CN109758437A - A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof - Google Patents
A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof Download PDFInfo
- Publication number
- CN109758437A CN109758437A CN201711099856.9A CN201711099856A CN109758437A CN 109758437 A CN109758437 A CN 109758437A CN 201711099856 A CN201711099856 A CN 201711099856A CN 109758437 A CN109758437 A CN 109758437A
- Authority
- CN
- China
- Prior art keywords
- preparation
- nintedanib
- freeze
- phosphatide
- lipid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Abstract
The invention discloses a kind of Neulized inhalation for treating pulmonary fibrosis Nintedanib freeze-dried lipidosome preparation and preparation method thereof, contain in the freeze-dried lipidosome preparation single dose: 10-80mg Nintedanib or its salt (being calculated with the amount for Nintedanib of dissociating), 25-250mg lipid, 100-1000mg phosphatide, 20-150mg isotonic agent.Said preparation stability prepared by the present invention is good, and partial size is small, is suitable for atomized medicine introducing, while the freeze-dried lipidosome preparation has the characteristics that efficient, low toxicity, degree of safety are high, significantly reduces the liver renal toxicity of patient medication.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and
Preparation method.
Background technique
Pulmonary fibrosis is a kind of a kind of final serious pathological feature for being clinically now commonly referred to as interstitial lung disease and sharing.
Interstitial lung disease may include caused by being primary in the treatments such as lung, adjoint system rheumatism is pathogenetic, drug or radiation, be adjoint
Seven major class such as environment or occupation occur, occur with Pulmonary Vascular, the cholestatic disease of alveolar and genetic disease.Different pathogeny
Cause the specific mechanism of pulmonary fibrosis unclear, is the initial inflammation damnification caused by a variety of causes with common characteristic
Normal alveolar structure, i.e. generation pulmonary alveolitis；The damage is repaired in instead collagen scar tissue accumulation, that is, is generated fibrosis and made
Lung tissue gradually loses normal respiratory function, generates the clinical symptoms such as expiratory dyspnea, anoxic, and finally to respiratory failure, i.e. lung is fine
Dimensionization is after lungs come to harm, and human body excessively repairs the result of generation.Pulmonary fibrosis frequently-occurring disease in 40-50 years old women,
Main symptom is expiratory dyspnea, cough, shortness of breath.Expiratory dyspnea is the most common symptom of pulmonary fibrosis.When slight pulmonary fibrosis, exhale
It inhales difficult to occur in aggravating activities, therefore usually ignored or mistaken diagnosis is other diseases.When pulmonary fibrosis progress, quiet
It also has difficulty in breathing when breath, and the entire course of disease is in the process that progressive aggravates, mean survival time (MST) is 5-6, separately there is minority
Acute case is in progress sharply, dead mostly in 6 months.
Nintedanib is the small molecule junket that idiopathic pulmonary fibrosis (IPF) exploitation is directed to by German Boehringer Ingelheim company
Histidine kinase inhibitor (TKI).The medicine be directed to have been found in pulmonary fibrosis pathomechanism with potential impact growth because
Sub- receptor plays a role, wherein mostly important is exactly platelet derived growth factor B (PDGFR), fibroblastic growth
Factor acceptor (FGFR) and vascular endothelial growth factor receptor (VEGFR).By blocking these to participate in the signal of progression of fibrosis
Signal Transduction Pathways, Nintedanib be considered being expected to can by reducing decline in pulmonary function speed, to slow down IPF progression of disease.?
The global III clinical trial phase (INPULSIS of two hadTM- 1 research and INPULSISTM- 2 researchs) it is controlled for Nintedanib
The efficacy and saferry for treating IPF is assessed, and the studies above result obtained is in May, 2014 in global science
It announces in conference American Thoracic Society (ATS) annual meeting and is delivered on NEJM magazine.Nintedanib is that acquisition clinical evidence is consistent
It is confirming, can be by substantially reducing lung function year rate of descent (reduce amplitude up to 50%) to delay the first of IPF progression of disease
IPF target therapeutic agent.
Patent CN105902507A discloses a kind of oral preparation of Nintedanib esilate for treating pulmonary fibrosis, but
Auxiliary material added by said preparation is more, and after gastrointestinal tract absorbs degradation, the effective dose for reaching active component is less, and can cause a system
The side effect of column, such as nausea, skin disease, abdominal pain, the infection of the upper respiratory tract, diarrhea, out of strength, headache, indigestion, dizziness, vomiting,
Loss of appetite, gastroesophageal reflux, nasosinusitis, insomnia, weight loss and arthralgia etc., and will appear more serious liver kidney damage
Wound, Long-term Oral medication will will lead to irreversible organ damage.
Summary of the invention
In view of the deficiencies in the prior art, the present invention provides a kind of for treating the Neulized inhalation Ni Dani of pulmonary fibrosis
Cloth freeze-dried lipidosome preparation, after said preparation is using preceding suitable solvent such as water for injection dissolution, combined atomizing device is used, by mouth and nose
It is directly sucked in, higher concentration can be gathered into lung, hence into breathing and blood circulation system, and then can reach systemic therapy
Purpose, avoid the destruction and degradation of the first pass effect and gastrointestinal tract of liver, and greatly reduce by liver kidney to drug
Metabolic process greatly reduces the organ damage to patient.The medicine is developed and solves it at freeze-dried lipidosome preparation by the present invention
The low problem of solubility in water also increases the stability of drug after freeze-drying for liposome, and compensates on domestic market
Blank, provide a kind of effective drug-delivery preparation of Nintedanib new type of safe and administration mode.
The first object of the present invention is to provide a kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation, and use is following
Technical solution:
It is a kind of for treating the Neulized inhalation Nintedanib freeze-dried lipidosome preparation of pulmonary fibrosis, it is main include below at
Point: Nintedanib or its salt, lipid, phosphatide and isotonic agent, preferably single-dose preparations.This product before use with appropriate solvent (such as
5mL water for injection) it is redissolved, it is used after shaking up.The preferred purified water of solvent, more preferable water for injection.
Neulized inhalation provided by the invention is packed with Nintedanib freeze-dried lipidosome preparation using single dose of drug, described
Single dose refers to the dosage of medicinal active ingredient used in A Single Intake by Inhalation.
The preparation may also include one or more pharmaceutic adjuvants suitable for pulmonary administration.
Contain in the freeze-dried lipidosome preparation single dose: 10-80mg Nintedanib or its salt are (with Nintedanib of dissociating
Amount calculate), 25-250mg lipid, 100-1000mg phosphatide, 20-150mg isotonic agent.
Contain in the freeze-dried lipidosome preparation single dose: 20-60mg Nintedanib or its salt are (with Nintedanib of dissociating
Amount calculate), 50-200mg lipid, 250-500mg phosphatide, 40-100mg isotonic agent.
Contain in the freeze-dried lipidosome preparation single dose: 40mg Nintedanib or its salt are (with the amount for Nintedanib of dissociating
Calculate), 75mg lipid, 300mg phosphatide, 60mg isotonic agent.
The mass ratio of the phosphatide and lipid is between 6:1-1:1, between preferably 4:1-5:2.
The salt of the Nintedanib is its pharmaceutically acceptable salt.Suitable pharmaceutically acceptable salt includes inorganic acid
With the salt of organic acid, including hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, Loprazolam, trifluoromethayl sulfonic acid, benzene sulfonic acid, to toluene sulphur
Acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, ethanedioic acid, succinic acid, richness
Horse acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.In addition, pharmaceutically acceptable salt includes inorganic base
Salt, such as containing base cations (such as Li+, Na+ or K+), alkaline earth cation (such as Mg2+, Ca2+ or Ba2+), ammonium cation
Salt；And the acid salt of organic base, including aliphatic and the substituted ammonium of aromatic series and quaternary ammonium cation, such as from three second
Amine, N, TMSDEA N diethylamine, N, N- dicyclohexyl amine, lysine, pyridine, N, N- dimethyl aminopyridine (DMAP), 1,4- diaza are double
Ring [2.2.2] octane (DABCO), 1,5- diazabicyclo [4,3,0] nonyl- 5- alkene (DBN) and 1,8- diazabicyclo [5.4.0]
The protonation of 11 carbon -7- alkene (DBU) or the salt of all alkyl.
The phosphatide includes natural phospholipid and synthetic phospholipid, and wherein natural phospholipid includes egg yolk lecithin, soybean lecithin；It closes
It include dipalmitoylphosphatidylcholine, Distearoyl Phosphatidylcholine, dimyristoyl phosphatidyl choline at phosphatide, wherein it is preferred that
Soybean lecithin in phosphatide.
The lipid can choose glycerin monostearate, triglycerides, olive oil, soybean oil, median chain triglyceride oil,
One of oleic acid or a variety of arbitrary proportions mixing, preferably glycerin monostearate and or triglycerides.
Liposome is made to facilitate administration in Nintedanib by the present invention, while solving its solubility.Form lipid
The phosphatide and lipid components good biocompatibility of body, it is safe and non-toxic, and phospholipids compounds have certain guarantor to lung organ
Shield and repair.By high pressure homogenization by the size controlling of liposome in a certain range, be conducive to drug in pulmonary deposition,
Improve bioavilability.
The isotonic agent is the mixing of one or both of sodium chloride, glucose, wherein it is preferred that sodium chloride.
Further, the preparation can also include pH adjusting agent, the pH adjusting agent be sodium hydroxide, sodium citrate,
One of citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid, sodium acetate, acetic acid are a variety of.The dosage of pH adjusting agent is
The preparation pH value is adjusted to the dosage of 5-8, preferable ph is adjusted to the dosage of 6-7.
In order to improve the safety of medication, solvent of the invention selects purified water or water for injection.This product is being used before use
Suitable solvent such as 5mL water for injection is redissolved, and is used after shaking up.
Another object of the present invention is to provide a kind of systems of Neulized inhalation Nintedanib freeze-dried lipidosome preparation
Preparation Method, method includes the following steps:
(1) in the case where being passed through condition of nitrogen gas, by the lipid of recipe quantity and phosphatide be added suitable ethyl acetate stir in ethyl alcohol
Dissolution, then be added recipe quantity Nintedanib stirring and dissolving after, be dried under reduced pressure at 30-35 DEG C about 2h remove ethyl acetate
Ethyl alcohol obtains film-form solid；
(2) water for injection of 35 DEG C of -60 DEG C of full dose 60%-80% is added in the film-form solid obtained to step (1), surpasses
Sound makes its aquation, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, uses the pH of pH adjusting agent regulation system later and determines
Hold；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
The present invention prepares Nintedanib liposome using the even technology of high pressure cream, so that partial size is less than 200nm.
Neulized inhalation provided by the invention is unit dose package with freeze-dried lipidosome preparation, and use process is convenient；It can be significantly
The microbial contamination and waste in use process are reduced, is avoided caused by the big packaging of multi-dose using the dosage of single medication
Measurement repeatedly, repeatedly dilution prepare easy cooperating microorganisms the drawbacks of.The present invention provides a kind of medicines that the prior art is lacked
Accurate with dosage, drug quality is high-quality, stablizes, clinical application safety, simple and direct novel formulation and preparation method thereof.
Compared with prior art, the beneficial effects of the present invention are:
(1) compared with other dosage forms, drug directly reaches target organ lung, avoids the first pass effect and gastrointestinal tract of liver
It destroys and degrades, reduce systemic organs' especially lesions of liver and kidney, medication is safer；
(2) present invention is due to being suction-type, compares mouth for the patient of lung organ's lesion, obstructive ventilatory disorder
Take quick, avoiding preparation needs first absorb through gastrointestinal tract, then plays general action with blood circulation again, and work slow lack
It falls into；
(3) freeze-dried powder is made in liposome by the present invention, and is preparing and be lyophilized nitrogen charging gas shielded in whole process, avoids liposome
Caused by long-term placement or environment temperature etc. change the problems such as oxidation stain, hydrolysis, drug leakage, stability is improved；
(4) liposome rapid dispersion is uniform after redissolving, and without significant changes, biological utilisation before the relatively freeze-drying of partial size and encapsulation rate
Degree is high, good effect.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is all according to the content of present invention into
The equivalent replacement of capable any this field, all belongs to the scope of protection of the present invention.
The person that is not specified actual conditions in embodiment, carries out according to conventional conditions or manufacturer's recommended conditions.Agents useful for same
Or production firm person is not specified in instrument, is the conventional products that can be obtained by commercially available purchase.
Embodiment 1: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, suitable acetic acid is added in the soybean lecithin of recipe quantity and glycerin monostearate
Stirring and dissolving in ethyl ester after the Nintedanib stirring and dissolving of recipe quantity is then added, is dried under reduced pressure about 2h removing at 30-35 DEG C
Ethyl acetate obtains film-form solid；
(2) water for injection of 50 DEG C of full doses 80% is added in the film-form solid obtained to step (1), ultrasound makes its water
Change, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, with the pH value of pH adjusting agent regulation system and uses injection later
Water is settled to 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Embodiment 2: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, suitable acetic acid is added in the soybean lecithin of recipe quantity and glycerin monostearate
Stirring and dissolving in ethyl ester after the Nintedanib stirring and dissolving of recipe quantity is then added, is dried under reduced pressure about 2h removing at 30-35 DEG C
Ethyl acetate obtains film-form solid；
(2) purified water of 60 DEG C of full doses 70% is added in the film-form solid obtained to step (1), ultrasound makes its aquation,
The isotonic agent stirring and dissolving of recipe quantity is added thereto again, later with the pH value of pH adjusting agent regulation system and with purified water constant volume
To 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Embodiment 3: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, suitable acetic acid is added in the soybean lecithin of recipe quantity and glycerin monostearate
Stirring and dissolving in ethyl ester after the Nintedanib stirring and dissolving of recipe quantity is then added, is dried under reduced pressure about 2h removing at 30-35 DEG C
Ethyl acetate obtains film-form solid；
(2) water for injection of 35 DEG C of full doses 60% is added in the film-form solid obtained to step (1), ultrasound makes its water
Change, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, with the pH value of pH adjusting agent regulation system and uses injection later
Water is settled to 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Embodiment 4: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, suitable acetic acid is added in the soybean lecithin of recipe quantity and glycerin monostearate
Stirring and dissolving in ethyl ester after the Nintedanib stirring and dissolving of recipe quantity is then added, is dried under reduced pressure about 2h removing at 30-35 DEG C
Ethyl acetate obtains film-form solid；
(2) purified water of 50 DEG C of full doses 80% is added in the film-form solid obtained to step (1), ultrasound makes its aquation,
The isotonic agent stirring and dissolving of recipe quantity is added thereto again, later with the pH value of pH adjusting agent regulation system and with purified water constant volume
To 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Embodiment 5: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, the soybean lecithin of recipe quantity and triglycerides is added in suitable ethyl alcohol and stirred
Dissolution after the Nintedanib stirring and dissolving of recipe quantity is then added, about 2h is dried under reduced pressure at 30-35 DEG C and removes ethyl alcohol, is obtained
Film-form solid；
(2) water for injection of 40 DEG C of full doses 70% is added in the film-form solid obtained to step (1), ultrasound makes its water
Change, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, with the pH value of pH adjusting agent regulation system and uses injection later
Water is settled to 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Embodiment 6: Neulized inhalation Nintedanib freeze-dried lipidosome preparation 200 is prepared
Preparation method:
(1) in the case where being passed through condition of nitrogen gas, the soybean lecithin of recipe quantity and triglycerides is added in suitable ethyl alcohol and stirred
Dissolution after the Nintedanib stirring and dissolving of recipe quantity is then added, about 2h is dried under reduced pressure at 30-35 DEG C and removes ethyl alcohol, is obtained
Film-form solid；
(2) water for injection of 50 DEG C of full doses 60% is added in the film-form solid obtained to step (1), ultrasound makes its water
Change, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, with the pH value of pH adjusting agent regulation system and uses injection later
Water is settled to 1L；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm
Polycarbonate membrane filtering, it is aseptic subpackaged, 5mL/ bottles, and be freeze-dried, after freeze-drying, tamponade is under nitrogen protection
?.
Technical effect in order to further illustrate the present invention provides experimental example in detail below.
1 stability test of test example
For the quality and stability for verifying Nintedanib freeze-dried lipidosome preparation prepared by the present invention, the present invention is made respectively
Standby low dosage, middle dosage, high dose freeze-dried lipidosome preparation have carried out study on the stability.
To the middle dosage Nintedanib lyophilized preparation of 3 preparation method of embodiment of the present invention preparation, accelerate and long-term steady
Qualitative test.
40 DEG C ± 2 DEG C of temperature are placed in, accelerated stability investigation is carried out under the conditions of humidity 75%, respectively at 0,1,2,3,6
Month sample detection relevant item, inspection result are shown in Table 1:
1. accelerated stability test result of table
25 DEG C ± 2 DEG C of temperature are placed in, long-time stability investigation is carried out under the conditions of humidity 60%, respectively at 0,6,12,18,24
A month sample detection relevant item, inspection result are shown in Table 2.
2. long-term stable experiment result of table
To by 1 low dosage of the embodiment of the present invention, the Nintedanib freeze-dried lipidosome preparation of 5 high dose of embodiment preparation is simultaneously
Identical stability test is carried out, each index has no significant change, no matter illustrating the height of said preparation dosage, chemical stability
Well, it is suitble to industrial production and long term storage.
Experimental example 2
Influence of the administration mode difference to hepatic injury
Mouse 50 (20 ± 2g) are selected, half male and half female is randomly divided into Normal group, oral administration group and atomized medicine introducing
5 groups of basic, normal, high dosage, every group 10.Nintedanib low, middle and high dose groups are respectively by embodiment 1, embodiment 3, embodiment
The Neulized inhalation freeze-dried lipidosome preparation of 5 preparations, atomized medicine introducing after being redissolved with 5mL water for injection, oral administration group stomach-filling is by reality
The Nintedanib of the equivalent of the preparation of example 3 is applied, the physiological saline of equivalent is injected intraperitoneally in Normal group, and be administered continuously 2 weeks 14d, often
Its morning 10.00, afternoon 4.00 each 1 times, each 0.1mL.After two weeks, to each administration group mouse model liver cell supernatant
In the numerical value of ALT, AST, ALP detected, influence of the Research on Statistics and Analysis Nintedanib to hepatic injury is caused.Experiment discovery mouth
It takes administration group mouse ALT, AST and ALP numerical value and significantly increases (P < 0.01), Neulized inhalation each group ALT, AST, ALP activity are therewith
Compared to significant lower (P < 0.01), it the results are shown in Table 3.
ALT, AST, ALP numerical value testing result in each administration group mouse model liver cell supernatant of table 3.
As seen from Table 3, Nintedanib Neulized inhalation preparation of the present invention is smaller compared with degree of the oral administration preparation to hepatic injury,
With the increase of atomized medicine introducing dosage, hepatic injury index accordingly slightly rises, and illustrates invention formulation in treatment pulmonary fibrosis disease
Caused organ toxicity is smaller when sick, safer.
Claims (12)
1. a kind of for treating the Nintedanib Neulized inhalation freeze-dried lipidosome preparation of pulmonary fibrosis, it is characterised in that the system
Agent includes: Nintedanib or its salt, lipid, phosphatide and isotonic agent.
2. preparation according to claim 1, it is characterised in that the preparation further include it is one or more suitable for lung to
The pharmaceutic adjuvant of medicine.
3. preparation according to claim 1 or 2, it is characterised in that contain in freeze-dried lipidosome preparation single dose: 10-80mg
Nintedanib or its salt (being calculated with the amount for Nintedanib of dissociating), 25-250mg lipid, 100-1000mg phosphatide, 20-150mg etc.
Penetration enhancer.
4. preparation according to claim 1-3, it is characterised in that contain in the freeze-dried lipidosome preparation single dose
Have: 20-60mg Nintedanib or its salt (being calculated with the amount for Nintedanib of dissociating), 50-200mg lipid, 250-500mg phosphatide,
40-100mg isotonic agent.
5. preparation according to claim 1-4, it is characterised in that contain in the freeze-dried lipidosome preparation single dose
Have: 40mg Nintedanib or its salt (being calculated with the amount for Nintedanib of dissociating), 75mg lipid, 300mg phosphatide, 60mg isotonic agent.
6. preparation according to claim 1-4, it is characterised in that the mass ratio of the phosphatide and lipid is 6:1-
1:1, preferably 4:1-5:2.
7. preparation according to claim 1-6, it is characterised in that the phosphatide includes natural phospholipid and synthesis phosphorus
Rouge, wherein the natural phospholipid includes egg yolk lecithin, soybean lecithin；The synthetic phospholipid includes two palmityl phosphatidyl gallbladders
Alkali, Distearoyl Phosphatidylcholine, dimyristoyl phosphatidyl choline；It is preferred that soybean lecithin.
8. preparation according to claim 1-7, it is characterised in that the lipid is glycerin monostearate, glycerol
One of three esters, olive oil, soybean oil, median chain triglyceride oil, oleic acid or the mixing of a variety of arbitrary proportions, it is preferably single stearic
Acid glyceride and or triglycerides.
9. preparation according to claim 1-8, it is characterised in that the isotonic agent is sodium chloride, in glucose
One or two mixing, preferably sodium chloride.
10. -9 described in any item preparations according to claim 1, it is characterised in that the preparation further includes pH adjusting agent, described
PH adjusting agent is sodium hydroxide, in sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, phosphoric acid, acetic acid
It is one or more.
11. -10 described in any item preparations according to claim 1, it is characterised in that the pH value of the preparation is 5-8, preferably pH
Value is 6-7.
12. -11 described in any item preparations according to claim 1, it is characterised in that the preparation method of the preparation includes as follows
Step:
(1) in the case where being passed through condition of nitrogen gas, by the lipid of recipe quantity and phosphatide be added suitable ethyl acetate stir in ethyl alcohol it is molten
Solution, then be added recipe quantity Nintedanib stirring and dissolving after, be dried under reduced pressure at 30-35 DEG C about 2h remove ethyl acetate second
Alcohol obtains film-form solid；
(2) water for injection of 35 DEG C of -60 DEG C of full dose 60%-80% is added in the film-form solid obtained to step (1), ultrasound makes
Its aquation, then the isotonic agent stirring and dissolving of recipe quantity is added thereto, later with the pH of pH adjusting agent regulation system and constant volume；
(3) after recycling gained sample twice at homogeneous pressure 8000bar using microjet homogenizer, with 0.22 μm of poly- carbon
The filtering of acid esters film, aseptic subpackaged, and be freeze-dried, after freeze-drying, tamponade under nitrogen protection to obtain the final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711099856.9A CN109758437A (en) | 2017-11-09 | 2017-11-09 | A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711099856.9A CN109758437A (en) | 2017-11-09 | 2017-11-09 | A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109758437A true CN109758437A (en) | 2019-05-17 |
Family
ID=66449456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711099856.9A Withdrawn CN109758437A (en) | 2017-11-09 | 2017-11-09 | A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109758437A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210070968A (en) * | 2019-07-18 | 2021-06-15 | 충북대학교 산학협력단 | Dry powder formulation for inhalation comprising fine particle of nintedanib or pharmaceutically acceptable salt thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466675A (en) * | 2006-06-08 | 2009-06-24 | 贝林格尔.英格海姆国际有限公司 | Salts and crystalline salt forms of an 2-indolinone derivative |
| US20150044288A1 (en) * | 2013-07-31 | 2015-02-12 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
| WO2016142708A2 (en) * | 2015-03-10 | 2016-09-15 | Cipla Limited | Pharmaceutical composition |
| CN107019697A (en) * | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | The pharmaceutical composition and its application of prevention or treatment fibrotic disease |
-
2017
- 2017-11-09 CN CN201711099856.9A patent/CN109758437A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466675A (en) * | 2006-06-08 | 2009-06-24 | 贝林格尔.英格海姆国际有限公司 | Salts and crystalline salt forms of an 2-indolinone derivative |
| US20150044288A1 (en) * | 2013-07-31 | 2015-02-12 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
| WO2016142708A2 (en) * | 2015-03-10 | 2016-09-15 | Cipla Limited | Pharmaceutical composition |
| CN107019697A (en) * | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | The pharmaceutical composition and its application of prevention or treatment fibrotic disease |
Non-Patent Citations (1)
| Title |
|---|
| 魏娜，等: "特发性肺纤维化治疗新药—尼达尼布", 《沈阳药科大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210070968A (en) * | 2019-07-18 | 2021-06-15 | 충북대학교 산학협력단 | Dry powder formulation for inhalation comprising fine particle of nintedanib or pharmaceutically acceptable salt thereof |
| KR102355128B1 (en) | 2019-07-18 | 2022-02-08 | 충북대학교 산학협력단 | Dry powder formulation for inhalation comprising fine particle of nintedanib or pharmaceutically acceptable salt thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI272106B (en) | New medicament compositions based on anticholinergically-effective compounds and beta-mimetics | |
| CN108743952B (en) | Phospholipid-miscible solvent-oil sustained-release drug delivery system formula of local anesthetic and preparation method thereof | |
| JP5981109B2 (en) | Inhalable preparations for the treatment of pulmonary hypertension and methods of use thereof | |
| US5162346A (en) | Pharmaceutical composition comprising flupirtine and its use to combat muscular tension | |
| US11819572B2 (en) | Treatment of pain by administration of sustained-release liposomal anesthetic compositions | |
| CN108379269A (en) | A kind of sustained release preparation and preparation method thereof for Postoperative Analgesia After | |
| JP2021522163A (en) | Inhalable liposome sustained release composition for use in the treatment of lung disease | |
| US11931459B2 (en) | Treatment of pain in pediatric patients by administration of sustained-release liposomal anesthetic compositions | |
| EP1477166A1 (en) | The use of riluzol combined with excipients and additives for the treatment of disorders characterised by hyperproliferation of keratinocytes, in particular neurodermitis and psoriasis | |
| US20200297697A1 (en) | Sublingual pharmaceutical compositions of edaravone and (+)-2-borneol | |
| JP2013529654A (en) | Pharmaceutical composition comprising levocarnitine and dobesylate | |
| WO2021143745A1 (en) | Long-acting ropivacaine pharmaceutical composition, preparation method therefor and use thereof | |
| CN101601654B (en) | Hydrochloric acid Fasudil liposome injection and new application thereof | |
| CN105769846A (en) | GPR35 agonist and application thereof | |
| CN109758436A (en) | A kind of Neulized inhalation pirfenidone freeze-dried lipidosome preparation and preparation method thereof | |
| CN102448309A (en) | Use of R-Bambuterol as inhaled medicament and combination therapies for treatment of respiratory disorders | |
| CN111825548A (en) | Pharmaceutical composition containing aryl propionic acid compounds | |
| JP4951350B2 (en) | Neutral endopeptidase (NEP) and human soluble endopeptidase (HSEP) inhibitors for the prevention and treatment of neurodegenerative disorders | |
| CN109758437A (en) | A kind of Neulized inhalation Nintedanib freeze-dried lipidosome preparation and preparation method thereof | |
| WO2024007801A1 (en) | Combination therapy of receptor tyrosine kinase inhibitor and biphenyl cyclooctadiene lignan and use thereof | |
| CN103054799B (en) | Amiodarone hydrochloride injection emulsion and preparation method thereof | |
| CN113559065B (en) | Preparation method and application of inhalation type lung surfactant nano bionic body | |
| WO2014075155A1 (en) | Pharmaceutical combination containing an analgesic agent and an antispasmodic agent | |
| CN106309410B (en) | A kind of monosialotetrahexose ganglioside sodium spansule and preparation method thereof | |
| CN106176608A (en) | Pemetrexed disodium injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40006615 Country of ref document: HK |
|
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20190517 |