Ziconotide temperature-sensitive nasal spray

Abstract

The invention relates to a Ziconotide temperature-sensitive nasal spray, which comprises a solvent, and Ziconotide, a first matrix, a second matrix, an absorption enhancer, a pH buffer system and a polypeptide stabilizer dispersed in the solvent, the first matrix is poloxamer 407, and the second matrix is poloxamer 188; the temperature-sensitive nasal spray comprises the following components in percentage by mass: 5%-20% of the first substrate, 0-5% of the second substrate, 0.01%-10% of the absorption enhancer, and the balance of the temperature-sensitive nasal spray, the pH buffer system is an acetic acid-acetate system or a lactic acid-lactate system. The ziconotide temperature-sensitive nasal spray can form a good spray form through a nasal spray device, the viscosity has a temperature-sensitive characteristic, and the ziconotide temperature-sensitive nasal spray is not easy to lose and has good stability.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulation technology, and in particular to a ziconopeptide temperature-sensitive nasal spray. Background Technology

[0002] Ziconovide, derived from the cone snail, is a novel polypeptide neurotherapeutic drug containing 25 amino acids. It reversibly blocks N-type voltage-sensitive calcium channels, thereby inhibiting the release of pain-inducing neurotransmitters. Its analgesic power is 1000 times that of morphine and it is not addictive. As a non-opioid analgesic, ziconovide has been proven effective in both non-clinical and clinical trials. Currently, the approved formulation of ziconovide is Prialt, manufactured by Ellan Pharmaceuticals, which is the only approved analgesic peptide drug on the market. It is administered via intrathecal infusion and is restricted to patients with severe pain who cannot tolerate morphine. Intrathecal infusion has significant side effects, including nausea, nystagmus, headache, and dizziness. It is dose-dependent, and continuous infusion can slowly infiltrate nerve tissue, causing severe psychiatric symptoms and neurological damage. Furthermore, this method of administration has extremely poor compliance, requiring patients to administer the medication independently, demanding high levels of surgical skill, and may also cause intracavitary infections such as meningitis. Therefore, it is necessary to improve the administration route of ziconotide.

[0003] Ziconotide has good water solubility but poor stability; temperature and light exposure affect its stability, and it is also easily degraded by phase I enzymes commonly found in the body. Furthermore, ziconotide exerts its effects in cerebrospinal fluid, so developing new routes of administration must consider the barriers of this route. Traditional routes of administration, such as oral administration, while offering advantages like high patient compliance, suffer from significant individual variability. The gastrointestinal environment limits transport time due to the mucus layer and epithelial cell barrier, and the first-pass effect often results in low bioavailability. Nasal administration allows for self-administration, addressing poor patient compliance and avoiding the first-pass effect. Additionally, this route involves fewer enzymes, improving bioavailability. Nasal administration bypasses the blood-brain barrier, allowing the drug to directly enter the brain, reducing systemic exposure and resulting in faster onset of action. However, nasal administration also presents obstacles, such as drug clearance by nasal mucus and cilia, and a smaller absorption area.

[0004] Another method provides an in-situ nasal spray of ziconovide, whose formulation includes ziconovide, Kolliphor P407 (poloxam 407), chitosan, etc., which can improve the bioavailability of the nasal spray and reduce the clearance rate. However, in practical application, this method cannot form a good spray pattern through the nasal spray device. When administering the drug using a nasal spray device, it is sprayed as a liquid column rather than dispersed as a mist, so most of the drug eventually enters the pharynx or flows out of the nostrils. At the same time, due to the poor stability of ziconovide itself, the compatibility and sealing of the packaging material of the nasal spray device may also lead to excessive levels of related substances. Therefore, ziconovide nasal spray also has the problem of high levels of related substances. Summary of the Invention

[0005] Based on this, this application provides a ziconopeptide temperature-sensitive nasal spray that can form a good spray pattern through a nasal spray device, has temperature-sensitive viscosity, is not easily lost as a drug, and has good stability.

[0006] The specific technical solution is as follows:

[0007] A ziconopeptide temperature-sensitive nasal spray includes a solvent, and ziconopeptide, a first matrix, a second matrix, an absorption enhancer, a pH buffer system, and a peptide stabilizer dispersed in the solvent;

[0008] The first matrix is ​​poloxamer 407, and the second matrix is ​​poloxamer 188;

[0009] The first matrix comprises 5% to 20% by mass percentage in the temperature-sensitive nasal spray, the second matrix comprises 0% to 5%, and the absorption enhancer comprises 0.01% to 10%.

[0010] The pH buffer system is either an acetic acid-acetate system or a lactic acid-lactate system.

[0011] In some embodiments, the second matrix is ​​0-3% by mass percentage in the temperature-sensitive nasal spray.

[0012] In some embodiments, the absorption enhancer is selected from one or more of chitosan, Kolliphor HS15, and dodecyl-β-D-maltodextrin.

[0013] In some embodiments, the absorption enhancer is chitosan, and the absorption enhancer is 0.01% to 1% by mass in the temperature-sensitive nasal spray.

[0014] In some embodiments, the absorption enhancer is Kolliphor HS15, and the absorption enhancer is 0.1% to 10% by mass in the temperature-sensitive nasal spray.

[0015] In some embodiments, the absorption enhancer is dodecyl-β-D-maltodextrin, and the absorption enhancer is 0.1% to 5% by mass percentage in the temperature-sensitive nasal spray.

[0016] In some embodiments, the polypeptide stabilizer has one or more of the following characteristics:

[0017] (1) The polypeptide stabilizer is one or more of methionine, sodium bisulfite and sodium metabisulfite, and may be selected from one or more of methionine and sodium bisulfite, and may be further selected from methionine;

[0018] (2) The polypeptide stabilizer is 0.005% to 10% by mass percentage in the temperature-sensitive nasal spray.

[0019] In some embodiments, the pH buffer system has one or more of the following characteristics:

[0020] (1) The pH buffer system is an acetic acid-sodium acetate system;

[0021] (2) Under the pH buffer system, the pH of the temperature-sensitive nasal spray is 3 to 6, preferably 3 to 5.5, and further preferably 3 to 4.5.

[0022] In some embodiments, the ziconopeptide is 0.01% to 10% by mass in the temperature-sensitive nasal spray.

[0023] In some embodiments, its viscosity at 25°C is less than its viscosity at 32°C, and the viscosity difference is ≥4.5Cp, optionally ≥10Cp.

[0024] This application combines a first matrix, a second matrix, an absorption enhancer, a pH buffer system, and a peptide stabilizer, and by rationally controlling the mass percentages of the first matrix, the second matrix, and the absorption enhancer, and by employing a suitable pH buffer system, the resulting ziconopeptide temperature-sensitive nasal spray can have the following advantages:

[0025] (1) On the one hand, it can significantly improve the viscosity of the liquid, so that it can be better matched with the nasal spray device and have a good spray effect and spray pattern. On the other hand, it has suitable temperature sensitivity. It is liquid at room temperature and can form a high viscosity adhesive in situ after entering the nasal cavity, making the drug less likely to be lost and staying in the nasal cavity for a long time, thus achieving high bioavailability.

[0026] (2) Effectively maintain the stability of the entire nasal spray formulation and control the generation of related substances;

[0027] (3) The presence of absorption enhancers can also effectively increase the speed at which drugs enter the cerebrospinal fluid, as well as the amount of drugs entering the cerebrospinal fluid and blood.

[0028] In addition, the viscosity of the overall formulation at room temperature can meet the requirements of the formulation process (such as filtration), and the equipment compatibility is good, which is conducive to continuous production. Compared with the traditional ziconopeptide intrathecal injection, which is inconvenient to use and has large side effects, the temperature-sensitive nasal spray of this application is safer and more convenient to use, and overcomes the disadvantage of poor compliance of intrathecal injection formulations. Detailed Implementation

[0029] The following detailed description, in conjunction with specific embodiments, illustrates the ziconopeptide temperature-sensitive nasal spray of this application, its preparation method, and its application. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0030] Unless otherwise defined, 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 application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0031] As used herein, the terms “and / or,” “or / and,” and “and / or” may include any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all the related listed items.

[0032] In this article, "one or more" refers to any one, two or more of the listed items.

[0033] In this application, terms such as "first aspect," "second aspect," and "third aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, terms such as "first," "second," and "third" serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0034] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0035] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0036] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0037] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0038] Unless otherwise specified, the temperature parameters in this application may be either constant-temperature processing or processing within a certain temperature range. The constant-temperature processing allows temperature fluctuations within the precision range controlled by the instrument.

[0039] In this application, room temperature generally refers to 4℃~30℃, and more preferably 20±5℃.

[0040] In-situ gels can be classified into temperature-sensitive, pH-sensitive, ion-sensitive, and multi-sensitive in-situ gels. Under storage conditions, in-situ gel formulations are in a solution state, facilitating the formulation into a spray for administration. In the nasal cavity, due to changes in temperature, pH, and ion concentration, the polymer matrix can undergo a phase transition from solution to open state, thereby prolonging the drug's residence time in the nasal cavity, reducing drug loss, and decreasing ciliary clearance, thus improving drug bioavailability. This application attempts to optimize a ziconopeptide temperature-sensitive nasal spray using a temperature-sensitive in-situ gel as the base dosage form, providing a ziconopeptide temperature-sensitive nasal spray that can form a good spray pattern through a nasal spray device, exhibits good temperature sensitivity, minimizes drug loss, and demonstrates good stability.

[0041] Some examples of this application provide a ziconopeptide temperature-sensitive nasal spray, comprising a solvent, and ziconopeptide, a first matrix, a second matrix, an absorption enhancer, a pH buffer system, and a peptide stabilizer dispersed in the solvent;

[0042] The first matrix is ​​poloxamer 407, and the second matrix is ​​poloxamer 188;

[0043] The first matrix comprises 5% to 20% by mass percentage in the temperature-sensitive nasal spray, the second matrix comprises 0% to 5%, and the absorption enhancer comprises 0.01% to 10%.

[0044] The pH buffer system is either an acetic acid-acetate system or a lactic acid-lactate system.

[0045] Specifically, the mass percentage of the first matrix includes, but is not limited to, 5%, 10%, 15%, 16%, 18%, 20%, or any two of the foregoing.

[0046] Specifically, the mass percentage of the second matrix includes, but is not limited to, 0%, 1%, 2%, 3%, 4%, 5%, or any combination thereof. Further, the mass percentage of the second matrix is ​​0-3%. Even further, the mass percentage of the second matrix is ​​0%. By omitting the second matrix, the formulation can be simplified, the overall stability of the nasal spray formulation can be improved, and the generation of related substances can be controlled.

[0047] In some examples, the absorption enhancer is selected from one or more of chitosan, Kolliphor HS15, and dodecyl-β-D-maltodextrin. Using a suitable type of absorption enhancer can improve the stability of the entire nasal spray formulation, control the production of related substances, and also increase the rate at which the drug enters the cerebrospinal fluid, as well as the amount of drug entering the cerebrospinal fluid and bloodstream.

[0048] In some examples, the absorption enhancer is chitosan, and the absorption enhancer is 0.01% to 1% by mass percentage in the temperature-sensitive nasal spray. Appropriately controlling the mass percentage of chitosan can further improve the spray morphology, resulting in a fine droplet spray with an elliptical mist shape. Specifically, the mass percentage of the absorption enhancer includes, but is not limited to: 0.01%, 0.05%, 0.1%, 0.3%, 0.5%, 0.7%, 1%, or any range between the foregoing.

[0049] In some examples, the absorption enhancer is Kolliphor HS15, and the absorption enhancer is 0.1% to 10% by mass percentage in the temperature-sensitive nasal spray. Appropriately controlling the mass percentage of Kolliphor HS15 can further improve the stability of the system and reduce the content of related substances. Specifically, the mass percentage of the absorption enhancer includes, but is not limited to: 0.1%, 0.3%, 0.5%, 0.7%, 1%, 3%, 5%, 7%, 10%, or any range between the foregoing.

[0050] In some examples, the absorption enhancer is dodecyl-β-D-maltose, and the absorption enhancer is 0.1% to 5% by mass percentage in the temperature-sensitive nasal spray. Appropriately controlling the mass percentage of dodecyl-β-D-maltose can further improve the stability of the system and reduce the content of related substances. Specifically, the mass percentage of the absorption enhancer includes, but is not limited to: 0.1%, 0.3%, 0.5%, 0.8%, 1%, 1.2%, 18%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any range between the foregoing.

[0051] In some examples, the peptide stabilizer is one or more of methionine, sodium bisulfite, and sodium metabisulfite. Using a suitable peptide stabilizer can further improve the stability of the system and reduce the content of related substances. Further, the peptide stabilizer is one or more of methionine and sodium bisulfite. Even further, the peptide stabilizer is methionine.

[0052] In some examples, the peptide stabilizer is 0.005% to 10% by mass percentage in the temperature-sensitive nasal spray. Specifically, the mass percentage of the peptide stabilizer includes, but is not limited to: 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.5%, 1%, 3%, 5%, 7%, 10%, or a range between any two of the foregoing.

[0053] In some examples, the pH buffer system is an acetic acid-acetate system. Using an acetic acid-acetate system as a pH buffer system can further improve the stability of the system and reduce the content of related substances.

[0054] In some examples, the pH of the temperature-sensitive nasal spray is 3–6 in the pH buffer system. Properly controlling the pH of the system can improve its stability, reduce the content of related substances, and prevent the precipitation of raw materials during preparation, thus facilitating process continuity. Specifically, the pH includes, but is not limited to: 3, 3.5, 4, 4.5, 5, 5.5, 6, or any range between the foregoing. Further, the pH of the temperature-sensitive nasal spray is 3–5.5 in the pH buffer system. Even further, the pH of the temperature-sensitive nasal spray is 3–4.5 in the pH buffer system.

[0055] In some of these examples, the ziconopeptide is 0.01% to 10% by mass percentage in the temperature-sensitive nasal spray. Specifically, the mass percentage of the ziconopeptide includes, but is not limited to, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 3%, 5%, 7%, 10%, or any range between the foregoing.

[0056] Additionally, without limitation, the ziconopeptide temperature-sensitive nasal spray may or may not include a preservative. The preservative may be one or more of benzalkonium chloride, chlorobutanol, and methylparaben. In some examples, the preservative is 0.005% to 0.1% by mass in the temperature-sensitive nasal spray. Specifically, the mass percentage of the preservative includes, but is not limited to: 0.005%, 0.01%, 0.015%, 0.02%, 0.05%, 0.7%, 0.1%, or a range between any two of the foregoing.

[0057] Without limitation, the solvent is water.

[0058] Without limitation, the temperature-sensitive nasal spray may also contain other functional additives, such as antioxidants, as needed.

[0059] In some examples, the ziconovide temperature-sensitive nasal spray exhibits temperature-sensitive properties, with low viscosity and good flowability at room temperature, facilitating the formation of a well-formed spray and simplifying processing, thus promoting continuous production. Simultaneously, its viscosity increases within the nasal cavity, enhancing adhesion and reducing drug loss. In some examples, the viscosity of the ziconovide temperature-sensitive nasal spray at 25°C is lower than its viscosity at 32°C, with a viscosity difference ≥4.5 Cp, optionally ≥10 Cp. Without limitation, the viscosity of the ziconovide temperature-sensitive nasal spray at 25°C is 5 Cp to 60 Cp. Without limitation, the viscosity of the ziconovide temperature-sensitive nasal spray at 32°C is 10 Cp to 100 Cp, optionally 35 Cp to 70 Cp.

[0060] Without limitation, the temperature-sensitive nasal spray can be used with traditional nasal spray devices to achieve good spraying effects, with a spherical or elliptical mist and fine droplets. Traditional nasal spray devices include, for example, multi-dose nasal spray pumps, single / double-dose nasal spray pumps, pre-filled nasal spray pumps, or other multi-dose nasal spray bottles. Furthermore, when selecting multi-dose nasal spray pumps, single / double-dose nasal spray pumps, and pre-filled nasal spray pumps with antibacterial properties, preservatives may not be added. When selecting other multi-dose nasal spray bottles, preservatives need to be added; preferably, multi-dose nasal spray pumps or single / double-dose nasal spray pumps with antibacterial properties are chosen.

[0061] Other examples of this application provide a method for preparing the ziconopeptide temperature-sensitive nasal spray as described above, comprising the following steps:

[0062] The solvent is mixed with a pH buffer system to prepare a first solution;

[0063] An absorption enhancer is added to the first solution and mixed to dissolve, thus preparing a second solution;

[0064] A swelling solution is prepared by adding a first matrix and a second matrix to the second solution and then allowing it to swell.

[0065] Add a polypeptide stabilizer and ziconopeptide to the swelling solution.

[0066] During the research, it was found that poloxamer and absorption promoters such as chitosan have unique solubility properties. The formulation preparation order is as follows: first adjust the pH, then mix and dissolve the solution with the absorption promoter, then add poloxamer to swell, and finally add ziconopeptide and peptide stabilizer. This is beneficial to the stability and continuity of the process.

[0067] In some examples, swelling after adding the first and second matrices to the second solution refers to placing the mixture under low-temperature conditions (0°C to 10°C). Without limitation, the placement time is ≤24 hours.

[0068] Understandably, the preparation method also includes the step of dispensing the product into a nasal spray device.

[0069] Other examples of this application also provide the use of the ziconopeptide temperature-sensitive nasal spray as described above in the preparation of medicaments for treating pain.

[0070] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0071] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods; the single-dose nasal spray device was purchased from Shanghai Huarui Aerosol Co., Ltd., model: B20240000429; the multi-dose nasal spray device was purchased from Aptar, model: APF.

[0072] Examples and Comparative Examples

[0073] The formulations of the ziconopeptide temperature-sensitive nasal sprays in the examples and comparative examples are shown in Table 1 below (mass percentage, balance is water).

[0074] Table 1

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] The preparation methods of the ziconopeptide temperature-sensitive nasal spray in the examples and comparative examples are as follows:

[0083] (1) Mix the pH adjuster of the formula with water to adjust the pH of the system to the preset value, and then add the absorption promoter to mix and dissolve;

[0084] (2) Add preservative to the solution obtained in step (1), stir evenly, then add the first matrix and the second matrix. After the solution is mixed and swollen at 4°C (not exceeding 24 hours), add peptide stabilizer and ziconopeptide to obtain the product.

[0085] (3) The product was packaged into single-dose nasal spray devices or multi-dose nasal spray devices. The single-dose nasal spray devices were purchased from Shanghai Huarui Aerosol Co., Ltd., model: B20240000429; the multi-dose nasal spray devices were purchased from Aptar, model: APF.

[0086] Effect test:

[0087] I. Quality Evaluation of the Formulation

[0088] Quality evaluation includes tests for properties, pH, viscosity, osmotic pressure, release rate, spray properties, and preliminary stability.

[0089] Test results:

[0090] The product is a transparent, clear liquid at room temperature and under refrigeration, and a solid state within the temperature range of the human nasal cavity. It meets the requirement that the pH of the preparation be measured at 25°C using a pH meter.

[0091] The viscosity was measured using a cone-plate viscometer at 25°C and 32°C. After the temperature of the measuring cup stabilized, about 0.5 mL of sample was placed in the measuring cup, allowed to equilibrate, and then the viscosity was measured.

[0092] The osmotic pressure measurement method involves adding approximately 50 microliters of sample to a dedicated sample tube using a pipette, ensuring there are no air bubbles, placing the sample tube into the instrument for measurement, and then displaying the osmotic pressure value after the instrument has cooled and frozen the sample.

[0093] Content and related substances determination method: HPLC method, using external standard method to calculate the concentration of the test sample by peak area, and using peak area normalization method to calculate the content of related substances.

[0094] The preliminary stability study mainly investigates the changes in the quality of the formulation, such as related substances, viscosity, osmotic pressure, and pH value, when stored at 4°C for 30 days. The detection methods are the same as above.

[0095] The test results are shown in Tables 2 and 3 below:

[0096] Table 2 Product Quality Evaluation on Day 0

[0097]

[0098]

[0099]

[0100] Table 3 Product Quality Evaluation on Day 30

[0101]

[0102]

[0103]

[0104] II. Discussion of Results

[0105] (1) Screening of poloxamer 407 concentration, as shown in Table 4 below.

[0106] Table 4

[0107]

[0108] As shown in Table 4, the viscosity increases with increasing poloxamer concentration. This indicates that, without adding poloxamer 188, the addition of poloxamer 407 should not exceed 20%. Exceeding 20% ​​results in a significant increase in the viscosity of the solution at room temperature, leading to a columnar spray pattern. Furthermore, at a viscosity of 5%, the temperature-sensitive properties of the solution are relatively low, and the retention effect of the solution in the nasal cavity is weak. Therefore, the poloxamer concentration should not be lower than 5%. Preferably, the mass percentage range of poloxamer 407 is 5% to 20%.

[0109] (2) Screening of poloxamer 188 concentration is shown in Table 5 below.

[0110] Table 5

[0111]

[0112] Based on a 16% concentration of poloxamer 407, different concentrations of poloxamer 188 were investigated, indicating that the addition of poloxamer 188 should not exceed 5%. Comparative Example 3 shows that concentrations exceeding 5% fail to achieve the desired temperature-sensitive effect. Viscosity data from Examples 7, 8, and 9 show that the addition of poloxamer 188 can reduce viscosity at 32°C, narrowing the temperature-sensitive variation range. This can be used for prescription adjustments. At nasal temperature, excessive viscosity results in poor comfort. Poloxamer 188 exhibits almost no temperature-sensitive behavior at a 7% concentration; therefore, a concentration range of ≤5% for poloxamer 188 is preferred. Example 10 shows that, at appropriate ratios, the temperature-sensitive properties of the solution can be maintained. Therefore, a concentration of 5%–20% for poloxamer 407 and 0–5% for poloxamer 188 are suitable options.

[0113] (3) Screening of absorption promoters

[0114] ① Screening of chitosan concentration, as shown in Table 6 below:

[0115] Table 6

[0116]

[0117] Based on poloxamer 407 at 16% and poloxamer 188 at 1%, different chitosan concentrations were investigated. The results show that when the chitosan concentration is greater than 1%, the viscosity is high, which introduces significant resistance to the filtration process and noticeably reduces the spraying effect. A further optimized range for the chitosan mass percentage is 0.01%–1%.

[0118] ② Kolliphor HS15 concentration screening, as shown in Table 7 below:

[0119] Table 7

[0120]

[0121] For Kolliphor HS15, the viscosity of the formulation remains relatively stable within the range of 0.1-10%, and the spray performance results in fine droplets with an elliptical mist shape. Therefore, a concentration range of 0.1-10% for Kolliphor HS1 is selected.

[0122] ③ Screening of dodecyl-β-D-maltodextrin concentration, as shown in Table 8 below:

[0123] Table 8

[0124]

[0125] The viscosity of the formulation remains relatively stable within the range of 0.1-5%, and the spray performance results in fine droplets with an elliptical mist shape. Therefore, a concentration range of 0.1-5% for dodecyl-β-D-maltose is selected.

[0126] (4) Screening of peptide stabilizers, as shown in Table 9 below:

[0127] Table 9

[0128]

[0129] Examples 29, 32, 33, and Comparative Example 5 demonstrate that different peptide stabilizers can improve the stability of the prescription solution. Furthermore, in Examples 32 and 33, sodium bisulfite and sodium metabisulfite were used as protein protectants, respectively. However, the content of related substances was significantly increased compared to using methionine as a protein protectant; therefore, methionine is preferred. According to the FDA's published guidelines for nasal sprays, the osmotic pressure of nasal spray formulations should not exceed 600 mOsm / kg. The osmotic pressure of the formulations with the selected methionine concentration all met the standard, and all exhibited good spray characteristics. The related substances data in the table above show that methionine can achieve a protective effect on the API within a certain range. Therefore, the preferred concentration range of methionine in the prescription is 0.005%–10%. Furthermore, the optimal stability of the prescription solution is achieved when the ratio of methionine to zicosinate is within a certain range.

[0130] (5) Screening of pH adjusters, as shown in Table 10 below:

[0131] Table 10

[0132]

[0133] Referring to Examples 19, 34, Comparative Examples 6 and 7, the acetate-sodium acetate and lactate-sodium lactate buffer systems showed a relatively slower increase in impurities after 30 days compared to the citric acid-sodium hydroxide and dilute hydrochloric acid-sodium hydroxide systems. Therefore, the acetate-sodium acetate and lactate-sodium lactate buffer systems are preferred solvents. Comparing Examples 19 and 34 with Comparative Example 8, the buffer systems formed by sodium acetate and acetic acid, as well as the buffer systems formed by lactic acid and sodium lactate, are more conducive to the stability of ziconopeptide.

[0134] (6) pH value screening, as shown in Table 11 below:

[0135] Table 11

[0136]

[0137] Referring to Examples 35, 19, 36, and 37, when the pH values ​​were 3.0, 4.5, 5.5, and 6.0, the total impurities at 4°C for 0 days were 0.58%, 0.57%, 0.56%, and 0.59%, respectively; and the total related substances impurities at 4°C for 30 days were 0.73%, 0.61%, 1.13%, and 3.03%, respectively. That is, as the pH value increases, the related substances in the solution increase. In Comparative Example 8, at a pH of 6.9, the impurities increased rapidly. Considering that the acceptable pH range for the human nasal cavity is 3.0–7.0, a pH range of 3.0–6.0 is preferred. Furthermore, by monitoring the impurity growth trend, a pH range of 3.0–5.5 is further preferred.

[0138] (7) The construction of the rat hot plate pain model is shown in Table 12 below:

[0139] Table 12

[0140]

[0141]

[0142] Experiments were conducted using Examples 27, 12, 38, 39, 13, 16, 17, 21, and Comparative Example 9. A rat hot plate pain model was established to evaluate the effects of analgesics. This model primarily induces pain responses in rats by administering thermal stimulation, thereby assessing the rats' sensitivity to thermal pain stimuli and the degree of pain. First, a specific temperature was set on the hot plate. Rats were placed on the hot plate, and a timer was started. When a pain response was observed, the time at which the rat lifted its paw or jumped was recorded. This time point was the rat's thermal pain response time. To avoid tissue damage, a maximum dwell time of 60 seconds was set. 50 μL of the drug was administered intranasally to the rats.

[0143] The results showed that the ziconovide nasal spray of this application can exert a good analgesic effect, and as the dosage of ziconovide increases, the percentage of pain threshold increase also increases.

[0144] (8) Pharmacokinetic experiments

[0145] Experiments were conducted using the above-described Examples 27, 38, 14, and 18, and the results are shown in Table 13 below.

[0146] Table 13

[0147]

[0148] A self-made drug delivery device was used to administer 50 μL of the drug to each SD rat via the nasal cavity. Plasma and cerebrospinal fluid were collected at 15 min, 30 min, 60 min, 120 min, 240 min, and 480 min, with n=6 at each time point. After processing the cerebrospinal fluid and plasma, the ziconopeptide content in the cerebrospinal fluid was detected using a ziconopeptide kit.

[0149] The results showed that the Ziconotide nasal spray of this application can enter the cerebrospinal fluid and blood. The added absorption enhancer can increase the speed at which the drug enters the cerebrospinal fluid, and at the same time increase the amount of drug entering the cerebrospinal fluid and blood.

[0150] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0151] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A ziconopeptide temperature-sensitive nasal spray, characterized in that, Includes a solvent, and ziconopeptide, a first matrix, a second matrix, an absorption enhancer, a pH buffer system, and a peptide stabilizer dispersed in the solvent; The first matrix is ​​poloxamer 407, and the second matrix is ​​poloxamer 188; The first matrix comprises 5% to 20% by mass percentage in the temperature-sensitive nasal spray, the second matrix comprises 0% to 5%, and the absorption enhancer comprises 0.01% to 10%. The pH buffer system is either an acetic acid-acetate system or a lactic acid-lactate system.

2. The ziconopeptide temperature-sensitive nasal spray according to claim 1, characterized in that, The second matrix is ​​0-3% by mass percentage in the temperature-sensitive nasal spray.

3. The ziconopeptide temperature-sensitive nasal spray according to claim 1, characterized in that, The absorption enhancer is selected from one or more of chitosan, Kolliphor HS15, and dodecyl-β-D-maltodextrin.

4. The ziconopeptide temperature-sensitive nasal spray according to claim 3, characterized in that, The absorption enhancer is chitosan, and the absorption enhancer is 0.01% to 1% by mass in the temperature-sensitive nasal spray.

5. The ziconopeptide temperature-sensitive nasal spray according to claim 3, characterized in that, The absorption enhancer is Kolliphor HS15, and its mass percentage in the temperature-sensitive nasal spray is 0.1% to 10%.

6. The ziconopeptide temperature-sensitive nasal spray according to claim 3, characterized in that, The absorption enhancer is dodecyl-β-D-maltodextrin, and the absorption enhancer is 0.1% to 5% by mass percentage in the temperature-sensitive nasal spray.

7. The ziconopeptide temperature-sensitive nasal spray according to any one of claims 1 to 6, characterized in that, The polypeptide stabilizer has one or more of the following characteristics: (1) The polypeptide stabilizer is one or more of methionine, sodium bisulfite and sodium metabisulfite, and may be selected from one or more of methionine and sodium bisulfite, and may be further selected from methionine; (2) The polypeptide stabilizer is 0.005% to 10% by mass percentage in the temperature-sensitive nasal spray.

8. The ziconopeptide temperature-sensitive nasal spray according to any one of claims 1 to 6, characterized in that, The pH buffer system has one or more of the following characteristics: (1) The pH buffer system is an acetic acid-sodium acetate system; (2) Under the pH buffer system, the pH of the temperature-sensitive nasal spray is 3 to 6, preferably 3 to 5.5, and further preferably 3 to 4.

5.

9. The ziconopeptide temperature-sensitive nasal spray according to any one of claims 1 to 6, characterized in that, The ziconopeptide is 0.01% to 10% by mass in the temperature-sensitive nasal spray.

10. The ziconopeptide temperature-sensitive nasal spray according to any one of claims 1 to 6, characterized in that, Its viscosity at 25°C is less than its viscosity at 32°C, and the viscosity difference is ≥4.5Cp, with an optional viscosity difference of ≥10Cp.

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