CN114364386B

CN114364386B - Antitumor pharmaceutical composition and method for improving solubility of compound

Info

Publication number: CN114364386B
Application number: CN202080063242.9A
Authority: CN
Inventors: 鹿宁; 程智慧; 杨红振; 胡怀忠
Original assignee: Beijing Konruns Pharmaceutical Co Ltd
Current assignee: Beijing Konruns Pharmaceutical Co Ltd
Priority date: 2019-12-30
Filing date: 2020-12-25
Publication date: 2023-06-16
Anticipated expiration: 2040-12-25
Also published as: CN113116894A; CN114364386A; WO2021136089A1

Abstract

The invention provides a quinoline antitumor pharmaceutical composition containing phosphorus substituent and a method for improving the solubility of bulk drugs in the pharmaceutical composition. According to the invention, the acid compound is added into the raw material medicine, so that the medicine can release acid after entering gastric juice, thereby improving the acidity of gastric juice and reducing the pH value of gastric juice. The reduction of the pH value of gastric juice provides a favorable environment for dissolution of the medicine, promotes dissolution and absorption of the raw material medicine in the stomach, and improves the bioavailability of the medicine in vivo. The invention also provides a method for improving the solubility of the quinoline antitumor drug containing the phosphorus substituent in water.

Description

Antitumor pharmaceutical composition and method for improving solubility of compound

The present application claims priority from chinese patent office, application number 201911399012.5, entitled "an anti-tumor pharmaceutical composition and method of increasing the solubility of a compound" filed on 12/30 2019, the entire contents of which are incorporated herein by reference.

Technical Field

The invention belongs to the technical field of pharmacy, and particularly relates to a quinoline antitumor pharmaceutical composition containing phosphorus substituent groups and a method for improving the solubility of bulk drugs in the antitumor pharmaceutical composition.

Background

The compound 1 is a quinoline antitumor drug containing phosphorus substituent, and mainly acts on a novel multi-target receptor tyrosine kinase inhibitor of hepatocyte growth factor receptor (hepatocyte growth factor receptor, HGFR or mesenchymal-epithelial transition factor, c-Met) and vascular endothelial growth factor 2 (vascular endothelial growth factor 2, VEGFR2 or KDR). The compound 1 is a dual inhibitor of c-Met and VEGFR2, and can effectively block two signal paths of the c-Met and the VEGFR2 which play different roles in tumors at the same time, thereby having unique pharmacological effects and clinical application prospects. The compound 1 has broad-spectrum anti-tumor effect, and has excellent anti-tumor effect and safety range in animal models of tumors such as gastric cancer, prostatic cancer bone metastasis, medullary thyroid cancer, non-small cell lung cancer, liver cancer, kidney cancer and the like.

The chemical name of compound 1 is: diethyl 1- [ [4- [ 2-fluoro-4- [ [1- [ (4-fluorophenyl) carbamoyl ] cyclopropanecarbonyl ] amino ] phenoxy ] -6-methoxy-7-quinolinyl ] oxymethyl ] piperidinyl ] methylphosphonate.

The chemical structure of compound 1 is shown in formula 1 below.

In clinical studies, it was found that the existing preparation of compound 1 has poor solubility, low bioavailability in human body and large individual difference, resulting in unstable clinical effects. In order to solve this problem, the inventors have further studied compound 1.

Disclosure of Invention

In view of the problems of the prior art, the applicant has conducted intensive studies to improve the solubility and bioavailability of compound 1.

In order to achieve the object of the present invention, the present invention provides an antitumor pharmaceutical composition comprising a compound represented by formula 1 and a pharmaceutically acceptable acid;

in one embodiment of the pharmaceutical composition of the present invention, the composition further comprises a coating layer coating the surface of the compound represented by formula 1. The material of the coating layer can be pharmaceutically acceptable pharmaceutical excipients commonly used in the art, such as silicon dioxide, titanium dioxide, hypromellose, hydroxypropyl cellulose, talcum powder, polyethylene glycol, polyvinyl alcohol or one or more combinations thereof; preferably, the material of the coating layer is selected from silica.

The main reason for isolating the bulk drug from pharmaceutically acceptable acid is that the bulk drug of the compound 1 has poor stability under acidic conditions and is easy to degrade after contacting with the acid for a long time, and the stability of the compound 1 in the preparation and storage processes can be ensured through the isolating effect of the coating layer. Among these coating materials, silica has a small particle diameter and a large specific surface area, and is easily adsorbed on the particle surface to isolate an acid from a drug substance. Thus, silica can be used as a material for the desired coating layer.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable acid in the pharmaceutical composition can make the compound represented by formula 1 have a saturated solubility of 0.5mg/ml or more, preferably 1.0mg/ml or more in water having a pH of 3.0 or less. According to clinical investigation, in a general clinical administration mode, the compound 1 is taken with 100ml to 200ml of warm water in a clinical maximum dose of not more than 200mg of the compound 1, and the compound 1 has a saturated solubility of 0.5mg/ml in water with a pH of 3.0, so that the expectation of improving the bioavailability can be reached, thereby meeting clinical requirements. When the pH increases, the saturated solubility of compound 1 in water is too small to meet clinical demands. Therefore, for clinical efficacy, the pharmaceutically acceptable acid in the composition can provide the compound of formula 1 with a saturated solubility of 0.5mg/ml or more, preferably 1.0mg/ml or more in water having a pH of 3.0 or less.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable acid may be an inorganic acid or an organic acid as long as it is suitable as a pharmaceutical excipient. Meanwhile, in the present invention, the form of the acid is not limited, and may be a solid acid or a liquid acid. For the purpose of the present invention, one requirement for the selection of acids is that the lower the pH of the acid, the better at the same acid concentration. In theory, acids having a pH below 3.0 after dissolution in water are all useful. Although strong acids (e.g., hydrochloric acid, acetic acid, etc.) perform better, strong acids are generally unsuitable for use as pharmaceutical excipients. In the present invention, acids that can be used include, but are not limited to, inorganic acids such as phosphoric acid and the like, organic acids such as alginic acid, citric acid, fumaric acid, glutamic acid, tartaric acid, malic acid and the like. Among these acids, citric acid is preferably used, for a number of reasons including: (1) The dissolution rate of citric acid in water is high, and the pH value of water can be reduced to below 3.0 by adding a small amount of citric acid. Considering that the active pharmaceutical compound 1 enters the stomach, the gastric emptying rate is high, and therefore a pharmaceutically acceptable acid is needed which will rapidly dissolve and rapidly lower the pH of the gastric juice, from this point of view citric acid meets this requirement. (2) The citric acid is widely used, is a pharmaceutical adjuvant with larger allowable dosage by FDA authentication, and has high safety.

In the pharmaceutical composition of the present invention, the dissolution and absorption of the compound represented by formula 1 in vivo can be promoted theoretically by adding an acid to the formulation. In order to better adapt to the stomach environment and achieve the desired bioavailability, the ratio of the compound of formula 1 to the pharmaceutically acceptable acid is preferably 1:2 to 1:6 by weight, more preferably 1:4. Specific addition ratios will vary depending on the type of acid.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable auxiliary materials may be various pharmaceutical auxiliary materials suitable for the formulation of compound 1 in the art, for example, fillers, disintegrants, lubricants, etc. used as tablets. In a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutically acceptable excipients are selected from one or more of microcrystalline cellulose, lactose, crospovidone, hydroxypropyl cellulose, magnesium stearate, povidone, croscarmellose sodium, and sodium carboxymethyl starch, and the use of these excipients facilitates the preparation of a suitable dosage form for the pharmaceutical and for administration via the gastrointestinal tract.

In view of the characteristics of the compound shown in formula 1 and making the pharmaceutical composition of the present invention more suitable for gastrointestinal administration, the composition of the present invention can be prepared into solid preparations such as tablets, capsules, granules, pills or powder.

Accordingly, another aspect of the present invention provides a method for increasing the solubility of a compound represented by formula 1 in water, the method comprising adding a pharmaceutically acceptable acid to the compound represented by formula 1.

In one embodiment of the method of preparing the pharmaceutical composition of the present invention, the method comprises: before adding the pharmaceutically acceptable acid, adding a coating material after wet granulating the compound shown in the formula 1, and mixing to coat the compound shown in the formula 1; wherein the coating material is at least one selected from silicon dioxide, titanium dioxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder, polyethylene glycol and polyvinyl alcohol, and preferably silicon dioxide. The bulk drug compound 1 can be isolated from pharmaceutically acceptable acids by the isolation of the coating.

For better achievement of the object of the present invention, the pharmaceutically acceptable acid added is required to be capable of giving the compound represented by formula 1 a saturated solubility of 0.5mg/ml or more, preferably 1.0mg/ml or more in water having a pH of 3.0 or less. Preferably, the ratio of the compound of formula 1 to the pharmaceutically acceptable acid is 1:2 to 1:6, more preferably 1:4.

The inventors found that the solubility of the bulk drug (API) of compound 1 was pH dependent during the study of antitumor drug compound 1, and that the solubility of compound 1 was much higher under acidic conditions than under neutral and alkaline conditions. Compound 1 is an antitumor drug that is more widely used in elderly patients with tumors, while the pH of the digestive system (stomach) of elderly patients is generally higher. According to the records of research literature, the pH value of gastric juice of middle-aged and elderly people can reach pH4-6, which is more unfavorable for the dissolution of the product. In the diagnosis and treatment progress of common digestive diseases of the elderly, gastric acidity measurement of the elderly over 60 years old by iron shaking force proves that the gastric acid concentration of most of the elderly is lower than that of young people, and the pH value of gastric juice can reach over pH4.

The invention can release acid after the active ingredients of the medicine enter gastric juice by adding the acid which is suitable for serving as auxiliary materials into the pharmaceutical composition, thereby reducing the pH value of the gastric juice and improving the acidity of the gastric juice. The reduction of gastric juice pH provides a favorable environment for dissolution of the drug compound 1, thereby promoting dissolution and absorption of the drug and improving the bioavailability of the active drug in vivo.

Drawings

FIG. 1 is a graph showing the relationship between the pH of a drug solution and the saturated solubility of Compound 1 of formula 1;

fig. 2 is a graph showing the change of the blood concentration of mice with time.

Detailed Description

The present invention is further illustrated by the following examples and comparative examples, which are only for illustration of the present invention, and the present invention is not limited to the following examples. All modifications and equivalent substitutions to the technical proposal of the invention are included in the protection scope of the invention without departing from the scope of the technical proposal of the invention.

Example 1

In vitro solubility assay of pharmaceutical compositions

The invention improves the solubility of the medicine in the dissolution medium with different pH values by adding acid into the raw medicine (compound 1). The effect of several acids on the saturated solubility of compound 1 was investigated below.

Table 1 saturation solubility of compound 1 in media with different pH values

Medium (D)	Saturation solubility (mg/ml)
		Hydrochloric acid solution with pH1.0	106.2
Hydrochloric acid solution with pH2.0	64.1
		Disodium hydrogen phosphate-citric acid buffer solution with pH of 3.0	1.0
Acetate buffer at pH4.5	3.1×10 ^-3
		Water and its preparation method	0.6×10 ^-3
phosphate buffer at pH6.8	0.7×10 ^-3

The relationship between the pH of the dissolution medium and the saturation solubility of the drug was made as a curve, as shown in FIG. 1.

As can be seen from fig. 1, at pH3, the solubility of the drug substance compound 1 in the dissolution medium has become small. According to clinical investigation, the compound 1 is taken with 100ml-200ml warm water in a clinical taking mode, and therefore, the compound 1 has 1mg/ml saturated solubility in a medium with pH of 3.0 so as to meet clinical requirements, wherein the clinical maximum dosage of the compound 1 is not more than 200 mg. When the pH value is increased, the saturated solubility of the compound 1 is too small to meet clinical requirements.

In addition, the inventors further tested the relationship between the pH of the dissolution medium and the saturation solubility of the drug in the numerical range of pH3.1 to pH4.0, and the results are shown in Table 2 below.

TABLE 2

Medium (D)	Saturation solubility (mg/ml)
		Disodium hydrogen phosphate-citric acid buffer solution with pH of 3.1	0.450
Disodium hydrogen phosphate-citric acid buffer solution with pH of 3.3	0.212
		Disodium hydrogen phosphate-citric acid buffer solution with pH of 3.5	0.093
Disodium hydrogen phosphate-citric acid buffer solution with pH of 3.8	0.034
		Acetate buffer at pH3.8	0.024
Acetate buffer at pH4.0	9×10 ^-3

As can be seen from tables 1, 2 and fig. 1, the solubility of the compound 1 is higher under acidic conditions, and the solubility tends to increase with decrease in pH, whereby it is known that the solubility of the compound 1 has a remarkable pH dependency.

Table 3 below lists the amounts of acid used when several common acid adjuvants are dissolved in 100ml of water and adjusted to a pH around 3.0. In choosing the pH value used for the test, the inventors found that the pH of the daily beverage cola was about 2.4, and therefore the amount of acid used in the measurement was based on the measurement result at ph=2.40.

TABLE 3 Table 3

From tables 1, 2 and 3, it can be presumed that the various acid solutions used and the curves of fig. 1 also achieve the objective of improving the in vivo bioavailability of the antitumor drug compound 1 in the formulation by other pharmaceutically acceptable acids listed in the present invention. It can be seen from table 3 that in order to reduce the pH of water to 2.40, the amount of tartaric acid and fumaric acid to be added exceeds the maximum oral dosage, and safety is considered. In addition, increasing the amount of glutamic acid also lowers the pH below 3.0, but the dissolution rate of glutamic acid is not suitable for practical clinical requirements.

Pharmacokinetic study experiments of drugs at different pH

The drug formulation a used in this experiment is shown in table 4 below.

Table 4 composition of prescription A

Experiment 1

Adding a sample of the compound 1 into a 0.9% NaCl injection, swirling for 5min, stirring for 5min, regulating the pH to 2.0 by using 1N HCl, carrying out ultrasonic treatment for 30min, regulating the pH to 3.0 by using 1N NaOH, and carrying out ultrasonic treatment for 10min to obtain a white suspension with the concentration of 5 mg/ml. And then the animals are orally irrigated to dogs with 6 samples. Plasma samples were taken and tested before and after 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, respectively.

Experiment 2

After grinding the sample of the compound 1, adding the ground sample into a 0.9% NaCl injection, stirring for 5min, and carrying out ultrasonic treatment for 20min to obtain a white suspension with the concentration of 5 mg/ml. And then the animals are orally irrigated to dogs with 3 samples. Plasma samples were taken and tested before and after 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, respectively.

Table 5 canine drug substitution result comparison

As can be seen from table 5, the bioavailability of the sample of compound 1 in dogs was significantly improved and the individual differences were smaller after adding a certain amount of hydrochloric acid to the solution (pH was adjusted to be no greater than 3.0) in prescription a.

Example 2

The inventors studied the effect of citric acid on the bioavailability of compound 1 after the addition of citric acid to the tablets, taking citric acid as an example. In this experiment, three tablet formulations were designed: prescription A, prescription A ₁ And prescription C. Prescription A and prescription A ₁ Prescription C changes the proportion of filler, binder and disintegrating agent in the prescription while keeping the prescription proportion of the crude drug of compound 1 substantially unchanged. The formulation of the tablets is shown in table 6.

TABLE 6

Adopts prescription A and prescription A ₁ And a tablet prepared by the formula C, and the bioavailability of the compound 1 in mice was measured.

Taking prescription A and prescription A respectively ₁ Grinding with tablet sample of prescription C, adding physiological saline, vortexing, and ultrasound to prepare 1mg/ml suspension, and oral gavaging 6 animal samples. At the time of 5min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h after administration, blood plasma was taken for sample detection.

Prescription A and prescription A are adopted ₁ The data of blood concentration-time at the time of measurement (10 mg/kg mice) are shown in Table 7 below.

TABLE 7 blood concentration-time data (10 mg/kg mice)

The average blood concentration versus time for drug compound 1 is plotted according to table 7, with specific curves shown in fig. 2.

As can be seen from Table 7 and FIG. 2, prescription A and prescription A ₁ In mice, the blood concentration of the tablet samples of the two prescriptions is changed for 24 hours, and the blood concentration values of the tablet samples of the two prescriptions are on the same horizontal line in the same time period, so that the change of the auxiliary materials (including polysorbate 80) in the prescriptions can not influence the pharmacokinetics of the compound 1 in animals. That is, the removal of polysorbate 80 in the adjuvant does not affect the in vivo absorption of compound 1 itself.

It is believed that polysorbate 80 as a surfactant may promote absorption of compound 1 in vivo, but the data of this experiment (tables 6 and 7) demonstrate that polysorbate 80 does not affect in vivo absorption of compound 1, providing a basis for removing polysorbate 80 from formulation C and avoiding the use of polysorbate 80.

On the premise that the pharmacokinetics of the compound 1 in animals are not significantly affected by several auxiliary materials in the prescription, the pharmacokinetics of the tablets prepared according to the prescription A and the prescription C in dogs are compared, and the results are shown in Table 8.

Table 8 comparison of canine pharmacokinetic experiment results for prescription a versus prescription C

As can be seen from Table 8, at the same dosage, formula C (with citric acid added) was higher than formula A C _max The results show that the in vivo bioavailability of the bulk drug of the compound 1 is higher by adding citric acid into the preparation of the compound 1.

In addition, combining the data of tables 7 and 8, it can be demonstrated that the added adjuvant citric acid in the tablets is a key parameter affecting the bioavailability of compound 1 in animals. Therefore, the invention can effectively increase the solubility and bioavailability of the compound 1 in vivo by combining the compound 1 with acid, and is beneficial to improving the clinical application effect of the medicine. Based on the above disclosure, it can be inferred that when a pharmaceutically acceptable acid is used in a solid preparation such as a capsule, granule, pill or powder, it is also possible to produce an increase in the solubility and bioavailability of compound 1 in vivo.

Example 3

Table 9 composition of prescriptions C and D

The preparation process of prescription D is as follows:

pretreatment: micronizing the crude drug of the compound 1; the anhydrous citric acid is filtered by 40 meshes for standby.

Premixing: the crude drug of the compound 1, microcrystalline cellulose 101, lactose monohydrate and croscarmellose sodium are added and mixed progressively, and the mixture is sieved by a 40-mesh sieve for 3 times and mixed to obtain mixed powder.

Granulating: adding 10% hydroxypropyl cellulose water solution into the mixed powder, sieving with 20 mesh sieve, and granulating to obtain wet granule.

And (3) drying: and (5) placing the wet particles into a 60 ℃ oven, and drying until the moisture of the materials is less than 3.0%, thus obtaining dry particles.

Finishing: sieving the dry granules with a 20-mesh sieve, and finishing the granules.

Total mixing: and (3) progressively mixing the dry particles with silicon dioxide, and then adding sodium carboxymethyl starch, microcrystalline cellulose 102, anhydrous citric acid and magnesium stearate, and uniformly mixing.

Tabletting: 11mm round dimple stamped sheet.

The stability of the tablets obtained from prescription C and prescription D was tested and the test results are shown in tables 10 and 11, respectively.

Table 10 stability of formulation C (direct blend granulation of drug substance of compound 1 with citric acid)

Table 11 stability of formula D (additional silica, citric acid after granulation of Compound 1 drug substance)

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As can be seen from tables 10 and 11, in the tablets in which the drug substance was coated with silica after granulating the drug substance of compound 1 to isolate the drug substance from the acid, the impurity condition was significantly better than that of the prescription C in which no silica was added. The main reason is that silicon dioxide is adsorbed on the surface of the prepared bulk drug particles to form a coating layer, so that the bulk drug is isolated from acid. From experimental data, it can be judged that the stability is poor when the bulk drug of the compound 1 is in direct contact with acid, and the bulk drug is isolated from the acid by coating the outer surface of the bulk drug particles, so that the solubility of the compound 1 can be improved, and the stability of the drug in the storage and transportation processes can be improved.

Claims

1. An antitumor pharmaceutical composition comprising a compound represented by formula 1 and a pharmaceutically acceptable acid selected from citric acid, the pharmaceutically acceptable acid being capable of providing a saturated solubility of the compound represented by formula 1 in water having a pH of 3.0 or less of 0.5mg/ml or more, the pharmaceutical composition further comprising a coating layer coating the surface of the compound represented by formula 1, the coating layer being for isolating the compound represented by formula 1 from the pharmaceutically acceptable acid;

formula 1.

2. The pharmaceutical composition according to claim 1, wherein the material of the coating layer is selected from one or more of silica, titanium dioxide, hypromellose, hydroxypropyl cellulose, talc, polyethylene glycol, polyvinyl alcohol.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable acid is capable of providing the compound of formula 1 with a saturated solubility of 1.0mg/ml or more in water at a pH of 3.0 or less.

4. The pharmaceutical composition according to claim 1, wherein the ratio of the compound of formula 1 to the pharmaceutically acceptable acid is 1:2 to 1:6 by weight.

5. The pharmaceutical composition of claim 1, wherein the ratio of the compound of formula 1 to the pharmaceutically acceptable acid is 1:4 by weight.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient;

the auxiliary materials are selected from one or more of microcrystalline cellulose, lactose, crosslinked povidone, hydroxypropyl cellulose, magnesium stearate, povidone, crosslinked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is a tablet, capsule, granule, pill or powder.

8. A method for improving the solubility of a compound represented by formula 1 in water, which is characterized in that the method comprises adding a pharmaceutically acceptable acid to the compound represented by formula 1, wherein the pharmaceutically acceptable acid can enable the compound represented by formula 1 to have a saturated solubility of 0.5mg/ml or more in water with a pH of 3.0 or less;

1 (1)

The method further comprises the steps of: before adding the pharmaceutically acceptable acid, wet granulating the compound shown in the formula 1, adding a coating material, and mixing to coat the compound shown in the formula 1; wherein the coating material is selected from at least one of silicon dioxide, titanium dioxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, talcum powder, polyethylene glycol and polyvinyl alcohol, and the pharmaceutically acceptable acid is selected from citric acid.

9. The method of claim 8, wherein the compound of formula 1 is added to the pharmaceutically acceptable acid in a ratio of 1:2 to 1:6 by weight.

10. The method of claim 8, wherein the compound of formula 1 is added to the pharmaceutically acceptable acid in a ratio of 1:4 by weight.