CN115350149A - Stable alfacalcidol water-based solution preparation and preparation method thereof - Google Patents

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

Info

Publication number
CN115350149A
CN115350149A CN202211048020.7A CN202211048020A CN115350149A CN 115350149 A CN115350149 A CN 115350149A CN 202211048020 A CN202211048020 A CN 202211048020A CN 115350149 A CN115350149 A CN 115350149A
Authority
CN
China
Prior art keywords
alfacalcidol
water
stable
cyclodextrin
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202211048020.7A
Other languages
Chinese (zh)
Other versions
CN115350149B (en
Inventor
施建飞
钱建
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nantong Huashan Pharmacy Co ltd
Original Assignee
Nantong Huashan Pharmacy Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nantong Huashan Pharmacy Co ltd filed Critical Nantong Huashan Pharmacy Co ltd
Priority to CN202211048020.7A priority Critical patent/CN115350149B/en
Publication of CN115350149A publication Critical patent/CN115350149A/en
Application granted granted Critical
Publication of CN115350149B publication Critical patent/CN115350149B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

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, sodium L-ascorbate, sodium benzoate, aspartame and water. According to the invention, the alfacalcidol which is difficult to dissolve in water is subjected to primary inclusion by using the water-soluble natural cyclodextrin gamma-cyclodextrin, and the addition of caffeine is discovered accidentally to greatly improve the inclusion efficiency of the gamma-cyclodextrin on the alfacalcidol and the stability of the inclusion compound. The adjuvants and process provided by the invention can be used to prepare stable alfacalcidol water-based solution formulations.

Description

Stable alfacalcidol water-based solution preparation and preparation method thereof
Technical Field
The invention belongs to the technical field of medicinal 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 skeletal metabolism. Alfacalcidol can be activated by 25-hydroxylase in the liver and exerts vitamin D effects in the whole body and osteoblasts. It exerts a unique pleiotropic effect in the intestine, bone, parathyroid, muscle and brain. Alfacalcidol can increase the calcium recovery of small intestine and renal tubule, inhibit parathyroid hyperplasia, reduce parathyroid hormone synthesis and release, and inhibit bone absorption; can also increase the synthesis of transforming growth factor and insulin-like growth factor, promote the synthesis of collagen and bone matrix protein; in addition, the medicine can also regulate muscle calcium metabolism, promote muscle cell differentiation, enhance muscle strength, increase neuromuscular coordination and reduce falling tendency. Based on these pharmacological mechanisms, alfacalcidol is now mainly used for improving symptoms caused by abnormal vitamin D metabolism (such as hypocalcemia, convulsion, bone pain and bone damage), and also for osteoporosis.
Alfacalcidol is a potent drug substance, but has poor water solubility. Alfacalcidol soft capsules on the market use vegetable oil to dissolve alfacalcidol, constituting the content of the soft capsule. Alfacalcidol drops marketed, solubilised with ethanol and polyethylene glycol 15-hydroxystearate. The alfacalcidol injection on the market also solubilizes alfacalcidol with ethanol and polyethylene glycol. Generally, the use of a certain amount of vegetable oil, ethanol, polyethylene glycol and other excipients to solubilize or solubilize alfacalcidol is not problematic for use as a formulation, but in some cases, these formulations are not suitable for the particular subject of use. For example, in the case of alfacalcidol soft capsules for treating osteoporosis, the subjects to which the soft capsules are applied are mainly elderly patients, but many elderly patients suffer from hyperlipidemia or atherosclerosis at the same time, and are not suitable for taking too much vegetable oil. When alfacalcidol drops are used for treating rickets and osteomalacia caused by nutrition and malabsorption, the applicable subjects are mainly infants, and some infants cannot accept the stimulation of ethanol in the alfacalcidol drops on oral mucosa. Therefore, there is a clinical need to develop a water-based alfacalcidol solution formulation.
Patent CN102781425a discloses a pharmaceutical composition for the treatment of skin diseases or disorders, which contains a vitamin D derivative or analog as an active ingredient dissolved in a three-component surfactant-solvent mixture. This patent uses a large amount of organic solvents and surfactants to increase the solubility of vitamin D derivatives or analogs for dermal administration. Patent CN 103110598a discloses alfacalcidol dispersible tablets with the advantages of rapid dissolution, fast absorption, high bioavailability, good stability, convenient administration and the like and a preparation method thereof, wherein the alfacalcidol dispersible tablets comprise: alfacalcidol inclusion compound and preparation auxiliary materials; wherein the alfacalcidol inclusion compound is obtained by including 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 pharmaceutical auxiliary material, the toxicity of the cyclodextrin is to be further researched, and the stability of the inclusion compound is unknown. Patent CN103127015B discloses alfacalcidol dropping pills and a preparation method thereof. The dripping pill comprises alfacalcidol inclusion compound, matrix and stabilizer. The alfacalcidol inclusion compound comprises an active ingredient and an inclusion material, wherein the inclusion material is alpha-cyclodextrin, beta-cyclodextrin or hydroxy beta-cyclodextrin. Since the main purpose of the invention is to prepare the cyclodextrin inclusion compound of alfacalcidol into the dropping pill, it is not mentioned whether the inclusion compound of alfacalcidol can exist stably in water for a long time or not, and whether the clathration of alfacalcidol by gamma-cyclodextrin is possible or not.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of how to improve the solubility of alfacalcidol, a water-insoluble drug, and prepare 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:
a stable alfacalcidol water-based solution formulation comprising the following components in parts by weight:
Figure BDA0003822758850000031
applicants have found in their studies that the inclusion of alfacalcidol by the natural cyclodextrin alpha-cyclodextrin is weak and that solubilization of alfacalcidol by the addition of alpha-cyclodextrin cannot be achieved. Natural cyclodextrin beta-cyclodextrin itself has poor solubility, and although it may form a certain inclusion compound with alfacalcidol, it exists in a precipitated state, and cannot form a uniform and clear solution state. In contrast, the semi-synthetic cyclodextrin hydroxypropyl- β -cyclodextrin included as a pharmaceutical excipient showed better solubilization of alfacalcidol, and the formed hydroxypropyl- β -cyclodextrin solution of alfacalcidol was able to exist stably in a clear state within 1 week, but gradually appeared to precipitate to the naked eye after 1 week. The semisynthetic cyclodextrin 2,6-dimethyl-beta-cyclodextrin, which has not been included as a pharmaceutical adjuvant, also exhibits good solubilization of alfacalcidol, but has problems similar to the hydroxypropyl-beta-cyclodextrin solution of alfacalcidol, neither of which can be stored stably in solution for a long period of time.
The natural cyclodextrin gamma-cyclodextrin which is added with the pharmaceutic adjuvant has a certain inclusion effect on alfacalcidol, but the inclusion efficiency is not high. The applicant has surprisingly found that when a certain amount of caffeine is added during the inclusion of gamma-cyclodextrin to alfacalcidol, the inclusion efficiency can be significantly improved. The specific expression is that when gamma-cyclodextrin is used for conventionally coating alfacalcidol, the methods such as stirring or homogenizing are adopted, so that alfacalcidol cannot be coated into the cyclodextrin in a short time, and the solution is not completely clear; however, after caffeine is added, the alfacalcidol can easily enter the gamma-cyclodextrin cavity by adopting a homogenization method to form a stable and clear solution, and the solution can keep a clear state in the dark condition for at least 6 months, so that the alfacalcidol has high physical stability. The specific mechanism by which caffeine promotes the entry of alfacalcidol into the gamma-cyclodextrin cavity is unknown and the applicant speculates that it is possible that alfacalcidol and caffeine form some form of interaction and are wholly incorporated into the gamma-cyclodextrin cavity in a supramolecular form. In addition, it is likely that 2 γ -cyclodextrins, in proportion to caffeine, will include 1 alfacalcidol molecule.
Applicants have also attempted to exchange caffeine for other substances to facilitate the act of entry of alfacalcidol into the cyclodextrin lumen. Among the small molecular compounds tried by the applicant, such as salicylic acid, acetaminophen, caffeic acid, malic acid, sucrose, glucose, theophylline, pentoxifylline, chlorogenic acid, epicatechin, etc., the effect of promoting the entry of alfacalcidol into the cavity of gamma-cyclodextrin is far less than that of caffeine, even some compounds adversely affect the entry behavior.
The applicant has also tried to add caffeine to the inclusion complex of alfacalcidol with hydroxypropyl- β -cyclodextrin and to the inclusion complex of alfacalcidol with 2,6-dimethyl- β -cyclodextrin, assuming that the addition of caffeine may promote the physical stability of the inclusion complex of alfacalcidol with these two cyclodextrins, prolonging their stable standing time. Unfortunately, contrary to applicants' hypothesis, the added caffeine instead excludes alfacalcidol from entering the two cyclodextrins as a competitor molecule. In addition, caffeine in any proportion also does not promote the inclusion of alfacalcidol by the native cyclodextrin α -cyclodextrin. Therefore, the fact that the addition of caffeine in a certain proportion can promote the inclusion of alfacalcidol by gamma-cyclodextrin is discovered by accident and has specificity.
As a more preferable embodiment of the present invention, the stable alfacalcidol water-based solution formulation comprises the following components by weight:
Figure BDA0003822758850000051
as the most preferred embodiment of the present invention, the stable alfacalcidol water-based solution formulation comprises the following components in parts by weight:
Figure BDA0003822758850000052
as a preferred 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 a high-speed shearing condition, quickly injecting the mixture into a high-pressure homogenizer, continuously homogenizing for 6 times under the pressure of 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) And mixing the mixture III and the mixture IV, uniformly stirring, adding the balance of water, and packaging to obtain the water-soluble organic silicon fertilizer.
As a preferred technical scheme, the alfacalcidol preparation can improve the water solubility of alfacalcidol, and compared with the unprocessed alfacalcidol, the alfacalcidol preparation is increased by more than 10 times.
As a preferable technical scheme, the alfacalcidol preparation can be stably stored at normal temperature for more than 6 months under the condition of being stored in the dark.
The invention has the beneficial effects that: the natural cyclodextrin gamma-cyclodextrin has a certain clathration effect on alfacalcidol, but the clathration efficiency is not high. Research shows that when a certain amount of caffeine is added in the process of clathrating alfacalcidol by gamma-cyclodextrin, alfacalcidol can easily enter a gamma-cyclodextrin cavity by adopting a homogenization method, and the clathration efficiency can be remarkably promoted. The process forms a stable clear solution, and the solution can remain clear for at least 6 months in the absence of light, indicating a high degree of physical stability. The method of the present invention can be used to prepare alfacalcidol oral solutions that are free of vegetable oils and other organic solvents for use by specific populations.
Drawings
Fig. 1 is a schematic diagram of the molecular structure of alfacalcidol of the present invention.
Detailed Description
The present invention will now be described in further detail with reference to the accompanying drawings. The preferred embodiments of the present invention are described below, and it should be understood that the preferred embodiments described herein are only for illustrating and explaining the present invention and are not to be construed as limiting the present invention.
Example 1: alfa ossifying alcohol solution
As shown in FIG. 1, the alfa ossification alcohol solution of the present embodiment is prepared according to the following formula:
Figure BDA0003822758850000071
the preparation method of the alfa ossification alcohol 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 a high-speed shearing condition, quickly injecting the mixture into a high-pressure homogenizer, continuously homogenizing for 6 times under the pressure of 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) And mixing the mixture III and the mixture IV, uniformly stirring, adding the balance of water, and packaging to obtain the water-soluble organic silicon fertilizer.
Example 2: alfa ossifying alcohol solution
As shown in FIG. 1, the alfa ossification alcohol solution of the embodiment is prepared according to the following formula:
TABLE 1 Alfa ossifying alcohol solution preparation table
Figure BDA0003822758850000081
The preparation method of the alfa ossified alcohol solution was the same as that of 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, all the solutions prepared by the recipe had extremely fine particles in a suspended state inside, and small white particles that had not been dissolved were present at the bottom of the solution. The results show that, in the absence of caffeine, inclusion of alfacalcidol with gamma-cyclodextrin alone results in low inclusion efficiency.
Example 3: alfa ossifying alcohol solution
As shown in FIG. 1, the alfa ossification alcohol solution of the present embodiment is prepared according to the following formula:
TABLE 2 preparation of alfacalcitonin solution
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
Alfacalcidol 2 portions of 2 portions of 2 portions of 2 portions of 2 portions of 2 portions of
Gamma-cyclodextrin 10 portions of 12 portions of 14 portions of 16 portions of 18 portions of 20 portions of
Caffeine 45 portions of 45 portions of 45 portions of 45 portions of 45 portions of 45 portions of
L-ascorbic acid sodium salt 3 portions of 3 portions of 3 portions of 3 portions of 3 portions of 3 portions of
Sodium benzoate 2 portions of 2 portions of 2 portions of 2 portions of 2 portions of 2 portions of
Aspartame 0.08 part of 0.08 part of 0.08 part of 0.08 portion of 0.08 portion of 0.08 portion of
Water (W) 1000 portions 1000 portions 1000 portions 1000 portions of 1000 portions 1000 portions
The preparation method of the alfa ossified alcohol solution was the same as that of 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 recipes 1 and 2 contained extremely fine particles in suspension, and small white particles that had not been dissolved were present at the bottom of the solutions. The remaining solutions were clear solutions. This indicates that formula 1 and formula 2 still do not add sufficient gamma-cyclodextrin to completely enclose alfacalcidol, while other formulas provide sufficient gamma-cyclodextrin to successfully encapsulate alfacalcidol into the cyclodextrin cavity with the assistance of caffeine.
Example 4: alfa ossifying alcohol solution
As shown in FIG. 1, the alfa ossification alcohol solution of the present embodiment is prepared according to the following formula:
TABLE 3 Alphaossifying alcohol solution preparation Table
Figure BDA0003822758850000091
Figure BDA0003822758850000101
The preparation method of the alfa ossified alcohol solution was the same as that of example 1.
After the preparation, the mixture was left to stand in the dark, and the solution state was observed at 0, 1, 4, 12 and 24 weeks, respectively. The results can be seen in the following table.
TABLE 4 Alfa ossifying alcohol solution preparation table
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
0 week √ √ √ √ √ √
1 week old √ √ √ √ √ √
1 month √ √ √ √ √ √
3 months old √ √ √ √ √ √
6 months old × × √ √ √ √
Note: "√" indicates clear, and "X" indicates turbid or fine particles at the bottom of the solution.
As can be seen from the results in the table above, formula 1 and formula 2 can successfully inclusion alfacalcidol into γ -cyclodextrin, and can also remain stable within 3 months, but in the stability test of 6 months, the bottom of the solution shows fine particles, indicating that the inclusion compound system constructed by the two formulas is not the most stable. The alfacalcidol cyclodextrin solutions obtained by other formulas can show better stability within 6 months.
Example 5: alfa ossifying alcohol solution
As shown in FIG. 1, the alfa ossol solution of the present embodiment is prepared according to the following formula:
TABLE 5 Alphaossifying alcohol solution preparation Table
Figure BDA0003822758850000102
Figure BDA0003822758850000111
The preparation method of the alfa ossified alcohol solution was the same as that of example 1.
After the preparation, the mixture was left standing in the dark, and the solution state was observed at 0, 1, 4, 12 and 24 weeks. The results can be seen in the following table.
TABLE 6 Alfa ossifying alcohol solution preparation table
Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6
0 week √ √ √ √ √ √
1 week old √ √ √ √ √ √
1 month √ √ √ √ √ √
3 months old √ √ √ √ √ √
6 months old × × × √ √ √
Note: "√" indicates a clear, and "×" indicates a cloudiness or a fine particle at the bottom of the solution.
As can be seen from the results in the table above, the alfacalcidol cyclodextrin solutions prepared from formula 1, formula 2, and formula 3 remained stable for less than 3 months after the reduction of the prescribed amount of caffeine, but showed the appearance of fine particles at the bottom of the solution in the 6-month stability experiment. The alfacalcidol cyclodextrin solutions obtained by other formulas can show better stability within 6 months. In view of the minimal amount of cyclodextrin vehicle required to achieve solubilization and physical stability of the solution for at least 6 months, applicants set the optimum ratio of alfacalcidol, gamma-cyclodextrin and caffeine to 2: 16.5: 40.
Experimental example 1: high temperature accelerated stability test
1.1 test sample: sample 1 is an alfa ossified alcohol solution prepared in example 1 of the present invention; control 1 was a cyclodextrin inclusion compound of alfacalcidol prepared according to the statement of CN 103110598a [0018] that when alfacalcidol was included with 2,6-dimethyl- β -cyclodextrin at a molar ratio of 1: 0.8, alfacalcidol solubility in water was the best with significant difference compared to other molar ratios (molar ratio of alfacalcidol: 2,6-dimethyl- β -cyclodextrin is 1: 0.8); control 2 was alfacalcidol cyclodextrin inclusion compound (alfacalcidol: hydroxypropyl-. Beta. -cyclodextrin 2: 3) prepared as in example 1 in patent CN 103127015B.
1.2 test methods: the mixture was left at 60 ℃ for 1 week, and the solution state was observed for 0, 1, 3 and 7 days, respectively. The sample was vortexed, 1mL was sampled, centrifuged, and the supernatant was taken. The alfacalcidol content in the supernatant was determined based on the alfacalcidol soft capsule content determination method on page 696 of the 2020 edition of Chinese pharmacopoeia (second part) with appropriate modifications.
1.3 test conditions: and (4) avoiding light. Chromatographic conditions are as follows: silica gel is used as a filling agent; petroleum ether (60-90 deg.c) -ethyl acetate-tetrahydrofuran (2: 1) as the mobile phase; the detection wavelength was 265nm. The number of theoretical plates is not less than 2500 calculated by alfacalcidol peak. The determination method comprises the following steps: 1mL of each sample solution is freeze-dried, added with mobile phase for dissolving and quantitatively diluted to prepare a solution (theoretical amount) containing 1 mu g of alfacalcidol in each 1mL, filtered, the subsequent filtrate is taken as a test solution, 20 mu L of the subsequent filtrate is precisely measured and injected into a liquid chromatograph, and a chromatogram is recorded; taking another appropriate amount of alfacalcidol reference substance, precisely stabilizing, adding mobile phase for dissolving, quantitatively diluting to obtain solution containing 1 μ g per 1mL, and determining by the same method. Calculating according to the peak area by an external standard method to obtain the product.
1.4 test results: see table below.
TABLE 7 percentage of alfacalcidol content in the indicated amounts (mean,%) of the samples
Figure BDA0003822758850000121
Figure BDA0003822758850000131
As a result, the 3 samples showed large differences in performance in the accelerated test. Sample 1 was always in a clear state in a 1 week high temperature accelerated test, after vortexing, it was sampled and centrifuged without precipitation at the bottom of the centrifuge tube, and the assay of the supernatant showed that the alfacalcidol content was 97.3% of the indicated amount. In contrast, in the high-temperature acceleration experiment of 1 week, the control 1 and the control 2 both produced fine particles at the bottom of the solution, sampled after vortexing, centrifuged, and found precipitates at the bottom of the centrifuge tube, and the determination of the content of the supernatant showed that the alfacalcidol content was 57.4% and 46.0% of the labeled amount, indicating that a large amount of alfacalcidol had been separated from the corresponding cyclodextrin inclusion system, and formed precipitates.
The experimental example shows that the alfacalcidol cyclodextrin inclusion compound solution prepared according to the embodiment 1 of the invention can solubilize insoluble alfacalcidol and prolong the physical stability of the alfacalcidol under certain conditions, and has higher patent value.

Claims (6)

1. A stable alfacalcidol water-based solution formulation characterized by: the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
Figure FDA0003822758840000011
2. the stable alfacalcidol water-based solution formulation of claim 1, wherein: the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
Figure FDA0003822758840000012
3. the stable alfacalcidol water-based solution formulation of claim 2, wherein: the stable alfacalcidol water-based solution preparation comprises the following components in parts by weight:
Figure FDA0003822758840000013
Figure FDA0003822758840000021
4. the method of preparing a stable alfacalcidol water-based solution formulation as claimed in any one of claims 1-3, wherein: 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 a high-speed shearing condition, quickly injecting the mixture into a high-pressure homogenizer, continuously homogenizing for 6 times under the pressure of 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) And mixing the mixture III and the mixture IV, uniformly stirring, adding the balance of water, and packaging to obtain the water-soluble organic silicon fertilizer.
5. The method of preparing a stable alfacalcidol water-based solution formulation as claimed in claim 4, wherein: the preparation can improve the water solubility of alfacalcidol, and compared with the alfacalcidol which is not processed, the water solubility of alfacalcidol is increased by more than 10 times.
6. The method of preparing a stable alfacalcidol water-based solution formulation as claimed in claim 4, wherein: the preparation can be stably stored at room temperature for more than 6 months 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)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211048020.7A CN115350149B (en) 2022-08-30 2022-08-30 Stable alfacalcidol water-based solution preparation and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211048020.7A CN115350149B (en) 2022-08-30 2022-08-30 Stable alfacalcidol water-based solution preparation and preparation method thereof

Publications (2)

Publication Number Publication Date
CN115350149A true CN115350149A (en) 2022-11-18
CN115350149B CN115350149B (en) 2023-12-15

Family

ID=84004302

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211048020.7A Active CN115350149B (en) 2022-08-30 2022-08-30 Stable alfacalcidol water-based solution preparation and preparation method thereof

Country Status (1)

Country Link
CN (1) CN115350149B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US20170202789A1 (en) * 2014-07-16 2017-07-20 New World Pharmaceuticals, Llc Methods and related compositions for improved drug bioavailability and disease treatment
US20170231996A1 (en) * 2015-10-08 2017-08-17 Inspired Brands International, Llc Stable edible supersaturated caffeine solutiuons and methods of making the same
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US20170202789A1 (en) * 2014-07-16 2017-07-20 New World Pharmaceuticals, Llc Methods and related compositions for improved drug bioavailability and disease treatment
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
US20170231996A1 (en) * 2015-10-08 2017-08-17 Inspired Brands International, Llc Stable edible supersaturated caffeine solutiuons and methods of making the same
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

Also Published As

Publication number Publication date
CN115350149B (en) 2023-12-15

Similar Documents

Publication Publication Date Title
Kar et al. Current developments in excipient science: implication of quantitative selection of each excipient in product development
EP3437637B1 (en) Pharmaceutical preparation of palbociclib and medical use thereof
EP1845787B1 (en) Formulations for injection of catecholic butanes, including ndga compounds, into animals
KR101865776B1 (en) Diethylstilbestrol dosage form and use for the treatment of prostate or breast cancer
EP1698329A1 (en) Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle
US20160206572A1 (en) Compositions comprising a dendrimer-resveratrol complex and methods for making and using the same
JP2003055203A (en) Ubiquinone-containing preparation
CN101848699A (en) Stabilized pediatric suspension of carisbamate
CN109662949B (en) Fluorohydrocortisone acetate orally disintegrating tablet and preparation method thereof
EP3419671B1 (en) High bioavailability oromucosal pharmaceutical preparations based on cyclodextrin and sucralose
EP1420802B1 (en) Increased solubility flavanolignan preparations
EP1858494B1 (en) New soft gelatin capsules
AU2002323517A1 (en) Increased solubility flavanolignan preparations
CN104721155A (en) Temozolomide lyophilized powder preparation and preparation method thereof
CN102481287B (en) Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof
EP3777862A1 (en) Meloxicam composition, preparation and preparation method and use thereof
CN115350149A (en) Stable alfacalcidol water-based solution preparation and preparation method thereof
AU2014239651A1 (en) Method of treating vitamin B12 deficiency
CN115607506A (en) Preparation method of anhydrous paste containing recombinant human basic fibroblast growth factor
CN107137349B (en) Gambogic acid nanosuspension and preparation method thereof
CN114377147A (en) Alvatripopa clathrate compound, composition and preparation method thereof
CN113925831A (en) High-stability phloretin nanosuspension, preparation method thereof and microneedle
CN102351722A (en) L-carnitine compound and composite thereof
EP3679925A1 (en) Pharmaceutical composition of docetaxel conjugate and preparation method
JP4475405B2 (en) Pharmaceutical composition

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant