CN110742875B - Pirfenidone solution preparation for inhalation and preparation method and application thereof - Google Patents
Pirfenidone solution preparation for inhalation and preparation method and application thereof Download PDFInfo
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
The invention belongs to the field of pharmaceutics, and particularly relates to a pirfenidone solution preparation for inhalation and a preparation method and application thereof. The first purpose of the invention is to provide a pirfenidone solution preparation for inhalation, which is realized by the following technical scheme: a pirfenidone solution formulation for inhalation, the pirfenidone solution comprising: 0.1-20mg/mL pirfenidone and solvent. The second object of the present invention is to provide a method for preparing a pirfenidone solution formulation for inhalation. The third purpose of the invention is to provide an application of the pirfenidone solution preparation for inhalation in the preparation of drugs for preventing and treating light and moderate idiopathic pulmonary interstitial fibrosis, hepatic fibrosis, renal fibrosis diseases, multiple sclerosis, myocardial tissue fibrosis, neoplastic diseases, fibrosis after organ transplantation, rheumatoid arthritis and other diseases. The pirfenidone solution for inhalation provided by the invention has the advantages of reliable quality, high safety, high stability and long storage time.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to a pirfenidone solution preparation for inhalation and a preparation method and application thereof.
Background
Pirfenidone (chemical name is 5-methyl-1-phenyl-2- (1H) -pyridone, molecular formula C 12 H 11 NO, CAS: 53179-13-8), is the first anti-fibrotic drug approved for idiopathic pulmonary fibrosis in the world. Research shows that the pirfenidone has anti-inflammatory, antioxidant and anti-fibrosis effects in vitro experiments and animal models. Pirfenidone exerts its anti-inflammatory effects by inhibiting inflammatory mediators; and exerts its antioxidant effect by scavenging free radicals, inhibiting lipid peroxidation and relieving oxidative stress; it is also a novel spectrum anti-fibrosis compound, and has anti-fibrosis effect by inhibiting mRNA expression of I type, II type, IV type and other subtypes of collagen, preventing collagen synthesis, and reducing proliferation of fibrin cytokine and fibroblast.
Pirfenidone tablets were marketed in japan in 2008 and widely used for pulmonary fibrosis, but many patients receiving this drug have shown side effects of drug-induced photodermatosis. At present, the trade name of the pirfenidone capsule sold in China is abresine, and the medicine specification of the abresine capsule clearly shows that the abresine has the adverse reaction of photosensitivity and rash. In order to reduce the risk of photodermatosis, patent ZL201280055619.1 provides a powder formulation comprising: (i) micronized particles having an average particle size of from 3 to 8 μm, the particles comprising: (i-1) pirfenidone and (i-2) an excipient, and (ii) a carrier having an average particle size of 10-200 μm; the ratio between the micronized particles and the carrier is in the range of 1:50 to 1:1 weight ratio; and the micronized particles and the carrier are specifically defined. According to the application, the powder preparation is delivered to the lung in an inhalation mode through a local targeted drug delivery mode, so that the dosage of pirfenidone can be obviously reduced, namely, the amount of pirfenidone moving to the skin is reduced, and the skin anaphylactic reaction caused by pirfenidone is further reduced.
However, the use of a special and complicated device is required for the inhalation of the dry powder preparation, so that the medication cost is increased, the popularization of the preparation is not facilitated, the complex structure reduces the compliance of a patient to the inhalation of the dry powder preparation, and in addition, the dry powder transfer technology at home and abroad is still in a development stage, and the use frequency of the dry powder preparation is limited by the reasons. The solution formulation for inhalation is not limited to the above. However, patent ZL201280055619.1 discloses that "pirfenidone solution is exposed to simulated sunlight (250W/m) 2 ) Can lead to the degradation of pirfenidone under the light intensity of the light of (1).
In summary, the present invention provides a pirfenidone solution formulation for inhalation in order to improve patient compliance and improve photostability of pirfenidone solution formulations.
Disclosure of Invention
In order to solve the technical problems, the invention provides a pirfenidone solution preparation for inhalation and a preparation method thereof. The pirfenidone solution preparation for inhalation has excellent physical property parameters, and is easy to atomize to form aerosol; it also has the advantages of reliable quality, high safety, high stability and long storage time.
The invention aims to provide a pirfenidone solution preparation for inhalation, which is realized by the following technical scheme:
a pirfenidone solution formulation for inhalation, the pirfenidone solution comprising: 0.1-20mg/mL (e.g., 0.2mg/mL, 0.3mg/mL, 0.5mg/mL, 0.7mg/mL, 0.9mg/mL, 1mg/mL, 2mg/mL, 4mg/mL, 6mg/mL, 8mg/mL, 9mg/mL, 11mg/mL, 13mg/mL, 15mg/mL, 17mg/mL, 19mg/mL) pirfenidone and a solvent.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution includes 0.1-15mg/mL pirfenidone, preferably 0.1-10mg/mL pirfenidone.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution further includes an isotonic agent; preferably, the isotonic agent is selected from one or more of sodium chloride, magnesium chloride, potassium chloride, calcium chloride, glucose, xylitol and sorbic acid; more preferably, the solution formulation contains 0.11-0.19mmol (such as 0.13mmol, 0.14mmol, 0.15mmol, 0.16mmol, 0.17mmol, 0.18mmol) of isotonicity agent per ml of solution formulation, more preferably 0.12-0.18 mmol.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the solvent is water or a mixed solvent composed of water and an appropriate amount of a co-solvent.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution further includes a stabilizer; preferably, the stabilizer is selected from one or more of lysine, tryptophan, phenylalanine, glycine, glutamic acid, leucine, isoleucine, serine, vitamin C, tea polyphenol, ascorbyl palmitate, methylparaben, hydroxyethyltetramethylpiperidinol, bis (2,2,6, 6-tetramethyl-4-piperidinyl) sebacate, polysuccinic acid (4-hydroxy-2, 2,6, 6-tetramethyl-1-piperidineethanol) ester, 2- [ 2-hydroxy-4- [3- (2-ethylhexyloxy) -2-hydroxypropoxy ] phenyl ] -4, 6-bis (2, 4-dimethylphenyl) -1,3, 5-triazine; more preferably, the solution formulation contains 0.005-0.02mmol (e.g., 0.006mmol, 0.008mmol, 0.01mmol, 0.012mmol, 0.015mmol, 0.017mmol) of the stabilizer per ml of the solution formulation.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution further includes a buffer; preferably, the buffer is citric acid-sodium citrate, citric acid-disodium hydrogen phosphate, potassium dihydrogen phosphate-disodium hydrogen phosphate, or citric acid-sodium hydroxide.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pH of the pirfenidone solution is from 4.5 to 7.5 (e.g., 4.6, 4.8, 5.0, 5.2, 5.3, 5.6, 5.8, 6.0, 6.2, 6.5, 6.7, 7.0, 7.2, 7.4), preferably from 5 to 6.5.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
and (3) water.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
a stabilizer; and water;
the pH value of the pirfenidone solution is 5-6.5.
In the above pirfenidone solution formulation for inhalation, as a preferred embodiment, the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
stabilizers, buffers; and water;
the pH value of the pirfenidone solution is 5-6.5.
In addition, one or more additives may be added to the pirfenidone solution for inhalation of the present invention according to application or form according to a conventional method without adverse effects. The additive may be, for example, one or more of a sweetener, a pH adjuster, a sugar alcohol, an acid mucopolysaccharide, a surfactant, a preservative, a disinfectant, a tonicity agent, and the like.
In the invention, an ultrasonic atomizer or an air compression atomizer is adopted, the pirfenidone solution preparation for inhalation is inhaled into a respiratory system in an atomization mode, can directly act on a focus part, and has quick response, safety and effectiveness. The pirfenidone can be directly delivered to the lung of a patient by an inhalation administration mode, thereby obviously relieving symptoms and shortening the course of disease. The medicine directly enters the respiratory tract, so that the toxic and side effects of the medicine are obviously reduced, which is particularly important for cancer patients.
The second object of the present invention is to provide a method for preparing a pirfenidone solution formulation for inhalation, comprising the steps of:
(1) weighing pirfenidone in a prescription amount, adding a solvent with the total amount of 80% -95%, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) adding an isotonic agent in a prescription amount into the pre-inhalation solution prepared in the step (1), stirring to dissolve the isotonic agent, adding a buffering agent, fixing the volume, filling and sealing to obtain the pirfenidone solution for inhalation.
In the above production method, as a preferred embodiment, in the step (2), the stabilizer is added before the buffer is added.
The third purpose of the invention is to provide the application of the pirfenidone solution preparation for inhalation in the preparation of medicines for preventing and treating light and moderate idiopathic pulmonary interstitial fibrosis, hepatic fibrosis, renal fibrosis diseases, multiple sclerosis, myocardial tissue fibrosis, neoplastic diseases, fibrosis after organ transplantation, rheumatoid arthritis and other diseases.
Compared with the prior art, the invention has the following technical effects:
1. the pirfenidone solution for inhalation provided by the invention has the advantages of reliable quality, high safety, high stability and long storage time.
2. The preparation method is simple and easy to operate, low in production cost and easy for industrial production.
Detailed Description
The preparation process and the materials used in the preparation or the dosage of the materials used in the preparation in the following examples of the pharmaceutical preparation are not limited to the words, and all methods containing the pharmaceutical preparation provided by the present invention are within the protection scope of the present invention.
The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Examples 1 to 9
The specific amounts of pirfenidone, isotonicity agent, stabilizer, buffer in the formulations of examples 1-9 are shown in Table 1.
(1) Weighing pirfenidone, adding 800ml of solvent, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) and (2) adding sodium chloride into the pre-inhalation solution prepared in the step (1), stirring to dissolve the sodium chloride, adding a formula amount of stabilizer and a proper amount of buffer, diluting to 1000mL, performing sterile subpackage, filling 5 mL/bottle, and pressing a plug under the protection of nitrogen to obtain the pirfenidone solution preparation for inhalation.
TABLE 1 specific amounts of pirfenidone, isotonicity agent, stabilizer, buffer in the formulations of examples 1-9
Example 10
(1) Weighing 2g of pirfenidone, adding 950ml of solvent, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) and (2) adding 9.35g of sodium chloride into the pre-inhalation solution prepared in the step (1), stirring to dissolve the sodium chloride, adding 150mg of glycine and a proper amount of citric acid/sodium citrate to adjust the pH value to 6.0, metering the volume to 1000mL, performing sterile subpackage, filling 5 mL/bottle, and pressing a plug under the protection of nitrogen to obtain the pirfenidone solution preparation for inhalation.
Example 11
(1) Weighing 12g of pirfenidone, adding 900ml of solvent, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) and (2) adding 7.6g of sodium chloride into the pre-inhalation solution prepared in the step (1), stirring to dissolve the sodium chloride, adding 750mg of glycine and a proper amount of citric acid/sodium citrate to adjust the pH value to 5.0, metering the volume to 1000mL, performing sterile subpackage, filling 5 mL/bottle, and pressing a plug under the protection of nitrogen to obtain the pirfenidone solution preparation for inhalation.
Example 12
(1) Weighing 8g of pirfenidone, adding 950ml of solvent, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) and (2) adding 9.93g of sodium chloride into the pre-inhalation solution prepared in the step (1), stirring to dissolve the sodium chloride, adding 450mg of glycine and a proper amount of citric acid/sodium citrate to adjust the pH value to 5.5, metering the volume to 1000mL, performing sterile subpackage, filling 5 mL/bottle, and pressing a plug under the protection of nitrogen to obtain the pirfenidone solution preparation for inhalation.
Example 13
(1) Weighing 20g of pirfenidone, adding 950ml of solvent, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) adding 8.18g of sodium chloride into the pre-inhalation solution prepared in the step (1), stirring to dissolve the sodium chloride, adding 1.125g of glycine and a proper amount of citric acid/sodium citrate to adjust the pH value to 6.5, metering the volume to 1000mL, performing sterile subpackage, filling 5 mL/bottle, and pressing a plug under the protection of nitrogen to obtain the pirfenidone solution preparation for inhalation.
Test examples light stability test
Taking 3 bottles of pirfenidone solution for inhalation prepared in example 6, and naming the bottles as groups 1-3; group 1 was control group; group 2 was placed under room temperature natural light conditions for 30 days; the 3 rd group is placed in a strong light stability test box and is illuminated for 10 days under the illumination intensity of 4500lx +/-500 lx; testing the content of pirfenidone at 0 th day in the 1 st group, the content of pirfenidone in the 2 nd group after 30 days under natural light condition, the content of pirfenidone in the 3 rd group after 10 days under strong light condition by LCMS, wherein the testing conditions are as follows: a chromatographic column: c18, 4.6X 250 mm; mobile phase: triethylamine aqueous solution: methanol: acetonitrile 650:130: 220; flow rate: 1.0 ml/min; column temperature: 40 ℃; detection wavelength: 220 nm; the results are shown in Table 2.
1 bottle of each pirfenidone solution preparation for inhalation prepared in examples 1-5 and 7-13 is named as group 4-15, and is placed in a strong light stability test box to be irradiated for 10 days under the illumination intensity of 4500lx +/-500 lx; detecting the content of pirfenidone and impurities in the pirfenidone solution preparation for inhalation in the 4 th to 15 th groups after illumination by adopting LCMS; detection conditions are as follows: a chromatographic column: c18, 4.6X 250 mm; mobile phase: triethylamine aqueous solution: methanol: 650:130: 220; flow rate: 1.0 ml/min; column temperature: 40 ℃; detection wavelength: 220 nm; the results are shown in Table 2.
TABLE 2 content of pirfenidone in solution formulations for inhalation after exposure to light
The light experiment shows that the stability of the inhalation solution preparation can be effectively improved by adding the stabilizer and the buffering agent into the pirfenidone solvent for inhalation, and the storage time of the inhalation solution preparation is further prolonged.
Claims (12)
1. A pirfenidone solution formulation for inhalation, the pirfenidone solution comprising: 0.1-20mg/mL pirfenidone, a stabilizer, a buffer solution and a solvent, wherein the stabilizer is glycine, and the buffer solution is citric acid-sodium citrate.
2. The formulation of pirfenidone solution for inhalation of claim 1 wherein the pirfenidone solution includes 0.1 to 15mg/mL pirfenidone.
3. The formulation of pirfenidone solution for inhalation of claim 1, wherein the pirfenidone solution further includes an isotonicity agent.
4. The formulation of pirfenidone solution for inhalation of claim 1, wherein the solvent is water or a mixed solvent consisting of water and an appropriate amount of co-solvent.
5. The formulation of pirfenidone solution for inhalation of claim 1, wherein the pH of the pirfenidone solution is from 4.5 to 7.5.
6. The formulation of a pirfenidone solution for inhalation of any one of claims 1-5, wherein the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
and (3) water.
7. The formulation of pirfenidone solution for inhalation of claim 6, wherein the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
a stabilizer; and water;
the pH value of the pirfenidone solution is 5-6.5.
8. The formulation of pirfenidone solution for inhalation of claim 7, wherein the pirfenidone solution includes:
0.2-10mg/mL pirfenidone;
0.12-0.18mmol/mL sodium chloride;
stabilizers, buffers; and water;
the pH value of the pirfenidone solution is 5-6.5.
9. The formulation of pirfenidone solution for inhalation of claim 1 further comprising an additive that is one or more of a sweetener, a pH adjuster, a sugar alcohol, an acidic mucopolysaccharide, a surfactant, a preservative, a disinfectant, a tonicity agent.
10. A method of preparing a pirfenidone solution formulation for inhalation of claim 8, comprising the steps of:
(1) weighing pirfenidone in a prescription amount, adding a solvent with the total amount of 80% -95%, and stirring to completely dissolve the pirfenidone to obtain a pre-inhalation solution;
(2) and (2) adding an isotonic agent in a prescription amount into the pre-inhalation solution prepared in the step (1), stirring to dissolve the isotonic agent, adding a buffering agent, fixing the volume, filling and sealing to obtain the pirfenidone solution for inhalation.
11. The method according to claim 10, wherein in the step (2), the stabilizer is added before the buffer is added.
12. Use of a pirfenidone solution formulation for inhalation according to any one of claims 1-9 in the manufacture of a medicament for the prevention and treatment of mild to moderate idiopathic pulmonary interstitial fibrosis, liver fibrosis, renal fibrotic diseases, multiple sclerosis, myocardial tissue fibrosis, neoplastic diseases, fibrosis after organ transplantation, rheumatoid arthritis.
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| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN103917223A (en) * | 2011-09-14 | 2014-07-09 | 盐野义制药株式会社 | Pharmaceutical composition for inhalation |
| WO2016142708A2 (en) * | 2015-03-10 | 2016-09-15 | Cipla Limited | Pharmaceutical composition |
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| NZ722927A (en) * | 2014-01-10 | 2022-07-29 | Avalyn Pharma Inc | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN103917223A (en) * | 2011-09-14 | 2014-07-09 | 盐野义制药株式会社 | Pharmaceutical composition for inhalation |
| WO2016142708A2 (en) * | 2015-03-10 | 2016-09-15 | Cipla Limited | Pharmaceutical composition |
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