CN111388456A - Sodium cromoglycate aerosol inhalation solution and preparation method thereof - Google Patents
Sodium cromoglycate aerosol inhalation solution and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Abstract
The invention relates to the field of medicines, and in particular relates to a cromolyn sodium aerosol inhalation solution which is characterized by comprising cromolyn sodium and an isotonic agent, wherein the content of the cromolyn sodium is 9.5-10.5 mg/ml; the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.8-1: 0.9. The atomized inhalation solution provided by the invention has the advantages of low irritation to the airway, high safety and good absorption, can overcome the problems in the prior art, and has good application prospect.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a cromolyn sodium aerosol inhalation solution and a preparation method thereof.
Background
Asthma is also called bronchial asthma, which is a chronic airway inflammation involving various cells and cell components, and the inflammation is often accompanied with the increase of airway reactivity, which causes symptoms of repeated wheezing, shortness of breath, chest distress, cough and the like, and the symptoms occur at night and/or in the morning, and are often accompanied with wide and variable airflow obstruction.
The cromolyn sodium is a cromolyn compound, which is called as cromolyn disodium and has good prevention and treatment effects on immediate-type anaphylaxis. The action mechanism of the drug is that the drug can stabilize the cell membrane of mast cells and prevent the mast cells from degranulation, thereby inhibiting the release of allergic reaction media such as histamine, 5-hydroxytryptamine, slow reaction substances and the like, and further inhibiting the adverse effect of the allergic reaction media on tissues. The effect of inhibiting the release of an allergic reaction medium is probably to inhibit intracellular cyclic phosphoryl glycoside phosphodiesterase so as to increase the concentration of intracellular cyclic phosphoryl glycoside (cAMP) and prevent calcium ions from being transported into mast cells, thereby stabilizing the mast cell membrane and preventing the release of the allergic reaction medium.
Cromolyn is used to prevent the onset of allergic asthma, improve subjective symptoms, increase the patient's tolerance to exercise, and to reduce or completely disable the corticosteroid-dependent patient after administration. Children with chronic intractable asthma mostly take partial or complete relief. When used together with isoproterenol, the Chinese medicine has obviously higher effective rate than that when used singly. But has slow effect and can take effect only after being used for several days. Clinical studies have found that cromolyn is effective not only in allergic asthma, where allergic factors play a major role, but also in chronic asthma, where allergic effects are not significant. It can be used for treating allergic rhinitis and seasonal pollinosis, and can rapidly control symptoms. However, already on the market
In the specification of the medicine, the sodium cromoglycate preparation has airway irritation, can cause irritant cough and has potential safety hazard, and even if the irritation can be improved by changing auxiliary materials, in view of the specificity of the medicine, the uncertainty of whether the absorption of the medicine can meet the requirement to ensure the effect is high.
Disclosure of Invention
In view of the above, the present invention aims to provide a cromolyn sodium preparation with low irritation and without affecting the absorption and therapeutic effect of the drug.
Specifically, the invention provides a sodium cromoglycate aerosol inhalation solution which is characterized by comprising sodium cromoglycate and an isotonic agent, wherein the content of the sodium cromoglycate is 9.5-10.5 mg/ml; the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.8-1: 0.9.
Preferably, the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.85.
In particular, the isotonic agent is selected from glycerol, glucose or sodium chloride, preferably sodium chloride.
Preferably, the osmotic pressure ratio of the atomized inhalation solution is 0.9-1.1, and the pH value is 4.0-7.0.
The invention also provides a preparation method of the cromolyn sodium aerosol inhalation solution, which is characterized in that,
(1) distilled water with the prescription amount of 70-95 percent is taken;
(2) adding cromolyn sodium, stirring to dissolve;
(3) adding an isotonic agent, and stirring until the isotonic agent is dissolved;
(4) adding distilled water to full amount;
(5) fine filtering, bottling, and sterilizing.
Preferably, the temperature of the solution preparation process in the steps (1), (2) and (3) is controlled to be 50 +/-10 ℃.
Specifically, the preparation process of the sodium cromoglycate atomized inhalation solution is not more than 10 hours, and preferably within 8 hours.
More specifically, the fine filtration process adopts a microfiltration membrane for filtration, wherein the microfiltration membrane is selected from a mixed cellulose membrane, polyether sulfone or nylon.
The potting is preferably: and filling the finely filtered liquid medicine into a 2ml neutral borosilicate glass ampoule.
The sterilization is preferably: sterilizing at 115 deg.C for 30 min.
Further, the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.8-1: 0.9, preferably 1: 0.85. The content of the cromolyn sodium is preferably 9.5 mg-10.5 mg/ml. The isotonic agent is selected from glycerol, glucose or sodium chloride, preferably sodium chloride.
Preferably, the content of the cromolyn sodium is 10.0 mg/ml.
The invention also provides an atomized inhalation solution prepared by the preparation method in any one of the preceding aspects.
The invention also provides an atomized inhalant which is characterized by comprising an atomizing cup and the sodium cromoglycate atomized inhalant solution sealed in the atomizing cup.
The invention prepares a new cromolyn sodium atomization inhalation solution and obtains the optimal preparation process thereof by screening, and the method is simple, convenient and feasible and is suitable for industrial expanded production. In addition, the atomized inhalation solution provided by the invention has low irritation to the airway, high safety and good absorption, can overcome various problems in the prior art, and has good application prospect.
Detailed Description
The invention discloses a cromolyn sodium atomized inhalation solution and a preparation method thereof, and a person skilled in the art can use the contents for reference and appropriately improve process parameters to realize the purpose. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention.
The medicines, reagents and instruments used in the preparation method of the cromolyn sodium composition provided by the invention can be purchased from the market.
EXAMPLE-preparation of cromolyn sodium inhalation solution
1. Screening of sodium chloride dosage
When the addition amount of sodium chloride in the formula is respectively 0.0%, 0.80%, 0.85% and 0.90%, the amount of sodium chloride is screened by taking the molar concentration of osmotic pressure as an index. Meanwhile, the quality conditions of appearance, pH value, clarity, color, related substances and the like of the preparation are inspected.
The process comprises the following steps: adding distilled water accounting for 80% of the prescription amount into a preparation container at room temperature, adding cromolyn sodium accounting for the prescription amount, and stirring to completely dissolve; adding sodium chloride according to the prescription amount, stirring to completely dissolve, measuring the pH value, and adding distilled water to full amount; fine filtering, filling into glass ampoule, and sealing. The results of the prescription screening test samples are shown in Table 1.
TABLE 1 screening test results for sodium chloride dosage (100 per prescription)
Remarking: the relative retention time of the impurity C is about 1.1, the impurity C is an impurity brought in the raw material process, and a system applicability test reference substance is used for positioning the impurity C; wherein, the system applicability test reference substance comprises cromolyn sodium and impurity C, and the separation degree is more than or equal to 5.0.
And (4) analyzing results: the samples prepared by different sodium chloride dosages have no obvious difference in indexes such as properties, pH values, related substances and the like. When the amount of sodium chloride is 0.85% (formula 3), the osmolality ratio is 0.9-1.1, so 8.5mg/ml (i.e. 0.85%) sodium chloride is selected as the osmotic pressure regulator.
2. Compounding liquid process screening (charging sequence)
The influence of the charging sequence of sodium chloride and cromolyn on the quality of the liquid medicine is inspected, the temperature of the prepared liquid is room temperature, the dissolution speed of the raw and auxiliary materials, the properties of the liquid medicine, the pH value and related substances are taken as inspection indexes, and different charging sequences and inspection results are shown in table 2.
TABLE 2 different charging sequences and their findings (100 per prescription)
From the above table, the sodium cromoglycate is dissolved firstly, and the dissolving speed is high; firstly dissolving sodium chloride and then dissolving cromolyn sodium, wherein the dissolving speed is slow; other parameters have no obvious difference, so the material preparation sequence of dissolving the cromolyn sodium first and then dissolving the sodium chloride is selected.
3. Temperature screening of the prepared solution
Adopting a determined prescription, preparing liquid medicine under the conditions of 25 ℃, 40 ℃, 60 ℃ and 80 ℃ according to the batching sequence of dissolving cromolyn sodium firstly and then dissolving sodium chloride, continuously placing for 8 hours at respective preparation temperature, and observing different preparation temperature by taking the dissolubility of raw and auxiliary materials, the properties and the content of finished products and related substances as indexes, wherein the results are shown in a table 2.
TABLE 3 influence of different compounding temperatures on the quality of the liquid medicine
At each preparation temperature, the related substances of the liquid medicine in 0h are not obviously different, but after the liquid medicine is continuously placed for 8h at each preparation temperature, the liquid medicine under the condition of 80 ℃ has another unknown single impurity and the total impurity is slightly increased compared with the liquid medicine under other conditions. As the solution preparation is feasible at 40-60 ℃ and the production operation is convenient, 50 +/-10 ℃ is selected as the solution preparation temperature.
4. Oxygen removal process screening
And preparing the liquid medicine under the preferable conditions, filling nitrogen into the liquid medicine in the liquid medicine preparation process, filling nitrogen into the packaging material during filling, and inspecting the influence of the oxygen content on the quality of the preparation. And screening the oxygen removal process by taking the product properties, the pH value and related substances as indexes.
TABLE 4 influence of oxygen removal process on the quality of the drug solutions
It can be seen from the above table that the nitrogen filling process is compared with the nitrogen non-filling process in the preparation and filling processes, and the product have no significant difference in the important indexes such as properties, related substances and the like after being placed under the accelerated condition, which proves that the oxygen content of the liquid medicine has no significant influence on the product quality in the process of product preparation, so that the nitrogen is not filled in the selection process.
5. Investigation test of material quality of prepared vessel
In order to examine the necessity of the disodium edetate containing the metal ion complexing agent in the formula, the invention also develops a comparative experiment between a stainless steel preparation container and a glass preparation container according to the preparation method under the preferable conditions, so as to confirm whether the stainless steel material has influence on the sodium cromoglycate inhalation solution.
TABLE 5 influence of different material containers on the quality of the liquid medicine (250 per prescription)
The results show that: under the condition that the sample is placed in two different containers for 8 hours, the properties, the pH value and related substances are not obviously different; the two batches of samples are placed at 60 ℃ for 30 days, the inter-batch differences of the detection items such as properties, pH values, related substances and the like are not obvious, and unknown impurities influenced by temperature appear in both batches; from this, it was found that the stainless steel container can be used as a preparation container for the cromolyn sodium inhalation solution.
6. Qualitative investigation of stably prepared liquid medicine
Preparing a solution according to the screened prescription process, standing at room temperature, observing the change condition of main quality indexes, and providing a basis for the storage time of an intermediate in the production process.
TABLE 6 test results of stability of drug solution
And (4) analyzing results: the sample has no obvious influence on related substances after being placed for 24 hours, and meanwhile, the storage time of the liquid medicine is not more than 8 hours during workshop production in order to ensure the product quality by combining the microbiological determination results of the liquid medicine placed in the workshop for different times.
7. Investigation of filtration Process (investigation of compatibility of filtration Membrane)
Preparing solution according to the screening prescription process, filtering the liquid medicine by adopting 3 material microporous filter membranes, and inspecting the adsorption of the filter membrane and the corrosion condition of the liquid medicine on the filter membrane by taking visible foreign matters, insoluble particles, contents, related substances and the like of the liquid medicine before and after filtration as indexes. The compatibility of the filtering material and the liquid medicine is inspected by selecting filter elements (mixed cellulose membranes, polyether sulfone and nylon, the aperture of the filter membrane is 0.22 mu m).
TABLE 7 results of the Filter Process investigation
And (4) analyzing results: the properties, pH value, visible foreign matters, insoluble particles, content and related substances of the liquid medicine before and after filtration are not obviously changed, which shows that the three filter membranes have no influence on the quality of the liquid medicine; after the liquid medicine is filtered, three filter membranes are observed under a microscope, and the filter membranes are complete and are not damaged; the basic physicochemical properties, market use conditions and the existing filter element use conditions of the companies of the three filter materials are comprehensively considered, and the polyether sulfone filter element is selected temporarily according to the principle of minimizing risks.
8. Screening for Sterilization conditions
And preparing a solution according to the screened prescription process, and inspecting the influence of different sterilization conditions on the quality of the preparation by adopting a medium borosilicate ampoule.
TABLE 8 results of screening tests under different sterilization conditions
As can be seen from the test results, after 30min of sterilization at 115 ℃, the properties of the liquid medicine and the non-sterilized liquid medicine are colorless clear liquid, and after 8min, 12min and 15min of sterilization at 121 ℃, the properties of the liquid medicine are yellowish clear liquid; under different sterilization conditions, the pH value of the liquid medicine is not changed greatly; the unsterilized samples and the samples sterilized under different conditions are respectively placed at 60 ℃ for 10 days and 30 days, and the experimental result shows that the related substances have no obvious difference. By analyzing the data, 115 ℃ and 30min are preliminarily selected as the sterilization conditions of the product. According to the three batches of pilot test data, the process can ensure the sterility of the product through the liquid medicine microorganism load test and the sterility test of the final product.
9. Determination of prescription process
Prescription:
the preparation process comprises the following steps:
(1) distilled water with the prescription amount of 80% is taken, and the temperature is controlled to be 50 +/-10 ℃;
(2) adding the prescription amount of sodium cromoglycate, and stirring until the sodium cromoglycate is dissolved;
(3) adding the sodium chloride with the prescription amount, and stirring until the sodium chloride is dissolved;
(4) adding distilled water to full amount;
(5) fine filtering, and encapsulating in 2ml neutral borosilicate glass ampoule;
(6) moist heat sterilization (115 ℃, 30 min).
10. Production process
The production process of the sodium cromoglycate inhalation solution is determined as follows:
10.1 examination of extraction solvent and extraction method
(1) Preparation of medicinal liquid
Adding the prescribed amount of water for injection into the liquid preparation tank, and controlling the water temperature to be 50 +/-10 ℃. Slowly adding the cromolyn sodium into a liquid preparation tank, starting a stirring paddle, stirring and mixing for about 15 minutes until the cromolyn sodium is dissolved, and clarifying the solution without visible particles. Slowly adding sodium chloride into the liquid preparation tank, stirring and mixing for about 15 minutes to dissolve the sodium chloride, and clarifying the solution without visible particles. Adding the water for injection to full volume, starting a stirring paddle, and stirring and mixing for 5 minutes. And (3) filtering: starting the stirring paddle, starting the circulating pump, and circulating and filtering the liquid medicine (filter material: PES, filter aperture: 0.45 μm (first pass) and 0.22 μm (second pass)) for 15 minutes to mix uniformly. Sampling and detecting the intermediate.
(2) Intermediate detection
The characteristics are as follows: should be colorless to yellowish clear liquid
pH value: should be 4.5 to 6.5
Osmolality: should be 270 to 310mOsmol/kg)
The content is as follows: the content of cromolyn sodium (C23H14Na2O11) in the product is 9.5-10.5 mg/ml.
(3) Encapsulation (encapsulation)
Starting circulation pump, filtering with 0.45 μm and 0.22 μm filter, filling into the liquid storage tank, introducing the rest medicinal liquid into the liquid storage tank, filtering with 0.22 μm filter, and packaging. And (4) adjusting the filling quantity before filling and sealing, and filling after the filling is qualified. And adjusting the sealing quality. The filling amount of the liquid medicine is 2 ml/branch, and the control range is 2.05-2.15 ml.
(4) Sterilization leak detection
And placing the encapsulated product on a sterilization frame of a sterilization vehicle, and pushing the encapsulated product into a sterilization cabinet for sterilization and leakage detection. Setting the moist heat sterilization parameters: the sterilization temperature is 115 ℃, the sterilization time is 30 minutes, and the sterilization pressure is 0.08 MPa.
(5) Lamp inspection
(6) Checking and packing
(7) And (7) warehousing.
10.2 quality inspection
TABLE 10 comparison of product quality of Process
10.3 compatibility
The product is administered by atomization, and the influence of the atomizing cup on the quality of the liquid medicine in the atomizing use process needs to be inspected, and the experimental design is as follows:
the product is sealed in an atomizing cup (Bairui, L CSPRINT), and then is placed for 1, 2, 3 and 4 hours (the atomizing time of the product is about 5min and is not more than 60min) at room temperature, and the influence of the atomizing cup on the quality of the liquid medicine in the atomizing use process is examined by examining the property, pH value, content and related substances of the liquid medicine.
TABLE 11 results of drug solution and drug administration device compatibility study
And (4) conclusion: after the liquid medicine is sealed in the atomizing cup and is respectively placed for 1, 2, 3 and 4 hours at room temperature, the properties, the pH value, the related substances and the content of the liquid medicine have no obvious change, which indicates that the atomizing cup does not influence the internal quality of the product in the atomizing use process.
EXAMPLE II rabbit inhalation of cromolyn sodium inhalation solution airway irritation test
1. Test and reference substances
Test article-sodium cromoglycate inhalation solution (2m L: 20mg, prepared according to the method of the examples).
Comparison products: 0.9% sodium chloride injection (commercially available, Shandongdu pharmaceutical Co., Ltd.)
2. Test method
Japanese big-ear white rabbit, normal grade, male, 12, 3-4 months old, body weight: 2.0-2.4 kg.
The test selects 12 male Japanese big-ear white rabbits which are divided into 2 groups, namely a control group and an administration group, wherein each group comprises 6 animals, the control group is administered with 0.9% sodium chloride injection, the administration group is administered with 20mg of cromolyn sodium inhalation solution per administration, the administration volume of each group is 2m L/animal, the administration group is atomized and inhaled by an ohm dragon compression type inhaler and administered for 4 times every day, twice in the morning and afternoon, the administration period and the recovery period are continuously administered for 7 days, the animals and the administration part are observed, 3 animals in each group are killed 24h after the last administration, the stimulation reactions of the oral cavity, the nose, the throat, the trachea, the bronchus and the lung of the animals are observed by naked eyes after dissection, the congestion, the red swelling and other stimulation reactions are observed, the materials are obtained for pathological histological examination, the same treatment is carried out after the rest animals are continuously observed for 14 days, and the final evaluation is carried out according to the results of the.
The frequency detection and the method are as follows: the observation frequency is 1 time per day, cage-side observation is carried out before and after administration, and the observation contents comprise animal appearance, hair, physical sign, behavior and activity, respiratory state, glandular secretion, animal posture, fecal character, administration local reaction, death condition and the like.
3. Respiratory tract irritation observation
(1) Observation times, time and contents: the animals were observed 4 times a day after each administration for the presence of symptoms such as asthma, cough, vomiting, asphyxia, etc., and the time of occurrence and recovery of symptoms were recorded. Anaesthetizing the animals 24h after the last administration by intravenous injection of 2% sodium pentobarbital (the anaesthesia dose is 40mg/kg), killing 3 animals in each group by femoral artery bleeding, observing the stimulation reaction of the oral cavity, the nose, the pharynx, the throat, the trachea, the bronchus and the lung of the animals by naked eyes after dissection, and observing whether the stimulation reaction of congestion, red swelling and the like exists or not; the above tissues and organs were collected and subjected to pathological examination. After the rest 3 animals in each group are observed for 14 days, the animals are killed by anesthesia and exsanguination, the stimulation reaction of the oral cavity, the nose, the pharynx, the larynx, the trachea, the bronchus and the lung is observed by naked eyes after dissection, and the tissue and the organ are taken for pathological examination.
(2) And (3) measuring the body weight: body weight was measured once a week using an electronic balance.
4. Judgment and evaluation of results
The local irritation of the drug was comprehensively evaluated based on the results of visual observation and pathological examination. 5. Results and discussion
(1) General observations of animals: in the test process, the appearance and behavior activities of the animals are normal, the health conditions are good, and the animals have no symptoms of asthma, cough, vomit, asphyxia and the like after each administration.
(2) Gross anatomical observation: at the end of the administration and recovery period, the animals in each group were observed visually after dissecting, and no obvious abnormality was found in oral cavity, nose, pharynx, larynx, trachea, bronchus, and lung, and no obvious edema, congestion or hemorrhage, purulent secretion, etc. were observed on the mucosal surface.
(3) Histopathological examination results:
analysis of local irritation upon administration:
at the end of the administration period, the rabbits of the control group and the administration group can see nasal mucosal cell infiltration and nasal inflammatory secretion, the pathological change degree is not obviously different, a small amount of inflammatory secretion can be seen on the throat surface of the other part of the rabbits, and 1 animal in the rabbits of the administration group has the blood vessel of the right bronchus mucosa of the right bronchus slightly dilated and hyperemic, so that the irritation reaction is related to the administration mode of atomized inhalation and the self health state of the rabbits.
At the end of the convalescent period, the rabbits of the control group and the administration group still have nasal inflammatory secretion and nasal mucositis cell infiltration.
Papillary hyperplasia of nasal mucosa:
the nasal mucosa papillary hyperplasia powder is distributed in control groups and administration groups of rabbits at the end of administration and recovery periods, the pathological change degrees of the rabbits are not obviously different, and the nasal mucosa papillary hyperplasia powder is considered as spontaneous pathological change of the rabbits and is unrelated to a tested object.
Fibrosis of nasal gland in the mucosa lamina propria of turbinate:
in the administration group, 1 rabbit had mild fibrosis of the mucosa lamina propria of the turbinate and mild hyperplasia of nasal glands. Under the condition of chronic inflammatory stimulation of the rabbits for a long time, fibroblasts can continuously secrete collagen, and finally fibrosis is caused. The tissue pathology was considered to be a spontaneous rabbit pathology, independent of the test substance.
(4) Conclusion
Under the test condition, the sodium cromoglycate inhalation solution sample for the atomizing inhalation of the rabbits has no obvious irritation to the respiratory tracts of the rabbits.
EXAMPLE III SD rat inhaled sodium cromoglycate inhalation solution drug substitution test
After the SD rat inhales the sodium cromoglycate inhalation solution, the blood concentration of the test sample in the SD rat body and the drug distribution condition in respiratory tract tissues (trachea, bronchus and lung) are compared.
The test sample is sodium cromoglycate inhalation solution (2m L: 20mg, prepared according to the method of the embodiment), 25 SD rats (5 blood-collected 20 tissues) are administrated for 6-7 weeks, male animals with the weight of 155-171 g are administrated with the test sample (sodium cromoglycate inhalation solution), each group is administrated by an ohm dragon compression type inhaler in an atomizing inhalation mode, the administration dose is 80mg/kg, the administration volume is 8m L/kg, and the administration is 1 time in total, blood is collected and separated from orbital venous plexus of the blood-collected animals before administration and after the administration is finished for 0min, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h, the tissue animals are anesthetized after the administration is finished for 0min, 30min, 1h and 4h, the trachea bronchus and lung tissues are dissected, and the sodium cromoglycate in the blood plasma, trachea bronchus and lung tissue samples is determined by a verified L C-MS/MS method.
Taking a test sample: 2.0% sodium pentobarbital is injected into the abdominal cavity for anesthesia (the anesthetic dose is 50mg/kg for male mice), and after the animals are completely anesthetized, the abdominal aorta is exsanguinated and killed, and then dissected. The respiratory system tissues of the experimental animal are dissected to be trachea, bronchus and lung (the trachea, the bronchus and the lung are separately obtained).
Tissue collection and treatment: after the material is taken, animal tissues are cleaned by 0.9% sodium chloride injection, then the 0.9% sodium chloride injection on the surface is absorbed by filter paper, and the tissue samples are frozen and stored at the temperature of minus 70 ℃.
The plasma sample processing method comprises the steps of putting 50 mu L SD rat plasma into a centrifuge tube, adding 10 mu L10% of ammonia water and 50 mu L acetonitrile, adding 250 mu L internal standard working solution (100ng/m L), whirling for 5min, centrifuging for 10 min at 4 ℃ (14000rpm), taking 100 mu L supernatant, adding the supernatant into 100 mu L ultrapure water, mixing uniformly, and carrying out L C-MS/MS analysis.
A method for processing a trachea and bronchus sample comprises the steps of putting 50 mu L SD rat trachea (g): physiological saline (m L): 1:10) into a centrifuge tube, adding 10 mu L10% of ammonia water and 50 mu L acetonitrile, adding 250 mu L internal standard working solution (100ng/m L), whirling for 5min, centrifuging at 4 ℃ for 10 min (14000rpm), taking 50 mu L supernatant, adding the supernatant into 150 mu L ultrapure water, mixing uniformly, and carrying out L C-MS/MS analysis.
A lung sample treatment method comprises the steps of putting 50 mu L SD rat lungs (lung (g): physiological saline (m L) ═ 1:5) into a centrifuge tube, adding 10 mu L10% of ammonia water and 50 mu L acetonitrile, adding 250 mu L internal standard working solution (100ng/m L), vortexing for 5min, centrifuging at 4 ℃ for 10 min (14000rpm), taking 50 mu L supernatant, adding the supernatant into 150 mu L ultrapure water, uniformly mixing, and carrying out L C-MS/MS analysis.
TABLE 12 statistics of the concentration of cromolyn sodium in blood after SD rats inhale cromolyn sodium inhalation solution (mean + -SD)
NA: no corresponding data exists; and (2) preparing: not detected.
TABLE 13 comparison between concentration groups of sodium cromoglycate in the bronchial bronchi after inhalation of sodium cromoglycate inhalation solution in SD rats (mean + -SD)
TABLE 14 comparison of sodium cromoglycate concentration in lungs after SD rats inhale solution (mean + -SD)
TABLE 15 statistical comparison of differences between the main pharmacokinetic parameters after inhalation of sodium cromoglycate inhalation solution in SD rats (mean + -SD, n ═ 5)
The blood concentration and the main drug-induced parameters of the drug administration group of the control group on the market are also measured according to the same method, and the blood concentration and the main drug-induced parameters are basically consistent with the sodium cromoglycate inhalation solution prepared by the invention; the blood concentration and the main drug-induced parameter distribution of the drug administration group in the trachea, the bronchus and the lung tissue are basically consistent, which shows that the invention not only can overcome the defect that the product in the prior art has irritation to the airway, but also can ensure the curative effect because the absorption of the prepared product is not influenced.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (10)
1. The sodium cromoglycate aerosol inhalation solution is characterized by comprising sodium cromoglycate and an isotonic agent, wherein the content of the sodium cromoglycate is 9.5-10.5 mg/ml; the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.8-1: 0.9.
2. The aerosolized inhalation solution of claim 1, wherein the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.85.
3. The aerosolized inhalation solution of claim 1 or 2, wherein the isotonic agent is selected from the group consisting of glycerol, glucose, or sodium chloride; the osmotic pressure ratio of the atomized inhalation solution is 0.9-1.1, and the pH value is 4.0-7.0.
4. A preparation method of sodium cromoglycate atomized inhalation solution is characterized in that,
(1) distilled water with the prescription amount of 70-95 percent is taken;
(2) adding cromolyn sodium, stirring to dissolve;
(3) adding an isotonic agent, and stirring until the isotonic agent is dissolved;
(4) adding distilled water to full amount;
(5) fine filtering, bottling, and sterilizing.
5. The method according to claim 4, wherein the temperature of the solution preparation process in the steps (1), (2) and (3) is controlled to be 50 ± 10 ℃, preferably 50 ℃.
6. The method of claim 4, wherein the cromolyn sodium nebulized inhalation solution is prepared for no more than 8 hours.
7. The production method according to claim 4,
the fine filtration process adopts a microporous filter membrane for filtration, wherein the microporous filter membrane is selected from a mixed cellulose membrane, polyether sulfone or nylon;
the encapsulation is as follows: filling and sealing the liquid medicine after fine filtration in a 2ml neutral borosilicate glass ampoule;
the sterilization comprises the following steps: sterilizing at 115 deg.C for 30 min.
8. The preparation method according to any one of claims 4 to 7, wherein the weight percentage of the cromolyn sodium to the isotonic agent is 1: 0.8-1: 0.9, preferably 1: 0.85; the content of the cromolyn sodium is 9.5 mg-10.5 mg/ml, preferably 10.0 mg/ml; the isotonic agent is selected from glycerol, glucose or sodium chloride.
9. An aerosolized inhalation solution prepared by the method of any one of claims 4 to 8.
10. An aerosol inhalation formulation comprising an aerosol cup and the cromolyn sodium aerosol inhalation solution of any one of claims 1-3 or 9 sealed in the aerosol cup.
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Citations (3)
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|---|---|---|---|---|
| WO2018044942A1 (en) * | 2016-08-31 | 2018-03-08 | Patara Pharma, LLC | Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis |
| CN107789340A (en) * | 2016-08-30 | 2018-03-13 | 北京盈科瑞创新医药股份有限公司 | A kind of Herba Andrographitis Neulized inhalation pharmaceutical solutions and preparation method thereof |
| WO2018067341A1 (en) * | 2016-10-07 | 2018-04-12 | Patara Pharma, LLC | Cromolyn compositions for treatment of pulmonary fibrosis |
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| CN107789340A (en) * | 2016-08-30 | 2018-03-13 | 北京盈科瑞创新医药股份有限公司 | A kind of Herba Andrographitis Neulized inhalation pharmaceutical solutions and preparation method thereof |
| WO2018044942A1 (en) * | 2016-08-31 | 2018-03-08 | Patara Pharma, LLC | Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis |
| WO2018067341A1 (en) * | 2016-10-07 | 2018-04-12 | Patara Pharma, LLC | Cromolyn compositions for treatment of pulmonary fibrosis |
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