CN105267179B - Stable solid pharmaceutical composition comprising a water-soluble vinorelbine salt and process for preparing same - Google Patents
Stable solid pharmaceutical composition comprising a water-soluble vinorelbine salt and process for preparing same Download PDFInfo
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Abstract
The invention provides a stable solid pharmaceutical composition containing a water-soluble vinorelbine salt and a preparation method thereof, wherein the pharmaceutical composition comprises the following components: (1) the drug-carrying pellet comprises a drug-carrying pellet containing vinorelbine or pharmaceutically acceptable salt or hydrate thereof, an adhesive and an inert core, a hard capsule and a film coating layer coated on the surface of the hard capsule, wherein the drug-carrying pellet is loaded in the hard capsule, and the film coating layer is formed by a specific high polymer material. The solid pharmaceutical composition has the advantages of good stability, low production cost and the like.
Description
Technical Field
The invention relates to a solid pharmaceutical composition containing vinorelbine or a salt thereof and a preparation method thereof.
Background
Cancer is a common disease that seriously threatens human health, and the mortality rate of human caused by cancer is the second of all disease mortality rates, and is second only to cardiovascular and cerebrovascular diseases. Cancer treatment methods include surgery, radiotherapy and chemotherapy (pharmacotherapy). Currently, chemotherapy remains the primary means of clinical treatment for cancer.
Anticancer chemotherapy was initially developed intravenously, with arguments supporting this route of administration being lower gastrointestinal toxicity, higher overall bioavailability, and potentially lower intra-and inter-patient exposure variability than the oral route. However, the intravenous route suffers from a number of serious drawbacks, such as: the incidence of venous access, possible complications of central venous access (infection, thrombosis), the risk of extravasation.
Over the years, oral dosage forms for anticancer chemotherapy have been developed with the real benefit to the patient. Further, pharmaceutical economics considerations are becoming increasingly important in selecting treatment strategies, which also led to the development of oral therapies.
Vinorelbine or 3 ', 4' -didehydro-4 '-deoxy-8' -norvinblastine, particularly its ditartrate, are derivatives of vinca alkaloids which inhibit cell growth by preventing the polymerization of tubulin. Vinorelbine, and in particular its salt, vinorelbine ditartrate, has efficacy in the treatment of non-small cell lung and breast cancer. Unfortunately, this salt is very unstable in the solid state.
Oral dosage forms of vinorelbine solutions were developed and marketed under the trade name Navelbine (WO 03/101383). It is a soft gelatin capsule containing vinorelbine ditartrate in dissolved form and a mixture of excipients comprising polyethylene glycol, glycerol, ethanol and water.
CN1638745A discloses an oral pharmaceutical composition containing vinorelbine tartrate for soft capsules, which comprises vinorelbine tartrate, ethanol, water, glycerol and polyethylene glycol. CN101134026 discloses a vinorelbine soft capsule with improved prescription, which contains vinorelbine or vinorelbine tartrate, ethanol and polyethylene glycol, and is free of water and glycerin. The soft capsule solves the problem of phlebitis existing in intravenous administration of vinorelbine, simplifies the prescription of the soft capsule filling composition, is beneficial to industrial manufacture, improves the stability of the preparation, and reduces adverse effects of auxiliary materials on patients.
However, the development of liquid-filled soft capsules has proven difficult. On the one hand, the liquid composition needs to take into account the material of the capsule and avoid the decomposition phenomena of the latter after it has been encapsulated. It should also avoid adverse chemical interactions between the excipients and the active ingredient. Finally, the biological activity of the active ingredients should not be seriously compromised.
CN101087591A discloses a stable solid dispersion of a water-soluble derivative of vinca alkaloid in at least one polyethylene glycol having a molecular weight of 800 to 30000. The preparation of dispersions of water-soluble derivatives of vinca alkaloids, in particular vinorelbine, more in particular vinorelbine ditartrate, usually starts with mixing the active ingredient with polyethylene glycol in the molten state. For this purpose, the polyethylene glycol will be preheated to a temperature slightly above its melting temperature, making it in a liquid state, so as to be miscible with the hydrosoluble derivative of vinca alkaloid under stirring. The process is terminated by an operation of cooling the dispersion to bring it into a solid state. If a high molar mass of polyethylene glycol is used, it is preferably heated in the presence of a plasticizer, which will bring the solid polyethylene glycol to a liquid state without exceeding temperatures of the order of 80 ℃.
CN101730534 discloses a pharmaceutical composition consisting of a water-soluble vinorelbine salt and at least one diluent and one lubricant, which is in a solid dosage form suitable for oral administration, preferably in a gelatin capsule or tablet dosage form. The dosage form is a solid dosage form consisting of conventional excipients (diluents, binders, flow agents, disintegrants, lubricants) for tableting or for gelatin capsules.
Although the above solid dosage forms may solve the problems of the commercially available soft capsule dosage forms, there still remain problems of dust contamination, cross-contamination, etc. during the process of the solid preparation, and thus there is a need to provide a solid dosage form which reduces the contamination problem and also reduces the production cost, while also having good storage stability.
Disclosure of Invention
In order to achieve the objects of improving stability, reducing contamination problems during the process and reducing production costs, the present invention provides, in one aspect, a stable solid pharmaceutical composition comprising a water-soluble vinorelbine salt, comprising: (1) the drug-carrying pellet comprises a drug-carrying pellet containing vinorelbine or pharmaceutically acceptable salt or hydrate thereof, an adhesive and an inert core, a hard capsule and a film coating layer coated on the surface of the hard capsule, wherein the drug-carrying pellet is loaded in the hard capsule, and the film coating layer is formed by a specific high polymer material.
In a preferred embodiment, the pharmaceutically acceptable salt of vinorelbine is vinorelbine tartrate or vinorelbine ditartrate.
In a preferred embodiment, the binder is a cellulose derivative, preferably hydroxypropylmethylcellulose.
In a preferred embodiment, the inert core is a pellet made from microcrystalline cellulose or sucrose, preferably having a particle size of from 100 μm to 1200 μm.
In a preferred embodiment, the drug-loaded pellets further comprise a plasticizer, preferably polyethylene glycol.
In a preferred embodiment, the capsule is a hard gelatin capsule or an HPMC plant capsule.
In a preferred embodiment, the specific polymeric material is HPMC, ethylcellulose, polyvinyl alcohol, opadry or ewing.
In another aspect, the present invention also provides a method for preparing the stable solid pharmaceutical composition containing the water-soluble vinorelbine salt, which comprises the following steps:
(1) providing an inert core;
(2) preparing a drug solution containing an active ingredient vinorelbine or a pharmaceutically acceptable salt thereof and an adhesive by using a proper solvent, and uniformly coating the prepared drug solution on the inert core provided in the step (1) by using a fluidized bed bottom spraying process to obtain a drug-loaded pellet;
(3) providing a hard gelatin or HPMC plant capsule;
(4) filling the drug-loaded pellets obtained in the step (2) into the hard gelatin capsule or HPMC plant capsule provided in the step (3) to obtain a hard capsule loaded with the drug-loaded pellets;
(5) preparing a coating solution containing a specific high polymer material, uniformly coating the coating solution on the hard capsule obtained in the step (4) by a high-efficiency coating pot coating process, and forming a film coating layer on the surface of the hard capsule.
In a preferred embodiment, the solvent of the active ingredient and the adhesive is water, ethanol or ethanol water solution. In a more preferred embodiment, the solvent for the active ingredient is water and the solvent for the binder is an aqueous ethanol solution.
The invention also provides application of the solid pharmaceutical composition in preparing antitumor drugs.
The solid pharmaceutical composition has good stability and lower production cost. Has good long-term storage stability under storage conditions without refrigeration and has the same bioavailability as the drug in the "soft capsule" dosage form on the market. Compared with the soft capsule preparation based on PEG and glycerin as main matrixes, the solid pharmaceutical composition provided by the invention has the advantages that the stability is greatly improved, and the defects of poor stability, aging of a capsule shell, reduction of dissolution rate, large variation of bioavailability and the like of the soft capsule preparation in the storage process can be avoided. In addition, compared with an injection, the self-administration of the oral preparation is highlighted, and the compliance is better.
The invention adopts the conventional fluidized bed preparation process, and has high automation degree; expensive freeze drying process is not needed, and the production cost is relatively low; dust pollution and the like in the process of other solid preparations can be avoided, and cross pollution is avoided; is beneficial to labor protection.
Drawings
FIG. 1 is a process flow diagram for preparing a solid pharmaceutical composition of the present invention;
FIG. 2 is a graph of mean plasma concentration versus time for a beagle oral test formulation (example 1A, example 2B) and a commercial soft capsule reference formulation (R).
Detailed Description
As used herein, the term "vinorelbine" encompasses vinorelbine or a pharmaceutically acceptable salt or hydrate thereof, for example vinorelbine tartrate, vinorelbine ditartrate, and in particular vinorelbine tartrate.
The drug-loaded pellet can be obtained by coating a drug solution containing vinorelbine or a pharmaceutically acceptable salt thereof, a solvent and an adhesive on an inert core through a fluidized bed bottom spraying process. The pharmaceutical solution may optionally be supplemented with other adjuvants, such as plasticizers, cosolvents, antiadherents. In a preferred embodiment, the solvent for the active ingredient is water and the solvent for the binder is aqueous ethanol.
The film coating layer outside the hard capsule in the solid pharmaceutical composition can be obtained by uniformly coating the coating liquid containing the specific high polymer material on the hard capsule through a high-efficiency coating pot coating process. The specific polymer material comprises HPMC, ethyl cellulose, polyvinyl alcohol, or common film coating pre-mixed powder such as Opadry, Ettch, etc.
Examples of solvents which can be used in the present invention include polar or non-polar solvents, preferably polar solvents such as water, ethanol, acetone or isopropanol or mixtures thereof, preferably water, ethanol or aqueous ethanol. According to one embodiment of the invention, the solvent of the drug solution is water and the solvent of the coating solution is an aqueous ethanol solution. The solvent is removed during the preparation process.
Binders useful in the present invention include any suitable binder for use in the preparation of a medicament, for example a cellulose derivative, such as hydroxypropylmethylcellulose, or povidone.
Examples of plasticizers useful in the present invention include polyethylene glycol, such as PEG200-400, or triethyl citrate.
Examples of cosolvents useful in the present invention include polyethylene glycol, poloxamers, hydroxypropyl β cyclodextrin, and the like.
Examples of antisticking agents useful in the present invention include talc, silica, and the like.
If necessary, the pharmaceutical composition of the present invention may further comprise stabilizers, lubricants, pH adjusters such as citric acid, succinic acid, tartaric acid, fumaric acid, aspartic acid and salts thereof, and the like.
The invention adopts a fluidized bed preparation process to prepare the solid preparation which has good stability and the same bioavailability as the soft capsule oral product on the market. The key process steps in the preparation process of the invention are that the vinorelbine or the solution of the pharmaceutically acceptable salt, the adhesive, the plasticizer and the solvent is uniformly deposited and coated on the inert pellets. After the gelatin capsule is filled, the surface of the capsule is uniformly coated with a layer of film, so that the content of the capsule can be prevented from being manually replaced or damaged, and the stability is improved.
The method of preparing the pharmaceutical composition of the present invention will now be described with reference to the process flow diagram of figure 1. An inert core, which may be a microparticle prepared from microcrystalline cellulose or sucrose as a starting material, is first prepared. In addition, the raw materials are weighed according to the prescription to prepare the vinorelbine drug solution. And then putting the inert core into a fluidized bed, and uniformly coating the vinorelbine drug solution on the inert core to obtain a drug-loaded pellet, wherein the step can be used for intermediate detection as required. Filling the drug-loaded pellets into prepared hard capsules, putting the capsules filled with the drug-loaded pellets into a coating pan, and uniformly coating the capsules with a pre-prepared coating solution to obtain the vinorelbine coated capsules.
In the method of the invention, the air inlet temperature in the pellet feeding step is about 40 ℃, preferably controlled between 35 ℃ and 45 ℃, and the key process parameters which can be implemented are shown in table 1. The air inlet temperature in the capsule coating step is below 40 ℃, preferably between 30 and 38 ℃, and the key process parameters which can be implemented are shown in table 2.
TABLE 1 Key Process parameters of the fluidized bed pellet Loading step
| Key process parameters | Range of |
| |
35～45℃ |
| Air inlet quantity | 600-800m3/h |
| Pressure of atomization | 0.22～0.30MPa |
TABLE 2 Key Process parameters for the Capsule coating step
| Key process parameters | Range of |
| Air intake temperature/. |
30～38 |
| Air intake/m of coating3/ |
25～30 |
| Atomization pressure/mbar | 1700～1800 |
| Sector pressure/mbar | 750～850 |
Abbreviations:
AUC(0-48)area under the curve of medicine (0-48)
AUC(0-∞)Area under the curve of the time of administration (0- ∞)
BLQ below the lower limit of quantitation
CLZ(CLZ/F) plasma clearance
Conc. concentration
Calc. calculation
CmaxPeak plasma drug concentration
Coefficient of variation of CV
F (%) bioavailability (%)
h (s)/hr(s) hours
IS internal standard
Kg of
L liter
LC-MS/MS liquid chromatography-mass spectrometry
Lower limit of LLOQ quantitation
MRM multiple reaction monitoring
MRT(0-t)Average residence time (0-t)
mg of
min for
mL of
NA is not applicable
ng nan Ke
PO for oral administration
QC quality control samples
Correlation coefficient of R
Relative deviation of% RE
T1/2ZHalf life in plasma
TmaxTime to peak plasma drug concentration
Microliter of μ L
Upper limit of ULOQ quantitation
VZ(VZ/F) apparent volume of distribution
HPMC hydroxypropyl methylcellulose
PEG polyethylene glycol
TPGS vitamin E polyethylene glycol succinate
To further illustrate the invention, a series of examples are given below. These examples are purely exemplary and are intended to illustrate the invention more specifically and not to limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and substitutions should be considered to be within the scope of the invention.
EXAMPLE 1 preparation of vinorelbine tartrate coated capsules A
The vinorelbine tartrate coated capsule a of the invention was prepared according to the process flow diagram of fig. 1.
TABLE 3 vinorelbine tartrate Capsule formulation A
Note: the water and ethanol in the prescription are removed during preparation
Description of the Process
a. Material pre-preparation: weighing hydroxypropyl methylcellulose according to the formula material number 3 of the formula in the table 3, dissolving the hydroxypropyl methylcellulose in the formula amount of purified water, wherein the preparation concentration is 3%, and swelling overnight for later use;
b. preparing materials: weighing vinorelbine tartrate according to a formula in a table 3 and placing the vinorelbine tartrate in a plastic bag; placing the microcrystalline cellulose core in another plastic bag; b, placing the hydroxypropyl methyl cellulose aqueous solution obtained in the step a into a stainless steel container; weighing polyethylene glycol-400 according to the prescription material number 4 and placing the polyethylene glycol-400 into a plastic bottle;
c. putting polyethylene glycol-400 and vinorelbine tartrate into a stainless steel container of hydroxypropyl methylcellulose aqueous solution, and stirring to dissolve the polyethylene glycol-400 and the vinorelbine tartrate;
d. putting the microcrystalline cellulose core into a fluidized bed, setting coating parameters, and uniformly coating the vinorelbine tartrate solution on the microcrystalline cellulose core;
e. detecting an intermediate;
f. and (3) filling capsules: calculating the weight of the particles to be filled according to the measured content of the main drug in the intermediate particles, and filling the particles into capsules to obtain vinorelbine tartrate capsules;
g. detecting an intermediate;
h. and (3) capsule coating:
1) material pre-preparation: weighing hydroxypropyl methylcellulose according to the formula material number 7 of the formula in the table 3, dissolving the hydroxypropyl methylcellulose into the formula amount of purified water and 95% ethanol (1:1), wherein the preparation concentration is 6%, and swelling overnight for later use;
2) preparing materials: placing the hydroxypropyl methyl cellulose aqueous solution obtained in the step 1) into a stainless steel container; weighing polyethylene glycol-400 according to the material number 8 of the prescription in the table 3 and placing the polyethylene glycol-400 in a plastic bottle;
3) adding polyethylene glycol-400 into hydroxypropyl methylcellulose aqueous solution under stirring, and mixing to obtain coating solution;
4) putting the vinorelbine tartrate capsule obtained in the step f into a coating pan, setting coating parameters, and uniformly coating the vinorelbine tartrate capsule with the coating solution obtained in the step h;
i. detecting an intermediate;
j. packaging;
k. and (5) detecting a finished product.
EXAMPLE 2 preparation of vinorelbine tartrate coated capsules B
TABLE 4 vinorelbine tartrate Capsule prescription B
Note: the water and ethanol in the prescription are removed during preparation
Description of the Process
Vinorelbine tartrate coated capsules B of the invention were prepared according to the process scheme of figure 1, analogously to example 1, following the recipe of table 4.
EXAMPLE 3 preparation of vinorelbine tartrate coated capsules C
TABLE 5 vinorelbine tartrate Capsule formulation C
Note: the water and ethanol in the prescription are removed during preparation
Description of the Process
Vinorelbine tartrate coated capsules C of the invention were prepared according to the process scheme of figure 1, analogously to example 1, following the recipe of table 5.
Example 4 comparison of the stability of uncoated capsules of vinorelbine tartrate according to the invention with a reference formulation
Samples of uncoated capsules R7-A, R10-A, R11-A (Table 6) and uncoated capsules R5, R12, R13, R14, R15 (Table 7) similar to the formulation of example 1 and similar to the formulation of example 2 were prepared.
TABLE 6 vinorelbine tartrate uncoated capsule formula
TABLE 7 vinorelbine tartrate uncoated capsule formula
Description of the Process
Vinorelbine tartrate uncoated capsules according to the invention were prepared analogously to a-g of example 1, according to the recipes of tables 6 and 7.
The uncoated capsule samples prepared above were subjected to stability examination under the standing condition of 40 ℃/75% RH, and sampled and tested at 0 day, 2 weeks, 4 weeks, 8 weeks, and 12 weeks, respectively, while the reference preparation (R drug: commercially available vinorelbine tartrate soft capsules,
) The sample is taken out and placed in a surface dish, and is placed in 40 ℃/75% RH with the self-made sample for parallel test, the stability of the self-made vinorelbine tartrate preparation is inspected, and the result is shown in table 8.
TABLE 8 stability test results of vinorelbine tartrate formulations (standing conditions: 40 ℃/75% RH)
The stability examination result shows that after the pellets are placed for 8 weeks, the total content of the reference preparation is 4.02%, and the R10-a added with vitamin C and TPGS during the pellet application is slightly poor in stability, while the total content of the R7-A, R11-a without vitamin C and TPGS is less than 2%, which is obviously better than that of the reference preparation.
The results show that the stability behaviour at 40 ℃/75% RH placement of the uncoated capsules based on the formulation similar to example 1R 7-A, R10-A, R11-a and of the uncoated capsules based on the formulation similar to example 2R 12, R13, R14, R15 is significantly better than that of the reference formulation.
Example 5 vinorelbine tartrate coated capsules of the invention stability test
The HPMC-coated hard capsules produced on the basis of the formulation process of example 1, containing vinorelbine tartrate about four times as much as the corresponding formulation R11-a of example 4, were subjected to stability studies, and the relevant material data for the conditions of 30 ℃/65% RH are shown in table 9.
TABLE 9 example 1 test results of related substances of self-made preparation stability test sample (standing condition: 30 ℃/65% RH)
The result shows that the total impurities of the vinorelbine tartrate capsule A prepared in the embodiment 1 of the invention are only 1.82% after 6 months under the standing condition of 30 ℃/65% RH, the stability is good, and the stability of the hard capsule can be improved after the hard capsule is coated.
Example 6 in vivo pharmacokinetic experiments on vinorelbine tartrate capsules in animals
(one) test drugs
Test formulation (drug a): vinorelbine tartrate capsules A prepared in example 1
Test formulation (drug B): vinorelbine tartrate capsules B prepared in example 2
Reference formulation (R drug): the vinorelbine tartrate soft capsule sold in the market,
(II) dosing regimens and blood sample Collection
The test uses a triple Latin square design with three cross and three cycles, with a 2 week washout period between each cycle. The study selected 12 healthy Beagle dogs, labeled, randomized into three groups of 4 dogs, and tested for relative bioavailability with a single dose (1 capsule containing 20mg vinorelbine). Before the experiment, the patient fasts for about 12 hours, drinks water freely, after the patient takes the medicine, the patient is forbidden to drink water within 2 hours, and fasts for 4 hours, and the patient takes a uniform meal during the period of the patient.
Administration was given in one group with the test formulation (drug a), one group with the test formulation (drug B), and one group with the reference formulation (drug R). Blank blood is taken before administration, the capsule is directly plugged into the pharyngeal portion by an experienced breeder when administration, the Beagle dog is automatically swallowed and is injected with 50mL of clear water for sending, 2mL of blood is taken from the subcutaneous vein on the inner side of forelimb after administration for 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48h, the blood is placed in a 40 muL NaF (200mmol/L) anticoagulation microtube containing 1.0mg of EDTA-K2, the blood sample is always placed on wet ice before centrifugal separation of the plasma, all blood samples are centrifuged for 3min at 13000rpm after collection, and the separated plasma sample is stored at-20 ℃ until LC-MS/MS detection and analysis are carried out. The samples were strictly protected from light throughout the sample handling process. After 2 weeks of wash-out period, the drug was administered alternately, and blood was collected in the same manner.
(III) method for measuring blood concentration and evaluation thereof
1. The instrument comprises the following steps:
API-3000 mass spectrometry detectors (Applied Biosystems, USA) and Analyst chromatography workstations (version 1.4.1, Applied Biosystems, USA), Agilent corporation model 1100 high performance liquid chromatography, including a G1312A quaternary pump, a G1316A column oven, a G1379A online degasser and a CTC HTS type temperature controlled autosampler (CTCAnalytics, Switzerland).
2. High performance liquid chromatography and mass spectrometry conditions:
chromatographic conditions are as follows: venusil XBP Phenyl column (100 mm. times.2.1 mm,5 μm) from Agela; mobile phase a (0.1% aqueous formic acid, 2mM ammonium acetate): b (0.1% formic acid in methanol) 30: 70; the flow rate is 0.35 mL/min; the column temperature is 40 ℃; the sample size was 5. mu.L.
Mass spectrum conditions: the ion source is an electrospray ionization (ESI) source; the detection mode is as follows: detecting positive ions; the scanning mode is as follows: multiple Reaction Monitoring (MRM); ejection voltage: 5500V; ion source temperature: 550 ℃; the air flow rate of the air curtain is 10L/min, and the atomization air flow rate is as follows: the ion conditions for quantification and characterization are shown in Table 10, with an airflow rate of 8L/min for collision at 4L/min and a scanning time of 0.2 s.
TABLE 10 Mass Spectrometry parameters
| Q1(m/z) | Q3(m/z) | CE(V) | DP(V) | EP(V) | CXP(V) | |
| Vinorelbine | 779.50 | 658.50 | 34 | 130 | 10 | 15 |
| Warfarin | 309.10 | 163.20 | 20 | 75 | 10 | 15 |
The results of the main pharmacokinetic parameters and bioavailability of the test preparation A, B and the reference preparation R of the present invention are summarized in tables 11 and 12.
TABLE 11 pharmacokinetic parameters and bioavailability of beagle oral test formulations (drug A) and reference formulations (drug R)
TABLE 12 pharmacokinetic parameters and bioavailability of beagle dogs after oral administration of test formulation (drug B) and reference formulation (drug R)
The pharmacokinetic parameters after oral administration of test formulation a to 12 dogs were: AUC0-48h185.6 + -76.6 ng/mL × h, AUC0-∞196.6 +/-81.4 ng/mL × h, CmaxIs 24.5 +/-11.6 ng/mL, TmaxIs 0.958 +/-0.424 h. The pharmacokinetic parameters after oral administration of test formulation B to 12 dogs were: AUC0-48h179.1 ± 73.3ng/mL × h, AUC0-∞195.9 + -92.3 ng/mL × h, Cmax 23.6 + -8.4 ng/mL, TmaxIs 1.000 plus or minus 0.337 h. The pharmacokinetic parameters after oral administration of reference formulation R for 12 dogs were: AUC0-48h187.3 + -90.5 ng/mL × h, AUC0-∞199.5 + -101.5 ng/mL × h, Cmax 25.2 + -9.4 ng/mL, TmaxIs 0.854 plus or minus 0.419 h.
The AUC of the test preparation (A medicine and B medicine) and the reference preparation (R medicine) are logarithmically converted and subjected to double single-side t test and confidence interval test, and the result shows that the AUC of the test preparation (A)0-48hThe 90% confidence limit of (D) falls within the range of 93.8% to 111.1% of the reference formulation (R drug), AUC0-∞A 90% confidence limit of (C) falls within the range of 93.5% to 112.8% of the reference formulation, CmaxThe 90% confidence limit of (A) falls within the range of 82.5% to 111.1% of the reference formulation, TmaxThere was no significant difference using the non-reference test, so the test formulation (drug A) was bioequivalent to the reference formulation (drug R). The mean relative bioavailability of the test formulation (drug a) was 103.6% ± 18.1% (n ═ 12, as AUC0-48hCalculation). The AUC of the test preparation (B medicine) and the reference preparation (R medicine) are subjected to logarithmic transformation and subjected to double-single-side t test and confidence interval test, and the result shows that the AUC of the test preparation (B medicine)0-48hThe 90% confidence limit of (D) falls within the range of 89.7% to 106.2% of the reference formulation (R drug), AUC0-∞A confidence limit of 90% falls within a range of 90.7% to 109.4% of the reference formulation, CmaxThe 90% confidence limit of (A) falls within the range of 80.9% to 109.0% of the reference formulation, TmaxThere is no significant difference by non-reference test, soThe test formulation (drug B) is bioequivalent to the reference formulation (drug R). The mean relative bioavailability of the test formulation (drug B) was 99.1% ± 17.9% (n ═ 12, as AUC0-48hCalculation).
From the above results, the test preparations (A medicine and B medicine) and the reference preparation (R medicine) have similar pharmacokinetic behaviors in vivo, and indicate that the preparation of the invention should have a curative effect equivalent to that of the reference preparation on the market clinically after being marketed in the future.
The vinorelbine tartrate coated hard capsule formulation is prepared by screening and optimizing the formulation and the prescription of the vinorelbine tartrate from the aspects of stability and animal PK, and the vinorelbine tartrate coated hard capsule formulation which is superior to a reference formulation in stability and is biologically equivalent to the reference formulation in a beagle dog is finally obtained. The coated hard capsule formulation of the invention improves the stability of the hard capsule and overcomes the defects of poor stability, aging of the capsule shell, reduced dissolution rate, large variation of bioavailability and the like of the soft capsule formulation in the storage process. In addition, the conventional fluidized bed preparation process is adopted, so that the automation degree is high; expensive freeze drying process is not needed, and the production cost is relatively low; dust pollution and the like in the process of other solid preparations can be avoided, and cross pollution is avoided; is beneficial to labor protection.
Claims (7)
1. A stable solid pharmaceutical composition comprising vinorelbine comprising: (1) the drug-loaded pellet comprises vinorelbine as an active ingredient or a pharmaceutically acceptable salt or hydrate thereof, an adhesive and an inert core, (2) a hard capsule and (3) a film coating layer coated on the surface of the hard capsule, wherein the drug-loaded pellet is loaded in the hard capsule, the film coating layer is formed by a specific high polymer material, and the specific high polymer material is selected from a group consisting of HPMC, polyvinyl alcohol, Opadry and Eudragit;
wherein the inert core is a pellet prepared from microcrystalline cellulose or sucrose as raw materials;
wherein the drug-loaded pellet further comprises a plasticizer which is PEG 200-400;
the solid pharmaceutical composition has good long-term storage stability under storage conditions that do not require refrigeration.
2. The solid pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of vinorelbine is vinorelbine tartrate or vinorelbine ditartrate.
3. The solid pharmaceutical composition of claim 1, wherein the binder is a cellulose derivative.
4. The solid pharmaceutical composition of claim 1, wherein the hard capsule is a hard gelatin capsule or an HPMC plant capsule.
5. A process for preparing the solid pharmaceutical composition of claim 1, comprising the steps of:
(1) providing an inert core;
(2) preparing a drug solution containing an active ingredient vinorelbine or a pharmaceutically acceptable salt thereof and an adhesive by using a proper solvent, and uniformly coating the prepared drug solution on the inert core provided in the step (1) by using a fluidized bed bottom spraying process to obtain a drug-loaded pellet; the set temperature in the fluidized bed bottom spraying process parameters is 35-45 ℃, and the air inlet quantity is 600-800m3H, the atomization pressure is 0.22-0.30 MPa;
(3) providing a hard gelatin or HPMC plant capsule;
(4) filling the drug-loaded pellets obtained in the step (2) into the hard gelatin capsule or HPMC plant capsule provided in the step (3) to obtain a hard capsule loaded with the drug-loaded pellets;
(5) preparing a coating solution containing a specific high polymer material, uniformly coating the coating solution on the hard capsule obtained in the step (4) by a high-efficiency coating pot coating process, and forming a film coating layer on the surface of the hard capsule; wherein the specific polymer material is selected from the group consisting of HPMC, polyvinyl alcohol, Opadry and Eudragit.
6. The method according to claim 5, wherein the solvent for the active ingredient and the binder is water, ethanol or an aqueous ethanol solution.
7. Use of the solid pharmaceutical composition of claim 1 for the preparation of an antitumor medicament.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005079384A2 (en) * | 2004-02-13 | 2005-09-01 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Expandable gastric retention device |
| CN101730534A (en) * | 2007-07-11 | 2010-06-09 | 皮埃尔法布雷医药公司 | Stable pharmaceutical composition of a water-soluble vinorelbine salt |
| CN102657615A (en) * | 2012-05-02 | 2012-09-12 | 上海智同医药科技有限公司 | Vincamine sustained-release pellet preparation and preparation method thereof |
| CN101087591B (en) * | 2004-12-30 | 2013-07-10 | 皮埃尔法博赫药品公司 | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005079384A2 (en) * | 2004-02-13 | 2005-09-01 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Expandable gastric retention device |
| CN101087591B (en) * | 2004-12-30 | 2013-07-10 | 皮埃尔法博赫药品公司 | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
| CN101730534A (en) * | 2007-07-11 | 2010-06-09 | 皮埃尔法布雷医药公司 | Stable pharmaceutical composition of a water-soluble vinorelbine salt |
| CN102657615A (en) * | 2012-05-02 | 2012-09-12 | 上海智同医药科技有限公司 | Vincamine sustained-release pellet preparation and preparation method thereof |
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