CN111467501A - Compositions with improved dissolution properties - Google Patents
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- CN111467501A CN111467501A CN202010442516.7A CN202010442516A CN111467501A CN 111467501 A CN111467501 A CN 111467501A CN 202010442516 A CN202010442516 A CN 202010442516A CN 111467501 A CN111467501 A CN 111467501A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a composition with improved dissolution property, which comprises a salt formed by basic tinib drug molecules and an acidic polymer. The composition with the improved dissolution property comprises a salt formed by basic tinib drug molecules and an acidic polymer, wherein the basic tinib drug is dispersed in the acidic polymer on the molecular level to form an amorphous solid dispersion, and an ionic bond is formed between the basic tinib drug molecules and the acidic polymer, so that the stability is good, the dissolution speed and the solubility of the composition are improved, and the composition is favorably absorbed by a patient.
Description
Technical Field
The present invention relates to the field of medicine, more specifically to a composition with improved dissolution properties.
Background
The tinib drug belongs to a tyrosine kinase inhibitor and is a revolution of the traditional cancer treatment scheme, because the selectivity of the tinib drug on cancer cells is very high, so that the tinib drug does not kill normal cells and is one of the first-line drugs for resisting tumors. Although widely used in clinic, the solid oral drugs of the tinib class have the problems of poor water solubility and low bioavailability, and the clinical dose is higher.
The recommended dose of commercially available sorafenib tablets is 400mg twice daily for the treatment of advanced renal cell carcinoma and primary hepatocellular carcinoma. The absolute bioavailability of this drug is low, generally considered to be less than 50%, and in rats is only 8.43% (Biomaterials 2014,35, 4565). Meanwhile, the medicine has obvious food effect and cannot be taken before or after eating.
The recommended dose of commercially available gefitinib tablets is 250mg once daily for the treatment of non-small cell lung cancer. The absolute bioavailability of this drug was approximately 50% (Drugs 2002,62, 2237). Also for the drug erlotinib hydrochloride for the treatment of non-small cell lung cancer, the dose is 150 mg/day, the oral bioavailability is about 59%, and there is a food effect (clinical pharmacology 2006,46, 282).
Polymorphic forms of the tinib drug exist. For example, polymorphs of sorafenib tosylate used in commercially available sorafenib tablets are disclosed in patent WO2006034797/CN101065360B (and its family patents); polymorphic forms of gefitinib are disclosed in patent CN1652790 (and its family patents); polymorphic forms of erlotinib hydrochloride are disclosed in patent US 69800221 (and its family patents). Despite the presence of polymorphs, the water solubility of the tinib class of drugs is poor. For poorly soluble drugs, water solubility is a key factor affecting bioavailability. Therefore, the water solubility of the medicine is improved, the bioavailability is improved, the medicine dosage can be reduced, the side effect caused by high dosage is reduced, and the cost of single-dose medicine can also be reduced.
The absorption of solid oral drugs must take into account the rate and solubility of drug release into the gastrointestinal tract, and drugs are usually first dissolved in the gastrointestinal tract to form a molecular state for absorption through the gastrointestinal mucosa. Thus, dissolution of the drug is a prerequisite for its absorption in the gastrointestinal tract. Because the circulation time of the medicine in the gastrointestinal tract is limited, on one hand, the medicine must ensure a certain dissolution speed so as to form a molecular state as soon as possible in the limited circulation time; on the other hand, the drug should be able to maintain a highly soluble state so that it is more absorbed in the gastrointestinal circulation.
Amorphous is a state of disordered array of drug molecules. Amorphous is a high energy state in terms of gibbs free energy, and its solubility may in some cases exceed the equilibrium solubility of the drug, reaching a "supersaturated solution" state. This improved dissolution profile is beneficial for enhanced bioavailability. However, also because of the high energy state, the amorphous drug molecules with fluidity can be recrystallized into a relatively more stable and lower energy level crystalline state, which results in unstable amorphous drug during storage, and the resulting crystalline impurities can affect the dissolution and in vivo bioavailability of the drug. By forming amorphous solid dispersoid, the medicine is dispersed in the polymer on the molecular level, the mobility of molecules can be reduced to a certain degree, and the recrystallization process is delayed; however, generally, molecules are bound to polymers by hydrogen bonds, pi-pi interactions, van der waals forces, etc., which are relatively weak, and the drug still has a risk of crystallization during long-term storage.
Patents CN107162965A and CN104761492A disclose amorphous forms of sorafenib hemitosylate and para-tosylate. Patent CN103958483A discloses amorphous forms of erlotinib in various salt forms. The above publications (including their family patents) have not been subjected to dissolution tests, nor have they been subjected to sufficient studies of physical stability.
In summary, there is a continuing need in the art to develop improved solid oral dosage forms for poorly soluble tinib drugs that have superior dissolution properties and bioavailability. Meanwhile, there is a need in the art to improve the dissolution properties of poorly soluble tinib drugs without compromising their physical stability.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a composition having improved dissolution properties in order to improve the dissolution properties of poorly soluble (tinib) drugs.
The technical scheme adopted by the invention for solving the technical problems is as follows: a composition having improved dissolution properties is constructed comprising a salt of a basic tinib-based drug molecule and an acidic polymer.
Preferably, the basic tinib drug is sorafenib, gefitinib or erlotinib.
Preferably, the acidic polymer is one of the following: hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), Methyl Cellulose Acetate Phthalate (MCAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS).
Preferably, the basic tinib drug is molecularly dispersed in the acidic polymer to form an amorphous solid dispersion and remains in the amorphous state for at least 6 months of accelerated stability testing (40 ℃, 75% relative humidity).
Preferably, the composition has a higher dissolution rate and solubility than the control composition in a dissolution test.
Preferably, the control composition is a basic tinib drug, or a corresponding salt form of hydrochloride, 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 composition comprises the basic tinib drug and the acidic polymer in a weight ratio of 20:1 to 1: 20; or the like, or, alternatively,
the composition comprises the basic tinib drug and the 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 300 mg;
the single dose comprises the basic tinib drug in a weight range of 1mg to 800mg, 20mg to 400mg, 1mg to 200mg, 1mg to 100mg, 1mg to 30 mg.
Preferably, wherein the particle size of the composition is greater than about 1 μm and is not a nanoparticle.
Preferably, the composition is in an oral dosage form, further comprising 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, and stabilizers against microbial attack, or combinations thereof.
The composition with improved dissolution properties embodying the present invention has the following beneficial effects: the composition with the improved dissolution property comprises a salt formed by basic tinib drug molecules and an acidic polymer, wherein the basic tinib drug is dispersed in the acidic polymer on the molecular level to form an amorphous solid dispersion, and an ionic bond is formed between the basic tinib drug molecules and the acidic polymer, so that the stability is good, the dissolution speed and the solubility of the composition are improved, and the composition is favorably absorbed by a patient.
Drawings
The invention will be further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a polarization micrograph of the sorafenib HPMCP salt of the present invention;
FIG. 2 is an X-ray powder diffraction pattern of the inventive sorafenib HPMCP salt measured after spray drying preparation;
FIG. 3 is an X-ray powder diffraction pattern of HPMCP salt of gefitinib of the present invention measured after spray drying preparation;
FIG. 4 is an X-ray powder diffraction pattern of a HPMCP salt of erlotinib of the present invention measured after spray drying preparation;
fig. 5A is sorafenib of the present invention: a comparison infrared spectrum of the HPMCP salt composition, sorafenib, the HPMCP physical mixture, sorafenib free base and HPMCP in one region;
fig. 5B is sorafenib of the present invention: a comparison infrared spectrum of the HPMCP salt composition, sorafenib, the HPMCP physical mixture, sorafenib free base and HPMCP in another region;
figure 6 is sorafenib of the invention: raman spectra contrast plot of HPMCP salt composition, sorafenib (amorphous): HPMCP physical mixture;
figure 7 is sorafenib of the invention: a plot comparing dissolution measurements for HPMCP salt composition and sorafenib;
fig. 8 is gefitinib of the present invention: a graph comparing dissolution measurements for HPMCP salt compositions and gefitinib;
figure 9 is erlotinib of the invention: a comparison of dissolution measurements for HPMCP salt composition and erlotinib.
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 composition with improved dissolution properties in a preferred embodiment of the invention comprises a salt of a basic tinib drug molecule and an acidic polymer.
The basic tinib drug is sorafenib, gefitinib or erlotinib. The basic tinib drug is molecularly dispersed in the acidic polymer to form an amorphous solid dispersion and remains in the amorphous state for at least 6 months of accelerated stability testing (40 ℃, 75% relative humidity).
The acidic polymer may be one of the following: hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), Methyl Cellulose Acetate Phthalate (MCAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS).
An ionic bond is formed between a basic tinib drug molecule and an acidic polymer, the composition has a higher dissolution rate and solubility in a dissolution test than a control composition, which is a basic tinib drug, or the corresponding salt forms of hydrochloride, p-toluenesulfonate, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinic acid, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, malonate, benzenesulfonate, butanedisulfonate, 1-5-naphthalenedisulfonate, naphthalene-1-sulfonate or 1-hydroxynaphthalene formate.
In some embodiments, the composition of the invention comprises a weight ratio of basic tinib drug to acidic polymer of from 20:1 to 1: 20. In other embodiments, the composition comprises a weight ratio of basic tinib drug to acidic polymer of 10:1 to 1: 10.
The acidic polymer may be included in a single dose in a weight range of 1mg to 10g, and in other embodiments, the acidic polymer may be included in a single dose in a weight range of 20mg to 1g, or the acidic polymer may be included in a single dose in a weight range of 20mg to 300 mg.
The basic tinib drug is contained in a single dose in a weight range of 1mg to 800mg, in other embodiments, the basic tinib drug is contained in a single dose in a weight range of 20mg to 400mg, or the basic tinib drug is contained in a single dose in a weight range of 1mg to 200mg, or the basic tinib drug is contained in a single dose in a weight range of 1mg to 100mg, or the basic tinib drug is contained in a single dose in a weight range of 1mg to 30 mg.
Further, the composition of the present invention has a particle size of greater than 1 μm and is not a nanoparticle. As shown in FIG. 1, the particle size of the composition was about 2 μm. Further, in other embodiments, the particle size of the composition may also be 2-100 μm, or may also be 5-50 μm.
The composition of the present invention is an oral dosage form further comprising 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, and stabilizers against microbial attack, or combinations thereof.
Further, the acid polymer was selected to be HPMCP as described above, and the following examples are given.
Example 1: sorafenib: preparation of HPMCP salts
Sorafenib free base and HPMCP are added into a mixed solvent of methanol and ethyl acetate (1:1 volume ratio) to form a solution, and ionic bonds are formed between alkaline sorafenib and an acidic polymer HPMCP.
1.2g HPMCP was dissolved in a volume of solvent by magnetic stirring, then 0.8g sorafenib free base was added and dissolved the solution was transferred to a 100m L volumetric flask and the volume was added to the volume.
The resulting sorafenib HPMCP salt containing 40% sorafenib (mass ratio) was passed through a B ü chi mini-spray dryer B290 (B) equipped with inert recycle B295
L abortechnik AG, switzerland) spray drying separation a high performance cyclone was used for separation and a 50m L blue bottle 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
After spray drying the product was placed in an oven at 50 ℃ for 1 hour to remove excess solvent before thermogravimetric analysis (TGA) was used to determine the solvent residue in the product. The physical state of the salt was then determined by XRPD and the results are shown in figure 2.
Example 2: gefitinib: preparation of HPMCP salts
Gefitinib 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 basic gefitinib and acidic polymer HPMCP.
1.2g HPMCP was dissolved in a volume of solvent by magnetic stirring, then 0.8g gefitinib free base was added and dissolved the solution was transferred to a 100m L volumetric flask and the volume was added.
The resulting gefitinib HPMCP salt containing 40% gefitinib (mass ratio) was passed through a B ü chi mini-spray dryer B290 (B) equipped with inert recycle B295
L abortechnik AG, switzerland) spray drying separation a high performance cyclone was used for separation and a 50m L blue bottle 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 | 52℃ |
| 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 before thermogravimetric analysis (TGA) was used to determine the solvent residue in the product. The physical state of the salt was then determined by XRPD and the results are shown in figure 3.
Example 3: erlotinib: preparation of HPMCP salts
Erlotinib 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 basic erlotinib and acidic polymer HPMCP.
0.8g HPMCP was dissolved in a volume of solvent by magnetic stirring, then 1.2g erlotinib free base was added and allowed to dissolve the solution was transferred to a 100m L volumetric flask and brought to volume by adding a volume of solvent.
The resulting erlotinib HPMCP salt containing 60% erlotinib (mass ratio) was passed through a B ü chi mini spray dryer B290 (B) equipped with inert recycle B295
L abortechnik AG, Switzerland) spray-dried separation, a high performance cyclone was used for separation, a 50m L blue bottle-capped flask could be mounted directly to the cyclone for product collection, spray-driedThe parameter settings of the program are shown in table 3.
TABLE 3
| Parameter(s) | Set value |
| Suction force | 40kg/h |
| Inlet temperature | 75℃ |
| Outlet temperature | 47℃ |
| Sample introduction rate | 5mL/min |
| Atomized gas flow | 0.5kg/h |
| Inert loop cooling temperature | -22℃ |
After spray drying the product was placed in an oven at 50 ℃ for 1 hour to remove excess solvent before thermogravimetric analysis (TGA) was used to determine the solvent residue in the product. The physical state of the salt was then determined by XRPD and the results are shown in figure 4.
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 sorafenib free base and HPMCP obtained by combining the dried components and then 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% sorafenib prepared in example 1: infrared spectra of HPMCP salt compositions with 40% sorafenib: the infrared spectra of HPMCP physical mixture, sorafenib free base, and HPMCP were compared as shown in fig. 5.
The pKa difference between sorafenib and HPMCP is more than 1, and the sorafenib and the HPMCP can form salts; the salt-forming site is the pyridine N atom (forming-NH) in sorafenib+) With carboxylic acid-COOH (forming-COO) in HPMCP-)。
As in FIG. 5A, at about 2647cm-1, the sorafenib: the HPMCP salt composition has a broad peak, and the broad peak is not present in sorafenib free base or physical mixture, because the salinized sorafenib contains-NH+A functional group.
As in fig. 5B, the present sorafenib: the HPMCP salt composition has a shoulder at 1670cm-1, which is absent from HPMCP or physical mixture, and which contains-COO-Contains the peak of non-salified-COOH and other carbonyl compounds in HPMCP.
Example 5: raman spectroscopy
The collection of the raman spectra was performed using a raney shaoxinvia raman microspectrometer equipped with a near infrared diode laser source and a Rencam Charge Coupled Device (CCD) silicon detector. Placing the sample on a microscope slide glass, carrying out focusing observation under a 50-time objective lens and carrying out Raman imaging detection under the following detection conditions: the detection wavelength is 785nm, and the detection range is 200cm-1-3600cm-1Laser intensity is 100%, exposure time is 3s, and 1 time of accumulation is carried out; and data acquisition and analysis software wire 4.3.
Mixing 40% sorafenib (amorphous): raman spectra of physical mixtures of HPMCP were compared to 40% sorafenib of the invention: raman spectra of HPMCP salt compositions were compared.
As shown in FIG. 6, at the vicinity of 1030cm-1 and at the vicinity of 1600cm-1, the pyridine ring in the sorafenib molecule stretches to form peaks, and a clear difference exists, which indicates that the sorafenib of the invention: the N atom of the sorafenib pyridine ring in the HPMCP salt composition is protonated, resulting in a change in the stretching peak of the pyridine ring.
Example 6: sorafenib: HPMCP salt composition dissolution test
The 40% sorafenib HPMCP salt composition from example 1 was subjected to dissolution testing using a dissolution apparatus with 900m L in 0.5% aqueous SDS (5g SDS fully dissolved in 1000m L deionized water), maintained at 37 ℃ ± 0.5 ℃ and adjusted to a rotational speed of 100 rpm.
62.5mg of the sorafenib HPMCP salt prepared in example 1 was used as a test group, and 25mg of sorafenib free base was used as a control group.
The test group and the control group were added to a dissolution cup, timing was started, and 1m L (supplemented with an equal amount of isothermal dissolution medium at the same time) was sampled at 5, 10, 15, 30, and 45min, respectively, and filtered (0.45 μm microporous membrane) to obtain a test solution.
Precisely injecting 10 μ L sample into high performance liquid chromatograph under conditions of Agilent EC-C18 chromatographic column, mobile phase pH2.5 phosphate buffer (20 mmol/L KH)2PO4Using H3PO4And (3) adjusting the pH to 2.5), namely, adjusting the ratio of methanol to 1:3, carrying out column temperature to 30 ℃, carrying out flow rate to 1.0m L/min, detecting the wavelength to 264nm, recording a chromatogram, calculating the release of each sample at different time according to the peak area by an external standard method, and carrying out parallel test on 2 results in each group to obtain an average value (shown in figure 7).
Example 7: gefitinib: HPMCP salt composition dissolution test
The 40% gefitinib-HPMCP salt composition prepared in example 2 was subjected to dissolution testing using a dissolution apparatus with 900m L in 0.1% aqueous SDS (1g SDS fully dissolved in 1000m L deionized water), maintained at 37 ℃. + -. 0.5 ℃ and adjusted to a rotational speed of 100 rpm.
125mg of the HPMCP salt of gefitinib prepared in example 1 was used as a test group, and 50mg of gefitinib free base was used as a control group.
The test group and the control group were added to a dissolution cup, timing was started, and 1m L samples were taken at 2.5, 5, 10, 15, 20, 30, and 45min, respectively, and filtered (0.45 μm microporous membrane) to be diluted by the same factor to be used as a test solution.
The absorption at 333.5nm was recorded using a UV spectrometer and the release at different times for each sample was calculated as UV absorption by the external standard method and 2 results were averaged for each set of replicates (see FIG. 8). The invention discloses gefitinib: the HPMCP salt composition achieves more than 80% release in 20 minutes, whereas the control composition releases only about 10% of the dissolution, representing the advantage of the present composition in terms of solubility.
Example 8: erlotinib: HPMCP salt composition dissolution test
The 60% erlotinib HPMCP salt composition prepared in example 3 was subjected to dissolution testing using a dissolution apparatus with 900m L aqueous 0.2% SDS (2g SDS fully dissolved in 1000m L deionized water), maintained at 37 ℃. + -. 0.5 ℃ and adjusted to a rotational speed of 100 rpm.
250mg of the erlotinib HPMCP salt prepared in example 1 was used as the test group and 150mg of the erlotinib free base was used as the control group.
The test group and the control group were added to a dissolution cup, timing was started, and 1m L samples were taken at 2.5, 5, 10, 15, 20, 30, and 45min, respectively, and filtered (0.45 μm microporous membrane) to be diluted by the same factor to be used as a test solution.
The absorbance at 336nm was recorded using a UV spectrometer and the release at different times for each sample was calculated as UV absorbance by the external standard method and 2 results were averaged for each set of replicates (see FIG. 9). The erlotinib of the present invention: the HPMCP salt composition achieves greater than 80% release at 2.5 minutes, while the control composition achieves about 80% release at 30 minutes, representing the advantage of the present composition in terms of dissolution rate.
Example 9: 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-K α radiation at a wavelength of
Divergence slit 1/8 °, X-ray tube voltage 45kV, X-ray tube current 40mA, scan range 2-40 ° (2 θ), step size 0.013 °, scan time 37.995s 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% sorafenib obtained by drying and separating in the embodiments 1, 2 and 3 of the invention: HPMCP salt, 40% gefitinib: HPMCP salt and 60% erlotinib: the HPMCP salt was subjected to XRPD testing and the results are shown in fig. 2, fig. 3 and fig. 4. The XRPD results show that the salts formed by the above-mentioned tinib drugs with HPMCP are amorphous, since the patterns are all diffuse peaks and do not contain visible sharp peaks.
50 mg/sample of the above salt was dispensed into glass vials and stored in a climate chamber at 40 deg.C/75% relative humidity without a lid to test physical stability over time. XRPD sampling was performed at time points of 7 days, 14 days, 1 month, 2 months, 4 months and 6 months, and diffraction patterns were obtained using the XRPD method described above. The compositions of the study remained completely amorphous throughout the study, i.e., no diffraction peaks were shown in the diffractogram at any time point.
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 (10)
1. A composition having improved dissolution properties comprising a salt of a basic tinib drug molecule and an acidic polymer.
2. The composition with improved dissolution properties according to claim 1, wherein the basic tinib drug is sorafenib, gefitinib or erlotinib.
3. The composition with improved dissolution properties according to claim 1, wherein the acidic polymer is one of the following: hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), Methyl Cellulose Acetate Phthalate (MCAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS).
4. The composition having improved dissolution properties according to claim 1, wherein the basic tinib drug is molecularly dispersed in the acidic polymer forming an amorphous solid dispersion and remains in the amorphous state for at least 6 months of accelerated stability testing (40 ℃, 75% relative humidity).
5. Composition with improved dissolution properties according to claim 1, characterized in that the composition has a higher dissolution rate and solubility in the dissolution test than the control composition.
6. Composition with improved dissolution properties according to claim 5, wherein the control composition is a basic tinib drug or the corresponding salt forms of hydrochloride, p-toluenesulfonate, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinic acid salt, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, malonate, benzenesulfonate, butanedisulfonate, 1-5-naphthalenedisulfonate, naphthalene-1-sulfonate or 1-hydroxynaphthoate.
7. The composition with improved dissolution properties according to any of claims 1 to 6, wherein the composition comprises a basic tinib drug to acidic polymer in a weight ratio of 20:1 to 1: 20; or the like, or, alternatively,
the composition comprises the basic tinib drug and the acidic polymer in a weight ratio of 10:1 to 1: 10.
8. Composition with improved dissolution properties according to any of claims 1 to 6, characterized in that the weight of acidic polymer contained in a single dose ranges from one of 1mg to 10g, 20mg to 1g, 20mg to 300 mg;
the single dose comprises the basic tinib drug in a weight range of 1mg to 800mg, 20mg to 400mg, 1mg to 200mg, 1mg to 100mg, 1mg to 30 mg.
9. The composition with improved dissolution properties according to any one of claims 1 to 6, wherein the particle size of the composition is greater than about 1 μm and is not a nanoparticle.
10. A composition with improved dissolution properties according to any of claims 1 to 6, wherein the composition is in oral dosage form further comprising one or more pharmaceutically acceptable excipients selected from 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 and stabilizers against microbial attack or combinations thereof.
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| CN111973596A (en) * | 2020-06-15 | 2020-11-24 | 深圳市泰力生物医药有限公司 | Anti-pulmonary fibrosis composition with improved dissolution property |
| CN112294971A (en) * | 2020-02-20 | 2021-02-02 | 深圳市泰力生物医药有限公司 | Nilotinib compositions having improved solubility |
| CN113181179A (en) * | 2021-04-08 | 2021-07-30 | 深圳市泰力生物医药有限公司 | Dihydropyridine calcium antagonist salt composition and preparation method and application thereof |
| CN113476453A (en) * | 2021-08-10 | 2021-10-08 | 深圳市泰力生物医药有限公司 | Panatinib, ibrutinib and vandetanib salt composition and preparation method and application thereof |
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