Fluticasone propionate suspension nasal spray

Abstract

The invention discloses a fluticasone propionate suspension nasal spray which is prepared by the following steps: on the basis of a prescription of fluticasone propionate micro powder, a suspending aid microcrystalline cellulose sodium carboxymethyl cellulose, an osmotic pressure regulator, a wetting agent and water, using a stabilizer methyl glucitol polyether-20 and hexanediol; the problem that the container adsorbs the fluticasone propionate micro powder in the preparation process is solved, and meanwhile degradation and particle size increase of the fluticasone propionate are effectively controlled.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical analysis technology, and in particular relates to a fluticasone propionate nasal spray suspension. Background Technology

[0002] Allergic rhinitis is a common chronic disease affecting 10% to 20% of the world's population, making it a global health problem. In China alone, there are as many as 250 million rhinitis patients. Fluticasone propionate is a glucocorticoid, appearing as a white or off-white powder, almost insoluble in water, readily soluble in dimethyl sulfoxide, and slightly soluble in methanol and ethanol. Its structural formula is as follows:

[0003] .

[0004] Fluticasone propionate nasal spray is mainly used for the prevention and treatment of seasonal and perennial allergic rhinitis. It can also relieve symptoms such as nasal congestion, sneezing, and runny nose caused by acute and chronic rhinitis or nasal surgery. Its potent anti-inflammatory and anti-allergic effects can effectively control nasal inflammatory reactions, and it is a first-line treatment drug recommended by clinical guidelines.

[0005] Fluticasone propionate nasal spray is a suspension spray. To ensure efficacy and product quality, the particle size of fluticasone propionate is usually required to be controlled at D90 < 5μm.

[0006] Chinese patent document CN1805730A discloses a fluticasone nasal pharmaceutical formulation with specific particle size distribution characteristics, comprising 0.04%-0.06% by weight of fluticasone or a pharmaceutically acceptable derivative thereof, with approximately 90% of the particles having a particle size of less than 5.3 micrometers. This nasal formulation may contain preservatives, suspending agents, humectants, stretching agents, and / or diluents. The pharmaceutical substance (fluticasone) is produced under aseptic conditions, micronized in an aseptic environment, and mixed and packaged under aseptic conditions. In an alternative embodiment, the suspension comprises microcrystalline cellulose, sodium carboxymethyl cellulose, glucose, benzalkonium chloride, polysorbate 80, and 0.25% v / w phenylethanol, with a pH between approximately 5 and 7.

[0007] The inventors of this application discovered in their research that when micronized active pharmaceutical ingredients are used to prepare suspensions, the preparation container may adsorb fluticasone propionate micronized powder during the preparation process. This not only causes serious loss of active pharmaceutical ingredients but also results in low and uneven drug content in the spray and changes in drug particle size, affecting product quality and clinical efficacy.

[0008] Chinese patent document CN116370411A discloses a fluticasone propionate nasal spray, comprising the following raw material components by weight: 3.5-4.5 parts fluticasone propionate, 110-130 parts sodium carboxymethyl cellulose microcrystalline cellulose, 390-420 parts glycerin, 1.5-1.8 parts polysorbate 80(II), 1.5-1.8 parts potassium sorbate, 0.7-0.9 parts disodium edetate, and 7400-7500 parts purified water. The patent document also discloses a corresponding preparation method, which involves first dissolving a suspending agent in water and subjecting it to high-speed shearing; dispersing fluticasone propionate in polysorbate 80(II) solution in portions and grinding it homogenously; mixing potassium sorbate and disodium edetate; and finally mixing the three components and subjecting them to high-speed shearing. However, fluticasone propionate is a glucocorticoid drug with high biological activity, strong sensitization, and potential occupational hazards (long-term exposure may lead to endocrine disorders, skin irritation, respiratory damage, etc.), requiring closed-loop feeding. The technical solution disclosed in the aforementioned patent literature adopts a preparation process of "adding a small amount of the prescribed amount of fluticasone propionate while stirring and grinding, and repeating the above operation until the active drug is completely dispersed after visual observation, then slowly transferring it to purified water in several batches, and then dispersing it evenly at high speed." This method of adding the drug in several batches is not conducive to personnel safety protection, the process is cumbersome, and it is not conducive to commercial production. The entire process relies on visual observation, making it difficult to guarantee batch-to-batch stability in commercial production. Summary of the Invention

[0009] To address the problems existing in the preparation process of fluticasone propionate nasal spray suspension, this invention has developed a new formulation and process for fluticasone propionate nasal spray based on the traditional formulation that uses sodium carboxymethyl cellulose microcrystalline cellulose as a suspending agent. This solves the problem of fluticasone propionate micropowder adsorption in the preparation tank, while also effectively controlling raw material degradation and particle size growth.

[0010] To achieve the above-mentioned objectives, the specific technical solution of this invention is as follows:

[0011] A fluticasone propionate nasal spray comprises fluticasone propionate, sodium carboxymethyl cellulose microcrystalline cellulose, stabilizer methyl gluceth-20 and hexanediol, an osmotic pressure regulator, a wetting agent and water. The weight percentage of fluticasone propionate is 0.03%~0.30%, the weight percentage of methyl gluceth-20 is 0.04%~0.40%, and the weight percentage of hexanediol is 0.02%~0.20%. Preferably, the weight percentage of methyl gluceth-20 in the nasal spray is 0.08%~0.32%, and the weight percentage of hexanediol is 0.04%~0.16%.

[0012] The osmotic pressure regulator described in this invention is selected from one or more of glucose, glycerol, sorbitol, and sodium chloride.

[0013] The wetting agent described in this invention is selected from one or more of polysorbate 80, polysorbate 60, and polysorbate 20.

[0014] The nasal spray of this invention further includes one or more of the following: preservatives and pH adjusters. The preservatives are selected from one or more of benzalkonium chloride, phenethyl alcohol, and benzyl alcohol. The pH adjusters are selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, phosphoric acid, citric acid, and boric acid. The weight percentage of the preservatives in the nasal spray is 0.02% to 2%. In a specific example of the present invention, the fluticasone propionate nasal spray comprises fluticasone propionate (0.05%~0.10%, w / w), sodium carboxymethyl cellulose microcrystalline cellulose (1.0%~2.0%, w / w), polysorbate 80 (0.005%~0.02%, w / w), methyl glucetol polyether-20 (0.08%~0.32%, w / w), hexanediol (0.04%~0.16%, w / w), anhydrous glucose (4.7%~5.3%, w / w), and benzalkonium chloride (0.02%~0.04%, w / w).

[0015] Another object of the present invention is to provide a method for preparing fluticasone propionate nasal spray, comprising the following steps:

[0016] 1) Solution preparation: Add osmotic pressure regulator, preservative, and methyl glucetol polyether-20 to purified water to prepare a basic solution;

[0017] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid paste;

[0018] 3) Pre-dispersion of raw materials: Fluticasone propionate micro powder is added to an aqueous solution containing a wetting agent and hexanediol, and stirred at a speed of 1500 rpm to 2500 rpm to prepare a premixed suspension;

[0019] 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, use a pH adjuster to adjust it.

[0020] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1. This invention optimizes the formulation based on the existing formulation of marketed drugs. Research results show that the adsorption problem of raw material micropowders cannot be improved by changing the suspending agent or wetting agent. This invention further screened different hydrophilic polymers, attempting to form a protective film on the particle surface to prevent direct contact and adhesion with equipment. Results showed that methyl glucetol polyether-20 has a stabilizing effect on drug particle size.

[0023] 2. In the process of screening preservatives, it was unexpectedly discovered that the weak antibacterial agent hexanediol can improve the problem of raw material adsorption.

[0024] 3. Further research in this invention revealed that when the weight percentage of methyl gluceth-20 is 0.04% to 0.4% and the weight percentage of hexanediol is 0.02% to 0.2%, the two can exert a synergistic effect to solve the raw material adsorption problem. Under this formulation, the growth of related substances in the drug is not significant, and the drug particle size stability is good.

[0025] 4. In conjunction with the formulation, this invention studied the preparation process. The results showed that adding fluticasone propionate micro powder to an aqueous solution containing a wetting agent and hexanediol in the raw material pre-dispersion step and stirring at a speed of 1500 rpm to 2500 rpm to prepare a premixed suspension can solve the problem of raw material adsorption. Detailed Implementation

[0026] The technical solution of the present invention will be further described in detail below with reference to specific examples and data. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention in any way. Unless otherwise stated, the terminology used in this invention generally has the meaning commonly understood by those skilled in the art.

[0027] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0028] Example 1: Investigating the effect of different suspending agents on improving the adsorption of raw material micro powders

[0029] By selecting different suspending agents, we attempted to improve the adsorption of raw material powder by increasing the solution viscosity, making it easier for particles to remain in the solution.

[0030] prescription:

[0031]

[0032] Process:

[0033] 1) Solution preparation: Add anhydrous glucose and benzalkonium chloride to purified water to prepare a solution.

[0034] 2) Colloid preparation: Different suspending agents (sodium carboxymethyl cellulose, carrageenan, sodium carboxymethyl cellulose, magnesium aluminum silicate, xanthan gum) are added to purified water to prepare colloids.

[0035] 3) Raw material pre-dispersion: Fluticasone propionate micro powder (D 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and a premixed suspension was prepared at a speed of 1500 rpm.

[0036] 4) Total mixing: Add the solution from step 1 and the suspension from step 3 to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0037] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0038] The drug content and stability (related substances, pH value, and drug particle size) of the formulation solution during the preparation of different prescription products are detected using the following methods:

[0039] (1) Content

[0040] The content was determined using HPLC, and the calculation formula is as follows:

[0041]

[0042]

[0043] In the formula:

[0044] C r : The concentration of the reference solution 1 is mg / ml;

[0045] m r Reference standard 1 mg;

[0046] B r : Content of reference standard, %

[0047] The average area of ​​the main peak in reference solution 1;

[0048] A i : The area of ​​the main peak in the test solution;

[0049] m i Mass of the medicine solution, in grams;

[0050] 0.05%: The indicated concentration of the drug solution, in g / g.

[0051] Three samples were taken from the top, middle, and bottom of the preparation tank to test the content, and the mean of the three sampling points was calculated. The results are shown in the table below. The results show that even with different types of suspending agents, there is still significant drug loss in the prescription, and the problem of equipment adsorption of raw material powder cannot be solved.

[0052]

[0053] (2) Stability test

[0054] Sodium carboxymethyl cellulose (CCMC) is a classic suspending agent. Samples prepared according to Formula 1 were tested at 50℃±2℃, and samples were taken at 15 and 30 days to determine related substances, pH value, and drug particle size. Related substances were detected by HPLC (as above). pH value was measured using a pH meter. Drug particle size was measured using microscopy.

[0055] The results are shown in the table below. The results show that the related substances increased significantly, the pH value decreased, and the drug particle size increased.

[0056]

[0057] Example 2: The effect of different wetting agents on improving the adsorption of raw materials

[0058] By selecting different wetting agents, we can try to reduce interfacial tension so that the liquid can spread better on the particle surface and improve dispersibility.

[0059] prescription:

[0060]

[0061] Process:

[0062] 1) Solution preparation: Add anhydrous glucose and benzalkonium chloride to purified water to prepare a solution.

[0063] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid.

[0064] 3) Raw material pre-dispersion: Fluticasone propionate micro powder (D 50 ≤2μm) were added to aqueous solutions of different wetting agents (polysorbate 20, poloxamer, sodium taurocholate, polyethylene glycol-40 hydrogenated castor oil, and vitamin E polyethylene glycol succinate) and a premixed suspension was prepared at a speed of 1500 rpm.

[0065] 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0066] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0067] The drug content of the liquid was tested during the preparation of different prescription products, referring to Example 1.

[0068] Three samples were taken from the top, middle, and bottom of the preparation tank to test the drug content, and the mean values ​​of the three sampling points are shown in the table below. The results show that significant drug loss still occurs even when different types of wetting agents are used in the formulation. Combining the results of Examples 1 and 2, it is shown that the problem of raw material adsorption by the equipment cannot be improved by adjusting the types of suspending agents and wetting agents.

[0069]

[0070] Example 3: Investigating the effect of different hydrophilic polymers on improving the adsorption of raw materials

[0071] Based on the formulation of suspending agent sodium carboxymethyl cellulose and wetting agent polysorbate 80, different high-molecular hydrophilic materials were added to attempt to form a protective film on the particle surface to prevent direct contact and adhesion with equipment.

[0072] prescription:

[0073]

[0074] Process:

[0075] 1) Solution preparation: Anhydrous glucose, benzalkonium chloride, and different hydrophilic polymer materials (polyethylene glycol 1000, hydroxypropyl methylcellulose E5, polyvinyl alcohol, methyl glucetol polyether-20) are added to purified water to prepare a solution.

[0076] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid.

[0077] 3) Raw material pre-dispersion: Fluticasone propionate micro powder (D 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and a premixed suspension was prepared at a speed of 1500 rpm.

[0078] 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0079] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0080] Referring to Example 1, the drug content and stability (related substances, pH value, and drug particle size) of the feed solution during the preparation of different prescription products were tested. Three samples were taken from the top, middle, and bottom of the preparation tank to test the drug content, and the mean values ​​of the three sampling points are shown in the table below. The results show that among the hydrophilic polymer materials, only methyl glucetol polyether-20 can significantly improve the adsorption problem of raw materials, while the improvement effect of other materials is not obvious.

[0081]

[0082] The sample prepared by Formula 14 was tested at 50℃±2℃. Samples were taken at 15 days and 30 days to detect related substances, pH value and drug particle size. The results are shown in the table below. The results showed that related substances increased significantly, but the drug particle size stability was good. The pH value decreased slowly, indicating that methyl glucetol polyether-20 can stabilize the drug particle size, but the drug stability is not good.

[0083]

[0084] Example 4: Effect of hexanediol on improving the adsorption of raw materials

[0085] To improve the antibacterial effect of conventional preservatives, we tried adding weak antibacterial agents: disodium edetate (0.02% w / w) or hexanediol (0.02% w / w) for combined antibacterial action. Unexpectedly, although the antibacterial effect was not significantly improved, hexanediol could improve the adsorption of raw materials.

[0086] prescription:

[0087]

[0088] Process:

[0089] 1) Solution preparation: Anhydrous glucose, benzalkonium chloride, and methyl glucetol polyether-20 are added to purified water to prepare a solution.

[0090] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid.

[0091] 3) Raw material pre-dispersion: Fluticasone propionate micro powder (D 50 Add ≤2μm) to an aqueous solution of polysorbate 80, disodium edetate or hexanediol, and prepare a premixed suspension at 1500 rpm.

[0092] 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0093] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0094] Referring to Example 1, the drug content of the liquid was tested during the preparation of different prescription products. Three samples were taken from the top, middle, and bottom of the preparation tank to test the drug content. The mean values ​​of the three sampling points are shown in the table below. The drug content of the prescription using hexanediol was 100.6%, indicating that hexanediol can further improve the adsorption of raw materials.

[0095]

[0096] The sample prepared by Formula 17 was tested at 50℃±2℃. Samples were taken at 15 days and 30 days to detect related substances, pH value and drug particle size. The results are shown in the table below. The results showed that the growth of related substances was not obvious, the drug particle size was stable, and the decrease in pH value was slowed down.

[0097]

[0098] Example 5: The dosage of methyl glucetol polyether-20 and hexanediol improves the adsorption effect of raw materials.

[0099] prescription:

[0100]

[0101] Process:

[0102] 1) Solution preparation: Anhydrous glucose, benzalkonium chloride, and methyl glucetol polyether-20 are added to purified water to prepare a solution.

[0103] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid.

[0104] 3) Raw material pre-dispersion: Fluticasone propionate micro powder (D 50 (≤2μm) was added to a polysorbate 80 and hexanediol aqueous solution and a premixed suspension was prepared at a speed of 1500 rpm.

[0105] 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0106] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0107] Referring to Example 1, the drug content and stability (related substances, pH value of the solution, and drug particle size) of the feed solution during the preparation of different prescription products were tested. Three samples were taken from the top, middle, and bottom of the preparation tank to test the drug content. The mean values ​​of the three sampling points are shown in the table below. When the weight percentage of methyl gluceth-20 is 0.04% to 0.4% and the weight percentage of hexanediol is 0.02% to 0.2%, the two can exert a synergistic effect to solve the problem of raw material adsorption.

[0108]

[0109] Samples prepared from prescriptions 19, 20, 23, and 24 were tested at 50℃±2℃. Samples were taken at 15 and 30 days to detect related substances, pH value, and drug particle size. The results are shown in the table below. The results showed that the growth of related substances in prescriptions 20, 23, and 24 was not significant, the drug particle size stability was good, and the pH value decreased more slowly.

[0110]

[0111] Example 6: Effect of Formulation Process on Raw Material Adsorption

[0112] Considering that the pre-dispersion treatment of raw materials may have a significant impact on the adsorption of raw materials, this study focuses on the preparation process, taking Formulation 21 as an example.

[0113] 1) Solution preparation: Anhydrous glucose, benzalkonium chloride, methyl glucetol polyether-20 and / or hexanediol are added to purified water to prepare a solution (in process 2, methyl glucetol polyether-20 is added in step 3; in processes 3-6, hexanediol is added in step 3).

[0114] 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid.

[0115] 3) Raw material pre-dispersion

[0116] Process 1: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and a premixed suspension was prepared at a speed of 1500 rpm.

[0117] Process 2: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and methyl glucetol polyether-20 and a premixed suspension was prepared at a speed of 1500 rpm.

[0118] Process 3: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and hexanediol and a premixed suspension was prepared at a speed of 1000 rpm.

[0119] Process 4: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to a polysorbate 80 and hexanediol aqueous solution and a premixed suspension was prepared at a speed of 2000 rpm.

[0120] Process 5: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to an aqueous solution of polysorbate 80 and hexanediol and a premixed suspension was prepared at a speed of 2500 rpm.

[0121] Process 6: Fluticasone propionate micro powder (D) 50 (≤2μm) was added to a polysorbate 80 and hexanediol aqueous solution and a premixed suspension was prepared at a speed of 3000 rpm.

[0122] 4) Total mixing: Add the solution from step 1 and the suspension from step 3 to the gel to make a drug solution. The pH should be within the range of 5.0 to 7.0. If it is not within the range, adjust it with hydrochloric acid.

[0123] 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

[0124] Referring to Example 1, the drug content of the liquid was detected during the product preparation process under different processes. Three samples were taken from the top, middle, and bottom of the preparation tank to detect the drug content. The average value of the three sampling points is shown in the table below. Combining the process of Formula 21 in Example 5, adding hexanediol in the raw material pre-dispersion process and stirring at a speed in the range of 1500 rpm to 2500 rpm can effectively solve the raw material adsorption problem.

[0125]

[0126] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A fluticasone propionate nasal spray suspension, characterized in that, The nasal spray comprises fluticasone propionate micropowder, suspending agent sodium carboxymethyl cellulose microcrystalline cellulose, stabilizers methyl gluceth-20 and hexanediol, osmotic pressure regulator, wetting agent and water, wherein the weight percentage of fluticasone propionate in the nasal spray is 0.03% to 0.30%, the weight percentage of methyl gluceth-20 is 0.04% to 0.40%, and the weight percentage of hexanediol is 0.02% to 0.20%.

2. The nasal spray according to claim 1, characterized in that, The nasal spray contains 0.08% to 0.32% by weight of methyl gluceth-20 and 0.04% to 0.16% by weight of hexanediol.

3. The nasal spray according to claim 1, characterized in that, The osmotic pressure regulator is selected from one or more of glucose, glycerol, sorbitol, and sodium chloride.

4. The nasal spray according to claim 1, characterized in that, The wetting agent is selected from one or more of polysorbate 80, polysorbate 60, and polysorbate 20.

5. The nasal spray according to claim 1, characterized in that, It also includes one or more of the following: preservatives and pH adjusters.

6. The nasal spray according to claim 5, characterized in that, The preservative is selected from one or more of benzalkonium chloride, phenylethanol, and benzyl alcohol.

7. The nasal spray according to claim 6, characterized in that, The pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, phosphoric acid, citric acid, and boric acid.

8. The nasal spray according to claim 5, characterized in that, The preservative content in nasal sprays is 0.02% to 2% by weight.

9. A method for preparing a fluticasone propionate nasal spray suspension, characterized in that, Includes the following steps: 1) Solution preparation: Add osmotic pressure regulator, preservative, and methyl glucetol polyether-20 to purified water to prepare a basic solution; 2) Colloid preparation: Sodium carboxymethyl cellulose microcrystalline cellulose is added to purified water to prepare a colloid paste; 3) Pre-dispersion of raw materials: Fluticasone propionate micro powder is added to an aqueous solution containing a wetting agent and hexanediol, and stirred at a speed of 1500 rpm to 2500 rpm to prepare a premixed suspension; 4) Total mixing: Add the solution from step 1) and the suspension from step 3) to the gel to make a solution. The pH should be within the range of 5.0 to 7.

0. If it is not within the range, use a pH adjuster to adjust it. 5) Filling: Fill the nasal spray bottle with the liquid medicine to obtain the product.

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