CN113491676B - Solution for atomizing inhalation of ribavirin and preparation method thereof - Google Patents
Solution for atomizing inhalation of ribavirin and preparation method thereof Download PDFInfo
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- A61K9/0012—Galenical forms characterised by the site of application
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- 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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Abstract
The invention discloses a solution for atomizing and inhaling ribavirin and a preparation method thereof, wherein each ml of the solution for atomizing and inhaling ribavirin comprises the following components: 1) 0.005-5g ribavirin or a pharmaceutically acceptable salt thereof; 2) 0.1-0.5mg isotonic agent; 3) 0.2-0.8mg buffer salt; 4) 0.3-4.0mg of penetration enhancer; 5) 0-50mg cyclodextrin; 6) 0.1-1.0mg of solvent; the other is water for injection. The innovative use of phospholipids as permeation enhancers of the present invention increases the solubility of the drug in the liquid state, increases the delivery rate of the drug in the respiratory tract, particularly the alveoli, and accelerates absorption. The pharmaceutical preparation provides a therapeutic drug and a therapeutic scheme which are lack of the prior art, accurate in medicinal dosage, high in quality, stable in medicine quality, safe and simple in clinical application.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to a solution for atomizing inhalation of ribavirin and a preparation method thereof.
Background
Ribavirin is an artificially synthesized chemical substance, also known as ribavirin, niscan and the like, is a broad-spectrum powerful antiviral drug, belongs to a synthetic nucleoside drug, has an inhibitory effect on a plurality of DNA and RNA viruses, and is successfully synthesized for the first time by Witkowski and the like in 1970 by ICN pharmaceutical companies. Is a nucleoside drug with broad-spectrum antiviral activity, has strong inhibition effect on influenza virus, herpes virus, adenovirus and measles, can competitively inhibit inosine monophosphate dehydrogenase and prevent the replication and synthesis of viral nucleic acid. Ribavirin Lin Jixing marketed abroad is in the form of oral dosage form or spray, and domestic injection liquid occupies a larger market. Ribavirin in the united states is commercially available as an aerosol inhalation solution: VIRAZOL (6 GM/VIAL), registered by VALEANT PHARM INTL, and approved by the FDA under the name of RLD, 12/31 in 1985, was administered as an aerosol cap with a dose of up to 20 mg/day for children. The ribavirin aerosol has a content of 0.5mg per press, and the daily children use no more than 40 presses and the total amount is 20mg calculated according to the maximum daily exposure in the specification. The product marketed in the United states is an aerosol inhalation product, is mainly distributed in the lung, has larger absorption area, and the aerosol marketed in domestic approval is local medicine such as oropharynx and nose.
The foreign market is sterile powder (after re-dissolution) aerosol inhalant, and because ribavirin droplets can directly act on a focus, higher medicine concentration is formed locally, and the medicine concentration is larger than that of local medicine in oral administration and injection administration forms, and the curative effect is obvious. In the prior art, ribavirin Lin Fenji is hydrated and re-dissolved before use to indirectly prepare an aerosol inhalation solution, and then aerosol inhalation treatment is carried out on patients, so that the problems of high production cost, complex operation, easy improper dosage use, larger packaging specification (6 g/bottle), easy secondary pollution and the like exist.
Most aerosol systems give a rate of deposition in the lungs of about 10-20%, for example, if using the correct technique, only 20-40 μg of 200 μg of drug ejected using a metered dose inhaler reaches the lungs, while the remainder is lost to the oropharynx, the device, the surrounding environment and is expelled with exhaled air. Fig. 1 is a graph of the rate of drug loss in the oropharynx, device, and exhaled air/environment for various aerosol devices, and the rate of drug deposition in the lungs was found to be similar for various device formats. Because ribavirin is administered in a relatively high dose, it is required to administer a relatively large dose (e.g., 500mg-6 g) in the treatment of severe infectious diseases such as new coronavirus (2019-CoV) or other viruses, and although such a large dose is still limited to be delivered to the alveoli, most of the drug will be deposited and adsorbed on the upper respiratory tract, so that the aerodynamic particle characteristics of the ribavirin need to be optimized, the atomized particles are ensured to have a proper particle size and a proper quality, and sufficient kinetic energy of the droplets is sufficient to deliver more drug to the deep alveoli (e.g., new coronavirus and the like are more hidden in the deep alveoli, and nucleic acid positivity can be detected by the deep alveolar perfusion method).
In addition, the problem of safety of large-dose aerosol inhalants is a need to solve and continuously improve the medical problem, and aerosol inhalation therapy is used for inhaling the medicine into the respiratory system after atomizing, forming higher concentration in local aggregation, directly acting on receptors or target receptors on the surface of the airway to play a role, and directly absorbing the medicine from the airway mucosa and the lung to quickly play a pharmacological role, and particularly, the safety of aerosol inhalation medicine should be paid attention to because the aerosol inhalation therapy plays a direct and quick role. Literature reports (Merkus p, classification of cilioinhibiting effects of nasal drugs, laryngosccope, 2001;111 (4 Pt 1): 595-602) report: the main components, preservative and additives (such as solubilizer, absorption promoter, etc.) in the nasal administration preparation all produce certain irritation symptoms to nasal cavity, and some substances can even inhibit the nasal cilia delivery system, thus causing cilia immobility. Although many studies have not found that formulations for aerosol inhalation of ribavirin lead to adverse effects during the treatment period, there is no effective evidence of safety against the nasal cavity and the entire respiratory system. The most marketed aerosol inhalation solutions are prescribed in multiple doses, which causes problems for clinical use. First, the most commercially available aerosol inhalation solution products are in the form of 20-250ml packages and even larger, which makes it possible to add up to 20-200 times for a single use, or even more. The repeated clinical use caused by the method greatly increases the possibility of microbial contamination in the use process and the difficulty of guaranteeing the quality stability of the liquid preparation, thereby greatly increasing the risk of inhalation administration of patients. Secondly, the use of large doses of aerosol inhalation formulations, often with preservatives and additives such as benzalkonium chloride and the like in the formulation, will increase the probability of clinical adverse effects of the inhaled drug, and studies have demonstrated that such preservatives will affect the effect of ciliated cells and will greatly affect the efficacy of aerosol inhalation therapy. For this reason, the amount of such preservatives to be added to inhaled medicines has been strictly limited in various countries such as the European Union. In addition, since the prescribed dose of the multi-dose inhalation formulation is large, unnecessary waste of the remaining medicine will be brought; and the medicine needs to be dissolved or diluted before use, which brings inconvenience and potential safety hazard to clinical administration.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a ribavirin atomized inhalation solution product which is safe, effective and excellent in quality.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an aerosol inhalation solution of ribavirin, comprising per ml of solution:
1) 0.005-5g ribavirin or a pharmaceutically acceptable salt thereof;
2) 0.1-0.5mg isotonic agent;
3) 0.2-0.8mg buffer salt;
4) 0.3-4.0mg of penetration enhancer;
5) 0-50mg cyclodextrin;
6) 0.1-1.0mg of solvent;
the other is water for injection.
Ribavirin or a pharmaceutically acceptable salt thereof according to the present invention is a clinically single-use, commonly used dosage of 0.15-5g, including but not limited to 150mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, etc., and in some preferred embodiments, ribavirin or a pharmaceutically acceptable salt thereof is 0.15-4g, including but not limited to 200mg, 1g, or 4g, etc., of ribavirin. Further preferably 0.2 to 0.3g.
Preferably, the penetration enhancer of the present invention is a phospholipid; preferably, the phospholipid is selected from one or more of yolk phospholipid, soybean phospholipid, cephalin, cardiolipin or synthetic phospholipid, and more preferably, the phospholipid is yolk phospholipid. The synthetic phospholipids are commonly used in the art, for example; the synthetic phospholipids include dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, and the like.
Preferably, the phospholipid is contained in an amount of 0.3-4.0mg per ml of solution, more preferably 0.5-3.0mg per ml of solution.
Preferably, 3-10mg cyclodextrin is contained in each ml of solution; further preferably, 4-6mg of cyclodextrin is contained.
Preferably, the isotonic agent used for the solution for aerosol inhalation of ribavirin is one or more selected from potassium chloride, sodium chloride, magnesium chloride, calcium chloride, glucose, xylitol and sorbitol; it is further preferred that 0.2-0.3mg per ml of solution is included.
Preferably, 0.1-0.5mg of vehicle is included per ml of solution.
Preferably, the solvent is selected from one or more of propylene glycol or glycerin; preferably, the propylene glycol and the glycerol are mixed, and more preferably, the mass ratio of the propylene glycol to the glycerol is 2-1:1.
The buffer salts of the present invention as pH adjusting agents to maintain stability of the solution may be buffer salts commonly used in the art, including, but not limited to: citric acid-sodium citrate, citric acid-disodium hydrogen phosphate, disodium hydrogen phosphate-sodium dihydrogen phosphate, acetic acid-sodium acetate, citric acid-sodium hydroxide-hydrochloric acid; preferably, 0.5-0.8mg buffer salt is included per ml of solution.
The pH value of the solution for aerosol inhalation of ribavirin is 4.5-6.5.
In some preferred embodiments, the solution for aerosol inhalation of ribavirin according to the present invention further comprises a single dose pharmaceutical package, such as a single dose, disposable pharmaceutical plastic ampoule package.
In some embodiments, the single dose pharmaceutical package of the present invention may ensure sterility assurance of the product after single dose independent filling, sealing using a sterile BLOW/Fill/Seal (BFS) technique.
The single dose according to the invention is a standard of care for single use in clinical practice, for example 1-30ml, including but not limited to 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 11ml, 12ml, 13ml, 14ml, 15ml, 16ml, 17ml, 18ml, 19ml, 20ml, 21ml, 22ml, 23ml, 24ml, 25ml, 26ml, 27ml, 28ml, 29ml, 30ml, in some preferred embodiments the standard is: 1ml,5ml,20ml.
The invention also provides a clinical use mode, wherein 20ml is inhaled by atomization for the first time, then the subsequent maintenance treatment is carried out at 1ml or 5ml (once daily), and the confirmation of treatment specification and scheme is confirmed by doctors.
The invention also provides a preparation method of the solution for aerosol inhalation of ribavirin, which comprises the following steps:
(1) The ribavirin or the pharmaceutically acceptable salt and the isotonic agent thereof are respectively weighed according to the prescription amount and added into the water for injection with the total volume of 50-65 percent, and the solution 1 is obtained by stirring evenly:
(2) In addition, taking water for injection, of which the prescription amount is 20-30%, stirring or high shearing or homogenizing the solvent, the permeation enhancer and the cyclodextrin at the temperature of 40-50 ℃ until the solvent, the permeation enhancer and the cyclodextrin are completely dissolved, so as to obtain solution 2;
(3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, adding a prescribed amount of buffer salt, and adjusting to a required pH range;
(4) Cooling to 20-25deg.C, adding injectable water to a specified volume, and stirring;
(5) And (5) respectively filling different specifications by using an integrated blowing filling and sealing machine after filtering.
In some embodiments, the format in step (5) of the method of the invention is a format for single treatment, e.g., 1-30ml, for single treatment commonly used in clinic, including but not limited to 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml, 11ml, 12ml, 13ml, 14ml, 15ml, 16ml, 17ml, 18ml, 19ml, 20ml, 21ml, 22ml, 23ml, 24ml, 25ml, 26ml, 27ml, 28ml, 29ml, 30ml, in some preferred embodiments, the format is: 1ml,5ml,20ml.
The invention has the beneficial effects that:
(1) In the conventional multi-dose inhalation formulation, due to possible clinical repeated use, the preservative benzalkonium chloride and the like are often added to ensure the stability of the medicament, but a plurality of safety defects exist; the single-dose disposable packaging is adopted, the single dose refers to the dose of the medicinal active ingredient used by single atomization inhalation, and the defects of repeated measurement, repeated dilution preparation and inaccurate dosage caused by multi-dose large-package solution are avoided because the dose of single administration is determined, so that a plurality of safety problems are thoroughly solved. Moreover, the preparation provided by the invention has the technical advantages of higher effective drug concentration, high concentration and excellent effective deposition effect.
(2) The innovative use of phospholipids as permeation enhancers of the present invention increases the solubility of the drug in the liquid state, increases the delivery rate of the drug in the respiratory tract, particularly the alveoli, and accelerates absorption. The invention obviously optimizes the particle size and particle morphology by adding substances such as phospholipid, cyclodextrin and the like, thereby leading to better aerodynamic distribution and delivering larger proportion of liquid drops to deep alveoli. The purpose of the phospholipid effect of the present invention, unlike liposomes or phospholipid complexes, or emulsions, is not to target or increase drug solubility, but to improve the aerodynamic characteristics of the particles after aerosolization. When the atomization effect is compared, the addition of the trace amount of phospholipid influences the surface tension of the inhalation preparation, so that the atomization particle size is more uniform and concentrated, and in-vitro model tests show that more aerosol particles reach alveoli, so that more drug droplets are beneficial to be adhered to and permeated on the surfaces of the alveoli, and the effective proportion of the formed fine particles is obviously higher than that of the fine drug particles specified in Chinese pharmacopoeia 2015 and is not lower than 10% of the marked content. Meanwhile, it is found by accident in experiments that the effective deposition rate of the atomized particles can be further improved remarkably after adding a proper amount of cyclodextrin when the amount of phospholipid is within the utility range.
(3) By adding substances such as phospholipid, the liquid drops reaching deep alveoli are promoted to be fused with the blood and oxygen interfaces on the surface of the alveoli more easily due to the action of the phospholipid surfactant, the adhesion of the liquid drops on the alveoli is promoted, and partial particles are prevented from being exhaled out of the body due to random movement. Furthermore, phospholipids are substances with affinity for human tissue cells, which tend to accelerate the entry of drugs into alveolar capillaries, resulting in rapid onset of action.
(4) Clinical data and literature both show that ribavirin has a half-life of about 30 minutes after intravenous injection and is rapidly metabolized, requiring a large dose to maintain local blood levels, leading to systemic side effects. The aerosol inhalation solution can send more aerosol particles into alveoli, can maintain higher drug concentration in the lower respiratory tract and alveoli without a large dosage, and effectively reduces systemic side effects. In addition, the single-dose atomization volume of the product is less (1, 5, 20 ml), compared with the atomization process of similar foreign products which needs atomization for 4-6 hours, the product can finish inhalation in a shorter time (20-30 min) and cooperate with intravenous injection, so that the treatment effect can be exerted in a shorter time, the treatment compliance of patients is improved, and the medical resource burden is reduced.
(6) The integrated blowing and filling technology ensures sterility assurance and avoids the disadvantages of similar products.
Drawings
Fig. 1 is a graph of the various ratios of aerosol device drug loss in the oropharynx, device, and exhaled air/environment.
Detailed Description
The present invention will be further illustrated by the following examples, which are to be understood as illustrative only and not limiting of the invention, and simple modifications of the process of preparation of the invention are within the scope of the invention without departing from the spirit of the invention. The following examples do not address the specific conditions of the experimental procedure, and are generally in accordance with means well known in the art. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores.
The preparation process of the following pharmaceutical examples and the dosage of the substances used in the preparation are not limited to the literal expression, and all the preparation methods containing the pharmaceutical composition provided by the invention belong to the protection scope of the invention, and specific experimental methods can refer to the books and the literature commonly used in pharmaceutical preparations.
The following examples are given, unless otherwise indicated, in which the specific methods for detecting items are:
MDI aerosol inhaler test employed:
westech anderson eight-stage impact aerosol sampler (compliant with USP Chapter <601> and EP Chapter 29.9.18). And detecting aerodynamic particle size distribution data after a sample to be detected is atomized by the Pari atomizer, wherein the average atomization rate of the atomizer is set as follows: 0.20ml/min. The NGI device was pre-chilled at 4 ℃ for 3 hours before measurement, then at room temperature: the gas flow rate was set at 28.+ -. 1.0L/min as measured at 22 ℃. Atomized particles are deposited at various collecting positions of the instrument: after the medicines introduced into the device, each stage of collecting tray and the microporous collector are collected, the content is measured by an HPLC method, and the medicine retention quantity and the proportion of each part can be obtained. By analyzing the deposition location of the particulate matter, information such as fine particle fraction, fine particulate matter dose, mass median diameter (MMAD), and geometric mean diameter (GSD) can be obtained to evaluate the particle performance of the aerosol. The data are as follows:
example 1
This example provides a single dose ribavirin aerosol inhalation solution in a single dose individual package and prescription. In the prior art, similar products of foreign manufacturers are powder, and are re-dissolved and diluted before use, and the powder is inconvenient to use due to the large package of 6 g/bottle.
The two are compared as in table 1:
[ Table 1 ]
EXAMPLE 2 formulation of non-phospholipid ribavirin nebulized inhalation solution
Prescription formulation ratios are shown in table 2:
[ Table 2 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Sodium chloride | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Yolk phospholipid | 0mg | 0mg | 0mg |
| Cyclodextrin | 0mg | 0mg | 0mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
(1) Respectively weighing ribavirin and sodium chloride according to the prescription amount, adding the ribavirin and the sodium chloride into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
(2) In addition, taking water for injection, of which the prescription amount is 30%, stirring or high shearing or homogenizing the propylene glycol and the glycerin at the temperature of 40-50 ℃ until the propylene glycol and the glycerin are completely dissolved, and obtaining solution 2;
(3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
(4) Cooling to 20-25deg.C, adding injectable water to a specified volume, and stirring;
(5) Passing through a 0.45um+0.22um filter;
(6) Respectively filling different specifications by using an integrated blowing filling and sealing machine: 1ml,5ml,20ml.
(7) Vacuum leakage detection; spraying characters and packaging (plastic ampoule packaging).
The ribavirin aerosol inhalation solution prepared in example 2 was subjected to effect test, and the results are shown in table 3:
[ Table 3 ]
| Inspection item | Example 2 |
| Traits (3) | Solution |
| pH | 5.3 |
| Average aerodynamic particle size (MMAD) | 0.86um |
| Geometric Standard Deviation (GSD) | 2.03 |
| Effective fraction deposition Rate of Fine Particles (FPF) | 28.2％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, a prescription without adding phospholipid is found, the average particle size is smaller, the deposition rate of effective parts of fine particles is not high (< 30%), and the fact that most of fine particles are deposited in the upper respiratory tract and do not reach the lower respiratory tract and alveoli after atomization is shown.
EXAMPLE 3 ribavirin aerosol inhalation solution containing egg yolk phospholipids
Prescription formulation ratios are shown in table 4:
[ Table 4 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.35mg | 1.75mg | 7mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Yolk phospholipid | 0.2mg | 1mg | 4mg |
| Cyclodextrin | 0mg | 0mg | 0mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or shearing or homogenizing the propylene glycol, the glycerol and the egg yolk phospholipids at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the egg yolk phospholipids are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The ribavirin aerosol inhalation solution prepared in example 1 was subjected to effect test, and the results are shown in table 5:
[ Table 5 ]
| Inspection item | Example 3 |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 1.27um |
| Geometric Standard Deviation (GSD) | 2.36 |
| Effective deposition Rate of Fine Particles (FPF) | 29.7％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the prescription with less phospholipid (0.2 mg/ml) is found, the average particle size is smaller, the effective part deposition rate of fine particles is still low (< 30%), so that most particles still deposit in the upper respiratory tract after atomization, and the trace amount of phospholipid in the prescription does not play a role in improving aerodynamic characteristics and does not reach the lower respiratory tract and alveoli.
EXAMPLE 4 ribavirin aerosol inhalation solution containing egg yolk phospholipids
Prescription formulation ratios are shown in table 6:
[ Table 6 ]
The preparation process comprises the following steps: respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
1) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or shearing or homogenizing the propylene glycol, the glycerol and the egg yolk phospholipids at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the egg yolk phospholipids are completely dissolved to obtain solution 2;
2) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
3) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
4) Passing through a 0.45um+0.22um filter;
5) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
6) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 4 was subjected to effect test, and the results are shown in table 7:
[ Table 7 ]
| Inspection item | Example 4 |
| Traits (3) | Solution |
| pH | 5.3 |
| Average aerodynamic particle size (MMAD) | 2.83 |
| Geometric Standard Deviation (GSD) | 2.74 |
| Effective deposition Rate of Fine Particles (FPF) | 57.3％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, the average particle size of a prescription for increasing the amount of phospholipid in the prescription to (0.5 mg/ml) is found to be large, the deposition rate of effective parts of fine particles is obviously improved (more than 50%), and the fact that most particles reach the lower respiratory tract and the alveoli after atomization is shown that a proper amount of phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 5 ribavirin aerosol inhalation solution containing egg yolk phospholipids and Cyclodextrin
Prescription formulation ratios are shown in table 8:
[ Table 8 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.1mg | 0.5mg | 2mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Yolk phospholipid | 0.5mg | 2.5mg | 10mg |
| Cyclodextrin | 5mg | 25mg | 100mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps: respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
7) In addition, taking water for injection, wherein the amount of the water for injection is 30%, stirring or high shearing or homogenizing the propylene glycol, the glycerol, the yolk phospholipids and the cyclodextrin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol, the yolk phospholipids and the cyclodextrin are completely dissolved to obtain solution 2;
8) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
9) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
10 0.45um +0.22um filter;
11 Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
12 Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 5 was subjected to effect test, and the results are shown in table 9:
[ Table 9 ]
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, the fact that the amount of phospholipid in a prescription is increased to (0.5 mg/ml) is found, and after cyclodextrin is added, the average particle size of the aerosol is increased, the deposition rate of effective parts of fine particles is obviously improved (more than 75%), and therefore most of particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 6 ribavirin aerosol inhalation solution containing egg yolk phospholipids
Prescription formulation ratio is shown in table 10:
[ Table 10 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.2mg | 1mg | 4mg |
| Yolk phospholipid | 3mg | 15mg | 60mg |
| Cyclodextrin | 0mg | 0mg | 0mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or shearing or homogenizing the propylene glycol, the glycerol and the egg yolk phospholipids at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the egg yolk phospholipids are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
[ Table 11 ]
| Inspection item | Example 4 |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 3.26 |
| Geometric Standard Deviation (GSD) | 2.07 |
| Effective deposition Rate of Fine Particles (FPF) | 52.6％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, the fact that the amount of phospholipid in a prescription is increased to (3 mg/ml) is found, the average particle size of the aerosol is increased, the deposition rate of effective parts of fine particles is obviously improved (more than 50%), and the fact that most particles reach the lower respiratory tract and the alveoli after atomization is shown, and a proper amount of phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 7 ribavirin aerosol inhalation solution containing egg yolk phospholipids and Cyclodextrin
Prescription formulation ratio is shown in table 12:
[ Table 12 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.1mg | 0.5mg | 2mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Yolk phospholipid | 3mg | 15mg | 60mg |
| Cyclodextrin | 5mg | 25mg | 100mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps: respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
8) In addition, taking water for injection, wherein the amount of the water for injection is 30%, stirring or high shearing or homogenizing the propylene glycol, the glycerol, the yolk phospholipids and the cyclodextrin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol, the yolk phospholipids and the cyclodextrin are completely dissolved to obtain solution 2;
9) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
10 After cooling to 20-25 ℃, adding water for injection to a specified volume;
11 0.45um +0.22um filter;
12 Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
13 Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 7 was subjected to effect test, and the results are shown in table 13:
[ Table 13 ]
| Inspection item | Example 7 |
| Traits (3) | Solution |
| pH | 5.3 |
| Average aerodynamic particle size (MMAD) | 3.31 |
| Geometric Standard Deviation (GSD) | 2.26 |
| Effective deposition Rate of Fine Particles (FPF) | 72.6％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, the fact that the amount of phospholipid in a prescription is increased to (3 mg/ml) is found, after cyclodextrin is added, the average particle size of the aerosol is increased, the effective part deposition rate of fine particles is obviously improved (more than 70%), and the fact that most particles after atomization reach the lower respiratory tract and alveoli is shown, and a proper amount of phospholipid and cyclodextrin in the prescription obviously play a role in improving aerodynamic characteristics.
EXAMPLE 8 ribavirin nebulized inhalation solution containing egg yolk excess phospholipids
The prescription formulation is shown in table 14:
[ Table 14 ]
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or shearing or homogenizing the propylene glycol, the glycerol and the egg yolk phospholipids at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the egg yolk phospholipids are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 8 was subjected to effect test, and the results are shown in table 15:
[ Table 15 ]
| Inspection item | Example 6 |
| Traits (3) | Solution, slightly opalescent |
| pH | 5.3 |
| Average aerodynamic particle size (MMAD) | 5.93 |
| Geometric Standard Deviation (GSD) | 1.81 |
| Effective deposition Rate of Fine Particles (FPF) | 27.8％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, the average particle size of the prescription is obviously increased to (5 mg/ml) by increasing the amount of yolk phospholipids in the prescription, the deposition rate of effective parts of fine particles is obviously reduced (less than 30%), and the fact that too many large particles do not reach the lower respiratory tract and the alveoli after atomization is shown, and the excessive phospholipids in the prescription do not play a role in improving aerodynamic characteristics.
EXAMPLE 9 ribavirin aerosol inhalation solution containing soybean phospholipids
Prescription formulation ratios are shown in table 16:
[ Table 16 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Soybean lecithin | 1mg | 5mg | 20mg |
| Cyclodextrin | 0mg | 0mg | 0mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the soybean lecithin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the soybean lecithin are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, adding injectable water to a specified volume, and stirring;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling different specifications by using an integrated blowing filling and sealing machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 9 was subjected to effect test, and the results are shown in table 17:
[ Table 17 ]
| Inspection item | Example 7 |
| Traits (3) | Solution |
| pH | 5.5 |
| Average aerodynamic particle size (MMAD) | 2.33 |
| Geometric Standard Deviation (GSD) | 2.64 |
| Effective deposition Rate of Fine Particles (FPF) | 51.7％ |
Experimental conclusion; after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of the prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to soybean phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 50%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of soybean phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 10 ribavirin aerosol inhalation solution containing soybean phospholipids
Prescription formulation ratio is shown in table 18:
[ Table 18 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.25mg | 1.25mg | 5mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Soybean lecithin | 1mg | 5mg | 20mg |
| Cyclodextrin | 0mg | 0mg | 0mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the soybean lecithin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the soybean lecithin are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 9 was subjected to effect test, and the results are shown in table 19:
[ Table 19 ]
| Inspection item | Example 8 |
| Traits (3) | Solution |
| pH | 5.5 |
| Average aerodynamic particle size (MMAD) | 2.07 |
| Geometric Standard Deviation (GSD) | 2.15 |
| Effective deposition Rate of Fine Particles (FPF) | 47.3％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of the prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to soybean phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 40%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of soybean phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 11 ribavirin aerosol inhalation solution containing soybean phospholipids
The prescription formulation is shown in table 20:
[ Table 20 ]
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1;
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol, the soybean lecithin and the cyclodextrin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol, the soybean lecithin and the cyclodextrin are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 11 was subjected to effect test, and the results are shown in table 21:
[ Table 21 ]
| Inspection item | Example 9 |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 3.89 |
| Geometric Standard Deviation (GSD) | 1.96 |
| Effective deposition Rate of Fine Particles (FPF) | 75.3％ |
Conclusion of experiment: after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size is increased after the phospholipid in the prescription is changed from yolk phospholipid to soybean phospholipid (1 mg/ml) and cyclodextrin is added is found, so that the deposition rate of effective parts of fine particles is obviously improved (more than 75%), the fact that most particles after atomization reach the lower respiratory tract and alveoli is shown, and a proper amount of soybean phospholipid and cyclodextrin in the prescription obviously play a role in improving aerodynamic characteristics.
EXAMPLE 12 ribavirin aerosol inhalation solution containing soybean phospholipids
The prescription formulation is shown in table 22:
[ Table 22 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.2mg | 1mg | 4mg |
| Glycerol | 0.2mg | 1mg | 4mg |
| Soybean lecithin | 1mg | 5mg | 20mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps: respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
1) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the soybean lecithin at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the soybean lecithin are completely dissolved to obtain solution 2;
2) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
3) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
4) Passing through a 0.45um+0.22um filter;
5) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
6) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 12 was subjected to effect test, and the results are shown in table 23:
[ Table 23 ]
Experimental conclusion; after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of the prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to soybean phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 40%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of soybean phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 13 ribavirin nebulized inhalation solution containing synthetic phospholipids
The prescription formulation is shown in table 24:
[ Table 24 ]
| Prescription of prescription | Specification 1ml | Specification of 5ml | Specification of 20ml |
| Ribavirin | 200mg | 1g | 4g |
| Xylitol | 0.2mg | 1mg | 4mg |
| Propylene glycol | 0.1mg | 0.5mg | 2mg |
| Glycerol | 0.1mg | 0.5mg | 2mg |
| Synthetic phospholipids | 1mg | 5mg | 20mg |
| Disodium hydrogen phosphate | 0.25mg | 1.25mg | 5mg |
| Sodium dihydrogen phosphate | 0.3mg | 1.5mg | 6mg |
| 4.5-6.5 | 4.5-6.5 | 4.5-6.5 | 4.5-6.5 |
| Water for injection | Constant volume to 1ml | Constant volume to 5ml | Constant volume to 20ml |
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the synthetic phospholipid at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the synthetic phospholipid are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 13 was subjected to effect test, and the results are shown in table 25:
[ Table 25 ]
| Inspection item | Example 11 |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 3.29um |
| Geometric Standard Deviation (GSD) | 2.35 |
| Effective deposition Rate of Fine Particles (FPF) | 46.7％ |
Experimental conclusion; after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of a prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to synthetic phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 45%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of synthetic phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 14 ribavirin nebulized inhalation solution containing synthetic phospholipids
The prescription formulation is shown in table 26:
[ Table 26 ]
The preparation process comprises the following steps:
1) Respectively weighing ribavirin and xylitol according to the prescription amount, adding the ribavirin and the xylitol into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
2) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the synthetic phospholipid at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the synthetic phospholipid are completely dissolved to obtain solution 2;
3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
4) Cooling to 20-25deg.C, and adding injectable water to a specified volume;
5) Passing through a 0.45um+0.22um filter;
6) Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
7) Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 14 was subjected to effect test, and the results are shown in table 27:
[ Table 27 ]
| Inspection item | Actual measurement |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 3.21um |
| Geometric Standard Deviation (GSD) | 2.39 |
| Effective deposition Rate of Fine Particles (FPF) | 46.6％ |
Experimental conclusion; after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of a prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to synthetic phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 45%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of synthetic phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
EXAMPLE 15 ribavirin nebulized inhalation solution containing synthetic phospholipids
The prescription formulation is shown in table 28:
[ Table 28 ]
The preparation process comprises the following steps:
8) Respectively weighing ribavirin and magnesium chloride according to the prescription amount, adding the ribavirin and the magnesium chloride into water for injection with the total volume of 60%, and uniformly stirring to obtain a solution 1:
9) In addition, taking water for injection, the amount of which is 30 percent of the amount of the prescription, stirring or high shearing or homogenizing the propylene glycol, the glycerol and the synthetic phospholipid at the temperature of 40-50 ℃ until the propylene glycol, the glycerol and the synthetic phospholipid are completely dissolved to obtain solution 2;
10 Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, and adding the prescription amount of disodium hydrogen phosphate and sodium dihydrogen phosphate to obtain the required pH range;
11 After cooling to 20-25 ℃, adding water for injection to a specified volume;
12 0.45um +0.22um filter;
13 Respectively filling with a blowing filling machine: 1ml,5ml,20ml.
14 Vacuum leakage detection, character spraying and packaging.
The test items were as follows: the ribavirin aerosol inhalation solution prepared in example 15 was subjected to effect test, and the results are shown in table 29:
[ Table 29 ]
| Inspection item | Actual measurement |
| Traits (3) | Solution |
| pH | 5.4 |
| Average aerodynamic particle size (MMAD) | 3.29um |
| Geometric Standard Deviation (GSD) | 2.02 |
| Effective deposition Rate of Fine Particles (FPF) | 60.1％ |
Experimental conclusion; after the medical atomizer is used for atomizing, the characteristics of aerosol particles after atomization are detected, and the fact that the average particle size of a prescription is increased after the phospholipid in the prescription is changed from egg yolk phospholipid to synthetic phospholipid (1 mg/ml) is found, the deposition rate of effective parts of fine particles is obviously improved (more than 60%), which indicates that most particles after atomization reach the lower respiratory tract and alveoli, and a proper amount of synthetic phospholipid in the prescription obviously plays a role in improving aerodynamic characteristics.
Conclusion:
the addition of the phospholipid auxiliary materials such as egg yolk phospholipid, soybean phospholipid, synthetic phospholipid and the like in the prescription of the atomized solution can optimize the aerodynamic distribution characteristics of the ribavirin atomized solution aerosol, promote a larger proportion of atomized aerosol particles to reach deep alveoli, and play an effective therapeutic role in the alveoli; meanwhile, part of the medicine permeates into pulmonary alveolus capillaries under the action of phospholipid, and plays a role in good systemic and local treatment effects in cooperation with intravenous administration treatment.
Optimal amount of phospholipid in the formulation: the 0.5mg/ml-3mg/ml can play a better prescription optimization role, and when the amount of added phospholipid is insufficient or the dosage is too large, the particle size characteristics of the atomized aerosol particles are changed, so that the aerosol particles are unfavorable for reaching the lower respiratory tract and the alveoli, most of large particles are trapped and adsorbed at the nasal cavity, the pharyngeal part and the upper respiratory tract, only play a role at the positions, and cannot be delivered to the deep alveoli for playing a role, namely the purposes and the therapeutic advantages of the patent cannot be achieved. Meanwhile, it was unexpectedly found that the addition of small amounts of cyclodextrin to the formulation can more optimize the aerodynamic properties of the aerosol particles, significantly increasing the effective fraction deposition rate (> 70%) of the fine particles.
Claims (16)
1. A solution for aerosol inhalation of ribavirin, comprising per ml of solution:
1) 0.15-4g ribavirin or a pharmaceutically acceptable salt thereof;
2) 0.1-0.5mg isotonic agent;
3) 0.2-0.8mg buffer salt;
4) 0.3-4.0mg of penetration enhancer;
5) 3-10mg cyclodextrin;
6) 0.1-1.0mg of a solvent selected from one or more of propylene glycol or glycerol;
the other is water for injection; the penetration enhancer is phospholipid.
2. The solution for aerosol inhalation of ribavirin according to claim 1, wherein the ribavirin or pharmaceutically acceptable salt thereof is in the range of 0.2 to 0.3g per ml of solution.
3. The solution for aerosol inhalation of ribavirin according to claim 1, wherein the phospholipid is selected from one or more of egg yolk phospholipids, soybean phospholipids, cephalins, cardiolipins or synthetic phospholipids.
4. A solution for aerosol inhalation of ribavirin according to claim 3 characterised in that the phospholipid is egg yolk phospholipid.
5. The solution for aerosol inhalation of ribavirin according to claim 1, characterized in that it contains 0.5-3.0. 3.0mg phospholipids per ml of solution.
6. The solution for aerosol inhalation of ribavirin according to claim 1, characterized in that it contains 4-6mg of cyclodextrin per ml of solution.
7. The solution for aerosol inhalation of ribavirin according to claim 1, wherein the isotonic agent is selected from one or more of potassium chloride, sodium chloride, magnesium chloride, calcium chloride, glucose, xylitol, sorbitol.
8. The solution for aerosol inhalation of ribavirin according to claim 1, comprising 0.2-0.3mg of isotonic agent per ml of solution.
9. The solution for aerosol inhalation of ribavirin according to claim 1, comprising 0.1-0.5mg of vehicle per ml of solution.
10. The solution for aerosol inhalation of ribavirin according to claim 1, wherein the vehicle is a mixture of propylene glycol and glycerin; the mass ratio of the propylene glycol to the glycerol is 2-1:1.
11. The solution for aerosol inhalation of ribavirin according to claim 1, characterized in that the buffer salt is selected from the group consisting of citric acid-sodium citrate, citric acid-disodium hydrogen phosphate, disodium hydrogen phosphate-sodium dihydrogen phosphate, acetic acid-sodium acetate, citric acid-sodium hydroxide-hydrochloric acid.
12. The solution for aerosol inhalation of ribavirin according to claim 1, comprising 0.5-0.8mg of buffer salt per ml of solution.
13. The solution for aerosol inhalation of ribavirin according to claim 1, characterized in that the pH is 4.5-6.5.
14. The solution for aerosol inhalation of ribavirin according to claim 1, further comprising a single dose of pharmaceutical packaging; the single dose is 1-30ml.
15. A method of preparing the solution for aerosol inhalation of ribavirin according to claim 1, comprising the steps of:
(1) The ribavirin or the pharmaceutically acceptable salt and the isotonic agent thereof are respectively weighed according to the prescription amount and added into the water for injection with the total volume of 50-65 percent, and the solution 1 is obtained by stirring evenly:
(2) In addition, taking water for injection, of which the prescription amount is 20-30%, stirring or high shearing or homogenizing the solvent, the permeation enhancer and the cyclodextrin at the temperature of 40-50 ℃ until the solvent, the permeation enhancer and the cyclodextrin are completely dissolved, so as to obtain solution 2;
(3) Adding the solution 2 into the solution 1, uniformly stirring at 30-40 ℃, adding a prescribed amount of buffer salt, and adjusting to a required pH range;
(4) Cooling to 20-25deg.C, adding injectable water to a specified volume, and stirring;
(5) And (5) respectively filling different specifications by using an integrated blowing filling and sealing machine after filtering.
16. The method of claim 15, wherein the size of step (5) is 1-30ml for single treatment.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385165A (en) * | 2002-06-05 | 2002-12-18 | 李大鹏 | Ribavirin aerosol inhalation solution |
| CN105055460A (en) * | 2015-07-21 | 2015-11-18 | 芝圣（天津）生物科技有限公司 | Niuzhangzhi essential oil inhalant |
| CN108904476A (en) * | 2018-08-01 | 2018-11-30 | 健民药业集团股份有限公司 | A kind of ambroxol hydrochloride aerosol inhalation solution agent and preparation method thereof |
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| US20190336443A1 (en) * | 2018-05-03 | 2019-11-07 | Navinta Iii Inc | Ready-To-Use Liquid Parenteral Formulations Of Ribavirin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385165A (en) * | 2002-06-05 | 2002-12-18 | 李大鹏 | Ribavirin aerosol inhalation solution |
| CN105055460A (en) * | 2015-07-21 | 2015-11-18 | 芝圣（天津）生物科技有限公司 | Niuzhangzhi essential oil inhalant |
| CN108904476A (en) * | 2018-08-01 | 2018-11-30 | 健民药业集团股份有限公司 | A kind of ambroxol hydrochloride aerosol inhalation solution agent and preparation method thereof |
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