Perohyclidine hydrochloride liquid preparation and quality stability control method thereof

Abstract

The invention provides a penehyclidine hydrochloride liquid preparation quality stability control method and a penehyclidine hydrochloride inhalation solution thereof. The preparation is packaged by adopting a plastic package or adding sodium chloride into a glass package. The packaging method can control the pH value of the preparation. The weight ratio of the water for injection to the penehyclidine hydrochloride to the sodium chloride of the inhalation preparation is 2000: 0.5-1: 18. The preparation can be used for treating chronic obstructive pulmonary disease.

Description

Technical Field

[0001] The invention relates to a drug quality control method, and more specifically to a method for controlling the quality stability of a penehyclidine hydrochloride liquid preparation. Background Art

[0002] Penehyclidine hydrochloride is a selective M1 and M3 receptor antagonist. The marketed product is penehyclidine hydrochloride injection, which is administered by intramuscular injection. Its indications are: (1) for administration before anesthesia to inhibit the secretion of salivary glands and airway glands; (2) for emergency treatment of organophosphorus poisoning (pesticides) and for maintaining atropine in the late stage of poisoning or after aging of cholinesterase (ChE). Literature reports show that penehyclidine hydrochloride is also commonly used in the clinical treatment of airway dysfunction diseases such as chronic obstructive pulmonary disease (COPD), and its clinical efficacy is significant. However, a major bottleneck that plagues the development of penehyclidine hydrochloride liquid preparations is that the pH value of penehyclidine hydrochloride injection is unstable during storage and is prone to increase.

[0003] The glass containers commonly used in medical treatment are boric acid glass, the main components of which are oxides (SiO2), boron oxides (B2O3) and alkali metal oxides (such as Na2O and K2O), in addition to a small amount of aluminum oxide (Al2O3), zinc oxide (ZnO) and sodium oxide (Na2O). The applicant has found in long-term research that the aqueous solution of penehyclidine hydrochloride will cause the sodium and potassium ions in the boric acid glass to be freed into the solution, resulting in changes in the pH value. The commercially available products directly fill the aqueous solution of penehyclidine hydrochloride into any existing ampoule bottles that have not been pre-treated. The stability is poor, and the pH value will increase significantly after long-term storage for 6-8 months, resulting in unqualified shelf life quality of the drug.

[0004] The applicant tested the Na ion concentration data in the solution, and the results showed that the pH value of penehyclidine hydrochloride injection was positively correlated with the sodium ion concentration data, as shown in the following table.

[0005] Penehyclidine hydrochloride injection batch number pH Na ion concentration (mg / L) Remark 130501 6.55 1.69 Long term 36 months 130502 6.51 1.44 Long term 36 months 200306 5.26 0.355 0 month 200502 5.28 0.419 0 month

[0006] The measures taken by the prior art are as follows: For example, the patent publication number CN103284943A discloses a novel preparation method for penehyclidine hydrochloride injection, in which the inner packaging material is pre-treated with acid, then penehyclidine hydrochloride is mixed with water for injection, a pH regulator is added to adjust the pH value, and the penehyclidine hydrochloride injection is obtained by filling and sterilization. Although this method can avoid the pH change of penehyclidine hydrochloride injection after short-term placement to a certain extent, it cannot solve the problem of long-term stability of penehyclidine hydrochloride injection; the patent publication number CN 112716889 A discloses a method of circulating filtration of the drug solution through a series of filter elements to ensure the uniformity and stability of the drug solution, but this method does not solve the problem of penehyclidine hydrochloride reacting with the packaging material. In the preparation method of penehyclidine hydrochloride injection disclosed in patent publication number CN102525910A, commercially available medicinal ampoules or glass vials are subjected to acidification and heat treatment, and then penehyclidine hydrochloride liquid is poured and sterilized to prepare penehyclidine hydrochloride injection. However, in the actual production process, this method of acid-treating commercially available medicinal ampoules is cumbersome to operate. At the same time, the uniformity and stability of the degree of acidification and heat treatment of the ampoule cannot be guaranteed, resulting in the risk of stability and uniformity of product quality. At the same time, the acidification process cost is relatively high, resulting in increased production costs; in addition, the long-term storage of penehyclidine hydrochloride injection for more than 36 months will still cause the problem of increased pH value. Summary of the invention

[0007] In order to solve the problem of poor stability or high manufacturing cost of the penehyclidine hydrochloride liquid preparation described in the background technology. After long-term research, the applicant found that after the existing penehyclidine hydrochloride liquid preparation is packaged in glass such as ampoules, during long-term storage, there is a problem that the positive ions in the boric acid glass are released and the pH value increases. The present invention provides a method for controlling the pH value of the penehyclidine hydrochloride liquid preparation to be 4.5-6.5, specifically to solve the problem of cations in the glass packaging material being released into the penehyclidine hydrochloride liquid preparation; further, it is one of the two methods of adding sodium chloride to the penehyclidine hydrochloride liquid preparation or using plastic materials as packaging materials.

[0008] Method 1 is: sodium chloride is added to the penehyclidine hydrochloride liquid preparation so that the content of sodium chloride is 0.5% to 1.0% (preferably 0.9%). According to this method, the liquid preparation is a penehyclidine hydrochloride inhalation liquid, which is specifically composed of penehyclidine hydrochloride, sodium chloride and water for injection; the weight ratio of the salt water for injection, acid penehyclidine and sodium chloride is 2000:0.5 to 1:18.

[0009] Method 2 is: the packaging material of the liquid preparation of penehyclidine hydrochloride is plastic. The packaging method using the plastic material as the packaging material is packaging using the BFS process. The plastic material used as the packaging material is one of polyvinyl chloride, polyethylene, polypropylene, polystyrene, polycarbonate, polyurethane, polyamide, thermoplastic elastomer, polysulfone or polyetheretherketone; preferably one of polyethylene and polypropylene.

[0010] Penehyclidine hydrochloride liquid preparation Penehyclidine hydrochloride inhalation solution is used in the treatment of chronic obstructive pulmonary disease.

[0011] The beneficial technical effects of the present invention are:

[0012] 1. The quality is controllable. The present invention adopts BFS process plastic packaging materials for packaging or adds sodium chloride to the liquid preparation of penehyclidine hydrochloride, which solves the problem of cations of packaging materials being freed into the solution. The pH value of the shelf life is controlled to be 4.5-6.5, which avoids the precipitation of penehyclidine hydrochloride due to the reduction of solubility due to the excessively high pH value of the solution, and safety accidents after use. At the same time, the cost is greatly reduced compared with the prior art, and the processing efficiency is higher.

[0013] 2. The penehyclidine hydrochloride inhalation solution preparation in the penehyclidine hydrochloride liquid preparation provided by the present invention not only solves the quality stability problem of the penehyclidine hydrochloride inhalation solution preparation, but also solves the isotonicity problem of the inhalation solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The production process flow chart of penehyclidine hydrochloride inhalation solution preparation with medium borosilicate glass ampoules (colorless) as packaging materials;

[0015] Figure 2 Lung tissue pathological section (HE, ×200);

[0016] Figure 3 Bronchial tissue pathological section (HE, ×200);

[0017] Figure 4 Histopathological sections of experimental rabbit lung tissue (HE, ×200);

[0018] Figure 5 Histopathological sections of experimental rabbit bronchial tissue (HE, ×200);

[0019] Figure 2 , 3 , 4, 5 as described in A. normal control group; B. model control group; C. ipratropium bromide solution for inhalation group; D. penehyclidine hydrochloride injection group; E. penehyclidine hydrochloride inhalation solution low-dose group; F. penehyclidine hydrochloride inhalation solution medium-dose group; G. penehyclidine hydrochloride inhalation solution high-dose group. DETAILED DESCRIPTION

[0020] Example 1 Study on the stability of glass-packaged penehyclidine hydrochloride inhalation solution

[0021] 1. Produce penehyclidine hydrochloride inhalation liquid preparation according to prescription table 1, using medium borosilicate glass ampoules (colorless) as packaging materials; the specific process flow is as follows Figure 1 shown.

[0022] Table 1

[0023]

[0024] 2. The penehyclidine hydrochloride inhalation solution was prepared according to the above preparation method, and the solution was sealed with a medium borosilicate glass ampoule to investigate the effect of adding sodium chloride on the stability (pH value) of the penehyclidine hydrochloride inhalation solution. The specific experimental scheme is shown in Table 2.

[0025] Table 2 Quality stability study plan of penehyclidine hydrochloride inhalation solution

[0026]

[0027] Experiments have shown that adding sodium chloride to the penehyclidine hydrochloride inhalation solution can effectively solve the problem of unstable pH value of penehyclidine hydrochloride during long-term storage. See Tables 3 to 10 for details.

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] In summary, adding sodium chloride to the penehyclidine hydrochloride inhalation solution can prevent the cations in the glass container from being released into the solution, thereby avoiding the change in pH value and controlling the quality of the penehyclidine hydrochloride inhalation solution.

[0034] Example 2 Investigation of the effect of plastic packaging on the quality stability of penehyclidine hydrochloride inhalation solution

[0035] The penehyclidine hydrochloride inhalation solution preparation was produced according to prescription table 11 and packaged by blow fill seal (BFS).

[0036] Table 11

[0037]

[0038] The penehyclidine hydrochloride inhalation solution was prepared by the preparation method described in Example 1 and packaged using BFS process plastic packaging materials. The stability of the penehyclidine hydrochloride inhalation solution packaged in plastic was investigated; the specific experimental scheme is shown in Table 11.

[0039] Table 12 Results of quality stability study on BFS plastic packaging penehyclidine inhalation solution

[0040]

[0041] Experiments have shown that the use of BFS process plastic packaging can effectively solve the problem of unstable pH value of penehyclidine hydrochloride inhalation solution during long-term storage. See Tables 13 to 16 for details.

[0042]

[0043]

[0044] In summary, the use of plastic containers to package penehyclidine hydrochloride inhalation solution can effectively control the pH change of penehyclidine hydrochloride inhalation solution because no positive ions are released from the container, thereby controlling the quality of penehyclidine hydrochloride inhalation solution.

[0045] Example 3 Study on the activity of penehyclidine hydrochloride inhalation solution on chronic obstructive pulmonary disease

[0046] 1. Effects of penehyclidine hydrochloride inhalation solution on the rat COPD model

[0047] The penehyclidine hydrochloride inhalation solution prepared in Example 1 was used as the experimental drug. 270 SPF male SD rats that passed the quarantine were selected, of which 255 rats were used as the model group. 0.2 mL / rat of 1 mg / mL lipopolysaccharide (LPS) solution was dripped into the nose on the 1st, 7th, 15th and 21st days, and the rats were placed in a smoking machine for fumigation once a day, 30 min / time / rat on the 2nd to 6th, 8th to 14th, 16th to 20th and 22nd to 56th days. The remaining 13 rats were used as the normal control group, and only the same volume of 0.9% sodium chloride injection was dripped into the nose by the same method on the 1st, 7th, 15th and 21st days. 56 days after modeling, three rats were randomly selected from the normal control group and the model group for lung function and lung tissue pathology examinations. The results showed that the lung function compliance (Cpyn), peak expiratory flow rate (PEF), peak inspiratory flow rate (PIF), and tidal volume (Vt) of the model group animals were significantly reduced, and the lung tissue pathology results showed mild congestion and mild to moderate emphysema, indicating that the COPD model was successfully replicated. A total of 232 model rats, weighing 349.3-477.6 g, were selected and randomly divided into pharmacodynamic group and pharmacokinetic group according to body weight. The animals in pharmacodynamic group were randomly divided into model control group (60 rats), ipratropium bromide solution for inhalation group (12 rats, theoretical dose of 0.074 mg / kg, actual dose of 0.069 mg / kg), penehyclidine hydrochloride injection group (12 rats, 0.07 mg / kg), low-, medium- and high-dose groups of penehyclidine hydrochloride inhalation solution (the corresponding number of animals was 12, 60, and 12, respectively, the theoretical dose was 0.025, 0.076, and 0.227 mg / kg, respectively, and the actual dose was 0.024, 0.073, and 0.218 mg / kg, respectively); a medium-dose group of penehyclidine hydrochloride inhalation solution (64 rats / group, theoretical dose of 0.076 mg / kg, actual dose of 0.072 mg / kg) was set up as a pharmacokinetic satellite group. The animals in the low, medium and high dose groups of penehyclidine hydrochloride inhalation solution inhaled penehyclidine hydrochloride inhalation solution with an aerosol concentration of 7.5 μg / L through the mouth and nose, and inhaled it continuously for 4.9 min, 15.0 min and 44.9 min, respectively. The animals in the ipratropium bromide solution for inhalation solution inhaled ipratropium bromide solution for inhalation with an aerosol concentration of 6.5 μg / L through the mouth and nose, and inhaled it continuously for 16.9 min. The rats in the penehyclidine hydrochloride injection group were injected intramuscularly with penehyclidine hydrochloride injection at 1 mL / kg. The normal control group and the model control group inhaled 0.9% sodium chloride injection for the same duration as the high dose group in the same way, once a day, for 28 consecutive days.The model control group and the medium-dose group of penehyclidine hydrochloride inhalation solution were subjected to pulmonary function tests before the first administration, at the end of administration, 1.5h, 5h, 7 days, 14 days, and 28 days (8 animals / group); after the last administration, the animals in each group were intraperitoneally injected with 60mg / kg of Zotai 50, anesthetized, and then bled from the abdominal aorta. The lungs and bronchi were dissected and stained with HE, and the pathological morphological changes of the bronchial and lung tissues were observed under a microscope; the 8 animals in the pharmacodynamic satellite group were tested before the first administration and the last administration, before administration (0h), 1 / 2 of the administration time, and after the last administration. Venous blood was collected at 15min, 30min, 1.5h, 3h, 5h, and 7h after the end of administration to detect plasma drug concentration; animals in the pharmacokinetic satellite group underwent right bronchial alveolar lavage (8 animals / time point) at the end of the first administration, 1.5h and 5h after the end of administration, on D7 and D14 (immediately after the end of administration), before the last administration, at the end of administration, 1.5h, and 5h, and the alveolar lavage fluid was collected. The left lung tissue was also collected to detect the drug concentration in the lung tissue and alveolar lavage fluid.

[0048] Low, medium and high doses of penehyclidine hydrochloride inhalation solution (the actual doses were 0.024, 0.073 and 0.218 mg / kg, respectively) can significantly increase the lung function Vt of COPD rats, among which medium and high doses (the actual doses were 0.073 and 0.218 mg / kg, respectively) can significantly increase PIF, PEF and Cpyn of COPD rats; low, medium and high doses of penehyclidine hydrochloride inhalation solution (the actual doses were 0.024, 0.073 and 0.218 mg / kg, respectively) can significantly reduce the degree of congestion and emphysema of lung tissue in COPD rats, and can reduce the incidence of lesions (specifically, Figure 3 shown).

[0049] The medium and high doses of penehyclidine hydrochloride inhalation solution (actual doses were 0.073 and 0.218 mg / kg, respectively) can significantly reduce the incidence of inflammatory cell infiltration in the bronchial mucosa of COPD rats, indicating that penehyclidine hydrochloride inhalation solution has a significant therapeutic effect on the rat chronic obstructive pulmonary disease (COPD) model (specifically, Figure 4 shown).

[0050] Concomitant pharmacokinetics showed that the in vivo exposure AUC0-t and local tissue concentration of COPD rats increased with the prolonged administration time. The pharmacodynamic effect of penehyclidine hydrochloride inhalation solution on improving the lung function of rat COPD model was positively correlated with the in vivo exposure AUC0-t and local tissue concentration. The pharmacodynamic effect of penehyclidine hydrochloride inhalation solution (0.076 mg / kg) on ​​reducing lung tissue lesions in rat COPD model was better than that of penehyclidine hydrochloride injection (0.07 mg / kg) at the same dose, increasing PEF and Cypn, and reducing lung tissue lesions was better than that of ipratropium bromide solution (0.074 mg / kg) at the same dose for inhalation.

[0051] 2. Effects of penehyclidine hydrochloride inhalation solution on the experimental rabbit COPD model

[0052] The penehyclidine hydrochloride inhalation solution prepared in Example 1 was used as the experimental drug. 76 male rabbits of ordinary grade that passed the quarantine were selected, of which 64 experimental rabbits were used as the model group, and 0.8% papain 1mL / kg was injected once through the ear vein. 7 days after the injection, 0.5% papain atomized by an ultrasonic nebulizer was inhaled (more than 90% of 5μm particles), 4h / time, inhaled once a week, for a total of 3 times. After the last inhalation, the animals were observed for 6 weeks, and 12 animals were set as the normal control group, and 0.9% sodium chloride injection was injected and inhaled in the same way. During the modeling period, 10 animals in the model group died. Pathological examination of bronchial and lung tissues was performed on the dead animals. The results showed varying degrees of lung congestion, mild to moderate emphysema, varying degrees of inflammatory cell infiltration in the alveolar wall, varying degrees of epithelial cell degeneration and necrosis, goblet cell metaplasia, infiltration of inflammatory cells in the wall and surrounding areas, and mucus and cell fragments in the lumen in the bronchial and bronchiolar tissues, indicating that the moderate to severe COPD model of experimental rabbits was successfully replicated. Forty-eight model experimental rabbits, weighing 2.4-3.7 kg, were selected and randomly divided into 6 groups according to their body weight, namely, model control group, ipratropium bromide solution for inhalation group (theoretical dose was 0.04 mg / kg, actual dose was 0.032 mg / kg), penehyclidine hydrochloride injection group (0.04 mg / kg), penehyclidine hydrochloride inhalation solution low-, medium- and high-dose groups (theoretical doses were 0.0165, 0.041 and 0.124 mg / kg, respectively, and actual doses were 0.0156, 0.039 and 0.117 mg / kg, respectively), with 8 animals in each group. The animals in the low, medium and high dose groups of penehyclidine hydrochloride inhalation solution inhaled penehyclidine hydrochloride inhalation solution with an aerosol concentration of 8 μg / L through the mouth and nose, and inhaled continuously for 4.4 minutes, 9.9 minutes and 30 minutes respectively. The animals in the ipratropium bromide inhalation solution group inhaled ipratropium bromide inhalation solution with an aerosol concentration of 6.5 μg / L through the mouth and nose, and inhaled continuously for 9.7 minutes. The experimental rabbits in the penehyclidine hydrochloride injection group were injected intramuscularly with penehyclidine hydrochloride injection at 0.5 mL / kg. The normal control group and the model control group were inhaled and given 0.9% sodium chloride injection for the same duration as the high dose group in the same way, once a day, for 28 consecutive days. After the last administration, the experimental rabbits in each group were injected with 15 mg / kg propofol emulsion injection through the ear vein anesthesia and then the pulmonary function test was performed; the femoral aorta was bled and euthanized, and the lung and bronchial tissues were dissected and stained with HE to observe the pathological morphological changes of the lung and bronchial tissues.

[0053] Low, medium and high doses of penehyclidine hydrochloride inhalation solution (the actual doses were 0.0156, 0.039 and 0.117 mg / kg, respectively) can significantly increase PIF, PEF and Vt of COPD experimental rabbits. Medium and high doses (the actual doses were 0.039 and 0.117 mg / kg, respectively) can significantly increase lung compliance of COPD experimental rabbits. Low dose (the actual dose was 0.0156 mg / kg) can significantly increase FEV200 / FVC of COPD experimental rabbits. High dose (the actual dose was 0.117 mg / kg) can significantly increase FEV200, FEV200 / FVC, medium and high doses of penehyclidine hydrochloride inhalation solution (actual dosages were 0.039 and 0.117 mg / kg, respectively) can significantly reduce the degree of bronchial and lung tissue lesions in COPD experimental rabbits (emphysema of the septal lobe and apical lobe, inflammatory cell infiltration of the alveolar wall of the septal lobe, congestion of the cardiac lobe, epithelial cell degeneration, inflammatory cell infiltration (tube wall and surrounding)), reduce the incidence of lesions, and can significantly reduce the bronchial lesion score and the total score of bronchial and lung tissue lesions, indicating that penehyclidine hydrochloride inhalation solution has a significant therapeutic effect on the experimental rabbit chronic obstructive pulmonary disease (COPD) model (specifically, Figure 5 shown).

[0054] The pharmacodynamic effect of penehyclidine hydrochloride inhalation solution in increasing PIF and PEF in the experimental rabbit COPD model is better than that of the same dose of ipratropium bromide solution for inhalation (0.04 mg / kg), and the pharmacodynamic effect of reducing lung tissue lesion score is better than that of the same dose (0.04 mg / kg) of penehyclidine hydrochloride injection and ipratropium bromide solution for inhalation.

Claims

1. A method for controlling the quality stability of a liquid preparation of penehyclidine hydrochloride, specifically for controlling the pH value of the liquid preparation of penehyclidine hydrochloride to be 4.5 to 6.5 during the shelf life, characterized in that: The method is to inhibit or avoid the problem of cations in glass packaging materials being freed into the liquid preparation of penehyclidine hydrochloride; further, one of the two methods is to add sodium chloride to the liquid preparation of penehyclidine hydrochloride or to use plastic materials as packaging materials.

2. The method for controlling the quality stability of the penehyclidine hydrochloride liquid preparation according to claim 1, characterized in that: Sodium chloride is added to the penehyclidine hydrochloride liquid preparation so that the content of sodium chloride is 0.5% to 1%.

3. The method for controlling the quality stability of the penehyclidine hydrochloride liquid preparation according to claim 2, characterized in that: Furthermore, sodium chloride is added to the penehyclidine hydrochloride liquid preparation so that the content of sodium chloride is 0.9%.

4. The method for controlling the quality stability of the penehyclidine hydrochloride liquid preparation according to claim 1, characterized in that: The packaging material of liquid preparations is plastic.

5. The method for controlling the quality stability of the penehyclidine hydrochloride liquid preparation according to claim 1, characterized in that: The packaging method using plastic material as packaging material is packaging using BFS process.

6. The method for controlling the quality stability of the penehyclidine hydrochloride liquid preparation according to claim 1, characterized in that: The plastic material used as the packaging material is one of polyvinyl chloride, polyethylene, polypropylene, polystyrene, polycarbonate, polyurethane, polyamide, polysulfone or polyetheretherketone.

7. A liquid preparation of penehyclidine hydrochloride, characterized in that: The liquid preparation is penehyclidine hydrochloride inhalation solution, which is specifically composed of penehyclidine hydrochloride, sodium chloride and water for injection.

8. The liquid preparation of penehyclidine hydrochloride according to claim 7, characterized in that: The weight ratio of the water for injection, penehyclidine hydrochloride and sodium chloride is 2000:0.5-1:

18.

9. Use of the penehyclidine hydrochloride liquid preparation according to claims 7 and 8 in the preparation of a drug for treating chronic obstructive pulmonary disease.

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