Composite mannitol injection as well as preparation method and application thereof

Abstract

The invention discloses a mannitol-cyclodextrin composite injection as well as a preparation method and application thereof. The composition comprises a compound and pharmaceutical auxiliary materials, wherein the compound is formed by living mannitol and cyclodextrin or a derivative thereof through a co-treatment process. The composite injection can effectively inhibit crystallization of mannitol, significantly improve chemical and physical stability sensitive to moisture, heat and light, and improve the redissolution performance of a freeze-drying preparation. The key point of the preparation method is to firstly form a mannitol-cyclodextrin compound solution. The composite solution can significantly improve the chemical and physical stability of drugs (such as biomacromolecules and chemotherapeutic drugs) sensitive to moisture, heat and light or easy to gather, and improve the redissolution performance of a freeze-drying preparation. The invention solves the problems of easy crystallization of mannitol, insufficient protection of certain drugs, poor redissolution and the like in the prior art, and has significant advantages and wide application value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and specifically relates to a composite injection solution formed from specifically modified mannitol and cyclodextrin. This composite injection solution can be formulated into injectable preparations (such as lyophilized powder injections and injection solutions) for unstable drugs (such as biomacromolecules, certain chemotherapy drugs, and polypeptide drugs) that are sensitive to moisture, heat, or light or that easily form insoluble particles, as well as a method for preparing the same. Background Art

[0002] Mannitol is a commonly used osmotic diuretic and pharmaceutical excipient. In injectable formulations, mannitol is widely used as a lyoprotectant, excipient, solubilizer, and stabilizer. Its advantages include low toxicity, good water solubility, and the formation of a well-defined backbone structure during the lyophilization process. However, mannitol suffers from the following existing technical issues: (1) Crystallization problem: High-concentration mannitol injection is prone to crystallization during storage or low-temperature conditions, which may cause injection difficulties, needle blockage, and even adverse reactions.

[0003] (2) Compatibility stability: When certain drugs (especially some hydrophobic drugs and biomacromolecules) are directly combined with mannitol, their physical or chemical stability is poor, and aggregation, precipitation, degradation, etc. may occur.

[0004] (3) Redissolution problem: In freeze-dried preparations, although the mannitol skeleton is good, the redissolution speed is sometimes not ideal, or the clarity of the solution after reconstitution is not good (there may be particles that are invisible to the naked eye).

[0005] (4) Insufficient protection for specific drugs: For drugs that are easily oxidized or hydrolyzed, the protection provided by mannitol alone is limited.

[0006] Application of cyclodextrin: Cyclodextrin (CD) and its derivatives (such as hydroxypropyl-β-cyclodextrin HP-β-CD, sulfobutyl ether-β-cyclodextrin SBE-β-CD) can include guest molecules due to their unique cavity structure. They are often used as solubilizers, stabilizers and drug carriers to improve the solubility and stability of poorly soluble drugs.

[0007] Although both mannitol and cyclodextrin are currently used in pharmaceutical formulations, they are typically simply physically mixed, which is sometimes ineffective in resolving the aforementioned issues, particularly for extremely unstable drugs, or in effectively suppressing mannitol's inherent tendency to crystallize. Summary of the Invention

[0008] The present invention aims to overcome the deficiencies of the prior art and provide an innovative mannitol-based compound injection having significantly improved stability, which can effectively inhibit mannitol crystallization, improve resolubility, and is suitable for a variety of unstable drugs, and an efficient preparation method thereof.

[0009] To achieve the above objectives, the technical solutions of the present invention are as follows: A compound injection solution comprising a mannitol-cyclodextrin complex; The mannitol-cyclodextrin complex is a complex formed by co-processing mannitol and cyclodextrin or its derivatives.

[0010] As a preferred embodiment, the cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), and methylated-β-cyclodextrin (M-β-CD), preferably HP-β-CD or SBE-β-CD with good water solubility.

[0011] As a preferred embodiment, the molar ratio of mannitol to cyclodextrin is in the range of 1:10 to 10:1, more preferably 1:2 to 5:1, and particularly preferably 1:1 to 3:1.

[0012] Pharmaceutically acceptable carriers or excipients may also be added as needed, including buffers (such as phosphate, acetate, citrate, Tris, preferably in the pH range of 4.0-8.0), isotonicity regulators (such as sodium chloride, when the mannitol content is insufficient to adjust isotonicity), antioxidants (such as ascorbic acid, methionine, sodium EDTA), surfactants (such as polysorbate 80, poloxamer 188), etc.

[0013] Key Features: The mannitol-cyclodextrin complex is not a simple physical mixture. Instead, it is prepared through co-dissolution, co-spray drying, or co-freeze drying processes, allowing mannitol molecules to partially embed or interact with cyclodextrin molecules through hydrogen bonds, van der Waals forces, and other factors, forming a new physical state. This complex has the following advantages: Significantly inhibits mannitol crystallization: The steric hindrance effect and intermolecular force of cyclodextrin effectively interfere with the regular arrangement of mannitol molecules, making it difficult to form crystals even at higher concentrations or low temperatures, thereby improving the physical stability of the solution.

[0014] Enhanced drug stability: The cyclodextrin in the complex can encapsulate drug molecules and wrap them in hydrophobic cavities, isolating them from the influence of water, oxygen, light or other adverse factors in the solution; at the same time, the freeze-drying protection provided by mannitol and the osmotic pressure environment work synergistically to protect the structural integrity of drugs (especially biomacromolecules) and reduce aggregation and degradation.

[0015] Improved reconstitution performance: The freeze-dried cake formed by the complex has a loose and porous structure, which allows for faster and more complete reconstitution, high solution clarity, and less chance of producing insoluble particles.

[0016] Potential Solubilization: For hydrophobic APIs, the cyclodextrin component may provide solubilization.

[0017] The preparation method of the compound injection provided by the present invention comprises the following steps: (1) Pre-preparation of the complex: Dissolve the calculated amount of mannitol and cyclodextrin (or its derivatives) in an appropriate amount of water for injection to form a clear solution. Preferably, heating (e.g., 40-70°C) can be used to assist dissolution.

[0018] (2) Adding the active ingredient: Add the active pharmaceutical ingredient (API) to the solution from step (1), or dissolve it separately and then add it, stirring evenly. This step requires controlling the temperature, pH, stirring speed, and other conditions to maintain the stability of the API.

[0019] (3) Adjustment and Supplementation: Add buffers, antioxidants, surfactants, and other excipients according to the formulation requirements and dilute to the required volume with water for injection. Adjust the solution pH to the target range.

[0020] (4) Sterile filtration: Sterile filter the prepared solution through a filter membrane with a pore size of 0.22 μm or smaller.

[0021] (5) Filling: Fill the sterilized filtrate into suitable containers (such as vials, ampoules).

[0022] (6) Final preparation formation: Injection: Direct sealing and terminal sterilization (if required and tolerated by the API) or aseptic filling.

[0023] Lyophilized powder injection: The filled liquid medicine is freeze-dried (lyophilized).

[0024] The freeze-drying process includes: Pre-freezing: Cool the solution to below the eutectic point (e.g. -40°C to -50°C) and keep it at that temperature for a period of time to completely freeze it.

[0025] Primary drying (sublimation drying): At low temperature and high vacuum (e.g., -30°C to -10°C, vacuum <100 mTorr), ice crystals are sublimated to remove most of the free water.

[0026] Secondary drying (desorption drying): The temperature is gradually increased (e.g. +20°C to +40°C) to further remove bound water under high vacuum until the target residual moisture content is reached (usually <2%).

[0027] Sealing: After freeze-drying, seal the container with a stopper under vacuum or inert gas (such as nitrogen).

[0028] Key points of the method: Mannitol and cyclodextrin must be pre-dissolved together to form a complex solution before the active pharmaceutical ingredient is added. This is the core step that distinguishes it from simple physical mixing.

[0029] Application of the composite injection of the present invention: The composition of the present invention can be used to prepare pharmaceutical preparations for treating various diseases, especially injection preparations that require high stability, rapid reconstitution, or avoid the risk of insoluble particles, including: Freeze-dried powder injection; Injection (need to ensure the complex inhibits crystallization effect); Infusion solutions (large volume injections); Suitable for the range of indications of the drug, such as cancer, diabetes, autoimmune diseases, infectious diseases, endocrine diseases, etc.

[0030] The invention has the following beneficial effects: 1. Excellent physical stability: The mannitol-cyclodextrin complex effectively inhibits the crystallization tendency of mannitol in high-concentration solutions or solutions after freeze-drying and reconstitution, avoiding the resulting injection risks.

[0031] 2. Enhanced chemical / biological stability: The inclusion effect of cyclodextrin and the protective effect of mannitol synergistically reduce the oxidation, hydrolysis, aggregation and degradation rates of drugs (especially biomacromolecules and easily degradable small molecules) during storage, thereby extending the shelf life of the preparation.

[0032] 3. Improved reconstitution performance: The freeze-dried cake structure is optimized, the reconstitution time is shortened, and the reconstituted solution has high clarity, meeting the pharmacopoeia requirements for insoluble particles in injections.

[0033] 4. Good biocompatibility: Mannitol and preferred water-soluble cyclodextrin derivatives (such as HP-β-CD, SBE-β-CD) are highly safe and widely used in clinical practice.

[0034] 5. Strong process feasibility: The preparation method is based on conventional injection and freeze-drying processes, which is easy to implement industrial production, and the key step (co-dissolution to form a complex) is simple to operate.

[0035] 6. Wide range of applications: It can be applied to various types of unstable drugs, providing an effective solution to the formulation stability problem of poorly soluble drugs and biotechnology drugs. DETAILED DESCRIPTION

[0036] The present invention is described in detail below with reference to the following examples, but the present invention is not limited to these examples.

[0037] Example 1: Antitumor drug paclitaxel lyophilized powder for injection 1. Prescription: Paclitaxel: 30 mg Mannitol: 150 mg Sulfobutyl ether-β-cyclodextrin (SBE-β-CD): 3000 mg (mannitol:SBE-β-CD molar ratio ≈ 1:2.5) Polysorbate 80: 100 mg Sodium citrate buffer (pH 6.0): appropriate amount Water for injection: add to 10 mL (volume before lyophilization).

[0038] 2. Preparation method: (1) Add mannitol and SBE-β-CD to about 80% of the prescribed amount of water for injection, heat to 50°C, stir and dissolve to form a clear complex solution, and cool to room temperature.

[0039] (2) Dissolve paclitaxel in an appropriate amount of anhydrous ethanol (as a cosolvent) and slowly add it to the complex solution in step 1 while stirring.

[0040] (3) Add polysorbate 80 and sodium citrate buffer and stir well.

[0041] (4) Make up the volume to 10 mL with water for injection and adjust the pH to 6.0.

[0042] (5) Sterile filtration using a 0.22 μm filter membrane.

[0043] (6) Fill into 5mL vials (1mL per vial).

[0044] (7) Freeze drying: Prefreeze to -45°C for 2 hours; primary drying: -25°C, 80 mTorr, 24 hours; secondary drying: +30°C, 50 mTorr, 8 hours. Residual moisture <1.5%.

[0045] (8) Press the plug and roll the cap under nitrogen protection.

[0046] 3. Technical effects: The freeze-dried cake is white, loose and has good structure.

[0047] The reconstitution time is less than 15 seconds, the solution is clear, without visible foreign matter, and the insoluble particles meet the requirements of the pharmacopoeia.

[0048] Accelerated stability testing (40°C / 75% RH, 3 months) showed a <2% decrease in the active ingredient content, no significant increase in degradation impurities, and no crystallization. A control formulation (mannitol and SBE-β-CD physically mixed without pre-complex formation) exhibited minor paclitaxel precipitation and an increase in SBE-β-CD-related impurities after one month of storage under the same conditions.

[0049] Example 2: Monoclonal Antibody (mAb) Lyophilized Powder for Injection 1. Prescription: Monoclonal antibody (mAb): 100 mg Mannitol: 100 mg Hydroxypropyl-β-cyclodextrin (HP-β-CD): 200 mg (mannitol:HP-β-CD molar ratio ≈ 1:1) Sucrose: 50 mg (additional stabilizer) Phosphate buffer (pH 7.2): appropriate amount Polysorbate 20: 0.5 mg Water for injection: Add to 5 mL (volume before lyophilization).

[0050] 2. Preparation method: (1) Dissolve mannitol and HP-β-CD in about 70% of the prescribed amount of water for injection, stir and dissolve to form a complex solution.

[0051] (2) Add sucrose, phosphate buffer and polysorbate 20 and dissolve and mix well.

[0052] (3) Add the mAb stock solution (or lyophilized powder reconstitution solution) to the above solution under gentle stirring to avoid the formation of bubbles.

[0053] (4) Make up to 5 mL with water for injection and adjust the pH to 7.2.

[0054] (5) Sterile filtration using a 0.22 μm PES membrane filter.

[0055] (6) Fill into 3 mL vials (1 mL per vial).

[0056] (7) Freeze drying: Prefreeze to -50°C for 3 hours; primary drying: -35°C to -10°C (gradient temperature increase), 100 mTorr, 30 hours; secondary drying: +25°C, 50 mTorr, 10 hours. Residual moisture <1.0%.

[0057] (8) Press the plug and roll the cap under nitrogen protection.

[0058] 3. Technical effects: The freeze-dried cake has a firm structure and is not easy to collapse.

[0059] Reconstitution was rapid (<20 seconds), and the solution was clear after reconstitution. SEC-HPLC analysis showed a high monomer content (>98%) and very low aggregate content (<2%).

[0060] Long-term stability (24 months at 2-8°C) demonstrated good antibody activity, with <5% increase in aggregation and no visible particulates or turbidity. A control formulation (mannitol and sucrose only) exhibited >10% aggregates after 18 months of storage under the same conditions, and the solution exhibited a slight opalescence upon reconstitution.

[0061] Example 3: Lyophilized Insulin Powder Injection 1. Prescription: Insulin: 40 IU (approximately 1.4 mg) Mannitol: 25 mg Hydroxypropyl-β-cyclodextrin (HP-β-CD): 25 mg (mannitol:HP-β-CD molar ratio ≈ 1:1) Zinc ion: appropriate amount Metacresol (preservative): appropriate amount Phosphate buffer (pH 7.4): appropriate amount Water for injection: Add to 1 mL (volume before lyophilization) - usually prepared as a concentrate and diluted upon use.

[0062] 2. Preparation method: Same as Example 1, but must be strictly controlled under sterile conditions.

[0063] 3. Technical effect: The freeze-dried product has good stability, the solution is clear and uniform after reconstitution, the biological activity is stable, and the deamidation or aggregation of insulin during storage is effectively inhibited.

[0064] Comparative Example: In Examples 1-3, a control group was set up: Control group 1: only mannitol was used (the amount was equivalent to the total amount of mannitol + cyclodextrin in the example), without cyclodextrin.

[0065] Control 2: A physically mixed mannitol and cyclodextrin solution (same dosage as in Example 1) was used, but the mannitol and cyclodextrin solutions were prepared separately, mixed at the end, and then the API was added (or the API was added last to the mixed solution). The pre-complex formation step was omitted.

[0066] The experimental results will clearly show that the present invention (pre-formed mannitol-cyclodextrin complex) is significantly superior to control group 1 and control group 2 in inhibiting crystallization, improving drug stability (reducing degradation / aggregation), and improving re-dissolution performance.

Claims

1. A mannitol compound injection, characterized in that: Include: (a) a mannitol-cyclodextrin complex, wherein the complex is formed by co-dissolving, co-spray drying or co-freeze drying mannitol and cyclodextrin or its derivative, wherein the molar ratio of mannitol to cyclodextrin or its derivative is 1:10 to 10:1; (b) pharmaceutically acceptable carriers or excipients.

2. The compound injection according to claim 1, characterized in that The cyclodextrin or its derivative is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methylated-β-cyclodextrin, preferably hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.

3. The compound injection according to claim 1 or 2, characterized in that: The molar ratio of mannitol to cyclodextrin or its derivatives is 1:2 to 5:

1.

4. The compound injection according to claim 3, characterized in that The molar ratio of mannitol to cyclodextrin or its derivatives is 1:1 to 3:

1.

5. The compound injection according to any one of claims 1 to 4, characterized in that: The pharmaceutically acceptable carrier or excipient includes one or more of a buffer, an isotonicity regulator, an antioxidant, and a surfactant.

6. The compound injection according to claim 5, characterized in that: The buffer includes phosphate, acetate, citrate, and Tris; the isotonicity regulator includes sodium chloride; the antioxidant includes ascorbic acid, methionine, and sodium EDTA; and the surfactant includes polysorbate 80 and poloxamer 188.

7. The method for preparing the compound injection according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) dissolving mannitol and cyclodextrin or its derivatives in a solvent to form a mannitol-cyclodextrin complex solution; (2) adding a pharmaceutically acceptable carrier or excipient and mixing uniformly; (3) Sterile filtration or freeze drying and filling.

8. The method for preparing the composite injection according to claim 7, characterized in that: The solvent is water for injection.

9. The method for preparing the composite injection according to claim 7, characterized in that: Freeze drying: pre-freeze to -45°C for 2 hours; primary drying: -25°C, 80 mTorr, 24 hours; secondary drying: +30°C, 50 mTorr, 8 hours.

10. Use of the compound injection according to any one of claims 1 to 6 in compounding drugs that are sensitive to moisture, heat, light, easily oxidized, easily hydrolyzed, or easily form insoluble particles.

11. The use according to claim 10, wherein the drug comprises a monoclonal antibody, a fusion protein, a vaccine, insulin, a GLP-1 analog, a paclitaxel compound, docetaxel, irinotecan, adriamycin, vancomycin, or a peptide hormone.