Dexamethasone sodium phosphate lyophilized composition suitable for administration to eardrum and preparation method therefor

Abstract

A dexamethasone sodium phosphate lyophilized composition suitable for administration to the eardrum and a preparation method therefor. Provided is a lyophilized powder injection preparation, the preparation being a dexamethasone drug lyophilized powder injection preparation which does not contain a lyophilization support agent or excipient or scaffolding agent, the lyophilized powder injection preparation containing the pharmaceutically acceptable excipient glycerol, and the glycerol being added before lyophilization of the lyophilized powder injection preparation. The provided lyophilized preparation does not contain a lyophilization support agent or an excipient, and the effect of increasing the stability of the drug is achieved by adding a small amount of glycerol before lyophilization of the preparation; in addition, the osmotic pressure can be adjusted to be closer to physiological osmotic pressure and prolong the local administration action time during intratympanic drug administration, increasing the safety and effectiveness of intratympanic drug administration.

Description

A dexamethasone sodium phosphate freeze-dried composition suitable for eardrum administration and its preparation method Technical Field

[0001] The present disclosure belongs to the field of biomedicine and relates to a dexamethasone sodium phosphate freeze-dried composition suitable for eardrum administration and a preparation method thereof. Background Art

[0002] In recent years, glucocorticoids have been widely used to treat a variety of inner ear diseases, such as deafness, Meniere's disease, and acute post-meningitic labyrinthitis. Sudden deafness is a sudden, non-fluctuating sensorineural hearing loss with an acute onset and rapid progression, resulting in a sudden loss of hearing within minutes, hours, or even three days. Common associated symptoms include tinnitus and vertigo. The etiology of sudden deafness is not yet fully understood, but the main causes include inner ear microcirculatory disorders, specific infections, immune factors, and psychological factors. Acute deafness and sudden hearing loss have similar etiologies, but some differences exist. Acute deafness is accompanied by tinnitus but not vertigo. Some researchers believe that the primary cause of acute deafness is middle ear disease. Both are currently treated with steroids. In the treatment of sudden deafness, steroids help interrupt the pathological damage process, protect, and promote the recovery of inner ear functions. However, their effectiveness is limited for irreversibly damaged inner ear tissues and organs. Steroids are effective for patients with severe sudden deafness, especially for those with mid- and low-frequency hearing loss. Glucocorticoids have been adopted as the standard treatment for sudden deafness internationally.

[0003] Dexamethasone, a synthetic adrenocortical hormone, has a strong anti-inflammatory effect on various organ systems. Compared with hydrocortisone and its derivatives, it has the weakest side effect of sodium and water retention and the strongest anti-inflammatory effect. Dexamethasone has a biological half-life of 36 to 54 hours and is a long-acting glucocorticoid (Chinese Medical Abstracts Otorhinolaryngology, 2014, 29(5): 280). Currently, oral dexamethasone tablets or intratympanic injection of dexamethasone sodium phosphate are often used in clinical practice to treat acute deafness. However, oral administration has significant systemic side effects and the drug has difficulty passing through the blood-labyrinth barrier to reach the inner ear and exert its effect. In addition, the excipients in the preparation are easily retained in the inner ear and cannot be metabolized, thereby causing inflammation and other inner ear diseases. Many injections are sterilized by high-pressure steam or circulating steam, which can easily destroy the stability of the drug and strengthen the interaction between the raw materials and excipients, making it difficult to control the related substances. However, studies have shown that dexamethasone can enter the inner ear through the tympanic membrane-tympanic cavity pathway (Journal of Audiology and Speech Pathology, 2005, 13(4): 260-263), thus providing a new approach for the treatment of inner ear diseases. Compared with intravenous infusion, the total effective rate of intratympanic injection in the treatment of sudden deafness can reach 92.5%, which is significantly better than intravenous administration (Jilin Medicine, 2013, 34(27): 5607).

[0004] Existing commercially available dexamethasone sodium phosphate injections have a low concentration and are not suitable for high-concentration intratympanic administration. Furthermore, the concentration issue cannot be resolved by simply stacking the concentrations of the lyophilized solution. Existing commercially available dexamethasone sodium phosphate lyophilized solutions all contain lyophilization excipients such as mannitol, lactose, and sorbitol. Furthermore, antioxidants are often added to enhance product stability. These substances can easily remain in the ear and cause inner ear inflammation, making them unsuitable for intratympanic administration.

[0005] Summary of the Invention

[0006] In some embodiments, the present disclosure provides a freeze-dried powder injection preparation, which is a freeze-dried powder injection of a dexamethasone-type drug, does not contain a freeze-drying support agent, excipient, or scaffold agent, and contains a pharmaceutically acceptable excipient glycerol, which is added before the freeze-dried powder injection preparation is freeze-dried.

[0007] In some embodiments, the excipient further includes a pH adjuster.

[0008] In some embodiments, the excipient does not include a chelating agent or an antioxidant.

[0009] In some embodiments, the dexamethasone-based drug is selected from one or more of dexamethasone, pharmaceutically acceptable derivatives of dexamethasone, or salts or esters thereof.

[0010] In some embodiments, the dexamethasone-based drug includes one or more of dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or salts thereof.

[0011] In some embodiments, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 99.9%.

[0012] In some embodiments, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 95%.

[0013] In some embodiments, the mass percentage of the dexamethasone sodium phosphate is about 60.0% to 90%.

[0014] In some embodiments, the mass percentage of the dexamethasone sodium phosphate is about 70.0% to 90%.

[0015] In some embodiments, the mass ratio of the dexamethasone-like drug to glycerol in the lyophilized powder injection preparation is about 8:1 to 2:1.

[0016] In some embodiments, the mass ratio of the dexamethasone-like drug to glycerol in the lyophilized powder injection preparation is about 8:1 to 2.5:1.

[0017] In some embodiments, the mass ratio of the dexamethasone-like drug to glycerol in the lyophilized powder injection preparation is about 6:1 to 6:2.4.

[0018] In some embodiments, the mass ratio of the dexamethasone-like drug to glycerol in the lyophilized powder injection preparation is about 6:1.4 to 6:2.

[0019] In some embodiments, the formulation is freeze-dried from a combined solution of a dexamethasone-like drug, water, and a pharmaceutically acceptable excipient.

[0020] In some embodiments, the dexamethasone-based drug is selected from one or more of dexamethasone, pharmaceutically acceptable derivatives of dexamethasone, or salts or esters thereof.

[0021] In some embodiments, the excipient further includes a pH adjuster.

[0022] In some embodiments, the osmotic pressure of the combined solution is about 60 mOsm / kg to about 449 mOsm / kg.

[0023] In some embodiments, the osmotic pressure of the combined solution is about 150 mOsm / kg to about 300 mOsm / kg.

[0024] In some embodiments, the osmotic pressure of the combined solution is about 240 mOsm / kg to 300 mOsm / kg.

[0025] In some embodiments, the dexamethasone-based drug includes one or more of dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or salts thereof.

[0026] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 15-80 mg / mL.

[0027] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 25-75 mg / mL.

[0028] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 25-65 mg / mL.

[0029] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 20-55 mg / mL.

[0030] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 20-45 mg / mL.

[0031] In some embodiments, the content of dexamethasone sodium phosphate in the combined solution is about 30 mg / mL.

[0032] In some embodiments, the glycerol content is about 0.01-3% w / v.

[0033] In some embodiments, the glycerol content is about 0.01-2% w / v.

[0034] In some embodiments, the glycerol content is about 0.01-1.45% w / v.

[0035] In some embodiments, the glycerol content is about 0.01-1.2% w / v.

[0036] In some embodiments, the pH adjuster is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, citric acid, or potassium dihydrogen phosphate.

[0037] In some embodiments, the pH adjuster added to the combined solution is about 0.05-0.2 MM hydrochloric acid.

[0038] In some embodiments, the lyophilized powder injection preparation is reconstituted with a solvent before use, and the solvent includes water, glycerol aqueous solution or sodium hyaluronate aqueous solution.

[0039] In some embodiments, the pH of the combined solution is in the range of about 6-9.

[0040] In some embodiments, the pH of the combined solution is in the range of about 7-9.

[0041] In some embodiments, the pH of the combined solution is in the range of about 7 to about 8.5.

[0042] In some embodiments, the pH of the combined solution is in the range of about 7.5 to about 8.2.

[0043] In some embodiments, the pH value of the reconstituted drug solution is in the range of about 6 to 9.

[0044] In some embodiments, the pH value of the reconstituted drug solution is in the range of about 7 to 9.

[0045] In some embodiments, the pH value of the reconstituted drug solution is in the range of about 7 to 8.5.

[0046] In some embodiments, the pH value of the reconstituted drug solution is in the range of about 7.5 to 8.2. In some embodiments, the osmotic pressure of the combined solution before lyophilization of the formulation is in the range of about 60 mOsm / kg to 449 mOsm / kg.

[0047] In some embodiments, the osmotic pressure of the combined solution before lyophilization of the formulation is about 150 mOsm / kg to 300 mOsm / kg.

[0048] In some embodiments, the osmotic pressure of the combined solution before lyophilization of the formulation is about 240 mOsm / kg to 300 mOsm / kg.

[0049] In some embodiments, the formulation is an otic injection.

[0050] In some embodiments, the preparation is an intra-intratympanic injection or intratympanic injection. Domestic databases show 89 records of quality failure in recent years of spot checks on commercially available dexamethasone sodium phosphate injection, primarily due to visible foreign matter and related substances. For intra-intra-intra-tympanic injections, impurities and excipients are easily retained in the inner ear due to low levels of fluid and enzymes, making them difficult to metabolize, thus affecting hearing. In the absence of other antioxidants or excipients, the injection is susceptible to oxidation or hydrolysis, which can also affect the stability of the active ingredient.

[0051] It can be seen from the existing technology that it is not easy to obtain a dexamethasone injection that meets the requirements (high efficacy, good stability, and few impurities or related substances).

[0052] During the research on dexamethasone injection, the inventors discovered in preliminary studies that when dexamethasone is freeze-dried, glycerol, which is often used as a protective agent for freeze-drying and preservation of red blood cells, is added to the freeze-dried injection solution to prevent it from forming, thus affecting the freeze-drying effect of dexamethasone.

[0053] In some embodiments, it is rare that the inventors were not limited by previous studies and continued to strive for excellence, obtaining a formulation that does not contain lyophilized support agents or excipients, and can improve the stability of the drug by simply adding a small amount of glycerol. At the same time, the osmotic pressure can be adjusted to make it closer to the physiological osmotic pressure during intratympanic administration and prolong the duration of local administration, thereby increasing the safety and effectiveness of intratympanic administration.

[0054] In some embodiments, it is particularly rare that the formulation obtained in the present disclosure can obtain an ideal white loose freeze-dried mass without causing the skeleton to collapse due to the addition of glycerol.

[0055] In some embodiments, the present disclosure provides a pharmaceutical set comprising: (1) the lyophilized powder injection preparation; and (2) a solvent; wherein the lyophilized powder injection preparation and the solvent are packaged separately in the pharmaceutical set.

[0056] In some embodiments, the drug delivery device of the pharmaceutical kit comprises one or more of a needle and syringe, a pump, and a microinjection device.

[0057] In some embodiments, the administration method of the drug set includes one or more of microsiphon / microcore administration, micropump injection administration, and reciprocating microfluidic administration.

[0058] In some embodiments, the vehicle comprises water, aqueous glycerol solution, or aqueous sodium hyaluronate solution.

[0059] In some embodiments, the present disclosure provides a method for preparing the freeze-dried powder injection preparation, comprising adding glycerol to water to obtain a glycerol aqueous solution; adding a dexamethasone-like drug to the glycerol aqueous solution, supplementing with water for injection, and then freeze-drying.

[0060] In some embodiments, the freeze-drying process employed in the present disclosure can solve the problem of product appearance shrinkage caused by the addition of glycerol.

[0061] In some embodiments, the freeze-drying step includes: pre-freezing, primary drying, and then desorption drying; the primary drying temperature is about -50°C to 10°C, and the time is about 1000 min to 2200 min.

[0062] In some embodiments, the primary drying temperature is about -30°C to 0°C, and the time is about 1000 min to 2000 min.

[0063] In some embodiments, the primary drying temperature is about -30°C to 0°C, and the time is about 1000 min to 1800 min.

[0064] In some embodiments, the primary drying temperature is about -20°C to 0°C, and the time is about 1000 min to 1500 min.

[0065] In some embodiments, the primary drying step includes: temperature -30°C to -15°C, time about 500min to 2000min; heating to -14°C to -6°C at a rate of 0.1 to 0.2°C / min, duration: 300 to 500min; heating to -5 to 10°C at a rate of 0.1 to 0.2°C / min, duration: 100min to 200min.

[0066] In some embodiments, the primary drying step includes: temperature -30°C to -18°C, time about 500min to 1200min; heating to -14°C to -8°C at a rate of 0.1 to 0.2°C / min, duration: 300 to 400min; heating to -5 to 5°C at a rate of 0.1 to 0.2°C / min, duration: 100min to 150min.

[0067] In some embodiments, the pre-freezing temperature is about -65°C to -20°C, and the pre-freezing time is about 50 minutes to 150 minutes.

[0068] In some embodiments, the pre-freezing temperature is about -65°C to -25°C, and the pre-freezing time is about 60 minutes to 500 minutes.

[0069] In some embodiments, the pre-freezing temperature is about -65°C to -25°C, and the pre-freezing time is about 670 minutes to 400 minutes.

[0070] In some embodiments, the pre-freezing temperature is about -50°C to -35°C, and the pre-freezing time is about 6070 minutes to 200 minutes.

[0071] In some embodiments, the pre-freezing temperature is about -65°C to -25°C, and the pre-freezing time is about 60 minutes to 120 minutes.

[0072] In some embodiments, the pre-freezing temperature is about -50°C to -35°C, and the pre-freezing time is about 60 minutes to 120 minutes.

[0073] In some embodiments, the desorption drying temperature is about 25° C. to 45° C., and the time is about 600 min to 700 min.

[0074] In some embodiments, the desorption drying temperature is about 25° C. to 40° C., and the time is about 600 min to 700 min.

[0075] In some embodiments, the desorption drying step includes: heating to 25° C. to 50° C. at a rate of 1 to 6° C. / min for about 600 to 800 minutes.

[0076] In some embodiments, the desorption drying step includes: heating to 25° C. to 40° C. at a rate of 1 to 3° C. / min for about 600 to 700 minutes.

[0077] In some embodiments, the freeze-drying step further comprises: vacuuming after desorption drying.

[0078] In some embodiments, the vacuum is drawn at 0.1 to 0.2 mbar.

[0079] In some embodiments, the freeze-drying time is about 1500 min to 5000 min.

[0080] In some embodiments, the freeze-drying time is about 1500 min to 4000 min.

[0081] In some embodiments, the freeze-drying time is about 1500 min to 3000 min.

[0082] In some embodiments, the present disclosure provides a lyophilized powder injection preparation obtained by the method.

[0083] In some embodiments, the present disclosure provides use of the freeze-dried powder injection preparation, the pharmaceutical set, or the preparation method in preparing a drug for preventing or treating ear diseases.

[0084] In some embodiments, the present disclosure provides a method for preventing or treating ear diseases, comprising providing the lyophilized powder injection preparation or the pharmaceutical set to a patient in need. DETAILED DESCRIPTION

[0085] The following is a detailed description of the technical solution of the present disclosure, which does not limit the scope of protection of the present disclosure. Non-essential modifications and adjustments made by others based on the concept of the present disclosure still fall within the scope of protection of the present disclosure.

[0086] Certain definitions

[0087] As used herein, amelioration or alleviation of the symptoms of a particular otic disease, disorder, or condition by administration of a particular formulation or medical kit refers to any reduction in severity, delayed onset, slowed progression, or shortened duration attributable to or caused by the administration of the formulation or medical kit, regardless of whether such effects are permanent or temporary, lasting or transient.

[0088] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods and reference to "the fragment" includes reference to one or more fragments and equivalents thereof known to those skilled in the art, and so forth.

[0089] Furthermore, the use of "or" means "and / or" unless stated otherwise. Similarly, "including," "comprising," and "comprising" are interchangeable and are not intended to be limiting.

[0090] It should be further understood that where the term "comprising" is used to describe various embodiments, those skilled in the art will understand that in some specific cases, the language "consisting essentially of" or "consisting of" may alternatively be used to describe the embodiment.

[0091] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although many methods and reagents are similar or equivalent to those described herein, exemplary methods and materials are disclosed herein.

[0092] It is to be understood that the present disclosure is not limited to the particular methodology, protocols, reagents, etc. described herein and that these may vary. The terminology used herein is for the purpose of describing particular embodiments or aspects only and is not intended to limit the scope of the present disclosure.

[0093] "Antioxidants" are oto-pharmaceutically acceptable antioxidants and include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability where desired. Antioxidants are also used to counteract the ototoxic effects of certain therapeutic agents, including agents used in combination with the corticosteroids disclosed herein.

[0094] The term "inner ear" refers to the inner ear, which includes the cochlea and vestibular labyrinth, as well as the round window connecting the cochlea to the middle ear.

[0095] The "round window membrane" is the membrane that covers the cochlear window (also called the round window, the right round window, or the round window) in humans. In humans, the thickness of the round window membrane is about 70 microns.

[0096] "Pharmacodynamics" refers to the factors that determine the biological response observed at the desired site within the target auris structure relative to the concentration of the drug.

[0097] "Pharmacokinetics" refers to the factors that determine whether an appropriate drug concentration is achieved and maintained at the desired site within the target auris structure.

[0098] As used herein, the term "treating" includes prophylactic and / or therapeutic alleviation, relief, or amelioration of symptoms of a disease or condition, prevention of additional symptoms, amelioration or prevention of underlying metabolic causes of symptoms, inhibition of the disease or condition (e.g., arresting the development of the disease or condition), palliation of the disease or condition, causing regression of the disease or condition, alleviation of symptoms caused by the disease or condition, or cessation of symptoms of the disease or condition.

[0099] In some embodiments, the present disclosure provides a pharmaceutical kit for treating tumors, comprising the lyophilized powder injection formulation and a solvent. In the pharmaceutical kit, the lyophilized powder injection formulation is not necessarily, and typically is not, mixed with the solvent, but is typically packaged separately. The separately packaged lyophilized powder injection formulation and the solvent may also contain their respective adjuvants. The adjuvant refers to a pharmaceutical agent that can assist the therapeutic effect of a drug. The pharmaceutical kit may also include a separately packaged lyophilized powder injection formulation and a separately packaged solvent.

[0100] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable (within the scope of sound medical judgment) for use in contact with the tissues of patients without causing excessive toxicity, irritation, allergic response or other problems or complications (i.e., with a reasonable risk / benefit ratio).

[0101] The term "prevent" or "prevent" has an art-recognized meaning and, when used in connection with a condition, disease, syndrome, or any other medical condition, has a meaning well known in the art and includes administering a drug such that the frequency of the medical condition occurs less frequently, or the onset or symptoms of the condition are delayed, in a patient who does not receive the drug.

[0102] As used herein, the term "treating" includes reversing, alleviating or inhibiting the symptoms, clinical features and underlying pathology of a disease in a manner that improves or stabilizes the patient's condition.

[0103] The terms "prevent or treat" and "treat" have their art-recognized meanings and include administering one or more of the disclosed agents to a recipient. If administered before clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in the recipient animal), such treatment is preventative (i.e., to prevent the development of an undesirable condition in the recipient). Conversely, if administered after clinical manifestation of an undesirable condition, such treatment is therapeutic (i.e., to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0104] In the examples herein, the freeze drying technology was operated according to the freeze drying machine operating procedures, and the setting of freeze drying curve 1 (specific details are based on curve 1 in Table 13 of Experimental Example 3) is shown in Table 1 below.

[0105] Table 1

[0106] Example 1 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0107] Table 2

[0108] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0109] Example 2 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0110] Table 3

[0111] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0112] Example 3 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0113] Table 4

[0114] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0115] Example 4 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0116] Table 5

[0117] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0118] Example 5 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0119] Table 6

[0120] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0121] Example 6 Formula and Preparation Method of Dexamethasone Sodium Phosphate Injection

[0122] Table 7

[0123] Preparation: According to the above formula, add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution. Add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0124] Example 7: Formula and Preparation Method of Dexamethasone Sodium Phosphate for Injection (Containing Chelating Agent EDTA-2NaCa)

[0125] Table 8

[0126] Preparation: Dissolve the prescribed amount of dexamethasone sodium phosphate and the excipient EDTA-2NaCa in room temperature water for injection. Adjust the pH of the solution to 8.0 with 0.1M HCl, and then add more water for injection. After complete dissolution, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry the vials in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0127] Example 8: Formula and Preparation Method of Dexamethasone Sodium Phosphate for Injection (Containing the Antioxidant Sodium Bisulfite)

[0128] Prescription composition:

[0129] Table 9

[0130] Preparation: Dissolve the prescribed amount of dexamethasone sodium phosphate and the excipient sodium bisulfite in 70% water for injection. Adjust the pH of the solution to 8.0 with 0.1M NaOH, and then add more water for injection. After complete dissolution, sterilize and filter the solution. Dispense 1 ml into vials and partially stopper. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper, and roll-on aluminum cap to obtain a sterile lyophilized preparation.

[0131] Example 9: Formula and Preparation Method of Dexamethasone Sodium Phosphate for Injection (Containing Hyaluronic Acid)

[0132] Table 10

[0133] Preparation: Dissolve the prescribed amount of dexamethasone sodium phosphate and the excipient hyaluronic acid in 70% water for injection. Adjust the pH of the solution to 8.0 with 0.1M HCl, and then add more water for injection. After complete dissolution, sterilize and filter the solution. Dispense 1 ml into vials and partially stopper. Freeze-dry in a lyophilizer using freeze-drying curve 1. After lyophilization, fill with nitrogen, stopper, and roll-on aluminum caps to obtain a sterile lyophilized preparation.

[0134] Test Example 1: Appearance and osmotic pressure of freeze-dried finished product

[0135] The finished dexamethasone sodium phosphate preparations (lyophilized powder injections) prepared according to Examples 1 to 9 were tested for moisture, osmotic pressure, and appearance. The results are shown in Table 11.

[0136] Table 11

[0137] From the appearance and osmotic pressure results in the above table, it can be seen that glycerol was added in Examples 1 to 6. As the amount of glycerol added increased, the effect on the formulation molding became greater. When the ratio of dexamethasone sodium phosphate to glycerol was 6:3, the freeze-dried block collapsed.

[0138] The addition of hyaluronic acid in Example 9 severely affected the formulation's molding process. Furthermore, glycerol is also an osmotic pressure regulator. The formulation without glycerol exhibited a significantly lower osmotic pressure of only about 150 mOsm / kg. When the ratio of dexamethasone sodium phosphate to glycerol reached 6:1 to 6:3, the osmotic pressure reached 240 to 300 mOsm / kg, approaching physiological osmotic pressure.

[0139] Test Example 2 Investigation of Related Substances in High-Temperature Test of Freeze-Dried Finished Products

[0140] Finished dexamethasone sodium phosphate preparations prepared according to Examples 1 to 8 were removed from their outer packaging and placed in a high-temperature (60°C) stability test chamber. Samples were taken on days 0, 5, and 10 to assess the content of related substances (including the degradation impurity dexamethasone and total impurities). The results are shown in Table 12.

[0141] Table 12

[0142] From the results of total impurities and content in the above table, it can be seen that the stability of the product prepared with the addition of glycerol is greatly improved compared with the product without glycerol. The total impurity content is significantly lower than that of the prescription with the addition of chelating agent EDTA and the prescription with antioxidant. The content of dexamethasone sodium phosphate is significantly higher than that of the prescription with the addition of chelating agent EDTA and the prescription with antioxidant.

[0143] Experimental Example 3 Comparison of different process embodiments (Example 4, Example 10, Example 11, Example 12)

[0144] The formulation used in Test Example 3 is shown in Table 13 below (formula of Example 4).

[0145] Table 13

[0146] Preparation method: Add glycerol to 70% of the prescribed volume of water to obtain a glycerol-water solution; add dexamethasone sodium phosphate to the glycerol-water solution, adjust the pH of the solution to 8.0 with 0.1M HCl, and supplement with water for injection. After the drug is completely dissolved, sterile filter the solution and dispense 1 ml into vials, partially stoppering them. Freeze-dry the vials in a lyophilizer using the freeze-drying curves shown in Table 14 below. After lyophilization, fill with nitrogen, stopper the vials, and roll on aluminum caps to obtain a sterile lyophilized preparation.

[0147] Table 14

[0148] The appearance and moisture content of the freeze-dried product are shown in Table 15.

[0149] Table 15

[0150] The results in the table above show that the primary drying temperature and drying time, two of the freeze-drying curve parameters, have a significant impact on the 1.0% (w / v) glycerol formulation. The primary drying temperature should be as low as possible, and the drying time should be as long as possible, with a total freeze-drying time of at least 2000 minutes.

[0151] Test Example 4 Pharmacodynamics Test of Dexamethasone Sodium Phosphate for Injection (Glycerol Prescription)

[0152] The finished dexamethasone sodium phosphate preparations prepared according to Examples 1 to 6 (containing glycerol in the formulation) and the finished dexamethasone sodium phosphate preparation prepared in Example 7 (containing the chelating agent edetate sodium calcium EDTA-2NaCa in the formulation) were taken. Before the experiment, these finished preparations were added to water for injection to prepare a dexamethasone sodium phosphate test solution with a concentration of 30 mg / ml, and set aside. Separately, commercially available dexamethasone sodium phosphate for injection (5 mg) was purchased and added to water for injection to prepare a dexamethasone sodium phosphate test solution with a concentration of 5 mg / ml, and set aside.

[0153] The noise-induced deafness model, commonly used in new drug evaluation, was used to evaluate the efficacy of the dexamethasone sodium phosphate experimental group on sudden deafness. A model group and a blank control water for injection group were also set up.

[0154] 1. Guinea pig noise-induced deafness model:

[0155] Guinea pigs with normal hearing were divided into nine groups: the first group was stimulated with 120 decibels of white noise for one hour. On the day of stimulation, the animals in the drug-treated group were anesthetized with ketamine and xylazine injected intraperitoneally according to body weight. Seven of the groups received a single intratympanic injection of different drugs from Examples 1 to 7, and one group received a single intratympanic injection of a commercially available drug. The model group was stimulated with 120 decibels of white noise for one hour and received no drug treatment. Fifteen days after stimulation, the guinea pigs' hearing had not returned to normal levels and showed significant hearing loss, indicating that noise modeling was successful.

[0156] Auditory brainstem response was used to measure hearing thresholds (dB) before and 15 days after noise exposure to assess hearing. The results are shown in Table 16. Before the noise exposure, the average hearing values ​​of the animals in each group were within the normal range of 21-26.1 dB. Immediately after the noise exposure, the average hearing value of the model group was 94-95 dB (total deafness). The average hearing values ​​of the drug-treated group and the commercially available group 15 days after administration were between 29-50 dB, respectively. This indicates that both the dexamethasone sodium phosphate-treated groups had a certain hearing protection effect. Among them, the 30 mg / mL dexamethasone sodium phosphate group had a better effect than the commercially available 5 mg / mL dexamethasone sodium phosphate-treated group.

[0157] Table 16 Guinea pig noise-induced deafness model test hearing threshold evaluation table (dB: mean ± standard deviation)

[0158] Test Example 5 Inner ear residue test

[0159] The finished dexamethasone sodium phosphate preparations prepared according to Examples 1 to 9 were prepared with water for injection to prepare a 30 mg / ml dexamethasone sodium phosphate test solution (Example 1 to Example 9 groups in Table 17) before the experiment, and set aside. Separately, commercially available dexamethasone sodium phosphate for injection (5 mg) was also prepared with water for injection to prepare a 5 mg / ml dexamethasone sodium phosphate test solution before the experiment (Commercial Group in Table 17). Simultaneously, 2% w / v glycerol aqueous solutions and 25% w / v glycerol aqueous solutions were prepared.

[0160] Preparation method of 2% w / v glycerol water reconstitution solution (2% w / v glycerol water group): take 2g glycerol and add injection water to 100ml to prepare 2% w / v glycerol water reconstitution solution.

[0161] Preparation method of 25% w / v glycerol water reconstitution solution (25% w / v glycerol water): take 25g glycerol and add water for injection to 100ml to prepare 2% w / v glycerol water reconstitution solution.

[0162] Inner Ear Residue Test: Guinea pigs were anesthetized and injected intratympanically with a single dose of the aforementioned dexamethasone sodium phosphate test solution, a commercially available test solution, and a 2% w / v glycerol-water solution and a 25% w / v glycerol-water solution. Residue and inflammation in the middle ear were observed 3 and 10 days after administration. The results are shown in Table 17. Formulations containing 2% w / v glycerol or less did not produce any inner ear residue or inflammation. When the glycerol content reached 25%, significant residue and inflammation occurred in the guinea pigs' inner ears, and hearing loss was also observed. Furthermore, formulations containing hyaluronic acid and, in the commercial version, mannitol also produced residue in the early stages of the inner ear. Formulations containing sodium bisulfite may induce inflammation in the guinea pigs' inner ears.

[0163] Table 17 Middle ear residual and inflammation after single intratympanic injection of various dexamethasone sodium phosphate

Claims

1. A freeze-dried powder injection preparation, wherein: The preparation is a dexamethasone-type drug freeze-dried powder injection, which does not contain a freeze-drying support agent, an excipient, or a scaffold agent. The freeze-dried powder injection preparation contains a pharmaceutically acceptable auxiliary material, glycerol, which is added before the freeze-dried powder injection preparation is freeze-dried.

2. The freeze-dried powder injection preparation according to claim 1, wherein The auxiliary materials also include a pH adjuster; Preferably, the excipient does not include a chelating agent or an antioxidant; Preferably, the dexamethasone-based drug is selected from one or more of dexamethasone, a pharmaceutically acceptable derivative of dexamethasone, or a salt or ester thereof; Preferably, the dexamethasone-based drug includes one or more of dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or their salts; Preferably, the mass percentage of dexamethasone sodium phosphate is 60.0% to 99.9%; Preferably, the mass percentage of dexamethasone sodium phosphate is 60.0% to 95%; Preferably, the mass percentage of dexamethasone sodium phosphate is about 60.0% to 90%; Preferably, the mass percentage of dexamethasone sodium phosphate is about 70.0% to 90%; Preferably, the mass ratio of dexamethasone to glycerol in the freeze-dried powder injection preparation is about 8:1 to 2:1; Preferably, the mass ratio of dexamethasone to glycerol in the freeze-dried powder injection preparation is about 8:1 to 2.5:1; Preferably, the mass ratio of dexamethasone to glycerol in the freeze-dried powder injection preparation is about 6:1 to 6:2.4; Preferably, the mass ratio of dexamethasone to glycerol in the freeze-dried powder injection preparation is about 6:1.4 to 6:

2.

3. The freeze-dried powder injection preparation according to any one of claims 1 to 2, wherein: The freeze-dried powder injection preparation is freeze-dried from a combined solution of a dexamethasone drug, water and a pharmaceutically acceptable excipient; The dexamethasone-based drug is selected from one or more of dexamethasone, pharmaceutically acceptable derivatives of dexamethasone, or salts or esters thereof; Preferably, the auxiliary material further comprises a pH adjuster; Preferably, the dexamethasone-based drug includes one or more of dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or their salts; Preferably, the osmotic pressure of the combined solution is about 60mOsm / kg to 449mOsm / kg; Preferably, the osmotic pressure of the combined solution is about 150mOsm / kg to 300mOsm / kg; Preferably, the osmotic pressure of the combined solution is about 240 mOsm / kg to 300 mOsm / kg.

4. The freeze-dried powder injection preparation according to any one of claims 1 to 3, wherein The content of dexamethasone sodium phosphate in the combined solution is about 15 to 80 mg / mL; Preferably, the content of dexamethasone sodium phosphate in the combined solution is about 25 to 75 mg / mL; Preferably, the content of dexamethasone sodium phosphate in the combined solution is about 25 to 65 mg / mL; Preferably, the content of dexamethasone sodium phosphate in the combined solution is about 20 to 55 mg / mL; Preferably, the content of dexamethasone sodium phosphate in the combined solution is about 20 to 45 mg / mL; Preferably, the content of dexamethasone sodium phosphate in the combined solution is about 30 mg / mL; Preferably, the content of glycerol is about 0.01-3% w / v; Preferably, the content of glycerol is about 0.01-2% w / v; Preferably, the content of glycerol is about 0.01-1.45% w / v; Preferably, the content of glycerol is about 0.01-1.2% w / v.

5. The freeze-dried powder injection preparation according to any one of claims 1 to 4, wherein The pH regulator is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, citric acid or potassium dihydrogen phosphate; Preferably, the pH adjuster added to the combined solution is about 0.05-0.2M hydrochloric acid; Preferably, the pH value of the combined solution ranges from about 6 to about 9; Preferably, the pH value of the combined solution ranges from about 7 to 9; Preferably, the pH value of the combined solution ranges from about 7 to 8.5; Preferably, the pH value of the combined solution ranges from about 7.5 to 8.2; Preferably, the lyophilized powder injection preparation is reconstituted with a solvent before use, and the solvent includes water, glycerol aqueous solution or sodium hyaluronate aqueous solution.

6. The freeze-dried powder injection preparation according to any one of claims 1 to 5, wherein The pH range of the reconstituted lyophilized powder injection preparation is about 6 to 9; Preferably, the pH value of the reconstituted drug solution is in the range of about 7 to 9; Preferably, the pH value of the reconstituted drug solution is in the range of about 7 to 8.5; Preferably, the pH value of the combined solution ranges from about 7.5 to 8.2; Preferably, the osmotic pressure of the combined solution of the lyophilized powder injection preparation before lyophilization is about 60mOsm / kg to 449mOsm / kg; Preferably, the osmotic pressure of the combined solution of the freeze-dried powder injection preparation before freeze-drying is about 150mOsm / kg to 300mOsm / kg; Preferably, the osmotic pressure of the combined solution of the lyophilized powder injection preparation before lyophilization is about 240mOsm / kg to 300mOsm / kg; Preferably, the preparation is an ear injection; Preferably, the preparation is an intra-auriculo-injection or an intratympanic-injection.

7. A pharmaceutical kit, wherein: include: (1) The lyophilized powder injection preparation according to any one of claims 1 to 6; (2) Solvent; In the pharmaceutical set, the freeze-dried powder injection preparation and the solvent are packaged separately; Preferably, the drug delivery device of the pharmaceutical kit comprises one or more of a needle and syringe, a pump, and a microinjection device; Preferably, the drug administration method of the drug set includes one or more of micro-siphon / micro-core administration, micro-pump injection administration and reciprocating microfluid administration; Preferably, the solvent includes water, aqueous glycerol solution or aqueous sodium hyaluronate solution.

8. [Corrected 22.10.2024 in accordance with Rule 26] A method for preparing a freeze-dried powder injection preparation according to any one of claims 1 to 6, wherein: The steps include: adding glycerol into water to obtain a glycerol aqueous solution; adding a dexamethasone-like drug into the glycerol aqueous solution, adding water, and then freeze-drying; The freeze-drying step includes: pre-freezing, primary drying, and analytical drying; the primary drying temperature is about -50°C to 10°C, and the time is about 1000min to 2200min; Preferably, the primary drying temperature is about -30°C to 0°C, and the time is about 1000min to 2000min; Preferably, the primary drying temperature is about -30°C to 0°C, and the time is about 1000min to 1800min; Preferably, the primary drying temperature is about -20°C to 0°C, and the time is about 1000min to 1500min; Preferably, the primary drying step comprises: temperature -30°C to -15°C, time about 500min to 2000min; heating to -14°C to -6°C at a rate of 0.1 to 0.2°C / min, duration: 300 to 500min; heating to -5 to 10°C at a rate of 0.1 to 0.2°C / min, duration: 100min to 200min; Preferably, the primary drying step includes: temperature -30°C to -18°C, time about 500min to 1200min; heating to -14°C to -8°C at a rate of 0.1 to 0.2°C / min, duration: 300 to 400min; heating to -5 to 5°C at a rate of 0.1 to 0.2°C / min, duration: 100min to 150min.

9. The method of claim 8, wherein: The pre-freezing temperature is about -65°C to -20°C, and the pre-freezing time is about 50min to 150min; Preferably, the pre-freezing temperature is about -65°C to -25°C, and the time is about 60min to 500min; Preferably, the pre-freezing temperature is about -65°C to -25°C, and the pre-freezing time is about 70min to 400min; Preferably, the pre-freezing temperature is about -50°C to -35°C, and the time is about 70min to 200min; Preferably, the analytical drying temperature is about 25°C to 45°C, and the time is about 600min to 700min; Preferably, the analytical drying temperature is about 25°C to 40°C, and the time is about 600min to 700min; Preferably, the analytical drying step comprises: heating to 25°C to 50°C at a rate of 1 to 6°C / min for a duration of about 600 to 800 minutes; Preferably, the analytical drying step comprises: heating to 25°C to 40°C at a rate of 1 to 3°C / min for a duration of about 600 to 700 minutes; Preferably, the freeze-drying step further comprises: vacuuming after analytical drying; Preferably, the vacuum is drawn at 0.1 mbar 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.

10. Use of the freeze-dried powder injection preparation according to any one of claims 1 to 6, the pharmaceutical set according to claim 7, or the preparation method according to claim 8 or 9 in preparing a drug for preventing or treating ear diseases.

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