CN115887667A - Medicine composition and application thereof - Google Patents
Medicine composition and application thereof Download PDFInfo
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- CN115887667A CN115887667A CN202211213443.XA CN202211213443A CN115887667A CN 115887667 A CN115887667 A CN 115887667A CN 202211213443 A CN202211213443 A CN 202211213443A CN 115887667 A CN115887667 A CN 115887667A
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Abstract
The invention discloses a pharmaceutical composition and application thereof. The invention provides a pharmaceutical combination comprising substance X and substance Y. Treatment of endocrine therapy in combination with CDK4/6 inhibitors treatment of breast cancer after development of resistance is better when the first therapeutic agent is used in combination with Fulvestrant.
Description
Technical Field
The invention relates to a pharmaceutical composition and application thereof.
Background
Hormone receptor positive, human epidermal growth factor receptor-2 negative (HR +/HER 2-) breast cancer is one of the most common breast cancers, accounting for approximately 70% of all breast cancers. Although early stage HR +/HER 2-breast cancer can be cured by surgery, some patients still have recurrence or metastasis after postoperative adjuvant endocrine therapy or chemotherapy. The pathogenic factors causing the HR +/HER 2-breast cancer are relatively clear at present, the partial advanced HR +/HER 2-breast cancer is sensitive to first-line endocrine therapy and endocrine and CDK4/6 inhibitor combined therapy, and the survival rate and the quality of life of patients are obviously improved. Currently, endocrine and CDK4/6 inhibitors in combination therapy have shown efficacy in the advanced HR +/HER 2-breast cancer over endocrine therapy, and in the triple phase clinical trial monallesa-2 study, ribociclib in combination with letrozole can increase median progression-free survival in patients from 16 months to 25.3 months of single letrozole. Endocrine therapy in combination with CDK4/6 inhibitors is becoming the first line of choice for HR +/HER 2-breast cancer.
Also the drug targeted against PI3K α, alpelisib, was approved by the FDA in 2019 in combination with Fulvestrant for the treatment of PIK3CA mutated, postmenopausal, advanced or metastatic HR +/HER 2-breast cancer that failed one endocrine therapy. In a three-phase clinical trial based on a mutation in the PIK3CA gene, the median progression-free survival in the Alpelisib in combination with Fulvestrant group was 11 months after first-line endocrine therapy resistance (ref Andre F et al, alpelisib for PIK3CA-Mutated cancer. Nengl J Med 2019. In comparison, also as a second-line clinical trial, endocrine and CDK4/6 inhibitor combination therapy had higher progression-free survival data, as in the monalleesi a-3study, the median progression-free survival in Ribociclib in combination with Fulvestrant was 20.5 months, and even in the PIK3CA-mutated population, the median progression-free survival reached 16.4 months, was more efficacious than in Alpelisib in combination with Fulvestrant, and became the first choice for breast cancer medication of HR +/HER2- (ref. New, P et al. Abstract PD 2-05.
During endocrine therapy in combination with CDK4/6 inhibitors, patients with advanced HR +/HER 2-breast cancer develop resistance at various times after dosing. The research on the mechanism of drug resistance and the search for new therapies to overcome drug resistance are clinical problems that need to be solved urgently.
Disclosure of Invention
The invention aims to solve the technical problem that the endocrine therapy and CDK4/6 inhibitor are combined to produce an effective treatment means for drug-resistant breast cancer, so that the invention provides a pharmaceutical composition and application thereof, and the pharmaceutical composition can treat the breast cancer after the endocrine therapy and CDK4/6 inhibitor are combined to produce drug resistance.
In a first aspect, the present invention provides a pharmaceutical combination comprising substance X and substance Y;
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof;
the structure of the compound I is shown as follows:
in some embodiments, the first therapeutic agent is compound I.
In some embodiments, the pharmaceutical combination consists of the substance X and the substance Y.
In the pharmaceutical combination, the substance X and the substance Y may be administered simultaneously or separately.
Said "simultaneous administration" e.g. substance X and substance Y comprises simultaneous administration in separate pharmaceutical compositions; alternatively, the "separate pharmaceutical composition comprising substance X" is administered simultaneously with the "separate pharmaceutical composition comprising substance Y".
Said "separate administration", e.g. "separate pharmaceutical composition comprising substance X" and "separate pharmaceutical composition comprising substance Y" are administered separately at different times, e.g.: one of the "separate pharmaceutical composition comprising substance X" and "separate pharmaceutical composition comprising substance Y" is administered first, the other subsequently. The separate administrations may be close in time or remote in time.
Whether administered simultaneously or separately, the administration regimen (including route of administration, dosage administered, interval of administration, etc.) of substance X and substance Y may be the same or different, and may be adjusted as needed by one skilled in the art to provide the optimal therapeutic effect.
In some embodiments, the substance X is administered orally.
In some embodiments, the substance Y is administered by injection (e.g., intravenous, subcutaneous, or intramuscular injection).
In some embodiments, the substance X is administered orally; and, said substance Y is administered by subcutaneous injection.
In some embodiments, the substance X is administered orally; and, the substance Y is administered by subcutaneous injection; the first therapeutic agent is compound I.
In another aspect, the present invention provides a pharmaceutical composition a comprising substance X, substance Y and a pharmaceutically acceptable excipient:
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition a consists of the substance X, the substance Y and a pharmaceutical excipient.
The pharmaceutical composition a is a single pharmaceutical composition.
The pharmaceutical composition A can be prepared into various suitable dosage forms according to different administration modes, including a gastrointestinal administration dosage form (such as an oral dosage form) and a parenteral administration dosage form (such as an injection dosage form).
In some embodiments, the pharmaceutical composition a is presented in an oral dosage form.
In some embodiments, the pharmaceutical composition a is presented in an injectable dosage form.
In some embodiments, the first therapeutic agent is compound I.
In another aspect, the present invention also provides a pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition;
the first pharmaceutical composition comprises a substance X and a pharmaceutical excipient, the substance X is a first therapeutic agent or a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtaliisib, AL58805, or HEC68498; and the combination of (a) and (b),
the second pharmaceutical composition comprises a substance Y and pharmaceutic adjuvant, wherein the substance Y is Fulvestrant or pharmaceutically acceptable salt thereof.
The first pharmaceutical composition is a single pharmaceutical composition; the second pharmaceutical composition is a single pharmaceutical composition.
In some embodiments, the pharmaceutical composition B consists of the first and second pharmaceutical compositions.
In some embodiments, the first therapeutic agent is compound I.
In some embodiments, the first pharmaceutical composition is presented in an oral dosage form.
In some embodiments, the second pharmaceutical composition is presented in an injectable (e.g., intravenous, subcutaneous, or intramuscular) dosage form.
In some embodiments, the first pharmaceutical composition is in an oral dosage form; and, the second pharmaceutical composition is presented in an injectable dosage form.
In some embodiments, the first pharmaceutical composition is presented in an oral dosage form; and, the second pharmaceutical composition is in the form of an injectable dosage form; the first therapeutic agent is compound I.
In another aspect, the invention provides the use of substance X, said substance X being a first therapeutic agent or a pharmaceutically acceptable salt thereof, said first therapeutic agent being compound I, samotolisib, copanisib, SHC 014m, pilalaisib, YZJ-0673, gedatolisib, omiplaisib, bimiralisib, voxtalisib, AL58805 or HEC68498, in the manufacture of a medicament for the treatment of breast cancer which is positive for HR, negative for HER2, altered for PIK3CA gene or resistant to treatment with an endocrine therapy in combination with a CDK4/6 inhibitor.
In another aspect, the present invention provides the use of a pharmaceutical combination, pharmaceutical composition a or pharmaceutical composition B as described herein for the manufacture of a medicament for the treatment of breast cancer.
In another aspect, the invention provides the use of substance X, said substance X being a first therapeutic agent, or a pharmaceutically acceptable salt thereof, said first therapeutic agent being compound I, samotolisib, copanisib, SHC014748M, pilalalisib, YZJ-0673, gedatolisib, omiplaisib, bimiralisib, voxtalisib, AL58805 or HEC68498, in the manufacture of a medicament for the treatment of breast cancer, wherein said substance X is in combination with substance Y, said substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof.
In some embodiments, the first therapeutic agent is compound I.
In another aspect, the present invention provides the use of substance Y, said substance Y being Fulvestrant or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of breast cancer, wherein substance Y is used in combination with substance X, said substance X being a first therapeutic agent or a pharmaceutically acceptable salt thereof, said first therapeutic agent being compound I, samotolisb, copanisib, SHC014748M, pilalalisib, YZJ-0673, gedatolisib, omipalisib, bimiralisb, voxalisib, AL58805 or HEC68498.
In some embodiments, the first therapeutic agent is compound I.
In another aspect, the present invention provides a method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical combination, pharmaceutical composition a or pharmaceutical composition B as described herein.
The above uses and methods of treatment:
the breast cancer may be HR positive, HER2 negative, PIK3CA gene altered breast cancer.
The breast cancer may be HR positive, HER2 negative, advanced breast cancer with altered PIK3CA gene.
The breast cancer may be resistant to treatment with an endocrine therapy in combination with a CDK4/6 inhibitor.
The breast cancer can be a breast cancer that is resistant to estradiol in combination with Palbociclib therapy.
The administration regimen (including route of administration, dosage administered, interval of administration, etc.) of substance X and substance Y may be the same or different, and may be adjusted as necessary by those skilled in the art to provide the optimal therapeutic effect.
The substance X and substance Y may be administered simultaneously or separately.
The substance X may be administered by any suitable route known in the art, including orally, by injection (e.g. intravenously, intramuscularly, subcutaneously), etc.
In some embodiments, the substance X is administered orally.
In some embodiments, the substance Y is administered by subcutaneous injection.
In some embodiments, the substance X is administered orally; and, said substance Y is administered by subcutaneous injection.
In some embodiments, substance X is administered orally and substance Y is administered by subcutaneous injection, and the first therapeutic agent is compound I.
The substance X may be administered according to the weight of the patient, and non-limiting example ranges may be 0.01-1mg/kg (meaning a single dose), such as 0.01mg/kg, 0.05mg/kg, 0.1mg/kg, 0.15mg/kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg or 1mg/kg.
In some embodiments, the dose of compound I is 0.05-0.5mg/kg, e.g., 0.2mg/kg.
The above doses of substance X may be administered as a frequent QD (once a day), QOD (every other day), or QW (once a week).
In some embodiments, the substance X is administered on a QD frequency basis.
In some embodiments, the substance X is administered orally at the doses, frequency, described above.
In some embodiments, substance X is administered orally at 0.2mg/kg, QD.
In some embodiments, substance X is administered orally at 0.2mg/kg, QD, and the first therapeutic agent is compound I.
The substance X may also be administered to the patient in a fixed dose, i.e. a fixed or predetermined amount of dose is administered to the patient. Non-limiting example ranges for a fixed dose (referring to a single dose) may be 0.01-50mg, such as 0.01mg, 0.1mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg.
The above-described fixed dose of substance X may be administered frequently with QD (once a day), QOD (every other day), or QW (once a week).
In some embodiments, the substance X is administered on a QD frequency basis.
In some embodiments, the substance X is administered orally in a fixed dose, frequent, as described above.
The substance Y may be administered by any suitable route known in the art, including orally, by injection (e.g. intravenously, intramuscularly, subcutaneously), and the like.
In some embodiments, the substance Y is administered by injection.
The substance Y may be administered according to the weight of the patient, non-limiting example ranges may be 0.01-20mg/kg (referring to a single dose), such as 0.1mg/kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 11mg/kg, 12mg/kg, 13mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 17mg/kg, 18mg/kg, 19mg/kg or 20mg/kg; preferably, the substance Y is administered in a single dose of 0.01-10mg/kg, e.g. 0.1mg/kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg or 10mg/kg, depending on the weight of the patient.
The above dose of substance Y may be administered on a frequent basis of QW (once weekly), BIW (twice weekly) or Q2W (once biweekly).
In some embodiments, the substance Y is administered at the QW frequency at the doses described above.
In some embodiments, the substance Y is administered by injection at the doses, frequency, described above.
The substance Y may also be administered to the patient in a fixed dose, i.e. a fixed or predetermined amount of dose is administered to the patient. Non-limiting example ranges for a fixed dose (meaning a single dose) may be 0.01-20mg, such as 0.01-10mg, e.g. 0.01mg, 0.1mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg. In some embodiments, the dose of substance Y is 1-10mg, e.g., 5mg.
The above-described fixed dose of substance Y may be administered at a frequency of QW (once weekly), BIW (twice weekly) or Q2W (once every two weeks).
In some embodiments, the substance Y is administered at the QW frequency in the above-described fixed dose.
In some embodiments, the substance Y is administered by injection (e.g., intravenously, subcutaneously, or intramuscularly) in a fixed dose, frequently as described above.
In some embodiments, the substance Y is administered by injection in accordance with the fixed dose, QW described above.
In some embodiments, substance Y is administered as a 5mg, QW injection.
In some embodiments, the substance X is administered orally; and, the substance Y is administered by injection (e.g. intravenously, subcutaneously or intramuscularly).
In some embodiments, substance X is administered orally at 0.05-0.5mg/kg, QD; also, the substance Y is administered by injection (e.g., intravenously, subcutaneously, or intramuscularly) at 1-10mg, QW.
In some embodiments, substance X is administered orally at 0.2mg/kg, QD; and, the substance Y was administered by injection (e.g., intravenously, subcutaneously, or intramuscularly) at 5mg.
In some embodiments, substance X is administered orally at 0.2mg/kg, QD, and the first therapeutic agent is compound I; and, the substance Y was administered by injection (e.g., intravenously, subcutaneously, or intramuscularly) at 5mg.
When substance X and substance Y are administered separately, they may be administered continuously according to the respective administration cycles. The administration cycles of substance X and substance Y may start at the same time or at different times. For example, substance X and substance Y may be administered sequentially on the same day, beginning with the respective dosing cycle; alternatively, substance X may be administered starting on the second day or the third day or more after the start of administration of substance Y, and then both are administered continuously according to the respective administration cycles.
A pharmaceutical combination comprising substance X and substance Y;
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof;
the structure of the compound I is shown as follows:
the pharmaceutical combination of claim 1, wherein the first therapeutic agent is compound I.
The pharmaceutical combination of claim 1, wherein substance X and substance Y are administered simultaneously or separately;
and/or, the pharmaceutical combination consists of the substance X and the substance Y.
The pharmaceutical combination according to any one of claims 1 to 3, wherein substance X is administered orally;
and/or, the substance Y is administered by subcutaneous injection.
Item 5. A pharmaceutical composition a comprising a substance X, a substance Y and a pharmaceutical excipient,
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof.
Item 6. The pharmaceutical composition a of item 5, wherein the first therapeutic agent is compound I.
The pharmaceutical composition a according to item 5 or 6, wherein the pharmaceutical composition a is in the form of an oral dosage form or an injectable dosage form;
and/or the pharmaceutical composition A consists of the substance X, the substance Y and a pharmaceutical excipient.
An item 8. A pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition;
the first pharmaceutical composition comprises a substance X and a pharmaceutical excipient, the substance X is a first therapeutic agent or a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtaliisib, AL58805, or HEC68498; and the combination of (a) and (b),
the second pharmaceutical composition comprises a substance Y and pharmaceutic adjuvant, wherein the substance Y is Fulvestrant or pharmaceutically acceptable salt thereof.
Item 9. The pharmaceutical composition B of item 8, wherein the first therapeutic agent is compound I.
The pharmaceutical composition B of any one of claims 8 to 9, wherein the first pharmaceutical composition is in an oral dosage form;
and/or, the second pharmaceutical composition is presented in an injectable dosage form.
Item 11. The pharmaceutical composition B of item 10, wherein the pharmaceutical composition B consists of the first pharmaceutical composition and a second pharmaceutical composition.
Use of a pharmaceutical combination according to any one of claims 1 to 4, a pharmaceutical composition a according to any one of claims 5 to 7 or a pharmaceutical composition B according to any one of claims 8 to 11 for the preparation of a medicament for the treatment of breast cancer.
Use of substance X, which is a first therapeutic agent, compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805, or HEC68498, in the manufacture of a medicament for the treatment of breast cancer, wherein substance X is in combination with substance Y, wherein substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof.
The use of item 14, wherein the first therapeutic agent is compound I.
Use of substance Y, which is Fulvestrant or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of breast cancer, wherein substance Y is used in combination with substance X, wherein substance X is a first therapeutic agent, which is compound I, samotolisb, copanisib, SHC014748M, pilalalisib, YZJ-0673, gedatolisib, omipalisib, bimiralisb, xtvoalilisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof.
The use of item 16, wherein the first therapeutic agent is compound I.
The use of any one of claims 12-16, wherein the breast cancer is HR positive, HER2 negative, PIK3CA gene modified breast cancer.
The use of any one of claims 12-16, wherein the breast cancer is HR positive, HER2 negative, advanced breast cancer with alterations in the PIK3CA gene.
The use of any one of claims 12 to 16, wherein the breast cancer is resistant to treatment with an endocrine therapy in combination with a CDK4/6 inhibitor.
The use of any one of claims 12-16, wherein the breast cancer is resistant to estradiol in combination with Palbociclib therapy.
Use according to any of claims 12 to 20, wherein substance X and substance Y are administered simultaneously or separately.
Use according to any of claims 12 to 20, wherein substance X is administered orally;
and/or, the substance Y is administered by subcutaneous injection.
The use of a substance X, said substance X being a first therapeutic agent or a pharmaceutically acceptable salt thereof, said first therapeutic agent being compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, for the manufacture of a medicament for the treatment of breast cancer which is HR positive, HER2 negative, PIK3CA gene altered or resistant to treatment with an endocrine therapy in combination with a CDK4/6 inhibitor.
The term "treatment" as used herein refers to therapeutic treatment. Where specific conditions are involved, treatment refers to: alleviating one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade leading to or causing the disorder or (b) one or more biological manifestations of the disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of the disorder or disorder.
The term "therapeutically effective amount" as used herein refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The amount of a compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The term "pharmaceutical composition" as used herein refers to a composition containing the specified active ingredient, which can be prepared in the same dosage form.
The term "patient" as used herein refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.
The term "pharmaceutical excipient" as used herein refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances contained in pharmaceutical formulations, except for the active ingredient. See pharmacopoeia of the people's republic of China (2020 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "pharmaceutically acceptable" as used herein means that the acid or base, solvent, adjuvant, etc. used in preparing the salt is generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound prepared with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, hydrogen sulfate, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When compounds contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See, in particular, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977), or, handbook of Pharmaceutical Salts: properties, selection, and Use (P.Heinrich Stahl and Camile G.Wermeth, ed., wiley-VCH, 2002).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: there is provided a pharmaceutical combination comprising a first therapeutic agent and Fulvestrant, the first therapeutic agent and Fulvestrant being more effective when used in combination in the treatment of endocrine therapy in combination with a CDK4/6 inhibitor in the treatment of breast cancer which develops resistance to drugs.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 evaluation of the antitumor Effect of oral Compound I and injection of Fulvestrant combination therapy in an animal model of subcutaneously xenografted female BALB/c nude mice with a CDK4/6 inhibitor-resistant strain of human Breast cancer MCF7 cells with altered HER2, PIK3CA Gene
Experimental materials: DMSO (Sigma), FBS (GIBCO), PRMI1640 (GIBCO), pancreatin (GIBCO), MCF7 cells (ATCC, HTB-22), 100U/mL penicillin and 100. Mu.g/mL streptomycin (GIBCO), estrogen (estradiol benzoate injection, sichuan gold, inc.), palbociclib (Shanghai leaf Biotech Co., ltd.), fulvestrant (Fulvestrant, shanghai Yi chemical Co., ltd.).
The experimental method comprises the following steps:
preparation of CDK4/6 drug-resistant MCF7 tumors: CDK4/6 drug-resistant MCF7 cells were cultured in vitro in monolayer in RPMI1640 medium supplemented with 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin at 37 ℃ with 5% CO 2 Culture under 95% relative humidity conditions, passage with pancreatin digestion twice a week, and digestion of cells for inoculation when the cells are in logarithmic growth phase. MCF7 cells were implanted subcutaneously to construct a CDX model and continued dosing with 100mg/kg palbociclib until tumors appeared to continue growing, defined as P0.After tumor re-passaging, P1 is defined, and so on, and the tumor after n passages is defined as Pn. Passaged tumors were treated with either 50mg/kg or 100mg/kg palbociclib continuously until resistance developed (palbociclib-treated versus solvent control group in animal models was not statistically different). The tumor used in this experiment was P6.
Experimental animals: BALB/c nude mice, female, 6-8 weeks (week old mice when tumor cells were inoculated), weight 17-23g, purchased from Shanghai Protococcurrence scientific institute.
Tumor inoculation: before tumor inoculation, experimental mice were injected subcutaneously with estrogen at an inoculation dose of 0.04mg twice a day. The experimental mice required continuous estrogen injection throughout the entire experimental period. Experimental mice were inoculated approximately 30mm subcutaneously 3 MCF7 tumors resistant to CDK4/6 inhibitors, and tumor growth was observed periodically. Average tumor volume of about 200mm 3 Time, groups were randomized according to tumor size.
Grouping experiments: the test was divided into a solvent control group, a test drug compound I (0.2 mg/kg) group, a test drug Fulvestrant (5 mg/mouse) group, a test drug Palbociclib (50 mg/kg) group, a Palbociclib (50 mg/kg) group in combination with Fulvestrant (5 mg/mouse) group, and a compound I (0.2 mg/kg) group in combination with Fulvestrant (5 mg/mouse) group, with 5 subjects per group, and the specific administration data are shown in Table 1 below. Disease model animals received different treatment regimens and tumor volumes were measured daily until the end of the experiment.
Table 1 example 1 dosing regimen
Remarking:
solvent one: 1% DMSO +99% double distilled water (1% methylcellulose)
Solvent II: 10% ethanol +90% peanut oil
Solvent three: physiological saline
The experimental results are as follows:
on day 21 post-dose, the mean tumor volume of the vehicle control group was 959mm 3 . The average tumor volume of the Palbociclib-treated group was 1091mm 3 There was no significant difference (p = 0.966) compared to the vehicle control group, further validating the model as a CDK4/6 inhibitor resistance model. On day 21 post-dose, the mean tumor volumes of compound I and Fulvestrant groups were 485mm 3 And 929mm 3 TGI was 61.05% and 3.85%, respectively. The p-values for compound I and Fulvestrant dosed groups were p =0.171 and p =1, respectively, statistically without significant difference relative to vehicle control group. The mean tumor volume of the Palbociclib and Fulvestrant combination group was 674mm 3 The TGI was 36.68%, and the combination group was not statistically different (p = 0.604) compared to the vehicle control group. While the mean tumor volume of the group of compound I in combination with Fulvestrant administration was 256mm 3 And the TGI is 90.64%. There was a significant difference (p = 0.021) compared to the control, detailed data as in tables 2 and 3.
TABLE 2
Table 3: evaluation of antitumor drug Effect of each treatment group (calculated based on tumor volume on day 21 after administration)
Note:
a. mean. + -. SEM.
b. Tumor growth inhibition was determined by T/C and TGI (TGI (%) = [1- (T) 21 -T 0 )/(V 21 -V 0 )]X 100).
P values were calculated from tumor volumes.
d. The dose of each test substance in the combination group was the same as that in the single-drug treatment group
And (4) experimental conclusion: taken together, at the end of the experiment, the TGI of compound I in combination with Fulvestrant was 90.64%, whereas the relative tumor proliferation rates (TGI) of compound I alone, fulvestrant alone, and Palbociclib in combination with Fulvestrant were 61.05%,3.85%, and 36.68%, respectively. Therefore, in a CDK4/6 inhibitor-resistant MCF7 cell line subcutaneous xenograft mouse model, compound I in combination with Fulvestrant exhibited significant cancer inhibitory efficacy, superior to compound I alone, fulvestrant alone, and Palbociclib in combination with Fulvestrant, respectively.
Example 2: testing of IC of Compound I in combination with Fulvestrant in MCF7 tumor cell line by CTG method 50
Experimental materials: cellTiter-Glo (CTG) (from Promega), FBS (fetal bovine serum) (from ExCell), 0.25% pancreatin-EDTA (from Gibco), DMSO (from Sigma), MEM medium (from Hyclone), NEAA (from Gibco), fulvestrant (Fulvestrant, from Shanghai Yi Chemicals, ltd.); compound I
The experimental method comprises the following steps:
1) Cell culture
Human breast cancer cells MCF7 in vitro monolayer culture in MEM medium supplemented with 10% fetal bovine serum and 1% NEAA,37 ℃,5% CO 2 Culture under 95% relative humidity conditions, passaging with 0.25% pancreatin-EDTA digested twice a week, and when the cells are in logarithmic growth phase, digesting the cells for inoculation.
2) Cell seeding
Cells in exponential growth phase were collected and counted for viable cells using a Vi-Cell XR Cell counter. The cell suspension is adjusted to the appropriate concentration with the corresponding medium. Add 80. Mu.L of cell suspension to 96-well cell culture plates per well, with a final cell concentration of 8000 cells/well.
3) Adding chemicals for treatment
Each test compound was dissolved in DMSO to prepare a 10mM stock solution. Serial 5-fold gradient dilutions were made in stock and DMSO. Then, the cells were diluted 100-fold in MEM medium. 96-MCF 7 tumor cells in well cell culture plates were added 10 μ L of 10-fold solution of compound I, respectively, in 6X6 format, followed by 10-fold solution of 10 μ L Fulvestrant, respectively, such that compound I in combination with Fulvestrant treated MCF7 tumor cells in 3 replicates per drug concentration, and finally tested for test compound concentration ranges see the compound formulation method and loading design in the following page. Test compounds were diluted to a final DMSO concentration of 0.2% per well. Standing at 37 deg.C, 5% CO 2 Incubate for 72 hours.
4) Read plate detection
After 72 hours of drug treatment, according to the CTG operation instruction, 50 μ L of CTG solution which is pre-melted and equilibrated to room temperature is added into each well, mixed uniformly for 2 minutes by a microplate shaker, placed at room temperature for 10 minutes, and then the fluorescence signal value is measured by an Envision2104 plate reader.
The experimental results are as follows:
the inhibition rate of compound I in combination with Fulvestrant for inhibition of MCF7 proliferation in vitro is shown in table 4 below. Inhibition of MCF7 cells by Fulvestrant single drug was saturated at 8nM with a maximum inhibition of 36.01%. After treatment of cells in combination with compound I, the increase in compound I concentration increased the inhibition to 48.23% (0.32 nM for compound I) at 8nM for Fulvestrant; 63.81% (1.6 nM for Compound I); 73.31% (compound I8 nM).
TABLE 4
And (4) experimental conclusion: taken together, the increase in compound I concentration after treatment of cells in combination with compound I at 8nM increased the inhibition to 48.23% (0.32 nM for compound I); 63.81% (compound I1.6 nM); 73.31% (8 nM for Compound I). In addition, compound i showed an in vitro inhibition of proliferation of 47.96% at a dose of 1.6 nM. At 8nM dose, fulvestrant inhibition was 36.01% in vitro. In contrast, compound I (1.6 nM) in combination with fulvestrant (8 nM) gave an in vitro inhibition of 63.81%.
The experimental results show that the combined treatment of the compound I and Fulvestrant has obviously improved capability of inhibiting the MCF7 cell proliferation in vitro compared with the two single drug groups.
Claims (15)
1. A pharmaceutical combination comprising substance X and substance Y;
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof;
the structure of the compound I is shown as follows:
2. the pharmaceutical combination of claim 1, wherein the first therapeutic agent is compound I;
and/or, the substance X and substance Y are administered simultaneously or separately;
and/or, the pharmaceutical combination consists of the substance X and the substance Y.
3. The pharmaceutical combination according to claim 1 or 2, wherein substance X is administered orally;
and/or, the substance Y is administered by subcutaneous injection.
4. A pharmaceutical composition A comprises substance X, substance Y and pharmaceutical adjuvants,
substance X is a first therapeutic agent which is Compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtalisib, AL58805 or HEC68498, or a pharmaceutically acceptable salt thereof; the first therapeutic agent is preferably compound I;
the substance Y is Fulvestrant or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition A according to claim 4, wherein the pharmaceutical composition A is in the form of an oral dosage form or an injectable dosage form;
and/or the pharmaceutical composition A consists of the substance X, the substance Y and a pharmaceutical excipient.
6. A pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition;
the first pharmaceutical composition comprises a substance X and a pharmaceutical excipient, the substance X is a first therapeutic agent or a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtaliisib, AL58805, or HEC68498; and the combination of (a) and (b),
the second pharmaceutical composition comprises a substance Y and pharmaceutic adjuvant, wherein the substance Y is Fulvestrant or pharmaceutically acceptable salt thereof;
the first therapeutic agent is preferably compound I.
7. The pharmaceutical composition B of claim 6, wherein the first pharmaceutical composition is in an oral dosage form;
and/or, the second pharmaceutical composition is presented in an injectable dosage form.
8. The pharmaceutical composition B of claim 7, wherein said pharmaceutical composition B consists of said first pharmaceutical composition and a second pharmaceutical composition.
9. Use of a pharmaceutical combination according to any one of claims 1 to 3, a pharmaceutical composition a according to claim 4 or 5 or a pharmaceutical composition B according to any one of claims 6 to 8 for the preparation of a medicament for the treatment of breast cancer.
10. Use of substance X, said substance X being a first therapeutic agent, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of breast cancer, said first therapeutic agent being compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, in combination with substance Y, wherein substance Y is fulvestrt or a pharmaceutically acceptable salt thereof; the first therapeutic agent is preferably compound I.
11. Use of substance Y, said substance Y being Fulvestrant or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of breast cancer, in combination with substance X, wherein substance X is a first therapeutic agent, said first therapeutic agent being compound I, samotolisib, copanilb, SHC014748M, pilalalisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498; the first therapeutic agent is preferably compound I.
12. The use of any one of claims 9-11, wherein the breast cancer is HR positive, HER2 negative, PIK3CA gene altered breast cancer;
and/or the breast cancer is advanced breast cancer with HR positive, HER2 negative and PIK3CA gene change;
and/or, the breast cancer is resistant to endocrine therapy in combination with CDK4/6 inhibitor therapy;
and/or, the breast cancer is resistant to estradiol in combination with Palbociclib therapy.
13. Use according to any one of claims 9 to 11, wherein substance X and substance Y are administered simultaneously or separately.
14. The use of any one of claims 9 to 11, wherein substance X is administered orally;
and/or, the substance Y is administered by subcutaneous injection;
and/or the substance X is administered to the patient in a fixed dose in a single dose of 0.01-50mg, such as 0.01mg, 0.1mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg;
and/or substance Y is administered in a single dose of 0.01-20mg/kg, such as 0.1mg/kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 11mg/kg, 12mg/kg, 13mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 17mg/kg, 18mg/kg, 19mg/kg or 20mg/kg, depending on the weight of the patient; preferably, the substance Y is administered in a single dose of 0.01-10mg/kg, e.g. 0.1mg/kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg or 10mg/kg, depending on the weight of the patient.
15. Use of substance X, said substance X being a first therapeutic agent or a pharmaceutically acceptable salt thereof, said first therapeutic agent being compound I, samotolisib, copanisib, SHC014748M, pilalaisib, YZJ-0673, gedatolisib, omipalisib, bimiraisib, voxtaliisib, AL58805 or HEC68498, for the manufacture of a medicament for the treatment of breast cancer which is HR positive, HER2 negative, altered in the PIK3CA gene or resistant to treatment with an endocrine therapy in combination with a CDK4/6 inhibitor.
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| WO2017101829A1 (en) * | 2015-12-16 | 2017-06-22 | 辰欣药业股份有限公司 | Crystal form of pyrido[1,2-a]pyrimidone analog, preparation method therefor and intermediate thereof |
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