Doxylamine injection and application thereof

Abstract

The present invention relates to an aqueous pharmaceutical composition for injection comprising doxylamine or a physiologically acceptable salt thereof wherein the concentration of doxylamine is in the range of from 5 mg / ml to 25 mg / ml, based on the weight of doxylamine free base and based on the total volume of the composition; wherein the pH value of the composition is in the range of 6.0 to 7.0. The pharmaceutical composition disclosed by the invention has the effects and effects of sedation, hypnosis, histamine resistance, choline resistance, allergy resistance and the like.

Description

TECHNICAL FIELD

[0001] The present invention relates to an injectable aqueous pharmaceutical composition comprising doxylamine or a physiologically acceptable salt thereof. The present invention also relates to the method of preparation of a small volume injection of a new dosage form of doxylamine and its use in the treatment of the following conditions: to improve the allergic reaction to blood or plasma; as an adjuvant to adrenaline and other standard measures after acute symptoms have been controlled; for other direct anaphylactic diseases without complications when oral treatment is not possible or contraindicated; for sedation and relief of anxiety and to produce light sleep, making it easy for the patient to be awakened; for the active treatment of motion sickness; for the prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery; as an adjuvant to analgesics, to control postoperative pain; preoperative, postoperative and obstetric (during labor) sedation; intravenous injection in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery and low-risk patients, to reduce the amount of meperidine or other narcotic analgesics, for use as an adjuvant in anesthesia and analgesia. BACKGROUND

[0002] Anaphylaxis, including anaphylaxis, is a systemic, immediate hypersensitivity reaction caused by exposure to a specific antigen. The immune system activates immunoglobulin E (IgE), which reacts with effector cells (mast cells and basophils). These cells, in turn, release histamine, serotonin, leukotrienes, and prostaglandins and induce a series of signs and symptoms such as facial flushing, hives (urticaria), edema, pruritus, bronchial constriction, cough, arrhythmia, hypotension, nausea, vomiting, and diarrhea. Cutaneous manifestations are the most common, with 88% or more of patients with acute anaphylaxis presenting with urticaria and angioedema. Airway swelling is the most life-threatening symptom, often leading to dyspnea, wheezing, stridor, and upper airway obstruction due to severe edema. Cardiovascular symptoms include dizziness, hypotension, and syncope associated with intravascular volume third spacing. Common gastrointestinal manifestations include nausea, vomiting, abdominal pain or cramping, and diarrhea. Although the symptoms of acute anaphylaxis vary from patient to patient, they usually occur within seconds to minutes after exposure to the antigen and require prompt treatment.

[0003] The true incidence of acute anaphylaxis, including anaphylaxis, is not known, in part because of a lack of precise definition of the syndrome. Some clinicians reserve the term anaphylaxis for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare, with the milder forms occurring more frequently. The frequency of acute anaphylaxis is increasing, attributed to the increased number of potential allergens to which people are exposed, such as the increase in food and drug varieties. A recent review concluded that the lifetime prevalence of acute anaphylaxis, including anaphylaxis, is 5% of the population, with higher prevalence in developed countries than in developing countries.

[0004] What is needed is additional treatment for severe allergic reactions including anaphylaxis.

[0005] The current treatment for acute allergic reactions is the use of antihistamines: Benadryl Injection, Chlortrimeton Injection, or Vistaril Injection. All three have been marketed as the standard of care for about 60 years. Specifically, Benadryl has been considered the "gold standard" among generations of antihistamines. Its sedative side effects are generally considered to be sometimes beneficial in treating acute allergic reactions by sedating and calming the patient, especially since many patients with this disease are children. Only first generation antihistamines have such sedative side effects. Because of the severity of acute allergic reactions, scientists believe that only Benadryl's efficacy is sufficient to treat acute allergic reactions. These factors can prevent scientists from attempting to make Doxylamine, its salts, polymorphs, and isomers thereof (i.e., Levodexylamine) into parenteral injection products for the treatment and / or prevention of acute allergic reactions or symptoms associated with acute allergic reactions (acute urticaria, angioedema, etc.), optionally including anaphylaxis. The old Benadryl Injection is the only antihistamine injection available for the treatment of acute allergic reactions (optionally including anaphylaxis) or symptoms associated with acute allergic reactions (acute urticaria, angioedema, etc.) (optionally) including anaphylaxis for the past 60 years.

[0006] The current treatment of Benadryl Injection has several drawbacks, including short half-life, potential drug / drug interactions, potential cardiotoxicity (QT interval prolongation), and other potential side effects. Therefore, there is a need for new therapies for acute allergic reactions, especially for use in emergency situations.

[0007] Surprisingly, the inventors have discovered and successfully formulated Doxylamine into parenteral injection products, particularly for intravenous injection. Our unique Doxylamine injection formulations have essentially no observed hemolysis. The Doxylamine injection and methods of treatment disclosed herein are effective in treating acute allergic reactions or symptoms associated with acute allergic reactions (acute urticaria, angioedema, pruritus, erythema, wheezing, or combinations thereof) that are safer than the current gold standard treatment.

[0008] Doxylamine is a small molecule drug developed by Sanofi, a HRH1 antagonist, marketed in the United States under the brand name Zzzquil®, in tablet dosage forms ranging from 12.5 mg and 25 mg. Zzzquil® tablets are immediate release formulations that are taken by patients two to three times a day. It is well absorbed orally with a bioavailability of about 24-40% and Tmax of 2-3 hours. EP2536401 discloses Doxylamine resin acid ester complexes such as chewable tablets or immediate release oral disintegrating tablets oral dosage forms.

[0009]

[0010] ​US6340695 discloses enteric coated pyridoxine hydrochloride and doxylamine succinate immediate release oral dosage forms.

[0011] WO / 2024 / 188269 discloses an immediate release doxylamine succinate composition and a method for preparing the same.

[0012] Although solid and liquid oral dosage forms of doxylamine are known, no injectable dosage form of doxylamine has been reported. Injectable dosage forms have their own advantages compared to other dosage forms. Injectable dosage forms have a fast onset of action compared to oral dosage forms. In addition, the therapeutic response of the drug is more easily controlled by injection administration as the irregularities of oral resistance post-intestinal absorption are avoided.

[0013] Injectable dosage forms are usually administered by a person trained in the art, so the dose is expected to be administered actually accurately. In addition, it is difficult to orally administer a drug to a patient when the patient is uncooperative or unconscious. In this case, an injectable dosage form is most suitable for administration.

[0014] The inventors of the present invention have prepared an injectable dosage form of doxylamine, which is stable and very suitable for administration to a patient. The injectable formulation can be administered intravenously, so the drug directly enters the blood through the vein. This results in a rapid onset of action of the drug and a faster therapeutic effect. SUMMARY

[0015] To improve the clinical application effect of doxylamine succinate, the present study is committed to modifying it from the traditional tablet dosage form to an injectable dosage form. The existing tablet needs to be digested and absorbed by the gastrointestinal tract to take effect, usually requiring a long time to take effect, and the bioavailability of the traditional doxylamine succinate tablet is about 24-40%, which is extremely low, and there are many individual differences. While the injectable dosage form can directly enter the blood circulation, bypassing the digestive process of the gastrointestinal tract, thereby achieving faster absorption and more rapid drug efficacy.

[0016] To ensure that the doxylamine injection meets the standards in terms of safety, effectiveness, quality control, and patient acceptance, the present invention has conducted a series of studies. Through the analysis of the physicochemical properties, toxicity, and other aspects of the drug, especially considering the need for rapid onset of action, intravenous injection becomes the most ideal administration method, as the drug can directly enter the blood and rapidly reach the therapeutic concentration.

[0017] On this basis, the present research carried out four stages (I phase, II / IIB phase, III phase and IV / IVB phase) animal experiments. The experimental results show that the injection liquid causes pain, swelling and other symptoms in the rat body, through further optimization of the drug preparation, formula design and stability research, we find that the present application has good stability in the range of pH value of 6.0-7.0. When the pH value of the drug solution is higher than 5.5, the generation of impurities is obviously increased, which may affect the drug efficacy. Too many impurities not only can reduce the active ingredients of the drug, reduce the treatment effect, but also can interfere with the absorption and distribution of the drug, reduce its bioavailability. In addition, the increase of impurities may cause the enhancement of side effects and toxicity, further increase the risk of clinical application.

[0018] Specifically, the purpose of the present application is to provide an aqueous pharmaceutical composition containing doxylamine or its physiologically acceptable salt, and the pH value of the composition is 6.0-7.0, which is suitable for injection administration. The composition provided by the present application is a stable, low-viscosity, high-concentration, injectable liquid pharmaceutical composition containing doxylamine, which has not been disclosed in the prior art.

[0019] The doxylamine or its physiologically acceptable salt of the present application is selected from one of hydrochloride, tartrate, hydrobromide, sulfate, phosphate, acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, mandelate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate, methanesulfonate, benzenesulfonate or toluenesulfonate, preferably succinate.

[0020] In some embodiments, the pharmaceutical composition of the present application comprises:

[0021] Doxylamine succinate 5-50 mg

[0022] Sodium hydroxide 1-6 mg

[0023] Sodium chloride 4 mg

[0024] Water to 1-2 ml.

[0025] In some embodiments, the pharmaceutical composition of the present application comprises:

[0026] Comprises:

[0027] Doxylamine succinate 5-50 mg

[0028] Sodium hydroxide 1-6 mg

[0029] Mannitol 34 mg

[0030] Water is added to 1-2 ml.

[0031] The present application also includes a unit dose pharmaceutical form comprising the aqueous pharmaceutical composition comprising the amount of 5 mg to 50 mg of doxylamine per unit volume of 1 to 2 ml, preferably 1 ml per unit. A typical dose, for example, intravenous administration, is 10 mg to 25 mg, up to 100 mg, preferably 15 mg to 25 mg, or as the case can be, 20 mg to 20 mg of human dose can be effective. The drug can be administered once, twice or more frequently per day, especially for postoperative nausea and vomiting. A single dose can be sufficient for the treatment of preventing postoperative nausea and vomiting. However, it is understood that the specific dose level for any particular patient will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, drug combination and the severity of the particular condition being treated.

[0032] The aqueous pharmaceutical composition injection comprising aqueous doxylamine or its physiologically acceptable salt according to the present application has a pH value of 6.0 to 7.0, and the doxylamine injection is most stable at this pH value range.

[0033] The aqueous pharmaceutical composition injection comprising aqueous doxylamine or its physiologically acceptable salt according to the present application is stable after autoclaving at 121℃ for 20 minutes, and shows the same pH value before and after sterilization.

[0034] The aqueous pharmaceutical composition injection comprising aqueous doxylamine or its physiologically acceptable salt according to the present application does not contain any preservative.

[0035] The aqueous pharmaceutical composition injection comprising aqueous doxylamine or its physiologically acceptable salt according to the present application has sodium hydroxide as a pH adjuster.

[0036] The aqueous pharmaceutical composition injection comprising aqueous doxylamine or its physiologically acceptable salt according to the present application can be administered by at least one route selected from the group consisting of intramuscular injection, intravenous, subcutaneous, epidural, intrathecal, intraspinal and intracerebroventricular.

[0037] Another aspect of the present application includes the use of the pharmaceutical composition in the manufacture of an antihistamine drug or a drug for preventing, alleviating, treating allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis, insomnia, and nausea and vomiting symptoms in the first, second and third trimester of pregnancy of pregnant women.

[0038] The aqueous pharmaceutical composition of the present application containing aqueous doxylamine or its physiologically acceptable salt is used for treating the following diseases: improving allergic reactions to blood or plasma; as an auxiliary allergic reaction to adrenaline and other standard measures after acute symptoms are controlled; for other uncomplicated direct type allergic diseases when oral treatment is impossible or contraindicated; for calming and relieving anxiety and producing light sleep so that the patient can be easily awakened; actively treating car sickness; preventing and controlling nausea and vomiting associated with certain types of anesthesia and surgery; controlling postoperative pain as an auxiliary means of analgesic; preoperative, postoperative and obstetric (during delivery) sedation; intravenous injection in special surgical cases, such as repeated bronchoscopy, ophthalmic surgery and low-risk patients, reducing the amount of meperidine or other narcotic analgesics, and use as an auxiliary means of anesthesia and analgesia.

[0039] The present application also provides a method for preparing the pharmaceutical composition, comprising the following steps: weighing a prescribed amount of doxylamine or its salt, dissolving it in an appropriate amount of water for injection, adjusting the pH value to 6.0-7.0 with 0.1N sodium hydroxide, adding water for injection to the full amount, determining the intermediate content and pH value, and filtering through a 0.22μm microporous filter after passing the quality control, filling 1ml per bottle, and heat sterilizing.

[0040] The aqueous pharmaceutical composition of the present application containing aqueous doxylamine or its physiologically acceptable salt has reasonable composition, simple process and good stability. After 6 months of 40℃ accelerated test, the appearance, pH, effective component content and related substances of the sample have no obvious changes. The further features and advantages of the present application will become apparent from the following detailed description. DETAILED DESCRIPTION

[0041] The following examples can further describe the present application, however, these examples should not be considered as limiting the scope of the present application.

[0042] 1 Solubility

[0043] The target preparation of the present application is an injection, so only its solubility in water is studied.

[0044] Detection method: high performance liquid chromatography (Chinese Pharmacopoeia 2025 edition four general rules 0512)

[0045] Chromatographic conditions: octadecylsilane bonded silica gel as the stationary phase (specification: 4.6mm x 15cm; 5μm); 50mmol / L ammonium acetate buffer (pH 4.0) as mobile phase A, acetonitrile as mobile phase B, gradient system; column temperature 30℃, flow rate 1.0ml per minute; detection wavelength 262nm; injection volume 20μl.

[0046] Time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 15 40 60 25 40 60 26 85 15 35 85 15

[0047] 1.1 Test protocol

[0048] Take water, adjust pH value to 4.0, 5.0, 6.0, 7.0, 8.0 with hydrochloric acid and sodium hydroxide respectively, and divide into two parts, one part is placed at room temperature, and the other part is placed in a 70°C water bath.

[0049] Take a certain amount of doxylamine succinate, add it to the aqueous solution of different pH values respectively, and constantly shake until saturated. Stand, and take the supernatant for detection.

[0050] 1.2 The results are shown in Table 1

[0051] Table 1 Solubility test results

[0052]

[0053] As a result, the product is extremely easy to dissolve in water, and the solubility of the raw material at room temperature and 70°C is greater than 1 g / ml under different pH values, which is much greater than the concentration of the concentrated solution (50 mg / ml), and there is no difference in solubility between pH 4.0 and 8.0 at the same temperature. Therefore, the raw material with a concentration of 50 mg / ml can be completely dissolved.

[0054] 2 Thermal stability

[0055] Since the injection needs terminal sterilization during production, the thermal stability of doxylamine succinate raw material is studied and summarized as follows:

[0056]

[0057] 2.1 During the study of the raw material, the sample in solid state was placed in an 80°C oven for about 24 hours; the solution was heated in an 80°C water bath for 24 hours, and the sample was taken for detection.

[0058] As a result, the thermal stability of the product in solid state is good, and the impurities are basically consistent with those of the unheated sample. The thermal stability of the solution under sterilization temperature is slightly poor, and the impurities increase slightly.

[0059] 3 Degradation pathway

[0060] 3.1 During the study of the raw material, the raw material was destroyed by strong light irradiation, high temperature, acid, base and oxidation, and the results are as follows: the stability of the sample under oxidation and strong acid conditions is poor, and the impurities increase significantly; the stability under high temperature, strong base and light is slightly poor, and the impurities increase slightly.

[0061] 3.2 The injection was subjected to degradation test, and the stability of the sample under oxidation and strong acid conditions was poor, and the impurities increased significantly; the stability under high temperature, strong base and light was slightly poor, and the impurities increased slightly.

[0062] ​Therefore, the product has certain sensitivity to oxidation, high temperature, light, strong acid and strong base, and will produce degradation impurities under these conditions.

[0063] 4Osmolality of the raw material and pH value

[0064] Take the product, add water to dissolve and dilute to prepare a solution containing 25 mg per 1 ml, determine the osmolality and pH value, the results are shown in Table 2.

[0065] Table 2 Osmolality and pH value

[0066] Concentration (mg / ml) pH Osmolarity (mOsmol / L) 0.0 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 25 4.89 110

[0067] Conclusion: The pH value of the aqueous solution of the product is 4.89, which is slightly acidic, and the osmolality is 110, which is a hypotonic solution; the preparation of the product is an injection, which requires the addition of an osmolality regulator to prepare an isotonic solution.

[0068] 5 Selection of osmolality regulator

[0069] According to the structure analysis of the product, the product contains tertiary amine groups which are easily oxidized, and if the auxiliary material contains trace amounts of metal ions, it may accelerate the oxidation of the sample, so the inorganic salt osmolality regulator and the organic osmolality regulator which may contain trace amounts of metal ions are selected for investigation.

[0070] 5.1 Small sample preparation

[0071] According to the osmolality of the aqueous solution of the raw material, the amount of sodium chloride and mannitol is designed according to the prescription of the isotonic solution, and the injection small sample is prepared.

[0072] 5.2 The results are shown in Table 3.

[0073]

[0074] Table 3 Test results

[0075] From the results, it can be seen that the amount of sodium chloride and mannitol required to adjust the solution of doxylamine succinate to an isotonic solution meets the FDA maximum usage range.

[0076] 6 Selection of pH value range

[0077] The pH value of the aqueous solution of the raw material is 4.89, combined with the commonly used range of pH value of injection, the pH value of the product is determined to be 4.0-7.0, and the difference before and after sterilization is investigated by using hydrochloric acid and sodium hydroxide to prepare samples with different pH values and different osmolality regulators, the results are shown in Table 47.

[0078] Table 4 Results of pH value selection

[0079]

[0080]

[0081]

[0082] Conclusion: The unknown impurities increased significantly after sterilization when the pH of the injection was acidic. The impurities increased basically consistently under the same pH conditions for the two osmotic pressure regulators. The impurities did not increase significantly before and after sterilization when the pH was neutral (6.0 and 7.0). The related substances were basically consistent under the same pH conditions for the two osmotic pressure regulators. Considering that the amount of sodium chloride is small and it is an inorganic salt, it does not introduce organic impurities. Therefore, sodium chloride is selected as the osmotic pressure regulator of the product. By comparing different pH values, the pH range of the injection is determined to be 6.0-7.0.

[0083] 6.1 Selection of Optimal pH Value

[0084] The stability of the product in solution is affected by pH. Strong acid or strong base conditions can accelerate degradation (hydrolysis or oxidation), and solutions close to neutral are usually the most stable. Therefore, pH values of 5.5, 6.0, 6.5, 7.0, and 7.5 are designed for comparative study to investigate the changes in pH before and after sterilization, the properties after sterilization, and impurities (normalization method) to select the optimal pH range.

[0085] 6.1.1 Test Operation

[0086] Sodium chloride was precisely weighed according to the prescription amount, dissolved in water for injection (about 65°C), and then the raw material drug (300 ml of preparation amount) was precisely weighed according to the prescription amount and added to the above solution. After stirring until complete dissolution, an appropriate amount was taken out, the pH was measured to be about 4.9, and sodium hydroxide solution was used to adjust the pH to about 5.5 for standby (1). The remaining solution was further adjusted to a pH of about 6.0 using sodium hydroxide solution, and an appropriate amount was taken out for standby (2). The remaining solution was further adjusted to a pH of about 6.5 using sodium hydroxide solution, and an appropriate amount was taken out for standby (3). This was repeated to adjust the pH to about 7.0 and 7.5. The above solutions were filtered and sealed into 1 ml, respectively, and sterilized at 121°C for 15 minutes.

[0087] 6.1.2 Test Results

[0088] The properties, pH value, and impurities (normalization method) were the main indicators for detection, and the results are shown in Table 5.

[0089] Table 5 Results of pH Value Study

[0090]

[0091]

[0092] From the above results, it can be seen that when the pH value of the injection is lower than 6.0 or greater than 7.0, the impurities before and after sterilization increase significantly, when the pH value is between 6.0 and 7.0, the impurities before and after sterilization change little, therefore, to make the product quality better, the pH value of the intermediate before filling is controlled between 6.3 and 6.8 in the process of production.

[0093] 7 Choice of nitrogen filling and non-nitrogen filling

[0094] The tertiary amine group of doxylamine succinate is easy to oxidize, so the nitrogen filling process needs to be investigated preliminarily; with doxylamine succinate, sodium chloride, sodium hydroxide and water for injection as raw and auxiliary materials, three solutions with pH values of 6.0, 6.5 and 7.0 are prepared, which are respectively divided into two groups, one group is filled with nitrogen and the other group is not filled with nitrogen, the difference before and after sterilization is investigated, the results are shown in Table 6.

[0095] Table 6 Results of nitrogen filling and non-nitrogen filling

[0096]

[0097]

[0098]

[0099] Conclusion: Through the test, within the pH value range of 6.0-7.0, there is basically no difference in the properties, pH value, osmolality, related substances before and after sterilization with or without nitrogen filling; therefore, the product process does not need to be filled with nitrogen.

[0100] 8 Sterilization process verification

[0101] According to the "Guidelines for Research and Verification of Sterilization and Aseptic Process of Chemical Injection", 121℃ / 15min and 121℃ / 30min are used for sterilization, the changes of properties, pH, related substances, content (100% of the solution before sterilization) before and after sterilization are investigated, the results are shown in Table 7.

[0102] Table 7 Results of sterilization process research

[0103]

[0104] The results show that under two specifications, the impurity levels under two sterilization conditions are basically equivalent, combined with the terminal sterilization requirements, 121℃ / 15min can meet the sterilization requirements of the product.

[0105] Examples 1-4:

[0106] 1. Prescription

[0107]

[0108]

[0109] 2. Preparation process

[0110] The prescribed amount of doxylamine succinate was weighed, dissolved in an appropriate amount of water for injection, and the pH value was adjusted to 6.0-7.0 using 0.1 N sodium hydroxide. The total amount was added with water for injection, and the intermediate content and pH value were determined. After passing through a 0.22 μm microporous filter, the product was filled into 1 ml ampoules, each containing 1 ml, and was subjected to heat sterilization at 121°C for 20 min. After labeling, packaging, and inspection, the finished product was obtained.

[0111] Examples 5-8:

[0112] 1. Prescription

[0113]

[0114] 2. Preparation process

[0115] The prescribed amount of doxylamine succinate was weighed, dissolved in an appropriate amount of water for injection, and the pH value was adjusted to 6.0-7.0 using 0.1 N sodium hydroxide. The total amount was added with water for injection, and the intermediate content and pH value were determined. After passing through a 0.22 μm microporous filter, the product was filled into 1 ml ampoules, each containing 1 ml, and was subjected to heat sterilization at 121°C for 20 min. After labeling, packaging, and inspection, the finished product was obtained.

[0116] Examples 9-12:

[0117] 1. Prescription

[0118]

[0119] 2. Preparation process

[0120] The prescribed amount of doxylamine succinate was weighed, dissolved in an appropriate amount of water for injection, and the pH value was adjusted to 6.0-7.0 using 0.1 N sodium hydroxide. The total amount was added with water for injection, and the intermediate content and pH value were determined. After passing through a 0.22 μm microporous filter, the product was filled into 1 ml ampoules, each containing 1 ml, and was subjected to heat sterilization at 121°C for 20 min. After labeling, packaging, and inspection, the finished product was obtained.

[0121] Comparative Example 1: Preparation of doxylamine succinate tablets

[0122] Unit prescription:

[0123]

[0124]

[0125] Preparation method:

[0126] The prescription amount of microcrystalline cellulose, doxylamine succinate (passing 200 mesh sieve), type A ethanol acid sodium starch (passing 100 mesh sieve) is placed in a wet mixing granulator, the mixing time is 20 min, the mixing speed is 120 rpm, to obtain material a; the material a, the prescription amount of anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, magnesium stearate and blue No. 1 aluminum ingot are placed in a total mixer, the mixing time is 20 min, the mixing speed is 120 rpm, to obtain material b; the material b is pressed into tablets, the weight difference is checked once every 10 min during the pressing process, and the appearance quality of the semi-finished product is checked at any time, and then it is packaged.

[0127] Comparative example 2-5: preparation of doxylamine injection

[0128] 1. Prescription

[0129]

[0130] 2. Preparation process

[0131] The prescription amount of doxylamine succinate is weighed, dissolved with an appropriate amount of water for injection, the pH value is adjusted with 0.1N sodium hydroxide, water for injection is added to the full amount, the intermediate content and pH value are determined, after passing the test, it is filtered through a 0.22 μm microporous filter, filled into 1 ml ampoules, each ampoule is filled with 1 ml, 121 ℃ hot pressure sterilization for 20 min, labeled, packaged, and inspected to obtain the finished product.

[0132] Example 13: stability study 1 influence factor test: in order to further investigate the stability of the process and product, the influence factor comparison test is carried out on the sample. The stability test of influence factors is generally to select representative examples to investigate the basic stability.

[0133] (I) Experimental conditions

[0134] Take doxylamine succinate injection (prepared in example 4), remove the packaging, respectively exposed to light (fluorescent lamp total illumination not less than 1.2 x 10 6 Lux·hr and near ultraviolet lamp energy not less than 200 w·hr / m 2 ) for 5, 10 and 30 days, high temperature (50℃) for 5, 10 and 30 days, freeze-thaw (including three cycles, each cycle is first placed at -20 to -10℃ for 2 days, then at 40℃ for 2 days) for 12 days. Take samples respectively, and take shape, pH value, content, impurity as detection index, and investigate their respective stability. The results are shown in table 8.

[0135] Table 8 influence factor results

[0136]

[0137]

[0138]

[0139] Table 9 Influence factor results of other examples

[0140]

[0141] The results show that the pH of the product is 6.0-7.0, which is placed under high temperature and freeze-thaw conditions, and the properties, pH value, content and impurities have no obvious change, but under light conditions, the pH value, properties and content have no obvious change, and the related substance impurities have a slight increasing trend, but it is not obvious; the storage condition of the product should be room temperature, sealed and light shielding.

[0142] 2 Accelerated test

[0143] Because of the examples 5-12 of the present application, the essential investigation has been investigated in the prescription process, which is basically the same as examples 1-4, and the biggest influence of the product is the selection range of pH and light. Therefore, the stability test is as follows:

[0144] Select typical examples, and perform accelerated test on the samples of examples 1, 2, 3 and 4. The self-made suspension injection is placed in a constant temperature and humidity incubator, the humidity is set to 65%±5%, and the temperature is set to 30℃±2℃, and the accelerated test is performed for 6 months. Sampling is performed at the end of 0, 1, 2, 3 and 6 months, and the appearance, insoluble particles, pH, content and related substances of the samples are determined, and the results are shown in Table 9.

[0145] Table 9 Accelerated test of samples

[0146]

[0147]

[0148] Conclusion: The composition of the present application is extremely stable under accelerated test. When the pH is greater than 7.0 or less than 6.0, the prepared injection is unstable, the impurities are seriously out of standard, and it does not meet the requirements of clinical use. There is a serious safety hazard.

[0149] Example 14: Preliminary safety evaluation

[0150] 1 Sprague-Dawley rat increasing dose and 7-day repeated dose intravenous administration toxicity study

[0151] The study was conducted in four phases (Phase I, Phase II / IIB, Phase III, and Phase IV / IVB) and involved intravenous injection of rats by different methods. The intravenous route of administration is the route of administration of the final product in humans. The objective of the dose escalation phase (Phase I) was to determine the maximum tolerated dose of the test article, doxylamine succinate, following a single bolus intravenous injection in rats. The objective of the repeat dose phases (Phase II / IIB and Phase III) was to determine the toxicity of the test article following daily intravenous injection in rats for 7 consecutive days. The Phase III study was conducted using the human clinical formulation prepared by the Company for repeat dose evaluation.

[0152] The Phase IV / IVB study was designed to test the feasibility of intravenous administration of the test article (i.e., 25 mg / mL doxylamine succinate injection prepared in Example 7, diluted with 0.9% saline when necessary) via the femoral vein for 5 consecutive days, with the primary observation being the resolution of hematuria (red urine) at a lower dose. Table 10 summarizes the study design for the four phases.

[0153] Table 10 Summary of the four study phases

[0154] Methods:

[0155] Phase I (Dose Escalation): The test article dose formulation was administered by slow intravenous injection (approximately 2 minutes) via a subcutaneous injection needle attached to a syringe into the tail vein in an escalating dose manner. An observation period of at least 24 hours was allowed between consecutive doses. The volume of administration for all animals was 5 mL / kg. The actual volume of administration for each rat was calculated based on its most recent measured body weight and adjusted accordingly. The specific schedule is described in Table 11.

[0156] Table 11 Phase I (Dose Escalation) Schedule

[0157] TK = Toxicokinetics

[0158] * Administration was by 2 minute slow bolus intravenous injection

[0159] All surviving main study animals were observed for 14 days post-dose and then euthanized and discarded without further examination.

[0160] TK animals were euthanized and discarded without further examination after the last blood sample was collected on Day 1.

[0161] Phase II (repeat): Once daily for 3 consecutive days, the test article dose formulation was slowly bolus injected into the tail vein using a subcutaneous injection needle attached to a syringe (approximately 2 minutes). The dose administered to all animals was 5 mL / kg. The actual dose administered to each rat was calculated and adjusted based on the most recent actual body weight of each animal. The schedule is shown in Table 12.

[0162] Table 12

[0163]

[0164] * Administered by slow bolus injection intravenously over 2 minutes

[0165] After 3 days of consecutive dosing, the injection site was no longer active. All surviving animals were euthanized and discarded without further examination.

[0166] Phase III (repeat): Once daily for 2 consecutive days, the test article dose formulation was slowly bolus injected into the tail vein using a subcutaneous injection needle attached to a syringe (approximately 2 minutes). The dose administered to all animals was 3 mL / kg. The actual dose administered to each rat was calculated and adjusted based on the most recent actual body weight of each animal. The schedule is shown in Table 13.

[0167] Table 13

[0168]

[0169] * Administered by slow bolus injection intravenously over 2 minutes

[0170] After 2 days of dosing, the injection site was no longer active. Animals were euthanized on Day 3 and necropsied.

[0171] Phase IIB (repeat): The test article dose formulation was administered once daily for 7 consecutive days via the tail vein using an intravenous infusion (approximately 20 minutes) via an Abbocath indwelling needle. The infusion rate for all animals was 30 mL / kg / hour (10 mL / kg or 0.5 mL / kg / minute). The actual infusion volume per hour for each animal was calculated and adjusted based on its most recent body weight. The infusion rate was controlled using an infusion pump. Prior to the start of each treatment, the infusion line was pre-charged with the appropriate dose formulation to ensure that dosing began immediately upon activation of the infusion pump. The schedule is shown in Table 14.

[0172] Table 14

[0173]

[0174] The infusion rate was 30 mL / kg / hour (0.5 mL / kg / minute) and the dose volume administered over 20 minutes was 10 mL / kg. After completion of the 7-day dosing period, all surviving animals were euthanized on Day 8 and necropsied.

[0175] Stage IV: Subjects were administered intravenously in a dosing volume of 3 mL / kg, for 5 consecutive days, with each injection lasting 2 minutes. The actual dosing volume was calculated and adjusted based on the most recent body weight of each animal. Prior to the start of each treatment, a bolus of drug solution was administered to prime the line. The remaining volume to be administered (minus the priming bolus) was then administered. The line was finally flushed with saline. The total injection time from the initial bolus of subject to the end of the saline flush was 2 minutes. After flushing was complete, the animals were connected to the infusion system for saline maintenance. The specific regimen is described in Table 15.

[0176] Table 15

[0177]

[0178]

[0179] The dosing volume was 3 mL / kg.

[0180] After the 5-day dosing period was complete, all surviving animals were euthanized on Day 6 and necropsied.

[0181] Stage IVB: Subjects were administered intravenously in a dosing volume of 1.75 or 1.5 mL / kg, for 5 consecutive days, with each injection lasting 2 minutes. The actual dosing volume was calculated and adjusted based on the most recent body weight of each animal. Prior to the start of each treatment, a bolus of drug solution was administered to prime the line. The remaining volume to be administered (minus the priming bolus) was then administered. The line was finally flushed with saline. The total injection time from the initial bolus of subject to the end of the saline flush was 2 minutes. After flushing was complete, the animals were connected to the infusion system for saline maintenance. The specific regimen is described in Table 16.

[0182] Table 16

[0183]

[0184] The dosing volume for Group 11 was 1.75 mL / kg and for Group 12 was 1.5 mL / kg.

[0185] After the 5-day dosing period was complete, all surviving animals were euthanized and discarded without further examination. Particular attention was paid to the clinical signs observed after dosing, with particular emphasis on the occurrence of hematuria.

[0186] The initial dose level (Phase I) was determined based on data from the human intravenous clinical dose of 0.572 mg / kg (25 mg per dose). While there is a significant amount of toxicology data for the oral route of doxorubicin, there is a lack of data for the intravenous route. Based on human pharmacokinetic studies, the AUC for 25 mg of doxorubicin administered intravenously is equivalent to 25 mg of the oral formulation, Cmax The dose levels in Phase IIB and III were based on the results of the Phase I and / or II studies. The dose level selected for Phase IV was based on the results of the Phase IIB and III studies. In the Phase IIB and III studies, local irritation at the site of administration (tail vein) was a limiting factor for the placement of the Abbocath indwelling needle. To avoid the local irritation effect, the Phase IV tested the administration of the test article by way of a surgically catheterized femoral vein injection. Because of the difference in circulation mechanism between the tail vein (very limited blood circulation) and the femoral vein (significantly better blood circulation than the tail vein), the femoral vein was considered to be more similar to the human intravenous injection site. The injected fluid was expected to be rapidly diluted by the blood circulation, thereby minimizing the possibility of local irritation. Therefore, it was considered that the probability of local irritation was lower when the test article was administered through the femoral vein.

[0187] The dose level selected for Phase IV was based on the results of the Phase IIB and III studies. In the Phase IIB and III studies, local irritation at the site of administration (tail vein) was a limiting factor for the placement of the Abbocath indwelling needle. To avoid the local irritation effect, the Phase IV tested the administration of the test article by way of a surgically catheterized femoral vein injection. Because of the difference in circulation mechanism between the tail vein (very limited blood circulation) and the femoral vein (significantly better blood circulation than the tail vein), the femoral vein was considered to be more similar to the human intravenous injection site. The injected fluid was expected to be rapidly diluted by the blood circulation, thereby minimizing the possibility of local irritation. Therefore, it was considered that the probability of local irritation was lower when the test article was administered through the femoral vein.

[0188] In all experiments, the test article was 25 mg / mL doxylamine succinate (dissolved in standard sodium chloride solution for injection) prepared as described in Example 7.

[0189] Experimental animals

[0190] All experiments used Sprague-Dawley rats.

[0191] Housing conditions: Rats were housed in groups of the same sex (except during specific procedures), up to 3 animals per group, in transparent plastic cages measuring 30 cm x 50 cm x 20 cm. The cages were equipped with an automatic water system and water bottles were replenished as necessary. The plastic cages were lined with at least 2 cm of bedding. The bedding was changed regularly to maintain hygienic conditions. After randomization, all cages were equipped with color-coded cage cards indicating the study number, group, animal number, sex, and group identification.

[0192] Room environment: The animal room environment was controlled (target range: temperature 21 ± 3 °C, relative humidity 50 ± 15%, 12 hours light / 12 hours dark, at least 10 air exchanges per hour) except during specific procedure periods (e.g., blood collection outside working hours). Temperature and relative humidity were continuously monitored by ITR and records were kept.

[0193] Feed / water: Standard certified commercial rodent feed was provided ad libitum except during specific procedures (e.g., when animals were removed from their home cages). The feed composition and the concentration of environmental contaminants were tested periodically by the manufacturer.

[0194] Environmental Enrichment: During the study, animals were provided with non-dietary items and certified treats according to the ITR Environmental Enrichment Plan on a regular basis, except during specific procedures.

[0195] Acclimation Period: An acclimation period of at least 2 weeks was allowed for animals to become accustomed to the laboratory environment prior to the start of treatment. Acclimation to the activity restriction and dosing procedures were performed according to ITR standard operating procedures (SOPs).

[0196] Study Group Assignment: During the I / II acclimation period, 17 male and 17 female rats were assigned to respective dose groups (1-7) in a stratified randomization by body weight. Male and female rats were randomized separately. During the III acclimation period, 5 male and 5 female rats were assigned to dose group 8. During the IIB acclimation period, 5 male and 5 female rats were assigned to dose group 9. During the IV acclimation period, 2 male and 2 female rats were assigned to dose group 10. During the IVB acclimation period, 2 male and 2 female rats from the ITR spare colony were assigned to dose groups 11 and 12. Some animals were replaced due to dosing difficulties or clinical signs at the injection site.

[0197] Toxicokinetics: Sample Collection, Processing and Bioanalysis: Five blood samples (approximately 0.4 mL each) were collected from each rat in Group 6 at the following time points: prior to dosing, 2, 6, 15 and 30 minutes post-dose. Thus, each rat was bled a total of 2.0 mL during the study. Blood was collected by venipuncture from the jugular vein (un-anesthetized) and placed in tubes containing the anticoagulant K2EDTA. The tubes were placed on wet ice until processing. Following the last blood collection, each animal was euthanized by CO2asphyxiation followed by cervical dislocation. The carcasses were discarded without further examination. In-life observations (clinical signs [if present] and body weights) were recorded but not reported for these animals. Following sample collection, the blood was processed by centrifugation (2500 rpm for 10 minutes at approximately 4°C) and the isolated plasma was recovered and stored frozen (≤ -60°C) in appropriately labeled tubes.

[0198] Procedure for necropsy: Gross necropsy: All surviving Phase I animals were observed for 14 days post-dose, then euthanized (Day 15) and their carcasses discarded without further examination. Phase IVB animals were euthanized and discarded at the end of the treatment period (Day 6) without further examination. All Phase IIB and III / IV animals were euthanized and necropsied at the end of the treatment period and after an overnight fast on Day 8. These animals were anesthetized with isoflurane and then euthanized by exsanguination. To avoid autolytic changes, all Phase IIB / III / IV animals euthanized at the end of the study were necropsied as soon as possible. Gross pathological examination included external examination (including identification of all clinically noted lesions) and detailed internal examination. A pathologist was available for consultation during all necropsies performed during normal working hours.

[0199] Tissue preservation: Following gross pathological examination and specific organ weighing, the following tissues and organs were retained. Fixation and preservation were performed using 10% neutral buffered formalin, unless otherwise specified.

[0200] Data evaluation and statistics: Numerical data obtained during the study were subjected to calculation of group means and standard deviations and presented in the final report along with all individual numerical and non-numerical results.

[0201] Results

[0202] Mortality: In the Phase I study, animal deaths were observed immediately after dosing at 87.5 mg / kg (Group 2) and 175 mg / kg (Group 4). Two of four animals in Group 2 and three of four animals in Group 4 died. Due to the observed mortality, animals surviving in Group 2 did not receive dosing. Clinical signs appeared rapidly, including dyspnea / weakness, tremors, loss of coordination and limb function, and severe decrease in mobility.

[0203] All Phase III animals (Group 8, dose of 75 mg / kg / day) were euthanized prior to death on Day 3. The reason for euthanasia of these animals was the development of test article-related clinical signs at the injection site (tail) from Day 2, which resulted in the inability to dose. Clinical signs at the injection site included: swelling, bruising, fluid accumulation, and discoloration. The discoloration was predominantly blue-black in color, suggesting the formation of pre-necrotic and necrotic tissue. Perivascular leakage was not the cause of these changes. These clinical signs were recorded from Day 2. An increase in activity and respiration was observed during dosing on Day 1.

[0204] Clinical signs: In the first phase, single doses of 1 (Group 1), 25 (Group 3), and 35 (Group 5 and Group 6) mg / kg of the test item were well tolerated and no adverse clinical signs were observed.

[0205] In the second phase, the caudal vein injection exceeded 2 minutes and, due to the observation of changes related to the test item at the site of administration, 3 / 5 males and 2 / 5 females (Group 7, dose of 75 mg / kg / day) were euthanized before death. To validate the preliminary results observed in the animals of Group 7, the euthanized animals were replaced and dosing was performed on the replacement animals. However, the preliminary observation of irritation at the site of injection observed in the original animals was confirmed in the replacement animals. The clinical signs in these animals included: increased activity, swelling at the site of injection, discoloration at the site of administration, lesions and erythema at the site of administration, sensitivity to touch at the site of administration, licking at the site of injection and vocalization prior to administration (indicative of a pain response). The clinical signs observed at the site of injection were observed as early as Day 2. Increased activity was observed from Day 1 during the administration.

[0206] For Phase IIB, the animals (Group 9, dose of 75 mg / kg / day) were infused in the caudal vein for 20 minutes and, from Day 2, clinical signs related to the test item were observed at the site of injection, including swelling, discoloration of the skin, lesions with discharge, bruising, sensitivity to touch, vocalization prior to administration (indicative of a pain response), presence of rings and liquid material. Increased activity was observed as early as Day 1 during the administration.

[0207] Due to the clinical signs observed after the caudal vein injection in Phases I / II / IIB / III, it was decided to validate the effectiveness of the injection of the test article formulation into the femoral vein. Therefore, Phases IV and IVB were performed.

[0208] For the animals of Phase IV, the dose was 30 mg / kg / day (Group 10) and the administration was performed through the femoral vein, with an administration time exceeding 2 minutes. The main clinical signs related to the test item were the presence of red liquid in the cage tray and urogenital area. This was interpreted as hematuria. This change was observed in all animals of Phase IV on Day 2. Increased activity and change in posture (hunched) were observed on Day 1, symptoms that cannot be ruled out as related to the test item.

[0209] At the lower doses of 7 (Group 11) and 15 (Group 12) mg / kg / day, the presence of red liquid in the cage tray (hematuria) was only noted from Day 1 at the dose of 15 mg / kg / day. At both doses, other clinical signs of change in posture (stretching) and increased activity were noted from Day 1.

[0210] Body weight: No effects related to the test item were observed in the phases in which the body weight was assessable. However, when comparing the body weight at the end of treatment with the body weight on Day 1, the body weight of the animals of Group 10 decreased by 2% to 6%.

[0211] Gross Observations: For the Stage III animals, numerous abnormalities were found at the site of administration (tail) at necropsy. A total of 8 / 10 animals were affected. These abnormalities included dark patches / areas / spots (8 / 10), thickening (6 / 10), and scabbing (1 / 10) and resulted in euthanasia.

[0212] For the Stage IIB animals, 2 / 10 animals at the 30 mg / kg / day dose were observed to have abnormalities at the site of administration (tail). These abnormalities included dark areas (2 / 10) and were accompanied by thickening and / or scabbing of the affected animals. Bronchial lymph node enlargement was observed in 2 / 10 animals. Although the cause of this abnormality is unknown, it cannot be confirmed or ruled out as related to the test article due to the lack of a control group and microscopic examination. The duodenal dark area in one of these animals was considered to be an incidental finding.

[0213] For the Stage IV animals, no abnormalities were observed at the site of administration. Dark lung foci were observed in 2 / 4 animals. Although the cause of this finding is unknown, it cannot be confirmed or ruled out as related to the test article due to the lack of a control group and microscopic examination. The thymic dark foci in one of these animals was considered to be an incidental finding or a finding related to handling.

[0214] Methods:

[0215] The rats in each group were dosed once daily by intravenous injection into the femoral vein with test article and control article for 2 minutes per injection for 14 consecutive days according to the schedule in Table 17.

[0216] Table 17

[0217]

[0218] 1 : Control animals were injected with saline only.

[0219] 2: Low dose = human clinical dose = 10 mg per day for a 70 kg body weight human = 0.86 mg / kg for the rat

[0220] 3: Mid dose = 7 times the clinical dose

[0221] 4: High dose = 15 times the clinical dose

[0222] Conclusion

[0223] Injection of Sprague Dawley rats with a single dose of 75 mg / kg of doxylamine succinate in the tail vein resulted in death.

[0224] Repeated injections of doxylamine succinate via the tail vein at doses of 30 and 35 mg / kg / day for 2 to 7 consecutive days resulted in swelling, necrosis, and discoloration of the injection site. These clinical signs resulted in the inability to complete two phases of the study, ultimately leading to the euthanasia of the animals prior to their death.

[0225] Repeated doses of doxylamine succinate via the femoral vein for 5 consecutive days at 15 and 30 mg / kg / day were observed to cause hematuria, while no hematuria was observed at 7 mg / kg / day. Changes in body position and increased activity were observed at 7, 15, and 30 mg / kg / day. Therefore, a conservative approach was recommended, and the 15 mg / kg / day and 30 mg / kg / day dose levels were selected as the mid and high dose levels for the 14-day repeat dose study.

[0226] The maximum tolerated dose (MTD) for a single tail vein injection was determined to be 75 mg / kg (41 times the human clinical dose).

[0227] Because of the complications observed with repeated injections of doxylamine succinate via the tail vein, it was recommended that the femoral vein route of administration be used for all repeat dose studies, as the femoral vein injection in rats is the most similar to intravenous injection in humans.

[0228] 2. 14-Day Intravenous Toxicity Study in Sprague Dawley Rats

[0229] This study was designed to determine the toxicity and toxicokinetic profile of the test article, doxylamine succinate. The test article, experimental animals, and clinical observations were as described in Example 1. Toxicokinetic time point data were collected and the following parameters were estimated: max : Time to reach maximum observed concentration post-dose

[0230] C max : Highest observed concentration measured post-dose

[0231] C max / D: C max divided by the dose administered last : Time of last quantifiable plasma concentration

[0232] AUC 0-t : Area under the concentration-time curve from the start of dosing to the time of last quantifiable concentration (calculated using the linear trapezoidal method)

[0233] AUC 0-t / D: AUC 0-t divided by the dose administered

[0234] When data permitted, the slope of the terminal elimination phase of the arithmetic mean concentration-time curve was determined by log regression, and the following additional parameters were estimated:

[0235] AUC 0-∞ : Area under the plasma concentration-time curve extrapolated to infinity, calculated using AUC 0-t +C last / λz formula calculation (where C) last For t last (Concentration measured at time)

[0236] AUC 0-∞ / D: AUC 0-∞ Divide by the dosage

[0237] AUC ％extrap Extrapolated AUC 0-∞ The relative percentage λz: the apparent elimination rate constant, estimated by linear regression of the linear portion at the end of the log-concentration-time curve. 1 / 2 The apparent terminal elimination half-life is calculated as ln(2) / λz.

[0238] MRT: Mean Time of Stay

[0239] V: Apparent Distributive Volume

[0240] CL: Overall clearance rate

[0241] All AUCs were calculated using the linear trapezoidal rule. Autopsy and tissue preservation methods were as described above.

[0242] Toxicokinetic results:

[0243] On day 1, rats were given a single dose of doxylamine succinate, either the control or at doses of 2.15, 15, or 32.5 mg / kg. Pre-administration concentrations in all dose groups were below the limit of quantitation (BLQ). Except for the 2.15 mg / kg dose group, plasma concentrations of doxylamine decreased in a biexponential manner. It is noteworthy that the last two time points (12 and 24 hours) in this group were the BLQ, while concentrations in the 15 and 32.5 mg / kg groups were still measurable within 12 hours. Within the dose range of 2.15 to 32.5 mg / kg, C... max and AUC 0-∞ The values ​​were 2.19-36.9 μg / mL and 0.89-62.25 μg·h / mL, respectively, indicating the systemic exposure (C... max and AUC 0-∞ The dosage ratio increases approximately: C max The concentrations increased 22-fold and 4.785-fold at 2.15, 15, and 32.5 mg / kg, respectively; AUC 0-∞ The concentration increased 7.415-fold between 15 and 32.5 mg / kg. The AUC between 2.15 and 15 mg / kg doses was [not specified]. 0-∞The increase was approximately 58.53 times, which may be due to the BLQ value appearing at the end of the time point in the 2.15 mg / kg group.

[0244] The terminal elimination phase has clear characteristics, and the extrapolated AUC value (AUC) is well-defined. ％extrap <10% across the entire dose range. Half-life (t) 1 / 2 The duration of action was 0.25–2.73 hours within the tested dose range. The 2.15 mg / kg group and the other two dose groups showed similar AUC values. 0-t and t 1 / 2 The differences in values ​​may be due to the BLQ effect, i.e., the concentration at the end of the curve in the 2.15 mg / kg group cannot be quantified. The apparent clearance and volume of distribution ranged from 1234.037 to 5964.17 mL / h / kg and 2.6289 to 5121.36 mL / kg, respectively.

[0245] Following oral administration of cetirizine, the mean peak concentrations were similar in males and females. However, the peak concentration decreased more rapidly in males at 15 mg / kg, while it decreased more rapidly in females at 32.5 mg / kg. This difference in curve morphology led to a decrease in AUC. 0-t Ratio change: Female / Male C max The ratio was 1.055–1.145 within the dose range, while the female / male AUC was [missing information]. 0-t The ratios were 4.11, 8.785, and 1.42 at doses of 2.15, 15, and 32.5 mg / kg, respectively.

[0246] Similar to day 1, on day 14, except for the 2.15 mg / kg dose group, cetirizine plasma concentrations decreased in a bi-exponential manner. However, it should be noted that the 2.15 mg / kg dose group had measurable concentrations only within the first hour, while the 15 and 32.5 mg / kg dose groups still had measurable concentrations within 12 hours.

[0247] Within the dosage range of 2.15 to 32.5 mg / kg, C max and AUC 0-∞ The values ​​were 2.16-33.435 μg / mL and 0.7225-74.4575 μg·h / mL, respectively. The exposure levels showed an increasing trend in the proportion of overdose: C max The dose increased 22.985-fold (overdose ratio) between the 2.15 and 15 mg / kg dose levels, and 1.8-fold (near-dose ratio) between the 15 and 32.5 mg / kg dose levels. AUC 0-∞ The overdose ratio increased across the entire dose range, with increases of 30-fold and 5-fold at the 2.15 mg / kg and 32.5 mg / kg dose groups, respectively.

[0248] The terminal elimination phase characteristics are clear, and the overall extrapolated AUC value (AUC) is... ％extrap<10% across the entire dose range. However, the AUC was <10% in both sexes in the 2.15 mg / kg group and in males in the 15 mg / kg group. ％extrap Values ​​range from 15.00% to 21.00%. Half-life (t) 1 / 2 The duration of action was 0.27–2.45 hours within the tested dose range. Consistent with observations on day 1, the 0.86 mg / kg group and the other two dose groups showed similar AUC values. 0- t and t 1 / 2 The differences in values ​​may be due to the BLQ effect, i.e., the concentration at the end of the curve in the 0.86 mg / kg group is not quantifiable. The apparent clearance and volume of distribution ranged from 415.178 to 2501.648 mL / h / kg and 976.380 to 1831.114 mL / kg, respectively.

[0249] Following oral administration of doxylamine, the mean peak concentrations were similar in males and females. However, the terminal phase of concentration decreased more rapidly in males at 15 mg / kg, while the decrease was more significant in females at 32.5 mg / kg. This difference in curve morphology led to a difference in AUC. 0-t Ratio change: Female / Male C max The ratio was 1.927–2.8075 over the dose range, while the female / male AUC was [missing information]. 0-t The ratios were 3.835, 8.16, and 1.48 at doses of 2.15, 15, and 32.5 mg / kg, respectively.

[0250] in conclusion

[0251] Rats tolerated doxylamine succinate via intravenous injection for 14 consecutive days at doses of 2.15, 15, and 32.5 mg / kg / day well. Based on the parameters monitored in this study, the no-observed-adverse-effect level (NOAEL) was determined to be 32.5 mg / kg / day (equivalent to 15 times the clinical human dose).

[0252] Example 15: Bioavailability Test

[0253] The absolute bioavailability of doxylamine injection in Examples 1 to 12 of the present invention and doxylamine succinate tablets in Comparative Example 1 were investigated. Table 18 Absolute Bioavailability

[0254]

[0255]

[0256] The absolute bioavailability results of doxylamine injections in Examples 1-12 and Comparative Example 1 (doxylamine succinate tablets) are shown in Table 18. The bioavailability of doxylamine injections in Examples 1-12 was 100%, while that of Comparative Example 1 (doxylamine succinate tablets) was 34%. Intravenous administration provides higher drug bioavailability compared to oral administration, which may result in faster onset of action and better control of drug concentration.

[0257] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition, characterized in that: It contains doxylamine or its physiologically acceptable salt and water, wherein the pH of the composition is 6.0 to 7.

0.

2. The pharmaceutical composition of claim 1, further comprising an osmotic pressure regulator and a pH regulator.

3. The pharmaceutical composition of claim 2, wherein the osmotic pressure regulator is selected from sodium chloride, mannitol, and glucose, preferably mannitol or sodium chloride; and the pH regulator is selected from sodium hydroxide or sodium bicarbonate, preferably sodium hydroxide.

4. The pharmaceutical composition according to claim 1, characterized in that: The concentration of doxylamine in the composition is from 5 mg / ml to 25 mg / ml.

5. The pharmaceutical composition according to claim 1, characterized in that: The physiologically acceptable salt of doxylamine is selected from one of the following: hydrochloride, tartrate, hydrobromide, sulfate, phosphate, acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, mandelate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate, methanesulfonate, benzenesulfonic acid, or toluenesulfonic acid, preferably succinate.

6. The pharmaceutical composition according to claim 1, characterized in that: The composition comprises: Doxylamine succinate 7.5-50mg Sodium hydroxide 1-6mg Sodium chloride 4mg Add water to 1-2 ml.

7. The pharmaceutical composition according to claim 1, characterized in that: The composition comprises: Doxylamine succinate 7.5-50mg Sodium hydroxide 1-6mg Mannitol 34mg Add water to 1-2 ml.

8. The pharmaceutical composition according to claim 1, characterized in that: The composition contains no preservatives.

9. The pharmaceutical composition according to claim 1, characterized in that: The composition is suitable for injection administration.

10. The pharmaceutical composition of claim 9, wherein, The composition is suitable for administration by at least one route selected from the group consisting of intramuscular injection, intravenous injection, subcutaneous injection, epidural injection, intrathecal injection, intraspinal injection, and intraventricular injection.

11. Use of the pharmaceutical composition according to any one of claims 1-10 in the preparation of an antihistamine or a medicament for the prevention, relief, or treatment of allergic dermatitis, hay fever, allergic rhinitis, asthmatic bronchitis, insomnia, and nausea and vomiting symptoms in pregnant women during the first, second, and third trimesters of pregnancy.

12. The method for preparing the pharmaceutical composition according to claim 1, characterized in that: The procedure includes the following steps: Weigh the prescribed amount of doxylamine or its salt, dissolve it in an appropriate amount of water for injection, adjust the pH value to 6.0-7.0 with 0.1N sodium hydroxide, add water for injection to the total volume, determine the intermediate content and pH value, filter through a 0.22μm microporous membrane after passing the test, fill each bottle with 1ml, and autoclave.

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