A lyophilized dexamethasone sodium phosphate composition suitable for intratympanic administration and a method for producing the same.

Abstract

A lyophilized composition of dexamethasone sodium phosphate suitable for intratympanic administration and a method for producing the same. This disclosure provides a lyophilized powder injection, the formulation being a lyophilized powder injection of a dexamethasone-based drug, free from lyophilization support agents, excipients, or matrix agents, the lyophilized powder injection containing glycerin, a pharmaceutically acceptable additive, the glycerin being added before lyophilization of the lyophilized powder injection. The provided lyophilized formulation is free from lyophilization support agents or excipients, and the addition of a small amount of glycerin before lyophilization improves the stability of the drug, further adjusts the osmotic pressure to approximate the physiological osmotic pressure during intratympanic administration, thereby extending the duration of action of local administration and enhancing the safety and efficacy of intratympanic administration.

Description

Technical Field

[0001] The present disclosure relates to the field of biopharmaceuticals, and specifically to a dexamethasone sodium phosphate lyophilized composition suitable for intratympanic administration and a method for producing the same.

Background Art

[0002] In recent years, glucocorticoids have been widely used in the treatment of inner ear diseases such as hearing loss, Meniere's disease, and labyrinthitis after acute meningitis. Sudden sensorineural hearing loss is a sudden-onset non-fluctuating sensorineural hearing loss, which has an acute onset and rapid progression: a patient's hearing decreases sharply within a few minutes, a few hours, or 3 days. The main accompanying symptoms are tinnitus and dizziness. At present, the cause of sudden sensorineural hearing loss has not been fully elucidated, but inner ear microcirculation disorder, specific infection, immune factors, psychopsychological factors and the like are cited as the main causes. Acute hearing loss has similar causes to sudden sensorineural hearing loss but differs therefrom. Its complications include tinnitus, but it is usually not accompanied by dizziness. Some theories hold that the cause of acute hearing loss is mainly middle ear lesions. Currently, hormonal therapy is applied for these diseases. In the treatment of sudden sensorineural hearing loss, hormonal therapy has the effect of interrupting the progression of pathological damage, and protecting and promoting the recovery of various functions of the inner ear. However, the therapeutic effect on inner ear tissues and organs that have already undergone irreversible damage is limited. Hormonal therapy is effective for patients with severe sudden sensorineural hearing loss, especially those presenting with hearing loss in the mid-low frequency range, and good recovery has been observed. Glucocorticoids are used as the international standard treatment for sudden sensorineural hearing loss.

[0003] Dexamethasone is a synthetic corticosteroid that exerts potent anti-inflammatory effects on various organ systems. Compared to hydrocortisone and its derivatives, it has the strongest anti-inflammatory effect while having the weakest side effects of water and sodium retention. The biological half-life of dexamethasone in plasma is 36-54 hours, classifying it as a long-acting glucocorticoid (Chinese Medical Abstracts, Otolaryngology, 2014, Vol.29(5), p.280). Currently, oral dexamethasone tablets or intratympanic injection of dexamethasone sodium phosphate are clinically used to treat sudden hearing loss. However, oral administration has significant systemic side effects, and the drug has difficulty crossing the blood-labyrinth barrier to reach the inner ear. Furthermore, with intratympanic injection, excipients in the formulation remain in the inner ear and are not easily metabolized, potentially causing other inner ear disorders such as inflammation. Furthermore, since many injectable solutions are sterilized by autoclaving or flow-through steam sterilization, drug stability is easily compromised, and at the same time, interactions between the active pharmaceutical ingredient and excipients are enhanced, making it difficult to control related substances. On the other hand, it has been reported that dexamethasone can be transferred to the inner ear via the tympanic membrane-tympanic pathway (Journal of Hearing and Speech Disorders, 2005, Vol.13(4), pp.260-263). This offers a new perspective on the treatment of inner ear disorders. Compared to intravenous infusion, the overall efficacy rate of intratympanic injection for the treatment of sudden hearing loss reaches 92.5%, and it has been reported that this is significantly superior to intravenous administration (Jilin Medical Journal, 2013, Vol.34(27), p.5607).

[0004] Existing commercially available dexamethasone sodium phosphate injections have low concentrations and do not meet the high-concentration requirements for intratympanic administration. Furthermore, simply increasing the concentration of the lyophilized preparation does not solve the administration concentration problem. Existing commercially available lyophilized dexamethasone sodium phosphate preparations contain excipients such as mannitol, lactose, and sorbitol as lyophilization support agents. In addition, substances such as antioxidants may be added to improve product stability, and these tend to remain in the inner ear and may cause inner ear inflammation, making them unsuitable for intratympanic administration. [Overview of the project]

[0005] In some embodiments, the Disclosure provides a lyophilized powder injection, the formulation being a lyophilized powder injection of a dexamethasone-based drug, free from lyophilization supporters, excipients, or matrix agents, the lyophilized powder injection comprising glycerin, which is a pharmaceutically acceptable additive, the glycerin being added before lyophilization of the lyophilized powder injection.

[0006] In some embodiments, the additive also includes a pH adjuster.

[0007] In some embodiments, the additive does not contain a chelating agent or an antioxidant.

[0008] In some embodiments, the dexamethasone-based drug is one or more selected from dexamethasone, pharmaceutically acceptable derivatives of dexamethasone, or salts or esters thereof.

[0009] In some embodiments, the dexamethasone-based drug is one or more selected from dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or salts thereof.

[0010] In some embodiments, the mass percentage of dexamethasone sodium phosphate is approximately 60.0% to 99.9%.

[0011] In some embodiments, the mass percentage of dexamethasone sodium phosphate is approximately 60.0% to 95%.

[0012] In some embodiments, the mass percentage of dexamethasone sodium phosphate is approximately 60.0% to 90%.

[0013] In some embodiments, the mass percentage of dexamethasone sodium phosphate is approximately 70.0% to 90%.

[0014] In some embodiments, the mass ratio of the dexamethasone-based drug to glycerin in the lyophilized powder injection is approximately 8:1 to 2:1.

[0015] In some embodiments, the mass ratio of dexamethasone-based drugs to glycerin in the lyophilized powder injection is approximately 8:1 to 2.5:1.

[0016] In some embodiments, the mass ratio of dexamethasone-based drugs to glycerin in the lyophilized powder injection is approximately 6:1 to 6:2.4.

[0017] In some embodiments, the mass ratio of dexamethasone-based drugs to glycerin in the lyophilized powder injection is approximately 6:1.4 to 6:2.

[0018] In some embodiments, the formulation is prepared by lyophilizing a combination solution comprising a dexamethasone-based drug, water, and a pharmaceutically acceptable additive.

[0019] In some embodiments, the dexamethasone-based drug is one or more selected from dexamethasone, pharmaceutically acceptable derivatives of dexamethasone, or salts or esters thereof.

[0020] In some embodiments, the additive also includes a pH adjuster.

[0021] In some embodiments, the osmotic pressure of the combination solution is approximately 60 mOsm / kg to 449 mOsm / kg.

[0022] In some embodiments, the osmotic pressure of the combination solution is approximately 150 mOsm / kg to 300 mOsm / kg.

[0023] In some embodiments, the osmotic pressure of the combination solution is approximately 240 mOsm / kg to 300 mOsm / kg.

[0024] In some embodiments, the dexamethasone-based drug is one or more selected from the group consisting of dexamethasone, sodium dexamethasone phosphate, dexamethasone acetate, and salts thereof.

[0025] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 15 to 80 mg / mL.

[0026] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 25 to 75 mg / mL.

[0027] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 25 to 65 mg / mL.

[0028] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 20 to 55 mg / mL.

[0029] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 20 to 45 mg / mL.

[0030] In some embodiments, the content of sodium dexamethasone phosphate in the combined solution is about 30 mg / mL.

[0031] In some embodiments, the content of glycerin is about 0.01 to 3% w / v.

[0032] In some embodiments, the content of glycerin is about 0.01 to 2% w / v.

[0033] In some embodiments, the content of glycerin is about 0.01 to 1.45% w / v.

[0034] In some embodiments, the content of glycerin is about 0.01 to 1.2% w / v.

[0035] In some embodiments, the pH adjusting agent described above is one or more selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, citric acid, or potassium dihydrogen phosphate.

[0036] In some embodiments, the pH adjusting agent added to the combination solution is hydrochloric acid at a concentration of approximately 0.05 to 0.2 M.

[0037] In some embodiments, the lyophilized powder injection is used after being redissolved in a solvent, the solvent being selected from water, an aqueous glycerin solution, or an aqueous sodium hyaluronate solution.

[0038] In some embodiments, the pH value of the combination solution is approximately 6 to 9.

[0039] In some embodiments, the pH value of the combination solution is approximately 7 to 9.

[0040] In some embodiments, the pH value of the combination solution is approximately 7 to 8.5.

[0041] In some embodiments, the pH value of the combination solution is approximately 7.5 to 8.2.

[0042] In some embodiments, the pH value of the drug solution after redissolution is approximately 6 to 9.

[0043] In some embodiments, the pH value of the drug solution after redissolution is approximately 7 to 9.

[0044] In some embodiments, the pH value of the drug solution after redissolution is approximately 7 to 8.5.

[0045] In some embodiments, the pH value of the drug solution after redissolution is approximately 7.5 to 8.2. In some embodiments, the osmotic pressure of the combination solution of the formulation before freeze-drying is approximately 60 mOsm / kg to 449 mOsm / kg.

[0046] In some embodiments, the osmotic pressure of the combination solution of the formulation before freeze-drying is approximately 150 mOsm / kg to 300 mOsm / kg.

[0047] In some embodiments, the osmotic pressure of the combination solution of the formulation before freeze-drying is approximately 240 mOsm / kg to 300 mOsm / kg.

[0048] In some embodiments, the formulation is an ear injection.

[0049] In some embodiments, the formulation is an inner ear injection or an intratympanic injection. Recent sampling tests of commercially available dexamethasone sodium phosphate injections searchable in the Chinese database recorded 89 cases of defective products, mainly due to "insoluble foreign matter" and "non-compliance with relevant substance standards." Regarding inner ear injections, because the inner ear has low fluid and enzyme content and slow metabolism, impurities and additives tend to remain in the inner ear, potentially affecting hearing. On the other hand, if no other antioxidants or additives are included, the injection solution is susceptible to oxidation or hydrolysis, affecting the stability of the active ingredient.

[0050] Prior art shows that obtaining a dexamethasone injection that meets the requirements (high efficacy, excellent stability, and low levels of impurities or related substances) is not easy.

[0051] In the research process for dexamethasone injection, preliminary studies by the inventor revealed that when glycerin, which is commonly used as a preservative for freeze-drying red blood cells, is added to the freeze-drying of the injection solution, it actually makes molding difficult and impairs the freeze-drying effect of dexamethasone.

[0052] In several embodiments, the inventors, unconstrained by prior research, continuously refined the formulation, achieving improved drug stability with only a small amount of glycerin added, without the need for lyophilized support agents or excipients. Furthermore, they adjusted the osmotic pressure to approximate the physiological osmotic pressure during intratympanic administration, thereby extending the duration of action of local administration and establishing a formulation that enhances the safety and efficacy of intratympanic administration.

[0053] In some embodiments, and particularly rarely, the formulations according to the present disclosure were able to produce an ideal white, porous freeze-dried mass without structural breakdown due to the addition of glycerin.

[0054] In some embodiments, the present disclosure provides a pharmaceutical kit comprising: (1) the lyophilized powder injection, and (2) a solvent, wherein the lyophilized powder injection and the solvent are packaged separately.

[0055] In some embodiments, the drug delivery device used in the drug kit includes one or more selected from needles, syringes, pumps, and microinjection devices.

[0056] In some embodiments, the administration method using the drug kit includes one or more selected from microcapillary / microchip administration, micropump injection administration, and reciprocating microfluidic administration.

[0057] In some embodiments, the solvent includes water, an aqueous solution of glycerin, or an aqueous solution of sodium hyaluronate.

[0058] In some embodiments, the Disclosure provides a method for preparing the lyophilized powder injection, the method comprising the steps of: adding glycerin to water to obtain an aqueous glycerin solution; adding a dexamethasone-based drug to the aqueous glycerin solution and adding water for injection; and subsequently performing lyophilization.

[0059] In some embodiments, the freeze-drying process employed in this disclosure can solve the problem of shrinkage of the product appearance caused by the addition of glycerin.

[0060] In some embodiments, the freeze-drying step includes first pre-freezing, then primary drying, and then secondary drying, wherein the temperature of the primary drying is approximately -50°C to 10°C and the duration is approximately 1000 min to 2200 min.

[0061] In some embodiments, the temperature of the primary drying is approximately -30°C to 0°C, and the time is approximately 1000 min to 2000 min.

[0062] In some embodiments, the temperature of the primary drying is approximately -30°C to 0°C, and the time is approximately 1000 min to 1800 min.

[0063] In some embodiments, the temperature of the primary drying is approximately -20°C to 0°C, and the time is approximately 1000 min to 1500 min.

[0064] In some embodiments, the primary drying step includes: holding at a temperature of -30°C to -15°C for about 500 min to 2000 min, raising the temperature to -14°C to -6°C at a rate of 0.1 to 0.2°C / min, holding for 300 min to 500 min, raising the temperature to -5°C to 10°C at a rate of 0.1 to 0.2°C / min, and holding for 100 min to 200 min.

[0065] In some embodiments, the primary drying step includes: holding at a temperature of -30°C to -18°C for about 500 min to 1200 min, raising the temperature to -14°C to -8°C at a rate of 0.1 to 0.2°C / min, holding for 300 min to 400 min, raising the temperature to -5°C to 5°C at a rate of 0.1 to 0.2°C / min, and holding for 100 min to 150 min.

[0066] In some embodiments, the pre-freezing temperature is approximately -65°C to -20°C, and the time is approximately 50 min to 150 min.

[0067] In some embodiments, the pre-freezing temperature is approximately -65°C to -25°C, and the time is approximately 60 min to 500 min.

[0068] In some embodiments, the pre-freezing temperature is approximately -65°C to -25°C, and the time is approximately 670 min to 400 min.

[0069] In some embodiments, the pre-freezing temperature is approximately -50°C to -35°C, and the time is approximately 6070 min to 200 min.

[0070] In some embodiments, the pre-freezing temperature is approximately -65°C to -25°C, and the time is approximately 60 min to 120 min.

[0071] In some embodiments, the pre-freezing temperature is approximately -50°C to -35°C, and the time is approximately 60 min to 120 min.

[0072] In some embodiments, the secondary drying temperature is approximately 25°C to 45°C, and the drying time is approximately 600 min to 700 min.

[0073] In some embodiments, the secondary drying temperature is approximately 25°C to 40°C, and the drying time is approximately 600 min to 700 min.

[0074] In some embodiments, the secondary drying step includes raising the temperature from 25°C to 50°C at a rate of 1 to 6°C / min and continuing for about 600 to 800 minutes.

[0075] In some embodiments, the secondary drying step includes raising the temperature to 25°C to 40°C at a rate of 1 to 3°C / min and continuing for about 600 to 700 minutes.

[0076] In some embodiments, the freeze-drying step further includes a step of vacuuming after secondary drying.

[0077] In some embodiments, vacuuming is performed at a vacuum level of 0.1 to 0.2 mbar.

[0078] In some embodiments, the freeze-drying time described above is approximately 1500 min to 5000 min.

[0079] In some embodiments, the freeze-drying time described above is approximately 1500 min to 4000 min.

[0080] In some embodiments, the freeze-drying time described above is approximately 1500 min to 3000 min.

[0081] In some embodiments, the present disclosure provides a lyophilized powder injection obtained by the method described above.

[0082] In some embodiments, the present disclosure provides the use of the lyophilized powder injection, the pharmaceutical kit, or the manufacturing method described above in the manufacture of a drug for preventing or treating ear diseases.

[0083] In some embodiments, the present disclosure provides a method for preventing or treating an ear disease, the method comprising administering the lyophilized powder injection or the drug kit to a patient in need. [Modes for carrying out the invention]

[0084] The following specific examples further illustrate the technical solutions of this disclosure, but these examples do not limit the scope of protection of this disclosure. Some non-essential modifications and adjustments made by others based on the principles of this disclosure also fall within the scope of protection of this disclosure.

[0085] definition As used herein, “improvement” or “reduction” of symptoms of a particular ear disorder, impairment, or condition by administration of a particular formulation or drug kit means any reduction in severity, delay in onset, delay in progression, or reduction in duration caused by or resulting from the administration of such formulation or drug kit, whether permanent or temporary, persistent or transient.

[0086] As used herein and in the appended claims, the singular forms “one / one kind,” “one / one kind,” and “the said” include plural references unless the context clearly specifies otherwise. Thus, for example, a reference to “one kind of method” includes multiple such methods, and a reference to “the said fragment” includes one or more fragments and their equivalents known to those skilled in the art.

[0087] In addition, unless otherwise specified, "or" means "and / or". Similarly, "include" and "have" are used interchangeably and do not imply any restriction.

[0088] Furthermore, when describing each embodiment using the term "including," those skilled in the art will understand that, under certain circumstances, the phrases "substantially consisting of..." or "consisting of..." may be used as alternatives.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in the field to which this disclosure pertains. While many methods and reagents similar to or equivalent to those described herein exist, this disclosure discloses exemplary methods and materials.

[0090] This disclosure is not limited to the specific methods, protocols, reagents, etc. described herein, and should be understood to be subject to change. The terms used herein are for the purpose of describing specific embodiments or aspects and are not intended to limit the scope of this disclosure.

[0091] "Antioxidants" refers to otologically pharmacologically acceptable antioxidants, including, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In some examples, antioxidants are used to enhance chemical stability as needed. Antioxidants are also used to counteract the ototoxic effects of certain therapeutic agents, including those used in combination with corticosteroids disclosed herein.

[0092] The term "inner ear" refers to the inner ear, cochlea, vestibular labyrinth, and the round window connecting the cochlea to the middle ear.

[0093] The "round window membrane" is the membrane that covers the cochlear window (also called the round window or circular window) in humans. In humans, the thickness of the round window membrane is approximately 70 micrometers.

[0094] "Pharmacodynamics" refers to the factors that determine the biological response observed to drug concentration in a desired location within the target ear structure.

[0095] "Pharmacokinetics" refers to the factors that determine how to achieve and maintain appropriate drug concentrations in desired locations within the target ear structure.

[0096] As used herein, the term “treatment” includes the preventive and / or therapeutic reduction, alleviation, or improvement of symptoms of a disease or condition; prevention of other symptoms; improvement or prevention of the underlying metabolic causes of symptoms; suppression of a disease or condition (e.g., halting the progression of a disease or condition); reduction of a disease or condition; resolution of a disease or condition; reduction of a condition caused by a disease or condition; or cessation of symptoms of a disease or condition.

[0097] In some embodiments, the Disclosure provides a therapeutic drug kit comprising the lyophilized powder injection and a solvent. In this drug kit, the lyophilized powder injection is not necessarily, and usually, mixed with the solvent, and is generally packaged separately. The separately packaged lyophilized powder injection and solvent may also contain their respective adjuvants. Here, “adjuvant” refers to a means of assisting the effect of a drug in pharmacy. The drug kit may also include separately packaged lyophilized powder injection and separately packaged solvent.

[0098] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that is suitable for contact with patient tissue (within reasonable medical judgment) and does not cause excessive toxicity, irritation, allergic reactions, or other problems or complications (i.e., has a reasonable risk / benefit ratio).

[0099] The term “prevention” has the meaning recognized in the art, and when used in relation to a medical condition, disease, syndrome, or other medical state, its meaning is well known to those skilled in the art, and includes a reduction in the incidence of a medical condition or a delay in its onset or symptoms in patients who have been administered the drug compared to patients who have not been administered the drug.

[0100] As used herein, the term “treatment” includes reversing, reducing, or suppressing the symptoms, clinical features, and underlying pathology of a disease by means of improving or stabilizing the patient’s condition.

[0101] The term “prevention or treatment” has the meaning recognized in the art and includes administering one or more of the drugs provided herein to a subject. If administered before the appearance of clinical signs of an undesirable condition (e.g., a disease or other undesirable condition in the animal being administered), the treatment is preventive (i.e., to prevent the subject being administered from developing the undesirable condition). Conversely, if administered after the appearance of clinical signs of an undesirable condition, the treatment is therapeutic (i.e., to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0102] In the examples described herein, the freeze-drying technique is performed according to the operating procedure of the freeze-dryer, and the setting of freeze-drying curve 1 (specific details are based on curve 1 in Table 13 of Test Example 3) is shown in Table 1 below.

[0103] [Table 1]

[0104] Example 1: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0105] [Table 2]

[0106] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0107] Example 2: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0108] [Table 3]

[0109] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0110] Example 3: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0111] [Table 4]

[0112] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0113] Example 4: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0114] [Table 5]

[0115] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0116] Example 5: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0117] [Table 6]

[0118] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0119] Example 6: Formulation and preparation method of dexamethasone sodium phosphate injection.

[0120] [Table 7]

[0121] Preparation method: According to the formulation table above, glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0122] Example 7: Formulation and preparation method of dexamethasone sodium phosphate for injection (containing the chelating agent calcium disodium edetate EDTA-2NaCa).

[0123] [Table 8]

[0124] Preparation method: The prescribed amounts of dexamethasone sodium phosphate and the additive calcium disodium edetate (EDTA-2NaCa) were dissolved in sterile water for injection at room temperature. The pH of the drug solution was adjusted to 8.0 with 0.1M hydrochloric acid (HCl), and then sterile water for injection was added. After the drug was completely dissolved, the solution was filtered sterile, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were then transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled into the oven, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0125] Example 8: Formulation and preparation method of dexamethasone sodium phosphate for injection (containing the antioxidant sodium bisulfite)

[0126] Ingredients:

[0127] [Table 9]

[0128] Preparation method: The prescribed amounts of dexamethasone sodium phosphate and the additive sodium bisulfite were dissolved in 70% sterile water for injection. The pH of the drug solution was adjusted to 8.0 with 0.1M sodium hydroxide (NaOH), and then sterile water for injection was added. After the drug was completely dissolved, the solution was filtered sterile, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were then transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled into the oven, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0129] Example 9: Formulation and preparation method of dexamethasone sodium phosphate (containing hyaluronic acid) for injection.

[0130] [Table 10]

[0131] Preparation method: The prescribed amounts of dexamethasone sodium phosphate and the hyaluronic acid additive were dissolved in 70% sterile water for injection. The pH of the drug solution was adjusted to 8.0 with 0.1M hydrochloric acid (HCl), and then sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to freeze-drying curve 1. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain a sterile freeze-dried preparation.

[0132] Test Example 1: Examination of the appearance and osmotic pressure of the freeze-dried finished product

[0133] The finished dexamethasone sodium phosphate preparations (lyophilized powder injection) prepared in Examples 1 to 9 above were examined for moisture content, osmotic pressure, and appearance. The results are shown in Table 11.

[0134] [Table 11]

[0135] As can be seen from the appearance and osmotic pressure results in the table above, glycerin was added in Examples 1 to 6, but the effect on the formulation's shape increased with increasing amounts of glycerin, and when the ratio of dexamethasone sodium phosphate to glycerin was 6:3, the freeze-dried mass disintegrated.

[0136] In Example 9, the addition of hyaluronic acid significantly hindered the formation of the formulation. Furthermore, glycerin is also an osmotic pressure regulator. In formulations without glycerin, the osmotic pressure was clearly low (approximately 150 mOsm / kg), while in a ratio of dexamethasone sodium phosphate to glycerin in the range of 6:1 to 6:3, the osmotic pressure reached 240 to 300 mOsm / kg, approaching the physiological osmotic pressure.

[0137] Test Example 2: Evaluation of related substances in high-temperature testing of freeze-dried final product

[0138] The final products of the dexamethasone sodium phosphate preparations prepared according to Examples 1 to 8 were sampled, the outer packaging was removed, and each product was placed in a high-temperature (60°C) stability tester to evaluate its stability. Samples were taken on day 0, day 5, and day 10, and the content of the relevant substances was measured (including dexamethasone as a decomposition impurity, total impurities, and their content). The results are shown in Table 12.

[0139] [Table 12]

[0140] From the results of the total impurities and their content described above, it can be seen that the product prepared with added glycerin has significantly improved stability compared to the product without added glycerin. The total impurity content is clearly lower compared to formulations with added chelating agent EDTA or antioxidants, while the dexamethasone sodium phosphate content is clearly higher compared to formulations with added chelating agent EDTA or antioxidants.

[0141] Comparison of different process examples of Test Example 3 (Examples 4, 10, 11, and 12)

[0142] The composition of the formulation used in Test Example 3 is shown in Table 13 (Formulation of Example 4).

[0143] [Table 13]

[0144] Preparation method: Glycerin was added to 70% of the amount of water to obtain a glycerin aqueous solution. Dexamethasone sodium phosphate was added to the glycerin aqueous solution, and the pH of the drug solution was adjusted to 8.0 with 0.1 M HCl, after which sterile water for injection was added. After the drug was completely dissolved, sterile filtration was performed, and 1 mL was dispensed into vials, with the stoppers pushed in halfway. These were transferred to a freeze-drying oven and freeze-dried according to the freeze-drying curve shown in Table 14 below. After freeze-drying was complete, nitrogen gas was filled, the stoppers were pushed in completely, and the aluminum caps were crimped to obtain sterile freeze-dried formulations.

[0145] [Table 14]

[0146] The results of the examination of the appearance and moisture content of the freeze-dried finished product are shown in Table 15.

[0147] [Table 15]

[0148] From the results above, it can be seen that the primary drying temperature and drying time, among the freeze-drying curve parameters, have a significant impact on the 1.0% (w / v) glycerin formulation. The primary drying temperature should be set as low as possible, and the drying time should be set as long as possible, with a total freeze-drying time of 2000 minutes or more.

[0149] Test Example 4: Pharmacodynamic study of injectable dexamethasone sodium phosphate (with glycerin)

[0150] Completed dexamethasone sodium phosphate preparations containing glycerin, prepared according to Examples 1 to 6, and completed dexamethasone sodium phosphate preparations containing a chelating agent (calcium disodium edetate, EDTA-2NaCa), prepared according to Example 7, were collected. These were dissolved in sterile water for injection before the experiment to prepare a 30 mg / mL dexamethasone sodium phosphate test solution, which was used for the test. In addition, commercially available dexamethasone sodium phosphate for injection (5 mg) was purchased and dissolved in sterile water for injection before the experiment to prepare a 5 mg / mL dexamethasone sodium phosphate test solution, which was used for the test.

[0151] The efficacy of the dexamethasone sodium phosphate experimental group for sudden hearing loss was evaluated using a noise-induced hearing loss model commonly used in new drug evaluation. Simultaneously, a model group and a blank control group (water for injection group) were established.

[0152] 1. A model of noise-induced hearing loss in guinea pigs:

[0153] Guinea pigs with normal hearing were divided into the following nine groups. After grouping, they were stimulated with 120 dB white noise for one hour. On the day of stimulation, the animals in the drug administration group were anesthetized by intraperitoneal injection of ketamine + xylazine according to their body weight. Seven of these groups received a single intratympanic injection of different drugs from Examples 1 to 7 into both ears, and one group received a single intratympanic injection of a commercially available drug into both ears. The model group was stimulated with 120 dB white noise for one hour, but no drug administration was performed. Even 15 days after stimulation exposure, the guinea pigs' hearing had not recovered to normal levels, and clear hearing loss persisted, leading to the conclusion that the noise-induced hearing loss model had been successfully created.

[0154] Auditory brainstem response was used to measure hearing thresholds (dB) before noise exposure and up to 15 days after exposure, and hearing was evaluated. The results are shown in Table 16. Before noise exposure, the average hearing threshold of animals in all groups was within the normal range (21-26.1 dB). Immediately after noise exposure, the average hearing threshold of the model group was 94-95 dB (total deaf). In contrast, the average hearing thresholds 15 days after administration in each treatment group and the commercially available product group were distributed in the range of 29-50 dB, and all groups administered dexamethasone sodium phosphate showed some degree of hearing protection. In particular, the group administered 30 mg / mL of dexamethasone sodium phosphate showed a better effect compared to the group administered the commercially available 5 mg / mL formulation.

[0155] [Table 16]

[0156] Test Example 5: Inner Ear Residue Test

[0157] Furthermore, the finished dexamethasone sodium phosphate preparations prepared according to Examples 1-9 were collected and similarly dissolved in sterile water for injection before the experiment to prepare a 30 mg / mL dexamethasone sodium phosphate test solution (Groups 1-9 in Table 17), which was then used for testing. In addition, commercially available dexamethasone sodium phosphate for injection (5 mg) was purchased and dissolved in sterile water for injection before the experiment to prepare a 5 mg / mL dexamethasone sodium phosphate test solution, which was then used for testing (Commercial products group in Table 17). Simultaneously, 2% w / v and 25% w / v glycerin aqueous redissolved solutions were prepared.

[0158] Method for preparing 2% w / v glycerin aqueous redissolving solution (2% glycerin aqueous solution): Take 2 g of glycerin, add sterile water for injection to make 100 mL, and prepare 2% w / v glycerin aqueous redissolving solution.

[0159] Method for preparing 25% w / v glycerin aqueous redissolving solution (25% glycerin aqueous solution): Add 25 g of glycerin to sterile water for injection to make 100 mL, and prepare a 2% w / v glycerin aqueous redissolving solution.

[0160] Method of inner ear residue test: Guinea pigs were used as a hearing loss model in the same manner as in Test Example 4. After anesthesia, the following solutions were administered by a single intratympanic injection: test solutions containing various dexamethasone sodium phosphates as described above, commercially available test solutions, and 2% (w / v) and 25% (w / v) glycerin aqueous solutions. On days 3 and 10 after administration, the drug residue and inflammation in the middle ear were observed. The results are shown in Table 17. When the glycerin concentration in the formulation was 2% (w / v) or less, no residue or inflammation in the inner ear was observed. However, when the glycerin concentration reached 25% (w / v), clear residue and inflammation occurred in the inner ear of the guinea pigs, and hearing impairment was also confirmed. Furthermore, formulations containing hyaluronic acid and formulations containing mannitol found in commercially available products resulted in inner ear residue in the early stages of administration. In addition, formulations containing sodium bisulfite had the potential to induce inflammation in the inner ear of guinea pigs.

[0161] [Table 17]

Claims

1. A lyophilized powder injection, wherein the preparation is a lyophilized powder injection of a dexamethasone-type drug, and does not contain a lyophilization support, excipient, or matrix agent, and the lyophilized powder injection contains glycerin, which is a pharmaceutically acceptable additive, and the glycerin is added before the lyophilization of the lyophilized powder injection.

2. The aforementioned additive further comprises a pH adjuster, Preferably, the additive does not contain a chelating agent or antioxidant. Preferably, the dexamethasone-based drug is one or more selected from dexamethasone, pharmaceutically acceptable dexamethasone derivatives or salts or esters thereof. Preferably, the dexamethasone-based drug is one or more selected from dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or salts thereof. Preferably, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 99.9%. Preferably, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 95%. Preferably, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 90%. Preferably, the mass percentage of the dexamethasone sodium phosphate is about 70.0% to 90%. Preferably, the mass ratio of the dexamethasone-based drug to glycerin in the lyophilized powder injection is about 8:1 to 2:

1. Preferably, the mass ratio of the dexamethasone-based drug to glycerin in the lyophilized powder injection is about 8:1 to 2.5:

1. Preferably, the mass ratio of the dexamethasone-based drug to glycerin in the lyophilized powder injection is approximately 6:1 to 6:2.

4. Preferably, the lyophilized powder injection according to claim 1, wherein the mass ratio of the dexamethasone-based drug to glycerin in the lyophilized powder injection is about 6:1.4 to 6:

2.

3. The aforementioned lyophilized powder injection is prepared by lyophilizing a combination solution comprising a dexamethasone-based drug, water, and a pharmaceutically acceptable additive. The aforementioned dexamethasone-based drug is one or more selected from dexamethasone, pharmaceutically acceptable dexamethasone derivatives, or salts or esters thereof. Preferably, the additive further comprises a pH adjusting agent. Preferably, the dexamethasone-based drug is one or more selected from dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or salts thereof. Preferably, the osmotic pressure of the combination solution is approximately 60 mOsm / kg to 449 mOsm / kg. Preferably, the osmotic pressure of the combination solution is approximately 150 mOsm / kg to 300 mOsm / kg. Preferably, the osmotic pressure of the combination solution is about 240 mOsm / kg to 300 mOsm / kg, the lyophilized powder injection according to any one of claims 1 to 2.

4. The amount of dexamethasone sodium phosphate in the aforementioned combination solution is approximately 15 to 80 mg / mL. Preferably, the content of dexamethasone sodium phosphate in the combination solution is about 25 to 75 mg / mL. Preferably, the content of dexamethasone sodium phosphate in the combination solution is about 25 to 65 mg / mL. Preferably, the content of dexamethasone sodium phosphate in the combination solution is about 20 to 55 mg / mL. Preferably, the content of dexamethasone sodium phosphate in the combination solution is about 20 to 45 mg / mL. Preferably, the content of dexamethasone sodium phosphate in the combination solution is about 30 mg / mL. Preferably, the glycerin content is about 0.01 to 3% w / v. Preferably, the glycerin content is about 0.01 to 2% w / v. Preferably, the glycerin content is about 0.01 to 1.45% w / v. Preferably, the glycerin content is about 0.01 to 1.2% w / v, the lyophilized powder injection according to any one of claims 1 to 3.

5. The pH adjusting agent is one or more selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, citric acid, or potassium dihydrogen phosphate. Preferably, the pH adjusting agent added to the combination solution is hydrochloric acid at a concentration of about 0.05 to 0.2 M. Preferably, the pH value of the combination solution is about 6 to 9. Preferably, the pH value of the combination solution is about 7 to 9. Preferably, the pH value of the combination solution is about 7 to 8.

5. Preferably, the pH value of the combination solution is about 7.5 to 8.

2. Preferably, the lyophilized powder injection according to any one of claims 1 to 4, wherein the lyophilized powder injection is used after being redissolved in a solvent, and the solvent is selected from water, an aqueous glycerin solution, or an aqueous sodium hyaluronate solution.

6. The pH value of the drug solution after the aforementioned freeze-dried powder injection is redissolved is approximately 6 to 9. Preferably, the pH value of the drug solution after redissolution is about 7 to 9. Preferably, the pH value of the drug solution after redissolution is about 7 to 8.

5. Preferably, the pH value of the combination solution is about 7.5 to 8.

2. Preferably, the osmotic pressure of the combination solution of the lyophilized powder injection before lyophilization is approximately 60 mOsm / kg to 449 mOsm / kg. Preferably, the osmotic pressure of the combination solution of the lyophilized powder injection before lyophilization is approximately 150 mOsm / kg to 300 mOsm / kg. Preferably, the osmotic pressure of the combination solution of the lyophilized powder injection before lyophilization is approximately 240 mOsm / kg to 300 mOsm / kg. Preferably, the preparation is an ear injection preparation. Preferably, the formulation is an inner ear injection or an intratympanic injection, according to any one of claims 1 to 5.

7. A pharmaceutical kit containing the following: (1) A lyophilized powder injection according to any one of claims 1 to 6, (2) Solvent, In the aforementioned pharmaceutical kit, the lyophilized powder injection and the solvent are packaged separately. Preferably, the drug delivery device used in the drug kit includes one or more selected from a needle, syringe, pump, and microinjection device. Preferably, the administration method using the drug kit includes one or more selected from microcapillary / microchip administration, micropump injection administration, and reciprocating microfluidic administration. Preferably, the solvent comprises water, an aqueous glycerin solution, or an aqueous sodium hyaluronate solution in the pharmaceutical kit.

8. A method for preparing a freeze-dried powder injection according to any one of claims 1 to 6, comprising the steps of: adding glycerin to water to obtain an aqueous glycerin solution; adding a dexamethasone-type drug to the aqueous glycerin solution and adding water; and subsequently freeze-drying, The freeze-drying step includes first pre-freezing, then primary drying, and finally secondary drying, wherein the temperature of the primary drying is approximately -50°C to 10°C, and the time is approximately 1000 min to 2200 min. Preferably, the temperature of the primary drying is about -30°C to 0°C, and the time is about 1000 min to 2000 min. Preferably, the temperature of the primary drying is about -30°C to 0°C, and the time is about 1000 min to 1800 min. Preferably, the temperature of the primary drying is about -20°C to 0°C, and the time is about 1000 min to 1500 min. Preferably, the primary drying step includes: holding at a temperature of -30°C to -15°C for about 500 min to 2000 min, raising the temperature to -14°C to -6°C at a rate of 0.1 to 0.2°C / min, holding for 300 min to 500 min, raising the temperature to -5°C to 10°C at a rate of 0.1 to 0.2°C / min, holding for 100 min to 200 min, Preferably, the primary drying step includes: preparing a lyophilized powder injection by holding at a temperature of -30°C to -18°C for about 500 min to 1200 min, raising the temperature to -14°C to -8°C at a rate of 0.1 to 0.2°C / min, holding for 300 min to 400 min, raising the temperature to -5°C to 5°C at a rate of 0.1 to 0.2°C / min, and holding for 100 min to 150 min.

9. The aforementioned pre-freezing temperature is approximately -65°C to -20°C, and the time is approximately 50 min to 150 min. Preferably, the pre-freezing temperature is approximately -65°C to -25°C, and the time is approximately 60 min to 500 min. Preferably, the pre-freezing temperature is approximately -65°C to -25°C, and the time is approximately 70 min to 400 min. Preferably, the pre-freezing temperature is about -50°C to -35°C, and the time is about 70 min to 200 min. Preferably, the secondary drying temperature is about 25°C to 45°C, and the drying time is about 600 min to 700 min. Preferably, the secondary drying temperature is about 25°C to 40°C, and the drying time is about 600 min to 700 min. Preferably, the secondary drying step includes raising the temperature to 25°C to 50°C at a rate of 1 to 6°C / min and continuing for about 600 to 800 minutes. Preferably, the secondary drying step includes raising the temperature to 25°C to 40°C at a rate of 1 to 3°C / min and continuing for about 600 to 700 minutes. Preferably, the freeze-drying step further includes a step of vacuuming after secondary drying. Preferably, the vacuum is drawn to a vacuum level of 0.1 to 0.2 mbar. Preferably, the freeze-drying time is about 1500 min to 5000 min. Preferably, the freeze-drying time is about 1500 min to 4000 min. Preferably, the freeze-drying time is about 1500 min to 3000 min, according to claim 8.

10. Use of the manufacturing method according to claim 8 or 9 in the manufacture of a lyophilized powder injection according to any one of claims 1 to 6, a pharmaceutical kit according to claim 7, or a drug for preventing or treating ear diseases.

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