CN106727363B - Pharmaceutical compositions of lyophilized forms of nucleoside phosphoramidate prodrugs - Google Patents
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Abstract
The present invention relates to a pharmaceutical composition of a nucleoside phosphoramidate prodrug in lyophilized form. The present invention relates to a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof and a β -cyclodextrin derivative, and a process for the preparation thereof. The pharmaceutical composition provided by the invention also comprises a pH regulator, when the weight ratio of the beta-cyclodextrin derivative to the compound I in the composition is 15-30:1, and the pH of the pharmaceutical composition in an aqueous solution is 4.0-8.0, the composition has good stability, the solubility is obviously improved, and the hemolytic activity is obviously reduced; the pharmaceutical composition provided by the invention is also significant in improving the safety of the compound I injection, and has great economic and social benefits.
Description
Technical Field
The present invention relates to a pharmaceutical composition of a nucleoside phosphoramidate prodrug in lyophilized form. More particularly, the present invention relates to pharmaceutical compositions comprising a nucleoside phosphoramidate prodrug, or a pharmaceutically acceptable salt thereof, and a beta-cyclodextrin derivative in lyophilized form.
Background
NUC-1031 is a gemcitabine prodrug, developed by NuCana BioMed, and currently in phase II of the clinic, for treating cancers such as advanced solid tumors, pancreatic cancer, breast cancer, and the like. The CAS of NUC-1031 is 840506-29-8, and has the structure shown in the following formula:
compound I is a single isomer of NUC-1031 chiral P having the structure:
WO2014076490A1 discloses the following method for preparing NUC-1031,
3' -Boc protected gemcitabine (100 mg) was reacted with 2mol equivalents of phenyl (benzyl-L-alanine) chlorophosphate (150 mg) with 0.5mol equivalent of tris (acetylacetonato) iron (III) (56 mg) as a catalyst, 1.5mol equivalent of DIPEA (55. mu.L) as a base, 10ml of THF as a reaction solvent, under nitrogen atmosphere at room temperature for 24 hours in 45% yield, wherein the isomer R wasp:Sp=3:1。
A document entitled Application of ProTide Technology to Gemcitabine A Successful Application to overview the Key Resistance Compounds Leads to a New Agent (NUC-1031) in Clinical Development (Journal of medical Chemistry, Volume 57, Issue 4, Pages 1531-1542) reports that the following compound 5f, using methylene chloride as solvent, is dehydroprotected in the presence of TFA and finally prepared NUC-1031 by silica gel column purification in a yield of 70% with isomer contents of 48% and 52%, respectively.
Through a large amount of research work, the inventor finds that the compound I has relatively stronger cytotoxic effect and IC (integrated circuit) on BxPC-3, MIA Paca-2 and OVCAR-3 tumor cells compared with NUC-103150The value is between about 0.01 nM and 0.05 nM; the inhibition effect of the compound on the proliferation activity of tumor cells in vitro is about 10 times of that of a compound with NUC-1031 chiral P in R configuration; the pharmacokinetic evaluation result shows that the concentration of an active metabolite dFdCTP of the compound I in the tumor tissue is obviously higher than that of a compound with NUC-1031 chiral P in R configuration.
Because the compound I and the salt thereof are generally unstable to light, heat, humidity, acid and the like, have poor water solubility and low oral bioavailability, no relevant research report exists at present on a method for providing the solubility of the compound I, increasing the drug stability, reducing toxic and side effects and improving the patient compliance by preparing a pharmaceutical composition of the compound I or the pharmaceutically acceptable salt thereof and beta-cyclodextrin or a derivative thereof. Therefore, the development of stable pharmaceutical compositions of the compound or the salt thereof which can meet the clinical medication needs is needed, and more choices are provided for clinical medication.
Natural Cyclodextrin Derivatives (CDs) are a general term for a series of cyclic oligosaccharides, and generally contain 6 to 12D-glucopyranose units, each of which is bonded to form a ring by an α - (1-4) glycosidic bond. These cyclic pyranose molecules form a lipophilic inner Cavity (Cavity) and a hydrophilic outer surface (T. Loftsson, M. Masson, The effects of water-soluble polymers on cyclic analogs and cyclic analogs of drugs, J. Drug Del. Sci. Technol. 14, 2004, pages 35-43). Its property of increasing water solubility can be explained by the kinetic inclusion mechanism of the lipophilic drug in its lumen, as well as by the drug-cyclodextrin polymer effect.
The cyclodextrin and the derivative thereof are low-toxicity, safe and effective drug solubilizers, have high water solubility, are stable to heat, are nontoxic to kidneys, and have no stimulation to muscles and mucous membranes, and the drug included by the cyclodextrin and the diffractometer thereof can improve the water solubility of the drug, improve the stability and bioavailability of the drug and reduce adverse reactions. Besides, cyclodextrin can solidify liquid medicine, change unpleasant odor of medicine, reduce volatilization loss of medicine, and store medicine-medicine, medicine-excipient or adjuvant interaction in preparation. The cyclodextrin derivatives currently under development have been hundreds in number.
Disclosure of Invention
In view of the above problems, the present invention provides a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof, which has good stability and good solubility after being prepared into an injection.
In particular, the invention provides a pharmaceutical composition comprising compound I as an active ingredient,
or a pharmaceutically acceptable salt thereof, and a beta-cyclodextrin derivative, wherein the weight ratio of the beta-cyclodextrin derivative to the compound I is 15-30: 1; in another embodiment, the weight ratio of the beta-cyclodextrin derivative to the compound I in the pharmaceutical composition is preferably 20-25: 1; more preferably, in the pharmaceutical composition, the weight ratio of the beta-cyclodextrin derivative to compound I is 20: 1;
in the above pharmaceutical composition, preferably, the β -cyclodextrin derivative is hydroxypropyl- β -cyclodextrin (HP- β -CD), hydroxybutenyl- β -cyclodextrin (HBen- β -CD), or sulfobutyl ether- β -cyclodextrin (SEB- β -CD).
Particularly suitable β -cyclodextrin derivatives include sulfobutyl ether (SBE) cyclodextrins such as SBE-1- β -cyclodextrin, SBE-4- β -cyclodextrin and SBE-7- β -cyclodextrin, wherein the 1, 4 and 7 designations denote the average degree of substitution/modification of the cyclodextrin (available from CyDex inc., KS USA, of Overland Park). Captisol (trade name sulfobutyl ether- β -cyclodextrin), sold by CyDex pharmaceuticals, inc., Lenexa, KS, CAS: 182410-00-0, name: sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) sodium salt.
The term "degree of substitution/modification" as it relates to a cyclodextrin derivative as used herein refers to the total number of OR groups per cyclodextrin molecule. It will be appreciated that commercially available cyclodextrin derivatives actually contain individual cyclodextrin molecules having different degrees of substitution/modification. For example, hydroxypropyl β -cyclodextrin having an average degree of substitution of 3 still contains non-derivatized β -cyclodextrin in an amount of about 5%, while hydroxypropyl β -cyclodextrin having an average degree of substitution of about 5 contains non-derivatized β -cyclodextrin in an amount of less than about 1%. The term "average degree of substitution/modification" thus relates to the average statistical distribution of the individual substituted/modified cyclodextrin molecules of a given cyclodextrin derivative.
Further, the pharmaceutical composition further comprises a pH adjusting agent, and specific pH adjusting agents include, but are not limited to, buffer solvents, acids, and bases. In some embodiments, the pharmaceutical combination has a pH in aqueous solution of about 4.0 to 8.0. In various embodiments, the pharmaceutical combination has a pH in aqueous solution of about 5.0 to 7.0. In some embodiments, the solution pH is about 6.5.
In another preferred embodiment of the present invention, the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof as an active ingredient, and sulfobutyl ether- β -cyclodextrin, wherein the weight ratio of sulfobutyl ether- β -cyclodextrin to compound I is 20: 1.
Furthermore, the pharmaceutical composition is a freeze-dried powder injection.
A preparation method of the pharmaceutical composition comprises the following steps:
adding the beta-cyclodextrin derivative into water for injection, stirring for dissolving, then adding the compound I or pharmaceutically acceptable salt thereof, stirring until the compound I or pharmaceutically acceptable salt thereof is completely dissolved, adjusting the pH value of the solution to 4.0-8.0 by using hydrochloric acid and/or sodium hydroxide, adding water for constant volume, filtering, filling and drying. Preferably the drying method is spray drying or freeze drying.
On the other hand, the invention also provides an injection which is prepared by dissolving the medicinal composition in isotonic sodium chloride, glucose solution or glucose sodium chloride injection.
In the pharmaceutical composition of the present invention, the β -cyclodextrin derivative corresponding to one part by weight of the compound I or a pharmaceutically acceptable salt thereof is at least sufficient. The solubilizing agent may also serve as a stabilizer, carrier or excipient. Therefore, the amount of the β -cyclodextrin derivative to be used does not have a specific upper limit, and may be determined in consideration of the weight or volume of the composition, etc., based on one unit dose of the compound. Preferably, the amount of the beta-cyclodextrin derivative of compound I or a pharmaceutically acceptable salt thereof is preferably 15 to 30 parts by weight, more preferably 20 to 25 parts by weight, and most preferably 20 parts by weight, based on one part by weight of the beta-cyclodextrin derivative.
The invention has the advantages that when the weight ratio of the prepared beta-cyclodextrin derivative to the compound I is 15-30:1, particularly 20-25: 1, the solubility of the compound I is increased; the stability is improved; through a great deal of experimental research, the inventor finds that the pH of the composition in water has a large influence on the stability and the solubility, and when the solubility in water is higher than 8.0 or lower than 4.0, the solubility and the stability of the pharmaceutical composition are remarkably reduced. The pharmaceutical composition provided by the invention can reduce the toxicity of the compound I to an expected target while maximally increasing the solubility of the compound I; and increases the stability of compound I.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be further illustrated by the following specific examples, which are intended to be illustrative only and not limiting.
Example 1: preparation of lyophilized formulation of compound I:
5000mg of Captisol (SBE-. beta. -CD) was dissolved in an appropriate amount of water for injection, 250mg of Compound I was added thereto and stirred until dissolved, and the pH of the solution was adjusted to 5.0 with hydrochloric acid or sodium hydroxide. The volume was adjusted to 12.5ml, stirred well, filtered through a 0.22 μm membrane, filled and the solution was lyophilized using a lyophilizer (model 2012 and 051B Lyo-0.5) using a conventional method to obtain a 250 mg/vial of the lyophilized composition.
Examples 2 to 14: preparation of lyophilized formulation of compound I:
the preparation method is similar to that of example 1, except that in the preparation process, the beta-cyclodextrin derivative is selected from hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxybutenyl-beta-cyclodextrin (HBen-beta-CD) and sulfobutyl ether-beta-cyclodextrin (SEB-beta-CD), and the weight-volume ratio of the beta-cyclodextrin derivative to the compound I is 15-30: 1. Thus, different formulations were formed, the formulations of each composition being as shown in table 1 below:
table 1:
example 15: photostability test drug content (%) change and appearance and hemolytic test:
the freeze-dried product is subjected to a light stability test according to the specification of the 2010 edition of Chinese pharmacopoeia, the compound I raw material medicine is used as a reference, the freeze-dried powder prepared in the examples 1 to 14 is used as a test group, and the results are shown in table 2.
Table 2 photostability test drug content (%) change and appearance:
as shown in the table above, the stability of the lyophilized powder prepared in examples 1 to 7 is significantly higher than that of the bulk drug, wherein the lyophilized powder prepared in examples 1 and 2 has the best stability, that is, when the weight ratio of SEB- β -CD to compound I is 20:1, and the pH of the lyophilized powder in an aqueous solution is 5.0 to 7.0, the stability of the prepared pharmaceutical composition is the best.
Taking a castor oil absolute ethyl alcohol solution of a compound I with the same concentration as a control, dissolving a freeze-dried powder injection (prepared by the method of example 1-7) of the compound I by using 1ml of sodium chloride (w/v) with the concentration of 0.9%, and performing systemic active anaphylactic reaction determination by using a guinea pig, wherein the determination results of a low-dose group are 1mg/kg and a high-dose group are 4mg/kg, the determination results of a freeze-dried powder injection test sample of the compound I are negative, and the determination results of the control are positive reactions; the hemolytic property of the erythrocyte suspension is measured, the lyophilized powder injection of the compound I has no erythrocyte hemolysis and erythrocyte coagulation phenomenon within 3 hours, and the contrast solution has obvious erythrocyte hemolysis phenomenon, so that the lyophilized powder injection of the compound I has obviously reduced toxicity and small toxicity compared with the contrast solution.
Example 16 stability study
The freeze-dried powder injection containing the compound I prepared by the methods of examples 1 to 7, 10, 12, 13 and 14 is used as a determination group; a pharmaceutical composition with polyethylene glycol or poloxamer as a carrier was used as a control group (prepared by substituting polyethylene glycol or poloxamer for the β -cyclodextrin derivative, similar to the method of example 1).
The drug stability detection method comprises the following steps: the same mass of the compound I pharmaceutical composition was taken, and the detection test was performed according to the drug stability detection method (chinese pharmacopoeia 2000 edition, appendix XLX C bulk drug and pharmaceutical formulation stability test guidelines), and 3 sets of data were measured for each example, and the total related substance content was determined by HPLC.
High temperature test
Placing the sample to be detected in a sealed clean container, standing at 60 ℃ for 10 days, sampling on 5 th and 30 th days, and detecting the total content of related substances. The test results are shown in Table 3.
Table 3: high temperature test results:
second, high humidity test
The sample opening to be detected is placed in a constant-humidity closed container, the container is placed for 10 days at 25 ℃ under the condition of 90% +/-5% relative humidity respectively, samples are taken on the 5 th day and the 10 th day to detect the total content of related substances, and the test results are shown in table 4.
TABLE 4 high humidity test results
As shown in the table above, when the cyclodextrin is SEB-beta-CD, the weight ratio of the SEB-beta-CD to the compound I is 15-30:1, particularly 20:1, and the pH value is 4.0-8.0, the pharmaceutical composition has better stability.
Three, long term test
Taking the freeze-dried powder injections prepared in the embodiments 1 to 7 and 12 to 14 as test samples, selecting three batches, placing the three batches at the temperature of 30 +/-2 ℃ and the relative humidity of 65 +/-5% for 12 months, sampling once every three months, and sampling and detecting the total amount of related substances in 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months respectively, wherein the test results show that the freeze-dried powder injection prepared by the method in the embodiment 1 is placed for 24 months, and the change of the total amount of the related substances is not more than 0.5% compared with 0 month; the freeze-dried powder injection prepared in the embodiment 2-7 is placed for 24 months, and compared with 0 month, the change of the total amount of related substances is not more than 0.15%; the freeze-dried powder injection prepared by the method in the embodiment 12-14 is placed for 6 months, the phenomenon of obviously related substance increase appears, and when the freeze-dried powder injection is placed for 24 months, the total amount of related substances is changed by more than 3.7% compared with 0 month.
Example 17 solubility test
The solubility of compound I in aqueous solutions of different Captisol concentrations was evaluated and it was found that the solubility of compound I varies with pH and Captisol concentration. However, the increase in solubility of compound I at each pH is non-linear with respect to Captisol and the concentration of compound I is greater than the linear increase at pH 4.0-8.0, especially at pH 5.0-7.0. At other pH values, however, the ratio of Captisol to dissolved Compound I decreases with increasing Captisol concentration.
However, if increasing the Captisol concentration has a more than linear effect on the solubility of compound I, the opposite effect is also expected, i.e. dilution of a Captisol solution containing compound I at or near the equilibrium solubility of compound I will result in precipitation of compound I. When the freeze-dried powder injection of the compound I is diluted by normal saline or 5 percent glucose injection or water for injection and then infused, the effect has important significance. Then, surprisingly, no precipitation was observed for at least 24 hours after dilution of the lyophilized powder injections containing compound I prepared in examples 1 to 7.
In the further improvement of the preparation, the influence of various cosolvents and nonionic surfactants on the solubility and stability of the compound I raw material drug and the freeze-dried powder injection containing the compound I prepared in the examples 1 to 7 is detected, hydrochloric acid or sodium hydroxide is used for conditioning the aqueous solution of the compound I raw material drug and the freeze-dried powder injection containing the compound I prepared in the examples 1 to 7 to the pH value of 5.0 to 7.0, then a proper amount of cosolvent is added, the solution is balanced for 3 days, then the content in a small bottle is subjected to centrifugal separation, and the compound I in the supernatant is measured.
The results of the experiments show that various co-solvents (e.g. 10% propylene glycol, 20% glycerol) and some surfactants (10% PEG, 0.1% v/v poloxamer F-68, tween 20 or tween 80) did not increase the solubility of compound I and that the co-solvents reduced the solubility.
The invention has better biocompatibility, compared with the injection solubilized by the organic solvent of the compound I and the surfactant, the invention has no anaphylactic reaction and obviously reduced hemolytic activity; the invention has good stability, which is also significant for improving the safety of the compound I injection, and has great economic and social benefits.
Claims (7)
1. A pharmaceutical composition characterized by comprising, as an active ingredient, compound I:
or pharmaceutically acceptable salt thereof, a pH regulator and a beta-cyclodextrin derivative, wherein the weight ratio of the beta-cyclodextrin derivative to the compound I is 15-30: 1; the beta-cyclodextrin derivative is one or a mixture of any more of hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxybutenyl-beta-cyclodextrin (HBen-beta-CD), sulfobutyl ether-beta-cyclodextrin (SEB-beta-CD);
wherein the composition has a pH of 4.0 to 8.0 in an aqueous solution.
2. The pharmaceutical composition of claim 1, wherein the β -cyclodextrin derivative is selected from sulfobutyl ether- β -cyclodextrin, and wherein the weight ratio of sulfobutyl ether- β -cyclodextrin to compound I is 20: 1.
3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH in aqueous solution of 5.0 to 7.0.
4. The pharmaceutical composition according to any one of claims 1 to 2, which is a lyophilized powder injection.
5. The composition according to any one of claims 1 to 2, wherein the composition is prepared by the steps of: adding the beta-cyclodextrin derivative into water for injection, stirring for dissolving, then adding the compound I or pharmaceutically acceptable salt thereof, stirring until the compound I or pharmaceutically acceptable salt thereof is completely dissolved, adjusting the pH value of the solution to 4.0-8.0 by using hydrochloric acid and/or sodium hydroxide, adding water for constant volume, filtering, filling and drying.
6. The method of claim 5, wherein the drying process is spray drying or freeze drying.
7. An injection comprising the pharmaceutical composition of any one of claims 1-2, wherein the injection is an aqueous injection, a glucose injection, a sodium chloride injection or a glucose sodium chloride injection of compound I or a pharmaceutically acceptable salt thereof.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579372A (en) * | 2012-03-15 | 2012-07-18 | 石药集团中奇制药技术（石家庄）有限公司 | Gemcitabine hydrochloride lyophilized composition and preparation method thereof |
| CN102949337A (en) * | 2012-11-05 | 2013-03-06 | 江苏豪森药业股份有限公司 | Gemcitabine hydrochloride injection and preparation method thereof |
| CN103356488A (en) * | 2012-04-05 | 2013-10-23 | 齐鲁制药(海南)有限公司 | Capecitabine granule and preparation method thereof |
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| US20120171184A1 (en) * | 2010-12-31 | 2012-07-05 | Lajos Szente | Cellular hydration compositions |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579372A (en) * | 2012-03-15 | 2012-07-18 | 石药集团中奇制药技术（石家庄）有限公司 | Gemcitabine hydrochloride lyophilized composition and preparation method thereof |
| CN103356488A (en) * | 2012-04-05 | 2013-10-23 | 齐鲁制药(海南)有限公司 | Capecitabine granule and preparation method thereof |
| CN102949337A (en) * | 2012-11-05 | 2013-03-06 | 江苏豪森药业股份有限公司 | Gemcitabine hydrochloride injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development;Magdalena Slusarczyk,et al;《Journal of Medicinal Chemistry》;20140128;第1531-1542页 * |
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