Sapropterin hydrochloride powder and preparation method thereof

Abstract

The invention relates to the technical field of medicines. The invention provides sapropterin hydrochloride powder and a preparation method thereof. The sapropterin hydrochloride powder comprises the following components in percentage by mass: 15%-30% of sapropterin hydrochloride, 50%-60% of a filler, 8%-18% of a cosolvent, 3%-6% of a lubricant, 1%-3% of a flavoring agent and 0.1%-1% of an antioxidant. The sapropterin hydrochloride powder prepared by adopting the technical scheme has the characteristics of good solubility, high stability, high bioavailability and convenience in taking.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a sapropterin hydrochloride powder and a preparation method thereof. Background Art

[0002] Phenylketonuria, a common amino acid metabolic disorder, can cause severe damage to the patient's nervous system. Sapropterin hydrochloride, an effective treatment for this disease, has numerous problems with its current formulations. In addition to unstable efficacy, poor solubility, and low bioavailability, existing tablets and capsules are difficult to administer for children and other patients with swallowing difficulties.

[0003] Powders, as oral preparations, offer advantages such as ease of administration and rapid onset of action. However, limited research exists on sapropterin hydrochloride powders. Existing powder preparation methods are relatively conventional, often employing simple mixing and conventional drying processes. This results in poor dispersion uniformity between the drug and excipients, leading to batch-to-batch RSD values ​​exceeding 15%. Furthermore, excipient selection is limited to conventional carriers such as lactose and starch, which fail to effectively improve drug dissolution characteristics. This makes it difficult to further improve the drug's solubility and stability, and it is also difficult to ensure the sterility of the formulation. Therefore, developing a sapropterin hydrochloride powder with excellent solubility, high stability, high bioavailability, and ease of administration, and a creative preparation method thereof, is of great significance. Summary of the Invention

[0004] The object of the present invention is to provide a sapropterin hydrochloride powder, which has the characteristics of good solubility, high stability, high bioavailability and easy administration.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The present invention provides a sapropterin hydrochloride powder, which comprises the following components in percentage by weight: 15%-30% of sapropterin hydrochloride, 50%-60% of a filler, 8%-18% of a cosolvent, 3%-6% of a lubricant, 1%-3% of a flavoring agent, and 0.1%-1% of an antioxidant.

[0006] Preferably, the filler is any one or more of pregelatinized starch, dextrin, and calcium hydrogen phosphate.

[0007] Preferably, the cosolvent is any one or more of cyclodextrin derivatives, polyethylene glycol 4000, Tween-80, and propylene glycol; and the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.

[0008] Preferably, the lubricant is any one or more of micro-powdered silica gel, talc, and magnesium stearate.

[0009] Preferably, the flavoring agent is any one or more of aspartame, steviol glycoside, and lemon essence.

[0010] Preferably, the antioxidant is any one or more of butylated hydroxyanisole, butylated hydroxytoluene, and sodium sulfite.

[0011] The present invention also provides a method for preparing the sapropterin hydrochloride powder, comprising the following steps: (1) mixing the crushed sapropterin hydrochloride with a cosolvent, homogenizing the mixture, and then spray drying the mixture to obtain inclusion compound powder; (2) mixing the inclusion compound powder with the filler to obtain a first mixed powder; (3) Mix the first mixed powder with the flavoring agent, lubricant, and antioxidant, then sterilize and package.

[0012] Preferably, purified water needs to be added before the homogenization treatment in step (1), and the amount of purified water added is 3-5 times the total mass of the crushed sapropterin hydrochloride and the co-solvent.

[0013] Preferably, the temperature of the homogenization treatment in step (1) is 40-50° C., the pressure of the homogenization treatment is 30-50 MPa, and the time of the homogenization treatment is 15-25 min.

[0014] Preferably, the mixing speed in step (2) is 800-1200 r / min, and the mixing time is 15-20 min.

[0015] Preferably, the mixing speed in step (3) is 600-1000 r / min, and the mixing time is 8-12 min.

[0016] By adopting the above technical solution, the present invention has the following beneficial effects: 1. The powder prepared by using the dosage ratio of sapropterin hydrochloride, filler, solubilizer, flavoring agent, lubricant and antioxidant in the present invention has the characteristics of good solubility, high stability, high bioavailability and easy administration.

[0017] 2. The technical solution of the present invention promotes the full contact between the ultrafinely pulverized sapropterin hydrochloride and the co-solvent through high-pressure homogenization treatment to form a stable inclusion complex, which can significantly improve the solubility of sapropterin hydrochloride, solve the problem of its inherent poor solubility, and thus improve the solubility and bioavailability of the drug. DETAILED DESCRIPTION

[0018] The present invention provides a sapropterin hydrochloride powder, which preferably comprises the following components in percentage by weight: 15%-30% of sapropterin hydrochloride, 50%-60% of a filler, 8%-18% of a cosolvent, 3%-6% of a lubricant, 1%-3% of a flavoring agent, and 0.1%-1% of an antioxidant; further preferably comprises 18%-28% of sapropterin hydrochloride, 52%-58% of a filler, 9%-16% of a cosolvent, 4%-5.5% of a lubricant, 1.5%-2.8% of a flavoring agent, and 0.2%-0.8% of an antioxidant; and even more preferably comprises 22% of sapropterin hydrochloride, 56% of a filler, 14% of a cosolvent, 5.2% of a lubricant, 2.4% of a flavoring agent, and 0.4% of an antioxidant.

[0019] In the present invention, the filler is any one or more of pregelatinized starch, dextrin, and calcium hydrogen phosphate. When the filler in the present invention is preferably pregelatinized starch and dextrin, the mass ratio of the pregelatinized starch to dextrin is preferably (2-5):1, further preferably (2.5-4.5):1, and further preferably 3:1. The present invention uses pregelatinized starch and dextrin as fillers to increase the fluidity and compressibility of the powder, making it easily soluble in water; it can also increase the viscosity of the powder and improve stability.

[0020] In the present invention, the cosolvent is any one or more of a cyclodextrin derivative, polyethylene glycol 4000, Tween-80, and propylene glycol; the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin. The cosolvent is preferably a cyclodextrin derivative. The cosolvent can form an inclusion complex with sapropterin hydrochloride or increase its solubility in water, thereby improving the drug's dissolution rate and bioavailability.

[0021] In the present invention, the lubricant is any one or more of micro powder silica gel, talc, and magnesium stearate. The lubricant of the present invention is preferably micro powder silica gel.

[0022] In the present invention, the flavoring agent is any one or more of aspartame, steviol glycoside, and lemon essence. When the flavoring agent is preferably steviol glycoside and lemon essence, the mass ratio of steviol glycoside to lemon essence is preferably (3-8):1, more preferably (4-7):1, and even more preferably 6:1. The flavoring agent of the present invention has a high sugar content and can effectively mask the bitter taste of the drug and improve the mouthfeel.

[0023] In the present invention, the antioxidant is any one or more of butylated 4-hydroxyanisole, butylated hydroxytoluene, and sodium sulfite. In the present invention, the antioxidant is preferably butylated 4-hydroxyanisole, which can effectively inhibit the oxidation reaction of sapropterin hydrochloride and extend the shelf life of the preparation.

[0024] The present invention also provides a method for preparing the above-mentioned sapropterin hydrochloride powder, comprising the following steps: (1) mixing the crushed sapropterin hydrochloride with a cosolvent, homogenizing the mixture, and then spray drying the mixture to obtain inclusion compound powder; (2) mixing the inclusion compound powder with the filler to obtain a first mixed powder; (3) Mix the first mixed powder with the flavoring agent, lubricant, and antioxidant, then sterilize and package.

[0025] In the present invention, sapropterin hydrochloride is pulverized, preferably by ultrafine grinding, to a particle size of 1-5 μm. The ultrafine grinding operation of the present invention can finely grind the raw material into high-quality ultrafine particles with uniform particle size and good dispersibility, significantly improving the physical and chemical properties of the material, enhancing its performance and use value, and increasing the utilization rate of the material. It can also greatly increase the specific surface area of ​​sapropterin hydrochloride and its contact area with the cosolvent, which is beneficial for subsequent inclusion reactions and also increases the dissolution rate of the drug.

[0026] In the present invention, the filler, cosolvent, lubricant, flavoring agent and antioxidant are sieved separately to remove impurities and ensure the purity of the raw materials. The mesh size of the sieve used in the sieving is preferably 80-100 mesh, more preferably 85-95 mesh, and even more preferably 90 mesh.

[0027] In the present invention, the crushed sapropterin hydrochloride is mixed with a cosolvent, purified water is added, and homogenization is performed, followed by spray drying to obtain inclusion complex powder. The amount of purified water added in the present invention is preferably 3-5 times the total mass of the crushed sapropterin hydrochloride and the cosolvent, and more preferably 4 times. The temperature of the homogenization treatment in the present invention is preferably 40-50°C, more preferably 42-48°C, and more preferably 45°C; the pressure of the homogenization treatment is preferably 30-50MPa, more preferably 35-45MPa, and more preferably 40MPa; the time of the homogenization treatment is preferably 15-25min, more preferably 18-22min, and more preferably 20min. The inlet air temperature in the spray drying process of the present invention is preferably 160-180°C, more preferably 165-175°C, and more preferably 170°C; the outlet air temperature is preferably 70-80°C, more preferably 72-78°C, and more preferably 75°C. The spray drying process of the present invention can quickly remove moisture and prevent the drug from being decomposed due to prolonged heating. At the same time, the obtained dry powder has uniform particle size and good fluidity.

[0028] In the present invention, the inclusion compound powder is mixed with a filler to obtain a first mixed powder. The mixing speed of the present invention is preferably 800-1200 r / min, more preferably 900-1100 r / min, and even more preferably 1000 r / min; and the mixing time is preferably 15-20 minutes, more preferably 16-19 minutes, and even more preferably 18 minutes.

[0029] In the present invention, the first mixed powder is mixed with a flavoring agent, a lubricant, and an antioxidant, and then sterilized and packaged to obtain the sapropterin hydrochloride powder. The mixing speed of the present invention is preferably 600-1000r / min, further preferably 700-900r / min, and further preferably 800r / min; the mixing time is preferably 8-12min, further preferably 9-11min, and further preferably 10min. The sterilization of the present invention is preferably low-temperature sterilization, and the sterilization time is preferably 15-30min, further preferably 18-26min, and further preferably 25min. In the packaging process of the present invention, the error of the packaging amount is controlled to be within ±2%.

[0030] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0031] Example 1

[0032] A sapropterin hydrochloride powder, comprising: 22% sapropterin hydrochloride, 56% filler, 14% hydroxypropyl-β-cyclodextrin, 5.2% micropowdered silica gel, 2.4% flavoring agent, and 0.4% butylated hydroxyanisole. The filler comprises pregelatinized starch and dextrin in a mass ratio of 3:1, and the flavoring agent comprises steviol glycoside and lemon essence in a mass ratio of 6:1. The preparation method of the sapropterin hydrochloride powder: (1) Ultrafine grinding of sapropterin hydrochloride to a particle size of 2-4 μm, and passing the filler, hydroxypropyl-β-cyclodextrin, micropowdered silica gel, flavoring agent and butylated hydroxyanisole through a 90-mesh sieve to remove impurities and ensure the purity of the raw materials; (2) The crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin were mixed, and purified water 4 times the total mass of the crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin was added, and homogenized at 45°C and 40 MPa for 20 minutes, and then spray-dried at an inlet air temperature of 170°C and an outlet air temperature of 75°C to obtain inclusion compound powder; (3) Mixing the inclusion compound powder and the filler at 1000 r / min for 18 min to obtain a first mixed powder; (4) Mix the first mixed powder with the flavoring agent, micro-powdered silica gel, and butylated hydroxyanisole, mix at 800 r / min for 10 minutes, and then sterilize for 25 minutes before packaging. Control the packaging amount error within ±2%.

[0033] Example 2

[0034] A sapropterin hydrochloride powder, comprising: 26% sapropterin hydrochloride, 52% filler, 15% hydroxypropyl-β-cyclodextrin, 4.2% micropowdered silica gel, 2% flavoring agent, and 0.8% butylated hydroxyanisole; the filler is pregelatinized starch and dextrin in a mass ratio of 2:1, and the flavoring agent is steviol glycoside and lemon essence in a mass ratio of 8:1. The preparation method of the sapropterin hydrochloride powder: (1) Sapropterin hydrochloride is ultrafinely ground to a particle size of 4 μm, and the filler, hydroxypropyl-β-cyclodextrin, micropowdered silica gel, flavoring agent, and butylated hydroxyanisole are sieved through a 90-mesh sieve to remove impurities and ensure the purity of the raw materials; (2) The crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin were mixed, and purified water 4 times the total mass of the crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin was added, and homogenized at 45°C and 40 MPa for 20 minutes, and then spray-dried at an inlet air temperature of 170°C and an outlet air temperature of 75°C to obtain inclusion compound powder; (3) Mixing the inclusion compound powder and the filler at 1000 r / min for 18 min to obtain a first mixed powder; (4) Mix the first mixed powder with the flavoring agent, micro-powdered silica gel, and butylated hydroxyanisole, mix at 800 r / min for 10 minutes, and then sterilize for 25 minutes before packaging. Control the packaging amount error within ±2%.

[0035] Example 3

[0036] A sapropterin hydrochloride powder, comprising: 22% sapropterin hydrochloride, 56% pregelatinized starch, 14% hydroxypropyl-β-cyclodextrin, 5.2% magnesium stearate, 2.4% steviol glycosides, and 0.4% butylated 4-hydroxyanisole; The preparation method of the sapropterin hydrochloride powder: (1) Sapropterin hydrochloride is ultrafinely ground to a particle size of 4 μm, and the pregelatinized starch, hydroxypropyl-β-cyclodextrin, magnesium stearate, steviol glycoside and butylated hydroxyanisole are respectively passed through a 90-mesh sieve to remove impurities and ensure the purity of the raw materials; (2) The crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin were mixed, and purified water 4 times the total mass of the crushed sapropterin hydrochloride and hydroxypropyl-β-cyclodextrin was added, and homogenized at 45°C and 40 MPa for 20 minutes, and then spray-dried at an inlet air temperature of 170°C and an outlet air temperature of 75°C to obtain inclusion compound powder; (3) mixing the inclusion compound powder with pregelatinized starch at 1000 r / min for 18 min to obtain a first mixed powder; (4) Mix the first mixed powder with stevioside, magnesium stearate, and butylated hydroxyanisole, mix at 800 r / min for 10 minutes, and then sterilize for 25 minutes before packaging. Control the packaging amount error within ±2%.

[0037] Example 4

[0038] A sapropterin hydrochloride powder, comprising: 22% sapropterin hydrochloride, 56% filler, 14% hydroxypropyl-β-cyclodextrin, 5.2% micropowdered silica gel, 2.4% flavoring agent, and 0.4% butylated hydroxyanisole. The filler comprises pregelatinized starch and dextrin in a mass ratio of 5:1, and the flavoring agent comprises steviol glycoside and lemon essence in a mass ratio of 7:1. The preparation method of the sapropterin hydrochloride powder: (1) Sapropterin hydrochloride is ultrafinely ground to a particle size of 2 μm, and the filler, hydroxypropyl-β-cyclodextrin, micropowdered silica gel, flavoring agent, and butylated hydroxyanisole are sieved through a 90-mesh sieve to remove impurities and ensure the purity of the raw materials; (2) The crushed sapropterin hydrochloride was mixed with hydroxypropyl-β-cyclodextrin, and purified water 4 times the total mass of the crushed sapropterin hydrochloride and the co-solvent was added, and homogenized at 40°C and 50 MPa for 15 minutes, and then spray-dried at an inlet air temperature of 170°C and an outlet air temperature of 70°C to obtain inclusion compound powder; (2) mixing the inclusion compound powder and the filler, and mixing at 800 r / min for 20 min to obtain a first mixed powder; (3) Mix the first mixed powder with the flavoring agent, micro-powdered silica gel, and butylated hydroxyanisole, mix at 600 r / min for 12 minutes, and then sterilize for 25 minutes before packaging. Control the packaging amount error within ±2%.

[0039] Example 5

[0040] A sapropterin hydrochloride powder, comprising: 26% sapropterin hydrochloride, 52% calcium hydrogen phosphate, 15% polyethylene glycol 4000, 4.2% micropowdered silica gel, 2% steviol glycoside, and 0.8% butylated hydroxytoluene; The preparation method of the sapropterin hydrochloride powder: (1) Ultrafine grinding of sapropterin hydrochloride to a particle size of 5 μm, and passing the calcium hydrogen phosphate, polyethylene glycol 4000, micropowder silica gel, steviol glycoside and butylated hydroxytoluene through a 90-mesh sieve to remove impurities and ensure the purity of the raw materials; (2) The crushed sapropterin hydrochloride was mixed with polyethylene glycol 4000, and purified water was added in an amount 3 times the total mass of the crushed sapropterin hydrochloride and polyethylene glycol 4000. The mixture was homogenized at 50°C and 30 MPa for 20 min, and then spray-dried at an inlet air temperature of 160°C and an outlet air temperature of 80°C to obtain inclusion compound powder. (2) mixing the inclusion compound powder with calcium hydrogen phosphate, and mixing at 1200 r / min for 15 minutes to obtain a first mixed powder; (3) Mix the first mixed powder with stevioside, micro-powdered silica gel and butylated hydroxytoluene, mix at 1000 r / min for 8 minutes, sterilize for 15 minutes and then package, controlling the packaging amount error within ±2%.

[0041] Test Example 1

[0042] (1) Solubility

[0043] 0.5 g of each of the powders prepared in Examples 1-5 was added to 100 ml of distilled water, placed in a constant temperature water bath at 37°C ± 0.5°C, and magnetically stirred at 300 r / min until completely dissolved. The dissolution time was recorded.

[0044] Control group 1: Same as Example 1, except that the preparation method is replaced by “mixing sapropterin hydrochloride with the filler, hydroxypropyl-β-cyclodextrin, micropowdered silica gel, flavoring agent and butylated hydroxyanisole uniformly and then tableting.”

[0045] Control group 2: The same as Example 1, except that the filler was replaced by microcrystalline cellulose, the cosolvent was replaced by guar gum, and the antioxidant was removed.

[0046] Table 1 Dissolution time of powders prepared in different groups

[0047] As shown in Table 1, the dissolution time of the powders prepared by the present invention in water is less than 2.5 minutes, and the solubility is significantly better than that of the control group. This is mainly attributed to the ultrafine grinding and high-pressure homogenization inclusion treatment, as well as the optimization of the raw material types, which greatly improve the dissolution rate of the drug.

[0048] (2) Stability

[0049] The powders prepared in Examples 1-5 and the control group were placed at 40°C and 75% relative humidity for 6 months. Samples were taken at the 0th, 3rd, and 6th months to determine the content of related substances (total impurities, %) in the powders. The color, uniformity, and other appearance properties of the powders were observed. The content was determined by high performance liquid chromatography. For specific operations, refer to "HPLC determination of related substances in sapropterin hydrochloride tablets" (Yuan Rong, Feng Zhong, Liu Kai, et al. HPLC determination of related substances in sapropterin hydrochloride tablets [J]. Chinese Journal of Pharmaceutical Industry, 2020, 51(7): 4. DOI: 10.16522 / j.cnki.cjph.2020.07.020.). The chromatographic conditions were as follows: C18 column (250 mm × 4.6 mm, 5 μm); mobile phase: methanol-water (20:80, v / v); detection wavelength: 254 nm; flow rate: 1.0 ml / min; column temperature: 30°C; injection volume: 20 μl.

[0050] Table 2 Stability of powders prepared in different groups

[0051] As shown in Table 2, under the influencing factor test conditions, the powder prepared by the present invention is placed under accelerated conditions for 6 months, and the related substances change little, and the properties remain stable without discoloration, agglomeration, etc., and the stability is good.

[0052] In summary, it can be seen that the sapropterin hydrochloride powder prepared by the technical solution of the present invention significantly improves the solubility, stability and taste of the drug by adding ingredients such as cosolvents, flavoring agents and antioxidants. It has the characteristics of good efficacy, high stability, high bioavailability and easy administration. The preparation method is simple and easy, suitable for industrial production, and has good application prospects in the treatment of phenylketonuria.

[0053] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A sapropterin hydrochloride powder, characterized in that: The invention comprises the following components in percentage by weight: 15%-30% of sapropterin hydrochloride, 50%-60% of a filler, 8%-18% of a cosolvent, 3%-6% of a lubricant, 1%-3% of a flavoring agent and 0.1%-1% of an antioxidant.

2. The powder according to claim 1, characterized in that The filler is any one or more of pregelatinized starch, dextrin, and calcium hydrogen phosphate.

3. The powder according to claim 1, characterized in that The cosolvent is any one or more of cyclodextrin derivatives, polyethylene glycol 4000, Tween-80, and propylene glycol; The cyclodextrin derivative is hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin.

4. The powder according to claim 1, characterized in that The lubricant is any one or more of micro-powdered silica gel, talc, and magnesium stearate; The flavoring agent is any one or more of aspartame, steviol glycoside, and lemon essence.

5. The powder according to claim 1, characterized in that The antioxidant is any one or more of butylated hydroxyanisole, butylated hydroxytoluene, and sodium sulfite.

6. The method for preparing the sapropterin hydrochloride powder according to any one of claims 1 to 5, characterized in that: The steps include: (1) mixing the crushed sapropterin hydrochloride with a cosolvent, homogenizing the mixture, and then spray drying the mixture to obtain inclusion compound powder; (2) mixing the inclusion compound powder with the filler to obtain a first mixed powder; (3) Mix the first mixed powder with the flavoring agent, lubricant, and antioxidant, then sterilize and package, controlling the packaging amount error within ±2%.

7. The preparation method according to claim 6, characterized in that Purified water needs to be added before the homogenization treatment in step (1), and the amount of purified water added is 3-5 times the total mass of the crushed sapropterin hydrochloride and the co-solvent.

8. The preparation method according to claim 6, characterized in that The temperature of the homogenization treatment in step (1) is 40-50° C., the pressure of the homogenization treatment is 30-50 MPa, and the time of the homogenization treatment is 15-25 min.

9. The preparation method according to claim 6, characterized in that The mixing speed in step (2) is 800-1200 r / min, and the mixing time is 15-20 min.

10. The preparation method according to claim 6, characterized in that The mixing speed in step (3) is 600-1000 r / min, and the mixing time is 8-12 min.

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