Fulvestrant sustained-release tablet and preparation method and application thereof

Abstract

The present invention provides a fulvestrant sustained-release tablet and a preparation method and application thereof, and relates to the field of medical technology. The fulvestrant sustained-release tablet comprises components, by mass fraction: 2%-10% fulvestrant, 10%-25% sustained-release skeleton material, 60%-80% cosolvent, 0.1%-1% glidant and 0.1%-1% lubricant; the sustained-release skeleton material is hydroxypropyl methylcellulose, selected from at least one of HPMC K100M and HPMC K100LV; the cosolvent is cyclodextrin or its derivatives. The technical scheme of the present invention enables the fulvestrant oral sustained-release tablet to achieve stable sustained release in vivo and maintain an effective blood drug concentration, thereby inhibiting the growth and spread of tumors.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a fulvestrant sustained-release tablet and a preparation method and application thereof. Background Art

[0002] Fulvestrant is a drug used to treat hormone receptor-positive, advanced or metastatic breast cancer. Its mechanism of action is to bind to and degrade estrogen receptors, block the stimulation of estrogen on breast cancer cells, and inhibit the growth and spread of tumors. Fulvestrant is metabolized rapidly in the body and usually requires frequent administration to maintain efficacy. In order to reduce the frequency of administration, it is urgent to develop a sustained-release formulation of fulvestrant that can be released continuously.

[0003] Fulvestrant is traditionally administered in the form of an injection, but there are some limitations and inconveniences in the use of injections. Injectable preparations require the injection of drugs through a needle puncture of the skin, which causes pain and discomfort to patients. Injectable preparations usually require professional medical personnel to operate and need to be performed in a medical institution, which puts a burden on patients in terms of time and energy. Moreover, injectable preparations are prone to infection risks due to improper needle puncture operations; local reactions at the injection site such as pain, redness, swelling and nodules also increase the patient's discomfort and the incidence of adverse reactions.

[0004] Oral preparations can be designed into a variety of release forms, such as sustained-release tablets, controlled-release tablets, etc. Oral preparations can continuously release drugs over a specific period of time through sustained-release technology, maintain a stable blood drug concentration, and reduce the peak-to-valley fluctuations of drug blood concentration.

[0005] Chinese invention patent CN103221052A discloses a fulvestrant composition, which is an inclusion complex comprising fulvestrant and cyclodextrin, wherein the molar ratio of fulvestrant to cyclodextrin is 1:1-300; the cyclodextrin is a water-soluble substituted α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin; and the carrier of the complex is selected from at least one of microcrystalline cellulose, glucose, sodium lauryl sulfate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, talc, magnesium stearate, sodium benzoate, magnesium aluminum silicate, lactose, dyes, polymer-based film coatings, methanol, ethanol, acetone, and propanol.

[0006] Chinese invention patent CN114099518A discloses an oral Fulvestrant pharmaceutical composition and a preparation method thereof. The oral Fulvestrant pharmaceutical composition comprises, by mass percentage, 0.01%-30% of Fulvestrant, 1%-60% of an oil phase, 20%-90% of a surfactant, and 1%-80% of a co-surfactant; the oral Fulvestrant pharmaceutical composition further comprises a stabilizer; the stabilizer is selected from the group consisting of sodium lauryl sulfate, sodium lauryl sulfonate, D-alpha-tocopheryl succinate polyethylene glycol ester, Tween, castor oil, hydrogenated castor oil, polyethylene glycol-15 hydroxystearate, poloxamer, hydroxypropyl-β-cyclodextrin, polyvinyl alcohol, copovidone, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and sodium carboxymethyl cellulose, or a mixture of the foregoing.

[0007] At present, there are few studies on oral drugs of Fulvestrant, and there is no relevant research on Fulvestrant oral sustained-release preparations in the prior art. Therefore, it is urgent to develop a Fulvestrant oral sustained-release tablet to replace the existing injection, improve the patient's comfort and treatment compliance, and reduce the risk of infection and medical costs. The present invention achieves stable release of Fulvestrant oral sustained-release tablets in vivo and maintains effective blood drug concentration by rationally designing the sustained-release skeleton material, cosolvent, glidant and lubricant of the oral sustained-release tablet. Summary of the invention

[0008] The present invention aims at the problems existing in the prior art, provides a fulvestrant sustained-release tablet and a preparation method and application thereof, reasonably selects and matches the sustained-release skeleton material, cosolvent, glidant and lubricant of the oral sustained-release tablet, synergizes and enhances the effect, realizes the stable sustained-release of the fulvestrant oral sustained-release tablet in the body, maintains an effective blood drug concentration, and thus achieves the therapeutic effect of inhibiting the growth and spread of tumors. The present invention provides a safer, more effective and more convenient therapeutic drug for breast cancer patients.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] First, the present invention provides a fulvestrant sustained-release tablet, which comprises the following components by mass fraction: 2%-10% fulvestrant, 10%-25% sustained-release skeleton material, 60%-80% cosolvent, 0.1%-1% glidant and 0.1%-1% lubricant;

[0011] The sustained-release matrix material is hydroxypropyl methylcellulose (HPMC), selected from at least one of HPMC K100M and HPMC K100LV;

[0012] The cosolvent is cyclodextrin or its derivatives.

[0013] Preferably, the co-solvent is selected from at least one of methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin and sulfobutyl β-cyclodextrin.

[0014] Preferably, the glidant is selected from at least one of colloidal silicon dioxide and talc.

[0015] Preferably, the lubricant is selected from at least one of magnesium stearate, calcium stearate and hard sodium fumarate.

[0016] Preferably, the fulvestrant sustained-release tablet comprises the following components, calculated by mass fraction: 2.92%-7.73% fulvestrant, 14.5%-20% sustained-release matrix material, 71.45%-78% cosolvent, 0.2%-0.7% glidant and 0.2%-0.7% lubricant.

[0017] Further preferably, the fulvestrant sustained-release tablet comprises the following components, calculated by mass fraction: 7.15%-7.73% fulvestrant, 14.5%-20% sustained-release matrix material, 71.45%-77.27% co-solvent, 0.25%-0.7% glidant and 0.25%-0.7% lubricant.

[0018] More preferably, the fulvestrant sustained-release tablet comprises the following components, calculated by mass: 7.35% fulvestrant, 17.7% sustained-release matrix material, 73.57% cosolvent, 0.69% glidant and 0.69% lubricant.

[0019] Preferably, the fulvestrant sustained-release tablet further comprises a component: a pH regulator.

[0020] Further preferably, the pH adjuster is not limited to sodium hydroxide, hydrochloric acid or other pharmaceutically acceptable pH adjusters.

[0021] The present invention does not require the dosage and concentration of the pH regulator. The pH regulator is used to adjust the pH of the fulvestrant sustained-release tablet to 9-11; preferably, the pH regulator is used to adjust the pH of the fulvestrant sustained-release tablet to 10.

[0022] Then, the present invention provides a method for preparing the above-mentioned fulvestrant sustained-release tablets, comprising the steps of:

[0023] (1) Preparation of co-solvent solution: Use sodium hydroxide solution to prepare a co-solvent solution with a mass concentration of 10%-60%;

[0024] (2) mixing fulvestrant with the co-solvent solution of step (1), heating to dissolve, adjusting the pH to 9-11, and drying to obtain a fulvestrant inclusion complex;

[0025] (3) mixing the fulvestrant inclusion compound of step (2) with the sustained-release matrix material and the glidant, and then adding a lubricant and mixing them evenly;

[0026] (4) Tableting to obtain fulvestrant sustained-release tablets.

[0027] Preferably, in step (1), the concentration of the sodium hydroxide solution is 0.01 mol / L-1 mol / L; further preferably, the concentration of the sodium hydroxide solution is 0.1 mol / L.

[0028] Preferably, in step (1), the mass concentration of the co-solvent solution is 40%.

[0029] Preferably, in step (2), the temperature for heating and dissolving is 50°C-70°C; further preferably, in step (2), the temperature for heating and dissolving is 60°C.

[0030] Preferably, in step (2), the pH is adjusted using hydrochloric acid at a concentration of 0.1 mol / L-0.5 mol / L; further preferably, in step (2), the pH is adjusted using hydrochloric acid at a concentration of 0.2 mol / L.

[0031] Preferably, in step (2), the pH=10.

[0032] Preferably, in step (2), the drying is freeze-drying or spray-drying.

[0033] Preferably, in step (2), filtering is also included before drying, specifically filtering using a 0.45 μm filter membrane.

[0034] Preferably, in step (4), the tableting is performed by using a rotary tablet press, with a tableting pressure of 8KN-11KN and a tableting time of 1s-3s.

[0035] Further preferably, the tableting pressure is 9.4 kN and the tableting time is 2 s.

[0036] Finally, the present invention provides the use of the above-mentioned Fulvestrant sustained-release tablets in drugs for treating breast cancer.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] 1. The present invention uses HPMC K100M or HPMC K100LV as a sustained-release skeleton material, uses cyclodextrin or its derivatives as a cosolvent, and reasonably controls the content of each component. The prepared fulvestrant sustained-release tablet achieves stable sustained release in vivo, thereby achieving a therapeutic effect of inhibiting the growth and spread of tumors.

[0039] 2. The present invention prepares the Fulvestrant sustained-release tablets by controlling the concentration of the co-solvent solution and the mixing order and mixing temperature of each component. The prepared Fulvestrant sustained-release tablets show good sustained-release properties in an in vitro dissolution test, can continuously release the active ingredient Fulvestrant within 24 hours, and can maintain a relatively stable blood drug concentration after oral administration. DETAILED DESCRIPTION

[0040] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0041] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0042] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels.

[0043] In the following examples, the HPMC K100M and HPMC K100LV were purchased from Ashland; the methyl β-cyclodextrin and hydroxypropyl β-cyclodextrin were purchased from Zibo Qianhui; and the sulfobutyl β-cyclodextrin was purchased from Ruisheng Pharmaceutical. Products from different manufacturers have no significant effect on the effect.

[0044] Dissolution behavior testing

[0045] The dissolution behavior of the fulvestrant inclusion complex and fulvestrant sustained-release tablets prepared in the examples and comparative examples was tested.

[0046] The dissolution media are:

[0047] ① pH 1.2 + 1% CTAB (hexadecyltrimethylammonium bromide): Add 8.3 mL of hydrochloric acid to 1 L of degassed water and adjust the pH to 1.2. Then add 10 g of CTAB and stir thoroughly.

[0048] ②pH4.5+1%CTAB: Weigh 5.99g of anhydrous sodium dihydrogen phosphate into 1L of water, stir to dissolve, then add 10g of CTAB and stir to mix thoroughly.

[0049] ③pH6.8+1%CTAB: Weigh 5.99g of anhydrous sodium dihydrogen phosphate and 0.9g of sodium hydroxide into 1L of water, stir to dissolve, then add 10g of CTAB and stir to mix thoroughly.

[0050] The dissolution behavior detection method is shown in Table 1:

[0051] Table 1

[0052]

[0053] Example 1

[0054] The components of Fulvestrant sustained-release tablets are shown in Table 2 according to mass fraction:

[0055] Table 2

[0056]

[0057] The preparation method of Fulvestrant sustained-release tablets is as follows:

[0058] (1) Preparation of co-solvent solution: Use 0.1 mol / L sodium hydroxide solution to prepare a co-solvent solution (methyl β-cyclodextrin solution) with a mass concentration of 40%;

[0059] (2) mixing fulvestrant with the co-solvent solution of step (1), heating at 60° C. to dissolve, adjusting the pH to 10 with 0.2 mol / L hydrochloric acid, filtering with a 0.45 μm filter membrane, aliquoting the filtrate, and freeze-drying to obtain a fulvestrant inclusion complex (lyophilized powder);

[0060] (3) mixing the fulvestrant inclusion complex prepared in step (2) with the sustained-release matrix material (HPMC K100M) and the glidant (colloidal silicon dioxide) and then adding a lubricant (magnesium stearate) and mixing them evenly;

[0061] (4) The tablets were compressed into tablets using a rotary tablet press with a compression pressure of 9.4 kN and a compression time of 2 s to 3 s to obtain Fulvestrant sustained-release tablets.

[0062] The dissolution behavior of the fulvestrant inclusion complex (lyophilized powder) and fulvestrant sustained-release tablets prepared in this example were tested, and the test results are shown in Tables 3 and 4.

[0063] Table 3

[0064]

[0065] Table 4

[0066]

[0067] Example 2

[0068] The components of Fulvestrant sustained-release tablets are shown in Table 5 according to mass fraction:

[0069] Table 5

[0070]

[0071] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0072] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this example was tested. The test results are shown in Table 6.

[0073] Table 6

[0074]

[0075] Example 3

[0076] The components of Fulvestrant sustained-release tablets are shown in Table 7 according to mass fraction:

[0077] Table 7

[0078]

[0079] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0080] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this example was tested. The test results are shown in Table 8.

[0081] Table 8

[0082]

[0083] Example 4

[0084] The components of Fulvestrant sustained-release tablets are shown in Table 9 according to mass fraction:

[0085] Table 9

[0086]

[0087] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0088] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this example was tested. The test results are shown in Table 10.

[0089] Table 10

[0090]

[0091] Example 5

[0092] The components of Fulvestrant sustained-release tablets are shown in Table 11 according to mass fraction:

[0093] Table 11

[0094]

[0095] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0096] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this example was tested. The test results are shown in Table 12.

[0097] Table 12

[0098]

[0099] Example 6

[0100] The difference from Example 1 is that the mass concentration of the co-solvent solution prepared in step (1) is 60%.

[0101] The rest are the same as in Example 1.

[0102] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 13.

[0103] Table 13

[0104]

[0105] The fulvestrant sustained-release tablets prepared in this comparative example showed good sustained-release properties in an in vitro dissolution test.

[0106] Comparative Example 1

[0107] Fulvestrant sustained-release tablets, calculated by mass fraction, the components are shown in Table 14:

[0108] Table 14

[0109]

[0110] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0111] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 15.

[0112] Table 15

[0113]

[0114] The fulvestrant sustained-release tablets prepared in this comparative example dissolved more than 85% of the drug within 2 hours, and the sustained-release effect was not obvious.

[0115] Comparative Example 2

[0116] Fulvestrant sustained-release tablets, calculated by mass fraction, the components are shown in Table 16:

[0117] Table 16

[0118]

[0119] The preparation method of Fulvestrant sustained-release tablets is the same as that in Example 1.

[0120] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 17.

[0121] Table 17

[0122]

[0123] The Fulvestrant sustained-release tablets prepared in this comparative example dissolved about 80% of the drug within 2 hours, and the sustained-release effect was not obvious.

[0124] Comparative Example 3

[0125] Different from Example 1, the mass fractions of the components in the Fulvestrant sustained-release tablets are different, as shown in Table 18 for details.

[0126] Table 18

[0127]

[0128] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 19.

[0129] Table 19

[0130]

[0131] The fulvestrant sustained-release tablets prepared in this comparative example had a 24-hour dissolution rate of only 30%, indicating incomplete dissolution.

[0132] Comparative Example 4

[0133] Different from Example 1, the preparation method of fulvestrant sustained-release tablets is different, specifically:

[0134] (1) Preparation of co-solvent solution: Use 0.1 mol / L sodium hydroxide solution to prepare a co-solvent solution (methyl β-cyclodextrin solution) with a mass concentration of 40%;

[0135] (2) Fulvestrant was mixed with the cosolvent solution of step (1), and after heating at 60°C to dissolve, the pH was adjusted to 10 with 0.2 mol / L hydrochloric acid, and filtered with a 0.45 μm filter membrane, and mixed evenly with a sustained-release matrix material (HPMC K100M), dried in an oven at 40°C, crushed, and a glidant (colloidal silicon dioxide) and a lubricant (magnesium stearate) were added to obtain a mixed powder;

[0136] (3) The tablets were compressed into tablets using a rotary tablet press with a compression pressure of 9.4 kN and a compression time of 2-3 seconds to obtain Fulvestrant sustained-release tablets.

[0137] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 20.

[0138] Table 20

[0139]

[0140] The fulvestrant sustained-release tablets prepared in this comparative example were not completely dissolved, and the release rate was too slow after 8 hours.

[0141] Comparative Example 5

[0142] Fulvestrant sustained-release tablets were prepared by the method of Example 11 in Chinese invention patent CN114099518A. The prescription is shown in Table 21.

[0143] Table 21

[0144]

[0145] The preparation method of Fulvestrant sustained-release tablets is as follows:

[0146] Preparation of a liquid self-emulsifying preparation of fulvestrant: weigh the prescribed amount of propylene glycol monocaprylate, Tween 80 and caprylic and capric mono- and diglycerides, stir and sonicate to a uniform transparent solution to prepare a self-emulsifying base; add the prescribed amount of fulvestrant to the self-emulsifying base, stir and sonicate, and mix evenly to prepare a liquid self-emulsifying preparation of fulvestrant.

[0147] The liquid self-emulsifying preparation of Fulvestrant was dissolved in ethanol, added dropwise to a container containing mannitol, stirred evenly, dried in an oven at 40°C, and passed through a 60-mesh sieve to obtain solid self-emulsifying granules; the granules were mixed evenly with the prescribed amount of ethyl cellulose and hydroxypropyl methylcellulose K100LV, and then dropped into an ethanol solution for wet granulation. After reaching the granulation endpoint, the granules were passed through a 30-mesh sieve, dried in an oven at 40°C, sieved for 30 days, and the prescribed amount of magnesium stearate was added to obtain solid self-emulsifying sustained-release granules. The granules were pressed into a 9.5mm shallow round mold according to a tablet weight of 1.23g to obtain a self-emulsifying sustained-release tablet.

[0148] The dissolution behavior of the Fulvestrant sustained-release tablets prepared in this comparative example was tested. The test results are shown in Table 22.

[0149] Table 22

[0150]

[0151] The fulvestrant sustained-release tablets prepared in this comparative example were not completely dissolved, and the dissolution rate was significantly reduced after 8 hours.

[0152] The sustained-release tablets prepared in the examples of the present invention showed good sustained-release properties in the in vitro dissolution test, which were significantly better than the fulvestrant inclusion compound and comparative examples 1 to 5, and were able to continuously release fulvestrant within 24 hours. The drug dissolution curve was smooth, and large fluctuations in blood drug concentration after oral administration could be avoided.

[0153] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A fulvestrant sustained-release tablet, characterized in that: According to the mass fraction, the components include: 2%-10% fulvestrant, 10%-25% sustained-release matrix material, 60%-80% cosolvent, 0.1%-1% glidant and 0.1%-1% lubricant; The sustained-release matrix material is hydroxypropyl methylcellulose, selected from at least one of HPMC K100M and HPMC K100LV; The cosolvent is selected from at least one of methyl β-cyclodextrin, hydroxypropyl β-cyclodextrin, and sulfobutyl β-cyclodextrin; The glidant is colloidal silicon dioxide; The lubricant is magnesium stearate.

2. The fulvestrant sustained-release tablet according to claim 1, characterized in that Calculated by mass, the ingredients include: 2.92%-7.73% fulvestrant, 14.5%-20% sustained-release skeleton material, 71.45%-78% solubility aid, 0.2%-0.7% glidant and 0.2%-0.7% lubricant.

3. The fulvestrant sustained-release tablet according to claim 2, characterized in that: Calculated by mass fraction, the components include: 7.15%-7.73% fulvestrant, 14.5%-20% sustained-release skeleton material, 71.45%-77.27% solubility aid, 0.25%-0.7% glidant and 0.25%-0.7% lubricant.

4. The fulvestrant sustained-release tablet according to claim 3, characterized in that: Calculated by mass, the composition includes: 7.35% fulvestrant, 17.7% sustained-release matrix material, 73.57% solubility aid, 0.69% glidant and 0.69% lubricant.

5. The method for preparing the fulvestrant sustained-release tablets according to any one of claims 1 to 4, characterized in that: Includes steps: (1) Preparation of co-solvent solution: Use sodium hydroxide solution to prepare a co-solvent solution with a mass concentration of 10%-60%; (2) mixing fulvestrant with the co-solvent solution of step (1), heating to dissolve, adjusting the pH to 9-11, and drying to obtain a fulvestrant inclusion complex; (3) mixing the fulvestrant inclusion compound of step (2) with the sustained-release matrix material and the glidant, and then adding a lubricant and mixing them evenly; (4) Tableting to obtain fulvestrant sustained-release tablets.

6. The preparation method according to claim 5, characterized in that: In step (1), the concentration of the sodium hydroxide solution is 0.01 mol / L-1 mol / L; In step (1), the mass concentration of the co-solvent solution is 40%.

7. The preparation method according to claim 5, characterized in that: In step (2), the temperature of heating and dissolving is 50°C-70°C; In step (2), the pH is adjusted using hydrochloric acid with a concentration of 0.1 mol / L-0.5 mol / L to adjust the pH to 10; In step (2), the drying is freeze-drying or spray-drying.

8. The preparation method according to claim 5, characterized in that: In step (4), the tableting is performed by using a rotary tablet press, with a tableting pressure of 8KN-11KN and a tableting time of 1s-3s.

9. Use of the fulvestrant sustained-release tablet according to any one of claims 1 to 4 in the preparation of a drug for treating breast cancer.

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