: extremely bitter, slightly bitter, virtually no bitterness, and no bitterness.

[0091] 4. This invention refers to the high-performance liquid chromatography (HPLC) method for detecting related substances in samples according to General Chapter 0512 of Part IV of the Chinese Pharmacopoeia (2025 Edition). Solvent: 4.3 g / L sodium dodecyl sulfate solution (adjusted to pH 2.0 with phosphoric acid) - acetonitrile (70:30). Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Chrom PAH C18, 250 mm × 4.6 mm, 5 μm); mobile phase A was 4.3 g / L sodium dodecyl sulfate solution (adjusted to pH 2.0 with phosphoric acid) - acetonitrile (80:20), and mobile phase B was 4.3 g / L sodium dodecyl sulfate solution (adjusted to pH 2.0 with phosphoric acid) - acetonitrile (20:80), with gradient elution (Table 1); flow rate was 1.0 mL / min; column temperature was 30 °C; detection wavelength was 220 nm; injection volume was 20 μL.

[0092] Table 1 Gradient elution

[0093] 0 85 15 25 78 22 40 60 40 45 60 40 46 85 15 55 85 15

[0094] Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms. Subtract the peaks of excipients and solvents, and calculate the contents of specific impurities 1 and 2 by peak area using the external standard method with correction factors (Table 2); calculate the contents of other individual impurities by peak area using the external standard method with principal components; and calculate the total amount of impurities.

[0095] Table 2

[0096]

[0097] 5. This invention refers to the high performance liquid chromatography (HPLC) method for detecting the content of pyridostigmine bromide in samples according to General Chapter 0512 of Part IV of the 2025 edition of the Chinese Pharmacopoeia. Chromatographic conditions: octadecylsilane-bonded silica gel was used as the stationary phase; the mobile phase was heptanesulfonate solution (1.0 g of heptanesulfonate was dissolved in 1000 ml of water, 5.0 ml of triethylamine was added, and the pH was adjusted to 3.0 with phosphoric acid) - acetonitrile (90:10); the flow rate was 1.0 ml / min; the column temperature was 30℃; the detection wavelength was 270 nm; and the injection volume was 20 μl.

[0098] System suitability requirements: The theoretical plate number, calculated based on the bright peak of pyridostigmine bromide, should be no less than 2000, and the tailing factor should be no greater than 1.5. Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results using peak area according to the external standard method.

[0099] 6. Method for detecting the concentration of pyridostigmine bromide in plasma:

[0100] Take 50 μL of plasma sample and add 150 μL of internal standard working solution (for blank samples, add an equal volume of methanol-acetonitrile (50:50, v / v)). Vortex for 5 min and centrifuge at 13000 rpm for 5 min at 4℃. Take 50 μL of the supernatant, add 50 μL of pure water, mix well, centrifuge again, and take 70 μL of the supernatant into a sample vial. Inject 5 μL for UPLC-MS / MS analysis.

[0101] The concentration of pyridostigmine bromide in beagle plasma was determined using a Waters UPLC H-Class PLUS (HPLC, detection conditions shown in Tables 1 and 2) coupled with a XevoTQD (triple quadrupole mass spectrometer) system. The linear range of the standard curve was 1–500 ng / mL. Samples were analyzed by UPLC-MS / M after protein precipitation (detection conditions as shown in 3-5). Lincomycin was used as an internal standard, and the standard curve was regressed using the weighted least squares method (weight factor W = 1 / X²). Quantification was based on the ratio of the peak area of ​​the target analyte to that of the internal standard. The retention times of the target analyte and the internal standard were approximately 0.59 min and 1.85 min, respectively.

[0102] Table 3

[0103] Analytical column ACQUITY UPLC® BEH C18 1.7 μm, 2.1×50mm, Waters mobile phase A (acetonitrile) - B (water, containing 2 mmol / L ammonium formate), gradient elution (see Table 2) Injection volume 5μL Column temperature 40℃ Runtime 5.0min Flow rate 0.4 mL / min Retention time <![CDATA[t R (A250101P5)≈0.59min,t R (Lincomycin)≈1.85min]]> Sample inlet temperature 10 ℃ Seal Wash Solution 10% acetonitrile solution Purge solution 10% acetonitrile solution

[0104] Table 4 UPLC gradient elution

[0105] 0 5 95 Initial 0.5 5 95 6 1.5 95 5 6 2.0 95 5 6 2.3 5 95 6 5.0 5 95 6

[0106] Table 5

[0107] ion source Electrospray ionization source (ESI) Scan time 5.0min Capillary voltage 3kV (positive ion) Ion source temperature 150 ℃ Desolvation temperature 500 ℃ Conical orifice airflow velocity 150 L / h Desolvent gas flow rate 1000 L / h Detection mode MRM Multi-Ion Reaction Monitoring Detection of ion pairs m / z 181.03→71.98 (A250101P5), m / z 407.17→126.11 (Lincomycin) Conical hole voltage 36V (A250101P5), 44V (Lincomycin) Collision energy 18eV (A250101P5), 34eV (Lincomycin)

[0108] The pyridostigmine bromide sublingual immediate-release tablets of the present invention have the following beneficial technical effects compared with the prior art:

[0109] 1. Overcoming technological biases, achieving rapid and efficient sublingual delivery of pyridostigmine bromide while completely masking its taste.

[0110] The "Guidelines for the Diagnosis and Treatment of Myasthenia Gravis in China (2025 Edition)" establishes pyridostigmine bromide as a cornerstone for "basic symptomatic treatment of MG patients," but its oral bioavailability is limited to only 11.5%~18.9%, and the maximum daily dose for adults does not exceed 480mg. The "China Food and Drug Administration" clearly states that "raw materials with particularly strong bitterness or requiring large doses are generally not suitable for development into sublingual tablets." This invention scientifically screens the components and proportions of pyridostigmine bromide sublingual immediate-release tablets, and rationally utilizes water-soluble cyclodextrin encapsulation for taste masking and an immediate-release matrix. It effectively addresses the needs of patients with myasthenia gravis (MG) who require rapid onset, high doses, frequent administration, and long-term use, due to the strong hygroscopicity and extremely bitter taste of pyridostigmine bromide. It successfully prepares pyridostigmine bromide, which has an extremely bitter taste and a conventional oral dose as high as 60–120 mg (maximum 480 mg per day), into a palatable sublingual immediate-release tablet. When placed under the tongue in saliva, it rapidly dissolves and disintegrates, allowing the drug to be absorbed through the sublingual mucosa to exert systemic effects while avoiding the first-pass effect, achieving the same drug loading in a single dose. This technology achieves higher plasma exposure, reduces absolute dosage, improves bioavailability, and lowers dosage, successfully enabling rapid and efficient sublingual delivery of pyridostigmine bromide with complete taste masking. It effectively solves the technical challenges of pyridostigmine bromide, such as strong hygroscopicity, extreme bitterness, and the need for rapid onset, high dosage, high frequency, long-term medication compliance, no need for water swallowing, and convenient administration in patients with myasthenia gravis (MG). It is easy for patients with dysphagia to take, has good palatability, excellent stability, improves compliance, and is safe for long-term use. It significantly improves the treatment effect and medication compliance in patients with myasthenia gravis (especially children and patients with dysphagia).

[0111] 2. Rapid onset of action and significantly improved bioavailability.

[0112] The pyridostigmine bromide sublingual immediate-release tablets of this invention rapidly disintegrate and dissolve in the patient's sublingual saliva and oral cavity, releasing the drug within 1 minute. The drug is directly absorbed into the systemic circulation via the rich capillary network of the sublingual mucosa, completely bypassing the first-pass effect of the liver. Compared to oral gavage administration, while ensuring the same pharmacological effects (such as improved muscle tone), the required dosage is significantly reduced, bioavailability is greatly improved, individual patient variability is effectively reduced, dosage is precisely controllable, and respiratory secretions are not increased. Furthermore, the sublingual dosage is far below the 480 mg / day safety limit stipulated in the "Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2025 Edition)," improving adherence and providing reliable assurance for the safety of long-term medication. This highly aligns with the guidelines' recommendation to "use rapid-onset therapy to achieve treatment goals as quickly as possible."

[0113] 3. Convenient to take, significantly improving medication adherence in special patient groups.

[0114] The Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2025 Edition) have updated the treatment goal to achieve minimal symptom expression (MSE), i.e., an MG-ADL score of 0 or 1, and treatment-related adverse reactions ≤ grade 1. This requires extremely high adherence to long-term medication. The pyridostigmine bromide sublingual immediate-release tablets of this invention rationally utilize water-soluble cyclodextrin encapsulation and taste masking + immediate-release matrix, effectively addressing the strong hygroscopicity and extremely bitter taste of pyridostigmine bromide, as well as the need for rapid onset, high doses, high frequency, and long-term medication in patients with myasthenia gravis (MG). It also boasts advantages such as excellent taste, superior stability, convenient administration and portability, and easier dosage control. It dissolves rapidly in the patient's mouth, and administration requires no drinking, eating, or swallowing. It is suitable for MG patients with dysphagia primarily affecting the pharyngeal and / or respiratory muscles (such as type IIb and IVb MG patients, who often have bulbar muscle weakness, resulting in chewing fatigue, dysphagia, and dysarthria), as well as pediatric JMG patients requiring precise dosage dispensing (guidelines recommend pyridostigmine bromide as the primary treatment for JMG). This significantly improves the accuracy, convenience, and long-term medication compliance of myasthenia gravis patients (especially type IIb / IVb dysphagia patients and pediatric JMG patients).

[0115] 4. Excellent stability, solving the problem of strong hygroscopicity of active pharmaceutical ingredients.

[0116] This invention creatively solves the technical problem of pyridostigmine bromide raw material being extremely hygroscopic and liquefied, significantly improving product stability, ensuring stable and controllable quality, and guaranteeing the reliability of long-term storage and safe use.

[0117] 5. The preparation process is simple and suitable for industrial production.

[0118] The preparation method of the pyridostigmine sublingual immediate-release tablets of the present invention is simple to operate, cost-controllable, green and environmentally friendly, easy to realize industrial scale-up production, and has good industrialization prospects. Detailed Implementation

[0119] The following are specific embodiments of the present invention to further illustrate the technical solution of the present invention.

[0120] ZLDBY fluidized bed granulation and coating machine (Chongqing Zhilong Pharmaceutical Machinery Equipment Co., Ltd.), SBH-10 three-dimensional mixer (Changzhou Lima Drying Equipment Co., Ltd.), ZP-10 rotary tablet press (Beijing Guoyao Longli Technology Co., Ltd.), GZ-5 spray dryer (Wuxi Feiyuan Drying Equipment Factory).

[0121] Example 1Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0122] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0123] Pyridostigmine 15 sulfobutyl betacyclodextrin 10 Hydroxypropyl betacyclodextrin 10 lactose 39 <![CDATA[Sodium carboxymethyl starch (d 90 ≤200 μm)]]> 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0124] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0125] (1) Under stirring conditions (80 rpm * 3 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin, sulfobutyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 °C, material temperature did not exceed 80 °C) to obtain pyridostigmine bromide inclusion complex (drying weight loss was less than 3%).

[0126] (2) Under stirring (10 rpm * 10 min), the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of lactose, sodium carboxymethyl starch, silicon dioxide and menthol, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0127] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 38 N, and a friability of 0.72%. The disintegration time is 50 seconds, and the dissolution rate at 15 minutes is 96.5%. The tablets have a good taste, with almost no bitterness or gritty texture.

[0128] Example 2 Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0129] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0130] Pyridostigmine 7.5 sulfobutyl betacyclodextrin 20 Mannitol 50.5 Sodium carboxymethyl starch (d90≤200μm) 8 Sodium deoxycholate 0.5 Stevioside 0.6 silicon dioxide 2 Sodium stearate 0.9

[0131] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0132] (1) Under stirring (80 rpm * 3 h), the required amounts of pyridostigmine bromide, sulfobutyl betacyclodextrin and steviol glycoside were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0133] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of mannitol, sodium carboxymethyl starch, silicon dioxide and sodium deoxycholate, and then the required amount of sodium stearate fumarate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0134] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 52 N, and a friability of 0.46%. The disintegration time is 88 seconds, and the dissolution rate at 15 minutes is 98.7%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0135] Example 3 Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0136] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0137] Pyridostigmine 5 sulfobutyl betacyclodextrin 15 Sorbitol 43 <![CDATA[Microcrystalline cellulose TC-S50 (d 90 ≤200 μm)]]> 14 Sodium dodecyl sulfate 0.5 Mixed Fruit Flavoring 1 silicon dioxide 1 Glyceryl behenate 0.5

[0138] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0139] (1) Under stirring (80 rpm * 3 h), the required amount of pyridostigmine bromide, sulfobutyl betacyclodextrin and mixed fruit flavor (powder) were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0140] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of sorbitol, microcrystalline cellulose TC-S50, silica and sodium dodecyl sulfate, and then the required amount of behenicol glyceride is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0141] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 80 mg, has a hardness of 36 N, and a friability of 0.81%. The disintegration time is 43 seconds, and the dissolution rate at 15 minutes is 99.6%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0142] Example 4 Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0143] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0144] Pyridostigmine 10 sulfobutyl betacyclodextrin 30 Xylitol 40 Chitosan 6.4 Low-substituted hydroxypropyl fibers (d90≤200μm) 14 Sodium 8-(2-hydroxyformamido)octanoate 8 Menthol 0.2 silicon dioxide 0.5 Sodium glycine 0.9

[0145] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0146] (1) Under stirring (80 rpm * 3 h), the required amount of pyridostigmine bromide and sulfobutyl betacyclodextrin were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0147] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amounts of chitosan, xylitol, low-substituted hydroxypropyl cellulose, silicon dioxide, sodium 8-(2-hydroxyformamido)octanoate and menthol, and then the required amount of sodium glycinate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0148] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 54 N, and a friability of 0.55%. The disintegration time is 45 seconds, and the dissolution rate at 15 minutes is 95.2%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0149] Example 5 Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0150] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0151] Pyridostigmine 6 Hydroxypropyl betacyclodextrin 12 sucrose 62.4 Microcrystalline cellulose KG1000 (d90≤200μm) 8 Twain 80 0.9 Sucralose 0.2 stearic acid 0.5

[0152] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0153] (1) Under stirring conditions (80 rpm * 3 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin, sucralose, and Tween 80 were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 °C, and material temperature did not exceed 80 °C) to obtain pyridostigmine bromide inclusion complex (drying weight loss was less than 3%).

[0154] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of sucrose and microcrystalline cellulose KG1000, and then the required amount of stearic acid is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0155] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 110 mg, has a hardness of 68 N, and a friability of 0.35%. The disintegration time is 92 seconds, and the dissolution rate at 15 minutes is 98.3%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0156] Example 6 Preparation of pyridostigmine sublingual immediate-release tablets according to the present invention

[0157] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0158] Pyridostigmine 15 Hydroxypropyl betacyclodextrin 35 Anhydrous lactose 24 Sodium carboxymethyl starch (d90≤200μm) 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0159] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0160] (1) Under stirring (30 rpm * 6 h), the required amount of pyridostigmine bromide, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0161] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0162] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 55 N, and a friability of 0.48%. The disintegration time is 52 seconds, and the dissolution rate at 15 minutes is 95.2%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0163] Example 7: Preparation of the pyridostigmine sublingual immediate-release tablets of the present invention

[0164] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0165] Pyridostigmine 15 Hydroxypropyl betacyclodextrin 35 Anhydrous lactose 24 Sodium carboxymethyl starch (d90≤200μm) 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0166] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0167] (1) Under stirring (80 rpm * 2 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0168] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0169] The tableting process of pyridostigmine bromide sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 72 N, and a friability of 0.27%. The disintegration time is 76 seconds, and the dissolution rate at 15 minutes is 96.73%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0170] Example 8: Preparation of the pyridostigmine sublingual immediate-release tablets of the present invention

[0171] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0172] Pyridostigmine 10 Hydroxypropyl betacyclodextrin 24 Anhydrous lactose 40 Sodium carboxymethyl starch (d90≤200μm) 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0173] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0174] (1) Under stirring conditions (120 rpm * 1 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0175] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0176] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighed 90 mg, had a hardness of 42 N, and a friability of 0.49%. The disintegration time was 58 seconds, and the dissolution rate at 15 minutes was 98.41%. The tablets had a good taste, with virtually no bitterness or gritty texture.

[0177] Example 9: Preparation of the pyridostigmine sublingual immediate-release tablets of the present invention

[0178] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0179] Pyridostigmine 5 Hydroxypropyl betacyclodextrin 12 Anhydrous lactose 57 Sodium carboxymethyl starch (d90≤200μm) 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0180] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0181] (1) Under stirring (100 rpm * 1.5 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0182] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0183] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 56 N, and a friability of 0.42%. The disintegration time is 63 seconds, and the dissolution rate at 15 minutes is 96.2%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0184] Example 10: Preparation of the pyridostigmine sublingual immediate-release tablets of the present invention

[0185] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0186] Pyridostigmine 15 sulfobutyl betacyclodextrin 15 Hydroxypropyl betacyclodextrin 5 Anhydrous lactose 39 Sodium carboxymethyl starch (d90≤200μm) 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0187] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0188] (1) Under stirring conditions (75 rpm * 8 h), the required amounts of pyridostigmine bromide, sulfobutyl betacyclodextrin, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 °C, material temperature did not exceed 80 °C) to obtain pyridostigmine bromide inclusion complex (drying weight loss was less than 3%).

[0189] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0190] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 66 N, and a friability of 0.36%. The disintegration time is 65 seconds, and the dissolution rate at 15 minutes is 97.2%. The tablets have a good taste, with virtually no bitterness or gritty texture.

[0191] Comparative Example 1 Preparation of pyridostigmine sublingual immediate-release tablets

[0192] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0193] Pyridostigmine 15 sulfobutyl betacyclodextrin 10 Sorbitol 57 Sodium carboxymethyl cellulose 4 Sodium deoxycholate 0.9 Sucralose 0.2 silicon dioxide 2 Sodium stearate 0.9

[0194] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0195] (1) Under stirring (80 rpm * 3 h), the required amount of pyridostigmine bromide, sulfobutyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 °C, material temperature did not exceed 80 °C) to obtain pyridostigmine bromide inclusion complex (drying weight loss was less than 3%).

[0196] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of sorbitol, sodium carboxymethyl cellulose, sodium deoxycholate and silicon dioxide, and then the required amount of sodium stearate fumarate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0197] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 75 N, and a friability of 0.43%. The disintegration time is 392 seconds, and the dissolution rate at 15 minutes is 81.8%. The taste is extremely bitter, without any gritty sensation.

[0198] Comparative Example 2: Preparation of Pyridostigmine Sublingual Immediate-Release Tablets

[0199] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0200] Pyridostigmine 15 Hydroxypropyl betacyclodextrin 17 Anhydrous lactose 44 Sodium carboxymethyl starch 8 Menthol 2 Stevioside 0.6 silicon dioxide 2 stearic acid 1.4 total 90

[0201] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0202] (1) Under stirring (80 rpm * 3 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin and steviol glycoside were dissolved in water, and the resulting solution was spray-dried (inlet air temperature was 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0203] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridostigmine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of stearic acid is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0204] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighed 90 mg, had a hardness of 65 N, and a friability of 0.38%. The disintegration time was 105 seconds, and the dissolution rate at 15 minutes was 93.8%. The tablets had a bitter taste without any gritty texture.

[0205] Preparation of pyridostigmine sublingual immediate-release tablets (comparative example)

[0206] Composition of pyridostigmine sublingual immediate-release tablets (1000 tablets):

[0207] Pyridostigmine 15 Hydroxypropyl betacyclodextrin 35 lactose 24 Sodium carboxymethyl starch 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0208] The preparation of pyridostigmine sublingual immediate-release tablets includes the following steps:

[0209] (1) Under stirring (30 rpm * 0.5 h), the required amounts of pyridostigmine bromide, hydroxypropyl betacyclodextrin and sucralose were dissolved in water, and the resulting solution was dried in a fluidized bed (inlet air temperature of 75 ± 15 ° C, material temperature not exceeding 80 ° C) to obtain pyridostigmine bromide inclusion complex (drying weight loss less than 3%).

[0210] (2) Under stirring conditions (10 rpm * 10 min), the prepared bromide pyridoxine inclusion complex is mixed evenly with the required amount of anhydrous lactose, sodium carboxymethyl starch, menthol and silicon dioxide, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0211] The tableting process of pyridostigmine sublingual immediate-release tablets was successful, and the resulting tablets were intact, without cracks or fragments. Each tablet weighs 90 mg, has a hardness of 44 N, a disintegration time of 52 seconds, and a 15-minute dissolution rate of 95.2%. It has an extremely bitter taste without any gritty sensation.

[0212] Comparative Example 4: Preparation of Pyridostigmine Bromide Oral Tablets. Composition of Pyridostigmine Bromide Oral Tablets (1000 tablets):

[0213] Pyridostigmine 15 lactose 59 <![CDATA[Sodium carboxymethyl starch (d 90 ≤200μm)]]> 12 Menthol 0.9 Sucralose 0.2 silicon dioxide 2 magnesium stearate 0.9

[0214] The preparation of pyridostigmine bromide oral tablets includes the following steps:

[0215] (1) Under stirring conditions (60 rpm * 4 h), the required amount of pyridostigmine bromide and sucralose were dissolved in water and the resulting mixed solution was set aside. Microcrystalline cellulose KG1000, lactose and sodium carboxymethyl starch were mixed and added to a fluidized bed for drying (inlet air temperature of 75 ± 15 ℃, material temperature not exceeding 80 ℃). The mixed solution was sprayed into the fluidized bed for one-step granulation to obtain pyridostigmine bromide granules (drying weight loss less than 3%).

[0216] (2) Under stirring conditions (10 rpm * 10 min), the prepared pyridostigmine granules are mixed evenly with the required amount of menthol and silica, and then the required amount of magnesium stearate is added and mixed evenly (10 rpm * 5 min), and then compressed into tablets to obtain the product.

[0217] The tableting process of pyridostigmine bromide tablets was successful, and the resulting tablets were intact. Each tablet weighed 110 mg, had a hardness of 47 N, a disintegration time of 56 s, and a dissolution rate of 98.45% at 15 min. The tablets had an extremely bitter taste and no gritty texture.

[0218] Experimental Example 1 Pharmacokinetic Study of Pyridostigmine Sublingual Immediate-Release Tablets of this Invention

[0219] Using the pyridostigmine bromide sublingual immediate-release tablet (15 mg / tablet) from Example 1 as an example, its pharmacokinetics were studied.

[0220] Two male Beagles of common grade, weighing 11-13 kg and approximately 8-9 months old, were randomly divided into two groups. Group 1 received one sublingual pyridostigmine bromide immediate-release tablet (15 mg / tablet) from Example 1, while Group 2 received one oral pyridostigmine bromide oral tablet (15 mg / tablet) from Comparative Example 4. The animals were fasted for 12 hours before administration but allowed normal water intake; they were fed and allowed normal water intake 6 hours after administration. After 7 days, the administration was reversed: Group 1 received one oral pyridostigmine bromide oral tablet (15 mg / tablet) from Comparative Example 4, while Group 2 received one sublingual pyridostigmine bromide immediate-release tablet (15 mg / tablet) from Example 1.

[0221] Oral administration method: Fix the dog's limbs to the support, open the dog's mouth with your hands and put the tablet into the base of the dog's tongue. Immediately close the dog's mouth tightly, stroke the dog's throat with one hand to help it swallow, and finally give the animal 5-10mL of drinking water with a syringe to confirm that the tablet has been swallowed. The dosage is 1 tablet, each containing 15mg of the drug.

[0222] Sublingual administration: Secure the dog's limbs to a support, gently separate the dog's mouth, and place one tablet under the tongue. Immediately close the dog's mouth tightly, keeping it slightly upward. After approximately 10 minutes, gently separate the mouth to check for complete disintegration of the medication. Single dose: one tablet containing 15 mg of medication.

[0223] Blood samples of 0.4 mL were collected from the cephalic vein of the right forelimb of the experimental animals at 0 min before administration and at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 8 h, 12 h, and 24 h after administration. The blood samples were anticoagulated with EDTA-2K, centrifuged (1800 g * 10 min, 4 ℃), and the supernatant (plasma sample) was collected. Pharmacokinetic parameters were then analyzed, and the results are shown in Table 6. Compared with an equivalent dose of conventional oral tablets, the in vivo Cmax and exposure (AUC) of the bromide pyridostigmine sublingual immediate-release tablets of this invention were significantly increased, with an AUC increase of approximately 1.9 times and a peak time of 0.5 h.

[0224] Table 6

[0225] <![CDATA[t 1 / 2 (h)]]> 3.55 4.04 <![CDATA[T max (h)]]> 0.50 4.00 <![CDATA[C max (ng / mL)]]> 209.46 115.91 <![CDATA[AUC 0-t (mg / mL)]]> 1918.04 1004.74 <![CDATA[AUC 0-inf (mg / mL)]]> 1991.87 1015.20

[0226] Experimental Example 2 Stability study of the pyridostigmine sublingual immediate-release tablets of this invention

[0227] Taking the pyridostigmine sublingual immediate-release tablets of Example 1 as an example, they were placed at (40°C, 65% relative humidity) for 6 months, and samples were taken at 1 month, 2 months, 3 months and 6 months to examine their stability. The results are shown in Table 7.

[0228] Table 7

[0229]

[0230] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A pyridostigmine sublingual immediate-release tablet, wherein, by weight percentage, the sublingual immediate-release tablet contains 15-60% pyridostigmine inclusion complex, 20-75% filler, 5-25% disintegrant, 0.1-10% penetration enhancer, 0-1.5% flavoring agent, 0.4-2% lubricant, and 0-5% flow aid, wherein, The weight ratio of pyridostigmine bromide to inclusion agent in the pyridostigmine bromide inclusion complex is 1:1.3-3.

2. The sublingual immediate-release tablet as described in claim 1, wherein the inclusion agent is selected from any one or a combination of sulfobutyl betacyclodextrin and hydroxypropyl betacyclodextrin.

3. The sublingual immediate-release tablet according to any one of claims 1-2, wherein the filler is selected from any one or a combination of mannitol, lactose, xylitol, glucose, sucrose, and sorbitol.

4. The sublingual immediate-release tablet according to any one of claims 1-3, wherein the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and chitosan.

5. The sublingual immediate-release tablet according to any one of claims 1-4, wherein the penetration enhancer is selected from any one or a combination of menthol, sodium deoxycholate, sodium dodecyl sulfate, polysorbate 80, sodium 8-(2-hydroxybenzamido)octanoate, and azone.

6. The sublingual immediate-release tablet according to any one of claims 1-5, wherein the lubricant is selected from any one or a combination of magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and sodium stearate fumarate.

7. The sublingual immediate-release tablet according to any one of claims 1-6, wherein the gliding agent is any one or a combination of silica, talc.

8. The method for preparing pyridostigmine sublingual immediate-release tablets according to any one of claims 1-7 specifically involves preparing an inclusion complex by spray drying and then preparing sublingual immediate-release tablets by mixing and compressing.

9. A pharmaceutical composition comprising a pyridostigmine sublingual immediate-release tablet as described in any one of claims 1-8 and a second drug.

10. The use of the pyridostigmine bromide sublingual immediate-release tablets as described in any one of claims 1-8 in the preparation of a medicament for the prevention and treatment of any one of myasthenia gravis, postoperative functional flatulence, urinary retention, or their complications.

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