CN100574757C - Composition of acetylcysteine or its salt and anti-infective drug - Google Patents

Abstract

The invention belongs to the technical field of medicine, and discloses a pharmaceutical composition containing an effective dose of acetylcysteine or a pharmaceutically acceptable salt thereof, and at least one anti-infection drug, as well as its preparation method and application, wherein the anti-infection The drug is selected from: neohouttuyfonate or its pharmaceutically acceptable salt and/or 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt and/or bitter One or several kinds of ginseng, the pharmaceutical composition can be made into various pharmaceutically acceptable dosage forms, and is used in the preparation and treatment of pneumonia, bronchial asthma, chronic obstructive pulmonary disease with pulmonary acute Inflammation and other diseases have a synergistic effect and good stability. Compared with the single use of the same dose of drugs, the effect is greatly improved, and unexpected effects have been produced. It has a wide application prospect.

Description

Composition of acetylcysteine or its salt and anti-infective drug

1. Technical field

The invention relates to a pharmaceutical composition containing acetylcysteine or a pharmaceutically acceptable salt thereof and at least one anti-infection drug, a preparation method and application thereof, belonging to the technical field of medicine.

2. Background technology

In my country's population statistics, respiratory diseases are the second cause of death, mainly including upper respiratory tract infection, acute and chronic bronchitis, pneumonia, etc. The main symptoms are cough, sputum, and asthma. Most are caused by viral infection, and a few are caused by direct bacterial infection. However, there are not many available drugs in clinical practice and their effects are slow.

Acetylcysteine, which is N-acetyl-L-cysteine. Acetylcysteine is a mucolytic agent, which has a strong effect of dissolving mucus. Viscosity of sputum and liquefaction. Acetylcysteine can also break DNA fibers in purulent sputum, so it can not only dissolve white sticky sputum but also purulent sputum. It is suitable for dyspnea caused by a large amount of sticky phlegm, such as difficulty in expectoration after surgery, acute and chronic bronchitis, bronchiectasis, tuberculosis, pneumonia, emphysema, etc. etc., can still be used for the detoxification of acetaminophen poisoning. The structural formula of acetylcysteine is as follows:

Acetylcysteine structural formula

Among them, anti-infective drugs: including neohouttuydine or its pharmaceutically acceptable salt, 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt, matrine .

Houttuynia cordata is the rooted whole herb of Houttuynia cordata Thunb, a plant of the family Sanbaiaceae. It has a pungent taste and a cool nature. Breathing and coughing, pyretic stranguria, carbuncle sore. Sodium New Houttuyfonat (Sodium New Houttuyfonat) is a chemical synthesis of a single active ingredient of aldehydes extracted from the whole grass of Houttuynia cordata. The chemical name is sodium bisulfite dodecylacetaldehyde, which has antibacterial, anti Anti-inflammatory and analgesic, anti-tumor, promoting immunity, and improving the immune function of the body; it has obvious inhibitory effects on Diplococcus pneumoniae, Salmonella typhi, Staphylococcus aureus, Escherichia coli and Sporothrix, etc. Phagocytosis function, improve serum properdin level, improve the body's non-specific immunity; for adnexitis, pelvic inflammatory disease, chronic cervicitis and other gynecological inflammation, and can be used for upper respiratory tract infection, chronic bronchial pneumonia, viral pneumonia, etc. Respiratory infection. At the same time, the new houttuyfonate sodium has good safety, no obvious toxic side effects or allergic reactions, and it is a substitute product of houttuyniatin sodium. The structural formula of new houttuyfonate sodium is as follows:

Structural formula of new houttuyfonate sodium

Andrographis paniculata (Burm.f.) Ness is the dry aerial part of the plant Andrographis paniculata (Burm.f.) Ness. It has the effects of clearing heat and detoxifying, cooling blood and reducing swelling. Its main active ingredient is andrographolide. 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt is the andrographolide extracted from Andrographis paniculata, which is made of Andrographis paniculata with high biological activity after semi-synthesis Derivatives make the route of administration more direct, have stronger pharmacological effects, less toxic and side effects, and have antipyretic, anti-inflammatory, bactericidal, and antiviral effects. Pharmacological studies have shown that its potassium sodium salt (i.e. Yanhuning) can inhibit early capillary permeability increase, inflammatory exudation and edema, can specifically stimulate the function of the pituitary-adrenal cortex, promote the release of ACTH, and increase the blood flow in the anterior pituitary gland. Biosynthesis of ACTH; it has the effect of inactivating adenovirus, influenza virus, respiratory virus and other viruses in vitro; its monopotassium salt (that is, Chuanhuning) has antipyretic, sedative, and increases the body's emergency response ability to pathogen infection, and is effective against influenza virus , pneumonia adenovirus, intestinal syncytial virus and respiratory syncytial virus have inactivation.

Matrine is an alkaloid extracted from the fruit or aerial parts of Sophora alopecuroides L., a leguminous plant. It contains not less than 98.0% C ₁₅ H ₂₄ N ₂ O. It has been used clinically as a chemical drug. Matrine has anti-virus, anti-inflammatory, anti-tumor effects, sedative, analgesic, antipyretic and cooling effects on the central nervous system, and various pharmacological effects such as strengthening the heart, lowering blood pressure, and anti-arrhythmia. It is also good for the treatment of chronic hepatitis. curative effect, and less adverse reactions. The structural formula of matrine is as follows:

Matrine structural formula

At present, acetylcysteine or its pharmaceutically acceptable salt and neohouttuydine or its pharmaceutically acceptable salt, 14-dehydroxy-11,12-didehydroandrographolide-3,19- The interaction of one or more of disuccinic acid half ester salts and matrine, compatible prescriptions, used for the treatment of pneumonia, bronchial asthma, chronic obstructive pulmonary disease with acute inflammation of the lungs caused by sensitive bacteria, etc. Drugs for diseases have not been reported yet.

3. Contents of the invention

In order to meet clinical needs, better treat respiratory diseases, and improve people's health, the invention provides a new pharmaceutical composition and its preparation method, the composition contains an effective dose of acetylcysteine or its pharmaceutical Acceptable salts, and at least one anti-infective drug, wherein the anti-infective drug is selected from: neohouttuyflon or its pharmaceutically acceptable salt and/or 14-dehydroxy-11,12-didehydroandrographis paniculata One or more of ester-3,19-disuccinic acid half ester salt and/or matrine.

The above-mentioned pharmaceutical composition, its parts by weight are: 20-1200 parts of acetylcysteine or its pharmaceutically acceptable salt, and the anti-infective drugs are different according to different drugs. The salt is 1-100 parts, for 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt is 10-200 parts, for matrine is 10-400 parts .

The above-mentioned pharmaceutical composition, its parts by weight is preferably: 50-600 parts of acetylcysteine or its pharmaceutically acceptable salt, and the anti-infective drugs are different according to different drugs. Accepted salts are 4-20 parts, for 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt is 20-80 parts, for matrine is 40-160 parts share.

The above-mentioned pharmaceutical composition, its parts by weight is more preferably: 100-300 parts of acetylcysteine or its pharmaceutically acceptable salt, and the anti-infective drugs are different according to different drugs. Acceptable salts are 8 parts, 40 parts for 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt, and 80 parts for matrine.

The above pharmaceutical composition, its parts by weight are particularly preferably: 100-300 parts of acetylcysteine or its pharmaceutically acceptable salt and 8 parts of neohouttuydine or its pharmaceutically acceptable salt; or : 100-300 parts of acetylcysteine or its pharmaceutically acceptable salt and 40 parts of 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt; or : A composition comprising 100-300 parts of acetylcysteine or a pharmaceutically acceptable salt thereof and 80 parts of matrine.

The above composition is proportioned by weight, and can be increased or decreased according to the corresponding proportion during production. For example, the unit of kilogram or ton can be used for large-scale production, and the unit of gram can also be used for small-scale production. The weight can be increased or decreased, but the ratio of the weight ratio among the components remains unchanged.

If the above composition is taken as a unit of gram, it can be made into a preparation of 100-10000 times, if it is used as an injection, it can be made into 100-10000 sticks, and the dosage is 1-10 sticks each time. As a tablet, it can be made into 100-10,000 tablets, and 1-10 tablets are taken each time.

The proportions of the above weight ratios are obtained through scientific screening. For special patients, the proportions of the composition can be adjusted accordingly, and the increase or decrease does not exceed 100%.

The dosage of the pharmaceutical components of the present invention is obtained through a lot of exploration by the inventor, and the dosage of each component has a good curative effect within the above-mentioned range of parts by weight.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of acetylcysteine can be organic nitrogen salt, hydrochloride, sulfate, acetate, methanesulfonate, tartrate, maleate, fumarate salt, hydrobromide, aspartate.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of neohouttuyonin may be sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, etc., preferably sodium salt.

In the pharmaceutical composition of the present invention, 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester salt is monopotassium salt, monosodium salt, potassium sodium salt, monomagnesium salt, Monocalcium salt, monozinc salt, preferably monopotassium salt (i.e. Chuanhuning), monosodium salt or potassium sodium salt (i.e. Yanhuning). At present, it has been proved by experiments that the monopotassium salt, monosodium salt or potassium sodium salt of 14-dehydroxy-11, 12-didehydroandrographolide-3, 19-disuccinic acid half ester, etc. Changes will not have a significant impact on its efficacy.

The present invention also provides the application of the above pharmaceutical composition in preparing and treating diseases caused by sensitive bacteria such as pneumonia, bronchial asthma, chronic obstructive pulmonary disease with pulmonary acute inflammation, and the like.

The pharmaceutical composition of the present invention can be added with one or more pharmaceutically acceptable carriers, and administered to patients in need of such treatment by oral administration, nasal inhalation or parenteral administration. For oral administration, it can be made into conventional solid preparations, such as tablets, capsules, soft capsules, dispersible tablets, oral liquids, granules, chewable tablets, orally disintegrating tablets, dropping pills, sustained-release tablets, sustained-release capsules, Controlled-release tablets, controlled-release capsules, made into liquid preparations such as water or oil suspensions or other liquid preparations such as syrups; for parenteral administration, they can be made into injection solutions, water or oil suspensions, etc. Such as water injection, freeze-dried powder injection, sterile powder injection, infusion, etc.; it can also be made into spray. The preferred dosage form of this composition is injection or oral preparation.

The pharmaceutical composition of the present invention can be produced by conventional methods in the existing pharmaceutical field, and various pharmaceutically acceptable carriers can be added when necessary. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.

When the pharmaceutical composition of the present invention is made into an injection, in order to increase its solubility, co-solvents such as polysorbate 80, polyethylene glycols, propylene glycol, and glycerin can be added. Isotonic regulators for adjusting osmotic pressure can be added to the infusion, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol and dextran, etc., preferably sodium chloride and glucose. Excipients such as mannitol, glucose, lactose, dextran, sorbitol, sucrose, glycine, sodium chloride, etc. can be added to the powder for injection.

When the pharmaceutical composition of the present invention is made into an oral preparation, optional fillers include: starch, powdered sugar, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, manna Alcohol, etc.; optional binders are: sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch etc.; optional disintegrants include: dry starch, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, etc.; optional lubricants include: Magnesium stearate, talc, sodium lauryl sulfate, micronized silica gel, etc.

The composition of the present invention has the following advantages:

(1) For the first time, a kind of acetylcysteine or its pharmaceutically acceptable salt and at least one anti-infective drug compatibility are provided for the preparation and treatment of pneumonia caused by sensitive bacteria, bronchial asthma, chronic obstructive pulmonary disease, The pharmaceutical composition and its preparation method and application for diseases associated with pulmonary acute inflammation and other aspects meet the urgent clinical needs;

(2) For the first time, pharmacodynamic studies have been carried out on the interaction and compatibility of the pharmaceutical composition of the present invention, and it has been found that the pharmaceutical composition has an obvious preventive effect on acute lung injury in rats caused by lipopolysaccharide, and the lung coefficient is extremely significantly reduced , the relative gray level of lung NF- _kB was significantly increased, the serum NO concentration was extremely significantly reduced, and the serum MDA concentration was extremely significantly reduced, which can significantly increase the secretion of respiratory tract sputum in rabbits, and has obvious protective effects on mice infected by bacteria It has obvious inhibitory effect on the pneumonia caused by virus infection in mice; it also has obvious inhibitory effect on the rise of rabbit body temperature caused by the bacterin; The statistical difference was significant (p<0.05) compared with the Houttuyfonate Sodium Group, the Yanhuning Group or the Matrine Group (p<0.05), indicating that the combined use of acetylcysteine and anti-infective drugs has a significant effect on the treatment of respiratory diseases , the result is unexpected by those of ordinary skill in the art;

(3) The preparation process of the present invention is simple, and the drug quality is uniform and stable;

(4) the stability experiment that carries out shows that every index of pharmaceutical composition injection of the present invention is all relatively stable, has guaranteed the safety of clinical medication;

(5) The combined medication of the composition of the present invention has definite curative effect, reduces the relative dosage, and has broad application prospects.

The beneficial effect of the pharmaceutical composition of the present invention will be further illustrated through experimental examples below. In the following experimental examples: the composition of acetylcysteine and neohouttuyfonate sodium is hereinafter referred to as the Bxin composition ; the composition of acetylcysteine and Yanhuning is hereinafter referred to as the Bitis composition ; acetylcysteine The composition of acid and matrine is hereinafter referred to as the ethyl ginseng composition .

Experimental Example 1 Prevention and Treatment Effects of Bxin Composition, Byan Composition and Bgin Composition on Acute Lung Injury in Rats Induced by Lipopolysaccharide

Test product: 0.9% normal saline injection, commercially available; lipopolysaccharide (LPS); acetylcysteine (NAC) injection, specification: 20ml: 4g, self-made; B new composition (acetylcysteine+ Sodium Houttuyniatin=100mg+8mg), self-made (see Example 2 for the preparation method); Bingyan composition (acetylcysteine+Yanhuning=100mg+40mg), self-made (see Example 2 for the preparation method ); Bginseng composition (acetylcysteine+matrine=100mg+80mg), self-made (see Example 2 for the preparation method).

Grouping of experimental animals: 120 healthy male SD rats, weighing 180-250, were randomly divided into 12 groups. Respectively, blank control group, rat lung injury model group (LPS group), NAC intervention group (N&L group), Bxin composition low, medium and high dose 3 groups (acetylcysteine & neohouttuyfonate sodium & lipopolysaccharide), 3 groups of low, medium and high doses of B-ginseng composition (acetylcysteine & Yanhuning & lipopolysaccharide), 3 groups of low, medium and high doses of B-ginseng composition (acetylcysteine & matrine & lipopolysaccharide), 10 rats in each group.

Experimental method: the replication of acute lung injury in rats was established by injecting LPS (5 mg/kg, LPS O ₅₅ : B ₅ , Sigma) into the tail vein of rats. 1h before injecting LPS, NAC intervention group (200mg/kg), low-dose group of Yixin composition (10mg/kg), middle-dose group (15mg/kg), high-dose group (20mg/kg), low-dose group of Yiyan composition group (10mg/kg), middle dose group (15mg/kg), high dose group (20mg/kg), B-ginseng composition low dose group (10mg/kg), middle dose group (15mg/kg), high dose group (20mg/kg) were given the corresponding drugs by intraperitoneal injection. The blank control group was given the same amount of normal saline.

Animals in each group were anesthetized by intraperitoneal injection of ketamine hydrochloride (100 mg/kg) 4 hours after injection of LPS or normal saline, the eyeballs were removed and blood was collected, and the serum was collected and stored in a -70°C refrigerator to be tested for nitric oxide (NO) and malondialdehyde (malondialdehyde, NDA) (NO and NDA test kits were purchased from Nanjing Jiancheng Institute of Bioengineering). After blood collection, the animals were sacrificed quickly by exsanguination from the abdominal aorta, and the lungs were quickly collected, observed and weighed to calculate the lung coefficient (lung coefficient: lung wet weight (g) ÷ rat body weight (g) × 100). The lower part of the left lung was fixed and embedded, then sliced to observe lung changes, and immunohistochemical method was used to detect nuclear factor (NF) _-kB staining intensity: ABC staining was performed according to the instructions of the SABC kit, and the primary antibody was rabbit anti-rat NF- _κ B P65 antibody, DAB color development (SABC, DAB kit, rabbit anti-rat NF- _κ B P65 antibody were all purchased from Wuhan Boster Company), and PBS was used instead of the primary antibody as a negative control. Then, the average gray value of the NF- _kB immunohistochemical slices and the corresponding negative control photos in each group was measured with a multifunctional true-color pathological image analysis system (Video pm 32, Australia), and the relative gray value (relative gray value) was calculated. = average gray value of NF- _kB immunohistochemical slides ÷ average gray value of corresponding negative control photos), the greater the relative gray value, the smaller the staining intensity.

Statistical analysis and processing: Quantitative data of each group are represented by x±s, comparison between two groups is performed by t test, significance test level a=0.05, and SPSS software is used for data calculation.

Experimental results: (1) Histopathological examination of the lungs and general observation of the lungs. The appearance of the lungs in the blank control group had no obvious abnormal changes. Yellow or light red liquid overflowed; the lesions in the NAC intervention group were significantly relieved compared with the LPS group, but there were still significant differences compared with the blank control group; Compared with the blank control group, there was no significant difference between the low, middle and high dose groups of Heyishen composition. Under the light microscope, the lung tissue structure of the blank control group was intact, there was no edema and inflammation in the alveolar septum, and the alveolar cavity was clear; the alveolar septum in the LPS group was widened, bleeding was seen in some alveoli, and a large number of inflammatory cell infiltration was seen in the pulmonary interstitium; the lungs of the NAC intervention group Inflammatory cell infiltration, exudation, and bleeding were significantly reduced compared with the LPS group, but there were still significant differences compared with the blank control group: Bxin composition low, medium, and high dose groups, Byan composition low, medium, and high dose groups, and Bshen combination Compared with the LPS group, the low, medium and high dose groups had extremely significant differences, had significant differences compared with the NAC intervention group, and had no significant difference compared with the blank control group.

(2) Changes in lung coefficient Compared with the blank control group, the lung coefficient of the LPS group was significantly increased ( ^** p<0.01); the NAC intervention group was significantly lower than that of the LPS group ( ^# p<0.05); but compared with the blank control group, there were still Significant difference ( ^* p<0.05); comparison of lung coefficient between low, medium and high dose groups of Bxin composition, low, medium and high dose group of Byan composition and low, medium and high dose group of Bgin composition and LPS group Very significantly decreased ( ^## p<0.01), significantly different from NAC intervention group ( ^& p<0.05), and no significant difference compared with blank control group (p>0.05). See Table 1.

(3) The positive staining of NF- _kB immunohistochemical detection in lung tissue was brownish yellow. In the blank control group, the cytoplasm had positive staining, and the nucleus staining was less; in the LPS group, the nucleus was obviously positively stained, and the cytoplasm was also positively stained; the nucleus staining in the NAC intervention group was significantly lower than that in the LPS group, and slightly higher than that in the blank control group; Compared with the LPS group, the low, medium and high dose groups of Yixin composition, the low, medium and high dose groups of Yiyan composition and the low, medium and high dose groups of Bginseng composition were significantly lower than those of the LPS group, and there was no significant difference compared with the blank control group . The relative gray value of NF- _kB staining in the LPS group was significantly lower than that in the blank control group ( ^** p<0.01), indicating that the NF- _kB staining intensity in the LPS group was significantly higher than that in the blank control group; the staining intensity in the NAC intervention group was higher than that in the LPS group Significantly decreased ( ^# p<0.05); but compared with the blank control group, there was still a significant difference ( ^* p<0.05); the low, medium and high dose groups of Bxin composition, the low, medium and high dose groups of Byan composition and Compared with the LPS group, the low, medium and high dose groups of Bginseng composition significantly decreased ( ^## p<0.01), compared with the NAC intervention group ( ^& p<0.05), and had no significant difference compared with the blank control group Sexual differences (p>0.05), among which the gray value is the largest and the staining intensity is the lowest at high doses. See Table 1.

(4) Changes in serum NO concentration Compared with the blank control group, the serum NO concentration in the LPS group was significantly increased ( ^** p<0.01); the NAC intervention group was significantly lower than the LPS group ( ^# p<0.05); but compared with the blank control group There are still significant differences ( ^* p<0.05); Bxin composition low, medium and high dose group, Byan composition low, medium and high dose group and Bshen composition low, medium and high dose group compared with LPS group The concentration of serum NO was significantly decreased ( ^## p<0.01), which was significantly different from the NAC intervention group ( ^& p<0.05), and had no significant difference compared with the blank control group (p>0.05). The serum NO concentration was the lowest. See Table 1.

(5) Changes in serum MDA concentration The serum MDA concentration in the LPS group was significantly higher than that in the blank control group ( ^** p<0.01); the NAC intervention group was significantly lower than that in the LPS group ( ^# p<0.05); but compared with the blank control group, there were still Significant difference ( ^* p<0.05); Bxin composition low, medium and high dose group, Byan composition low, medium and high dose group and Bshen composition low, medium and high dose group compared with LPS group serum MDA The concentration was significantly decreased ( ^## p<0.01), which was significantly different from the NAC intervention group ( ^& p<0.05), and had no significant difference compared with the blank control group (p>0.05). MDA concentration is minimal. See Table 1.

Conclusion: The experimental results show that the Yixin composition, the Yiyan composition and the Yishen composition have obvious preventive and therapeutic effects on the acute lung injury induced by lipopolysaccharide in rats, significantly reducing the lung coefficient and the relative gray level of lung NF- _kB . Significantly increased, serum NO concentration was extremely significantly decreased, serum MDA concentration was extremely significantly decreased, compared with the LPS group ( ^## p<0.01), and compared with the NAC intervention group ( ^& p<0.05), and Compared with the blank control group, there was no significant difference (p>0.05).

Table 1 Comparison of lung coefficient, relative gray scale of lung NF- _kB , serum NO and MDA concentration in each group of rats (x±s, n=10)

Note: ^* p<0.05, ^** p<0.01 compared with blank control group; ^# p<0.05, ^## p<0.01, compared with LPS group; ^& p<0.05, compared with NAC intervention group.

Experimental Example 2 Effects of the second new composition on the secretion of sputum in rabbits

Test article and material: 0.9% normal saline injection, commercially available; Acetylcysteine (NAC) injection, specification: 20ml: 4g, self-made; Yixin composition injection (acetylcysteine+new fish Hsycin Sodium=100mg+8mg), self-made (see Example 2 for the preparation method).

Experimental method: 50 rabbits were randomly divided into 5 groups, 10 in each group, which were blank control group, acetylcysteine group, and three groups of low, medium and high doses of Bxin composition. Animals were anesthetized with urethane ear vein, inserted endotracheal tube, connected to a device that constantly provided preheated (37°C) and constant temperature (80%) breathing air, and connected a fixed scale to the lower end of the cross-shaped endotracheal tube Graduated cylinder, used to collect secretions. To prevent condensation, all animals breathed freely and provided the required amount of breathing air in a cotton-padded enclosure. After 2 hours of stable observation, the experimental drug was administered by intraperitoneal injection, and the dosage is shown in the table below. Immediately after administration, the secretions were collected continuously for 3 hours, and the secretion amount was measured. The rate of change in sputum secretion was calculated. Rate of change = (mean value of sputum volume in each experimental group - mean value of sputum volume in normal saline group)/average value of sputum volume in normal saline group × 100%

Statistical analysis All data were expressed as mean ± standard deviation (x ± s), and statistical analysis of data was performed by t test.

The impact of table 2 B new composition on the secretion of rabbit sputum (x±s, n=10)

Note: ^* p<0.05, ^** p<0.01, compared with blank control group; ^& p<0.05, compared with acetylcysteine group.

Experimental results and conclusions: The experimental results are shown in Table 2. The experimental results show that each administration group can increase the amount of sputum secretion in the rabbit respiratory tract. Compared with the blank control group, the rate of change in the amount of secretion of acetylcysteine is significant ( ^* p<0.05), and the second new composition is low, The rate of change in the amount of secretion in the middle and high dose groups is extremely significant ( ^** p<0.01), and compared with the acetylcysteine group, the difference is also significant ( ^& p<0.05). The experiment shows that the second composition has a strong The effect of promoting sputum secretion, and the effect of promoting sputum secretion of the second composition is significantly positively correlated with the dose, and the effect is the strongest at high doses.

Experimental Example 3 In vivo antibacterial experiment of Byan composition in mice

Test article and material: 0.9% normal saline injection, commercially available; Yanhuning injection, specification: 5ml: 80mg, Hainan Lingkang Pharmaceutical Co., Ltd.; Byan composition (acetylcysteine+yanhuning= 100mg+40mg), self-made (see Example 2 for the preparation method).

Test animals: 200 healthy mice, weighing 18-22g, both male and female.

Bacteria liquid: Dilute Staphylococcus aureus and Diplococcus pneumoniae suspensions with 5% peptin, and the bacteria content is ¹⁰¹⁰ /ml.

Experimental method: 200 mice were randomly divided into 10 groups, namely blank control group, Yanhuning group, and three dose groups of low, medium and high doses of Yiyan composition, with 20 mice in each group. Each mouse was infected by intraperitoneal injection of 0.5ml of bacterial solution, and 1 and 6 hours after the injection of bacterial solution, three doses of 0.9% normal saline, Yanhuning, and Yiyan composition were given by intragastric administration, respectively. The dosages are shown in the table. 3. Observe the survival number of animals 24 hours after infection to judge the protective effect of the drug.

The protective effect of table 3 B inflammation composition on infected mice

Experimental results and conclusions: See Table 3 for the results. In each treatment group of mice infected with Staphylococcus aureus and Streptococcus pneumoniae, the protective effects of the low, medium and high doses of the acetylene composition on the mice were stronger than those of the Yanhuning group and the blank control group. The compatibility of cystine and Yanhuning has a strong protective effect on mice infected with Staphylococcus aureus and Streptococcus pneumoniae, and the effect is related to the dosage of the composition, and the high dosage has the best effect.

Experimental Example 4 In vivo antiviral experiment of Bginseng composition

Test items and materials: 0.9% normal saline injection, commercially available; influenza virus liquid (FM ₁ ), commercially available; matrine injection, specification: 5ml: 80mg, Ningbo Tianheng Pharmaceutical Co., Ltd.; (acetylcysteine+matrine=100mg+80mg), self-made (see Example 2 for the preparation method).

Test animals: 60 Kunming mice, half male and half male, weighing 18-22 g.

Experimental method: Take 60 Kunming mice, half male and half male, and randomly divide them into 6 groups, which are respectively infection control group, normal control group, matrine group, three groups of low, medium and high doses of B-ginseng composition, 10 in each group. Except the normal group, the mice were lightly anesthetized with ether, and infected with 1/5 LD ₅₀ influenza virus fluid (FM ₁ ) by intranasal drip. The drug was given by intragastric administration from the day before the infection, twice a day for 5 consecutive days, and the infection group and the normal control group were given the same volume of normal saline. On the 6th day, the mice were weighed and dissected, the whole lungs were removed and weighed, the lung index values were calculated one by one, and the lung index inhibition rate was calculated. Formula: lung index=lung weight (g)/body weight (g)×100, lung index inhibition rate%=(mean value of lung index of virus control group-mean value of lung index of experimental group)/mean value of lung index of virus control group×100%. (Note: A large lung index indicates a large lung weight and severe lung disease)

The influence of table 4 Bginseng composition on the lung inflammation of influenza virus infected mice (x±s, n=10)

Note: ^* p<0.05, ^** p<0.01 compared with normal control group; ^# p<0.05, ^## p<0.01 compared with infected control group; ^& p<0.05 compared with matrine group.

Experimental results and conclusions: See Table 4 for the results. The lung index value of the infected mice increased significantly, compared with the normal control group, the difference was significant ( ^** p<0.01). Compared with the infection control group, each administration group has obvious antiviral infection effect ( ^# p<0.05 and ^## p<0.01), and the antiviral infection effect of the second ginseng composition is compared with matrine alone , the difference was significant ( ^& p<0.05). It shows that the compatibility of acetylcysteine and matrine has obvious inhibitory effect on the pneumonia caused by virus infection in mice, the lung index value is significantly reduced, and the degree of lung tissue lesions is significantly reduced, and the effect is related to the dosage of the composition , works best at high doses.

Experimental Example 5 Antipyretic Experiment of Bginseng Composition

Test article and material: 0.9% normal saline injection, commercially available; Matrine injection, specification: 5ml: 80mg, Ningbo Tianheng Pharmaceutical Co., Ltd.; B-ginseng composition (acetylcysteine+matrine =100mg+80mg), self-made (see Example 2 for the preparation method).

Pyrogenic source: typhoid, paratyphoid A, B triple vaccine, commercially available.

Test animals: healthy big-eared white rabbits, both male and female, weighing 2.4-2.8kg.

Experimental method: Two days before the experiment, the normal anal temperature of rabbits was measured 4 times a day, and 40 rabbits whose anal temperature fluctuated no more than 0.2°C per day were selected and randomly divided into 5 groups, namely the control group, matrine group, B-ginseng composition low, medium and high dose groups, 8 rats in each group. On the morning of the experiment, the basal body temperature of the animal was first measured, and 0.5ml/kg of typhoid, paratyphoid A, and B triple vaccine was injected into the ear vein of the rabbit to cause heat. After half an hour, the rectal temperature was measured respectively, and the corresponding drug was given by intragastric administration. . After administration, the rectal temperature was measured every 1 hour for a total of 4 times. The difference between the rectal temperature measured at different times and the basic rectal temperature was used as an indicator of body temperature change.

Experimental results and conclusions: See Table 5 for the results. Each administration group had obvious antipyretic effect, and the difference was significant compared with the control group ( ^* p<0.05 and ^** p<0.01). Wherein the B-ginseng composition has obvious antipyretic effect on the rise of rabbit body temperature caused by the bacterin, and is longer than that of matrine alone, and still has an antipyretic effect after 4 hours of medication, and the effect is the same as that of the composition The dose is related, and the effect is best at high doses.

Antipyretic effect of table 5 ginseng composition on bacterin-induced fever rabbits (x±s, n=8)

Note: ^* p<0.05, ^** p<0.01 compared with the control group; ^& p<0.05, compared with the matrine group.

Experimental Example 6 Stability Experiment of Yixin Composition Injection, Yiyan Composition Injection, and Bgin Composition Injection

Test product: Yixin Composition Injection (self-made, 5ml: acetylcysteine + neohouttuyfonate sodium = 100mg + 8mg);

Yiyan Composition Injection (self-made, 5ml: acetylcysteine + Yanhuning = 100mg + 40mg);

B-ginseng composition injection (homemade, 5ml: acetylcysteine + matrine = 100mg + 80mg).

Inspection items: traits, pH value, clarity.

Long-term stability test methods and results: each composition of this product was placed under the conditions of temperature 25°C±2°C and relative humidity 60%±10% for 6 months and 12 months, and there was no significant change in each index. Show that each composition injection of this product is placed basically stable for a long time.

4. Specific implementation

The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. The auxiliary materials of each dosage form in the following examples can be replaced with pharmaceutically acceptable auxiliary materials, or decreased or increased.

The preparation of embodiment 1 composition powder injection of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 100g

New Houttuyniatin Sodium 20g

Polysorbate 80 50g

Mannitol 300g

Add sterile water for injection to 3000ml

           

A total of 1000 sticks were prepared

Bacterial composition prescription

Acetylcysteine 100g

Yanhuning 80g

Mannitol 300g

Add sterile water for injection to 3000ml

           

A total of 1000 sticks were prepared

Prescription of Bginseng Composition

Acetylcysteine 100g

Matrine 160g

Polysorbate 80 50g

Mannitol 300g

Add sterile water for injection to 3000ml

           

A total of 1000 sticks were prepared

2. Specific steps:

1) First, aseptically process the containers used for liquid preparation, antibiotic glass bottles, rubber stoppers, etc.

2) Weigh the raw materials and auxiliary materials according to the prescription quantity.

3) Take sterile water for injection with a dosing volume of 80%, add mannitol and polysorbate 80 (according to the requirements of the prescription) and heat and stir to dissolve completely. Add matrine and stir to dissolve completely, and add sterile water for injection to the full amount.

4) Add activated carbon for needles with a dosing volume of 0.05%, and stir for 15 minutes.

5) Filtration and decarburization. Measure and adjust the pH of the solution.

6) Fine filtration through a 0.22 μm microporous membrane.

7) Check the clarity of the solution and test the semi-finished product.

8) Divide into antibiotic glass vials and stopper halfway. Place the samples in a lyophilizer for freeze drying. Pre-freeze at -40°C for 5 hours, vacuum dry at low temperature at -40°C to 0°C for 35 hours, then heat up to 25°C and dry in vacuum for 4 hours.

9) After the freeze-drying is completed, press the stopper and roll the cap.

10) Full inspection of finished products, packaging and storage.

Embodiment 2 Preparation of the composition aqueous injection of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 100g

New Houttuyniatin Sodium 8g

Polysorbate 80 30g

Add water for injection to 5000ml

           

A total of 1000 sticks were prepared

Bacterial composition prescription

Acetylcysteine 100g

Yanhuning 40g

Add water for injection to 5000ml

           

A total of 1000 sticks were prepared

Prescription of Bginseng Composition

Acetylcysteine 100g

Matrine 80g

Ethanol 80ml

Add sterile water for injection to 5000ml

           

A total of 1000 sticks were prepared

2. Specific steps:

1) Dispose of the pipes and containers used for liquid preparation one day in advance, and rinse them with fresh water for injection before use.

2) Take 80% of the water for injection, add the prescribed amount of acetylcysteine, neohouttuydin sodium or Yanhuning or matrine, add the prescribed amount of polysorbate 80 or ethanol (according to the prescription Need) heat and stir to dissolve completely, and add water for injection to the full amount.

3) Add activated carbon for needles with a dosing volume of 0.05%, and stir for 15 minutes.

4) Filtration and decarburization. Measure and adjust the pH of the solution.

5) Fine filtration through a 0.45 μm microporous membrane.

6) Check the clarity of the solution and test the semi-finished product.

7) Seal the solution in a glass ampoule.

8) Sterilize with circulating steam at 100°C for 30 minutes.

9) Put the sample into 0.01% methylene blue solution to check for leaks while it is hot.

10) Light inspection, full inspection of finished products, packaging and storage.

Embodiment 3 The preparation of composition sodium chloride infusion of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 300g

New Houttuyniatin Sodium 4g

Polysorbate 80 30g

Sodium chloride 900g

Add water for injection to 100000ml

             

A total of 1000 bottles were prepared

Bacterial composition prescription

Acetylcysteine 300g

Yanhuning 20g

Sodium chloride 900g

Add water for injection to 100000ml

           

A total of 1000 bottles were prepared

Prescription of Bginseng Composition

Acetylcysteine 300g

Matrine 40g

Sodium chloride 900g

Add water for injection to 100000ml

           

A total of 1000 bottles were prepared

2. Specific steps:

1) Dispose of the pipes and containers used for liquid preparation the day before, and rinse them with fresh water for injection before use.

2) Make polysorbate 80 into a 20% solution with water for injection, add acetylcysteine and neohouttuyfonate sodium to heat and stir to dissolve completely, and dissolve sodium chloride with 40% water for injection Completely, combine the above solutions and add water for injection to the full amount;

Alternatively: add Yanhuning or Matrine to water for injection with a dosing volume of 20%, heat and stir to dissolve completely, dissolve sodium chloride with water for injection with a dosing volume of 40%, combine the above solutions, and add water for injection to Full amount.

3) Add activated carbon for needles with a dosing volume of 0.05%, and stir for 15 minutes.

4) Decarburization by sand filter rod filtration. Measure and adjust the pH of the solution.

5) Fine filtration through a 0.45 μm microporous membrane.

6) Check the clarity of the solution and test the semi-finished product.

7) Fill in an infusion bottle of corresponding volume.

8) Autoclave at 115°C for 30 minutes.

9) Light inspection, full inspection of finished products, packaging and storage.

Embodiment 4 The preparation of composition glucose infusion of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 50g

New Houttuyniatin Sodium 8g

Polysorbate 80 50g

Glucose 5000g

Add water for injection to 100000ml

             

A total of 1000 bottles were prepared

Bacterial composition prescription

Acetylcysteine 50g

Yanhuning 40g

Glucose 5000g

Add water for injection to 100000ml

             

A total of 1000 bottles were prepared

Prescription of Bginseng Composition

Acetylcysteine 50g

Matrine 80g

Glucose 5000g

Add water for injection to 100000ml

             

A total of 1000 bottles were prepared

2. Specific steps:

1) Dispose of the pipes and containers used for liquid preparation one day in advance, and rinse them with fresh water for injection before use.

2) Make polysorbate 80 into a 20% solution with water for injection, add neohouttuydin sodium, heat and stir to dissolve, then add 40% water for injection, add acetylcysteine to dissolve, and mix the glucose with the solution amount 20% of the water for injection is completely dissolved, and the above solutions are combined and added with water for injection to the full amount;

Alternatively: add acetylcysteine and Yanhuning or matrine to heat and stir to dissolve completely, and dissolve glucose completely with 40% water for injection. Combine the above solutions and add water for injection to the full amount.

3) Add activated carbon for needles with a dosing volume of 0.05%, and stir for 15 minutes.

4) Decarburization by sand filter rod filtration. Measure and adjust the pH of the solution.

5) Fine filtration through a 0.45 μm microporous membrane.

6) Check the clarity of the solution and test the semi-finished product.

7) Fill in an infusion bottle of corresponding volume.

8) Autoclave at 115°C for 30 minutes.

9) Light inspection, full inspection of finished products, packaging and storage.

The preparation of embodiment 5 composition tablet of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 200g

New Houttuyniatin Sodium 8g

Pregelatinized starch 120.0g

Low-substituted hydroxypropyl cellulose 20g

Microcrystalline Cellulose 40.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 4.0g

Sodium starch glycolate 16.0g

             

A total of 1000 pieces were prepared

Bacterial composition prescription

Acetylcysteine 200g

Yanhuning 40g

Pregelatinized starch 120.0g

Low-substituted hydroxypropyl cellulose 20g

Microcrystalline Cellulose 40.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 4.0g

Sodium starch glycolate 16.0g

             

A total of 1000 pieces were prepared

B-ginseng composition prescription

Acetylcysteine 200g

Matrine 80g

Pregelatinized starch 120.0g

Low-substituted hydroxypropyl cellulose 20g

Microcrystalline Cellulose 40.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 4.0g

Sodium starch glycolate 16.0g

             

A total of 1000 pieces were prepared

2. Specific steps:

1) Grind acetylcysteine and neohouttuydin sodium or Yanhuning or matrine through a 100-mesh sieve for later use.

2) Weigh the raw materials and auxiliary materials according to the prescription quantity.

3) Dissolving hypromellose in water to make a 2% aqueous solution for later use.

4) Mix acetylcysteine, neohouttuydin sodium or yanhuning or matrine, pregelatinized starch and microcrystalline cellulose evenly, add an appropriate amount of 2% HPMC aqueous solution, stir evenly, and make suitable soft material.

5) Pass through a 20-mesh sieve to make granules.

6) The particles are dried at 60°C.

7) Add magnesium stearate and sodium starch glycolate to the dried granules, pass through a 18-mesh sieve for granulation, and mix well.

8) Sampling and testing of semi-finished products.

9) Compress the tablet according to the tablet weight determined by the assay.

10) Full inspection of finished products, packaging and storage.

The preparation of embodiment 6 composition capsules of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 100g

New Houttuyniatin Sodium 8g

Pregelatinized starch 60.0g

Microcrystalline cellulose 20.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 2.0g

Micropowder silica gel 4.0g

           

A total of 1000 capsules were prepared

Bacterial composition prescription

Acetylcysteine 100g

Yanhuning 40g

Pregelatinized starch 60.0g

Microcrystalline cellulose 20.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 2.0g

Micropowder silica gel 4.0g

             

A total of 1000 capsules were prepared

Prescription of Bginseng Composition

Acetylcysteine 100g

Matrine 80g

Pregelatinized starch 60.0g

Microcrystalline cellulose 20.0g

2% HPMC aqueous solution Appropriate amount

Magnesium stearate 2.0g

Micropowder silica gel 4.0g

           

A total of 1000 capsules were prepared

2. Specific steps:

1) Grind acetylcysteine and neohouttuydin sodium or Yanhuning or matrine through a 100-mesh sieve for later use.

2) Weigh the raw materials and auxiliary materials according to the prescription quantity.

3) Dissolving hypromellose in water to make a 2% aqueous solution for later use.

4) Mix acetylcysteine, neohouttuydin sodium or yanhuning or matrine, pregelatinized starch and microcrystalline cellulose evenly, add an appropriate amount of 2% HPMC aqueous solution, stir evenly, and make suitable soft material.

5) Pass through a 20-mesh sieve to make granules.

6) The particles are dried at 60°C.

7) Add magnesium stearate and micropowder silica gel to the dried granules, pass through a 18-mesh sieve for granulation, and mix well.

8) Sampling and testing of semi-finished products.

9) Pack into capsules according to the loading determined by the assay.

10) Full inspection of finished products, packaging and storage.

The preparation of embodiment 7 composition granules of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 100g

New Houttuyniatin Sodium 8g

Powdered sugar 2000.0g

Stevia 10g

2% HPMC50% ethanol solution appropriate amount

             

A total of 1000 packs were prepared

Bacterial composition prescription

Acetylcysteine 100g

Yanhuning 40g

Powdered sugar 2000.0g

Stevia 10g

2% HPMC50% ethanol solution appropriate amount

             

A total of 1000 packs were prepared

Prescription of Bginseng Composition

Acetylcysteine 100g

Matrine 80g

Powdered sugar 2000.0g

Stevia 10g

2% HPMC50% ethanol solution appropriate amount

             

A total of 1000 packs were prepared

2. Specific steps:

1) Crushing the sucrose through a 100-mesh sieve for later use. Grind acetylcysteine and neohouttuydin sodium or Yanhuning or matrine through a 100-mesh sieve for later use.

2) Weigh the raw materials and auxiliary materials according to the prescription quantity.

3) Mix acetylcysteine, neohouttuydin sodium or yanhuning or matrine with powdered sugar and stevioside in equal increments, add an appropriate amount of 2% HPMC50% ethanol solution, and stir well , made of suitable soft materials.

4) Pass through a 20-mesh sieve to make granules.

5) The particles are dried at 60°C.

6) The dry granules are passed through a 18-mesh sieve for granulation.

7) Take samples, test the content of the main drug in the semi-finished product, and determine the loading.

8) Packaging, full inspection of finished products, packaging and storage.

Embodiment 8 Preparation of composition spray of the present invention

1. Prescription:

B new composition prescription

Acetylcysteine 100g

New Houttuyniatin Sodium 8g

Polyethylene glycol 400 100g

Sodium chloride 65g

Methylparaben 0.5g

Ethylparaben 0.5g

Add purified water to 10000ml

             

A total of 1000 bottles were prepared

Bacterial composition prescription

Acetylcysteine 100g

Yanhuning 40g

Sodium chloride 65g

Methylparaben 0.5g

Ethylparaben 0.5g

Add purified water to 10000ml

             

A total of 1000 bottles were prepared

Prescription of Bginseng Composition

Acetylcysteine 100g

Matrine 80g

Sodium chloride 65g

Methylparaben 0.5g

Ethylparaben 0.5g

Add purified water to 10000ml

             

A total of 1000 bottles were prepared

2. Specific steps:

1) Weigh the raw materials and auxiliary materials according to the prescription quantity.

2) Add new houttuyfonate sodium into the prescribed amount of polyethylene glycol 400, heat and dissolve completely, and add purified water while stirring, to 500ml, to obtain a clear liquid;

Alternatively: Add Yanhuning or Matrine into purified water and heat to dissolve completely to 500ml to obtain a clear liquid.

3) Add acetylcysteine, sodium chloride, methylparaben and ethylparaben into 200ml of purified water, heat and stir to dissolve completely, and mix with the above solution evenly.

4) Measure the pH value of the solution, adjust the pH value of the solution to about 6.0 with 1mol/L sodium hydroxide solution.

5) Add purified water to 10000ml and stir well.

6) The solution is finely filtered through a 0.8 micron filter membrane, and the semi-finished product is tested.

7) Divide into spray bottles and screw the caps on.

8) Full inspection of finished products, packaging and storage.

Claims (7)

1. the pharmaceutical composition formed of an acetylcysteine or its pharmaceutically acceptable salt and at least a anti-infectives, it is characterized in that, described anti-infectives is selected from: neo-houttuyninum or its pharmaceutically acceptable salt and/or 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester salt and/or matrine, wherein the parts by weight of compositions are: 50～600 parts of acetylcysteine or its pharmaceutically acceptable salts, anti-infectives is different and different according to medicine, for neo-houttuyninum or its pharmaceutically acceptable salt is 4～20 parts, for 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester salt is 20～80 parts, is 40～160 parts for matrine.

2. pharmaceutical composition as claimed in claim 1, the parts by weight that it is characterized in that described compositions are: 100～300 parts of acetylcysteine or its pharmaceutically acceptable salts, anti-infectives is different and different according to medicine, for neo-houttuyninum or its pharmaceutically acceptable salt is 8 parts, for 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester salt is 40 parts, is 80 parts for matrine.

3. as each described pharmaceutical composition of claim 1～2, it is characterized in that described acetylcysteine pharmaceutically acceptable salt is hydrochlorate, sulfate, acetate, mesylate, tartrate, maleate, fumarate, hydrobromate, aspartate.

4. as each described pharmaceutical composition of claim 1～2, it is characterized in that described neo-houttuyninum pharmaceutically acceptable salt is sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt.

5. as each described pharmaceutical composition of claim 1～2, it is characterized in that described 14-deshydroxy-11,12-two dehydrogenation andrographolide-3,19-disuccinic acid half ester salt is its monopotassium salt, single sodium salt, k-na salt, single magnesium salt, single calcium salt, single zinc salt.

6. as each described pharmaceutical composition of claim 1～2, it is characterized in that described pharmaceutical composition and mixing acceptable accessories make clinically any or pharmaceutically acceptable dosage form.

7. pharmaceutical composition as claimed in claim 6 is characterized in that clinically described or pharmaceutically acceptable dosage form is injection and peroral dosage form.