CN111973596B - Anti-pulmonary fibrosis composition with improved dissolution property - Google Patents
Anti-pulmonary fibrosis composition with improved dissolution property Download PDFInfo
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- CN111973596B CN111973596B CN202011015991.2A CN202011015991A CN111973596B CN 111973596 B CN111973596 B CN 111973596B CN 202011015991 A CN202011015991 A CN 202011015991A CN 111973596 B CN111973596 B CN 111973596B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Abstract
The invention relates to an anti-pulmonary fibrosis composition with improved dissolution property, which comprises a salt formed by nintedanib and an acidic polymer. The salt formed by the nintedanib and the acidic polymer has higher solubility and certain stability. The composition of the invention can be used for oral administration, and is helpful for the dissolution and absorption of the medicine in the gastrointestinal tract.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to an anti-pulmonary fibrosis composition with improved dissolution property.
Background
Idiopathic Pulmonary Fibrosis (IPF) is a progressive dyspnea and deterioration of lung function. The common characteristic of pulmonary fibrosis caused by various causes is that inflammation caused by various reasons at first damages the normal alveolar structure to generate alveolitis; the body repairs inflammatory injury by collagen scar tissue accumulation, fibrosis is generated, so that clinical symptoms such as dyspnea, hypoxia and the like are caused, and finally respiratory failure is caused.
When pulmonary fibrosis is mild, it manifests as dyspnea and only occurs during vigorous activity; if pulmonary fibrosis is worsened, dyspnea may occur at rest, and the overall course of the disease may become progressively worse.
The average survival time of the disease is 5-6 years, and a few acute cases die within 6 months. Thus, pulmonary fibrosis is one of the great threats to human health.
Nintedanib, methyl (3Z) -2, 3-dihydro-3- [ [ [4- [ methyl [2- (4-methyl-1-piperazinyl) acetyl ] amino ] phenyl ] amino ] benzylidene ] -2-oxo-1H-indole-6-carboxylate, has the following structural formula:
nintedanib is a triple tyrosine kinase and growth factor antagonist developed by Boringer Vargohne. On 15 days 10 months 2014, nedanib ethanesulfonate (trade name of Ofev) was approved by the FDA for oral drug use in idiopathic pulmonary fibrosis treatment. The nintedanib has poor solubility in the small intestine environment and is not easy to absorb, so that the bioavailability is low, the in-vivo bioavailability is only 4.7%, the doses of the nintedanib sold in the market are 100mg and 150mg, and the price of the raw material medicine is high. Therefore, the important work is to seek to improve the oral bioavailability of the nintedanib, thereby reducing the administration dosage and reducing the production cost.
Patents WO2018/165865a1 and WO2016/178064a1 disclose various crystal forms of esylate nintedanib and a preparation method thereof, and patent WO2004013099a1 discloses esylate nintedanib monohydrate. The existing various crystal forms can not solve the problem of poor water solubility of nintedani. The absorption of solid oral drugs must take into account the dissolution of the drug in the gastrointestinal tract, where the drug is usually first dissolved to form a molecular state before being absorbed through the gastrointestinal mucosa. Thus, dissolution of the drug is a prerequisite for its absorption in the gastrointestinal tract. For high-dose medicines, the bioavailability is improved, the dosage can be reduced, so that the side effect caused by high dose is reduced, the single dose cost is reduced, and patients are benefited.
Various methods have been reported for improving the dissolution properties of nintedanib. For example, patent CN105963268A discloses a nitanib ethanesulfonate dispersible tablet, which is prepared from lactose, low-substituted hydroxypropyl cellulose, povidone, SDS, and magnesium stearate to accelerate drug dispersion, but the preparation must rely on the solubilization of surfactant to increase drug dissolution. The document International Journal of Nanomedicine 2018: 138379-containing 8393 introduces an electrospray technology to prepare the nintedanib solid dispersion, which can accelerate the dispersion and dissolution of the drug under proper conditions, but does not consider the stability of the formed dispersion and the interaction with a carrier, recrystallization can occur in the process and the storage process, but the dissolution is influenced, and the method has high equipment cost and is not easy to amplify the production. Other patents also disclose the preparation of nintedanib liposome, cyclodextrin inclusion compound, microemulsion and their preparation technology, but only increase the drug dissolution by physical means.
In summary, there is a need in the art for improved solid oral dosage forms for anti-pulmonary fibrosis drugs, such as nintedanib, that have improved solubility to improve bioavailability, while having certain stability. Meanwhile, there is a need in the art to improve the dissolution rate of nintedanib and to increase its physical stability.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide an anti-pulmonary fibrosis composition with improved dissolution property.
The technical scheme adopted by the invention for solving the technical problems is as follows: an anti-pulmonary fibrosis composition with improved dissolution properties is constructed, comprising a salt of nintedanib and an acidic polymer.
Preferably, the nintedanib is dispersed in the acidic polymer at the molecular level.
Preferably, the nintedanib acidic polymer salt is an amorphous dispersion and remains amorphous for at least 1 month of an accelerated stability test.
Preferably, the nintedanib composition has a release at equilibrium dissolution of the acidic polymer salt composition of at least 2-fold greater than the control composition in a dissolution test.
Preferably, the control composition is alkaline nintedanib, or the corresponding salt forms: hydrochloride, ethanesulfonate, p-toluenesulfonate, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinite, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, malonate, benzenesulfonate, butanedisulfonate, 1-5-naphthalenedisulfonate, naphthalene-1-sulfonate or 1-hydroxynaphthoate.
Preferably, the nintedanib acidic polymer salt composition comprises the nintedanib acidic polymer in a weight ratio of 20:1 to 1:20, or the nintedanib acidic polymer salt composition comprises the nintedanib acidic polymer in a weight ratio of 10:1 to 1: 10.
Preferably, the acidic polymer is included in a single dose in a weight range of one of 1mg to 10g, 20mg to 1g, 20mg to 200 mg;
the single dose comprises one of the weight ranges of nintedanib from 1mg to 800mg, from 20mg to 600mg, from 1mg to 200mg, from 1mg to 100mg, from 1mg to 30 mg.
Preferably, the acidic polymer is one of the following:
hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCP) and Methyl Cellulose Acetate Phthalate (MCAP).
Preferably, the nintedanib: the acidic polymer salt composition is in an oral dosage form.
Preferably, the nintedanib acidic polymer salt composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of colloidal silicon dioxide, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film forming polymers, antioxidants, light stabilizers, free radical scavengers, surfactants, pH adjusting agents, drug complexing agents, stabilizers against microbial attack, or combinations thereof.
The anti-pulmonary fibrosis composition with the improved dissolution property has the following beneficial effects: the salt formed by the nintedanib and the acidic polymer has higher solubility, and compared with amorphous nintedanib, the composition has obvious stability advantage. The improvement of the solubility is beneficial to the dissolution and absorption of the medicine in the gastrointestinal tract, and the good stability is beneficial to the long-term storage of the medicine.
Drawings
The invention will be further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is an X-ray powder diffraction pattern of HPMCAS salt of the present invention measured after spray drying preparation;
FIG. 2 is an X-ray powder diffraction pattern of HPMCP salt of nintedanib of the present invention measured after spray drying preparation;
FIG. 3 is an X-ray powder diffraction pattern measured after spray drying of Nintedanib free base;
FIG. 4 is a schematic representation of the present invention 40% Nintedanib: infrared spectra of HPMCAS salt composition with 40% nintedanib (amorphous): comparing infrared spectra of the HPMCAS physical mixture, the Nintedanib free base and the HPMCAS;
FIG. 5 is a graph comparing dissolution measurements for HPMCAS salt compositions and nintedanib;
FIG. 6 is a comparison of X-ray powder diffraction patterns of the nintedanib salt composition of the present invention measured at 40 deg.C and 75% relative humidity for 1 month versus 7 days at room temperature for nintedanib free base (amorphous).
Detailed Description
For a more clear understanding of the technical features, objects and effects of the present invention, embodiments of the present invention will now be described in detail with reference to the accompanying drawings.
The anti-pulmonary fibrosis composition with improved dissolution property in one preferred embodiment of the present invention comprises a salt formed by nintedanib and an acidic polymer. The salt formed by the nintedanib and the acidic polymer has higher solubility, and is beneficial to the dissolution and absorption of the drug in the gastrointestinal tract; compared with amorphous nintedanib, the composition has obvious stability advantage and is beneficial to long-term storage of the medicine.
The nintedanib is molecularly dispersed in the acidic polymer. Nintedanib acidic polymer salts are amorphous dispersions and remain amorphous in accelerated stability testing (40 ℃, 75% relative humidity) for at least 1 month.
The acidic polymer is one of the following:
hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCP) and Methyl Cellulose Acetate Phthalate (MCAP).
The release rate of the acid polymer salt composition to equilibrium dissolution is at least 2 times that of the control composition in the dissolution test, e.g., the release rate of the acid polymer salt composition to equilibrium dissolution is 2 times, 3 times, etc. that of the control composition.
The control composition was basic nintedanib, or the corresponding salt forms: hydrochloride, ethanesulfonate, p-toluenesulfonate, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinite, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, malonate, benzenesulfonate, butanedisulfonate, 1-5-naphthalenedisulfonate, naphthalene-1-sulfonate or 1-hydroxynaphthoate.
The nintedanib acidic polymer salt composition comprises a nintedanib acidic polymer in a weight ratio of 20:1 to 1:20, or the nintedanib acidic polymer salt composition comprises a nintedanib acidic polymer in a weight ratio of 10:1 to 1: 10.
A single dose comprises one of a weight range of 1mg to 10g, 20mg to 1g, 20mg to 200mg of the acidic polymer;
the single dose comprises one of the weight ranges of nintedanib from 1mg to 800mg, from 20mg to 600mg, from 1mg to 200mg, from 1mg to 100mg, from 1mg to 30 mg.
Nintedanib: the acidic polymer salt composition is in an oral dosage form.
The acid polymer salt composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of colloidal silicon dioxide, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film forming polymers, antioxidants, light stabilizers, free radical scavengers, surfactants, pH adjusters, drug complexing agents, and stabilizers against microbial attack, or combinations thereof.
Further, the acid polymer was selected from the HPMCAS and HPMCP described above, and the following examples are given.
Example 1: nintedanib: preparation of HPMCAS salts
The Nintedanib free base and HPMCAS are added into a mixed solvent of methanol and dichloromethane (1:1 volume ratio) to form a solution, and an ionic bond is formed between the basic Nintedanib and the acidic polymer HPMCAS.
1.2g of HPMCAS was dissolved in a volume of the mixed solvent by magnetic stirring, and then 0.8g of nintedanib free base was added and dissolved.
The obtained nintedanib containing 40% nintedanib (mass ratio): HPMCAS salt is passed through a Buchi mini-spray dryer B290 (B) equipped with an inert circulation B295
Labortechnik AG, Switzerland). A high performance cyclone was used for separation and a 50mL blue cap flask could be fitted directly to the cyclone for product collection. The parameter settings for the spray-drying process are shown in table 1.
TABLE 1
| Parameter(s) | Set value |
| Suction force | 40kg/h |
| Inlet temperature | 85℃ |
| Outlet temperature | 62℃ |
| Sample introduction rate | 5mL/min |
| Atomized gas flow | 0.5kg/h |
| Inert loop cooling temperature | -20℃ |
After spray drying the product was placed in an oven at 50 ℃ for 1 hour to remove excess solvent, followed by physical determination of the salt by XRPD, the results are shown in figure 1.
Example 2: nintedanib: preparation of HPMCP salts
The Nintedanib free base and HPMCP are added into a mixed solvent of methanol and dichloromethane (1:1 volume ratio) to form a solution, and an ionic bond is formed between the basic Nintedanib and the acidic polymer HPMCP.
1.0g of HPMCP was dissolved in a volume of the mixed solvent by magnetic stirring, and then 1.0g of nintedanib free base was added and dissolved.
The obtained nintedanib containing 50% nintedanib (mass ratio): HPMCP salt is passed through a B290 (B) Huchi mini-spray dryer equipped with inert circulation B295
Labortechnik AG, Switzerland). A high performance cyclone was used for separation and a 50mL blue cap flask could be fitted directly to the cyclone for product collection. The parameter settings for the spray-drying process are shown in table 2.
TABLE 2
| Parameter(s) | Set value |
| Suction force | 40kg/ |
| Inlet temperature | |
| 80℃ | |
| Outlet temperature | 56℃ |
| Sample introduction rate | 5mL/min |
| Atomized gas flow | 0.5kg/h |
| Inert loop cooling temperature | -20℃ |
After spray drying the product was placed in an oven at 50 ℃ for 1 hour to remove excess solvent, followed by physical determination of the salt by XRPD, the results are shown in figure 2.
Example 3: preparation of amorphous Nintedanib
Nintedanib free base is added to a volume of dichloromethane to form a solution which is then passed through a Buchi mini-spray dryer B290 (B) equipped with an inert circulation B295
Labortechnik AG, Switzerland). A high performance cyclone was used for separation and a 50mL blue cap flask could be fitted directly to the cyclone for product collection. The parameter settings for the spray-drying process are shown in table 3.
TABLE 3
| Parameter(s) | Set value |
| Suction force | 40kg/h |
| Inlet temperature | 85 |
| Outlet temperature | |
| 60℃ | |
| Sample introduction rate | 5mL/min |
| Atomized gas flow | 0.5kg/h |
| Inert loop cooling temperature | -20℃ |
After spray drying the product was placed in an oven at 50 ℃ for 1 hour to remove excess solvent, followed by physical determination with XRPD, the results are shown in figure 3.
Example 4: infrared spectroscopic analysis
A fourier transform infrared spectrometer (shimadzu) was used, matched with an attenuated internal reflectance accessory equipped with diamond crystals. The spectrum collection range is 4000-400cm < -1 >, the scanning is carried out for 32 times, and the spectral resolution is 4.0cm < -1 >. Measurements were made with an air blank before recording the spectra for each sample.
In the present disclosure, the term "mixture" or "physical mixture" refers to a simple physical mixture of amorphous nintedanib free base and HPMCAS obtained by combining the dried components and physically stirring them together.
As is known in the art, the powder blend does not substantially change the physical form of the drug, e.g., its crystalline or amorphous characteristics. The powder blend is not intended to produce an amorphous drug/polymer dispersion.
The 40% nintedanib prepared in example 1: infrared spectra of HPMCAS salt composition with 40% nintedanib (amorphous): the infrared spectra of the physical mixture of HPMCAS, nintedanib free base, and HPMCAS are compared and shown in fig. 4.
As shown in fig. 4, the nintedanib of the present invention: the HPMCAS salt composition shows characteristic peaks at 1624cm-1 and 1312cm-1, and the characteristic peaks are not present in a physical mixture, a nintedanib free base or a HPMCAS atlas; wherein the peak at 1624cm-1 is represented by-COO-The asymmetric stretching vibration is generated, and the peak at 1312cm-1 is formed by-COO-Symmetric stretching vibrations are generated.
The invention discloses a Nintedanib: the HPMCAS salt composition has a shoulder at 1595cm-1, which is-NH 2+Superposition of the deformation vibration and the 1592cm-1 signal of the nintedanib free base itself.
The invention discloses a Nintedanib: the HPMCAS salt composition has characteristic peaks at 779cm-1 and 702cm-1, and the characteristic peaks are not present in physical mixture, nintedanib free base or HPMCAS atlas; wherein the peak at 779cm-1 is represented by-COO-Shear mode vibration is generated, and the peak at 702cm-1 is formed by-COO-The rocking vibration is generated.
In summary, the IR spectra show that the Indonepezil and HPMCAS in the compositions of the invention form ionic bonds.
Example 5: nintedanib: dissolution testing of HPMCAS salt compositions
The 40% HPMCAS salt composition of example 1 was subjected to dissolution testing using a dissolution apparatus. 150mg of HPMCAS salt of nintedanib prepared in example 1 and 60mg of nintedanib were used as a control group.
The dissolution medium is 500mL of phosphate buffer solution with pH value of 6.8 (0.5% Tween 80 is added), the temperature is kept at 37 +/-0.5 ℃, and the rotating speed of the rotating pulp is adjusted to be 75 r/m. After the addition of the substance to be measured to the dissolution cup, 5mL of the sample was sampled (simultaneously with the addition of an equal amount of isothermal dissolution medium) for 0.5, 1, 2, 4, 6, 8, 12 and 16 hours, and the sample was filtered through a 0.45 μm microporous membrane to prepare a test solution.
The absorbance of the samples was measured at 395nm wavelength using a UV spectrophotometer, the release of each sample at different times was calculated as UV absorption by the external standard method, and the results were averaged for 3 parallel tests per group (see FIG. 5).
The results show that the release of nintedanib is less than 30% throughout the dissolution process, while nintedanib: the HPMCAS salt composition has a release rate of 80% or more, showing an advantage in solubility.
Example 6: x-ray powder diffraction (XRPD)
X-ray powder diffraction was carried out using a Dutch Pasnake X' Pert sharp X-ray powder diffractometer (PW3040/60) using Cu-Ka radiation at a wavelength of
The divergence slit 1/8 degrees, the X-ray light tube voltage 45kV, the X-ray light tube current 40mA, the scanning range 2-40 degrees (2 theta), the step size 0.026 degrees, and the scanning time 36.465s per step. The samples were spread on sample trays for testing. Data acquisition software X' Pert Data Collector, Data viewing software HighScore Plus.
The 40% nintedanib obtained by drying and separating in examples 1, 2 and 3 of the present invention: HPMCAS salt, 50% nintedanib: the results of XRPD testing of HPMCP salt and nintedanib free base are shown in fig. 1, fig. 2 and fig. 3. XRPD results showed that the nintedanib salt with HPMCAS, HPMCP and spray dried nintedanib were amorphous, as the spectra were all diffuse peaks and contained no visible sharp peaks.
The preparation method comprises the following steps of (1) preparing 40% of nintedanib in the embodiments 1 and 2 of the invention: HPMCAS salt, 50% nintedanib: respectively taking 50mg of HPMCP salt, subpackaging into glass vials, and storing in a constant temperature and humidity box with relative humidity of 40 ℃/75% under the condition of no cover; the amorphous nintedanib of example 3 was additionally stored in vials sealed at room temperature to test physical stability.
XRPD sampling was performed at 7 day, 14 day, 1 month time point and diffraction patterns were obtained using the XRPD method described above. Throughout the study, the present study nintedanib: the acidic polymer salt remains completely amorphous, i.e. no diffraction peaks are shown in the diffractogram at any point in time; but amorphous nintedanib recrystallized.
As shown in fig. 6, wherein a is nintedanib: XRPD pattern detected after HPMCAS salt is stored for 1 month in a constant temperature and humidity chamber at 40 ℃/75% relative humidity, b is nintedanib: the HPMCP salt composition is stored in a constant temperature and humidity chamber at 40 ℃/75% relative humidity for 1 month to detect the XRPD pattern, and c is the XRPD pattern detected after the amorphous Nintedanib is sealed and placed at room temperature for 7 days.
The results show that the nintedanib prepared by the invention: the acidic polymer salt is still amorphous after being kept for 1 month at 40 ℃/75% relative humidity, while the amorphous nintedanib which is not salified with the acidic polymer is detected to be converted into a crystalline state at 7 days, which proves that the nintedanib of the invention: the acidic polymer salt has excellent physical stability.
It is to be understood that the above-described respective technical features may be used in any combination without limitation.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (9)
1. An anti-pulmonary fibrosis composition with improved dissolution property, which is characterized by comprising a salt formed by basic nintedanib and an acidic polymer; the alkaline nintedanib and the acidic polymer are added into a mixed solvent of methanol and dichloromethane in a volume ratio of 1:1 to form a solution, an ionic bond is formed between the alkaline nintedanib and the acidic polymer, the alkaline nintedanib and acidic polymer salt is an amorphous dispersion, and the acidic polymer is one of the following polymers: hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP).
2. The anti-pulmonary fibrosis composition with improved dissolution properties of claim 1, wherein the nintedanib is dispersed in the acidic polymer at a molecular level.
3. The anti-pulmonary fibrosis composition with improved dissolution properties of claim 1, wherein the nintedanib acidic polymeric salt is an amorphous dispersion and remains amorphous in an accelerated stability test for at least 1 month.
4. The anti-pulmonary fibrosis composition with improved dissolution properties of claim 1, wherein the nintedanib acidic polymer salt composition releases at least 2 times more upon reaching equilibrium dissolution than the control composition in a dissolution test.
5. The anti-pulmonary fibrosis composition with improved dissolution properties according to claim 4, wherein the control composition is alkaline nintedanib, or the corresponding salt forms: hydrochloride, ethanesulfonate, p-toluenesulfonate, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinite, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, malonate, benzenesulfonate, butanedisulfonate, 1-5-naphthalenedisulfonate, naphthalene-1-sulfonate or 1-hydroxynaphthoate.
6. The anti-pulmonary fibrosis composition with improved dissolution properties according to claim 1, wherein the nintedanib acidic polymer salt composition comprises the nintedanib acidic polymer in a weight ratio of 20:1 to 1:20, or the nintedanib acidic polymer salt composition comprises the nintedanib acidic polymer in a weight ratio of 10:1 to 1: 10.
7. The anti-pulmonary fibrosis composition with improved dissolution properties according to claim 1, wherein the acidic polymer is included in a single dose in a weight range of one of 1mg to 10g, 20mg to 1g, 20mg to 200 mg;
the single dose comprises one of the weight ranges of nintedanib from 1mg to 800mg, from 20mg to 600mg, from 1mg to 200mg, from 1mg to 100mg, from 1mg to 30 mg.
8. The anti-pulmonary fibrosis composition with improved dissolution properties according to any one of claims 1 to 7, wherein the nintedanib: the acidic polymer salt composition is in an oral dosage form.
9. The anti-pulmonary fibrosis composition with improved dissolution properties according to claim 8, wherein the nintedanib acidic polymeric salt composition further comprises one or more pharmaceutically acceptable excipients selected from lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, flavoring agents, binders, film forming polymers, antioxidants, light stabilizers, free radical scavengers, surfactants, pH modifiers, drug complexing agents, and stabilizers against microbial attack, or combinations thereof.
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