CN114939108A - Fulvestrant-containing pharmaceutical composition, fulvestrant-containing oral drug delivery system, and preparation method and application thereof - Google Patents

Fulvestrant-containing pharmaceutical composition, fulvestrant-containing oral drug delivery system, and preparation method and application thereof Download PDF

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CN114939108A
CN114939108A CN202210066765.XA CN202210066765A CN114939108A CN 114939108 A CN114939108 A CN 114939108A CN 202210066765 A CN202210066765 A CN 202210066765A CN 114939108 A CN114939108 A CN 114939108A
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fulvestrant
castor oil
pharmaceutical composition
polyethylene glycol
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张闯
吴茂江
郭玉申
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Shanghai Yahong Pharmaceutical Technology Co ltd
Jiangsu Yahong Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a fulvestrant-containing pharmaceutical composition, a fulvestrant-containing oral drug delivery system, a preparation method and application thereof. The fulvestrant-containing pharmaceutical composition comprises or consists of the following components: 5-11% of fulvestrant, 9-19% of oil phase, 45-55% of emulsifier and 22-38% of co-emulsifier. The fulvestrant-containing pharmaceutical composition can be prepared into self-microemulsifying solution suitable for oral administration, so that the defects of fulvestrant injection preparations in the prior art can be overcome.

Description

Fulvestrant-containing pharmaceutical composition, fulvestrant-containing oral drug delivery system, and preparation method and application thereof
Technical Field
The invention relates to a pharmaceutical composition containing fulvestrant, an oral administration system containing fulvestrant, a preparation method and application thereof.
Background
Estrogen Receptor (ER) positive breast cancer accounts for 70% -75% of all breast cancers, and endocrine therapy is the primary recommendation for this group of patients in clinical guidelines at home and abroad. The therapeutic mechanism for estrogen receptor positive breast cancer is as follows: because the estrogen receptor binds to estrogen and then undergoes physiological changes at local tissue sites to promote the growth of cancer tissues and increase of cells, estrogen receptor antagonists are the main clinical drugs for current treatments, and counteract the effects of estrogen by directly binding to estrogen receptor, thereby exerting antagonistic action and inhibiting the growth of cancer tissues.
Fulvestrant is a relatively common clinical drug, generally used in estrogen receptor positive breast cancer therapyIs a common estrogen receptor antagonist and can combine with estrogen receptor with high affinity, block and down regulate the estrogen receptor and prevent or delay the drug resistance of endocrine treatment adopting other estrogen receptor antagonists. Fulvestrant injection developed by astrazeneca in 2002 was approved by FDA and marketed under the trade name
Figure BDA0003480502400000011
For use in locally advanced or metastatic breast cancer that is estrogen receptor positive following or during estrogen-resistant adjuvant therapy or that is post-menopausal (including natural menopause and artificial menopause) that has progressed on estrogen-resistant therapy. CFDA import approval at that time, trade name, was obtained in 2010
Figure BDA0003480502400000012
The water solubility of fulvestrant is quite low, about 1.8 mug/mL, the defect of extremely low solubility is difficult to overcome by a common preparation, and the bioavailability and curative effect of fulvestrant in vivo are improved by adopting an injection form in the original research company; the prescription comprises the following components: fulvestrant 96%, ethanol, benzyl alcohol, benzyl benzoate and castor oil, and is administered by intramuscular injection.
US2018289721a1 discloses ready-to-use injectable fulvestrant compositions having improved solubility and stability and methods for their preparation. The composition comprises fulvestrant at a concentration greater than 100mg/mL and maintains fulvestrant degradation at a level below 5% by mass when stored for at least three months at 25 ℃, improving fulvestrant solubility and stability, but still presenting the inconvenience of administration by injection.
CN104337761B discloses a pharmaceutical composition containing fulvestrant for intramuscular injection, which contains fulvestrant, castor oil matrix, at least one pharmaceutically acceptable alcohol and one or any mixture selected from medium chain triglyceride, triglycerol octadecanoate, triacetin, ethyl acetate, isopropyl myristate. The pharmaceutical composition has excellent safety and stability, the solubility of fulvestrant is greatly improved, the drug release is increased, but the pharmaceutical composition is still administered by injection and has great inconvenience.
In conclusion, most researches develop fulvestrant into an intramuscular oily injection to improve the bioavailability due to extremely low water solubility. However, the injection administration mode has the following defects: inconvenience, medication pain for patients, irritation of each auxiliary material to muscles, and increased cost for production, storage and transportation, and the existence of these defects all limit the use of this type of preparation for the patient population.
Therefore, the search for a fulvestrant-containing formulation suitable for oral administration has become a technical problem to be solved in the art.
Disclosure of Invention
The invention aims to overcome the defect that no fulvestrant-containing preparation suitable for oral administration exists in the prior art, and provides a fulvestrant-containing pharmaceutical composition, a fulvestrant-containing oral administration system, a preparation method and application thereof.
The invention solves the technical problems through the following technical scheme:
in a first aspect, the present invention provides a pharmaceutical composition comprising fulvestrant, comprising or consisting of: fulvestrant and adjuvants; wherein the auxiliary material can enable the fulvestrant-containing pharmaceutical composition to form a self-microemulsifying solution.
The invention also provides a fulvestrant-containing pharmaceutical composition comprising or consisting of the following components:
Figure BDA0003480502400000031
the sum of the mass percentages of the components is 100 percent;
the percentages refer to the mass percentage of the corresponding components in the fulvestrant-containing pharmaceutical composition.
The invention also provides a fulvestrant-containing pharmaceutical composition which comprises or consists of the following components:
Figure BDA0003480502400000032
the percentages refer to the mass percentage of the corresponding components in the fulvestrant-containing pharmaceutical composition.
In some preferred embodiments, the mass percentage of fulvestrant in the pharmaceutical composition is 5.7%, 7.4%, 9.1%, 9.9% or 10.7%.
In some preferred embodiments, the fulvestrant-containing pharmaceutical composition is a self-microemulsifying solution of fulvestrant. The average value of the particle size of the self-microemulsifying solution is preferably 22-97nm, more preferably 40-70nm, and even more preferably 52-63 nm. In some preferred embodiments, the oil phase is selected from medium chain triglyceride C 8 -C 10 (MCT), oleic acid, ethyl oleate, ethyl linoleate, isopropyl myristate, glyceryl linoleate (Maisine CC), caprylic capric triglyceride (Labrafac lipoile WL 1349), propylene glycol caprylic caprate (Labrafac PG), propylene glycol monocaprylate (Capryol 90), soybean oil, castor oil and olive oil; preferably medium chain triglyceride C 8 -C 10 One or more of ethyl linoleate, isopropyl myristate, glyceryl linoleate, propylene glycol caprylic caprate, propylene glycol monocaprylate and castor oil; more preferably medium chain triglyceride C 8 -C 10 And/or castor oil; more preferably still, it is a medium chain triglyceride C 8 -C 10 Or castor oil.
In some preferred embodiments, the oil phase is 9%, 9.1%, 9.4%, 11.1%, 13.4%, 13.5%, 13.6%, 14.1%, 18.2%, or 18.5% by mass of the pharmaceutical composition.
In some preferred embodiments, the emulsifier is selected from one or more of polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40), castor oil polyoxyl ester 35(Kolliphor ELP), tween 80, caprylic capric macrogol glyceride (Labrasol), 15-hydroxystearate macrogol ester (Kolliphor HS 15), and laurin macrogol glyceride; preferably one or more of polyoxyethylene 40 hydrogenated castor oil, castor oil polyoxyl 35 and caprylic capric acid polyethylene glycol glyceride; more preferably polyoxyethylene 40 hydrogenated castor oil and/or castor oil polyoxyl ester 35; even more preferably polyoxyethylene 40 hydrogenated castor oil or castor oil polyoxyl ester 35.
In some preferred embodiments, the mass percentage of the emulsifier in the pharmaceutical composition is 45.1%, 45.4%, 45.5%, 46.3%, 47.2%, 49.6%, 53.6%, 53.7% or 54.5%.
In some preferred embodiments, the co-emulsifier is selected from one or more of ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol glyceryl oleate (Labrafil M1944CS), and diethylene glycol monoethyl ether (Transcutol P); preferably one or more of ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol glyceryl oleate and diethylene glycol monoethyl ether; more preferably one or more of propylene glycol, polyethylene glycol 400 and diethylene glycol monoethyl ether; still more preferably propylene glycol and/or diethylene glycol monoethyl ether; still more preferably propylene glycol or diethylene glycol monoethyl ether.
In some preferred embodiments, the mass percentage of the co-emulsifier in the pharmaceutical composition is 22.3%, 27.3%, 27.8%, 31.5%, 31.8%, 33%, or 37.7%.
In some preferred embodiments, the fulvestrant-containing pharmaceutical composition comprises or consists of:
Figure BDA0003480502400000041
the percentages refer to the mass percentage of the corresponding components in the fulvestrant-containing pharmaceutical composition.
In some preferred embodiments, the fulvestrant-containing pharmaceutical composition comprises or consists of:
Figure BDA0003480502400000051
the oil phase is preferably selected from one or more of medium chain triglyceride C8-C10, ethyl linoleate, isopropyl myristate, glyceryl linoleate, propylene glycol caprylic caprate, propylene glycol monocaprylate and castor oil;
and/or the emulsifier is preferably one or more of polyoxyethylene 40 hydrogenated castor oil, castor oil polyoxyl 35, tween 80, caprylic/capric macrogol glyceride, 15-hydroxystearate macrogol ester and lauric macrogol glyceride;
and/or the coemulsifier is preferably one or more selected from ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol glyceryl oleate and diethylene glycol monoethyl ether.
In some preferred embodiments, the fulvestrant-containing pharmaceutical composition comprises or consists of:
fulvestrant 9.1-10.9 mass%, castor oil 18.1-19 mass%, polyoxyethylene 40 hydrogenated castor oil 45.4-55.5 mass% and diethylene glycol monoethyl ether 27.3-30.5 mass%;
9.1-10.9 mass% fulvestrant, 18.1-19 mass% medium chain triglyceride, 45.4-55.5 mass% castor oil polyoxyl ester 35, and 27.3-30.5 mass% propylene glycol;
7.4-8.5 mass% fulvestrant, 18.5-19 mass% medium chain triglyceride, 46.3-55.5 mass% castor oil polyoxyl 35 and 27.8-30.9 mass% polyethylene glycol 400;
fulvestrant 9.9-11.9 mass%, castor oil 9.0-11.0 mass%, polyoxyethylene 40 hydrogenated castor oil 49.6-55.5 mass% and propylene glycol 31.5-35.9 mass%;
9.9-11.9 mass% fulvestrant, 13.5-15.5 mass% castor oil, 45.1-50.9 mass% caprylic capric polyethylene glycol glyceride and 31.5-36.5 mass% diethylene glycol monoethyl ether;
fulvestrant 9.1-10.9 mass%, propylene glycol monocaprylate 13.6-15.5 mass%, polyoxyethylene 40 hydrogenated castor oil 45.5-51.5 mass%, and diethylene glycol monoethyl ether 31.8-35.5 mass%;
5.7-6.5 mass% fulvestrant, 9.4-10.5 mass% medium chain triglyceride, 47.2-50.9 mass% tween 80 and 37.7-38 mass% polyethylene glycol 400;
fulvestrant 7.4-8.5 wt%, linoleic acid glyceride 11.1-12.5 wt%, 15-hydroxystearate polyethylene glycol ester 53.7-58.9 wt% and oleic acid polyethylene glycol glyceride 27.8-31.9 wt%;
fulvestrant 9.1-11.1 mass%, isopropyl myristate 9.1-10.9 mass%, macrogol glyceride laurate 54.5-60.5 mass% and glycerol 27.3-30.5 mass%;
fulvestrant 10.7-12.5 mass%, ethyl linoleate 13.4-16.5 mass%, macrogol glyceride laurate 53.6-61.5 mass% and ethanol 22.3-27.5 mass%;
or 5.7-6.5 mass% fulvestrant, 14.1-16.0 mass% propylene glycol caprylic acid decanoate, 47.2-50.5 mass% 15-hydroxystearate polyethylene glycol ester and 33.0-36.0 mass% polyethylene glycol 200;
the percentages refer to the mass percentage of the corresponding components in the fulvestrant-containing pharmaceutical composition.
In some preferred embodiments, the fulvestrant-containing pharmaceutical composition consists of:
9.1 mass% fulvestrant, 18.2 mass% castor oil, 45.4 mass% polyoxyethylene 40 hydrogenated castor oil and 27.3 mass% diethylene glycol monoethyl ether;
9.1 mass% fulvestrant, 18.2 mass% medium chain triglyceride, 45.4 mass% castor oil polyoxyl ester 35, and 27.3 mass% propylene glycol;
7.4 mass% fulvestrant, 18.5 mass% medium chain triglyceride, 46.3 mass% castor oil alkoxylate 35 and 27.8 mass% polyethylene glycol 400;
9.9 mass% fulvestrant, 9.0 mass% castor oil, 49.6 mass% polyoxyethylene 40 hydrogenated castor oil and 31.5 mass% propylene glycol;
9.9 mass% fulvestrant, 13.5 mass% castor oil, 45.1 mass% caprylic/capric macrogolglycerides and 31.5 mass% diethylene glycol monoethyl ether;
9.1 mass% fulvestrant, 13.6 mass% propylene glycol monocaprylate, 45.5 mass% polyoxyethylene 40 hydrogenated castor oil, and 31.8 mass% diethylene glycol monoethyl ether;
5.7 mass% fulvestrant, 9.4 mass% medium chain triglyceride, 47.2 mass% tween 80 and 37.7 mass% polyethylene glycol 400;
7.4 mass% fulvestrant, 11.1 mass% glyceryl linoleate, 53.7 mass% polyethylene glycol 15-hydroxystearate and 27.8 mass% macrogol oleate;
9.1 mass% fulvestrant, 9.1 mass% isopropyl myristate, 54.5 mass% macrogol glyceride laurate and 27.3 mass% glycerol;
10.7 mass% fulvestrant, 13.4 mass% ethyl linoleate, 53.6 mass% macrogolglycerides laurate and 22.3 mass% ethanol; or,
5.7 mass% fulvestrant, 14.1 mass% propylene glycol caprylic decanoate, 47.2 mass% polyethylene glycol 15-hydroxystearate and 33 mass% polyethylene glycol 200;
the percentages refer to the mass percentage of the corresponding components in the fulvestrant-containing pharmaceutical composition.
In the above pharmaceutical composition of the present invention, the fulvestrant may be replaced with a pharmaceutically acceptable salt of fulvestrant.
The term "pharmaceutically acceptable salt" should be understood to refer to salts which are pharmaceutically acceptable salts and which possess the pharmacological activity of the intended parent compound (referring to fulvestrant). Such salts include:
(1) acid addition salts with inorganic acids, or acid addition salts with organic acids; wherein, the inorganic acid can be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; the organic acid may be one or more of formic acid, oxalic acid, succinic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid; and,
(2) the acid proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., Na) + 、K + Or Li + ) Alkaline earth metal ion (e.g. Ca) 2+ Or Mg 2+ ) Or aluminum ion substitution; or, a salt formed when coordinated with an organic or inorganic base; wherein the organic base can be one or more of pyridine, imidazole, pyrazine, indole, purine, tertiary amine and aniline organic bases, and is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine, 2-methyl-5-ethylpyridine, triethylamine, N-diisopropylethylamine, N-dimethylaniline, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine and tromethamine; the inorganic base may be one or more of aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
In a second aspect, the present invention provides a method for preparing a fulvestrant-containing self-microemulsifying solution, wherein the preparation method uses the above fulvestrant-containing pharmaceutical composition, and the preparation method comprises the following steps: mixing the components of the pharmaceutical composition.
In some preferred embodiments, when the active pharmaceutical ingredient in the pharmaceutical composition is fulvestrant, the method of preparation comprises the steps of:
1) mixing an emulsifier and an auxiliary emulsifier to obtain a mixed solution I;
2) mixing the mixed solution I with an oil phase to obtain a mixed solution II;
3) mixing the mixed solution II with fulvestrant until the fulvestrant is dissolved to obtain fulvestrant;
when the active pharmaceutical ingredient in the pharmaceutical composition is fulvestrant pharmaceutically acceptable salt, the preparation method comprises the following steps:
1) mixing an emulsifier and an auxiliary emulsifier to obtain a mixed solution I;
2) mixing the mixed solution I with an oil phase to obtain a mixed solution II;
3) and mixing the mixed solution II with fulvestrant pharmaceutically acceptable salt until the fulvestrant pharmaceutically acceptable salt is dissolved to obtain the fulvestrant.
Wherein, preferably, the pharmaceutical composition comprises or consists of the following components: fulvestrant, castor oil, polyoxyethylene 40 hydrogenated castor oil, and diethylene glycol monoethyl ether.
Wherein, in the step 1), the mixing temperature is preferably 30-40 ℃.
Wherein, in the step 1), the mixing is preferably stirring, and the rotation speed of the stirring is preferably 1000-2000rpm, such as 1500 rpm.
In step 2), the end point of the mixing is preferably a uniform and clear state of the mixed solution II.
Wherein, in the step 3), the mixing temperature is preferably 30-40 ℃.
Wherein, in the step 3), the mixing is preferably stirring, and the rotation speed of the stirring is preferably 1000-2000rpm, for example 1500 rpm.
In the second aspect, the mixing is as conventionally understood in the art, as long as the mixing is uniform.
In a third aspect, the present invention provides a fulvestrant-containing delivery system comprising a therapeutically effective amount of the aforementioned fulvestrant-containing pharmaceutical composition and a pharmaceutically acceptable carrier.
In some preferred embodiments, the carrier includes a filler, which is preferably one or more of microcrystalline cellulose, pregelatinized starch, and mannitol.
In some preferred embodiments, the carrier comprises a binder, preferably one or more of corn starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
In some preferred embodiments, the carrier comprises a disintegrant, preferably one or more of croscarmellose sodium, crospovidone, and sodium starch glycolate.
In some preferred embodiments, the carrier comprises an adsorbent, preferably magnesium aluminum silicate and/or fumed silica.
In some preferred embodiments, the carrier includes a lubricant, which is preferably magnesium stearate and/or sodium stearyl fumarate.
In some preferred embodiments, the delivery system is a tablet, granule, hard capsule, or soft capsule.
In some preferred embodiments, the delivery system is an oral delivery system.
In a fourth aspect, the present invention provides a method for preparing the aforementioned fulvestrant-containing delivery system, wherein the delivery system is a tablet, a granule, a hard capsule or a soft capsule;
when the drug delivery system is a tablet, a granule or a hard capsule, the preparation method comprises the following steps: mixing the fulvestrant-containing pharmaceutical composition with the pharmaceutically acceptable carrier;
when the drug delivery system is a soft capsule, the preparation method comprises the following steps: and filling the fulvestrant-containing pharmaceutical composition into soft capsules.
In a fifth aspect, the present invention also provides the use of the aforementioned pharmaceutical composition comprising fulvestrant or the aforementioned delivery system comprising fulvestrant in the manufacture of a medicament for the treatment of breast cancer.
The term "pharmaceutically acceptable" means that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, biologically desirable and acceptable for human pharmaceutical use.
The positive progress effects of the invention are as follows:
(1) after extensive and intensive research, the inventor obtains the fulvestrant-containing pharmaceutical composition of the present invention and prepares the fulvestrant-containing pharmaceutical composition into a thermodynamically stable, uniform, transparent or translucent homogeneous self-microemulsifying solution. Furthermore, the present inventors have found that a solution having an emulsion droplet size of less than 100nm and excellent stability can be spontaneously formed in an environment of about 37 ℃ under mild stirring after adding an aqueous medium to the self-microemulsifying solution of the present invention.
Compared with the drug loading (40mg/g-80mg/g) of related preparations reported in literatures, the drug loading (57mg/g-107mg/g) of the self-microemulsifying solution is obviously improved; compared with fulvestrant bulk drug powder, the self-microemulsifying solution provided by the invention has better dissolution rate; compared with fulvestrant solution, the self-microemulsifying solution provided by the invention has better bioavailability.
In conclusion, the fulvestrant-containing pharmaceutical composition can be prepared into self-microemulsifying solution suitable for oral administration, so that the defects of fulvestrant injection preparations in the prior art can be overcome.
(2) The preparation method of the fulvestrant-containing self-microemulsifying solution is very simple and convenient and is easy to operate.
Drawings
FIG. 1 is a graph showing the dissolution profiles of fulvestrant-containing self-microemulsifying solutions and fulvestrant bulk drug powder in purified water according to examples 1-5;
FIG. 2 is the dissolution curve of fulvestrant-containing self-microemulsifying solution and fulvestrant bulk drug powder in 0.1mol/L hydrochloric acid solution of examples 1-3;
fig. 3 is a blood concentration-time curve of fulvestrant-containing self-microemulsifying solution and fulvestrant solution of examples 1-2 in rats.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions. Known reagents, solvents, materials in the examples can be synthesized using or according to methods known in the art, or are commercially available.
Hereinafter, fulvestrant is available from Haimen Huiypolymer pharmaceutical Co.Ltd;
medium Chain Triglycerides (MCT), propylene glycol monocaprylate (caprol 90), propylene glycol caprylic decanoate (Labrafac PG), diethylene glycol monoethyl ether (Transcutol P), polyethylene glycol glyceryl oleate (Labrafil M1944CS), polyethylene glycol glyceryl laurate (Gelucire 44/14), polyethylene glycol glyceryl caprylate/caprate (Labrasol), all available from gale lion, france;
hydrogenated castor oil polyoxy ester 35(kolliphe ELP), hydrogenated castor oil polyoxy ester 40 (kolliphe RH40), polyethylene glycol 15-hydroxystearate (kolliphe HS 15), all from BASF, germany;
isopropyl myristate, Castor oil (Castor oil), tween 80, propylene glycol, glycerol, polyethylene glycol 200(PEG200), polyethylene glycol 400(PEG400), ethanol, all available from national pharmaceutical chemicals, ltd.
Example 1
Prescription composition
Components Name (R) Quality (g) Mass percent%
Raw material medicine Fulvestrant 10 9.1
Oil phase Castor oil (Castor oil) 20 18.2
Emulsifier Polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40) 50 45.4
Auxiliary emulsifier Diethylene glycol monoethyl ether (Transcutol P) 30 27.3
The preparation process comprises the following steps: mixing emulsifier and co-emulsifier, heating to 30-40 deg.C, stirring at 1500rpm, adding oil phase, stirring to obtain homogeneous clear state, adding fulvestrant, and stirring at 30-40 deg.C at 1500rpm until the drug is dissolved to obtain self-microemulsion containing fulvestrant.
Example 2
Prescription composition
Components Name (R) Mass (g) Mass percent%
Crude drug Fulvestrant 10 9.1
Oil phase Medium Chain Triglycerides (MCT) 20 18.2
Emulsifier Castor oil polyoxyl ester 35(Kolliphor ELP) 50 45.4
Auxiliary emulsifier Propylene glycol 30 27.3
The preparation process is the same as in example 1.
Example 3
Prescription composition
Components Name (R) Quality (g) Mass percent%
Raw material medicine Fulvestrant 8 7.4
Oil phase Medium Chain Triglycerides (MCT) 20 18.5
Emulsifier Castor oil polyoxyl ester 35(Kolliphor ELP) 50 46.3
Auxiliary emulsifier Polyethylene glycol 400(PEG400) 30 27.8
The preparation process is the same as in example 1.
Example 4
Prescription composition
Components Name (R) Quality (g) Mass percent%
Crude drug Fulvestrant 11 9.9
Oil phase Castor oil (Castor oil) 10 9.0
Emulsifier Polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40) 55 49.6
Auxiliary emulsifier Propylene glycol 35 31.5
The preparation process is the same as in example 1.
Example 5
Prescription composition
Components Name (R) Quality (g) Mass percent%
Raw material medicine Fulvestrant 11 9.9
Oil phase Castor oil (Castor oil) 15 13.5
Emulsifying agent Caprylic capric acid polyethylene glycol glyceride (Labrasol) 50 45.1
Auxiliary emulsifier Diethylene glycol monoethyl ether (Transcutol P) 35 31.5
The preparation process is the same as in example 1.
Example 6
Prescription composition
Figure BDA0003480502400000121
The preparation process is the same as in example 1.
Example 7
Prescription composition
Components Name (R) Mass (g) Mass percent%
Raw material medicine Fulvestrant 6 5.7
Oil phase Medium Chain Triglycerides (MCT) 10 9.4
Emulsifier Tween 80 50 47.2
Auxiliary emulsifier Polyethylene glycol 400(PEG400) 40 37.7
The preparation process is the same as in example 1.
Example 8
Prescription composition
Figure BDA0003480502400000131
The preparation process is the same as in example 1.
Example 9
Prescription composition
Components Name (R) Mass (g) Mass percent%
Raw material medicine Fulvestrant 10 9.1
Oil phase Myristic acid isopropyl ester 10 9.1
Emulsifying agent Lauric acid polyethylene glycol glyceride (Gelucire 44/14) 60 54.5
Auxiliary emulsifier Glycerol 30 27.3
The preparation process is the same as in example 1.
Example 10
Prescription composition
Components Name (R) Mass (g) Mass percent%
Raw material medicine Fulvestrant 12 10.7
Oil phase Linoleic acid ethyl ester 15 13.4
Emulsifying agent Lauric acid polyethylene glycol glyceride (Gelucire 44/14) 60 53.6
Auxiliary emulsifier Ethanol 25 22.3
The preparation process is the same as in example 1.
Example 11
Prescription composition
Figure BDA0003480502400000132
The preparation process is the same as in example 1.
The description about the state of the pharmaceutical composition obtained after the completion of the preparation in examples 1 to 11 is as follows: the obtained medicinal compositions are homogeneous self-microemulsifying solutions which are thermodynamically stable, uniform, transparent or semitransparent; the drug loading of the self-microemulsifying solution obtained in the examples 1-11 is 57-107 mg/g, which is obviously improved compared with the drug loading (40-80 mg/g) of related preparations reported in the literature.
Effect example 1
Physicochemical characteristics of fulvestrant-containing self-microemulsifying solutions prepared in examples 1-5:
about 0.5mL of fulvestrant-containing self-microemulsifying solution is taken and dripped into 50mL of aqueous solution at the temperature of 37 +/-5 ℃ and under the stirring condition of 200rpm to obtain clear and transparent bluish opalescent solution. This shows that the fulvestrant-containing self-microemulsifying solution of the present invention has excellent stability.
The solution is measured by a laser scattering particle size analyzer to obtain the average value of the particle size of 40-70nm, and the particle size distribution result is shown in the following table:
sample (I) Particle size (average nm. + -. SD)
Examples1 52.26±3.54
Example 2 62.17±0.78
Example 3 43.91±4.62
Example 4 68.43±3.75
Example 5 50.32±2.38
Effect example 2
The dissolution curves of the fulvestrant-containing self-microemulsifying solutions prepared in examples 1-5 and the bulk drug powder in different dissolution media are compared:
the method is carried out according to the second regulation in XC in appendix of China Pharmacopeia (2020 edition), the rotating speed of a stirring paddle is 75rpm, the temperature of a water bath is 37 +/-0.5 ℃, dissolution media are purified water and 0.1mol/L hydrochloric acid solution, and the volume of the dissolution media is 900 mL. Respectively adding 1mL of fulvestrant-containing self-microemulsifying solution (containing 100mg of fulvestrant) and 100mg of fulvestrant raw material powder, sampling for 5mL at 5 min, 10min, 15 min, 20 min, 30 min, 45 min and 60min, filtering with 0.45 μm microporous membrane, discarding 2mL of primary filtrate, and taking the subsequent filtrate for HPLC determination. HPLC analytical method: agilent chromatography column XDB-C18; column temperature: 40 ℃, flow rate: 1.5mL/min, detection wavelength: 225nm, sample size: 20 mu L of the solution; mobile phase: 0.05 v% aqueous trifluoroacetic acid: acetonitrile 75:25 (volume ratio).
The dissolution curves of the fulvestrant-containing self-microemulsifying solution and the fulvestrant bulk drug powder in purified water and 0.1mol/L hydrochloric acid solution are respectively shown in figure 1 and figure 2.
The experimental results show that: the dissolution rate (53-54.31%) of the fulvestrant-containing self-microemulsifying solution in purified water for 60min is higher than that of fulvestrant bulk drug powder (4.43%); through conversion, the dissolution rate of the fulvestrant-containing self-microemulsifying solution in purified water for 60min is about 12 times of that of fulvestrant bulk drug powder; the dissolution rate (38.09% -43.76%) of the fulvestrant-containing self-microemulsifying solution in 0.1mol/L hydrochloric acid solution for 60min is higher than that of fulvestrant bulk drug powder (4.10%); through conversion, the dissolution rate of the fulvestrant-containing self-microemulsifying solution in 0.1mol/L hydrochloric acid solution for 60min is 9.3 to 10.7 times of that of fulvestrant raw material medicine powder.
Effect example 3
In this effect example, the area under the plasma concentration-time curve (AUC) of the fulvestrant-containing self-microemulsifying solution prepared in example 1-2 and the fulvestrant solution in rats was determined.
Wherein, the fulvestrant solution is prepared as follows: fulvestrant bulk drug powder was mixed with a mixture (prepared by mixing DMSO, Kolliphor HS 15, and a physiological saline solution in a mass ratio of 5:10: 85) at a fulvestrant concentration of 1 mg/mL.
The specific experiment is as follows:
healthy rats 6 (SD rats, SPF grade, 180-.
The self-microemulsifying solution containing fulvestrant and fulvestrant solution are separately infused into the stomach with an empty stomach, and the water is not forbidden in the whole experimental process. Administering for 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h, collecting 0.2mL by jugular vein blood collection or other vein blood collection modes, placing in an EDTA-K2 anticoagulation tube containing a mark, slightly reversing the upper part and the lower part to fully mix the anticoagulation agent and the blood, and centrifugally separating plasma within 1h after blood collection, wherein the centrifugal conditions are set to 3500g and 10 min. And (3) placing the plasma obtained by centrifugation and separation into a marked EP tube, and storing the plasma sample in an ultra-low temperature refrigerator within 2h after blood collection until the sample is analyzed.
The blood concentration-time curves of the fulvestrant-containing self-microemulsifying solution and fulvestrant solution of examples 1 and 2 in rats are shown in fig. 3 (the "solution group" in fig. 3 is the experimental group corresponding to the "fulvestrant solution"). The experimental results show that: after administration of the fulvestrant-containing self-microemulsifying solutions of examples 1 and 2, the area under the plasma concentration-time curve (AUC) was 413% and 462% of the fulvestrant-containing solution administered, respectively. Therefore, the fulvestrant-containing self-microemulsifying solution can obviously improve the bioavailability of fulvestrant orally taken on an empty stomach.
Effect example 4
The fulvestrant-containing self-microemulsifying solutions prepared in examples 6-11 were tested for the physicochemical properties described in effect example 1. The experimental results show that: the average particle size distribution range of the fulvestrant-containing self-microemulsifying solution prepared in examples 6-11 is 22-97 nm.
The fulvestrant-containing self-microemulsifying solutions prepared in examples 6-11 were tested for dissolution in purified water and 0.1mol/L hydrochloric acid solution as described in effect example 2. The experimental results show that: the dissolution curve of the fulvestrant-containing self-microemulsifying solution in purified water and 0.1mol/L hydrochloric acid solution is higher than that of fulvestrant bulk drug powder.
The experiments described in effect example 3 were carried out on fulvestrant-containing self-microemulsifying solutions prepared in examples 3-11. The experimental results show that: the AUC of the fulvestrant-containing self-microemulsifying solution is higher than that of the fulvestrant solution, so that the fulvestrant-containing self-microemulsifying solution is higher in absorption degree in vivo and obviously improved in bioavailability.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes or modifications to these embodiments may be made by those skilled in the art without departing from the principle and spirit of this invention, and these changes and modifications are within the scope of this invention.

Claims (12)

1. A fulvestrant-containing pharmaceutical composition comprising or consisting of:
Figure FDA0003480502390000011
the sum of the mass percentages of the components is 100 percent.
2. A fulvestrant-containing pharmaceutical composition comprising or consisting of:
Figure FDA0003480502390000012
3. the fulvestrant-containing pharmaceutical composition according to claim 1 or 2, wherein:
the fulvestrant is 5.7%, 7.4%, 9.1%, 9.9% or 10.7% by mass of the pharmaceutical composition;
and/or the pharmaceutical composition containing fulvestrant is a self-microemulsifying solution containing fulvestrant; the average value of the particle size of the self-microemulsifying solution is preferably 22-97nm, more preferably 40-70nm, and even more preferably 52-63 nm;
and/or, the oil phase is selected from medium chain triglyceride C 8 -C 10 One or more of oleic acid, ethyl oleate, ethyl linoleate, isopropyl myristate, glyceryl linoleate, caprylic capric triglyceride, propylene glycol caprylic caprate, propylene glycol monocaprylate, soybean oil, castor oil and olive oil; preferably medium chain triglyceride C 8 -C 10 One or more of ethyl linoleate, isopropyl myristate, glyceryl linoleate, propylene glycol caprylic caprate, propylene glycol monocaprylate and castor oil; more preferably medium chain triglyceride C 8 -C 10 And/or castor oil; more preferably still, it is a medium chain triglyceride C 8 -C 10 Or castor oil;
and/or the oil phase is 9%, 9.1%, 9.4%, 11.1%, 13.4%, 13.5%, 13.6%, 14.1%, 18.2% or 18.5% by mass of the pharmaceutical composition;
and/or the emulsifier is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, castor oil polyoxyl 35, tween 80, caprylic/capric polyethylene glycol glyceride, 15-hydroxystearate polyethylene glycol ester and lauric polyethylene glycol glyceride; preferably one or more of polyoxyethylene 40 hydrogenated castor oil, castor oil polyoxyl 35 and caprylic capric acid polyethylene glycol glyceride; more preferably polyoxyethylene 40 hydrogenated castor oil and/or castor oil polyoxyl ester 35; further more preferably polyoxyethylene 40 hydrogenated castor oil or castor oil polyoxyl ester 35;
and/or the mass percentage of the emulsifier in the pharmaceutical composition is 45.1%, 45.4%, 45.5%, 46.3%, 47.2%, 49.6%, 53.6%, 53.7% or 54.5%;
and/or the coemulsifier is selected from one or more of ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol glyceryl oleate and diethylene glycol monoethyl ether; preferably one or more of ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol glyceryl oleate and diethylene glycol monoethyl ether; more preferably one or more of propylene glycol, polyethylene glycol 400 and diethylene glycol monoethyl ether; still more preferably propylene glycol and/or diethylene glycol monoethyl ether; still more preferably propylene glycol or diethylene glycol monoethyl ether;
and/or the mass percentage of the co-emulsifier in the pharmaceutical composition is 22.3%, 27.3%, 27.8%, 31.5%, 31.8%, 33% or 37.7%.
4. The fulvestrant-containing pharmaceutical composition according to any one of claims 2 to 3 comprising or consisting of:
Figure FDA0003480502390000021
5. the fulvestrant-containing pharmaceutical composition according to claim 2 comprising or consisting of:
Figure FDA0003480502390000022
the oil phase is preferably selected from medium chain triglycerides C 8 -C 10 One or more of ethyl linoleate, isopropyl myristate, glyceryl linoleate, propylene glycol caprylic caprate, propylene glycol monocaprylate and castor oil;
and/or the emulsifier is preferably one or more of polyoxyethylene 40 hydrogenated castor oil, castor oil polyoxyl 35, tween 80, caprylic/capric macrogol glyceride, 15-hydroxystearate macrogol ester and lauric macrogol glyceride;
and/or the coemulsifier is preferably one or more selected from ethanol, glycerol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol glyceryl oleate and diethylene glycol monoethyl ether.
6. The fulvestrant-containing pharmaceutical composition according to any one of claims 2 to 5 comprising or consisting of:
fulvestrant 9.1-10.9 mass%, castor oil 18.1-19 mass%, polyoxyethylene 40 hydrogenated castor oil 45.4-55.5 mass% and diethylene glycol monoethyl ether 27.3-30.5 mass%;
9.1-10.9 mass% fulvestrant, 18.1-19 mass% medium chain triglycerides, 45.4-55.5 mass% castor oil polyoxyl 35, and 27.3-30.5 mass% propylene glycol;
7.4-8.5 mass% fulvestrant, 18.5-19 mass% medium chain triglyceride, 46.3-55.5 mass% castor oil polyoxyl 35 and 27.8-30.9 mass% polyethylene glycol 400;
fulvestrant 9.9-11.9 mass%, castor oil 9.0-11.0 mass%, polyoxyethylene 40 hydrogenated castor oil 49.6-55.5 mass% and propylene glycol 31.5-35.9 mass%;
9.9 to 11.9 mass percent of fulvestrant, 13.5 to 15.5 mass percent of castor oil, 45.1 to 50.9 mass percent of caprylic/capric macrogol glyceride and 31.5 to 36.5 mass percent of diethylene glycol monoethyl ether;
fulvestrant 9.1-10.9 mass%, propylene glycol monocaprylate 13.6-15.5 mass%, polyoxyethylene 40 hydrogenated castor oil 45.5-51.5 mass%, and diethylene glycol monoethyl ether 31.8-35.5 mass%;
5.7-6.5 mass% fulvestrant, 9.4-10.5 mass% medium chain triglyceride, 47.2-50.9 mass% tween 80 and 37.7-38 mass% polyethylene glycol 400;
7.4 to 8.5 mass percent of fulvestrant, 11.1 to 12.5 mass percent of linoleic acid glyceride, 53.7 to 58.9 mass percent of 15-hydroxystearate polyethylene glycol ester and 27.8 to 31.9 mass percent of oleic acid polyethylene glycol glyceride;
fulvestrant 9.1-11.1 mass%, isopropyl myristate 9.1-10.9 mass%, macrogol glyceride laurate 54.5-60.5 mass% and glycerol 27.3-30.5 mass%;
fulvestrant 10.7-12.5 mass%, ethyl linoleate 13.4-16.5 mass%, macrogol glyceride laurate 53.6-61.5 mass% and ethanol 22.3-27.5 mass%; or,
5.7-6.5 mass% fulvestrant, 14.1-16.0 mass% propylene glycol caprylic acid decanoate, 47.2-50.5 mass% 15-hydroxystearate polyethylene glycol ester and 33.0-36.0 mass% polyethylene glycol 200.
7. The fulvestrant-containing pharmaceutical composition according to any one of claims 2 to 6 consisting of:
9.1 mass% fulvestrant, 18.2 mass% castor oil, 45.4 mass% polyoxyethylene 40 hydrogenated castor oil and 27.3 mass% diethylene glycol monoethyl ether;
9.1 mass% fulvestrant, 18.2 mass% medium chain triglyceride, 45.4 mass% castor oil alkoxylate 35 and 27.3 mass% propylene glycol;
7.4 mass% fulvestrant, 18.5 mass% medium chain triglyceride, 46.3 mass% castor oil alkoxylate 35 and 27.8 mass% polyethylene glycol 400;
9.9 mass% fulvestrant, 9.0 mass% castor oil, 49.6 mass% polyoxyethylene 40 hydrogenated castor oil and 31.5 mass% propylene glycol;
9.9 mass% fulvestrant, 13.5 mass% castor oil, 45.1 mass% caprylic capric polyethylene glycol glyceride and 31.5 mass% diethylene glycol monoethyl ether;
9.1 mass% fulvestrant, 13.6 mass% propylene glycol monocaprylate, 45.5 mass% polyoxyethylene 40 hydrogenated castor oil, and 31.8 mass% diethylene glycol monoethyl ether;
5.7 mass% fulvestrant, 9.4 mass% medium chain triglyceride, 47.2 mass% tween 80 and 37.7 mass% polyethylene glycol 400;
7.4 mass% fulvestrant, 11.1 mass% glyceryl linoleate, 53.7 mass% polyethylene glycol 15-hydroxystearate and 27.8 mass% macrogol oleate;
9.1 mass% fulvestrant, 9.1 mass% isopropyl myristate, 54.5 mass% macrogolglyceride laurate and 27.3 mass% glycerol;
10.7 mass% fulvestrant, 13.4 mass% ethyl linoleate, 53.6 mass% macrogolglycerides laurate and 22.3 mass% ethanol; or,
5.7 mass% fulvestrant, 14.1 mass% propylene glycol caprylic decanoate, 47.2 mass% polyethylene glycol 15-hydroxystearate and 33 mass% polyethylene glycol 200.
8. The fulvestrant-containing pharmaceutical composition according to any one of claims 1 to 7, wherein the fulvestrant is replaced with a pharmaceutically acceptable salt of fulvestrant.
9. A process for the preparation of a fulvestrant-containing self-microemulsifying solution using a fulvestrant-containing pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of: mixing the components of the pharmaceutical composition;
in particular, when the active pharmaceutical ingredient in the pharmaceutical composition is fulvestrant, the preparation method comprises the following steps:
1) mixing an emulsifier and an auxiliary emulsifier to obtain a mixed solution I;
2) mixing the mixed solution I with an oil phase to obtain a mixed solution II;
3) mixing the mixed solution II with fulvestrant until the fulvestrant is dissolved to obtain fulvestrant;
when the active pharmaceutical ingredient in the pharmaceutical composition is a pharmaceutically acceptable salt of fulvestrant, the preparation method comprises the following steps:
1) mixing an emulsifier and an auxiliary emulsifier to obtain a mixed solution I;
2) mixing the mixed solution I with an oil phase to obtain a mixed solution II;
3) mixing the mixed solution II with fulvestrant pharmaceutically acceptable salt until the fulvestrant pharmaceutically acceptable salt is dissolved to obtain fulvestrant pharmaceutically acceptable salt;
wherein, the medicine composition preferably comprises or consists of the following components: fulvestrant, castor oil, polyoxyethylene 40 hydrogenated castor oil, and diethylene glycol monoethyl ether;
wherein, in the step 1), the mixing temperature is preferably 30-40 ℃;
wherein, in the step 1), the mixing is preferably stirring, and the rotation speed of the stirring is preferably 1000-2000rpm, such as 1500 rpm;
in the step 2), the end point of the mixing is preferably that the mixed solution II is in a uniform and clear state;
wherein, in the step 3), the mixing temperature is preferably 30-40 ℃;
wherein, in the step 3), the mixing is preferably stirring, and the rotation speed of the stirring is preferably 1000-2000rpm, for example 1500 rpm.
10. A fulvestrant-containing drug delivery system comprising a therapeutically effective amount of a fulvestrant-containing pharmaceutical composition according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier;
in particular, the carrier comprises a filler, preferably one or more of microcrystalline cellulose, pregelatinized starch and mannitol, and/or,
the carrier comprises a binder, preferably one or more of corn starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose, and/or,
the carrier comprises a disintegrant, preferably one or more of croscarmellose sodium, crospovidone and sodium starch glycolate, and/or,
the carrier comprises an adsorbent, preferably magnesium aluminium silicate and/or fumed silica, and/or,
the carrier comprises a lubricant, preferably magnesium stearate and/or sodium stearyl fumarate;
more particularly, the drug delivery system is a tablet, a granule, a hard capsule or a soft capsule;
even more particularly, the delivery system is an oral delivery system.
11. A method of preparing a fulvestrant-containing delivery system according to claim 10 in the form of a tablet, granule, hard or soft capsule;
when the drug delivery system is a tablet, a granule or a hard capsule, the preparation method comprises the following steps: mixing the fulvestrant-containing pharmaceutical composition with the pharmaceutically acceptable carrier;
when the drug delivery system is a soft capsule, the preparation method comprises the following steps: and filling the fulvestrant-containing pharmaceutical composition into soft capsules.
12. Use of the fulvestrant-containing pharmaceutical composition according to any one of claims 1 to 8 and/or the fulvestrant-containing delivery system according to claim 10 in the manufacture of a medicament for the treatment of breast cancer.
CN202210066765.XA 2021-02-07 2022-01-20 Fulvestrant-containing pharmaceutical composition, fulvestrant-containing oral drug delivery system, and preparation method and application thereof Pending CN114939108A (en)

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Publication number Priority date Publication date Assignee Title
WO2024149260A1 (en) * 2023-01-09 2024-07-18 上海润石医药科技有限公司 Self-emulsifying pharmaceutical composition, preparation method therefor, and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024149260A1 (en) * 2023-01-09 2024-07-18 上海润石医药科技有限公司 Self-emulsifying pharmaceutical composition, preparation method therefor, and application thereof

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