CN108096251B - Gefitinib pharmaceutical composition and preparation method thereof - Google Patents
Gefitinib pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN108096251B CN108096251B CN201711181774.9A CN201711181774A CN108096251B CN 108096251 B CN108096251 B CN 108096251B CN 201711181774 A CN201711181774 A CN 201711181774A CN 108096251 B CN108096251 B CN 108096251B
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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Abstract
The invention relates to a gefitinib medicinal composition and a preparation method thereof. Specifically, the invention relates to a composition containing a pharmaceutical active ingredient and a hydrophilic copolymer, wherein the pharmaceutical active ingredient is gefitinib or a pharmaceutically acceptable salt or a solvate thereof, and the hydrophilic copolymer can inhibit the sedimentation phenomenon of the active ingredient in the pharmaceutical composition in vivo due to the change of pH value and improve the in vivo bioavailability of the pharmaceutical active agent.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a gefitinib pharmaceutical composition.
Background
Gefitinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor with the chemical name N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine and has the following structure:
gefitinib is currently marketed in the form of tablets for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has previously been treated with chemotherapy or is otherwise unsuited for chemotherapy, under the trade name iressa.
CN1326569C discloses a pharmaceutical composition containing gefitinib and water-soluble cellulose ether or ester thereof, wherein the water-soluble cellulose ether or ester thereof can prevent gefitinib precipitation, improve solubility of gefitinib in intestinal tract, and improve bioavailability.
CN103845335A discloses adding polyacrylic resin substance in gefitinib preparation to reduce gefitinib precipitation in medicine, and the preparation has good dissolution and stability.
However, the method can only slow down the precipitation of gefitinib under a neutral condition to a certain extent, the effect of improving the bioavailability of gefitinib cannot be achieved in clinical use, and the uniformity among product batches is not good, so that the effect of slowing down the precipitation of gefitinib is not realized.
Therefore, it is a challenge for drug researchers to provide a new pharmaceutical composition of gefitinib to reduce the rate of gefitinib precipitation out of solution due to inter-gastrointestinal pH changes, to prolong the retention time in solution, and to improve or improve its pharmacokinetics.
Disclosure of Invention
The present invention provides a pharmaceutical composition comprising the active ingredient gefitinib or a pharmaceutically acceptable salt or solvate thereof, and a hydrophilic copolymer, wherein the hydrophilic copolymer ensures that the active agent remains in solution for a longer period of time after entering the intestinal tract, prolongs the retention time in solution, and enhances or improves the pharmacokinetics and inter-patient variability of the bioavailability and/or plasma concentration of the active agent. Further, the hydrophilic copolymer of the present invention is at least one selected from the group consisting of a polyvinylpyrrolidone copolymer, an ethyl acrylate copolymer, and a polyvinyl alcohol copolymer, and is preferably a copolymer of polyvinylpyrrolidone.
In an embodiment, the content of the active ingredient of the present invention is 10 to 74%, which may be 10, 12, 15, 17, 20, 22, 25, 27, 30, 33, 35, 38, 40, 42, 45, 47, 50, 53, 55, 57, 60, 65, 67, 70, 72, 74%, preferably 30 to 60%, by weight of the pharmaceutical composition; in the specific experimental examples, the weight of the active ingredient according to the invention is 50mg and 250 mg.
Further, the polyvinylpyrrolidone copolymer of the present invention is a polyvinylpyrrolidone/vinyl acetate copolymer (also known as copovidone, such as copovidone sold under the tradenames Kollidon VA 64 and Plasdone S630). Preferably, the hydrophilic copolymer is used in an amount of 0.01% to 20%, preferably 0.1% to 15%, more preferably 0.1 to 10%, by weight of the pharmaceutical composition, and in specific embodiments, may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10%.
The pharmaceutical composition also contains pharmaceutic adjuvants, and the pharmaceutic adjuvants are known by people in the technical field and are selected from at least one of filling agent, disintegrating agent, adhesive, lubricant and wetting agent
The filler is water-soluble or water-swellable filler, and the water-swellable filler is a pharmaceutic adjuvant which swells after water is added. Water soluble fillers include, but are not limited to, dextrin, lactose, sucrose, mannitol, dibasic calcium phosphate. Water-swellable fillers include, but are not limited to, pregelatinized starch, gelatinized starch, microcrystalline (crystalline) cellulose, starch, hydroxypropylmethyl cellulose (HPMC-K100LV), calcium sulfate, dibasic calcium phosphate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), calcium carboxymethyl cellulose, croscarmellose sodium (croscarmellose sodium), soy lecithin, low-substituted hydroxypropyl cellulose, tragacanth powder, and bentonite. These water-soluble or water-swellable additives may be used alone or in combination of two or more types, preferably one or more selected from microcrystalline cellulose, pregelatinized starch, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, and in a preferred embodiment at least one selected from lactose or microcrystalline cellulose; preferably, the amount of the filler is 10 to 80% by weight, more preferably 25 to 50% by weight, of the pharmaceutical composition, and specific examples may be 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50% by weight of the pharmaceutical composition.
The numerical range of the dosage of the active ingredients or other types of pharmaceutical excipients calculated by the weight of the tablet core without the coating agent is shown in example 1.
The binder is selected from at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxyl cellulose, hydroxypropyl methylcellulose and alginate, preferably, the amount of the binder is 0.5-20% by weight of the pharmaceutical composition, and in specific embodiments, the amount of the binder is 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% by weight of the pharmaceutical composition.
The disintegrant is at least one selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, pregelatinized starch and alginic acid, preferably, the amount of the disintegrant is 0.5 to 20% by weight of the pharmaceutical composition, and specific examples of the disintegrant are 0.5, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20% by weight of the pharmaceutical composition.
The wetting agent used in the invention is selected from at least one of alcohols, polysorbates, polyoxyethylene fatty alcohols, polyoxyethylene castor oils, phospholipids, sulfates or poloxamers, and specifically can be selected from but not limited to one or more of ethanol, glycerol, fatty acids, span, tween 80, polyoxyethylene, aluminum hydroxide xerogel, sodium potassium tartrate, polyethylene glycol 6000 and polyethylene glycol 40 stearate; preferably, the amount of the wetting agent used in the present invention is 0.1 to 3% by weight of the pharmaceutical composition, and specific examples may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.3, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3% by weight of the pharmaceutical composition.
The lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talcum powder, carnauba wax, sodium stearyl fumarate and silicon dioxide; preferably, the lubricant of the present invention is used in an amount of 0.1 to 5% by weight of the pharmaceutical composition, and specific examples may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% by weight of the pharmaceutical composition.
The wetting agent of the present invention may be added directly to the pharmaceutical composition to provide a wetting effect, or may be mixed with other types of solvents (e.g., water) or wetting agents and then added to the pharmaceutical composition to provide a wetting effect.
The "copolymer" according to the present invention is a copolymer obtained by copolymerizing two or more kinds of polymers, and for example, a polyvinylpyrrolidone (povidone) copolymer means a copolymer obtained by copolymerizing povidone with any kind of polymer.
In an embodiment of the present invention, the pharmaceutical composition comprises:
a) gefitinib or a pharmaceutically acceptable salt thereof or a solvate thereof,
b)0.1 to 10% by weight of a hydrophilic copolymer, preferably copovidone,
c)25 to 50% by weight of a filler, preferably at least one of lactose and microcrystalline cellulose,
d) 0.5-20% by weight of a disintegrant, preferably at least one of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium,
e) 0.5-20% of binder, wherein the binder is preferably at least one of polyvinylpyrrolidone, starch and carboxymethyl cellulose,
f)0.1 to 3% by weight of a wetting agent, preferably sodium lauryl sulfate,
g) 0.1-5% by weight of a lubricant, preferably at least one of magnesium stearate, stearic acid and silicon dioxide.
Wherein, the content of the active ingredient is 10-74%, which can be 10, 12, 15, 17, 20, 22, 25, 27, 30, 33, 35, 38, 40, 42, 45, 47, 50, 53, 55, 57, 60, 65, 67, 70, 72, 74%, preferably 30-60%, based on the weight of the pharmaceutical composition.
Further, the pharmaceutical composition of the present invention further comprises a coating agent, and the coating agent (non-positioning release coating) used may be, but not limited to, hypromellose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropylcellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin or polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion, and the saccharide includes sugar alcohol sucrose, mannitol paste, or is commercially available as opadry II, preferably opadry II.
The present invention also provides a process for preparing a pharmaceutical composition according to the invention, which process comprises: 1) mixing gefitinib or a pharmaceutically acceptable salt or solvate thereof with a hydrophilic copolymer, a filler, a disintegrant and optionally at least one excipient selected from a binder, a lubricant and a wetting agent, 2) granulating the mixture obtained in 1) and tabletting or encapsulating, directly tabletting or directly encapsulating.
Further, the granulating step is followed by a coating step, and the coating agent is selected from Opadry II, ethyl cellulose or polyvinyl alcohol, preferably Opadry II.
The granulation mode adopted by the invention can be wet granulation and dry granulation, when a wet granulation scheme is selected, fluidized bed granulation or high-shear wet granulation can be adopted, and the hydrophilic copolymer can be added in any mode, including internal addition, external addition or separate internal and external addition. For example, the hydrophilic copolymer can be dissolved in water and added with the premixed other auxiliary materials to prepare the granules by a high-shear wet granulation process; or the hydrophilic copolymer can be directly premixed with other raw and auxiliary materials and then added with water for granulation, or the copolymer can be added in a powder form and then mixed after the granulation of other components is finished, so as to prepare tablets; or directly encapsulating after granulating.
In another embodiment, when the post-dry granulation tableting scheme is selected for the present invention, the hydrophilic copolymer may be added before or after dry granulation. For example, one or more copolymers may be roller compacted with pre-blended additional excipients; or the other raw auxiliary materials can be rolled and granulated together, and the selected hydrophilic auxiliary materials are added in a powder form and then mixed, so that the expected effect of the invention can be achieved.
When the scheme of directly tabletting powder is adopted, the hydrophilic copolymer is directly added and uniformly mixed with other raw and auxiliary materials, and then tabletting is carried out.
In the embodiment of the invention, the high-speed shearing granulation process comprises the following steps:
1) mixing gefitinib or medicinal salt or solvate thereof with filler and disintegrant,
2) adding solution containing binder and wetting agent or wetting agent into the mixture 1 to obtain soft material, wet granulating, drying, granulating,
3) adding a lubricant to the pellets in step 2 and mixing.
4) Compressing the mixture of step 3 into tablets.
In the embodiment of the invention, the fluidized bed granulation process is adopted and comprises the following steps:
1) mixing gefitinib or medicinal salt or solvate thereof with filler and disintegrant,
2) fluidizing the powder mixture in the step 1, spraying the solution containing the adhesive solution and the wetting agent to the powder mixing surface, drying, grading,
3) adding a lubricant to the pellets in step 2 and mixing.
4) Compressing the mixture of step 3 into tablets.
The pharmaceutical composition of the invention is a solid preparation, preferably a tablet, a granule, a powder (including a fine granule), or a capsule. The solid preparation can be obtained by a widely known preparation method, and can be prepared into capsules after granulation or directly packaged into granules. When the pharmaceutical composition of the present invention is a tablet, it can be prepared by compressing the granules obtained as described above. The pressure of the compression can be determined within a proper range, and the pressure is preferably 5-15 kN. Further, the tablet shape is not particularly limited, and is preferably a lenticular shape, a disc shape, a circular shape, an oval shape (e.g., a caplet), a teardrop shape or a polygonal shape (e.g., a triangle or a diamond shape). The tablets prepared may be coated by spraying a suspension/solution of the coating agent through a pan coater.
When the pharmaceutical composition of the present invention employs granules, the granules obtained as described above may be used directly or may be granulated into desired granules by an appropriate technique. Alternatively, the granules thus prepared may be coated with a coating agent by spraying a suspension/solution of the coating agent.
The hydrophilic copolymer is added to effectively improve the precipitation phenomenon of the gefitinib preparation in a physiological medium simulating the intestinal tract of a human body, and further improve the absorption state of the gefitinib preparation after entering the intestinal tract. The dissolution test is carried out under the condition of a medium simulating conversion of fasting gastrointestinal fluids, namely, a paddle method dissolution test with the rotating speed of 50rpm is carried out, the pharmaceutical composition is dissolved in a FaSSGF (medium simulating fasting gastric juice) solution with the pH value of 1.6 and 300mL for 15min, then a FaSSIF (medium simulating fasting intestinal fluid) solution is added to 900mL (the pH value is adjusted to 6.5), and the dissolution is continued, wherein in the dissolution test of 1h, preferably, the dissolution percentage (or referred to as cumulative release percentage) of gefitinib in the pharmaceutical composition keeps 70% or more, and in the dissolution test of 2h, the average dissolution percentage of gefitinib is 85% or more.
In the experimental example of the invention, under the medium condition simulating the conversion of the fasting gastrointestinal fluids, the cumulative release percentage (%) of gefitinib in the pharmaceutical composition is kept at 90% or higher for 30min, and can be greater than or equal to 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%; at 60min, 80% or more, preferably 88% or more, and may be 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more.
Further, the cumulative percent (%) release of gefitinib in the pharmaceutical composition of the present invention remains 85% or more at 120min, and may be greater than or equal to 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%; remains at 80% or higher at 180min, can be greater than or equal to 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%; at 240min, 78% or higher, and may be greater than or equal to 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%.
More preferably, it is maintained at 75% or higher at 300min, and may be greater than or equal to 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%.
The dissolution rate of the pharmaceutical composition of the invention is expressed in terms of the percentage dissolution or the cumulative release percentage of the active ingredient.
The HPLC detection conditions of the invention are as follows:
a chromatographic column: inertsil ODS-3, 3.0X 100mm, 3 μm; flow rate: 0.7 ml/min; sample introduction amount: 10 mu l of the mixture; column temperature: 45 ℃; detection wavelength: 247 nm; diluting liquid: 0.2% (v/v) trifluoroacetic acid-acetonitrile (60: 40); mobile phase: 0.02mol/L ammonium acetate solution (pH adjusted to 5.6 with dilute hydrochloric acid) -acetonitrile (67: 33).
Gefitinib or a pharmaceutically acceptable salt or solvate thereof and the like according to the present invention can be obtained according to the method described in US5770599 or commercially available. The hydrophilic copolymer pharmaceutical excipients used in the present invention are commercially available, such as copovidone S630 and the like, and other conventional pharmaceutical excipients are also commercially available.
Drawings
FIG. 1: the dissolution curves of the gefitinib tablets in example 1 and comparative example 1 in a medium simulating physiological conditions;
FIG. 2: the dissolution curves of the gefitinib tablet in example 1 and the commercially available gefitinib tablet in a medium simulating physiological conditions;
FIG. 3: example 3 inhibition of precipitation profile of gefitinib in medium mimicking physiological conditions.
Detailed Description
The present invention is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and do not limit the scope of the present invention.
Example 1
According to the proportion in the table 1, gefitinib, lactose, microcrystalline cellulose, croscarmellose sodium, copovidone S630 and sodium lauryl sulfate are granulated by purified water by adopting a high-speed shearing wet granulation process, then dried, dried and granulated, and the dry granules (the moisture content is less than 2 percent) are added with magnesium stearate with the prescription amount and mixed by adopting a rotary total mixer. The obtained total mixed granules were tableted and coated with opadry (polyvinyl alcohol as a main ingredient).
TABLE 1
The dissolution rate of the gefitinib tablet simulated physiological medium in example 1 is examined, and a dissolution test of paddle method with 50rpm is performed by adopting the second method of Chinese pharmacopoeia dissolution rate determination method. Samples were taken at 5, 10, 15, 20, 25, 30, 45, 60, 120, 180, 240, 300min, respectively, and dissolution was measured by HPLC.
The dissolution rate measurement data of the experimental examples a to D of example 1 are shown in table 2, and a dissolution curve is plotted as shown in fig. 1, in which the ordinate is the dissolution rate (%) of gefitinib and the abscissa is time (min). The results show that the experimental examples A to C of the invention can obviously slow down the precipitation rate of the active ingredient after the active ingredient enters neutral conditions from acidic conditions, the results are obviously superior to the experimental examples a and b in the comparative examples, and when the addition amount of the hydrophilic copolymer is only 0.2 percent (relative to the weight of the pharmaceutical composition), the good precipitation inhibition effect can be achieved, and meanwhile, the dissolution rate can still be kept above 80 percent in 300min (min). Experimental example D, which did not employ the present invention, precipitated rapidly after entering neutral conditions, and the active ingredient remained dissolved after 5 hours was less than 50%.
TABLE 2
Comparative example 1: reference is made to the embodiment of patent CN1326569C
Gefitinib, lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate are granulated by a high-speed shearing wet granulation process according to the proportion in table 3 with purified water, and then dried, dry granules (the moisture content is less than 2%) are subjected to dry granulation, magnesium stearate with the amount of the prescription is added, and a rotary total mixer is adopted for mixing. The resulting total blended granules were tableted and coated with a coating agent containing HPMC.
TABLE 3
The dissolution rate of the gefitinib tablet simulated physiological medium in comparative example 1 was examined, and the dissolution test was performed by the paddle method of the second method of the dissolution rate determination method of the Chinese pharmacopoeia, i.e., the paddle method with the rotation speed of 50 rpm. Samples were taken at 5, 10, 15, 20, 25, 30, 45, 60, 120, 180, 240, 300min, respectively, and dissolution was measured by HPLC.
Dissolution rate measurement data of experimental examples a and b of comparative example 1 and a dissolution curve were plotted as shown in fig. 1, with the dissolution rate (%) of gefitinib being plotted on the ordinate and time (min) being plotted on the abscissa. The results show that the active ingredients can play a certain role in inhibiting precipitation after entering neutral conditions from acidic conditions, but the precipitation rate of the active ingredients is obviously faster than that of experimental examples A-C adopting the invention, and the overall effect of inhibition by the formulas A-C adopting the invention is better than that of the preparation adopting HPMC as a precipitation inhibitor in comparative examples.
Example 2
According to the proportion in the table 4, gefitinib, lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate are granulated by high-speed shearing wet granulation process with purified water, then dried, dry granules (the water content is less than 2%) are subjected to dry granulation, copovidone S630 and magnesium stearate in the formula amount are added, a rotary total mixer is adopted for mixing, the obtained total mixed granules are tableted, and coating is carried out by Opadry II.
TABLE 4
The dissolution rate of the gefitinib tablet simulated physiological medium in example 2 is examined, and a paddle dissolution test with the rotating speed of 50rpm is performed by adopting the second method of the Chinese pharmacopoeia dissolution rate determination method, namely the paddle method. Samples were taken at 5, 10, 15, 20, 25, 30, 45, 60, 120, 180, 240, 300min, respectively, and dissolution was measured by HPLC.
The dissolution rate measurement data of the experimental examples E to G of example 2 are shown in table 5, and a dissolution curve is plotted as shown in fig. 2, in which the ordinate represents the dissolution rate (%) of gefitinib and the abscissa represents time (min). The results show that the experimental examples E and F can obviously slow down the precipitation rate of the active ingredient after the active ingredient enters the neutral condition from the acidic condition, the results have better effect of inhibiting the precipitation, and the dissolution rate can be kept above 80% at 300min (min), while the dissolution data of the experimental example G is poorer.
TABLE 5
Example 3
Gefitinib 250mg was mixed with the pharmaceutical excipients described in table 6, respectively, and dissolution rates of its simulated physiological media were examined. Adopting a second method paddle method of the Chinese pharmacopoeia dissolution rate determination method, namely carrying out a paddle method dissolution test with the rotating speed of 50 rpm. Samples were taken at 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 180, 240, 300min and dissolution was measured by HPLC to examine the sedimentation inhibitory effect of different pharmaceutical excipient components on gefitinib.
TABLE 6
The dissolution test data for experiments H to M of example 3 are shown in table 7, and the dissolution curves are plotted as shown in fig. 3, with the ordinate representing the percentage (%) of gefitinib maintained in a dissolved state and the abscissa representing time (min). The result shows that the copovidone S630 can remarkably slow down the precipitation rate of the active ingredient after the active ingredient enters neutral conditions from acidic conditions, the effect is remarkably superior to that of water-soluble cellulose hydroxypropyl methylcellulose and polyvinylpyrrolidone K30, and meanwhile, when the addition amount is only 0.5mg, the gefitinib can be kept in a dissolved state and not precipitated after 300 min.
TABLE 7
Claims (9)
1. A pharmaceutical composition characterized in that said pharmaceutical composition comprises:
a) gefitinib or medicinal salt thereof, wherein the content of the active ingredient is 30-60%,
b)0.1 to 10% by weight of a hydrophilic copolymer selected from polyvinylpyrrolidone/vinyl acetate copolymers,
c)25 to 50% by weight of a filler selected from at least one of lactose and microcrystalline cellulose,
d) 0.5-20% by weight of a disintegrant selected from at least one of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium,
e) 0.5-20% by weight of a binder selected from at least one of polyvinylpyrrolidone, starch, and carboxymethylcellulose,
f)0.1 to 3% by weight of a wetting agent which is sodium lauryl sulfate,
g) 0.1-5% by weight of a lubricant selected from at least one of magnesium stearate, silicon dioxide, stearic acid.
2. A process for preparing the pharmaceutical composition of claim 1, comprising: 1) mixing gefitinib or a pharmaceutically acceptable salt thereof with a hydrophilic copolymer, a filler, a disintegrant, a binder, a lubricant and a wetting agent, 2) granulating the mixture obtained in 1) and tabletting or encapsulating.
3. The method of claim 2, further comprising a coating step after said tableting step, said coating agent selected from the group consisting of opadry II, ethylcellulose, and polyvinyl alcohol.
4. The method of claim 2, further comprising a coating step after said compressing step, wherein said coating agent is Opadry II.
5. The pharmaceutical composition according to claim 1, wherein the percentage of gefitinib cumulative release in said pharmaceutical composition is greater than or equal to 75% at 300 minutes under medium conditions mimicking fasting gastrointestinal fluid turnover.
6. The pharmaceutical composition according to claim 1, wherein the percentage of gefitinib cumulative release in said pharmaceutical composition is greater than or equal to 78% at 300 minutes under medium conditions mimicking fasting gastrointestinal fluid turnover.
7. The pharmaceutical composition according to claim 1, characterized in that the cumulative release percentage of gefitinib in said pharmaceutical composition is greater than or equal to 85% at 120 minutes.
8. The pharmaceutical composition according to claim 1, characterized in that the cumulative release percentage of gefitinib in said pharmaceutical composition is greater than or equal to 90% at 30 minutes.
9. The pharmaceutical composition according to claim 1, characterized in that the cumulative release percentage of gefitinib in said pharmaceutical composition is greater than or equal to 92% at 30 minutes.
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|---|---|---|---|---|
| CN1638805A (en) * | 2002-02-26 | 2005-07-13 | 阿斯特拉曾尼卡有限公司 | Pharmaceutical formulation of IRESSA comprising a water-soluble cellulose derivative |
| CN102266300A (en) * | 2011-07-14 | 2011-12-07 | 广东药学院 | Gefitinib dispersible tablet and preparation method and application thereof |
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| JP6739289B2 (en) * | 2016-08-25 | 2020-08-12 | 日本化薬株式会社 | Process for producing pharmaceutical tablet containing gefitinib as active ingredient |
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- 2017-11-23 CN CN201711181774.9A patent/CN108096251B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1638805A (en) * | 2002-02-26 | 2005-07-13 | 阿斯特拉曾尼卡有限公司 | Pharmaceutical formulation of IRESSA comprising a water-soluble cellulose derivative |
| CN102266300A (en) * | 2011-07-14 | 2011-12-07 | 广东药学院 | Gefitinib dispersible tablet and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| Evaluating supersaturation in vitro and predicting its performance in vivo with Biphasic gastrointestinal Simulator: A case study of a BCS IIB drug;Yanxiong Gan等;《International Journal of Pharmaceutics》;20200118;第578卷;第119043页 * |
| Solution Behavior of PVP-VA and HPMC-AS-Based Amorphous Solid Dispersions and Their Bioavailability Implications;Feng Qian 等;《Pharm Res》;20120208;第29卷;第2766-2776页 * |
| 共聚维酮在药物制剂中应用的研究进展;姜文雅 等;《中国医药工业杂志》;20151231;第46卷(第8期);第898-903页 * |
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| CN108096251A (en) | 2018-06-01 |
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