CN112843007A - Olapari tablet - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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Abstract
The invention provides an olaparide tablet, which adopts copovidone and povidone K17 in a certain weight ratio as matrix polymers, can increase the stability of the olaparide solid dispersion, reduce the hygroscopicity of the solid dispersion and the tablet formed by the solid dispersion, and avoid the obvious change of dissolution rate.
Description
Technical Field
The invention belongs to the field of preparations, and particularly relates to an olaparide tablet.
Background
Olaparide was developed by astrazen, sweden, and was approved for import and marketing in chinese tablets (100mg, 150mg) in 2018, under the trade name of liptropin, for use in maintenance therapy of platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in adult patients with platinum-containing chemotherapy to achieve complete or partial remission.
Solid dispersion refers to a system in which a drug is highly uniformly dispersed in a solid carrier in a molecular, amorphous or microcrystalline state. Since 1961 the solid dispersion is first used for improving the dissolution rate and oral bioavailability of a poorly soluble drug, a plurality of researchers extensively and deeply research the solid dispersion, and further prove that the preparation of the poorly soluble drug into the solid dispersion is one of the most application potential methods for improving the solubility and dissolution rate of the poorly soluble drug.
Olaparide is an insoluble BSC II medicament, and in order to increase the solubility and the dissolution rate, the olaparide is mostly prepared into amorphous solid dispersion in the prior art. Amorphous compounds are thermodynamically less stable than crystalline compounds, and the addition of polymers is often used to improve dissolution and stability. However, the prepared solid dispersion is easy to absorb water during preparation and storage, so that crystals are precipitated, and the dissolution rate and the bioavailability are greatly reduced.
Patent CN102238945A discloses an olaparide composition in which copovidone is selected as the matrix polymer, and the amount is 57.5% by weight of the total weight of the tablet. In CN106137998A, copovidone is a linear copolymer of N-Vinyl Pyrrolidone (VP) Vinyl Acetate (VA), and although widely used in formulations at present, clinical studies have shown that it causes gastric discomfort after oral administration.
Therefore, CN106137998A tends to completely replace the carrier of copovidone with other matrix polymers (e.g. povidone K12PF, povidone K17, soluplus, povidone K25), and the problem of hygroscopicity is obviously improved after the olaparide and the matrix polymers are prepared into a solid dispersion, and then the solid dispersion is further mixed with other pharmaceutical excipients for granulation, so as to obtain the olaparide pharmaceutical composition. However, an example 12 replacing part of the copovidone is also described in the patent, in which the matrix polymer is povidone K12/copovidone (API: copovidone: povidone K12 in a weight percentage ratio of 1:1.3:0.7) in an amount of 54.6% by weight of the total weight of the tablet. The hygroscopicity data in the patent are all from hygroscopicity research under aluminum plastic packaging, which requires a long time to find the difference between prescriptions, but according to the hygroscopicity experimental data in the specification shown in the table 17, the hygroscopicity data is 1.2-1.3% in 1 month-12 months at 25 ℃/RH 60% and 1.2-1.3% in 1 month-6 months at 40 ℃/RH 60%, and the hygroscopicity data is not obviously different from the hygroscopicity data in the patent.
The patent CN102238945A has studied the bioavailability of different carriers (see table 28 in the specification), and the bioavailability of different carriers in vivo is different, wherein the bioavailability of the solid dispersion taking povidone as the carrier is only 87% relative to the bioavailability of the copovidone solid dispersion, therefore, the complete replacement of copovidone by povidone has a great influence on the bioavailability in vivo.
Disclosure of Invention
The invention provides an olaparide tablet, which adopts copovidone and povidone K17 in a certain weight proportion as matrix polymers under the condition of not influencing the bioavailability as much as possible, can increase the stability of the olaparide solid dispersion, reduce the hygroscopicity of the solid dispersion and the tablet prepared from the solid dispersion, and avoid the obvious change of the dissolution rate.
The invention provides an olaparide tablet, which is prepared from a solid dispersion and an additional auxiliary material, wherein the solid dispersion contains olaparide and a matrix polymer, and is characterized in that the matrix polymer consists of copovidone and povidone K17, and the ratio of the olaparide: and (3) co-povidone: the weight percentage of the povidone K17 is 1 (2.0-1.5) to 0.3-0.8.
Furthermore, the added auxiliary materials mainly comprise a filling agent, a glidant and a lubricant, wherein the filling agent is selected from one or more of mannitol, lactose, starch and microcrystalline cellulose; the glidant is selected from one or more of talcum powder and colloidal silicon dioxide; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, polyethylene glycol and poloxamer. Further, the weight percentage of each component of the olaparide tablet is as follows based on the weight of the bare tablet:
further, the weight percentage of each component of the olaparide tablet is as follows based on the weight of the bare tablet:
further, the weight percentage of each component of the olaparide tablet is as follows based on the weight of the bare tablet:
further, the weight percentage of each component of the olaparide tablet is as follows based on the weight of the bare tablet:
| name of material | Percent by weight/%) |
| Olapari | 25.0 |
| Co-polyvidone | 50.0 |
| Povidone K17 | 7.5 |
| Mannitol | 14.67 |
| Colloidal silica | 1.83 |
| Hard sodium fumarate | 1.0 |
。
Optionally, the olaparide tablets according to the invention contain a coating layer. The coating layer is Opadry.
Further, the olaparide tablet is prepared by the following method: (1) preparing solid dispersion from olaparide and a matrix polymer, and crushing; (2) uniformly mixing the crushed solid dispersoid with an additional auxiliary material; (3) the mixture was tabletted. Optionally, step (3) is followed by step (4) of coating.
Drawings
FIG. 1: XRD pattern of comparative example 1 for 32 days in Table 1
FIG. 2: XRD pattern of comparative example 2 for 32 days in Table 1
FIG. 3: XRD pattern of comparative example 4 for 32 days in Table 1
FIG. 4: XRD pattern for 32 days of comparative example 4-1 in Table 1
FIG. 5: XRD patterns for 32 days of comparative examples 4-2 in Table 1
FIG. 6: XRD pattern of comparative example 5 for 32 days in Table 1
FIG. 7: XRD pattern for 32 days of comparative example 6-1 in Table 1
FIG. 8: XRD patterns for 45 days for examples 1-4 in Table 4
Detailed Description
The following examples are intended to illustrate the preparation of olaparide tablets according to the invention, but the invention is not limited to the following examples. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The dissolution method comprises the following steps: placing into 900ml phosphate dissolution medium with pH6.8 at 37 deg.C and 100rpm stirring speed by basket method, sampling at 15, 30, 45, 60, and 90min, and detecting with ultraviolet spectrophotometer.
An XRD measuring method comprises the following steps: taking a proper amount of the product, placing the product on a sample carrier, flattening the sample on the sample carrier, measuring by an X-ray diffraction method (0451 in the four-part general rule of 2020 edition of Chinese pharmacopoeia), taking Cu-Ka as a light source, setting the voltage and current of a light pipe to be 30kV and 10mA respectively, setting a fixed emission slit of an emitter, an air scattering prevention slit and a low-angle measurement slit for a detector to be 1mm, 1mm and 8mm respectively (or corresponding parameter requirements), scanning within the range of a diffraction angle (2 theta) of 3-40 degrees, and recording a diffraction pattern.
Comparative example 1: original prescription
The prescription is as follows (original prescription):
comparative example 2: (CN106137998A example 12)
The prescription information is as follows (wherein the weight percentage ratio of API: copovidone: povidone K12 is 1:1.3: 0.7):
comparative example 3: complete replacement of the copovidone in comparative example 1 by soluplus
Comparative example 4: replacement of all or part of the copovidone of comparative example 1 by povidone K12
Prescription information is as follows:
wherein the ratio of olaparide in comparative example 4-1 to comparative example 4-2: and (3) co-povidone: the weight ratio of the povidone K12 is 1 (0-1.8) to 2.3-0.5.
Comparative example 5: (CN106137998A example 6)
Comparative example 6: replacement of part of the copovidone in comparative example 1 by povidone K25
Prescription information is as follows:
wherein the ratio of olaparide in comparative example 6-1 to comparative example 6-2: and (3) co-povidone: the ratio of the povidone K25 is 1 (1.3-1.8) to 0.5-1.0.
Test experiment 1:
tablets were prepared using the above formulations of comparative examples 1-6 by the following preparation method:
(1) the materials for preparing the solid dispersion were weighed according to the recipe, prepared into a solid dispersion, and pulverized.
(2) Mixing the above solid dispersion with adjuvants (mannitol, colloidal silicon dioxide, and sodium stearyl fumarate).
(3) The mixture was tabletted.
The solid dispersion and the tablet prepared in the comparative examples 1 to 6 are packaged in a double-layer self-sealing bag, and are placed at 40 ℃/75% RH, and samples are taken at different times (0 day, 7 days, 14 days, 32 days and 45 days) to detect the moisture absorption weight gain and the dissolution rate of the sample. The moisture absorption weight increment experimental data of the solid dispersion and the preparation are respectively shown in the table 1 and the table 2, and the dissolution result is shown in the table 3. The XRD patterns of comparative example 1, comparative example 4-1, comparative example 4-2, comparative example 5 and comparative example 6-1 for 32 days in Table 1 are shown in FIGS. 1 to 7.
Table 1 moisture absorption weight gain and PXRD experimental data for solid dispersions
Table 2 moisture absorption weight gain experimental data of olapari tablets
Table 3 dissolution test data of olapari tablets
Table 3 the results of the experiments show that in API: on the premise that the matrix polymer is 1:2.3, in comparative example 3, the co-povidone is completely replaced by the soluplus as the matrix polymer, and the prepared tablet cannot be completely dissolved in 0 day, so that the stability study of the prescription is not performed any more.
Table 1 the experimental results show that when copovidone is completely used (comparative example 1) as matrix polymer, or completely or partially replaced with povidone K12 or povidone K25 (comparative example 2, comparative example 4-1, comparative example 4-2, comparative example 5, comparative example 6-1, comparative example 6-2), the solid dispersion absorbs moisture and increases by 9% to 11% when left for 14 days, but olaparide is still present in amorphous form; the solid dispersion increases hygroscopic weight by about 12-15% when left for 32 days and amorphous olaparide begins to convert to crystalline form, the presence of which will affect the solubility of the solid dispersion. When the time is prolonged to 45 days, the solid dispersion is increased in viscosity due to a serious moisture absorption phenomenon, and grinding and XRD inspection cannot be performed. However, according to the characteristics of the crystal form of olaparide and the detection data of 32 days of standing, the proportion of amorphous olaparide in the solid dispersion converted into the crystal form is further increased when the solid dispersion is placed for 45 days.
The data in table 2 show that the solid dispersion was further tableted and the tablet hygroscopic weight gain increased with longer standing time.
The dissolution data in table 3 show that the dissolution rate of each prescription tablet is not significantly changed after being placed for 7 days and 14 days, respectively; the dissolution rate of each prescription tablet is reduced when the tablet is placed for 32 days; after being placed for 45 days, the dissolution rate of each prescription tablet is obviously reduced. By combining the data in table 1, it can be inferred that during the placing process, amorphous olapari is converted into a crystalline form due to moisture absorption of the product, and the dissolution rate of the olapari solid dispersible tablet is greatly reduced. And with the time prolongation, the more the moisture absorption weight gain is, the more the precipitated crystals are, and the more obvious the dissolution is influenced.
In summary, the dissolution of the resulting tablets was incomplete with soluplus as the matrix polymer. By using the copovidone as a matrix polymer, or completely replacing or partially replacing the copovidone by the copovidone K12 or the povidone K25, although a product with qualified dissolution in 0 day can be obtained, the hygroscopicity of the olaparide solid dispersion and the tablets can not be well reduced, and the dissolution rate of the tablets is greatly reduced along with the prolonging of the placing time. .
Example 1: replacement of all or part of copovidone by povidone K17
Prescription information:
wherein the olaparide in examples 1-1 to 1-5: and (3) co-povidone: the weight ratio of the povidone K17 is 1 (0-2.0) to 2.3-0.3.
The preparation method comprises the following steps:
(1) weighing the materials for preparing solid dispersion according to the prescription, preparing solid dispersion from the olaparide, copovidone and/or povidone K17, and pulverizing.
(2) Mixing the above solid dispersion with other medicinal adjuvants (mannitol, colloidal silicon dioxide, and sodium stearyl fumarate).
(3) The mixture was tabletted.
The prepared solid dispersion and tablet are packaged in a double-layer self-sealing bag, placed at 40 ℃/75% RH, and sampled at different times (0 day, 7 days, 14 days, 32 days and 45 days) to detect the moisture absorption weight gain and the dissolution rate of the sample. The moisture absorption weight increment experimental data of the solid dispersion and the preparation are respectively shown in tables 4 and 5, and the dissolution result is shown in table 6. The XRD pattern for 45 days for examples 1-4 in Table 4 is shown in FIG. 8.
TABLE 4 moisture absorption weight gain and XRD test data for solid dispersions
TABLE 5 Olapari tablet moisture absorption weight gain test data
Table 6 dissolution test data of olapari tablets
According to the experimental data of table 6, at API: matrix polymer 1:2.3, when povidone K17 was used alone as the polymer matrix, or olapari: and (3) co-povidone: povidone K17 was not subjected to the subsequent stability test because about 80% of the tablets were dissolved out at 90min at 0 days and the dissolution was incomplete, as compared with the tablets prepared in comparative example-1 (using copovidone as the matrix polymer).
With the combination of copovidone and povidone K17 as the matrix polymer, when the ratio of povidone K17 to API (olaparide) is in the range of 0.3 to 0.8 (examples 1-3, 1-4, 1-5), although the moisture absorption weight gain of the solid dispersant is not significantly different when the solid dispersant is placed for 7 days compared with that of comparative example 1, the test data of the solid dispersant after being placed for 14 days, 32 days, and 45 days show that the moisture absorption weight gain of examples 1-3 to 1-5 is significantly reduced, and no crystal of olaparide is detected (see table 4). The moisture absorption gain of examples 1-3 to 1-5 was also significantly lower than that of comparative example 1 (see table 5) when the solid dispersion was further tableted. The data in table 6 show that the tablets prepared in examples 1-3 to 1-5 were completely dissolved at 0 day, and when they were left for 45 days, the dissolution profile was consistent with that of 0 day, there was no significant change in dissolution rate, and the dissolution stability was significantly superior to that of comparative example 1.
Therefore, with olapari: and (3) co-povidone: when the weight ratio of the povidone K17 is within the range of 1 (2.0-1.5) to 0.3-0.8, the prepared solid dispersion is more stable, the hygroscopicity is lower, and the dissolution rate is not obviously changed.
Claims (9)
1. An olaparide tablet, which is prepared from a solid dispersion and an external auxiliary material, wherein the solid dispersion contains olaparide and a matrix polymer, and is characterized in that the matrix polymer consists of copovidone and povidone K17, and the ratio of the olaparide: and (3) co-povidone: the weight percentage of the povidone K17 is 1 (2.0-1.5) to 0.3-0.8.
2. The olaparide tablet according to claim 1, wherein the additional excipients mainly comprise a filler, a glidant and a lubricant, wherein the filler is one or more selected from mannitol, lactose, starch and microcrystalline cellulose; the glidant is selected from one or more of talcum powder and colloidal silicon dioxide; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, polyethylene glycol and poloxamer.
3. The olaparide tablet of claim 2, wherein the weight percentages of the components, based on the weight of the die tablet, are as follows:
4. the olaparide tablet of claim 3, wherein the weight percentages of the components, based on the weight of the die tablet, are as follows:
5. the olaparide tablet of claim 3, wherein the weight percentages of the components, based on the weight of the die tablet, are as follows:
6. the olaparide tablet of claim 3, wherein the weight percentages of the components, based on the weight of the die tablet, are as follows:
7. olaparide tablets according to any of claims 1 to 6, optionally containing a coating layer.
8. The process for the preparation of olaparide tablets as claimed in any one of claims 1 to 6, comprising the following steps: (1) preparing solid dispersion from olaparide and a matrix polymer, and crushing; (2) uniformly mixing the crushed solid dispersoid with an additional auxiliary material; (3) the mixture was tabletted.
9. The method of claim 8, optionally comprising step (4) coating.
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| CN202110154649.9A CN112843007A (en) | 2021-02-04 | 2021-02-04 | Olapari tablet |
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| CN202110154649.9A CN112843007A (en) | 2021-02-04 | 2021-02-04 | Olapari tablet |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114931558A (en) * | 2022-05-31 | 2022-08-23 | 石药集团中奇制药技术（石家庄）有限公司 | Olapari pharmaceutical composition and preparation method thereof |
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| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| CN104434809A (en) * | 2014-12-10 | 2015-03-25 | 北京科莱博医药开发有限责任公司 | Olaparib solid dispersion preparation and preparation method thereof |
| CN106137998A (en) * | 2015-03-30 | 2016-11-23 | 江苏豪森药业集团有限公司 | Aura handkerchief Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN106692066A (en) * | 2016-12-30 | 2017-05-24 | 江苏开元医药化工有限公司 | Preparation method of olaparib solid dispersoid and product thereof |
| CN110840845A (en) * | 2018-11-16 | 2020-02-28 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing PARP inhibitor |
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2021
- 2021-02-04 CN CN202110154649.9A patent/CN112843007A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| CN104434809A (en) * | 2014-12-10 | 2015-03-25 | 北京科莱博医药开发有限责任公司 | Olaparib solid dispersion preparation and preparation method thereof |
| CN106137998A (en) * | 2015-03-30 | 2016-11-23 | 江苏豪森药业集团有限公司 | Aura handkerchief Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN106692066A (en) * | 2016-12-30 | 2017-05-24 | 江苏开元医药化工有限公司 | Preparation method of olaparib solid dispersoid and product thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114931558A (en) * | 2022-05-31 | 2022-08-23 | 石药集团中奇制药技术（石家庄）有限公司 | Olapari pharmaceutical composition and preparation method thereof |
| CN114931558B (en) * | 2022-05-31 | 2024-07-16 | 石药集团中奇制药技术（石家庄）有限公司 | Olaparib pharmaceutical composition and preparation method thereof |
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Application publication date: 20210528 |
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