Oxazepam tablet compositions and methods of their preparation and stabilization

Abstract

This invention relates to oxazepam tablet compositions and methods for their preparation and stabilization. Specifically, this invention relates to pharmaceutical compositions in tablet form comprising: oxazepam, sodium lauryl sulfate, citric acid, starch, povidone K30, microcrystalline cellulose, lactose, calcium hydrogen phosphate, sodium carboxymethyl starch, and polyethylene glycol 6000. This invention also relates to methods for preparing the pharmaceutical compositions in tablet form, and the use of the pharmaceutical compositions in the preparation of remedies for anxiety, anticonvulsant, sedative, hypnotic, and alcohol withdrawal symptoms. The pharmaceutical compositions in tablet form of this invention possess excellent pharmaceutical properties, such as excellent stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a central nervous system drug oxazepam tablet composition for short-term relief of anxiety, tension, and agitation, and can also be used as an adjunct to hypnosis, anxiety accompanied by depression, and to relieve acute alcohol withdrawal symptoms. It also relates to its preparation method and stabilization method. Background Technology

[0002] Oxazepam, chemical name: 5-phenyl-3-hydroxy-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, (±)-7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, molecular formula C15H11ClN2O2, molecular weight 286.71, its chemical structural formula is:

[0003] Oxazepam active pharmaceutical ingredient (API) is a white or off-white granular powder; practically odorless. Oxazepam API is slightly soluble in ethanol, chloroform, or acetone; very slightly soluble in ether; and practically insoluble in water. The melting point of oxazepam API is 198-202°C; it decomposes upon melting.

[0004] Oxazepam is a benzodiazepine hypnotic and sedative. It has anticonvulsant, antiepileptic, anti-anxiety, sedative-hypnotic, central skeletal muscle relaxant, and temporary amnesia effects. This drug acts on benzodiazepine receptors (BZRs) in the central nervous system, enhancing the binding of the central inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to GABA receptors, thereby increasing the activity of the GABA system. BZRs are classified into type I and type II. It is believed that type I receptor excitation can explain the anti-anxiety effect of BZ drugs, while type II receptors are related to the sedative and skeletal muscle relaxant effects of this class of drugs. With increasing dosage, clinical manifestations can range from mild sedation to hypnosis and even coma; long-term use can lead to dependence. Clinically, oxazepam is mainly used for short-term relief of anxiety, tension, and agitation. It can also be used as an adjunct to hypnosis and anxiety accompanied by depression, and can relieve acute alcohol withdrawal symptoms. Oxazepam's muscle relaxant effect is stronger than other benzodiazepines. Generally, the usual adult dosage for clinical use is as follows: For anti-anxiety, 15-30 mg three to four times a day; for sedation and hypnosis, and acute alcohol withdrawal symptoms, 15-30 mg three to four times a day; for general insomnia, 15 mg, taken before bedtime.

[0005] The 2020 edition of the Chinese Pharmacopoeia, Part II, includes the active pharmaceutical ingredient (API) and tablets of oxazepam, with each tablet containing 15 mg. Both the API and tablets undergo related substance testing, and specific limits are specified for impurity I (also referred to as impurity B or oxazepam related substance B in this article, referring to EP10.0 and USP40) and impurity II (also referred to as impurity C or oxazepam related substance C in this article, referring to EP10.0 and USP40). Their chemical structures are as follows:

[0006] Furthermore, due to the poor solubility of oxazepam, all versions of the pharmacopoeia require dissolution testing for oxazepam tablets. For example, the 2020 edition of the Chinese Pharmacopoeia stipulates that the dissolution rate of oxazepam tablets in 1000 ml of 0.1 mol / L hydrochloric acid solution using the slurry method at 50 rpm for 60 minutes should be greater than 70% of the labeled amount. The United States Pharmacopeia (USP) 40 stipulates that the dissolution rate of oxazepam tablets in 1000 ml of 0.1 mol / L hydrochloric acid solution using the slurry method at 50 rpm for 60 minutes should be greater than 80% of the labeled amount.

[0007] In addition, it is known that the typical degradation product of oxazepam is impurity II, namely impurity C of USP40: 6-chloro-4-phenylquinazoline-2-carboxaldehyde. Therefore, it is valuable to monitor this impurity C during the preparation of oxazepam tablets.

[0008] Given that oxazepam is a commonly used antipsychotic drug in clinical practice, the preparation of an oxazepam tablet with excellent properties, such as a tablet with excellent stability, is something that those skilled in the art urgently desire. Summary of the Invention

[0009] The present invention aims to provide an oxazepam tablet pharmaceutical composition with excellent properties, such as an oxazepam tablet pharmaceutical composition with excellent stability. Another object of the present invention is to provide a method for preparing the tablet pharmaceutical composition. A further object of the present invention is to provide the use of the oxazepam tablet pharmaceutical composition obtained by the present invention in the preparation of medicaments for the treatment or prevention of mental illness. It has been unexpectedly found that the oxazepam tablet pharmaceutical composition prepared by the method of the present invention exhibits one or more excellent effects as described in the context herein.

[0010] Therefore, a first aspect of the present invention provides a pharmaceutical composition in tablet form, comprising: oxazepam, sodium lauryl sulfate, citric acid, starch, povidone K30, microcrystalline cellulose, lactose, calcium hydrogen phosphate, sodium carboxymethyl starch, and polyethylene glycol 6000.

[0011] According to a pharmaceutical composition of the first aspect of the present invention, the composition comprises: 15 parts by weight of oxazepam, 0.9 to 1.1 parts by weight of sodium lauryl sulfate, 1.8 to 2.2 parts by weight of citric acid, 4 to 6 parts by weight of starch, 3.6 to 4.4 parts by weight of povidone K30, 24 to 36 parts by weight of microcrystalline cellulose, 16 to 24 parts by weight of lactose, 20 to 30 parts by weight of dicalcium phosphate, 6.3 to 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

[0012] According to a pharmaceutical composition of the first aspect of the present invention, the composition comprises: 15 parts by weight of oxazepam, 0.9 to 1.1 parts by weight of sodium lauryl sulfate, 1.8 to 2.2 parts by weight of citric acid, 4.5 to 5.5 parts by weight of starch, 3.6 to 4.4 parts by weight of povidone K30, 27 to 33 parts by weight of microcrystalline cellulose, 18 to 22 parts by weight of lactose, 22.5 to 27.5 parts by weight of dicalcium phosphate, 6.3 to 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

[0013] The pharmaceutical composition according to a first aspect of the present invention comprises: 15 parts by weight of oxazepam, 1 part by weight of sodium lauryl sulfate, 2 parts by weight of citric acid, 5 parts by weight of starch, 4 parts by weight of povidone K30, 30 parts by weight of microcrystalline cellulose, 20 parts by weight of lactose, 25 parts by weight of dicalcium phosphate, 7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 1.

[0014] The pharmaceutical composition according to a first aspect of the present invention comprises: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4.5 parts by weight of starch, 3.6 parts by weight of povidone K30, 33 parts by weight of microcrystalline cellulose, 18 parts by weight of lactose, 27.5 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 2.

[0015] The pharmaceutical composition according to a first aspect of the present invention comprises: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 5.5 parts by weight of starch, 4.4 parts by weight of povidone K30, 27 parts by weight of microcrystalline cellulose, 22 parts by weight of lactose, 22.5 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 3.

[0016] The pharmaceutical composition according to a first aspect of the present invention comprises: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 6 parts by weight of starch, 4.4 parts by weight of povidone K30, 24 parts by weight of microcrystalline cellulose, 24 parts by weight of lactose, 20 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 4.

[0017] The pharmaceutical composition according to a first aspect of the present invention comprises: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4 parts by weight of starch, 3.6 parts by weight of povidone K30, 36 parts by weight of microcrystalline cellulose, 16 parts by weight of lactose, 30 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 5.

[0018] According to the pharmaceutical composition of the first aspect of the invention, each tablet contains 5 to 50 mg of oxazepam, for example, 10 to 30 mg of oxazepam per tablet, for example, 10 mg, 15 mg or 30 mg of oxazepam per tablet.

[0019] The pharmaceutical composition according to a first aspect of the present invention is prepared by a method comprising the steps of: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 10-14%, for example 11-13%, for example 12%, as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly and place them in a fluidized bed dryer granulator. Adjust the fan frequency to keep the material in a fluidized state. Turn on the heater to make the material temperature reach and maintain at 38~42℃, for example, 39~41℃. Spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.4MPa, for example, 0.15~0.25MPa, for example, 0.2~0.3MPa, for example, 0.3~0.4MPa. Maintain the aforementioned humidity and continue fluidizing until dry (moisture content less than 5%) to obtain granules A. Then add microcrystalline cellulose, lactose, and dicalcium phosphate to the fluidized bed dryer and mix with granules A. Spray binder B into the fluidized drug powder at the aforementioned temperature and atomization pressure. Maintain the aforementioned temperature and continue fluidizing until the material is dried until the granule moisture content is less than 2.0%. Then, granulate the material through a φ1.0mm stainless steel screen to obtain granules B. (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules is determined and the tablet weight is calculated. The tablets are then compressed into tablets using a tableting machine.

[0020] According to the pharmaceutical composition of the first aspect of the present invention, step (4) is prepared as follows: the drug content in the final mixed granules is determined and the tablet weight is calculated, and the tablets are compressed with a φ6.5mm flat oblique die to a hardness of 6.5±0.5kg to obtain oxazepam tablets, each containing 15mg of oxazepam, and the tablets are packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0021] Furthermore, a second aspect of the present invention provides a method for preparing a pharmaceutical composition in tablet form, the pharmaceutical composition comprising: oxazepam, sodium lauryl sulfate, citric acid, starch, povidone K30, microcrystalline cellulose, lactose, calcium hydrogen phosphate, sodium carboxymethyl starch, and polyethylene glycol 6000; the method comprising the following steps: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 10-14%, for example 11-13%, for example 12%, as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly and place them in a fluidized bed dryer granulator. Adjust the fan frequency to keep the material in a fluidized state. Turn on the heater to make the material temperature reach and maintain at 38~42℃, for example, 39~41℃. Spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.4MPa, for example, 0.15~0.25MPa, for example, 0.2~0.3MPa, for example, 0.3~0.4MPa. Maintain the aforementioned humidity and continue fluidizing until dry (moisture content less than 5%) to obtain granules A. Then add microcrystalline cellulose, lactose, and dicalcium phosphate to the fluidized bed dryer and mix with granules A. Spray binder B into the fluidized drug powder at the aforementioned temperature and atomization pressure. Maintain the aforementioned temperature and continue fluidizing until the material is dried until the granule moisture content is less than 2.0%. Then, granulate the material through a φ1.0mm stainless steel screen to obtain granules B. (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules is determined and the tablet weight is calculated. The tablets are then compressed into tablets using a tableting machine.

[0022] According to the method of the second aspect of the present invention, step (4) is carried out as follows: the drug content in the final mixed granules is determined and the tablet weight is calculated, and the tablets are compressed with a φ6.5mm flat oblique die at a hardness of 6.5±0.5kg to obtain oxazepam tablets, each containing 15mg of oxazepam, and the tablets are packaged in PVC solid pharmaceutical hard sheet / pharmaceutical aluminum foil blister packs.

[0023] According to a second aspect of the present invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 0.9 to 1.1 parts by weight of sodium dodecyl sulfate, 1.8 to 2.2 parts by weight of citric acid, 4 to 6 parts by weight of starch, 3.6 to 4.4 parts by weight of povidone K30, 24 to 36 parts by weight of microcrystalline cellulose, 16 to 24 parts by weight of lactose, 20 to 30 parts by weight of dicalcium phosphate, 6.3 to 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

[0024] According to a second aspect of the present invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 0.9 to 1.1 parts by weight of sodium lauryl sulfate, 1.8 to 2.2 parts by weight of citric acid, 4.5 to 5.5 parts by weight of starch, 3.6 to 4.4 parts by weight of povidone K30, 27 to 33 parts by weight of microcrystalline cellulose, 18 to 22 parts by weight of lactose, 22.5 to 27.5 parts by weight of dicalcium phosphate, 6.3 to 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

[0025] According to a second aspect of the invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 1 part by weight of sodium lauryl sulfate, 2 parts by weight of citric acid, 5 parts by weight of starch, 4 parts by weight of povidone K30, 30 parts by weight of microcrystalline cellulose, 20 parts by weight of lactose, 25 parts by weight of dicalcium phosphate, 7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 1.

[0026] According to a second aspect of the invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4.5 parts by weight of starch, 3.6 parts by weight of povidone K30, 33 parts by weight of microcrystalline cellulose, 18 parts by weight of lactose, 27.5 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 2.

[0027] According to a second aspect of the invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 5.5 parts by weight of starch, 4.4 parts by weight of povidone K30, 27 parts by weight of microcrystalline cellulose, 22 parts by weight of lactose, 22.5 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 3.

[0028] According to a second aspect of the invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 6 parts by weight of starch, 4.4 parts by weight of povidone K30, 24 parts by weight of microcrystalline cellulose, 24 parts by weight of lactose, 20 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 4.

[0029] According to a second aspect of the invention, the pharmaceutical composition comprises: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4 parts by weight of starch, 3.6 parts by weight of povidone K30, 36 parts by weight of microcrystalline cellulose, 16 parts by weight of lactose, 30 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000. For example, it is a tablet prepared according to Example 5.

[0030] According to the method of the second aspect of the present invention, each tablet of the pharmaceutical composition contains 5 to 50 mg of oxazepam, for example, 10 to 30 mg of oxazepam per tablet, for example, 10 mg, 15 mg or 30 mg of oxazepam per tablet.

[0031] The third aspect of the present invention provides the use of the pharmaceutical composition of any one of the first aspects of the present invention in the preparation of a medicament for the treatment of anxiety, anticonvulsant, sedation, hypnosis, and relief of alcohol withdrawal symptoms.

[0032] Although the specific steps described in the preparation method of the present invention differ in some details or language from the steps described in the preparation examples in the detailed embodiments section below, those skilled in the art can fully summarize the above-described method steps based on the detailed disclosure of the entire present invention.

[0033] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of the present invention can be applied to the same technical feature in other embodiments, as long as they do not contradict each other. The present invention will now be further described.

[0034] All references cited in this invention are incorporated herein by reference in their entirety, and in the event of any inconsistency between the meanings expressed in these references and those expressed herein, the meanings expressed herein shall prevail. Furthermore, the various terms and phrases used in this invention have their general meanings known to those skilled in the art; however, this invention still seeks to provide a more detailed explanation and interpretation of these terms and phrases, and in the event of any inconsistency between the mentioned terms and their known meanings and those expressed herein, the meanings expressed herein shall prevail.

[0035] Oxazepam, also known as desmethylolpropionate, is a short-acting benzodiazepine. It is a metabolite of several benzodiazepines, such as diazepam, temazepam, and prazolam, and has anti-anxiety, anticonvulsant, sedative, hypnotic, and alcohol withdrawal symptom relief effects. Since its introduction to the US and Europe in the 1960s, it has become one of the most widely used benzodiazepines, and its use in my country began in the 1980s. Clinically, it is mainly used to treat anxiety disorders, insomnia, and alcohol withdrawal.

[0036] Oxazepam is absorbed slowly via oral administration, with peak absorption occurring 1–4 hours later, a half-life of 5–15 hours, and a surface distribution of 0.6–2.0 L / kg. After entering the body, oxazepam primarily binds to plasma proteins, with an affinity constant of 3.5 × 10⁻⁶. 5 Oxazepam, in its free form, accounts for 2-4%. Oxazepam is not metabolized by cytochrome P450 enzymes but is directly covalently bound to glucuronic acid in the liver and excreted by the kidneys, with a plasma clearance rate of 0.9-2.0 ml / min / kg. The pharmacokinetics of oxazepam in humans are less affected by age and liver function, but exhibit gender differences. S-glucuronide oxazepam is the main metabolite of oxazepam, metabolized by UDP-glucuronyltransferase 2B15. Polymorphisms in the UGT2B15 gene affect oxazepam metabolism. Court et al. performed genotype-phenotype analysis on tissue samples from the same site in the livers of 54 healthy subjects and found three variants in the UGT2B15 gene sequence: D85Y, T352I, and K523T, with frequencies of 0.56, 0.02, and 0.40, respectively. Among them, the Y / Y type of the D85Y gene has a higher S-glucosidation level than the D / D type, and oxazepam is metabolized faster, while the D / Y type is in between; the T / I type of the T352I gene has a higher S-glucosidation level than the T / T type; while the K523T gene variation has no significant effect on the S-glucosidation level of oxazepam.

[0037] Oxazepam is an exogenous inhibitory neurotransmitter that primarily works by binding to benzodiazepine receptors in the central nervous system. This promotes the binding of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to GABA A receptors, increasing the opening frequency of chloride channels and causing postsynaptic hyperpolarization, thereby producing central inhibitory and skeletal muscle relaxant effects. Oxazepam mainly acts on the mesolimbic system, thalamus, and hypothalamus, producing anti-anxiety, anticonvulsant, antiepileptic, sedative, hypnotic, and temporary amnesia effects. Oxazepam also blocks spinal cord afferent pathways and relaxes skeletal muscles. Oxazepam can inhibit the central nervous system to varying degrees, from mild sedation to coma.

[0038] Animal studies have shown that oxazepam is a non-genotoxic carcinogen in rodents. It promotes cell mitosis, causing excessive cell proliferation and leading to cancer. Experiments have shown that oxazepam is associated with an increased incidence of hepatocellular carcinoma and hepatocellular adenoma in both male and female Swiss-Webster mice; it is also associated with an increased incidence of hepatoblastoma, hepatoblastic adenoma, hepatocellular carcinoma, and hepatocellular adenoma in both male and female B6C3F1 mice; oxazepam exposure also increased the incidence of thyroid follicular hyperplasia and follicular adenoma in female B6C3F1 mice. Currently, it is believed that the occurrence of rodent tumors is related to oxazepam's induction of cytochrome P450, CYP2B, CYP4A, glutathione transferase, glucuronyl transferase activity, and an increased liver-to-body weight ratio.

[0039] Oxazepam is a benzodiazepine used to treat various anxiety disorders, such as generalized anxiety disorder, panic attacks, social or simple phobias, obsessive-compulsive disorder, and anxiety related to physical illness or perioperative periods; sleep disorders; various status epilepticus, such as status epilepticus, neonatal febrile seizures, eclampsia, and tetanus; various paralytic disorders, such as cerebral palsy, multiple sclerosis, and paraplegia due to spinal cord injury; various involuntary motor disorders, such as restless legs syndrome, akathisia caused by antipsychotic drugs, chorea, and muscle spasms; and withdrawal from alcohol and other substance abuse. Clinically, oxazepam is mainly used to treat anxiety disorders, insomnia, and alcohol withdrawal. For patients with anxiety disorders, due to the fluctuating symptoms and episodic nature of the disease, anti-anxiety medications require greater flexibility. Oxazepam, with its short duration of action, simple metabolism, and low accumulation, has become an ideal anti-anxiety drug. Clinical drug trials have shown that oxazepam's anti-anxiety effect is superior to buspirone. As a sedative-hypnotic drug, oxazepam can shorten sleep latency, reduce the number of awakenings during the night, and improve sleep quality, with no significant discomfort upon waking; only a few patients experience nausea and headache. Oxazepam's overall efficacy in treating insomnia is comparable to midazolam, and patient satisfaction with both drugs is high. However, due to its longer absorption time and slower onset of action, oxazepam is not suitable for patients with sleep disorders who require immediate sleep. Oxazepam has a synergistic effect with alcohol and carries a lower risk of abuse; therefore, it is often used to treat alcohol withdrawal and alleviate withdrawal symptoms such as delirium tremens and alcohol-induced hallucinations and delusions. Studies have shown that for patients with alcohol withdrawal, administration at the onset of symptoms is safe and effective, and it is more helpful in preventing drug tolerance than regular administration.

[0040] Because oxazepam has low addictive potential, its exposure has minimal impact on conditioned position preference (CPP) and conditioned position aversion (CPA) in animals. When used in combination with other substances, it has minimal interference with the formation of CPP or CPA in the latter. Therefore, it is often used as a representative of benzodiazepines. Since its introduction in the 1960s, oxazepam has been favored by doctors, patients, and researchers due to its superior properties, quickly becoming one of the most widely used benzodiazepines in Europe and America. Oxazepam's advantages are mainly reflected in its simple metabolic process, less affected by age and liver function; short half-life, making it less prone to accumulation in the body; low addictive potential, and difficulty in forming CPP or CPA in animals. Clinically, it is most commonly used to treat anxiety disorders, insomnia, and alcohol withdrawal, especially suitable for patients with mild liver impairment and the elderly. Attached Figure Description

[0041] Figure 1 Example 1: Typical UV-Vis spectrophotometric scan of tablets.

[0042] Figure 2 Typical chromatogram for tablet content determination.

[0043] Figure 3 A typical system suitability solution chromatogram for related substance testing.

[0044] Figure 4 Typical chromatograms of test solutions for related substances testing. Detailed Implementation

[0045] The following embodiments provided in this invention are for illustrative purposes only and are not intended to be used, nor should they be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention. The materials and methods used in the experiments are described generally and / or specifically in this invention. While many of the materials and methods of operation used to achieve the objectives of this invention are well known in the art, the invention is still described in as much detail as possible herein. It will be apparent to those skilled in the art that, unless otherwise stated, the materials and methods of operation used in this invention are well known in the art.

[0046] In the specific examples of oxazepam tablet preparation described below, the dosage is expressed as one tablet when the prescription is written, but in actual production, the dosage is 50,000 tablets per batch to achieve pilot-scale specifications. For ease of description, this invention prepares oxazepam tablets with a specification of 15 mg oxazepam per tablet. In the specific examples of oxazepam tablet preparation in this invention, unless otherwise stated, the oxazepam active pharmaceutical ingredient used is from the same batch. In the specific examples of this invention, unless otherwise stated, all raw and excipient materials used are pretreated using processes commonly used in the pharmaceutical field, such as pulverization and sieving (each excipient is pre-pulverized to pass through 80 mesh, and oxazepam is pre-pulverized to pass through 120 mesh, which is a conventional operation in the field).

[0047] Example 1: Preparation of Oxazepam Tablets Prescription (per tablet): Oxazepam: 15mg Sodium dodecyl sulfate: 1 mg Citric acid: 2mg Starch: 5mg Povidone K30: 4mg Microcrystalline cellulose: 30mg Lactose: 20mg Calcium hydrogen phosphate: 25mg Sodium carboxymethyl starch: 7mg Polyethylene glycol 6000: 1mg Water: in appropriate amounts, eventually removed.

[0048] Preparation method: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 12%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place in a fluidized bed dryer granulator, adjust the fan frequency to keep the material in a fluidized state, turn on the heater to make the material temperature reach and maintain at 39~41℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.2~0.3MPa, maintain the above humidity and continue fluidization until dry (moisture content less than 5%) to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried until the granule moisture content is less than 2.0%, and then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules was determined and the tablet weight was calculated. The tablets were compressed using a φ6.5mm flat slant die with a hardness of 6.5±0.5kg to obtain oxazepam tablets. Each tablet contained 15mg of oxazepam. The tablets were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0049] Of course, during tableting, larger or smaller dies can be selected to compress tablets containing 10mg or 30mg of tranexamic acid per tablet, or to compress tablets of other content specifications, which can be done by those skilled in the art based on conventional experience.

[0050] Example 2: Preparation of Oxazepam Tablets Prescription (per tablet): Oxazepam: 15mg Sodium dodecyl sulfate: 0.9 mg Citric acid: 2.2mg Starch: 4.5mg Povidone K30: 3.6mg Microcrystalline cellulose: 33mg Lactose: 18mg Calcium hydrogen phosphate: 27.5 mg Sodium carboxymethyl starch: 6.3 mg Polyethylene glycol 6000: 1mg Water: in appropriate amounts, eventually removed.

[0051] Preparation method: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 10%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place them in a fluidized bed dryer granulator, adjust the fan frequency to keep the material in a fluidized state, turn on the heater to make the material temperature reach and maintain at 40~42℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.3~0.4MPa, maintain the above humidity and continue fluidization until dry (moisture content less than 5%) to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried until the granule moisture content is less than 2.0%, and then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules was determined and the tablet weight was calculated. The tablets were compressed using a φ6.5mm flat slant die with a hardness of 6.5±0.5kg to obtain oxazepam tablets. Each tablet contained 15mg of oxazepam. The tablets were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0052] Example 3: Preparation of Oxazepam Tablets Prescription (per tablet): Oxazepam: 15mg Sodium dodecyl sulfate: 1.1 mg Citric acid: 1.8mg Starch: 5.5mg Povidone K30: 4.4mg Microcrystalline cellulose: 27mg Lactose: 22mg Calcium hydrogen phosphate: 22.5mg Sodium carboxymethyl starch: 7.7 mg Polyethylene glycol 6000: 1mg Water: in appropriate amounts, eventually removed.

[0053] Preparation method: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 14%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly and place them in a fluidized bed dryer granulator. Adjust the fan frequency to keep the material in a fluidized state. Turn on the heater to make the material temperature reach and maintain at 38~40℃. Spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.25MPa. Maintain the above humidity and continue fluidizing until dry (moisture content less than 5%) to obtain granules A. Then add microcrystalline cellulose, lactose, and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Spray binder B into the fluidized drug powder at the above temperature and atomization pressure. Maintain the above temperature and continue fluidizing until the material is dried until the granule moisture content is less than 2.0%. Then granulate the material through a φ1.0mm stainless steel screen to obtain granules B. (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules was determined and the tablet weight was calculated. The tablets were compressed using a φ6.5mm flat slant die with a hardness of 6.5±0.5kg to obtain oxazepam tablets. Each tablet contained 15mg of oxazepam. The tablets were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0054] Example 4: Preparation of Oxazepam Tablets Prescription (per tablet): Oxazepam: 15mg Sodium dodecyl sulfate: 1.1 mg Citric acid: 1.8mg Starch: 6mg Povidone K30: 4.4mg Microcrystalline cellulose: 24mg Lactose: 24mg Calcium hydrogen phosphate: 20mg Sodium carboxymethyl starch: 6.3 mg Polyethylene glycol 6000: 1mg Water: in appropriate amounts, eventually removed.

[0055] Preparation method: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 11%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place in a fluidized bed dryer granulator, adjust the fan frequency to keep the material in a fluidized state, turn on the heater to make the material temperature reach and maintain at 40~42℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.25MPa, maintain the above humidity and continue fluidization until dry (moisture content less than 5%) to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried until the granule moisture content is less than 2.0%, and then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules was determined and the tablet weight was calculated. The tablets were compressed using a φ6.5mm flat slant die with a hardness of 6.5±0.5kg to obtain oxazepam tablets. Each tablet contained 15mg of oxazepam. The tablets were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0056] Example 5: Preparation of Oxazepam Tablets Prescription (per tablet): Oxazepam: 15mg Sodium dodecyl sulfate: 0.9 mg Citric acid: 2.2mg Starch: 4mg Povidone K30: 3.6mg Microcrystalline cellulose: 36mg Lactose: 16mg Calcium hydrogen phosphate: 30mg Sodium carboxymethyl starch: 7.7 mg Polyethylene glycol 6000: 1mg Water: in appropriate amounts, eventually removed.

[0057] Preparation method: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 13%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place in a fluidized bed dryer granulator, adjust the fan frequency to keep the material in a fluidized state, turn on the heater to make the material temperature reach and maintain at 38~40℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.3~0.4MPa, maintain the above humidity and continue fluidization until dry (moisture content less than 5%) to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried until the granule moisture content is less than 2.0%, and then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules was determined and the tablet weight was calculated. The tablets were compressed using a φ6.5mm flat slant die with a hardness of 6.5±0.5kg to obtain oxazepam tablets. Each tablet contained 15mg of oxazepam. The tablets were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

[0058] Example 1: Quality Testing of Oxazepam Tablets Referring to the methods in the Chinese Pharmacopoeia 2020 edition and the United States Pharmacopeia (USP) 40 under the section on oxazepam and oxazepam tablets, the oxazepam tablets obtained in Examples 1-5 were subjected to quality testing, and some typical results are as follows.

[0059] 1. Appearance: When observed with the naked eye, all five batches of tablets in Examples 1-5 were white tablets.

[0060] 2. Colorimetric Identification: Take approximately 15 mg of oxazepam tablet powder, place it in a separatory funnel, add 2 ml of water, and extract with approximately 15 ml of chloroform by shaking. Separate the chloroform layer, filter, and evaporate the filtrate to dryness on a water bath. Add 15 ml of hydrochloric acid solution (1→2) to the residue, slowly boil, cool in ice water, add 4 ml of sodium nitrite test solution, dilute with water to 20 ml, and place in an ice bath. After 10 minutes, add alkaline β-naphthol test solution and observe the color change. The results showed that all five batches of tablets from Examples 1 to 5 produced an orange-red precipitate, which gradually darkened upon standing, conforming to the general requirements for this product.

[0061] 3. Spectrophotometric Identification (UV-Vis Identification): Take one 15mg oxazepam tablet, place it in a 200ml volumetric flask, add 150ml of ethanol, sonicate to dissolve the oxazepam, cool, dilute to the mark with ethanol, shake well, filter, accurately measure 5ml of the filtrate, place it in a 50ml volumetric flask, dilute to the mark with ethanol, shake well, and determine by UV-Vis spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0401). The results showed that all five batches of tablets from Examples 1-5 had maximum absorption at a wavelength of 229nm, which meets the general requirements for this product. For example, the typical UV-Vis spectrophotometric scan of the tablet from Example 1 is shown below. Figure 1 .

[0062] 4. Content determination The determination was performed according to the standard procedure of high performance liquid chromatography in General Chapter 0512 of Part IV of the Chinese Pharmacopoeia 2020. Test solution: Weigh 5 tablets of 15mg oxazepam, place them in a 200ml volumetric flask, add an appropriate amount of 90% methanol, sonicate to dissolve, let stand at room temperature, dilute to the mark with 90% methanol, shake well, filter, accurately measure an appropriate amount of the filtrate, and quantitatively dilute with 90% methanol to prepare a solution containing approximately 75μg per ml. Reference solution: Weigh an appropriate amount of oxazepam reference standard accurately, dissolve it in 90% methanol and dilute quantitatively to prepare a solution containing approximately 75 μg per ml; Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (4.6 mm × 150 mm, 5 μm), and the mobile phase was 8.5 g / L potassium dihydrogen phosphate aqueous solution (adjusted to pH 6.5 with 1 mol / L sodium hydroxide)-methanol (2:3). The flow rate was 1.0 mL / min, the detection wavelength was 232 nm, the column temperature was 25 °C, and the injection volume was 20 μL. System suitability requirements: In the chromatogram of the reference solution, the tailing factor of the main peak should not be greater than 1.5; Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, record the chromatograms, calculate the percentage of oxazepam in each tablet relative to its labeled amount according to the external standard method, i.e., the percentage content.

[0063] The content of oxazepam tablets in Examples 1-5 was determined to be 100.62%, 99.84%, 101.17%, 99.16%, and 100.38%, respectively, which meets the requirements for this product to contain oxazepam (C). 15 H 11 The content of ClN2O2 should generally be 90.0% to 110.0% of the labeled amount. For example, a typical chromatogram for the tablet content determination in Example 1 is shown below. Figure 2 As shown.

[0064] 5. Content uniformity Take one 15mg oxazepam tablet, place it in a 200ml volumetric flask, add an appropriate amount of 90% methanol, sonicate to dissolve, let stand to room temperature, dilute to the mark with 90% methanol, shake well, filter, and take the filtrate as the test solution; determine according to the method under the content determination section, and it should meet the requirements.

[0065] The A+2.2S values ​​of the five oxazepam tablets in Examples 1-5 were measured to be 2.83, 3.17, 2.58, 3.62, and 3.14, respectively, all less than 15.0, which meets the general requirements for this product.

[0066] 6. Tablet friability Take 6.5g of oxazepam tablets, blow away the powder that has fallen off the tablets with a hair dryer, weigh accurately, and place the tablets in a cylinder according to the tablet friability test method in General Chapter 0923 of Part IV of the Chinese Pharmacopoeia 2020 edition. Rotate the cylinder 100 times, take it out, remove the powder in the same way, weigh accurately, and observe whether there are any broken, cracked or pulverized tablets, and calculate the weight loss of the tablets.

[0067] Tests showed that none of the five types of oxazepam tablets in Examples 1-5 were found to be broken, cracked, or pulverized, and the weight loss was 0.22%, 0.17%, 0.31%, 0.19%, and 0.27%, respectively, all of which met the general requirements for this product.

[0068] 7. Dissolution rate The determination was performed according to Method II of Dissolution and Release Determination, Part IV, General Chapter 0931, Chinese Pharmacopoeia 2020 Edition; Dissolution conditions: 1000 ml of pH 1.0 hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 rpm. The procedure was followed, and samples were taken after 60 minutes; Test solution: The dissolution solution was taken, filtered, and 3 ml of the filtrate was accurately measured and placed in a 10 ml volumetric flask. The solution was diluted to the mark with the dissolution medium and shaken well; Reference solution: An appropriate amount of oxazepam reference standard was accurately measured... Weigh the sample, dissolve and quantitatively dilute it in ethanol to prepare a solution containing approximately 225 μg per ml, shake well, and use it as a reference stock solution. Accurately measure an appropriate amount of the reference stock solution, quantitatively dilute it with dissolution medium to prepare a solution containing approximately 4.5 μg per ml, and shake well. Assay: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 229 nm according to the UV-Vis spectrophotometry method in General Chapter 0401 of Part IV of the Chinese Pharmacopoeia 2020, and calculate the dissolution amount of each tablet.

[0069] The dissolution rates of the five oxazepam tablets in Examples 1-5 were measured to be 90.3%, 92.6%, 91.4%, 89.7%, and 90.7%, respectively, all of which met the general requirements for this product.

[0070] 8. Related substances: Determined by high performance liquid chromatography according to Section 0512 of the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia; Test solution: Prepare fresh before use. Take 5 tablets of 15mg oxazepam, place them in a 100ml volumetric flask, add an appropriate amount of 50% acetonitrile, sonicate to dissolve, dilute to the mark with 50% acetonitrile, shake well, filter, and take the filtrate as the test solution (750μg / ml). Reference solution: Weigh an appropriate amount of oxazepam reference standard accurately, dissolve it in 50% acetonitrile and dilute quantitatively to prepare a solution containing approximately 1.5 μg per ml, which is used as the reference solution (1.5 μg / ml). System suitability solution: Take appropriate amounts of oxazepam reference standard, impurity B reference standard, and impurity C reference standard, dissolve them in 50% acetonitrile, and quantitatively dilute to prepare a solution containing approximately 0.75 mg of oxazepam, 3.75 μg of impurity B, and 1.5 μg of impurity C per 1 ml; Chromatographic conditions: Octadecylsilane-bonded silica gel (4.6 mm × 250 mm, 5 μm) was used as the packing material. A trapping column (4.6 mm × 50 mm, Ghost-Buster Column II from Yuexu Technology) was installed between the gradient mixer and the injector. The detection wavelength was 235 nm, the column temperature was 20 °C, the sample tray temperature was 5 °C, and the injection volume was 10 μl. Dipotassium hydrogen phosphate solution (3.48 g of anhydrous dipotassium hydrogen phosphate was dissolved in 900 ml of water, the pH was adjusted to 10.0 with 40 g / L sodium hydroxide solution, and the volume was brought to 1000 ml with water) was used as mobile phase A, and acetonitrile-methanol (2:1) was used as mobile phase B. Gradient elution was performed according to the table below:

[0071]

[0072] System suitability requirements: In the system suitability solution chromatogram, the elution order is oxazepam, impurity B, and impurity C, and the resolution between impurity B and impurity C peaks shall not be less than 1.5. Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and read the peak areas of impurity B and impurity C appearing in the chromatogram of the test solution. The peak area of ​​impurity B is multiplied by a correction factor of 1.2 and then calculated using the principal component peak area according to the external standard method (generally, it should not exceed 0.5%). The peak area of ​​impurity C is multiplied by a correction factor of 0.8 and then calculated using the external standard method based on the peak area of ​​the principal component (generally, it should not exceed 0.2%).

[0073] Impurities B and C in the active pharmaceutical ingredient can also be determined using the above method.

[0074] The contents of impurity B and impurity C in the oxazepam raw material used to prepare the tablets were determined to be 0.098% and 0.047%, respectively. The contents of impurity B in the five tablets of Examples 1-5 were 0.108%, 0.096%, 0.117%, 0.112%, and 0.094%, respectively, and the contents of impurity C in the five tablets of Examples 1-5 were 0.049%, 0.047%, 0.052%, 0.044%, and 0.048%, respectively. According to the above results, the contents of impurity B and impurity C remained basically unchanged during the tablet preparation process, and were essentially the same as those in the raw material.

[0075] Figure 3 This is a typical system suitability solution chromatogram, in which the peak at 28.35 min is impurity B and the peak at 29.87 min is impurity C; Figure 4 This is a typical related substances test chromatogram of the sample solution for the tablets in Example 1.

[0076] Experimental Example 2: Stability Study of Oxazepam Tablets Oxazepam raw material or oxazepam tablets or other forms of composition were packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs (simulating commercially available packaging), and then placed in a light-protected environment at 40°C and 75% relative humidity for 6 months. The various items of each test sample were measured at 0 months and 6 months, referring to the test method of Test Example 1.

[0077] For impurities B and C, the increase in impurity content is expressed as a percentage, which is calculated using the following formula: The percentage increase of a certain impurity = [(the content of the impurity in June - the content of the impurity in October) ÷ the content of the impurity in October] × 100%.

[0078] The percentage increase in impurities can reflect the changes in impurities during long-term storage.

[0079] Results for October are shown in Experiment 1, and results for June are shown in the table below: (1) Appearance: All five batches of tablets in Examples 1-5 were white tablets. (2) Color identification: All five batches of tablets in Examples 1 to 5 produced an orange-red precipitate, which gradually darkened upon standing, in accordance with the general requirements for this product.

[0080] (3) UV-Vis identification: All five batches of tablets in Examples 1 to 5 showed maximum absorption at a wavelength of 229 nm, which is in line with the general requirements for this product.

[0081] (4) Content: The contents of the five oxazepam tablets in Examples 1-5 were 99.94%, 99.67%, 100.04%, 98.97%, and 99.87%, respectively, all of which met the general requirements for this product.

[0082] (5) Friability: No broken, cracked or pulverized tablets were detected in any of the five types of oxazepam tablets in Examples 1 to 5. The weight loss was 0.27%, 0.22%, 0.36%, 0.36% and 0.32% respectively, which all met the general requirements for this product.

[0083] (6) Dissolution: The dissolution rates of the five oxazepam tablets in Examples 1-5 were 87.7%, 89.2%, 88.1%, 86.9%, and 88.1%, respectively, which all met the general requirements for this product, but all showed a slight decrease of 2-3 percentage points.

[0084] (7) Related substances: The percentage increases in impurity B were 58.6%, 56.4%, 49.8%, 60.2%, and 54.7%, respectively, and the percentage increases in impurity C were 73.2%, 69.7%, 76.6%, 74.8%, and 71.4%, respectively. After the active pharmaceutical ingredient was stored in a light-protected environment at 40°C and 75% relative humidity for 6 months, the percentage increases in impurities B and C were 13.2% and 21.4%, respectively. Since the background levels of impurities B and C in the tablets at month 0 were relatively low, the above increases in impurities B and C will not exceed the general requirements for impurity control in this field. It should also be noted that the increase in one molecule of impurity is not necessarily equal to the decrease in one molecule of oxazepam in the tablet. This is because the amount of oxazepam is very large relative to the amount of impurities, and impurity detection is more sensitive than content detection. In addition, there is the influence of detection error. Therefore, those skilled in the art usually do not consider the direct relationship between impurity changes and content changes when conducting formulation research.

[0085] Furthermore, the inventors have discovered in some studies that the choice of formulation and process has different effects on changes in dissolution and stability of related substances, and these experimental studies are provided below. Given that there is no significant difference in content between 0 and 6 months, the present invention focuses on dissolution and related substances—two sensitive parameters for this product's tablets—during the optimization of the formulation and process.

[0086] Experimental Example 3: Formulation Process and Tablet Performance Evaluation Referring to Examples 1-5 respectively, except that citric acid was not added, five batches of tablets were prepared (which may be referred to as Supplementary Examples a1-a5 respectively; in this document, when similar situations occur and relevant data are provided, they are provided in the order of the tablets of the five reference examples or in the order of description). Then, following the methods of Test Examples 1 and 2, the content, dissolution rate, and related substances and their changes in the five batches of tablets of Supplementary Examples a1-a5 were tested, and the results are as follows: The 0-month content of the five batches of tablets was in the range of 99-102%, and the 6-month content was in the range of 99-101%. For example, the 0-month and 6-month contents of the tablets obtained by referring to Example 1 were 101.24% and 100.43%, respectively, with no significant change. The dissolution rates of the five batches of tablets were all in the range of 89-92% in 0 months and 77-81% in 6 months. For example, the dissolution rates of the tablets obtained in Example 1 were 89.8% and 79.4% in 0 months and 6 months, respectively, showing that the dissolution rate dropped significantly to near the limit value of 80%. The content of impurity B in the five batches of tablets at month 0 was all in the range of 0.09~0.11%, and the percentage increase of impurity B at month 6 was all in the range of 67~72%. For example, the tablets obtained by referring to Example 1 had an impurity B content of 0.104% at month 0 and an increase of 67.4% at month 6. The content of impurity C in the five batches of tablets was in the range of 0.04% to 0.06% in 0 months, and the percentage increase of impurity C in 6 months was in the range of 78% to 86%. For example, the tablets obtained by referring to Example 1 had an impurity C content of 0.056% in 0 months and an increase of 83.2% in 6 months.

[0087] The above results indicate that, compared with Examples 1-5, the addition of citric acid helps maintain the stability of tablet dissolution performance, while tablets without citric acid show a significant decrease in dissolution after long-term storage. However, the addition or absence of citric acid does not significantly affect the stability of content and impurities.

[0088] In the above investigation of the case without citric acid, the inventors also found that when citric acid is dissolved in binder B to prepare tablets, the stability of the tablet dissolution performance also deteriorates. The specific experiment was conducted according to Examples 1 to 5, with the only difference being in step (1) when preparing the adhesive: 1 / 4 of the amount of povidone K30 and sodium dodecyl sulfate were dissolved in an appropriate amount of water to prepare a solution with a solid concentration of 13%, which was used as adhesive A; the remaining amount of povidone K30 and citric acid were dissolved in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which was used as adhesive B; the rest of the operation remained unchanged, and 5 batches of tablets were obtained (which can be referred to as Supplementary Examples b1 to Supplementary Examples b5 respectively); then, the dissolution rate and its changes of the 5 batches of tablets were tested according to the methods of Experimental Examples 1 and 2, and the results are as follows: the dissolution rate of the five batches of tablets in Supplementary Examples b1 to Supplementary Examples b5 in 0 months was in the range of 90 to 93%, and the dissolution rate in 6 months was in the range of 83 to 85%. For example, the dissolution rate of the tablets obtained in Example 1 in 0 months and 6 months was 91.6% and 84.3% respectively, showing a significant decrease in dissolution rate, although it has not yet dropped to the limit of 80%.

[0089] Experimental Example 4: Formulation Process and Tablet Performance Evaluation As is well known, to prevent die sticking during tableting, approximately 1-3% lubricant is usually added during the preparation of the final granule mixture. Classic lubricants in the tablet manufacturing industry are stearic acid and its salts, especially magnesium stearate. However, the inventors have discovered that when using stearic acid and its salts as lubricants, the resulting tablets show a significantly higher increase in impurity C during long-term storage. In contrast, when polyethylene glycol is used as the lubricant, the increase in impurity C is not significant. Specifically, referring to the formulation and preparation method of Example 1, the only difference was that the polyethylene glycol used was replaced with 0.5 mg, 1 mg, and 2 mg of magnesium stearate, resulting in three batches of tablets. Then, following the methods of Example 1 and Example 2, their related substances and changes were tested, and the results are as follows: The content of impurity B in the three batches of tablets was in the range of 0.09-0.12% at month 0, and the percentage increase of impurity B in June was in the range of 69-73%. For example, the tablets made with 1 mg of magnesium stearate had an impurity B content of 0.113% at month 0 and an increase of 71.7% in June. The impurity C content of the three batches of tablets at 0 months was 0.052%, 0.049%, and 0.054%, respectively. The percentage increase in impurity C at 6 months for the three batches of tablets was 161.5%, 293.9%, and 320.4%, respectively (the impurity C content of the three samples at 6 months was 0.136%, 0.193%, and 0.227%, respectively). These results indicate that the use of magnesium stearate in the tablets of this invention significantly increases impurity C, and the increase is positively correlated with the amount used.

[0090] Referring to the formulation and preparation method of Example 1, the only difference was that the polyethylene glycol used was replaced with an equal amount of magnesium stearate (i.e., the 1 mg magnesium stearate example mentioned above), sodium stearate fumarate, stearic acid, calcium stearate, and zinc stearate, resulting in 5 batches of tablets (which can be referred to as Supplementary Examples c1 to c5, respectively). Then, following the methods of Experimental Examples 1 and 2, their related substances and changes were tested, and the results are as follows: The content of impurity B in the five batches of tablets at month 0 was all in the range of 0.09-0.12%, and the percentage increase of impurity B at month 6 was all in the range of 68-72%. For example, the tablets made with 1 mg of magnesium stearate had an impurity B content of 0.113% at month 0 and an increase of 71.7% at month 6. For example, the tablets made with stearic acid had an impurity B content of 0.106% at month 0 and an increase of 68.5% at month 6. The monthly impurity C content of the five batches of tablets was 0.049%, 0.053%, 0.051%, 0.048%, and 0.055%, respectively. The percentage increase in impurity C in June for the five batches of tablets was 293.9%, 286.8%, 284.3%, 293.8%, and 303.6%, respectively (the monthly impurity C content of the five samples in June was 0.193%, 0.205%, 0.196%, 0.189%, and 0.222%, respectively). These results indicate that the use of stearic acid and its salts in the tablets of this invention significantly increases impurity C.

[0091] Experimental Example 5: Formulation Process and Tablet Performance Evaluation In the stability tests of Examples 1-4 above, the stability was assessed under accelerated conditions of 6 months in a dark environment at 40°C and 75% relative humidity. Based on the results above, this test attempt uses accelerated conditions of 1 month in a dark environment at 60°C and 85% relative humidity (referred to as 60°C accelerated for 1 month in this document) for stability assessment. The packaging conditions remain unchanged. The dissolution rate and impurity C of the tablets obtained in Examples 1-5 were assessed and compared after 0 months (results are above). The dissolution rate of five batches of tablets from Supplementary Examples a1-a5 were also assessed and compared after 0 months (results are above). Similarly, the impurity C of five batches of tablets from Supplementary Examples c1-c5 were assessed and compared after 0 months (results are above). The testing methods and data processing methods are the same as in Examples 1-4. The results are as follows: The dissolution rates of the five oxazepam tablets in Examples 1-5 after one month of accelerated dissolution at 60°C were 88.5%, 89.6%, 87.5%, 87.6%, and 88.7%, respectively, all of which met the general requirements for this product, but all showed a slight decrease. In Examples 1-5, the percentage increase in impurity C of the five types of oxazepam tablets after one month of accelerated 60°C was 68.8%, 70.2%, 74.3%, 72.3%, and 73.1%, respectively, while the percentage increase in impurity C of the active pharmaceutical ingredient after one month of accelerated 60°C was 18.7%. The dissolution rates of the five batches of tablets in Supplementary Examples a1 to a5 after one month of accelerated dissolution at 60°C were all in the range of 81% to 83%. For example, the dissolution rate of the tablets in Supplementary Example a1 after one month of accelerated dissolution was 82.3%, indicating that the dissolution rate had decreased significantly to near the limit value of 80%. The percentage increases in impurity C in five batches of tablets after one month of accelerated 60°C in Supplementary Examples c1 to c5 were 271.3%, 264.8%, 286.6%, 274.1%, and 283.7%, respectively.

[0092] These results indicate that the various tablets prepared according to this invention exhibit similar performance change trends under different acceleration conditions as under classic stability test conditions. Specifically, adding citric acid to the binder in close contact with the active ingredient during tablet preparation helps improve the dissolution stability of the tablets. Furthermore, using polyethylene glycol as a tablet lubricant is significantly superior to using classic stearic acid and its salts, avoiding a significant increase in impurity C. This finding is something that the prior art simply cannot teach.

[0093] The present invention has been illustrated with the above embodiments to explain the detailed method of the present invention. However, the present invention is not limited to the detailed method described above, that is, it does not mean that the present invention must rely on the detailed method described above to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A pharmaceutical composition in tablet form, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 0.9-1.1 parts by weight of sodium lauryl sulfate, 1.8-2.2 parts by weight of citric acid, 4-6 parts by weight of starch, 3.6-4.4 parts by weight of povidone K30, 24-36 parts by weight of microcrystalline cellulose, 16-24 parts by weight of lactose, 20-30 parts by weight of dicalcium phosphate, 6.3-7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000; the pharmaceutical composition is prepared by a method comprising the following steps: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solid concentration of 10-14%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place in a fluidized bed dryer granulator, adjust the fan frequency to make the material fluidized, turn on the heater to make the material temperature reach and maintain at 38~42℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.4MPa, maintain the above temperature and continue fluidization until dry to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried to less than 2.0% moisture content, then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules is determined and the tablet weight is calculated. The tablets are then compressed into tablets using a tableting machine.

2. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 0.9-1.1 parts by weight of sodium lauryl sulfate, 1.8-2.2 parts by weight of citric acid, 4.5-5.5 parts by weight of starch, 3.6-4.4 parts by weight of povidone K30, 27-33 parts by weight of microcrystalline cellulose, 18-22 parts by weight of lactose, 22.5-27.5 parts by weight of dicalcium phosphate, 6.3-7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

3. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 1 part by weight of sodium lauryl sulfate, 2 parts by weight of citric acid, 5 parts by weight of starch, 4 parts by weight of povidone K30, 30 parts by weight of microcrystalline cellulose, 20 parts by weight of lactose, 25 parts by weight of dicalcium phosphate, 7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

4. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4.5 parts by weight of starch, 3.6 parts by weight of povidone K30, 33 parts by weight of microcrystalline cellulose, 18 parts by weight of lactose, 27.5 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

5. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 5.5 parts by weight of starch, 4.4 parts by weight of povidone K30, 27 parts by weight of microcrystalline cellulose, 22 parts by weight of lactose, 22.5 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

6. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 1.1 parts by weight of sodium lauryl sulfate, 1.8 parts by weight of citric acid, 6 parts by weight of starch, 4.4 parts by weight of povidone K30, 24 parts by weight of microcrystalline cellulose, 24 parts by weight of lactose, 20 parts by weight of dicalcium phosphate, 6.3 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

7. The pharmaceutical composition according to claim 1, comprising the following components in the indicated weight proportions: 15 parts by weight of oxazepam, 0.9 parts by weight of sodium lauryl sulfate, 2.2 parts by weight of citric acid, 4 parts by weight of starch, 3.6 parts by weight of povidone K30, 36 parts by weight of microcrystalline cellulose, 16 parts by weight of lactose, 30 parts by weight of dicalcium phosphate, 7.7 parts by weight of sodium carboxymethyl starch, and 1 part by weight of polyethylene glycol 6000.

8. The pharmaceutical composition according to claim 1, wherein each tablet contains 5 to 50 mg of oxazepam.

9. The pharmaceutical composition according to claim 1, wherein each tablet contains 10-30 mg of oxazepam.

10. The pharmaceutical composition of claim 1, wherein each tablet contains 10 mg, 15 mg, or 30 mg of oxazepam.

11. The pharmaceutical composition according to claim 1, wherein step (4) is prepared as follows: the drug content in the final mixed granules is determined and the tablet weight is calculated, and the tablets are compressed with a φ6.5mm flat oblique die to a hardness of 6.5±0.5kg to obtain oxazepam tablets, each containing 15mg of oxazepam, and the tablets are packaged in PVC solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

12. A method for preparing the pharmaceutical composition according to any one of claims 1 to 11, comprising the following steps: (1) Adhesive preparation: Dissolve 1 / 4 of the amount of povidone K30 with sodium dodecyl sulfate and citric acid in an appropriate amount of water to prepare a solution with a solid concentration of 10-14%, which is used as adhesive A; dissolve the remaining amount of povidone K30 in an appropriate amount of water to prepare a solution with a solid concentration of 3%, which is used as adhesive B; set aside. (2) Granulation: Mix oxazepam and starch evenly, place in a fluidized bed dryer granulator, adjust the fan frequency to make the material fluidized, turn on the heater to make the material temperature reach and maintain at 38~42℃, spray binder A into the fluidized drug powder with an atomization pressure of 0.15~0.4MPa, maintain the above temperature and continue fluidization until dry to obtain granules A; then add microcrystalline cellulose, lactose and dicalcium phosphate into the fluidized bed dryer and mix with granules A. Under the above temperature and atomization pressure, spray binder B into the fluidized drug powder, maintain the above temperature and continue fluidization until the material is dried to less than 2.0% moisture content, then granulate the material through a φ1.0mm stainless steel screen to obtain granules B; (3) Mixing: Mix the granulated particles B with sodium carboxymethyl starch and polyethylene glycol 6000 evenly to obtain the final mixed particles; (4) Tableting: The drug content in the final mixed granules is determined and the tablet weight is calculated. The tablets are then compressed into tablets using a tableting machine.

13. The method according to claim 12, wherein step (4) is performed as follows: determining the drug content in the final mixed granules and calculating the tablet weight, compressing the tablets with a hardness of 6.5 ± 0.5 kg using a φ6.5 mm flat oblique die to obtain oxazepam tablets, each containing 15 mg of oxazepam, and packaging the tablets with polyvinyl chloride solid pharmaceutical hard sheets / pharmaceutical aluminum foil blister packs.

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