CN115350149B - Stable alfacalcidol water-based solution preparation and preparation method thereof - Google Patents

Stable alfacalcidol water-based solution preparation and preparation method thereof Download PDF

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CN115350149B
CN115350149B CN202211048020.7A CN202211048020A CN115350149B CN 115350149 B CN115350149 B CN 115350149B CN 202211048020 A CN202211048020 A CN 202211048020A CN 115350149 B CN115350149 B CN 115350149B
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alfacalcidol
water
cyclodextrin
mixture
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CN115350149A (en
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施建飞
钱建
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Nantong Huashan Pharmacy Co ltd
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Abstract

The invention relates to a stable alfacalcidol water-based solution preparation and a preparation method thereof. The alfacalcidol water-based solution preparation consists of alfacalcidol, gamma-cyclodextrin, caffeine, L-sodium ascorbate, sodium benzoate, aspartame and water. According to the invention, water-soluble natural cyclodextrin gamma-cyclodextrin is used for carrying out primary inclusion on the water-insoluble alfacalcidol, and the fact that caffeine is added can greatly improve the inclusion efficiency of the gamma-cyclodextrin on the alfacalcidol and the stability of inclusion compounds is discovered by accident. The auxiliary materials and the process provided by the invention can be used for preparing a stable alfacalcidol water-based solution preparation.

Description

Stable alfacalcidol water-based solution preparation and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a stable alfacalcidol water-based solution preparation and a preparation method thereof.
Background
Alfacalcidol is an active metabolite of vitamin D and plays an important role in regulating calcium balance and bone metabolism. Alfacalcidol is activated by 25-hydroxylase in the liver and exerts vitamin D effects in the whole body and in osteoblasts. It exerts unique pleiotropic effects in the intestines, bones, parathyroid glands, muscles and brain. Alfacalcidol can increase the reabsorption of calcium by small intestine and renal tubule, inhibit parathyroid hyperplasia, reduce parathyroid hormone synthesis and release, and inhibit bone resorption; can also increase the synthesis of transforming growth factors and insulin-like growth factors, promote the synthesis of collagen and bone matrix proteins; in addition, the medicine can regulate muscle calcium metabolism, promote muscle cell differentiation, strengthen muscle strength, increase neuromuscular coordination and reduce falling tendency. Based on these pharmacological mechanisms, alfacalcidol is currently mainly used for improving symptoms caused by abnormal vitamin D metabolism (such as hypocalcemia, convulsion, bone pain and bone damage), and can also be used for osteoporosis.
Alfacalcidol is a potent pharmaceutical substance, but poorly water-soluble. The alfacalcidol soft capsules on the market use vegetable oil to dissolve alfacalcidol, so that the contents of the soft capsules are formed. The alfacalcidol drops on the market were solubilized using ethanol and 15-hydroxystearic acid polyethylene glycol ester. The alfacalcidol injection on the market is also added with ethanol and polyethylene glycol to solubilize the alfacalcidol. In general, the use of a certain amount of adjuvants such as vegetable oil, ethanol and polyethylene glycol is not problematic for the dissolution or solubilization of alfacalcidol for use as a preparation, but in some cases, these preparations are unsuitable for a specific subject to be used. For example, when using alfacalcidol soft capsules for treating osteoporosis, the subjects are mainly elderly patients, but many elderly patients suffer from hyperlipidemia or atherosclerosis at the same time, and vegetable oil is not suitable for overtaking. When the alfacalcidol drops are used for treating rickets and osteomalacia caused by nutrition and malabsorption, the applicable subjects are mainly infants, and some infants can not receive the stimulation of ethanol in the alfacalcidol drops on oral mucosa. Therefore, a water-based alfacalcidol solution preparation is developed, and has certain clinical requirements.
Patent CN102781425a discloses a pharmaceutical composition for treating skin diseases or disorders, which contains vitamin D derivatives or analogues as active ingredient dissolved in a three-component surfactant-solvent mixture. The patent uses a large amount of organic solvents and surfactants to increase the solubility of vitamin D derivatives or analogues for application to skin. Patent CN 103110598A discloses an alfacalcidol dispersible tablet and a preparation method thereof, wherein the alfacalcidol dispersible tablet has the advantages of rapid dissolution, quick absorption, high bioavailability, good stability, convenient administration and the like, and comprises: alfacalcidol inclusion compound and preparation auxiliary materials; wherein the alfacalcidol inclusion compound is obtained by inclusion of alfacalcidol and 2, 6-dimethyl-beta-cyclodextrin according to the molar ratio of 4:1-0.5:3. The main auxiliary material 2, 6-dimethyl-beta-cyclodextrin used in the patent is not approved as a medicinal auxiliary material, the toxicity of the main auxiliary material is to be further researched, and the stability of the inclusion compound is not known. Patent CN103127015B discloses an alfacalcidol dripping pill and a preparation method thereof. The dripping pill comprises alfacalcidol inclusion compound, a matrix and a stabilizer. The alfacalcidol inclusion compound comprises an active ingredient and inclusion materials, wherein the inclusion materials are alpha-cyclodextrin, beta-cyclodextrin and hydroxy beta-cyclodextrin. Since the main purpose of the invention is to prepare the cyclodextrin inclusion compound of alfacalcidol into dripping pills, the invention does not mention whether the alfacalcidol inclusion compound can exist stably in water for a long time or not, and does not mention whether gamma-cyclodextrin has a possible inclusion effect on alfacalcidol.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problems of improving the solubility of the water-insoluble medicine alfacalcidol, and preparing a stable inclusion compound by using natural (non-chemically modified) cyclodextrin, so that the alfacalcidol can exist in an aqueous solution stably for a long time, and is convenient for specific people to use.
In order to solve the technical problems, the invention provides the following technical scheme:
the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
the applicant found in the research that the inclusion effect of natural cyclodextrin alpha-cyclodextrin on alfacalcidol is weak, and the solubilization effect on alfacalcidol cannot be realized by adding alpha-cyclodextrin. The natural cyclodextrin beta-cyclodextrin itself has poor solubility, and although some inclusion compound may be formed on alfacalcidol, the natural cyclodextrin beta-cyclodextrin exists in a precipitated state, and cannot form a uniform and clear solution state. In contrast, semi-synthetic cyclodextrin hydroxypropyl-beta-cyclodextrin, which is included as a pharmaceutical adjuvant, exhibits a better solubilization of alfacalcidol, and the hydroxypropyl-beta-cyclodextrin solution of alfacalcidol formed can exist stably in a clear state within 1 week, but gradually undergoes macroscopic precipitation after 1 week. The semi-synthetic cyclodextrin 2, 6-dimethyl-beta-cyclodextrin which is not listed as a pharmaceutical auxiliary material can also have better solubilization effect on alfacalcidol, but the problem is similar to that of the hydroxypropyl-beta-cyclodextrin solution of alfacalcidol, and the alfacalcidol cannot be stored in a solution form stably for a long time.
The natural cyclodextrin gamma-cyclodextrin which is added with the pharmaceutical auxiliary materials has certain inclusion effect on alfacalcidol, but the inclusion efficiency is not high. The applicant has surprisingly found that inclusion efficiency can be significantly enhanced when an amount of caffeine is added during the inclusion of alfacalcidol by gamma-cyclodextrin. The method is characterized in that when the gamma-cyclodextrin is used for carrying out conventional inclusion on the alfacalcidol, the alfacalcidol cannot be included in the cyclodextrin in a short period by adopting means of stirring or homogenizing and the like, and the solution is not completely clarified; however, after caffeine is added, alfacalcidol easily enters a gamma-cyclodextrin cavity by adopting a homogenizing method to form a stable and clear solution, and the solution can be kept in a clear state in a dark condition for at least 6 months, so that the alfacalcidol has high physical stability. The specific mechanism by which caffeine facilitates the entry of alfacalcidol into the gamma-cyclodextrin cavity is unknown, and the applicant has hypothesized that it is possible that alfacalcidol forms some form of interaction with caffeine, and that it enters the gamma-cyclodextrin cavity as a whole in the form of a supramolecule. In addition, from the ratio, it is highly probable that 2 gamma-cyclodextrin includes 1 alfacalcidol molecule in combination with caffeine.
Applicants have also attempted to exchange caffeine for other substances to promote the action of alfacalcidol entering the cyclodextrin cavity. Among the small molecule compounds that applicant tried, such as salicylic acid, acetaminophen, caffeic acid, malic acid, sucrose, glucose, theophylline, pentoxifylline, chlorogenic acid, epicatechin, etc., none of them has much less effect on facilitating the penetration of alfacalcidol into the gamma-cyclodextrin cavity than caffeine, even some of them have a negative effect on this cavity-entering behaviour.
The applicant also tried to add caffeine to the inclusion compound of alfacalcidol and hydroxypropyl-beta-cyclodextrin, and to the inclusion compound of alfacalcidol and 2, 6-dimethyl-beta-cyclodextrin, and envisaged that the addition of caffeine might promote the physical stability of the inclusion compound of alfacalcidol and these two cyclodextrins, prolonging its stable standing time. Unfortunately, contrary to the applicant's mind, the added caffeine instead repels alfacalcidol into the two cyclodextrins in the form of competing molecules forming a clathrate. In addition, any proportion of caffeine also does not promote the inclusion of alfacalcidol by the natural cyclodextrin α -cyclodextrin. Therefore, the inclusion of the alfacalcidol by gamma-cyclodextrin can be promoted by adding a certain proportion of caffeine, which is found accidentally and has specificity.
As a more preferable scheme of the invention, the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
as the most preferable scheme of the invention, the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
as a preferable technical scheme, the preparation method of the stable alfacalcidol water-based solution preparation comprises the following steps:
(1) Mixing the total amount of alfacalcidol and the total amount of gamma-cyclodextrin, adding 50 parts of water, grinding and pulping at normal temperature, and heating to 60 ℃ to form a mixture I;
(2) Dissolving the total amount of caffeine in 50 parts of water, and heating to 60 ℃ to form a mixture II;
(3) Mixing the mixture I and the mixture II under high-speed shearing, rapidly injecting into a high-pressure homogenizer, continuously homogenizing for 6 times under 80MPa, and cooling to room temperature to form a mixture III;
(4) Dissolving the total amount of sodium L-ascorbate, sodium benzoate and aspartame in 50 parts of water at room temperature to form a mixture IV;
(5) Mixing the mixture III and the mixture IV, stirring uniformly, adding the rest of water, and packaging.
As a preferable technical scheme, the alfacalcidol preparation can improve the water solubility of alfacalcidol, and the water solubility is increased by more than 10 times compared with that of the alfacalcidol which is not processed.
As a preferable technical scheme, the alfacalcidol preparation can be stably stored for more than 6 months at normal temperature under the condition of light-proof storage.
The invention has the beneficial effects that: the natural cyclodextrin gamma-cyclodextrin has certain inclusion effect on alfacalcidol, but the inclusion efficiency is not high. It is found that when a certain amount of caffeine is added in the process of clathrating alfacalcidol by gamma-cyclodextrin, the alfacalcidol easily enters the gamma-cyclodextrin cavity by adopting a homogenizing method, and the clathration efficiency can be obviously promoted. The process forms a stable clear solution, and the solution can remain clear for at least 6 months under light-shielding conditions, indicating that it has a high degree of physical stability. The method can be used for preparing the alfacalcidol oral solution without vegetable oil and other organic solvents, and is convenient for specific people to use.
Drawings
FIG. 1 is a schematic diagram of the molecular structure of alfacalcidol of the present invention.
Detailed Description
The invention will now be described in further detail with reference to the accompanying drawings. The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and explanation only and is not intended to limit the present invention.
Example 1: alfacalcidol solution
As shown in fig. 1, the alfacalcidol solution in this example was prepared according to the following formulation:
the preparation method of the alfacalcidol solution comprises the following steps:
(1) Mixing the total amount of alfacalcidol and the total amount of gamma-cyclodextrin, adding 50 parts of water, grinding and pulping at normal temperature, and heating to 60 ℃ to form a mixture I;
(2) Dissolving the total amount of caffeine in 50 parts of water, and heating to 60 ℃ to form a mixture II;
(3) Mixing the mixture I and the mixture II under high-speed shearing, rapidly injecting into a high-pressure homogenizer, continuously homogenizing for 6 times under 80MPa, and cooling to room temperature to form a mixture III;
(4) Dissolving the total amount of sodium L-ascorbate, sodium benzoate and aspartame in 50 parts of water at room temperature to form a mixture IV;
(5) Mixing the mixture III and the mixture IV, stirring uniformly, adding the rest of water, and packaging.
Example 2: alfacalcidol solution
As shown in fig. 1, the alfacalcidol solution in this example was prepared according to the following formulation:
TABLE 1 configuration of alfacalcidol solution
The preparation method of the alfacalcidol solution is the same as that of the example 1.
After the preparation, the mixture was allowed to stand for 1 hour, and the state of the solution was observed. As a result, it was found that all the solutions prepared by the formulations had extremely fine small particles in a suspended state inside, and white small particles which were not dissolved were present at the bottom of the solution. The results indicate that inclusion of alfacalcidol by gamma-cyclodextrin alone is inefficient in the absence of caffeine.
Example 3: alfacalcidol solution
As shown in fig. 1, the alfacalcidol solution in this example was prepared according to the following formulation:
TABLE 2 configuration of alfacalcidol solution
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
Alfacalcidol 2 parts of 2 parts of 2 parts of 2 parts of 2 parts of 2 parts of
Gamma-cyclodextrin 10 parts of 12 parts of 14 parts of 16 parts of 18 parts of 20 parts of
Caffeine and its preparation method 45 parts of 45 parts of 45 parts of 45 parts of 45 parts of 45 parts of
L-ascorbic acid sodium salt 3 parts of 3 parts of 3 parts of 3 parts of 3 parts of 3 parts of
Sodium benzoate 2 parts of 2 parts of 2 parts of 2 parts of 2 parts of 2 parts of
Aspartame 0.08 part 0.08 part 0.08 part 0.08 part 0.08 part 0.08 part
Water and its preparation method 1000 parts 1000 parts 1000 parts 1000 parts 1000 parts 1000 parts
The preparation method of the alfacalcidol solution is the same as that of the example 1.
After the preparation, the mixture was allowed to stand for 1 hour, and the state of the solution was observed. As a result, the solutions prepared in the formulations 1 and 2 had extremely fine small particles in a suspended state, and the solution had white small particles at the bottom which were not dissolved. The remaining solutions were clear solutions. This suggests that the gamma cyclodextrin addition of formulas 1 and 2 is still insufficient to completely encapsulate alfacalcidol, while other formulas provide sufficient gamma cyclodextrin and successfully encapsulate alfacalcidol in the cyclodextrin cavity with the aid of caffeine.
Example 4: alfacalcidol solution
As shown in fig. 1, the alfacalcidol solution in this example was prepared according to the following formulation:
TABLE 3 configuration of alfacalcidol solution
The preparation method of the alfacalcidol solution is the same as that of the example 1.
After the preparation, the solution is kept stand in a dark place, and the solution states are observed at 0, 1, 4, 12 and 24 weeks respectively. The results are shown in the following table.
TABLE 4 configuration of alfacalcidol solution
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
0 week √ √ √ √ √ √
For 1 week √ √ √ √ √ √
1 month √ √ √ √ √ √
For 3 months √ √ √ √ √ √
6 months of × × √ √ √ √
Note that: "v" indicates clear and "x" indicates cloudiness or fine particles at the bottom of the solution.
As can be seen from the results of the table above, prescription 1 and prescription 2 can successfully clathrate alfacalcidol into gamma-cyclodextrin and also remain stable for less than 3 months, but in a 6 month stability experiment, fine particles appear at the bottom of the solution, which indicates that the clathrate system constructed by both prescriptions is not yet the most stable. The alfacalcidol cyclodextrin solutions obtained by other prescriptions can all show better stability in 6 months.
Example 5: alfacalcidol solution
As shown in fig. 1, the alfacalcidol solution in this example was prepared according to the following formulation:
TABLE 5 configuration of alfacalcidol solution
The preparation method of the alfacalcidol solution is the same as that of the example 1.
After the preparation, the solution is kept stand in a dark place, and the solution states are observed at 0, 1, 4, 12 and 24 weeks respectively. The results are shown in the following table.
TABLE 6 configuration of alfacalcidol solution
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
0 week √ √ √ √ √ √
For 1 week √ √ √ √ √ √
1 month √ √ √ √ √ √
For 3 months √ √ √ √ √ √
6 months of × × × √ √ √
Note that: "v" indicates clear and "x" indicates cloudiness or fine particles at the bottom of the solution.
As can be seen from the above table, the alfacalcidol cyclodextrin solutions prepared from prescription 1, prescription 2 and prescription 3 can remain stable for less than 3 months after the prescription amount of caffeine is reduced, but show fine particles at the bottom of the solution in the stability test for 6 months. The alfacalcidol cyclodextrin solutions obtained by other prescriptions can all show better stability in 6 months. In view of both achieving solubilization with a minimum amount of cyclodextrin adjuvant and maintaining the solution physically stable for at least 6 months, the applicant has set the optimum ratio of alfacalcidol, gamma-cyclodextrin and caffeine to be 2:16.5:40.
Experimental example 1: high temperature accelerated stability test
1.1 test sample: sample 1 is an alfacalcidol solution prepared in example 1 of the present invention; control 1 is an alfacalcidol cyclodextrin inclusion compound (molar ratio of alfacalcidol: 2, 6-dimethyl-beta-cyclodextrin is 1:0.8) prepared according to patent CN 103110598A [0018] that when alfacalcidol and 2, 6-dimethyl-beta-cyclodextrin are included according to a molar ratio of 1:0.8, the dissolution performance of alfacalcidol in water is best, compared with other molar ratios, there is a significant difference; control 2 was an alfacalcidol cyclodextrin inclusion compound prepared according to example 1 in patent CN103127015B (alfacalcidol: hydroxypropyl-beta-cyclodextrin 2:3).
1.2 test method: the solution was left at 60℃for 1 week, and the state of the solution was observed at 0, 1, 3 and 7 days, respectively. The sample was vortexed, sampled 1mL, centrifuged, and the supernatant was taken. The content of alfacalcidol in the supernatant is determined after the content determination method of alfacalcidol soft capsules is properly modified based on the 2020 edition of Chinese pharmacopoeia (second part) page 696.
1.3 test conditions: and (5) operating in a dark place. Chromatographic conditions: silica gel is used as a filler; petroleum ether (60-90 ℃) ethyl acetate-tetrahydrofuran (2:1:1) is taken as a mobile phase; the detection wavelength was 265nm. The theoretical plate number is not lower than 2500 calculated according to the peak of alfacalcidol. Assay: 1mL of each sample solution is freeze-dried, mobile phase is added for dissolution and quantitative dilution to prepare a solution (theoretical amount) containing 1 mug of alfacalcidol in each 1mL, the solution is filtered, the subsequent filtrate is taken as a sample solution, 20 mug of the sample solution is precisely measured and injected into a liquid chromatograph, and a chromatogram is recorded; and taking a proper amount of alfacalcidol reference substance, precisely stabilizing, adding a mobile phase for dissolving, quantitatively diluting to prepare a solution containing 1 mug per 1mL, and determining by the same method. And calculating according to an external standard method and peak area to obtain the product.
1.4 test results: see table below.
TABLE 7 alfacalcidol content in% of the indicated amount (average,%)
The results show that the 3 samples have large differences in performance in the acceleration experiments. Sample 1 was always in a clear state in a 1 week high temperature acceleration experiment, after vortexing, sampling, centrifuging, and no precipitation at the bottom of the centrifuge tube, and supernatant content measurement showed that the alfacalcidol content was 97.3% of the indicated amount. In contrast, in the high temperature acceleration experiment for 1 week, both the control 1 and the control 2 produced fine particles at the bottom of the solution, sampling after vortexing, centrifuging, found precipitation at the bottom of the centrifuge tube, and the supernatant content measurement showed that the alfacalcidol content was 57.4% and 46.0% of the labeled amount, showing that a large amount of alfacalcidol had been separated from the corresponding cyclodextrin inclusion system, and formed precipitation.
The experimental example shows that the alfacalcidol cyclodextrin inclusion compound solution prepared according to the embodiment 1 of the invention can solubilize insoluble alfacalcidol, can prolong the physical stability of the alfacalcidol under certain conditions, and has higher patent value.

Claims (4)

1. A stable aqueous solution formulation of alfacalcidol, characterized in that: the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
2. the method for preparing the stable aqueous solution formulation of alfacalcidol according to claim 1, characterized in that: the method comprises the following steps:
(1) Mixing the total amount of alfacalcidol and the total amount of gamma-cyclodextrin, adding 50 parts of water, grinding and pulping at normal temperature, and heating to 60 ℃ to form a mixture I;
(2) Dissolving the total amount of caffeine in 50 parts of water, and heating to 60 ℃ to form a mixture II;
(3) Mixing the mixture I and the mixture II under high-speed shearing, rapidly injecting into a high-pressure homogenizer, continuously homogenizing for 6 times under 80MPa, and cooling to room temperature to form a mixture III;
(4) Dissolving the total amount of sodium L-ascorbate, sodium benzoate and aspartame in 50 parts of water at room temperature to form a mixture IV;
(5) Mixing the mixture III and the mixture IV, stirring uniformly, adding the rest of water, and packaging.
3. The method for preparing the stable aqueous solution formulation of alfacalcidol according to claim 2, characterized in that: the preparation can improve water solubility of alfacalcidol, and increase the water solubility by more than 10 times compared with untreated alfacalcidol.
4. The method for preparing the stable aqueous solution formulation of alfacalcidol according to claim 2, characterized in that: the preparation can be stably stored for more than 6 months at normal temperature under the condition of light-proof storage.
CN202211048020.7A 2022-08-30 2022-08-30 Stable alfacalcidol water-based solution preparation and preparation method thereof Active CN115350149B (en)

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CN104800156A (en) * 2015-04-22 2015-07-29 青岛正大海尔制药有限公司 Alfacalcidol solution and preparation method thereof
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CN103127015A (en) * 2013-02-19 2013-06-05 青岛正大海尔制药有限公司 Alfacalcidol dropping pill and preparation method thereof
CN104800156A (en) * 2015-04-22 2015-07-29 青岛正大海尔制药有限公司 Alfacalcidol solution and preparation method thereof
CN112546011A (en) * 2020-12-14 2021-03-26 正大制药（青岛）有限公司 Novel alfacalcidol enteric-coated preparation and preparation method thereof

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