A stable freeze-dried preparation and its preparation method and application

Abstract

The present invention discloses a stable lyophilized preparation and a preparation method and application thereof. The lyophilized pharmaceutical composition comprises meloxicam and a pharmaceutically acceptable pharmaceutical excipient thereof; the meloxicam uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.5±0.2°, 13.1±0.2°, 14.9±0.2°, 18.6±0.2°, 19.2±0.2°, 22.0±0.2°, and 25.8±0.2°; the D50 particle size of the lyophilized pharmaceutical composition is not less than 10 μm. The composition / preparation has good stability and excellent long-acting sustained-release analgesic effect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a stable freeze-dried preparation and a preparation method and application thereof. Background Art

[0002] Meloxicam, also known as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, is a known nonsteroidal anti-inflammatory drug (NSAIDs). Meloxicam is superior to traditional non-selective NSAIDs. Traditional NSAIDs further inhibit the synthesis of prostaglandins by inhibiting the activity of cyclooxygenase. Most of the adverse reactions of NSAIDs are caused by the inhibition of type I cyclooxygenase (COX-1). Meloxicam has a greater inhibitory activity on type II cyclooxygenase (COX-2) than COX-1, which effectively reduces the side effects of COX-1 inhibition. Meloxicam is commonly used in clinical practice to treat osteoarthritis, ankylosing spondylitis, rheumatoid arthritis and other diseases such as muscle or bone pain. In recent years, it has also been used in the combined treatment of postoperative pain. The treatment of joint inflammation and postoperative pain requires drugs that take effect quickly and last for a long time to relieve the patient's pain as quickly as possible and avoid the inconvenience and serious side effects caused by frequent dosing.

[0003] Providing a meloxicam lyophilized preparation with high stability, good storage property and excellent sustained-release effect has always been pursued by those skilled in the art. Summary of the invention

[0004] In order to improve the above technical problems, the present invention provides a freeze-dried pharmaceutical composition, comprising meloxicam and pharmaceutically acceptable pharmaceutical excipients thereof;

[0005] The meloxicam uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 6.5±0.2°, 13.1±0.2°, 14.9±0.2°, 18.6±0.2°, 19.2±0.2°, 22.0±0.2°, and 25.8±0.2°; preferably, the meloxicam has substantially Figure 7 The XRPD spectrum shown;

[0006] The D50 particle size of the lyophilized pharmaceutical composition is ≥5 μm, for example, 10-20 μm, for example, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm or 19 μm.

[0007] According to an embodiment of the present invention, the pharmaceutical excipient can be selected from one or more of a suspending agent, a surfactant, a lyophilizing excipient, and the like.

[0008] According to an embodiment of the present invention, the suspending agent is a cellulose suspending agent, for example, at least one selected from carboxymethyl cellulose and its sodium salt, hydroxypropyl cellulose and its sodium salt, hydroxypropyl methyl cellulose and its sodium salt, methyl cellulose and its sodium salt, hydroxyethyl cellulose and its sodium salt, sodium hyaluronate and polyvinyl pyrrolidone, for example, at least one selected from methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl cellulose.

[0009] According to an embodiment of the present invention, the weight ratio of the suspending agent to meloxicam is 1:(10-30), for example 1:(12-25), such as 1:15, 1:16, 1:18, 1:20, 1:22.

[0010] According to an embodiment of the present invention, the surfactant can be selected from one or more of poloxamer, lecithin, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyvinyl pyrrolidone, polyethylene glycols and polyethylene glycol 15-hydroxystearate; as an example, the surfactant can be polysorbate 80.

[0011] According to an embodiment of the present invention, the weight ratio of the surfactant agent to meloxicam is 1:(40-150), for example 1:(60-120), such as 1:70, 1:80, 1:90, 1:100, 1:110.

[0012] According to an embodiment of the present invention, the lyophilization excipient is selected from at least one of mannitol, trehalose, glucose and amino acids.

[0013] According to an embodiment of the present invention, the weight ratio of the lyophilized excipient to meloxicam is 1:(2-10), for example 1:(3-8), such as 1:4, 1:4.5, 1:5, 1:6, 1:7.

[0014] According to an embodiment of the present invention, the pharmaceutical excipient may further include an isotonicity regulator.

[0015] According to an embodiment of the present invention, the isotonicity adjusting agent may be selected from one or more of sodium chloride, mannitol, sorbitol, glucose, sucrose, fructose and lactose; as an example, the isotonicity adjusting agent may be mannitol.

[0016] In some embodiments, the lyophilization excipient and the isotonicity adjusting agent are the same substance, for example, mannitol.

[0017] According to an embodiment of the present invention, the lyophilized pharmaceutical composition comprises meloxicam, a suspending agent, a surfactant and a lyophilization excipient;

[0018] The meloxicam uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.5±0.2°, 13.1±0.2°, 14.9±0.2°, 18.6±0.2°, 19.2±0.2°, 22.0±0.2°, and 25.8±0.2°;

[0019] The D50 particle size of the freeze-dried pharmaceutical composition is 10-20 μm;

[0020] The suspending agent is sodium carboxymethylcellulose, the surfactant is polysorbate 80, and the lyophilizing excipient is mannitol;

[0021] Preferably, the weight ratio of the suspending agent to meloxicam is 1:(12-25), the weight ratio of the surfactant to meloxicam is 1:(60-120), and the weight ratio of the lyophilizing excipient to meloxicam is 1:(3-8).

[0022] The present invention also provides a method for preparing the above-mentioned freeze-dried pharmaceutical composition, comprising the following steps:

[0023] (1) dissolving the meloxicam API in a mixed solution of alkali and PEG (polyethylene glycol), adding hydrochloric acid dropwise to the mixed solution under shear dispersion conditions until solids are precipitated, and keeping the mixture warm;

[0024] (2) After washing, the solid is mixed and dispersed with pharmaceutical excipients and water, the pH is adjusted, and freeze-dried to obtain the freeze-dried pharmaceutical composition.

[0025] According to an embodiment of the present invention, the alkali is one or more of sodium hydroxide, potassium hydroxide and calcium hydroxide.

[0026] According to an embodiment of the present invention, the rotation speed of the shear dispersion is 2000-5000 rpm, for example, 3000 rpm, 3500 rpm, 4000 rpm, 4500 rpm.

[0027] According to an embodiment of the present invention, the insulation temperature is ≥50°C, for example, 50-60°C, such as 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C.

[0028] According to an embodiment of the present invention, the insulation time is 30-120 min, for example, 40 min, 60 min, 80 min, 100 min.

[0029] According to an embodiment of the present invention, the incubation is performed under stirring.

[0030] According to an embodiment of the present invention, in step (2), the pharmaceutical excipient may be first mixed with water to form a pharmaceutical excipient solution, and then mixed and dispersed with the washed solid.

[0031] According to an embodiment of the present invention, the rotation speed of the mixing and dispersing is 6000-10000 rpm, for example, 6500 rpm, 7000 rpm, 7500 rpm, 8000 rpm, 9000 rpm.

[0032] According to an embodiment of the present invention, the mixing and dispersing time is 5-15 min, for example, 7 min, 8 min, 9 min, 10 min.

[0033] According to an embodiment of the present invention, the reagent used to adjust the pH is one or more of sodium hydroxide, potassium hydroxide and calcium hydroxide.

[0034] According to an embodiment of the present invention, the pH value is adjusted to 7.0-9.0, for example 7.2, 7.5, 8.0, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7.

[0035] According to an embodiment of the present invention, the volume is adjusted before the pH is adjusted.

[0036] According to an embodiment of the present invention, the freeze-drying includes pre-freezing, first drying, and second drying; for example, the pre-freezing temperature is -60 to -35°C, and the time is 60-120 min; for example, the first drying temperature is -15 to 10°C, and the time is 60-1000 min; for example, the second drying temperature is 30 to 40°C, and the time is 30-90 min.

[0037] Preferably, the first drying is divided into two stages: the temperature of the first stage is -15 to -1°C, and the time is 700-900 min; the temperature of the second stage is 0 to 10°C, and the time is 30-90 min.

[0038] According to an exemplary embodiment of the present invention, the freeze-drying includes pre-freezing, first drying, and second drying; for example, the pre-freezing temperature is -45°C and the time is 90 minutes; for example, the first drying temperature is -5 to 5°C and the time is 860 minutes; for example, the second drying temperature is 35°C and the time is 60 minutes.

[0039] Preferably, the first drying is divided into two stages: the temperature of the first stage is -5°C and the time is 800 min; the temperature of the second stage is 8°C and the time is 80 min.

[0040] The present invention also provides the use of the freeze-dried pharmaceutical composition in preparing a pharmaceutical preparation, wherein the pharmaceutical preparation is used to prevent and / or treat diseases such as osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, other muscle or bone pain, or diseases caused by combined treatment of postoperative pain.

[0041] According to an embodiment of the present invention, the pharmaceutical preparation is an injectable powder.

[0042] According to an embodiment of the present invention, the pharmaceutical preparation may be administered by intramuscular injection.

[0043] Beneficial Effects

[0044] The freeze-dried pharmaceutical composition / pharmaceutical preparation provided by the present invention has good stability and long storage time, and also has excellent long-acting sustained-release analgesic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is the appearance of the meloxicam powder preparation after reconstitution in Example 1;

[0046] Figure 2 This is the appearance of the meloxicam powder preparation after reconstitution in Comparative Example 2;

[0047] Figure 3 This is the appearance of the meloxicam powder preparation after reconstitution in Comparative Example 3;

[0048] Figure 4 This is a microscope micrograph of the meloxicam powder preparation of Example 1 (scale 20 μm);

[0049] Figure 5 This is a microscope micrograph of the meloxicam raw material of Example 1 (scale 50 μm);

[0050] Figure 6 This is a microscope micrograph of the meloxicam powder preparation of Comparative Example 2 (scale 20 μm);

[0051] Figure 7 This is the XRPD diffraction pattern of the meloxicam powder preparation of Example 1 (Crystal Form I);

[0052] Figure 8 The XRPD superposition diffraction pattern of the meloxicam powder preparation of Example 1 after being placed under high temperature, high humidity and light conditions for 10 days;

[0053] Fig. 9 This is the XRPD diffraction pattern of the meloxicam powder preparation of Comparative Example 2 (Crystal Form II).

[0054] Fig.10 This is the XRPD diffraction pattern of the meloxicam powder preparation of Comparative Example 3 (Crystal Form IV).

[0055] Fig.11 It is the drug-time curve diagram of Example 1 and Comparative Example 1 and Comparative Example 3. DETAILED DESCRIPTION

[0056] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0057] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0058] Meloxicam API is a commercially available product (Shandong Xinhua Pharmaceutical Co., Ltd.).

[0059] Example 1

[0060] 9.0g of meloxicam API was dissolved in 938g of a mixed solution containing 14g of 2M sodium hydroxide solution and 24g of PEG. Hydrochloric acid solution was added dropwise to the dissolved meloxicam solution to precipitate solids, and high shear dispersion was performed at 4000rpm, stirring at 50°C for 90min. The precipitated product was filtered to remove the solvent, and the solid was washed several times. 0.5g of sodium carboxymethyl cellulose, 0.10g of polysorbate 80 and 2.0g of mannitol were completely dissolved and dispersed in water, and the auxiliary material solution was added to the solid product of the previous step, and high shear was performed at 6000rpm for 10min to fully disperse the above mixture, and ultrapure water was used to weigh 100g. After constant volume, sodium hydroxide was added to adjust the pH to about 7.0. Meloxicam powder preparation was obtained by freeze drying, and the freeze drying process parameters are shown in Table 1.

[0061] Table 1. Freeze drying process parameters

[0062] XRPD characterization showed that the active ingredient crystalline form of the meloxicam powder preparation obtained in the above example was crystalline form I ( Figure 7 ).

[0063] Example 2

[0064] The difference between this embodiment and embodiment 1 is that: after the first high shear dispersion, stirring is performed at 60° C. for 60 minutes; after ultrapure water is used to make up the volume, sodium hydroxide is added to adjust the pH to about 8.6.

[0065] Example 3

[0066] The difference between this embodiment and embodiment 1 is that: the first high shear dispersion is performed at a rotation speed of 4500 rpm, and stirring is performed at 53° C. for 60 min; and sodium hydroxide is added to adjust the pH to about 8.6 after the ultrapure water is used to make up the volume.

[0067] Example 4

[0068] The difference between this embodiment and embodiment 1 is that: the first high shear dispersion is performed at a rotation speed of 4500 rpm and stirring is performed at 53° C.; sodium hydroxide is added to adjust the pH to about 8.6 after ultrapure water is used to make the volume.

[0069] Example 5

[0070] The difference between this embodiment and embodiment 1 is that sodium hydroxide is added to adjust the pH to about 8.6 after ultrapure water is made up to volume.

[0071] Example 6

[0072] The difference between this embodiment and embodiment 1 is that: the first high shear dispersion is performed at a rotation speed of 4500 rpm and stirring is performed at 60° C.; sodium hydroxide is added to adjust the pH to about 8.6 after ultrapure water is used to make the volume.

[0073] XRPD characterization showed that the active ingredient crystalline form of the meloxicam powder preparations obtained in the above Examples 2-6 was also crystalline form I.

[0074] Comparative Example 1: Commercially available meloxicam suspension injection

[0075] Anjeso meloxicam nanosuspension (Pfizer), the meloxicam in this preparation is in the form I ( Figure 7 ).

[0076] Comparative Example 2

[0077] The difference from Example 1 is that: the first high shear dispersion is carried out at a rotation speed of 4000 rpm, the precipitated product is directly filtered to remove the solvent without heat preservation, and the solid is washed several times; ultrapure water is added to the volume and sodium hydroxide is added to adjust the pH to about 7.0.

[0078] XRPD characterization showed that the crystalline form of the active ingredient in the obtained meloxicam powder preparation was crystalline form II ( Fig. 9 ).

[0079] Comparative Example 3

[0080] 9.0g of meloxicam raw material was dissolved in a solution containing 62.5g of N,N-dimethylacetamide, and the dissolved solution was slowly added to 1000ml of cold water for precipitation, and high shear dispersion was performed at 4000rpm. The precipitated product was directly filtered to remove the solvent without heat preservation, and the solid was washed several times. 0.5g of sodium carboxymethyl cellulose, 0.1g of polysorbate 80 and 2.0g of mannitol were completely dissolved and dispersed in water, and the auxiliary material solution was added to the solid product of the previous step, and high shear was performed at 6000rpm for 10min to fully disperse the above mixture, and ultrapure water was used to weigh 100g. After constant volume, sodium hydroxide was added to adjust the pH to about 7.0. Meloxicam powder preparation was obtained by freeze drying, and the freeze drying process parameters are shown in Table 1 of Example 1.

[0081] XRPD characterization showed that the active ingredient in the obtained meloxicam powder preparation was in the form of Form IV ( Fig.10 ).

[0082] Results

[0083] The summary results of the appearance and particle size of the meloxicam powder preparation samples prepared under various process conditions are shown in Table 2. The meloxicam powder preparation and the API were subjected to microscopic morphology and stability tests: the crystal form changes of the 0-day sample of the meloxicam powder preparation and the sample placed under high temperature, high humidity and light conditions for 10 days were tested.

[0084] Table 2 Summary results of various embodiments and comparative examples

[0085]

[0086] It can be seen from Table 2 that the particle size of the powder preparations obtained under the heat preservation process of Examples 1-6 can be within a relatively stable range, which proves that the process can obtain preparation products with relatively stable and uniform particle size and meet the requirement of controlling the particle size to a large extent.

[0087] Depend on Figure 1 , Figure 2 and Figure 3 It can be found from the appearance photos that under the same reconstitution conditions, the product of Example 1 has a better appearance after reconstitution than the products of Comparative Examples 2-3, and the liquid is more uniform.

[0088] Figure 4 and Figure 5 By comparison, it can be seen that the microscopic morphology of the preparation product of Example 1 is consistent with that of the raw material drug, and the raw material drug is crystal form I, so Example 1 with the same microscopic morphology is also crystal form I.

[0089] According to the 0 day ( Figure 7 ) and the XRPD pattern after being placed under high temperature, high humidity and light conditions for 10 days ( Figure 8) Comparison shows that the preparation sample prepared by the embodiment method has good stability and the active ingredient is stable in crystal form.

[0090] Pharmacokinetic studies

[0091] The pharmacodynamics of the preparation products of Example 1, Comparative Example 1 and Comparative Example 3 were studied, and the drugs were administered to SD rats. Example 1 was administered by intramuscular injection (dosage of 9.0 mg / kg), Comparative Example 1 was administered by intravenous injection (dosage of 3.0 mg / kg), and Comparative Example 3 was administered by intramuscular injection (dosage of 9.0 mg / kg). Plasma was collected at different time points and detected by LC-MS / MS method. WinNonlin 8.0 was used to calculate the pharmacokinetic parameters using non-compartmental model, and the blood drug concentration data and pharmacokinetic parameters of different preparation groups in SD rats were obtained to investigate the plasma absorption pharmacokinetic characteristics under the set dosage form. Compared with Comparative Example 3, Example 1 has a significantly lower Cmax and a slower drug release rate at the same dosage, while its sustained release effect is better than that of Comparative Example 1. It can be seen that Example 1 has better drug safety and sustained release effect. The experimental results are as follows. Fig.11 and Table 3.

[0092] Table 3. Pharmacokinetic parameters

[0093] Pharmacokinetic parameters unit Example 1 Comparative Example 1 Comparative Example 3 <![CDATA[T 1 / 2 ]]> h 32.28 13.28 21.07 <![CDATA[T max ]]> h 11.00 0.03 1.50 <![CDATA[C max ]]> μg / mL 40.05 12.97 57.64 <![CDATA[AUC (0-t) ]]> h*μg / mL 2055.07 95.46 1493.61 <![CDATA[AUC (0-∞) ]]> h*μg / mL 2576.02 133.33 1557.37 Cl / Cl_F mL / h / kg 5.04 23.39 7.38 <![CDATA[MRT (0-∞) ]]> h 50.73 18.71 28.24

[0094] In summary, the meloxicam powder preparation of the present invention has good stability, the active ingredient crystal form remains unchanged, and has a better sustained-release effect than the existing injection.

[0095] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A freeze-dried pharmaceutical composition, characterized in that The freeze-dried pharmaceutical composition comprises meloxicam, a suspending agent, a surfactant and a freeze-drying excipient; The meloxicam uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.5±0.2°, 13.1±0.2°, 14.9±0.2°, 18.6±0.2°, 19.2±0.2°, 22.0±0.2°, and 25.8±0.2°; The D50 particle size of the lyophilized pharmaceutical composition is greater than 10 μm and not more than 20 μm; The suspending agent is sodium carboxymethylcellulose, the surfactant is polysorbate 80, and the lyophilizing excipient is mannitol; The weight ratio of the suspending agent to meloxicam is 1:(12-25), the weight ratio of the surfactant to meloxicam is 1:(60-120), and the weight ratio of the lyophilized excipient to meloxicam is 1:(3-8).

2. The freeze-dried pharmaceutical composition according to claim 1, characterized in that The meloxicam has an XRPD pattern substantially as shown in Figure 7; And / or, the D50 particle size of the lyophilized pharmaceutical composition is 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm or 19 μm.

3. The freeze-dried pharmaceutical composition according to claim 1, characterized in that The weight ratio of the suspending agent to meloxicam is 1:(15-20); The weight ratio of the surfactant to meloxicam is 1:(80-100); The weight ratio of the lyophilized excipient to meloxicam is 1:(3-6).

4. The freeze-dried pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical excipients also include isotonicity regulators.

5. The method for preparing the freeze-dried pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: (1) dissolving the meloxicam API in a mixed solution of alkali and PEG, adding hydrochloric acid dropwise to the mixed solution under shear dispersion conditions until solids precipitate, and keeping the mixture warm; The insulation temperature is ≥50°C, and the insulation time is 30-120min; (2) After washing, the solid is dispersed with pharmaceutical excipients and water, the pH is adjusted to 6.8-9.0, and freeze-dried to obtain the freeze-dried pharmaceutical composition.

6. Use of the freeze-dried pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a pharmaceutical preparation for the prevention and / or treatment of osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, other muscle or bone pain, or combined treatment of postoperative pain.

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