CN115303644A - Method for reducing impurity growth rate of levocetirizine capsule - Google Patents
Method for reducing impurity growth rate of levocetirizine capsule Download PDFInfo
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- CN115303644A CN115303644A CN202211065413.9A CN202211065413A CN115303644A CN 115303644 A CN115303644 A CN 115303644A CN 202211065413 A CN202211065413 A CN 202211065413A CN 115303644 A CN115303644 A CN 115303644A
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Images
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/24—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants
- B65D81/26—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators
- B65D81/266—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators for absorbing gases, e.g. oxygen absorbers or desiccants
- B65D81/268—Adaptations for preventing deterioration or decay of contents; Applications to the container or packaging material of food preservatives, fungicides, pesticides or animal repellants with provision for draining away, or absorbing, or removing by ventilation, fluids, e.g. exuded by contents; Applications of corrosion inhibitors or desiccators for absorbing gases, e.g. oxygen absorbers or desiccants the absorber being enclosed in a small pack, e.g. bag, included in the package
Abstract
The invention discloses a method for reducing the impurity growth rate of a levocetirizine capsule, which comprises the following steps of packaging the levocetirizine capsule, packaging the capsule in a blister of a blister plate, packaging the blister plate in a composite film bag, and placing a double-suction type deoxidizer in the composite film bag; or encapsulating the capsule in a medicine packaging bottle, and placing double-absorption deoxidizer in the medicine packaging bottle. The invention utilizes the strong deoxidation capability and the weak dehydration capability of the double-absorption type deoxidizer to ensure that the active drug, namely the levocetirizine in the capsule is moisture-proof and oxygen-insulating, thereby avoiding the contact of the levocetirizine hydrochloride and oxygen in the air, greatly slowing down the growth of oxidative degradation impurities, simultaneously maintaining the moisture content of the capsule, preventing the drug quality problem caused by the change of the properties of the capsule shell, improving the drug quality of the levocetirizine hydrochloride capsule, and simultaneously prolonging the shelf life of the drug.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for reducing the impurity growth rate of levocetirizine capsules.
Background
Levocetirizine hydrochloride, is a selective histamine H1 receptor antagonist. The traditional Chinese medicine composition is mainly used for relieving allergic symptoms of allergic diseases, is clinically used for treating skin and mucosa allergic diseases such as allergic rhinitis, urticaria, angioneurotic edema and the like, and is also used for relieving the allergic symptoms during cold. The levocetirizine was firstly approved by UCB company in Germany for marketing in 2 months in 2001, is sold under the name of Xyzal, is in the form of tablets, is marketed in Switzerland, ireland and British in the same year, and is subsequently marketed in France, european Union and other countries. In 2005, UCB marketed levocetirizine oral liquid in germany, specification was 0.5mg/ml; in 2006, levocetirizine oral liquid was marketed in ireland. At present, levocetirizine is marketed in more than 90 countries around the world, and the dosage forms originally researched and marketed at home and abroad comprise tablets, oral liquid, syrup and the like, but are not marketed as capsules.
In the process of researching and developing levocetirizine hydrochloride capsules, the inventor finds that the capsules are poor in stability and high in impurity growth speed, and after 12 months of storage at normal temperature, the results of related substances are close to the upper limit of quality standards, so that the quality guarantee period of the medicines is short, and the market circulation of the medicines is influenced. In order to ensure that the quality of levocetirizine hydrochloride capsules in market circulation meets the quality standard, the problem that the impurities of the levocetirizine hydrochloride capsules grow too fast must be solved. The conventional solution is to adjust the formulation process or to improve the packaging quality. The workload of adjusting the prescription process of the preparation is large, and the bioequivalence evaluation is needed after the prescription process is changed, so the development period is long and the cost is high. Through research and research, the stability problem cannot be solved by changing the material of the packaging material, adding a drying agent or adding a deoxidizing agent and the like.
Disclosure of Invention
Aiming at the defects, the invention aims to solve the problem that the impurity grows too fast in the storage process of the levocetirizine capsule, and provides a method for reducing the impurity growth speed of the levocetirizine capsule.
According to one aspect of the invention, the method for reducing the impurity growth rate of the levocetirizine capsule comprises the following steps of packaging the capsule in a bubble cap of a bubble cap plate in a levocetirizine capsule packaging process, and packaging the bubble cap plate in a composite film bag, wherein a double-suction type deoxidizer is placed in the composite film bag.
Further, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the bagged amount of the composite film, and preferably, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 50% of the bagged amount of the composite film.
Further, under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50 +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not higher than 15%;
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 90% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not lower than 20%.
Furthermore, the impurities of the levocetirizine capsule are mainly oxidation impurities, and the oxidation impurities are p-chlorobenzophenone.
Further, after the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.1%, the increase amplitude of the total impurities is less than 0.2%, and the properties and dissolution rate of the capsule meet the quality standard.
Further, after the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.05%, the increase amplitude of the total impurities is less than 0.1%, and the properties and the dissolution rate of the capsule meet the quality standard.
According to another aspect of the invention, another method for reducing the growth rate of the oxidized impurities of the levocetirizine capsules is provided, wherein in the levocetirizine capsule packaging process, the capsules are packaged in a medicine packaging bottle, and a double-absorption type deoxidizer is placed in the medicine packaging bottle.
Further, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the volume of the medicine packaging bottle, and preferably not less than 50% of the volume of the medicine packaging bottle.
Further, under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50 +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not higher than 15%;
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 90% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not lower than 20%.
Further, the impurities of the levocetirizine capsule are mainly oxidation impurities, and the oxidation impurities are p-chlorobenzophenone.
After the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.1 percent, the increase amplitude of the total impurities is less than 0.2 percent, and the properties and the dissolution rate of the capsule meet the quality standard.
Further, after the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.05 percent, the increase amplitude of the total impurities is less than 0.1 percent, and the properties and the dissolution rate of the capsule meet the quality standard.
The invention has the beneficial effects that:
according to the method for reducing the growth rate of the impurities in the levocetirizine capsule, the double-absorption type deoxidizer is placed in the medicine packaging container, the medicine packaging container has a barrier property for air, the double-absorption type deoxidizer has strong deoxidizing capacity and weak dehydrating capacity, the active medicine levocetirizine in the capsule is enabled to insulate moisture and eliminate oxygen, the levocetirizine hydrochloride is prevented from contacting with oxygen in the air, the growth rate of oxidative degradation impurities is greatly reduced, the medicine quality is improved, meanwhile, the moisture content of the capsule can be maintained, the capsule shell is prevented from losing moisture and becoming brittle, the capsule properties and the medicine dissolution are further influenced, the medicine quality of the levocetirizine hydrochloride capsule is improved, and meanwhile, the quality guarantee period of the medicine is also prolonged.
Drawings
FIG. 1 is a graph comparing the increase in p-chlorobenzophenone and total impurities in an accelerated test of X200101 batches of levocetirizine hydrochloride capsule blister samples.
FIG. 2 is a graph comparing the growth of p-chlorobenzophenone and total impurities in a long term test of X200101 batches of levocetirizine hydrochloride capsule blister samples.
FIG. 3 is a graph comparing the increase of p-chlorobenzophenone and total impurities in an accelerated test of X200101 batches of levocetirizine hydrochloride capsule HDPE bottle packaging samples.
FIG. 4 is a graph comparing the growth of p-chlorobenzophenone and total impurities in a long-term test of X200101 batches of levocetirizine hydrochloride capsule HDPE bottle packaging samples.
Detailed Description
In the storage process of the levocetirizine hydrochloride capsule preparation, the impurities are obviously increased, and experimental researches show that the oxidative degradation impurities in the levocetirizine hydrochloride capsule preparation are main increasing impurities of p-chlorobenzophenone, and the corresponding total impurities are also increased. The p-chlorobenzophenone is known from the structure of p-chlorobenzophenone, is an oxidative degradation impurity of levocetirizine, and is mainly obtained by oxidizing levocetirizine after the molecular structure of levocetirizine is broken.
P-chlorobenzophenone levocetirizine hydrochloride.
In one embodiment of the invention, a method for reducing the growth rate of impurities in levocetirizine capsules is provided, which comprises the following steps: in the process of packaging the levocetirizine capsule, the prepared capsule is packaged in a bubble cap of a bubble cap plate, the bubble cap plate is packaged in a composite film bag, and a double-absorption deoxidizer is placed in the composite film bag.
The double-absorption type deoxidizer is also called a dry type deoxidizer, has strong deoxidizing capacity and weak dehydrating capacity, is prepared by mixing reduced iron powder, silica gel fine powder, salt, water and resin as main raw materials and packaging the main raw materials by adopting a solid medicinal polyethylene composite bag, can absorb moisture in the air and oxygen in the air, enables the medicine to insulate moisture and eliminate oxygen, and inhibits the active ingredients of the medicine in the levocetirizine capsule from contacting with the oxygen in the air, thereby avoiding the oxidative degradation of the levocetirizine to generate impurities, improving the quality of the medicine, prolonging the storage time of the levocetirizine capsule preparation and prolonging the shelf life of the medicine.
In the invention, the bubble cap plate is preferably an aluminum-plastic bubble cap plate, the composite film bag is preferably in a self-sealing bag form, the composite film bag is a first barrier for isolating the medicine from air, and the composite film bag in the self-sealing bag form is adopted, so that the medicine can still maintain the integrity of the package during the medicine taking period after reaching the hands of a consumer, and the degree of oxygen contact of capsules can be further reduced, but the dosage of each bag of capsules is not necessary, and the dosage of the medicine can be enough to maintain that the related substances of the medicine cannot be increased beyond the limit during the period. According to the embodiment of the invention, the packaging process of the composite film bag is added only after the original bubble cap process, the operation is simple and convenient, and the production efficiency is maintained unchanged.
Preferably, the total oxygen uptake of the double-uptake type deoxidizer is not less than 20% of the bagged amount of the composite film, more preferably, the total oxygen uptake of the double-uptake type deoxidizer is not less than 50% of the bagged amount of the composite film, and even more preferably, the total oxygen uptake of the double-uptake type deoxidizer is not less than the bagged amount of the composite film. The filling amount of the composite film bag refers to the volume of the composite film bag filled with oxygen (or air).
Preferably, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not higher than 15% under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50% +/-5%; the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not lower than 20 percent under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 90% +/-5%. The double-absorption type deoxidizer has the total oxygen absorption amount and the moisture absorption rate, and can effectively prolong the shelf life of the capsule medicine. The total oxygen absorption and the moisture absorption rate are measured according to the conventional measuring method. The determination of the moisture absorption rate is provided here only for reference as: taking a proper amount of samples (2 bags with the specification of less than 3 g/bag, and 1 bag with the specification of more than 3 g/bag), spreading the samples on a surface dish (or a suitable container), drying the samples at 150 +/-5 ℃ for 2 hours, cooling the dried samples to room temperature, quickly and precisely weighing the samples (m 1), putting the samples in a constant temperature and humidity box, and preparing two samples by the same method. The two samples are respectively placed for 48 hours under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50% +/-5% and 90% +/-5%, and then are taken out to be quickly and precisely weighed as (m 2). Calculated as follows: moisture absorption rate = (m 2-m 1)/m 1 × 100%.
The capsule shell of the levocetirizine hydrochloride capsule adopts a gelatin hollow capsule. The method adopts the double-absorption type deoxidizer, can prevent the oxidation degradation of the oxygen in the air to cause the increase of related substances, simultaneously keeps the medicine at proper relative humidity, prevents the capsule shell from losing moisture and becoming brittle, further influences the properties, dissolution and the like, and effectively maintains the medicine quality.
In another embodiment of the present invention, there is provided a method for reducing the rate of increase of the oxidized impurities in levocetirizine capsules, the method comprising: in the process of packaging the levocetirizine capsule, the capsule is packaged in a medicine packaging bottle, and a double-absorption deoxidizing agent is placed in the medicine packaging bottle. The medicine packaging bottle is a first barrier for the levocetirizine capsule and air, the material of the medicine packaging bottle is not limited, and the medicine packaging bottle can be used as a glass bottle, a plastic bottle or other materials for medicine packaging in the prior art. The embodiment is the same except that the blister plate and the composite film bag are replaced by the medicine packaging bottle.
After the prepared levocetirizine capsule is stored for 12 months at normal temperature, the capsule has no abnormal property, the increase amplitude of the oxidation impurities is less than 0.1 percent, preferably less than 0.05 percent, the increase amplitude of the total impurities is less than 0.2 percent, preferably less than 0.1 percent. The long-term 24-month stability test result shows that the related substance results are not obviously increased, and the properties, dissolution and the like of the capsule all meet the quality standard. By combining the analysis of the variation trend of each impurity, the shelf life of the levocetirizine capsule can be prolonged by at least 2 times to 36 months.
The following examples are merely illustrative of the present invention and should not be construed as limiting thereof.
Example 1
Preparing a batch of levocetirizine hydrochloride capsules, wherein the batch number is marked as X200101, and the capsule shells adopt gelatin hollow capsules (Ningbo broad-peak capsules Co., ltd.), packaging by bubble caps, and placing in 30ml composite membrane bags. A group of double-absorption deoxidizers added into the composite film bag is marked as A, a group of common deoxidizers added is marked as B, a group of common deoxidizers and drying agents added is marked as C, and a group of deoxidizers not added is marked as D. The total oxygen absorption amount of the double-absorption deoxidizer and the common deoxidizer is 30ml. Under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50 +/-5% or 90 +/-5%, the moisture absorption rates of the double-absorption type deoxidizer in 48 hours are respectively 13.5% and 28.1%; the moisture absorption rates of the common deoxidizer in 48 hours are respectively 1.3 percent and 3.9 percent; the moisture absorption rates of the desiccant for 48 hours were 27.6% and 40.1%, respectively.
Stability tests were conducted separately to examine the changes in finished product quality under accelerated conditions (40 ℃ C. + -. 2 ℃ C., RH75% + -. 5 ℃ C.) and long-term conditions (25 ℃ C. + -. 2 ℃ C., RH60% + -. 10 ℃ C.).
Table 1 is a table of accelerated test results of X200101 batches of blister samples, and tables 2 and 3 are tables of long-term test results of X200101 batches of blister samples.
FIG. 1 is a graph comparing the growth amplitude of p-chlorobenzophenone and total impurities in an accelerated test of X200101 blister samples, and FIG. 2 is a graph comparing the growth amplitude of p-chlorobenzophenone and total impurities in a long-term test of X200101 blister samples.
TABLE 1 table of results of accelerated test of blister-packed levocetirizine hydrochloride capsules for 6 months
TABLE 2 table of the test results of long-term test for 12 months for levocetirizine hydrochloride capsules packed in blister packs
TABLE 3 blister-packed levocetirizine hydrochloride capsule accelerated test results table for 18 months and 24 months
Example 2
A batch of levocetirizine hydrochloride capsules are prepared, the batch number is marked as X200101, the capsule shells adopt gelatin hollow capsules (Ningbo broad-peak capsules Co., ltd.), and 60ml high-density polyethylene (HDPE) bottles are adopted for packaging the capsules. A group of double-absorption deoxidizers added into the HDPE bottle is marked as A, a group of common deoxidizers added into the HDPE bottle is marked as B, a group of common deoxidizers added into the HDPE bottle is marked as C, and a group of common deoxidizers and drying agents added into the HDPE bottle is marked as D. The total oxygen absorption amount of the double-absorption type deoxidizer and the common deoxidizer is 30ml. Under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50 +/-5% or 90 +/-5%, the moisture absorption rates of the double-absorption type deoxidizer in 48 hours are 8.5% and 21.6% respectively; the moisture absorption rates of the common deoxidizer in 48 hours are respectively 2.1 percent and 4.0 percent; the moisture absorption rates of the desiccant for 48 hours were 19.6% and 31.6%, respectively.
Stability tests were conducted separately to examine the changes in finished product quality under accelerated conditions (40 ℃ C. + -. 2 ℃ C., RH75% + -. 5 ℃ C.) and long-term conditions (25 ℃ C. + -. 2 ℃ C., RH60% + -. 10 ℃ C.).
Table 4 is a table of results of accelerated test investigation of HDPE bottle packaging samples in X200101 batches, and table 5 is a table of results of long-term test investigation of HDPE bottle packaging samples in X200101 batches.
FIG. 3 is a graph showing the comparison of the growth rate of p-chlorobenzophenone and total impurities in an accelerated test for HDPE bottle packaging samples from batch X200101, and FIG. 4 is a graph showing the comparison of the growth rate of p-chlorobenzophenone and total impurities in a long-term test for HDPE bottle packaging samples from batch X200101.
TABLE 4 detection results of HDPE-packaged levocetirizine hydrochloride capsule accelerated test for 6 months
TABLE 5 detection results of HDPE-packaged levocetirizine hydrochloride capsules tested for 12 months
The results of example 1 and example 2 show that, after the common deoxidizer is added into the levocetirizine hydrochloride capsule, the moisture content of the capsule content is obviously increased, the capsule is bonded, and the impurity growth speed is faster. Because the common deoxidizer contains water, the deoxidizer releases water during oxygen absorption, so that the content or the shell of the capsule absorbs moisture and is damped, even the capsule bonding phenomenon occurs, the final finished product has obvious quality change, and the capsule bonding phenomenon under the bottling condition is more prominent. Meanwhile, the deoxidizer and the desiccant are added, so that although the increase speed of impurities is inhibited, the properties and dissolution of the capsule are problematic, because the levocetirizine hydrochloride capsule uses a gelatin hollow capsule, the requirement on environmental moisture is met, and the storage of the levocetirizine capsule preparation is not facilitated due to overhigh or overlow environmental moisture; the desiccant has strong moisture absorption capacity, so that the capsule shell is easily embrittled and the dissolution is slowed down, and the product quality is obviously changed. The double-absorption type deoxidizer is placed in the medicine package of the levocetirizine capsule, so that the deoxidizer can absorb oxygen, prevent the levocetirizine from oxidative degradation, has weak moisture absorption capacity, solves the problem of the increase of related substances of the levocetirizine hydrochloride capsule, and does not influence the quality of the capsule, and the results in table 2 show that 2 forms of adding the common deoxidizer, adding the common deoxidizer and the drying agent can not solve the problem, and the quality guarantee period of the capsule is less than 12 months. Table 3 the results of the long-term tests of the levocetirizine hydrochloride capsules packed by the blister for 18 months and 24 months show that the p-chlorobenzophenone and the total impurities of the capsules without the addition of the deoxidizer are close to the upper limit of the quality standard, the shelf life is only 18 months, while the impurity level of the capsules in 24 months is only slightly increased after the addition of the double-absorption deoxidizer, the impurity level has a large difference with the upper limit of the quality standard, the shelf life is expected to be more than 36 months, and the shelf life of the levocetirizine hydrochloride capsule preparation is at least prolonged by 2 times to 36 months.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.
Claims (10)
1. A method for reducing the growth rate of impurities in levocetirizine capsules is characterized in that in the levocetirizine capsule packaging process, the capsules are packaged in blisters of blister plates, the blister plates are packaged in composite film bags, and double-absorption type deoxidizing agents are placed in the composite film bags.
2. The method of reducing the rate of impurity growth in levocetirizine capsules according to claim 1,
the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the bagged amount of the composite film, and preferably, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 50% of the bagged amount of the composite film.
3. The method for reducing the rate of impurity growth in levocetirizine capsules according to claim 2,
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not higher than 15%;
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 90% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not lower than 20%.
4. The method for reducing the growth rate of impurities in levocetirizine capsules according to any one of claims 1 to 3, characterized in that,
the impurities of the levocetirizine capsule are mainly oxidation impurities, and the oxidation impurities are p-chlorobenzophenone.
5. The method of reducing the rate of impurity growth in levocetirizine capsules according to claim 4,
after the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.1 percent, the increase amplitude of the total impurities is less than 0.2 percent, and the properties and the dissolution rate of the capsule meet the quality standard.
6. A method for reducing the growth rate of impurities in levocetirizine capsules is characterized in that in the levocetirizine capsule packaging process, the capsules are packaged in a medicine packaging bottle, and a double-absorption type deoxidizing agent is placed in the medicine packaging bottle.
7. The method for reducing the rate of impurity growth in levocetirizine capsules according to claim 6,
the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the volume of the medicine packaging bottle, and preferably, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 50% of the volume of the medicine packaging bottle.
8. The method for reducing the rate of impurity growth in levocetirizine capsules according to claim 6,
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not higher than 15%;
under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 90% +/-5%, the moisture absorption rate of the double-absorption type deoxidizer in 48 hours is not lower than 20%.
9. The method for reducing the growth rate of the impurities in the levocetirizine capsule according to any one of claims 6 to 8, which is characterized in that,
the impurities of the levocetirizine capsule are mainly oxidation impurities, and the oxidation impurities are p-chlorobenzophenone.
10. The method for reducing the rate of impurity growth in levocetirizine capsules according to claim 9,
after the levocetirizine capsule is stored for 12 months at normal temperature, the increase amplitude of the oxidized impurities is less than 0.1 percent, the increase amplitude of the total impurities is less than 0.2 percent, and the properties and the dissolution rate of the capsule meet the quality standard.
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Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005296381A (en) * | 2004-04-13 | 2005-10-27 | Nippon Kayaku Co Ltd | Container and method for preserving capsule |
| CN202802161U (en) * | 2012-04-24 | 2013-03-20 | 上海樱琦干燥剂有限公司 | Medicine bottle filled with solid silica tablet desiccant |
| CN103153259A (en) * | 2010-10-12 | 2013-06-12 | 印度鲁宾有限公司 | Desiccant container |
| CN203486346U (en) * | 2013-04-03 | 2014-03-19 | 南京正大天晴制药有限公司 | Package improving stability of azelnidipine tablets |
| CN203698932U (en) * | 2014-02-27 | 2014-07-09 | 河北昆泰生物科技有限公司 | Safe medicine packaging bottle |
| CN203781034U (en) * | 2014-04-28 | 2014-08-20 | 吴蒙 | Double-bag deoxidizer-desiccant package bag |
| JP2015003753A (en) * | 2013-06-21 | 2015-01-08 | 三菱瓦斯化学株式会社 | Container and container including solid matter |
| CN106492620A (en) * | 2016-10-20 | 2017-03-15 | 干霸干燥剂(深圳)有限公司 | A kind of deoxidation type drier |
| CN206579982U (en) * | 2017-02-20 | 2017-10-24 | 重庆市药研院制药有限公司 | It is a kind of that there is the medicine bottle for buffering moistureproof adiabatic anti-oxidation function |
| US20170304150A1 (en) * | 2016-04-19 | 2017-10-26 | Ascent Pharmaceuticals, Inc. | Stable packaging system for moisture and oxygen sensitive pharmaceutical dosage forms |
| CN109499280A (en) * | 2018-10-23 | 2019-03-22 | 东莞理工学院 | A kind of deoxidation drying agent and preparation method thereof |
| CN110726788A (en) * | 2019-11-15 | 2020-01-24 | 湖南九典制药股份有限公司 | Method for separating and measuring levocetirizine hydrochloride and related substances thereof by high performance liquid chromatography |
| CN111186632A (en) * | 2018-11-15 | 2020-05-22 | 珠海润都制药股份有限公司 | Package for improving stability of medicine |
| US20210015776A1 (en) * | 2019-07-15 | 2021-01-21 | Ascent Pharmaceuticals, Inc. | Methods of stabilization of levothyroxine sodium tablets |
| CN214190807U (en) * | 2020-12-31 | 2021-09-14 | 鲁南制药集团股份有限公司 | Medicine packaging bag |
-
2022
- 2022-09-01 CN CN202211065413.9A patent/CN115303644A/en active Pending
Patent Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005296381A (en) * | 2004-04-13 | 2005-10-27 | Nippon Kayaku Co Ltd | Container and method for preserving capsule |
| CN103153259A (en) * | 2010-10-12 | 2013-06-12 | 印度鲁宾有限公司 | Desiccant container |
| CN202802161U (en) * | 2012-04-24 | 2013-03-20 | 上海樱琦干燥剂有限公司 | Medicine bottle filled with solid silica tablet desiccant |
| CN203486346U (en) * | 2013-04-03 | 2014-03-19 | 南京正大天晴制药有限公司 | Package improving stability of azelnidipine tablets |
| JP2015003753A (en) * | 2013-06-21 | 2015-01-08 | 三菱瓦斯化学株式会社 | Container and container including solid matter |
| CN203698932U (en) * | 2014-02-27 | 2014-07-09 | 河北昆泰生物科技有限公司 | Safe medicine packaging bottle |
| CN203781034U (en) * | 2014-04-28 | 2014-08-20 | 吴蒙 | Double-bag deoxidizer-desiccant package bag |
| US20170304150A1 (en) * | 2016-04-19 | 2017-10-26 | Ascent Pharmaceuticals, Inc. | Stable packaging system for moisture and oxygen sensitive pharmaceutical dosage forms |
| CN106492620A (en) * | 2016-10-20 | 2017-03-15 | 干霸干燥剂(深圳)有限公司 | A kind of deoxidation type drier |
| CN206579982U (en) * | 2017-02-20 | 2017-10-24 | 重庆市药研院制药有限公司 | It is a kind of that there is the medicine bottle for buffering moistureproof adiabatic anti-oxidation function |
| CN109499280A (en) * | 2018-10-23 | 2019-03-22 | 东莞理工学院 | A kind of deoxidation drying agent and preparation method thereof |
| CN111186632A (en) * | 2018-11-15 | 2020-05-22 | 珠海润都制药股份有限公司 | Package for improving stability of medicine |
| US20210015776A1 (en) * | 2019-07-15 | 2021-01-21 | Ascent Pharmaceuticals, Inc. | Methods of stabilization of levothyroxine sodium tablets |
| CN110726788A (en) * | 2019-11-15 | 2020-01-24 | 湖南九典制药股份有限公司 | Method for separating and measuring levocetirizine hydrochloride and related substances thereof by high performance liquid chromatography |
| CN214190807U (en) * | 2020-12-31 | 2021-09-14 | 鲁南制药集团股份有限公司 | Medicine packaging bag |
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