CN114796109A - Method for preparing glucocorticoid suspension - Google Patents
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- CN114796109A CN114796109A CN202210466085.7A CN202210466085A CN114796109A CN 114796109 A CN114796109 A CN 114796109A CN 202210466085 A CN202210466085 A CN 202210466085A CN 114796109 A CN114796109 A CN 114796109A
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract
The invention relates to a glucocorticoid preparation, in particular to a preparation method of a glucocorticoid suspension, which relates to a moist heat sterilization method of insoluble glucocorticoid, wherein little or no water which can be used for dissolving non-electrolyte is contained in saturated sodium chloride, so that the insoluble glucocorticoid can be prevented from being dissolved at high temperature in a supersaturated sodium chloride solution, the enlargement of the particle size caused by recrystallization in the cooling process after dissolution is eliminated, the particle size distribution of betamethasone acetate in a betamethasone acetate suspension is not changed, the influence of overlarge particle size on the safety of patients and the influence of drug release speed are not caused, the sterilization effect of insoluble betamethasone acetate is achieved, and the sterility guarantee level is improved while a bacteriostatic agent is removed.
Description
Technical Field
The invention relates to a glucocorticoid preparation, in particular to a preparation method for preparing a glucocorticoid suspension.
Background
Glucocorticoid (GC) is an extremely important regulatory molecule in organisms, plays an important role in regulating development, growth, metabolism, immune function and the like of the organisms, is the most important regulatory hormone for stress response of the organisms, is also the most widely and effectively anti-inflammatory and immunosuppressive agent clinically used, is often the first choice in emergency or critical conditions, is clinically common glucocorticoid medicaments such as prednisone, methylprednisolone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone and the like, has multiple effects of resisting inflammation, resisting toxicity, resisting allergy, resisting shock, nonspecifically inhibiting immunity, reducing fever and the like, can prevent and prevent immune inflammatory reaction and pathologic immune reaction, and is almost effective for any type of allergic diseases.
The suspension is one of the main dosage forms of glucocorticoid preparations, the injection is directly injected into human bodies, microorganisms bring serious harm to the safety of patients, and bacteriostatic agents are commonly introduced into products in the industry to ensure the sterile effect, for example, the product name of the Organon LLC company on the market of the US FDA is as follows: CELESTONE ® SOLUSPAN ® The betamethasone sodium phosphate and betamethasone acetate injection suspension has the specification: 30mg/5ml, benzalkonium chloride (addition amount is 0.2 mg/ml) is added as a bacteriostatic agent, and the bacteriostatic agent has toxicity and potential risk to the safety of patients.
In order to avoid the introduction of bacteriostatic agents, different sterilization schemes such as high-temperature sterilization are researched in the industry, and products are stored after being sterilized at high temperature, because the insoluble glucocorticoid cannot be sterilized and filtered; the dry heat sterilization has poor penetrability and poor sterilization effect, and the active ingredients can be damaged by increasing the sterilization temperature and time; the problem of wet heat sterilization is that the active ingredients are dissolved at high temperature and are separated out when the temperature is reduced, so that the particle size is increased, and the safety and the effectiveness of the medicine cannot be guaranteed.
Insoluble glucocorticoid betamethasone acetate can be subjected to moist heat sterilization with F0 value more than 121 ℃ without obvious change of raw material impurities, the maximum single impurity is changed from 0.340% to 0.348%, the total amount of impurities is increased from 0.778% to 0.792%, the insoluble glucocorticoid is dispersed in supersaturated sodium chloride solution for moist heat sterilization, because of the existence of the supersaturated sodium chloride, the dissolution of insoluble glucocorticoid during high-temperature sterilization is avoided, thereby avoiding the increase of the grain diameter during recrystallization, therefore, the insoluble glucocorticoid betamethasone acetate is sterilized by high temperature and moist heat, and because the heat stability of the soluble glucocorticoid is poor, after the wet heat sterilization is carried out by the F0 value residual probability method of 8-12, the maximum single impurity is increased from 0.224% to 3.658%, the total impurity is increased from 1.158% to 6.088%, and the wet heat sterilization is not suitable, so that the bacteriostatic agent is introduced into the soluble betamethasone sodium phosphate for bacteriostasis.
In order to avoid the damage of soluble glucocorticoid at high temperature, the prior art 202111372944.8 discloses a betamethasone sodium phosphate and betamethasone acetate suspension injection and a preparation method thereof, wherein sterile betamethasone acetate is selected, benzalkonium chloride is used as a bactericide, so that the sterilization effect is ensured, although the damage of high temperature to the betamethasone sodium phosphate is avoided, benzalkonium chloride bactericide components are introduced, and the bacteriostatic agent has toxicity and potential risk to the safety of patients.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a method for sterilizing insoluble glucocorticoid by moist heat, which can not change the particle size of the insoluble glucocorticoid by moist heat sterilization, improve the sterility guarantee level of the suspension and remove a bacteriostatic agent.
The invention is realized by the following technical scheme: a method for preparing a glucocorticoid suspension comprises the following steps,
mixing an electrolyte and water to obtain a refractory glucocorticoid high-temperature protection solution;
step two, putting 0.25-0.35wt% of insoluble glucocorticoid into the insoluble glucocorticoid high-temperature protection solution obtained in the step one, wherein the dosage of the insoluble glucocorticoid high-temperature protection solution is 1.3-1.6 wt%, sealing and treating for 10-30min at the temperature of 115-125 ℃, and cooling to room temperature to obtain a pretreated insoluble glucocorticoid sterilization mixture;
step three, sequentially adding a buffering agent and a metal ion complexing agent into 90wt% of water for injection to obtain a base solution;
step four, adding 0.25-0.35wt% of soluble glucocorticoid into the base solution, adjusting the pH to 6.6-7.5, and sterilizing and filtering to obtain a sterilized mixture of the soluble glucocorticoid;
and step five, mixing the sterilized mixture of the soluble glucocorticoid and the sterilized mixture of the insoluble glucocorticoid, supplementing the water for injection to full dose, homogenizing and packaging.
Furthermore, the electrolyte is selected from one of sodium salt, potassium salt, calcium salt and phosphate.
Further, the electrolyte is selected from one of potassium chloride, calcium chloride, disodium hydrogen phosphate and sodium chloride.
Further, the insoluble glucocorticoid is one of betamethasone acetate, prednisone acetate and hydrocortisone.
Further, the buffer is one of disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate and disodium hydrogen phosphate.
Further, the metal ion complexing agent is disodium edetate.
Further, the soluble glucocorticoid is selected from one of betamethasone sodium phosphate and dexamethasone.
The invention has the beneficial effects that: in the preparation method of the glucocorticoid suspension, because the solubility of the insoluble glucocorticoid is reduced because the solution contains electrolyte, the ionization of the electrolyte in the solution needs water for supplement, and little or no water can be used for dissolving non-electrolyte in saturated sodium chloride, so that betamethasone acetate can be prevented from being dissolved at high temperature in the supersaturated sodium chloride solution, thereby eliminating the increase of the particle size caused by recrystallization in the cooling process after the dissolution, not changing the particle size distribution of the betamethasone acetate in the betamethasone acetate suspension, and improving the sterility guarantee level while removing the bacteriostatic agent.
Drawings
FIG. 1 is a schematic view showing the particle size distribution before the sealing treatment in step two of example 1;
FIG. 2 is a schematic view showing the particle size distribution after the sealing treatment in step two of example 1;
FIG. 3 is a graph showing the results of accelerated test testing of glucocorticoid suspending agent in example 1;
FIG. 4 is a schematic representation of the dissolution profile of the glucocorticoid suspension according to example 1;
FIG. 5 is a schematic view showing the particle size distribution before the second sealing treatment in example 2;
FIG. 6 is a schematic view showing the particle size distribution after the second sealing treatment in example 2;
FIG. 7 is a graph showing the results of accelerated test testing of glucocorticoid suspending agent in example 2;
FIG. 8 is a schematic representation of the dissolution profile of the glucocorticoid suspension of example 2;
FIG. 9 is a schematic view showing the particle size distribution after the three-stage sealing treatment in comparative example 1
Detailed Description
In each of the following examples,
the insoluble glucocorticoid is betamethasone acetate, specifically betamethasone acetate of Shanghai New Hualian pharmaceutical Co., Ltd, and pulverized by jet mill to obtain powder with particle diameter X 99 The particle size distribution is less than or equal to 20 mu m and obeys normal distribution, and the particle size is controlled, so that the safety and the effectiveness of the suspension can be ensured.
The soluble glucocorticoid is betamethasone sodium phosphate, specifically betamethasone sodium phosphate from Zhejiang Xianju pharmaceutical Co., Ltd.
The buffer agent is one of disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate and disodium hydrogen phosphate, the mass concentration of the disodium hydrogen phosphate dihydrate is 0.85% -0.95% (m/v), the mass concentration of the disodium hydrogen phosphate dodecahydrate is 1.75% -1.85% (m/v), and the mass concentration of the disodium hydrogen phosphate is 0.7% -0.8% (m/v).
The metal ion complexing agent is disodium edetate with the mass concentration of 0.009% -0.011% (m/v).
In the first step, the electrolyte is sodium chloride with the dosage of 0.4-0.5wt%, the dosage of water is 0.9-1.1wt%, when 0.4-0.5wt% of sodium chloride is put into 0.9-1.1wt% of water for injection, the sodium chloride solution is still supersaturated sodium chloride solution under the high-temperature environment of 125 ℃, because the solubility of betamethasone acetate is reduced because of the electrolyte contained in the solution, the ionization of the electrolyte in the solution needs water for supplement, for example, in saturated sodium chloride, water which can be used for dissolving non-electrolyte is lacked, therefore, in the supersaturated sodium chloride solution, betamethasone acetate can be prevented from being dissolved under the high temperature, the problem that the grain size is enlarged due to recrystallization in the cooling process after the dissolution is solved, in addition, the supersaturated sodium chloride solution has the sterilization effect, and under the supersaturated sodium chloride environment, the sealing treatment can be carried out for 10-30min under the environment of raising the temperature to 115 ℃ and 125 ℃ to achieve good sterilization effect, the cost is reduced, the damage to betamethasone acetate is reduced, and sodium chloride is used as an osmotic pressure regulator in the product.
And step two is carried out in a high-pressure reaction kettle, steam is generated in the heating process, and then moist heat sterilization is carried out.
In the fourth step, the filtration is firstly rough filtration through a 0.45 micron filter membrane, and then sterilization filtration through a 0.22 micron filter membrane, so that bacteria can be effectively filtered.
The homogenization step in the fifth step is carried out in a homogenizer at the stirring speed of 15000-.
Example 1
A method for preparing a glucocorticoid suspension comprises the following steps,
step one, 0.45 wt% of sodium chloride is put into 1wt% of water for injection and mixed to obtain insoluble glucocorticoid high-temperature protective solution;
step two, 0.3wt% of slightly soluble glucocorticoid is put into the slightly soluble glucocorticoid high-temperature protection solution obtained in the step one, wherein the particle size X is controlled 99 Less than or equal to 20 microns, the particle size distribution is shown in figure 1, the mixture is subjected to sealing treatment for 25min at the temperature of 121 ℃, and is cooled to room temperature, so that a pretreated insoluble glucocorticoid sterilization mixture is obtained, the particle size distribution of betamethasone acetate in the insoluble glucocorticoid sterilization mixture is shown in figure 2, and as can be seen from figures 1 and 2, the particle size distribution of betamethasone acetate after moist heat sterilization is not significantly changed;
step three, sequentially adding a buffering agent disodium hydrogen phosphate dihydrate and a metal ion complexing agent disodium edetate into 90wt% of injection water at the temperature of 30 ℃ to obtain a base solution;
step four, adding 0.3wt% of soluble glucocorticoid into the base solution, adjusting the pH to 6.8, and sterilizing and filtering to obtain a sterilized mixture of the soluble glucocorticoid;
and step five, mixing the sterilized mixture of the soluble glucocorticoid and the sterilized mixture of the insoluble glucocorticoid, supplementing the water for injection to the full amount, homogenizing and then packaging, wherein the homogenizing rotating speed is 18000r/min, and the homogenizing time is 20 min.
The test result of the acceleration experiment of the glucocorticoid suspension obtained in the embodiment is shown in figure 3, the acceleration condition is 40 +/-2 ℃/75% RH +/-5% RH, and the dissolution curve is shown in figure 4.
Example 2
A method for preparing a glucocorticoid suspension comprises the following steps,
step one, 0.45 wt% of sodium chloride is put into 1wt% of water for injection and mixed to obtain insoluble glucocorticoid high-temperature protective solution;
step two, 0.3wt% of slightly soluble glucocorticoid is put into the slightly soluble glucocorticoid high-temperature protection solution obtained in the step one, wherein the particle size X is controlled 99 Less than or equal to 10 mu m, the particle size distribution is shown in figure 5, the mixture is sealed for 25min at 121 ℃, and is cooled to room temperature, so that a pretreated insoluble glucocorticoid sterilization mixture is obtained, the particle size distribution of betamethasone acetate in the insoluble glucocorticoid sterilization mixture is shown in figure 6, and as can be seen from figures 5 and 6, the particle size distribution of betamethasone acetate after moist heat sterilization has no significant change;
step three, sequentially adding a buffering agent disodium hydrogen phosphate dihydrate and a metal ion complexing agent disodium edetate into 90wt% of injection water at the temperature of 30 ℃ to obtain a base solution;
step four, adding 0.3wt% of soluble glucocorticoid into the base solution, adjusting the pH to 6.8, and sterilizing and filtering to obtain a sterilized mixture of the soluble glucocorticoid;
and step five, mixing the sterilized mixture of the soluble glucocorticoid and the sterilized mixture of the insoluble glucocorticoid, supplementing the water for injection to the full amount, homogenizing and then packaging, wherein the homogenizing rotating speed is 18000r/min, and the homogenizing time is 20 min.
The test result of the acceleration experiment of the glucocorticoid suspension obtained in the embodiment is shown in figure 7, the acceleration condition is 40 +/-2 ℃/75% RH +/-5% RH, and the dissolution curve is shown in figure 8.
As can be seen from FIGS. 4 and 8, the obtained sample can stably and continuously release the active ingredient within 6 hours, and is safe and effective.
Comparative example 1
Step one, crushing betamethasone acetate by using a jet mill, and controlling the particle size X of the betamethasone acetate 99 Less than or equal to 10 μm. The particle size distribution after crushing is shown in figure 5;
step two, taking 20wt% of water for injection into a high-pressure reaction kettle;
step three, adding 0.3wt% of insoluble glucocorticoid with the prescription amount into the water for injection in step two, wherein the insoluble glucocorticoid selects betamethasone acetate, and the particle size X is controlled 99 Less than or equal to 10 mu m, sealing for 15min at 121 ℃, cooling to room temperature to obtain a pretreated slightly soluble glucocorticoid sterilization mixture, wherein the grain size distribution of betamethasone acetate in the slightly soluble glucocorticoid sterilization mixture is shown in figure 9, as can be seen from figures 5 and 9, the grain size distribution of betamethasone acetate after moist heat sterilization is obviously increased;
sequentially adding a buffering agent disodium hydrogen phosphate dihydrate, a metal ion complexing agent disodium edetate and an osmotic pressure regulator sodium chloride into 90wt% of injection water at the temperature of 30 ℃ to obtain a base solution;
step five, adding 0.3wt% of soluble glucocorticoid betamethasone sodium phosphate into the base solution, adjusting the pH to 6.8 by using a phosphoric acid solution, and performing sterilization and filtration to obtain a soluble glucocorticoid sterilized mixture;
and step six, mixing the soluble glucocorticoid mixture and the insoluble glucocorticoid sterilized mixture, supplementing the injection water to the full amount, homogenizing and then packaging, wherein the homogenizing rotating speed is 18000r/min, and the homogenizing time is 20 min.
Due to the fact that the insoluble glucocorticoid betamethasone acetate is subjected to moist heat sterilization in a sodium chloride supersaturated solution, the particle size is remarkably increased after sterilization, filling is caused to block a needle, and the product cannot be injected for use when in use.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.
Claims (8)
1. A method for preparing a glucocorticoid suspension is characterized by comprising the following steps,
mixing electrolyte and water to obtain a refractory glucocorticoid high-temperature protection solution;
step two, adding 0.25-0.35wt% of insoluble glucocorticoid into the insoluble glucocorticoid high-temperature protection solution obtained in the step one, wherein the dosage of the insoluble glucocorticoid high-temperature protection solution is 1.3-1.6 wt%, sealing and treating for 10-30min at the temperature of 115-125 ℃, and cooling to room temperature to obtain a pretreated insoluble glucocorticoid sterilization mixture;
step three, sequentially adding a buffering agent and a metal ion complexing agent into 90wt% of water for injection to obtain a base solution;
step four, adding 0.25-0.35wt% of soluble glucocorticoid into the base solution, adjusting the pH to 6.6-7.5, and sterilizing and filtering to obtain a sterilized mixture of the soluble glucocorticoid;
and step five, mixing the sterilized mixture of the soluble glucocorticoid and the sterilized mixture of the insoluble glucocorticoid, supplementing the water for injection to full dose, homogenizing and packaging.
2. The process for preparing a glucocorticoid suspension formulation according to claim 1, wherein the electrolyte is selected from one of sodium salts, potassium salts, calcium salts, and phosphate salts.
3. The process for preparing a glucocorticoid suspension formulation according to claim 2, wherein the electrolyte is one of potassium chloride, calcium chloride, disodium hydrogen phosphate, and sodium chloride.
4. The method for preparing a glucocorticoid suspension formulation according to claim 1, wherein the poorly soluble glucocorticoid is selected from one of betamethasone acetate, prednisone acetate, and hydrocortisone.
5. The process for preparing a glucocorticoid suspension formulation according to claim 1, wherein the buffering agent is one of disodium phosphate dihydrate, disodium phosphate dodecahydrate, and disodium phosphate.
6. The method for preparing a glucocorticoid suspension according to claim 1, characterized in that the metal ion complexing agent is disodium edetate.
7. The process for preparing a glucocorticoid suspension formulation according to claim 1, wherein the osmolality adjusting agent is sodium chloride.
8. The method for preparing a glucocorticoid suspension formulation according to claim 1, wherein the soluble glucocorticoid is selected from one of betamethasone sodium phosphate and dexamethasone.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962430A (en) * | 1974-08-07 | 1976-06-08 | Merck & Co., Inc. | Sterilization of solid non-electrolyte medicinal agents employing sodium chloride |
| CN102526078A (en) * | 2010-12-15 | 2012-07-04 | 重庆华邦制药股份有限公司 | Compound betamethasone suspension injection and preparation method thereof |
| CN113855630A (en) * | 2021-11-19 | 2021-12-31 | 莱默(北京)药业科技有限公司 | Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof |
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- 2022-04-29 CN CN202210466085.7A patent/CN114796109A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3962430A (en) * | 1974-08-07 | 1976-06-08 | Merck & Co., Inc. | Sterilization of solid non-electrolyte medicinal agents employing sodium chloride |
| CN102526078A (en) * | 2010-12-15 | 2012-07-04 | 重庆华邦制药股份有限公司 | Compound betamethasone suspension injection and preparation method thereof |
| CN113855630A (en) * | 2021-11-19 | 2021-12-31 | 莱默(北京)药业科技有限公司 | Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof |
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