WO2024066734A1

WO2024066734A1 - High-stability alfacalcidol liquid oral formulation and preparation method therefor

Info

Publication number: WO2024066734A1
Application number: PCT/CN2023/110923
Authority: WO
Inventors: 李永进; 陈言德
Original assignee: 湖北欣泽霏药业有限公司
Priority date: 2022-09-29
Filing date: 2023-08-03
Publication date: 2024-04-04
Also published as: CN115350151B; CN115350151A

Abstract

The present invention relates to a high-stability alfacalcidol liquid oral formulation and a preparation method therefor. Each 100 mL of the liquid oral formulation comprises the following raw materials by weight: less than or equal to 0.002 g of alfacalcidol, 8-15 g of ethanol, 1-3.5 g of polyoxyethylene hydrogenated castor oil, 0.001-0.0025 g of DL-α-tocopherol, 0.1-0.2 g of a bacteriostatic agent, 35-45 g of sorbitol, 0.01-0.05 g of citric acid or a sodium salt thereof, and the balance of purified water. The pH value of the liquid oral formulation is 6.0-7.5. The pH value of the alfacalcidol liquid oral formulation of the present invention is neutral. The purity of the medicament is still higher than 97 wt% after 18 months of stable storage. The alfacalcidol liquid oral formulation has good stability and can be stably stored for 18 months.

Description

A high-stability alfacalcidol liquid oral preparation and preparation method thereof

Technical Field

The present invention relates to the technical field of pharmaceutical preparations, and in particular to a high-stability alfacalcidol liquid oral preparation and a preparation method thereof.

Background technique

Alfacalcidol, chemical name is (5Z,7E)-9,10-open-cholester-5,7,10(19)-triene-1α,3β-diol, molecular formula is C ₂₇ H ₄₄ O ₂ , structural formula:

Alfacalcidol is used to treat calcium metabolism disorders caused by insufficient endogenous 1,25-dihydroxyvitamin D3 production, such as renal osteodystrophy, postoperative or idiopathic hypoparathyroidism, pseudohypoparathyroidism, as an adjunct to tertiary hyperparathyroidism, vitamin D-resistant rickets or osteomalacia, vitamin D-dependent rickets, neonatal hypocalcemia or rickets, calcium malabsorption, osteoporosis, malabsorptive and nutritional rickets and osteomalacia.

Oral solution refers to a clear liquid preparation for oral administration made by dissolving the raw drug in a suitable solvent. The dispersion medium of oral solution is generally water, and appropriate additives such as antibacterial agents, dispersants, suspending agents, thickeners, wetting agents, buffers, emulsifiers, stabilizers, flavoring agents and pigments can be added as needed. The types and dosages of these additives should comply with the relevant provisions of national standards.

Alfacalcidol is a white crystalline powder that is easily deteriorated when exposed to light, moisture, and heat, and is almost insoluble in water, making it difficult to prepare an aqueous oral solution. Since alfacalcidol is almost insoluble in water, it is usually prepared into soft capsules and tablets. However, capsules and tablet bases have poor compliance for infants and patients with dysphagia, and due to the small dosage, tablets are prone to uneven mixing, resulting in unqualified content uniformity, which is a high risk.

Prior art CN1846671A discloses an oral solution containing alfacalcidol, which has good stability in the pH range of 2-4, but is highly acidic and has a poor taste. Moreover, after 6 months of stable existence, the drug residual rate is less than 95%, and the stability is still not very ideal.

Summary of the invention

In order to solve the technical problems of strong acidity, poor taste and poor stability of alfacalcidol liquid oral preparations, a high-stability alfacalcidol liquid oral preparation and a preparation method thereof are provided. The pH value of the alfacalcidol liquid oral preparation of the present invention is neutral, and the drug purity is still higher than 97wt% after stable storage for 18 months.

In order to achieve the above objectives, the present invention is implemented by the following technical solutions:

A highly stable alfacalcidol liquid oral preparation, wherein each 100 mL of the liquid oral preparation comprises the following raw materials by weight: alfacalcidol ≤0.002 g, ethanol 8-15 g, polyoxyethylene hydrogenated castor oil 1-3.5 g, DL-α-tocopherol 0.001-0.0025 g, antibacterial agent 0.1-0.2 g, sorbitol 35-45 g, citric acid or its sodium salt 0.01-0.05 g, and the balance is purified water; the pH value of the liquid oral preparation is 6.0-7.5.

Furthermore, each 100 mL of the liquid oral preparation includes the following raw materials by weight: 0.002 g of alfacalcidol, 9-14 g of ethanol, 1-3.5 g of polyoxyethylene hydrogenated castor oil, 0.001-0.0025 g of DL-α-tocopherol, 0.15 g of antibacterial agent, 45 g of sorbitol, 0.022-0.05 g of sodium citrate, and the remainder is purified water; the pH value of the liquid oral preparation is 6.5-7.5.

Furthermore, each 100 mL of the liquid oral preparation includes the following raw materials by weight: 0.002 g of alfacalcidol, 11-14 g of ethanol, 1-2.5 g of polyoxyethylene hydrogenated castor oil, 0.001-0.0022 g of DL-α-tocopherol, 0.15 g of antibacterial agent, 45 g of sorbitol, 0.022-0.035 of sodium citrate, and the remainder is purified water; the pH value of the liquid oral preparation is 6.5-7.0.

Furthermore, the antibacterial agent is a paraben ester compound.

Preferably, the paraben compound is one or more of methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, benzyl alcohol, and potassium sorbate.

Furthermore, the viscosity of the liquid oral preparation is 6.5-8.0 mPa·s and the relative density is 1.10-1.15.

The present invention provides a method for preparing the above-mentioned high-stability alfacalcidol liquid oral preparation, comprising the following steps:

Take part of the purified water, add sorbitol and citric acid or its salt, stir and dissolve to obtain solution A;

Add polyoxyethylene hydrogenated castor oil, DL-α-tocopherol and antibacterial agent to ethanol, stir to dissolve, then add alfacalcidol, continue to stir to dissolve, to obtain solution B;

The B solution is added to the A solution, and the remaining amount of purified water is added, mixed evenly, the pH value of the solution is monitored, and if necessary, citric acid or its sodium salt is added to achieve a pH value within the range of 6.0-7.5, thereby obtaining a highly stable alfacalcidol liquid oral preparation.

Beneficial technical effects:

The present invention uses DL-α-tocopherol as an antioxidant, uses ethanol as a solvent to dissolve alfacalcidol, and uses poly The invention discloses a method for preparing an oral alfacalcidol liquid preparation by using oxyethylene hydrogenated castor oil to solubilize alfacalcidol in ethanol, and combining sorbitol as a thickener and flavoring agent to achieve a certain viscosity, using paraben compounds as antibacterial agents, and using citric acid or its salts to adjust the pH of the liquid to a neutral condition. The coordination of various substances can make the alfacalcidol liquid oral preparation have a better taste, and the drug purity is still higher than 97wt% after stable storage for 18 months, and the preparation has good stability and can be stably stored for 18 months or even longer.

Detailed ways

The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Unless otherwise specifically stated, the numerical value set forth in these embodiments does not limit the scope of the present invention. The technology and method known to those of ordinary skill in the relevant art may not be discussed in detail, but in appropriate cases, the technology and method should be considered as a part of the specification. In all examples shown and discussed here, any specific value should be interpreted as being merely exemplary, rather than as a limitation. Therefore, other examples of exemplary embodiments may have different values.

The experimental methods in the following examples without specifying specific conditions are usually measured according to national standards; if there is no corresponding national standard, it is carried out according to the general international standards or the standard requirements proposed by relevant enterprises. Unless otherwise specified, all parts are by weight and all percentages are by weight.

The concentration of ethanol used below is above 95 wt %.

Example 1

A highly stable alfacalcidol liquid oral preparation, wherein each 100 mL of the liquid oral preparation comprises the following raw materials by weight: 0.2 mg of alfacalcidol, 11.3 g of ethanol, 2.3 g of polyoxyethylene hydrogenated castor oil, 1.2 mg of DL-α-tocopherol, 0.15 g of methylparaben, 45 g of sorbitol, 24 mg of sodium citrate, and purified water added to 100 mL; the pH value of the liquid oral preparation of this embodiment is 6.5.

The preparation method of the above liquid oral preparation is:

Add polyoxyethylene hydrogenated castor oil, DL-α-tocopherol, and methylparaben antibacterial agent to ethanol, stir to dissolve, then add alfacalcidol, continue stirring to dissolve, and obtain solution B;

Add the B solution to the A solution, add the remaining amount of purified water, mix well, and monitor The pH value of the solution is adjusted to 6.5 by adding sodium citrate if necessary, thereby obtaining a highly stable alfacalcidol liquid oral preparation.

Embodiment 2-8

The prescriptions of the alfacalcidol liquid oral preparations of Examples 2-8 are shown in Table 1.

Comparative Example 1

The formulation and preparation method of the alfacalcidol liquid oral preparation of this comparative example are the same as those of Example 1, except that D-α-tocopherol is not added.

Comparative Example 2

The formulation and preparation method of the alfacalcidol liquid oral preparation of this comparative example are the same as those of Example 1, except that D-α-tocopherol is replaced by D-α-tocopherol acetate.

Comparative Example 3

The prescription and preparation method of the alfacalcidol liquid oral preparation of this comparative example are the same as those of Example 8, except that 50 mg of sodium citrate in Example 8 is replaced by 30 mg of citric acid, and the pH value of the preparation is 4.5.

Table 1 Examples 1-8 and Comparative Examples 1-3

(Note: "/" indicates no addition; Alfa indicates alfacalcidol; EtOH indicates ethanol; Sor indicates sorbitol; RH40 indicates polyoxyethylene hydrogenated castor oil; MP indicates methylparaben; D-α-Ta indicates D-α-tocopherol acetate; D-α indicates D-α-tocopherol; SC indicates citric acid or its sodium salt, comparative examples 1-2 and embodiments 1-8 all use sodium citrate, and comparative example 3 uses citric acid.)

The physical properties of the above embodiments and comparative examples are shown in Table 2.

Table 2 Physical properties of examples and comparative examples

Test Example 1

The liquid oral preparations of Comparative Examples 1-2 and Examples 1-3 were placed at a constant temperature of 30° C. for 0 months (initial), 3 months, 6 months, 9 months, 12 months, and 18 months, and samples were taken to detect the residual rate of alfacalcidol in the samples. The results are shown in Table 3.

The mass volume concentration of the drug in the alfacalcidol liquid oral preparation of the above embodiment and comparative example is 0.2% (w/v). The alfacalcidol liquid oral preparation is subjected to a stability test at a constant temperature, and the true content of the drug in the alfacalcidol liquid oral preparation after being placed for a period of time is detected. The ratio of the true content to the specification content is defined as the surplus rate. For example, if the specification of the drug is 0.2% (i.e., the proportion of the main drug), if the main drug accounts for 0.21% during the actual measurement, the content of the main drug exceeds 100%. The content of general drugs will fluctuate around 100%, which is allowed. The specific allowable range is based on the 2020 edition of the "Chinese Pharmacopoeia" General Chapter 0512 High Performance Liquid Chromatography: When the impurity content is measured, the test solution is diluted to a solution equivalent to the impurity limit according to the impurity limit specified under each variety, as a control solution, sampled, and the chromatogram is recorded. If necessary, the ordinate range is adjusted (limited by acceptable noise level) so that the peak height of the main component chromatographic peak of the control solution is about 10% to 25% of the full scale. Unless otherwise specified, for impurities with a content lower than 0.5%, the relative standard deviation (RSD) of the peak area measurement value should be less than 10%; for impurities with a content between 0.5% and 2%, the RSD of the peak area measurement value should be less than 5%; for impurities with a content greater than 2%, the RSD of the peak area measurement value should be less than 2%.

The chemical structures of impurities A and B are as follows:

Table 3 Residual rate of alfacalcidol in the liquid oral preparations of Comparative Examples 1-2 and Examples 1-3

(Note: “--” indicates the absence of impurities; “/” indicates that no test was conducted; Alfa indicates alfacalcidol.)

As shown in Table 3, no antioxidant was added to Comparative Example 1, and the related impurities increased significantly during the test period, and the content of alfacalcidol decreased by about 40% after 18 months. Comparative Example 2 used D-α-tocopherol acetate as an antioxidant, and the related impurities also increased significantly during the test period, and the content of alfacalcidol decreased by about 35% after 18 months. Examples 1-3 used DL-α-tocopherol as an antioxidant, and the content of alfacalcidol and related impurities during the test period were basically unchanged compared with the initial period.

The liquid oral preparations of Comparative Example 3 and Examples 4-8 were placed at a constant temperature of 30° C. for 0 months (initial), 3 months, 6 months, 9 months, 12 months, and 18 months, and samples were taken to detect the residual amount of alfacalcidol in the samples. The results are shown in Table 4.

Table 4 Residual rate of alfacalcidol in the liquid oral preparations of Comparative Example 3 and Examples 4-8

(Note: “--” indicates the absence of impurities; “/” indicates that no test was conducted; Alfa indicates alfacalcidol.)

As shown in Table 4, the long-term stability of alfacalcidol is not good under the condition of slightly acidic pH value in comparative example 3. The oral alfacalcidol liquid preparation of the present invention has a longer stability under neutral conditions, and the drug purity is still higher than 97wt% after stable storage for 18 months.

The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

A high-stability alfacalcidol liquid oral preparation, characterized in that each 100 mL of the liquid oral preparation comprises the following raw materials by weight: alfacalcidol ≤ 0.002 g, ethanol 8-15 g, polyoxyethylene hydrogenated castor oil 1-3.5 g, DL-α-tocopherol 0.001-0.0025 g, antibacterial agent 0.1-0.2 g, sorbitol 35-45 g, citric acid or its sodium salt 0.01-0.05 g, and the balance is purified water; the pH value of the liquid oral preparation is 6.0-7.5.
A highly stable alfacalcidol liquid oral preparation according to claim 1, characterized in that each 100 mL of the liquid oral preparation comprises the following raw materials by weight: alfacalcidol 0.002 g, ethanol 9-14 g, polyoxyethylene hydrogenated castor oil 1-3.5 g, DL-α-tocopherol 0.001-0.0025 g, antibacterial agent 0.15 g, sorbitol 45 g, sodium citrate 0.022-0.05 g, and the balance is purified water; the pH value of the liquid oral preparation is 6.5-7.5.
A highly stable alfacalcidol liquid oral preparation according to claim 2, characterized in that each 100 mL of the liquid oral preparation comprises the following raw materials by weight: alfacalcidol 0.002 g, ethanol 11-14 g, polyoxyethylene hydrogenated castor oil 1-2.5 g, DL-α-tocopherol 0.001-0.0022 g, antibacterial agent 0.15 g, sorbitol 45 g, sodium citrate 0.022-0.035, and the remainder is purified water; the pH value of the liquid oral preparation is 6.5-7.0.
A highly stable alfacalcidol liquid oral preparation according to any one of claims 1 to 3, characterized in that the antibacterial agent is a paraben ester compound.
A highly stable alfacalcidol liquid oral preparation according to claim 4, characterized in that the paraben compound is one or more of methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, benzyl alcohol, and potassium sorbate.
A highly stable alfacalcidol liquid oral preparation according to claim 4, characterized in that the viscosity of the liquid oral preparation is 6.5-8.0 mPa·s and the relative density is 1.10-1.15.
A method for preparing a highly stable alfacalcidol oral liquid preparation according to any one of claims 1 to 6, characterized in that it comprises the following steps: taking part of purified water, adding sorbitol and citric acid or its salt, stirring and dissolving to obtain solution A;

Add polyoxyethylene hydrogenated castor oil, DL-α-tocopherol and antibacterial agent to ethanol, stir to dissolve, then add alfacalcidol, continue to stir to dissolve, to obtain solution B;

The B solution is added to the A solution, and the remaining amount of purified water is added, mixed evenly, the pH value of the solution is monitored, and if necessary, citric acid or its sodium salt is added to achieve a pH value within the range of 6.0-7.5, thereby obtaining a highly stable alfacalcidol liquid oral preparation.