CN112370422A - Drotaverine hydrochloride injection stabilized by substituted beta-cyclodextrin and preparation method thereof - Google Patents
Drotaverine hydrochloride injection stabilized by substituted beta-cyclodextrin and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and provides a drotaverine hydrochloride injection stabilized by substituted beta-cyclodextrin and a preparation method thereof. The invention relates to a drotaverine hydrochloride injection stabilized by substituted beta-cyclodextrin, which comprises drotaverine hydrochloride, sodium metabisulfite, a solubilizer, a pH regulator and water for injection; the solubilizer is beta-cyclodextrin or derivatives thereof, preferably sulfobutyl-beta-cyclodextrin or sodium salt thereof. The drotaverine hydrochloride injection can effectively improve the compliance of patients in the using process, has no adverse reaction of vascular stimulation and has low hemolysis risk.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a drotaverine hydrochloride injection stabilized by substituted beta-cyclodextrin and a preparation method thereof.
Background
Drotaverine hydrochloride (Drotaverine hydrochloride), chemical name: 1- { (3, 4-diethoxyphenyl) methylene } -6, 7-diethoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride, which is sold under the trade name of Noishapa (RNO-SPA), is a novel spasmolytic drug developed by Chinoin pharmaceutical factory, a joint venture company, Hungary, of France. The medicine is isoquinoline derivative, and is different from the traditional anticholinergic spasm relieving medicines such as anisodamine, atropine and the like, the medicine directly acts on smooth muscle cells, and the action mechanism of relaxing the smooth muscle is as follows: acting on the surface of smooth muscle cells to change the membrane potential and permeability of the cells; inhibiting phosphodiesterase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels; inhibit the initial calcium ion reaction in cells, relax smooth muscle, and relieve spasm. The method is characterized in that: (1) the medicine has comprehensive effects and lasting curative effect, the drotaverine hydrochloride has effects on each link of spastic contraction of smooth muscle, especially high-tension smooth muscle, the elimination half-life period is 9-11h, and the effective period is long; (2) the adverse reaction is small, the drotaverine hydrochloride does not influence the autonomic nervous system, has no influence on normal smooth muscle of gastrointestinal tract, and has no adverse reaction of M receptor antagonist. The medicine has indications including coronary insufficiency, obliterative endarteritis, angina pectoris, gastrointestinal smooth muscle spasm, irritable bowel syndrome, biliary colic, renal colic, urinary tract spasm, uterine spasm, dysmenorrhea, etc. Its advantages are no serious cardiovascular reaction, no parasympathetic block, no enlargement of pupil, no acute attack of glaucoma, no expansion of urinary bladder, quickly taking its effect and less untoward reaction.
Because the drotaverine hydrochloride has low solubility and poor stability in water, oxidation reaction is easy to occur, and the safety and the effective use of the product are influenced. The existing original research preparation and other marketed drotaverine hydrochloride injection adopt ethanol as solubilizer, and patients have severe pain and poor compliance during subcutaneous and intramuscular injection.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a drotaverine hydrochloride injection with stable substituted beta-cyclodextrin and a preparation method thereof, wherein a solubilizer in the original preparation is changed from ethanol to sulfobutyl-beta-cyclodextrin, so that the pain in the use process is reduced and the compliance of a patient is improved while the medicine is dissolved.
The invention is realized by the following technical scheme.
The drotaverine hydrochloride injection stabilized by the substituted beta-cyclodextrin is characterized by comprising drotaverine hydrochloride, sodium metabisulfite, a solubilizer, a pH regulator and water for injection; the solubilizer is beta-cyclodextrin or derivatives thereof.
Further, the solubilizer is preferably sulfobutyl-beta-cyclodextrin or sodium salt thereof.
Further, the solubilizer is used in an amount of 0.6% to 10%, preferably 1.0% to 8.0%, more preferably 2.0% to 5.0%, most preferably 3.0%.
Further, the pH regulator is selected from one or more of sodium hydroxide, hydrochloric acid, arginine, citric acid, lactic acid, tartaric acid, malic acid, sodium citrate and potassium citrate.
Further, the pH of the drotaverine hydrochloride injection is preferably 3.0-7.0, and more preferably 4.0-6.0.
Furthermore, the preparation volume of the drotaverine hydrochloride injection is preferably 2mL, 5mL, 10mL, 50mL or 100 mL.
Furthermore, the drotaverine hydrochloride injection can be diluted by adopting normal saline or a glucose sodium chloride solution according to the actual use requirement.
On the other hand, the invention also provides a preparation method of the drotaverine hydrochloride injection stabilized by the substituted beta-cyclodextrin, which is characterized by comprising the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) adding sodium metabisulfite and a solubilizer into the water for injection, and uniformly mixing;
(3) adding the formula amount of drotaverine hydrochloride, and uniformly stirring;
(4) adjusting pH, fixing volume, encapsulating and sterilizing.
Further, the preparation method comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) adding sodium metabisulfite and sulfobutyl-beta-cyclodextrin sodium in the prescribed amount into 80 percent of water for injection, and stirring until the sodium metabisulfite and the sulfobutyl-beta-cyclodextrin sodium are completely dissolved;
(3) adding the formula amount of drotaverine hydrochloride, and stirring to completely dissolve;
(4) adjusting pH to 4.0-6.0 with the pH regulator, adding cooled water for injection to make the total amount of the solution, sealing, and sterilizing at 121 deg.C for 15 min.
The invention has the beneficial effects that:
(1) compared with ethanol as a solubilizer, the sulfobutyl-beta-cyclodextrin is used as the solubilizer, so that the compliance of a patient in the using process can be effectively improved;
(2) compared with the possible adverse reactions of ethanol, such as vascular stimulation and hemolysis risk, the beta-cyclodextrin has better safety;
(3) the solubilization effect is stronger, and the cyclodextrin only needs lower dosage to meet the solubilization effect.
Drawings
FIG. 1 shows the results of a pre-shaking hemolysis assay, tubes 1-8 in sequence from left to right, where tubes 1-2 are commercially available control samples; test tubes 3-5 are samples of examples 3-5 of the present invention; tube 6 is a negative control sample and tube 7 is a positive control; tube 8 is a blank sample.
FIG. 2 shows the results of the hemolysis test after shaking, which are test tubes 1-8 in turn from left to right, wherein test tube 1-2 is a commercial control sample; test tubes 3-5 are samples of examples 3-5 of the present invention; tube 6 is a negative control sample and tube 7 is a positive control; tube 8 is a blank sample.
Detailed Description
The paliperidone sustained-release composition and the preparation method thereof according to the present invention will be further explained and illustrated by examples. It should be understood that: the embodiments of the present invention are given for illustration only and not for limitation, and any simple modification of the present invention based on the technical solution of the present invention falls within the protection scope of the present invention.
EXAMPLE 1 sulfobutyl-beta-cyclodextrin solubilizer usage
Prepared according to the prescription of the table 1, and the process comprises the following steps: adding 100mL of water for injection into a 250mL beaker, and adding sodium metabisulfite with a prescription amount and sulfobutyl-beta-cyclodextrin sodium with different prescription amounts at room temperature, wherein the dosage of the sulfobutyl-beta-cyclodextrin sodium is respectively as follows: 0.5%, 0.9%, 1.5%, 3.0% and 5.0%, stirring for dissolving, adding formula amount of drotaverine hydrochloride, stirring, and observing the solvent condition of each formula.
The dosage and results are shown in Table 1.
TABLE 1 examination of the amount of sulfobutyl-beta-cyclodextrin solubilizer used
The test phenomenon shows that 0.9% -5% of sulfobutyl-beta-cyclodextrin sodium generates obvious solubilization action on the dissolution of the drotaverine hydrochloride raw material medicine, and no test is carried out for more than 5% of dosage, so that firstly, the production requirement can be completely met by 5% of dosage, and secondly, the cost is controlled.
Example 2 different formulations and pH investigation
Prepared according to the prescription of the table 2, and the process comprises the following steps: adding 200mL of purified water into a 250mL beaker, adding a prescribed amount of sodium metabisulfite and sulfobutyl-beta-cyclodextrin sodium at room temperature, stirring to dissolve, adding a prescribed amount of drotaverine hydrochloride, stirring to dissolve completely, adjusting the pH value of the liquid medicine to 5, 6,7 and 8 by using 1mol/L sodium hydroxide solution, filling 3 samples of five pH values of 5, 6,7 and 8 which are not adjusted, rolling a cover, sterilizing at 121 ℃ for 15min, observing the properties of the sample after sterilization, and carrying out a freeze-thaw test.
TABLE 2 drotaverine hydrochloride injection with different prescriptions
| Name of raw and auxiliary materials | Prescription one | Prescription two | Prescription three | Prescription four |
| Drotaverine hydrochloride | 4.0g | 4.0g | 4.0g | 4.0g |
| Sodium metabisulfite | 0.3g | 0.3g | 0.3g | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 4.0g | 6.0g | 10.0g | 14.0g |
| 1mol/L sodium hydroxide solution | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Purified water usage | 200mL | 200mL | 200mL | 200mL |
The results are shown in Table 3.
In the current range, the pH of the finished product is almost not influenced by the dosage of different sulfobutyl-beta-cyclodextrin sodium, the pH is about 4.5 when alkali liquor is not added, and turbidity appears when the pH is adjusted to 6.7-6.8; the results of freeze-thaw tests (12 h at-20 ℃ night and 12h at 40 ℃ day for 2 cycles) show that no turbidity is generated in each small sample batch under the three conditions of no adjustment, pH5.0 and pH6.0, and the solution remains clear.
TABLE 3 pH value investigation results for different sodium sulfobutyl-beta-cyclodextrin dosages
| Preparation process | Is not regulated | pH5.0 | pH6.0 | pH7.0 | pH8.0 |
| Prescription one (2%) | Clarification | Clarification | Clarification | Turbidity | - |
| Prescription two (3%) | Clarification | Clarification | Clarification | Turbidity | - |
| Prescription three (5%) | Clarification | Clarification | Clarification | Turbidity | - |
| Prescription four (7%) | Clarification | Clarification | Clarification | Turbidity | - |
Example 3
The prescription is as follows:
the preparation process comprises the following steps:
the water is added, and 80 percent of water for injection is automatically injected. And opening a nitrogen valve, adding nitrogen, and filling nitrogen into the liquid preparation tank for 40-45 minutes. Opening a freezing water valve, cooling the solution in the solution preparation tank, adding sodium metabisulfite and sulfobutyl-beta-cyclodextrin sodium in the amount of a prescription when the water temperature is 20-45 ℃, stirring to completely dissolve, adding drotaverine hydrochloride in the amount of the prescription, stirring to completely dissolve, adjusting the pH to 4.0-6.0 by using 1mol/L sodium hydroxide, performing constant volume, supplementing the cooled injection water to ensure that the total amount of the solution in the solution preparation tank is up to the total amount of the solution preparation, and sterilizing at the temperature of 121 ℃ for 15min after encapsulation.
Example 4
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 1.2g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 5
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 2.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 6
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 4.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 7
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 8.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 8
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 10.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 9
The prescription is as follows:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 16.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Example 10 the recipe is:
| name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 20.0g |
| 1mol/L sodium hydroxide solution | Proper amount of |
| Water for injection | Is added to200mL |
The preparation process is the same as in example 3.
Example 11
| Name of raw and auxiliary materials | Dosage of |
| Drotaverine hydrochloride | 4.0g |
| Sodium metabisulfite | 0.3g |
| Sulfobutyl-beta-cyclodextrin sodium | 6.0g |
| Arginine | 0.1g |
| Water for injection | Adding to 200mL |
The preparation process is the same as in example 3.
Test example 1 hemolysis test of drotaverine hydrochloride injection
In vitro experiments were performed using 2% erythrocyte suspensions, with a negative control (0.9% sodium chloride injection), a positive control (sterile water for injection), a test sample (examples 3-5, preparation stock solution) and a commercially available control (nospora, preparation stock solution), loaded as required, placed in an electric-thermal incubator at 37 ℃ and incubated for 3h to observe the presence or absence of erythrocyte hemolysis and aggregation.
After each test tube is loaded, the commercial control group and the positive control group are partially hemolyzed and/or totally hemolyzed, and the test group and the negative control group are not hemolyzed and agglutinated (see fig. 1-fig. 2).
Test example 2 irritation test of drotaverine hydrochloride injection
10 healthy New Zealand rabbits (for both males and females) were divided into a test group (example 3) and a commercial control group (Noishapa), each of which was 5 rabbits. The test sample or the stock solution of the commercial control preparation is administered to the left ear of each group by means of auricular marginal intravenous infusion at a dose of 4mg/kg for 1 time per day for 7 days. The right side of the same body was given 0.9% sodium chloride injection per se for the comparative mode of administration, the method of administration being the same as that on the left side. Detailed clinical symptom observations were made once a day, and local irritation responses at the injection site were visually observed 1 time per day before and on non-dosing days on a daily basis. At 72h after the last administration, after each group of euthanized animals, the rabbit ears were cut together at the ear roots for histopathological examination, and the remaining animals were recovered.
During the test, there was no abnormality at the administration site on the control side, and local edema was observed on the administration side of the commercial control group. 72h after the last administration, the irritation such as administration position, blood vessel or surrounding tissue edema at the proximal end and distal end of the administration side, vascular endothelium damage, inflammatory cell infiltration and the like can be seen through gross anatomical macroscopic observation and pathological histological microscopic examination, and the contrast side has no abnormality basically. The test article group had no abnormality. This indicates that: the commercial control group can cause vascular irritation, and the test group has no abnormality.
Test example 3 active systemic anaphylaxis test of drotaverine hydrochloride injection
24 guinea pigs which were qualified for quarantine were divided into a negative control group (0.9% sodium chloride injection), a positive control group (bovine serum albumin, 20 mg/guinea pig), a test sample group (example 3, 10 mg/guinea pig) and a commercial control group (nosepar, 10 mg/guinea pig) by a general latin method, each group was 6 animals, and each animal was male and female. The preparation is administrated by intraperitoneal injection of 0.5mL per group, 1 time every other day, and 3 times of sensitization. On 14 days and 21 days after the last sensitization, 1.0 mL/volume of the preparation is rapidly administered by intraperitoneal injection to corresponding groups for excitation, 1 time is observed after each sensitization during sensitization, 1 time is observed every day on non-administration days, and 3 hours is observed immediately after excitation. And body weights were measured on the day of group, first and last sensitization and challenge.
During the test period, all animals did not show abnormal symptoms due to the administration, and the weight gain was normal. After the negative control group, the test sample group and the commercial control group are stimulated, the systemic anaphylactic reaction grade is negative, the anaphylactic reaction grade is negative, after the positive control group is stimulated, the reaction grade is positive, and the anaphylactic reaction is positive. The result of the active systemic anaphylactic reaction of the tested guinea pig sample of the flexovirin hydrochloride injection is negative, and has no difference compared with the contrast product sold in the market.
While the preferred embodiments and principles of this invention have been described in detail, it will be apparent to those skilled in the art that variations may be made in the embodiments based on the teachings of the invention and such variations are considered to be within the scope of the invention.
Claims (9)
1. A substituted beta-cyclodextrin stabilized drotaverine hydrochloride injection, which is characterized in that the components of the injection comprise drotaverine hydrochloride, sodium metabisulfite, solubilizer, pH regulator and water for injection; the solubilizer is beta-cyclodextrin or derivatives thereof.
2. Drotaverine hydrochloride injection according to claim 1, characterized in that the solubilizer is preferably sulfobutyl- β -cyclodextrin or its sodium salt.
3. Drotaverine hydrochloride injection according to claim 1, characterized in that the amount of the solubilizer is 0.6% -10%, preferably 1.0% -8.0%, more preferably 2.0-5.0%, most preferably 3.0%.
4. The drotaverine hydrochloride injection as claimed in claim 1, wherein the pH regulator is selected from one or more of sodium hydroxide, hydrochloric acid, arginine, citric acid, lactic acid, tartaric acid, malic acid, sodium citrate and potassium citrate.
5. Drotaverine hydrochloride injection according to claim 1, characterized in that the pH of the drotaverine hydrochloride injection is preferably 3.0-7.0, more preferably 4.0-6.0.
6. Drotaverine hydrochloride injection according to claim 1, wherein the formulation volume of the drotaverine hydrochloride injection is preferably 2mL, 5mL, 10mL, 50mL or 100 mL.
7. The drotaverine hydrochloride injection as claimed in claim 1, wherein the drotaverine hydrochloride injection can be diluted with physiological saline or dextrose and sodium chloride solution according to actual use requirements.
8. A process for the preparation of the drotaverine hydrochloride injection according to any one of claims 1 to 7, comprising the steps of:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) adding sodium metabisulfite and a solubilizer into the water for injection, and uniformly mixing;
(3) adding the formula amount of drotaverine hydrochloride, and uniformly stirring;
(4) adjusting pH, fixing volume, encapsulating and sterilizing.
9. The method of claim 8, comprising the steps of:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) adding sodium metabisulfite and sulfobutyl-beta-cyclodextrin sodium in the prescribed amount into 80 percent of water for injection, and stirring until the sodium metabisulfite and the sulfobutyl-beta-cyclodextrin sodium are completely dissolved;
(3) adding the formula amount of drotaverine hydrochloride, and stirring to completely dissolve;
(4) adjusting pH to 4.0-6.0 with the pH regulator, adding cooled water for injection to make the total amount of the solution, sealing, and sterilizing at 121 deg.C for 15 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105392469A (en) * | 2013-04-02 | 2016-03-09 | 西弥斯医疗有限公司 | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
| CN110054714A (en) * | 2019-01-30 | 2019-07-26 | 宁夏医科大学 | A kind of preparation method of Hydrogen sulfobutyl ether beta-cyclodextrin |
-
2020
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105392469A (en) * | 2013-04-02 | 2016-03-09 | 西弥斯医疗有限公司 | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
| CN110054714A (en) * | 2019-01-30 | 2019-07-26 | 宁夏医科大学 | A kind of preparation method of Hydrogen sulfobutyl ether beta-cyclodextrin |
Non-Patent Citations (1)
| Title |
|---|
| 刘晓玲等: "盐酸屈他维林致严重肌肉疼痛2例", 《医药导报》 * |
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