CN115258421A

CN115258421A - Packaging method for improving capsule stability

Info

Publication number: CN115258421A
Application number: CN202211060926.0A
Authority: CN
Inventors: 王铁闯; 苏艳红; 曾琳; 唐湘; 胡艳霞
Original assignee: HUNAN PUDAO MEDICAL TECHNOLOGY CO LTD; Hunan Jiudian Pharmaceutical Co Ltd
Current assignee: HUNAN PUDAO MEDICAL TECHNOLOGY CO LTD; Hunan Jiudian Pharmaceutical Co Ltd
Priority date: 2022-09-01
Filing date: 2022-09-01
Publication date: 2022-11-01
Anticipated expiration: 2042-09-01
Also published as: CN115258421B

Abstract

The invention discloses a packaging method for improving capsule stability and a capsule adopting the packaging method, wherein the active pharmaceutical ingredient of the capsule is an oxygen sensitive medicament, the packaging method comprises the step of encapsulating the capsule in a medicine packaging container, and a double-absorption deoxidizer is placed in the medicine packaging container. The packaging method can prevent the oxygen sensitive medicine from being oxidized due to the contact with oxygen in the air to increase related substances, simultaneously keep proper relative humidity, and prevent the capsule shell from losing moisture and becoming brittle so as to influence the medicine property, dissolution and the like, thereby effectively maintaining the medicine quality. Compared with the method of directly adding the antioxidant in the prescription of the medicine, the method can avoid the problem of compatibility of raw and auxiliary materials possibly caused by adding auxiliary materials, and can also avoid reevaluation caused by changing the prescription process of the preparation.

Description

Packaging method for improving capsule stability

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a packaging method for improving capsule stability, a capsule adopting the packaging method, and application of a double-absorption type deoxidizer in preparation of an oxygen sensitive type pharmaceutical capsule medicament.

Background

Drug stability is a major and difficult point in drug development. The drug can introduce moisture and oxygen in the links of production, storage, circulation and the like, so that impurities grow and exceed the limit of quality standards, and the stability problem of the drug can be solved by controlling a preparation process, packaging, a drying agent and the like. Oxygen sensitive drugs often require additional excipients, packaging and/or manufacturing steps for enhanced stability. Chemical methods such as pH control, addition of antioxidants, and control components are generally considered first as a means of enhancing the stability of oxygen sensitive drugs. The chemical method has the disadvantages that the compatibility of raw materials and auxiliary materials can be caused by adding new auxiliary materials, and the reevaluation can be caused by changing the prescription process of the preparation.

Oxygen sensitive pharmaceutical formulations also require extra care to exclude air and oxygen during storage and circulation. Oxygen sensitive active pharmaceutical ingredients are susceptible to oxidation by oxygen to produce impurities that result in the related substances growing too rapidly to exceed quality standards. Packaging of medicines is an important factor for preventing the occurrence of such variations in storage and distribution of medicines beyond the limits. Generally, the medicines are directly packaged into a packaging box after being packaged by a blister, but the medicines still have certain permeability after being packaged by the blister due to the barrier property of a packaging material, a packaging process and the like, and can still contact moisture or oxygen, so that the medicines are degraded or deteriorated. Sealing the blister card within the composite film pouch can further reduce the degree of contact between the drug and moisture and oxygen, but the risk of degradation or spoilage of the highly active pharmaceutical ingredient is still high. In order to further reduce the risk that the quality of the medicine exceeds the quality standard, a drying agent and/or a deoxidizing agent can be added into the composite film bag for the tablet or the preparation which is not sensitive to moisture enough, so that moisture and/or oxygen can be continuously absorbed, and the stability of the preparation is improved.

However, for oxygen sensitive drug capsules, the common deoxidizer still cannot solve the problem of impurity growth during long-term storage. Meanwhile, the desiccant is added, so that the characteristics of the capsule shell can be changed, and the properties of the capsule, the dissolution of the medicine and the like are influenced.

Disclosure of Invention

The invention aims to provide a packaging method for improving the stability of capsules and capsules adopting the packaging method, wherein the packaging method can prevent or reduce the oxidation impurities generated by oxidation of oxygen-sensitive medicines in the capsules and prevent the quality of medicines from being influenced by the denaturation of capsule shells.

The invention also aims to provide the application of the double-absorption type deoxidizer in the preparation of oxygen sensitive medicine capsules.

According to one aspect of the invention, a packaging method for improving the stability of a capsule is provided, wherein the pharmaceutically active ingredient of the capsule is an oxygen-sensitive medicament, the packaging method is that the capsule is packaged in a medicine packaging container, and a double-absorption type deoxidizer is placed in the medicine packaging container.

Further, the capsule shell of the capsule contains gelatin. The capsule can be a hard capsule or a soft capsule.

Further, the capsule is one of a gelatin hollow capsule, an enteric gelatin hollow capsule or a gelatin soft capsule.

Further, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the packaging container.

Further, the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 50% of the packaging container.

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, in one embodiment, the medicine packing container is a medicine packing bottle.

Further, in another embodiment, the pharmaceutical packaging container is a composite film bag, and the capsule is first enclosed in a blister of a blister sheet, and the blister sheet is then enclosed in the composite film bag.

Further, the oxygen-sensitive drug is selected from at least one of the following: cetirizine, levocetirizine, acetaminophen, ibuprofen, acetylcysteine, carbamazepine, verapamil, selegiline, ephedrine, oxybutynin, diltiazem, mexiletine, emedastine.

According to another aspect of the invention, a capsule is also provided, and the capsule is packaged by adopting the packaging method for improving the stability of the capsule.

According to another aspect of the present invention, there is provided the use of a dual-absorption type deoxidizer in the preparation of an oxygen sensitive pharmaceutical capsule medicament for slowing the rate of growth of the oxidative impurities of the medicament and preventing the denaturation of the capsule shell, thereby improving the stability and safety of the capsule medicament.

The invention has the beneficial effects that:

according to the packaging method for improving the capsule stability, the active pharmaceutical ingredient of the capsule is an oxygen-sensitive drug, the capsule is packaged in a drug packaging container, a double-absorption type deoxidizer is placed in the drug packaging container, the drug packaging container has a barrier property to air, and the double-absorption type deoxidizer has strong deoxidizing capacity and weak dehydrating capacity, so that the drug is moisture-proof and oxygen-insulating, the active pharmaceutical ingredient in the capsule is inhibited from being in contact with oxygen in the air to be oxidized and degraded to generate impurities, the drug quality is improved, meanwhile, the moisture of the capsule can be maintained, the capsule shell is prevented from losing moisture and becoming brittle, the quality such as properties and dissolution is further influenced, and the drug shelf life of the capsule is effectively prolonged. Compared with the method of directly adding the deoxidizer in the prescription of the medicine, the deoxidizer can not only avoid the problem of compatibility of raw materials and auxiliary materials possibly caused by adding auxiliary materials, but also avoid the reevaluation caused by changing the prescription process of the preparation.

Drawings

FIG. 1 is a graph showing the comparison of the growth rate of p-chlorobenzophenone and total impurities in an accelerated test of X200101 batches of levocetirizine hydrochloride blister samples.

FIG. 2 is a graph showing the comparison of the growth rate 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.

Fig. 5 is a graph comparing the increase of impurity C and total impurities in the accelerated test of X201101 batch acetylcysteine capsule blister sample.

Figure 6 is a graph comparing the magnitude of the increase in impurity C and total impurities in the long-term test of batch X201101 acetylcysteine capsule blister samples.

Detailed Description

The invention provides a packaging method for improving capsule stability, wherein the active pharmaceutical ingredient of a capsule is an oxygen-sensitive medicament, the oxygen-sensitive medicament is oxidized and degraded when contacting with oxygen in the air, so that related impurities and total impurities are increased, and the quality of the medicament is influenced. The capsule is packaged in a medicine packaging container, and a double-absorption type deoxidizer is placed in the medicine packaging container.

The double-absorption type deoxidant, also called dry type deoxidant, has strong deoxidant ability and weak dehydration ability, is prepared by mixing reduced iron powder, silica gel fine powder, salt, resin and water as main raw materials and packaging the main raw materials by adopting a solid medicinal polyethylene composite bag, and can absorb moisture and oxygen in the air, so that the medicine can insulate moisture and insulate oxygen, inhibit the contact oxidation and degradation of active ingredients in the capsule and oxygen in the air to generate impurities and improve the quality of the medicine.

The packaging method for improving the capsule stability can be used for preparing hard capsules or soft capsules, and is particularly suitable for capsules of which the capsule shells contain gelatin, such as gelatin empty capsules, enteric gelatin empty capsules, gelatin soft capsules and the like. If a drying agent is added into the capsule, the capsule shell becomes brittle when the water weight loss is lower than the lower limit, and even the dissolution speed of the medicine can be influenced, so that the medicine quality is unqualified.

One embodiment of the invention is that the packaging container is a medicine packaging bottle. Directly packaging the capsule in a medicine packaging bottle, and placing double-absorption deoxidizer in the medicine packaging bottle. The medicine packaging bottle has a blocking function on 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.

Another embodiment of the invention is that the capsule is firstly packaged in the bubble cap of the bubble cap plate, the bubble cap plate is sealed and arranged in the composite film bag, the composite film bag has the air barrier property, and the double-absorption type deoxidizer is placed in the composite film bag. The composite film bag is preferably in the form of a self-sealing bag so that the integrity of the package is maintained after the medication reaches the consumer's hand, reducing the exposure of the capsules to oxygen, but not necessarily, the dosage of each capsule is sufficient to maintain the medication in the bag without increasing beyond its limits with respect to the substances involved. 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 kept unchanged.

Preferably, the total oxygen absorption amount of the double absorption type deoxidizer is not less than 20% of the content of the packaging container, more preferably not less than 50% of the content of the packaging container. When the medicine packaging container is a medicine packaging bottle, the filling amount of the medicine packaging container refers to the volume of the medicine packaging bottle; when the medicine packaging container is a composite film bag, the filling amount of the medicine packaging container refers to the volume of the composite film bag filled with oxygen (or air).

Preferably, the double-absorption type deoxidizer has the moisture absorption rate of not higher than 15 percent in 48 hours under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 50 +/-5 percent; 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%. 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. Only one method for determining moisture absorption rate is provided herein for reference: taking a proper amount of samples (2 bags with the specification of below 3 g/bag, and 1 bag with the specification of above 3g and 3 g/bag), flatly spreading the samples on a surface dish (or a suitable container), drying the samples at the temperature of 150 +/-5 ℃ for 2 hours, cooling the dried samples to room temperature, quickly and precisely weighing the samples (m 1), flatly placing the dried 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 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%.

In the invention, the active pharmaceutical ingredient of the capsule is an oxygen sensitive medicament. The oxygen sensitive drug is selected from at least one of the following: cetirizine, levocetirizine, acetaminophen, ibuprofen, acetylcysteine, carbamazepine, verapamil, selegiline, ephedrine, oxybutynin, diltiazem, mexiletine, emedastine. The above-mentioned medicines are all oxygen sensitive medicines, and the capsules are already on the market, and there is a possibility that impurities are generated by oxidation degradation in circulation.

The invention also provides a capsule, and the capsule is packaged by adopting the packaging method for improving the stability of the capsule.

The present application is further detailed below with reference to levocetirizine capsules and acetylcysteine capsules as examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the invention, and the packaging principles for other oxygen sensitive drugs are similar and therefore not described in detail.

The oxidative degradation impurity in the levocetirizine capsule preparation is p-chlorobenzophenone which is a main growth impurity, 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.

According to the structural analysis of acetylcysteine, the degradation route may be as follows:

。

example 1

A batch of levocetirizine hydrochloride capsules are prepared, the batch number is marked as X200101, the capsule shell adopts a gelatin hollow capsule (Ningbo broad-peak capsule Co., ltd.), and the capsules are placed in a 30ml composite film bag after being packaged by a blister. 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 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 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 results of accelerated test investigation of blister samples of X200101 batches, and table 2 is a table of results of long-term test investigation of blister samples of X200101 batches.

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.

Watch (A)

Test result table of blister-packaged levocetirizine hydrochloride capsule accelerated test for 6 months

。

TABLE 2 detection results of long-term test 12 months for blister-packaged levocetirizine dihydrochloride capsules

。

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 added into the HDPE bottle 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.

Table 3 is a table of results of accelerated testing investigation of HDPE bottle packaging samples of X200101 batches, and table 4 is a table of results of long-term testing investigation of HDPE bottle packaging samples of 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 3 table of results of 6-month accelerated testing of levocetirizine hydrochloride capsules packed in HDPE bottles

。

Table 4 table of the results of 12 months long-term test of levocetirizine hydrochloride capsules packed in HDPE bottles

。

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 while absorbing oxygen, so that the capsule content or the capsule shell 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 growth rate of impurities is inhibited, the properties and dissolution of the capsule are problematic, and the levocetirizine hydrochloride capsule uses a gelatin hollow capsule, so that the requirement on environmental moisture is met, and the situation that the levocetirizine hydrochloride capsule is too high or too low cannot be met; the desiccant has strong moisture absorption capacity, so that the capsule shell becomes brittle and the dissolution is slowed down, and the product quality is obviously changed. The invention adopts double-absorption deoxidizer, which can absorb oxygen and prevent the oxidative degradation of the active components of the oxygen-sensitive medicine, has weaker moisture absorption capacity, solves the problem of the growth of the related substances of the levocetirizine hydrochloride capsule, does not influence the quality of the capsule, and effectively prolongs the shelf life of the capsule.

Example 3

Preparing a batch of acetylcysteine capsules, wherein the batch number is marked as X201101, and the capsule shells adopt enteric gelatin hollow capsules (Anhui Huangshan capsules, inc.), packaging by using blisters, and placing into 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 type deoxidizer and the common deoxidizer is 30ml. Under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 50 +/-5% or 90 +/-5%, the moisture absorption rates of the double-absorption type deoxidizer in 48 hours are respectively 8.9% and 22.1%; the moisture absorption rates of the common deoxidizer in 48 hours are respectively 1.9 percent and 3.5 percent; the moisture absorption rate of the drying agent in 48 hours is 22.9 percent and 34.8 percent respectively.

Table 5 is a table of accelerated test results of X201101 batches of blister samples, and table 6 is a table of long-term test results of X201101 batches of blister samples.

Fig. 5 is a graph comparing the increase amplitude of impurity C and total impurities in the acceleration test of blister samples of X201101 batches, and fig. 6 is a graph comparing the increase amplitude of impurity C and total impurities in the long-term test of blister samples of X201101 batches.

TABLE 5 Table of results of accelerated test of acetylcysteine capsules packed in blister pack for 6 months

。

TABLE 6 Table of the test results of long-term test for 12 months for acetylcysteine capsules packaged in blisters

。

The result shows that after the acetylcysteine capsule is added with the common deoxidizer, the moisture content of the capsule is obviously increased, the capsule has a bonding phenomenon, and the impurity growth speed is higher. 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 is bonded, and the final finished product has obvious quality change. Meanwhile, a deoxidizing agent and a drying agent are added, so that although the increase speed of impurities is inhibited, the properties and dissolution of the capsule are problematic, because the acetylcysteine capsule uses an enteric gelatin hollow capsule, the environment moisture is required, and the situation that the content is too high or too low is not good; the desiccant has strong moisture absorption capacity, so that the capsule shell becomes brittle and the dissolution is slowed down, and the product quality is obviously changed. The double-absorption deoxidizer is adopted, so that the deoxidizer can absorb oxygen and prevent the oxidative degradation of active ingredients of oxygen-sensitive medicaments, has weaker moisture absorption capacity, solves the problem of the increase of related substances of acetylcysteine capsules, does not influence the quality of the capsules, and effectively prolongs the shelf life of the capsules.

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 can be made without departing from the concept of the present application, which should be considered as belonging to the protection scope of the present application.

Claims

1. A packaging method for improving capsule stability is characterized in that a capsule is packaged in a medicine packaging container, and a double-absorption type deoxidizer is placed in the medicine packaging container.

2. The packaging method for improving capsule stability according to claim 1,

the capsule shell of the capsule contains gelatin.

3. The packaging method for improving capsule stability according to claim 2,

the capsule is one of gelatin hollow capsule, enteric gelatin hollow capsule or gelatin soft capsule.

4. The packaging method for improving capsule stability according to any one of claims 1 to 3, wherein the packaging method comprises the steps of,

the total oxygen absorption amount of the double-absorption type deoxidizer is not less than 20% of the packaging container, preferably not less than 50% of the packaging container.

5. The packaging method for improving the stability of a capsule according to any one of claims 1 to 4, wherein,

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%.

6. The packaging method for improving capsule stability according to claim 5,

the medicine packaging container is a medicine packaging bottle.

7. The packaging method for improving capsule stability according to claim 5,

the medicine packaging container is a composite film bag, the capsules are packaged in bubble caps of a bubble cap plate, and then the bubble cap plate is packaged in the composite film bag.

8. The packaging method for improving capsule stability according to claim 6 or 7,

the oxygen sensitive drug is selected from at least one of the following: cetirizine, levocetirizine, acetaminophen, ibuprofen, acetylcysteine, carbamazepine, verapamil, selegiline, ephedrine, oxybutynin, diltiazem, mexiletine, emedastine.

9. A capsule which is packaged by the packaging method for improving the stability of a capsule according to any one of claims 1 to 8.

10. The application of double-absorption deoxidizer in the preparation of oxygen sensitive medicine capsule medicine is provided.