WO2016175042A1

WO2016175042A1 - Medicinal agent containing magnesium compound as active ingredient

Info

Publication number: WO2016175042A1
Application number: PCT/JP2016/062053
Authority: WO
Inventors: 勇哉吉村; 孝輔藤崎
Original assignee: 協和化学工業株式会社
Priority date: 2015-04-30
Filing date: 2016-04-15
Publication date: 2016-11-03
Also published as: TW201642877A

Abstract

Provided is an orally administered tablet or granules for preventing or treating renal disorders caused by a platinum-containing chemical agent, the tablet or granules containing 80 mass% or more of at least one magnesium compound selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium silicate, and magnesium citrate.

Description

Pharmaceutical preparation containing magnesium compound as active ingredient

The present invention relates to a pharmaceutical preparation containing a specific magnesium compound that reduces renal damage caused by a drug. More specifically, specific magnesium as an active ingredient for maintaining renal function without reducing renal function in patients with platinum compound-induced renal damage expressed in patients receiving platinum-containing chemical preparations in anticipation of anticancer effects The present invention relates to a pharmaceutical preparation containing a compound.

In recent years, various anti-cancer drug treatments have been performed for the purpose of curing or maintaining malignant tumors and prolonging life or complete cure. Among them, platinum compound responsive malignant tumors (testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, small Platinum-containing chemicals are often prescribed for patients with (cell lung cancer, osteosarcoma, germ cell tumor, malignant pleural mesothelioma, biliary tract cancer). This platinum-containing chemical preparation has a strong anti-cancer action against platinum compound-responsive malignant tumors and is an indispensable anti-cancer agent for treatment, but it often shows severe kidney damage as a side effect. Renal function decline is common in patients undergoing treatment.
Decreased renal function varies from mild to severe, but kidney function deteriorates irreversibly and often causes chronic renal failure. The quality of life (QOL) is greatly reduced. In particular, when platinum-containing chemicals are administered repeatedly over a long period of time, the cumulative toxicity of these drugs necessitates dose reductions and changes to other drugs depending on the patients who have developed renal impairment. It may cause a decrease in Therefore, deterioration of kidney function is considered as a serious side effect that may lead to shortening of life span.
In clinical settings, therapies that promote the excretion of platinum compounds from the kidney include the use of diuretics and hydration therapy in which water is applied by infusion before and after administration of platinum-containing chemicals. A short hydration method with reduced time has also been devised, but it is not enough to prevent renal function decline, and patients are forced to be restrained for a long time by medical practice, and there is a need for alternative measures to reduce kidney damage. It was done.

WO2011 / 052765 gazette

The present inventor prevents or reduces renal damage caused by a platinum-containing chemical preparation by orally administering to a patient, reduces the burden on the patient, eases the time restriction of receiving platinum compound excretion therapy such as hydration, and the like. The development of a formulation that improves the quality of life was promoted.
As a result, it has been found that oral administration of specific magnesium compounds can prevent or reduce the above-mentioned renal damage caused by platinum compounds, ease the burden on patients and time constraints, and improve the acceptability of treatment with anticancer agents. Has developed a pharmaceutical preparation containing a magnesium compound. This pharmaceutical preparation of the present invention can reduce platinum compound-induced renal injury by the action of a specific magnesium compound, can be released from the time restriction of platinum compound excretion therapy of patients in order to reduce renal damage, For example, since it can be taken in the form of tablets or granules, it has been found that the burden on patients can be reduced and the acceptability of anticancer drug treatment can be improved.

The present invention has been achieved based on the above findings, and according to the present invention, the following pharmaceutical preparations and methods for using the same are provided.
(1) 80 or more of at least one magnesium compound selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate for prevention or treatment of renal damage caused by a platinum-containing chemical preparation Tablets or granules for oral administration containing at least mass%.
(2) The tablet or granule according to (1), wherein the magnesium compound is at least one selected from the group consisting of magnesium oxide, magnesium hydroxide, and magnesium citrate.
(3) The tablet or granule according to (1), wherein the magnesium compound is magnesium oxide.
(4) The tablet or granule according to the above (1), which further contains a binder, a disintegrant and a lubricant as additive components.
(5) The tablet or granule according to (1), wherein the disintegration time measured in water does not exceed 30 seconds.
(6) The platinum-containing chemical preparation includes cisplatin (cis-diamine dichloroplatinum), oxaliplatin (cis-1,2-cyclohexanediamine-oxalate platinum), carboplatin (cis-diamine-1,1-cyclobutanedicarboxalate). The tablet or granule according to the above (1), comprising as an active ingredient at least one selected from the group consisting of platinum) and nedaplatin (cis-diamine glycolate platinum).
(7) Orally administering a tablet or granule containing 80% by mass or more of at least one magnesium compound selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate A method for preventing or treating renal damage caused by a platinum-containing chemical preparation.
(8)
80% by mass or more of (A) at least one magnesium compound selected from the group consisting of platinum-containing chemical preparations for cancer prevention or treatment and (B) magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate A pharmaceutical composition comprising a combination of tablets or granules for oral administration.

The tablet or granule of the present invention has an effect of suppressing or reducing platinum compound-induced renal damage by taking a magnesium compound before or during treatment by administration of a platinum-containing chemical preparation as an anticancer agent. The ability to relieve the patient from the time-constrained platinum compound excretion therapy to suppress or alleviate kidney damage, significantly reduce the burden on patients because it can be taken in an oral form, and improve the acceptability of anticancer drug treatment Has the advantage of being able to.
In addition, the tablet or granule of the present invention is excellent in disintegration, and has an advantage that the disintegration time (in water) does not exceed 30 seconds, and preferably 20 seconds or less.

In clinical practice, it has been confirmed that a renal failure is caused by a platinum compound as an anticancer agent, and a method by rapidly excreting and removing the administered platinum compound has been implemented. Specifically, as a therapy to promote the excretion of platinum compounds from the kidney, a therapy using a diuretic or a hydration therapy in which water is loaded by instillation before and after administration of a platinum-containing chemical preparation, in recent years, a short in which the amount of loaded water and loading time are reduced Hydration methods have also been proposed. However, although some of these effects are observed, it is not sufficient to prevent renal function deterioration, and patients are forced to restrain time for long-term medical practices, and alternative measures for reducing kidney damage have been sought. .
It has been found that the tablet or granule containing the magnesium compound of the present invention can be easily taken orally and can reduce the platinum compound-induced renal damage caused by administering the platinum compound before treatment. As a result, it was found that the burden on the platinum compound can be reduced and the acceptability of the anticancer drug treatment can be improved.

The tablet or granule of the present invention contains magnesium oxide, magnesium hydroxide, magnesium silicate, magnesium citrate, or a mixture of two or more thereof as active ingredients. Of these magnesium compounds, magnesium oxide, magnesium hydroxide, or magnesium silicate is preferable, and magnesium oxide is particularly preferable.
The content of the magnesium compound contained in the tablet or granule of the present invention is 80% by mass or more, preferably 80 to 95% by mass, particularly preferably 83 to 92% by mass.

The particle diameter of the magnesium compound for formulating a tablet or granule will be described. In the case of magnesium oxide, the average secondary particle diameter is preferably 0.5 to 10 μm, particularly preferably 1.0 to 7.0 μm. It is.
In the case of magnesium hydroxide, the average secondary particle diameter is preferably 0.5 to 20 μm, particularly preferably 1.0 to 15.0 μm.
In the case of magnesium silicate, the average secondary particle size is preferably 0.5 to 20 μm, particularly preferably 1.0 to 15.0 μm.
In the case of magnesium citrate, the average secondary particle size is preferably 10.0 to 200.0 μm, particularly preferably 50.0 to 150.0 μm.

In order to formulate the tablet or granule of the present invention, the tablet may be tableted or granulated according to an ordinary method using the predetermined ratio of the magnesium compound described above. Specifically, additive components such as a binder, a disintegrant, and a lubricant may be mixed with the magnesium compound particles, and the resulting mixture may be formulated.
The kind and ratio of the additive component at that time will be described.
Binders include sodium carboxymethylcellulose, low substituted hydroxypropylcellulose, corn starch, potato starch, D-mannitol and crystalline cellulose, preferably corn starch, D-mannitol and crystalline cellulose, particularly preferably D-mannitol. And crystalline cellulose. The content of the binder is 1 to 10% by mass, preferably 1.2 to 5% by mass, particularly preferably 1.5 to 3% by mass.
Disintegrants include croscarmellose sodium, carboxymethylcellulose calcium, carmellose, carboxystarch sodium, low-substituted hydroxypropylcellulose and insoluble polyvinylpyrrolidone, preferably croscarmellose sodium, carboxystarch sodium and insoluble polyvinylpyrrolidone, particularly preferably cross Carmellose sodium and insoluble polyvinylpyrrolidone. The content of the disintegrant is 1 to 20% by mass, preferably 5 to 20% by mass, particularly preferably 5 to 10% by mass.
Examples of the lubricant include calcium stearate and magnesium stearate, preferably calcium stearate. The content of the lubricant is 0.5 to 2% by mass, preferably 0.7 to 1.8% by mass, and particularly preferably 0.8 to 1.6% by mass.

Regarding some representative examples of the magnesium compound, the daily intake per person will be described. In the case of magnesium oxide, the lower limit is 0.5 g, preferably 1 g, and the upper limit is 6 g, preferably 5 g. . In the case of magnesium hydroxide, the lower limit is 1 g, preferably 1.5 g, and the upper limit is 8 g, preferably 7 g. In the case of magnesium citrate, the lower limit is 5 g, preferably 10 g, and the upper limit is 75 g, preferably 60 g. In the case of magnesium silicate, the lower limit is 2 g, preferably 4.5 g, and the upper limit is 25 g, preferably 20 g. It should be understood that these lower and upper limit values are general amounts and will vary depending on the extent of renal injury and the patient's condition with the platinum-containing chemical.

The medicament of the present invention contains a magnesium compound as an active ingredient. In order to alleviate platinum compound-induced renal damage, the magnesium compound as an active ingredient is 10 mg, preferably 30 mg, more preferably 50 mg, more preferably 650 mg, preferably 600 mg as the upper limit, in terms of magnesium metal per dose. More preferably, it is desirable to take 500 mg. Desirably, the magnesium concentration in the blood after administration of the pharmaceutical composition of the present invention is 0.75 mmol / L, preferably 0.8 mmol / L, more preferably 0.9 mmol / L, and 2 as the upper limit. It is preferable to administer such that it is maintained at 3 mmol / L, preferably 2.2 mmol / L, more preferably 2.0 mmol / L.
The amount of magnesium described above is the total amount maintained in the blood when used for a single administration, and may be administered as a sustained release preparation that can be absorbed slowly or divided into 2 to 3 portions. it can. When taking in sustained release or divided, the magnesium concentration in the blood is 0.75 mmol / L as a lower limit, preferably 0.8 mmol / L, more preferably 0.9 mmol / L, 2.3 mmol / L as an upper limit, If it can be preferably maintained at 2.2 mmol / L, more preferably 2.0 mmol / L, the amount of medicine to be administered at each time does not need to be equal, and may be appropriately changed. In addition, the medicament of the present invention can be continuously administered 1 to 3 days before administration of the platinum-containing chemical preparation, more preferably from one week before, and can also be continuously administered after administration of the platinum-containing chemical preparation. .

Platinum-containing chemical preparations as anticancer agents are usually mixed with physiological saline or glucose-saline and administered by intravenous infusion. The usage and dose of the platinum-containing chemical preparation may be determined depending on the type of preparation, the type of tumor, the condition of the patient, the presence or absence of concomitant use with other tumor agents, and the dose and frequency are not in a certain range. Specifically, it is prescribed in the Japanese Pharmacopoeia. In the case of cisplatin, the lower limit is 10 mg / m ² once a day (the body surface area, hereinafter the unit of “m ² ” indicates the body surface area), preferably The upper limit is 15 mg / m ² , and the upper limit is 100 mg / m ² , preferably 90 mg / m ² . In the case of oxaliplatin, it is 80 to 150 mg / m ² once a day, in the case of carboplatin, 300 to 400 mg / m ² once a day, and in the case of nedaplatin, 80 to 100 mg / m ² once a day. It is.

Hereinafter, the present invention will be described in detail with reference to examples.

Example 1
(I) Examination method Animal test rats were allowed to take magnesium oxide as a magnesium compound, and the serum magnesium concentration at a predetermined time point from 5 minutes to 72 hours was measured.
(Ii) Magnesium compound used This evaluation relates to a preparation containing magnesium oxide as the magnesium compound. A magnesium oxide preparation in the form of a tablet containing 500 mg of magnesium oxide per tablet was used as the magnesium oxide preparation, and a suspension-disintegrated solution was used for administration to rats. The magnesium oxide used consists of magnesium oxide particles having an average secondary particle size of 0.5 to 10 μm.

Example 1
In order to clarify the migration of magnesium from the magnesium compound into the blood, rats were given a magnesium oxide preparation at a dose of 200 mg / kg or 400 mg / kg, and the serum magnesium concentration was measured. The total dose of each test group was constant (5 mL / kg). Blood was collected every predetermined time, and the magnesium concentration (mmol / L) in serum was evaluated.
Table 1 shows the serum magnesium concentration (mmol / L) of rats administered orally with magnesium oxide.

By taking magnesium oxide as a magnesium compound, the magnesium concentration in the blood can be increased, the blood concentration can be controlled in relation to the dose, and if overdose, the administration of the magnesium can be stopped promptly It was confirmed that it was excreted.

Example 2
(I) Testing method Magnesium oxide was administered as a magnesium compound to the animal test rats, and the amount of magnesium in urine and feces excreted by 72 hours was measured.
(Ii) Magnesium oxide particles used The present evaluation relates to a preparation containing magnesium oxide as a magnesium compound. A magnesium oxide preparation in the form of a tablet containing 500 mg of magnesium oxide per tablet was used as the magnesium oxide preparation, and a suspension-disintegrated solution was used for administration to rats. The magnesium oxide used consists of magnesium oxide particles having an average secondary particle size of 0.5 to 10 μm.

Example 2
In order to clarify the migration rate of magnesium from the magnesium compound, the magnesium oxide preparation was administered to rats at 400 mg / kg as the amount of magnesium oxide, and the amount of magnesium in urine and feces excreted by 72 hours was measured. The total liquid dose was constant (5 mL / kg). Urine and feces were collected every 24 hours, and after measuring the amount of magnesium in each sample, the average values of control urine and fecal magnesium were subtracted, respectively, and the ratio to the dose of magnesium was calculated and evaluated.
Table 2 shows the ratio of magnesium excreted in urine and feces of rats administered orally with magnesium oxide to the dose.

Each data was an average value ± standard deviation.
By taking magnesium oxide as a magnesium compound, about 15% of magnesium is transferred into the blood, and the transfer into blood from Example 1 depends on the dose, so the blood correlated with the dose. It was confirmed that concentration control was possible.

Example 3
(I) Examination Method Rats for animal test were given magnesium oxide as a magnesium compound repeatedly once a day for 7 days, and the serum magnesium concentration was measured 2-3 hours after administration on each day.
(Ii) Magnesium oxide particles used The present evaluation relates to a preparation containing magnesium oxide as a magnesium compound. A magnesium oxide preparation in the form of a tablet containing 500 mg of magnesium oxide per tablet was used as the magnesium oxide preparation, and a suspension-disintegrated solution was used for administration to rats. The magnesium oxide used consists of magnesium oxide particles having an average secondary particle size of 0.5 to 10 μm.

Example 3
In order to clarify the retention in blood after repeated administration of magnesium oxide particles, the magnesium oxide preparation was administered to rats at a dose of 200 mg / kg or 400 mg / kg as the amount of magnesium oxide once a day. It was measured. The dose of each dose was fixed (5 mL / kg). Serum was taken once a day for 7 days, blood was collected every 2-3 hours after administration on each administration day, and the magnesium concentration (mmol / L) in the serum for 7 days was evaluated.
Table 3 below shows the serum magnesium concentration (mmol / L) of rats subjected to repeated oral administration of magnesium oxide for 7 days.

It was confirmed that by taking magnesium oxide as a magnesium compound, the serum magnesium concentration can be increased, the serum magnesium concentration can be maintained continuously by repeated administration for 7 days, and the blood concentration can be controlled in relation to the dose. .

<Elution rate of magnesium compound particles>
Example 4
(I) Test method Based on the Japanese Pharmacopoeia dissolution test method, the amount of magnesium eluted in the first dissolution test solution was measured, and the dissolution rate was calculated from the sample. The dissolution test was carried out using a dissolution tester (NTR-8000AC; Toyama Sangyo Co., Ltd.) and the first dissolution solution (pH 1.2) at a paddle method of 50 rpm. The test preparation is supplied to a dissolution test solution, and a part of the test solution is collected at predetermined time intervals, and the collected test solution is appropriately diluted and measured by an atomic absorption photometry (atomic absorption photometer AA-6300; Shimadzu Corporation). Quantified.
(Ii) Magnesium Compound Particles Used As the magnesium compound particles, magnesium oxide, magnesium hydroxide, magnesium silicate, or magnesium citrate particles were used. Further, as a preparation containing a magnesium compound, a magnesium oxide preparation in the form of a tablet containing 500 mg of magnesium oxide particles per tablet was used as a magnesium oxide preparation.

Example 4
In order to clarify the elution property of magnesium from the magnesium compound, a Japanese Pharmacopoeia elution test was conducted, and the magnesium concentration eluted in the elution test solution was measured. The magnesium concentration was converted with respect to the sample amount, and the elution rate of the magnesium compound was calculated.
The elution rate (%) of the magnesium compound is shown in Table 4 below.

It was suggested that by taking magnesium compound particles, magnesium is eluted in the stomach and the concentration of magnesium in the blood can be increased.

Example 5
(I) Test method Magnesium oxide-containing food was given to 8-week-old SD male rats. This diet contained 400 mg / kg of magnesium oxide as a daily dose. On the other hand, cisplatin 7.0 mg / kg was intraperitoneally administered and blood was collected to evaluate renal function. The diet was given and acclimatized from one week before cisplatin administration and continued from the end of cisplatin administration until the end of the study. The time of blood collection was before cisplatin administration and 1, 3, 5, 7, 14, 21, and 28 days after administration, and renal function evaluation items were creatinine (Cre) and blood urea nitrogen (BUN).
(Ii) Magnesium oxide used In this evaluation, a feed in which magnesium oxide sold as a food additive was kneaded into an animal feed was used, and a feed corresponding to the daily feed amount was given as a feed.

Reference example 1:
In Example 5, renal function was evaluated in the same manner as in Example 5 except that a normal diet containing no magnesium oxide was given.
The results of Example 5 and Reference Example 1 are collectively shown in Tables 5 and 6 below.

Results of Example 5

Results of Reference Example 1

Comparison of Evaluation between Example 5 and Reference Example 1 In Example 5, it was shown that an increase in creatinine and an increase in blood urea nitrogen were clearly suppressed, and renal damage caused by cisplatin was reduced. In addition, since magnesium was rapidly excreted even when it moved into the blood, it did not accumulate, indicating the effectiveness of a diet containing MgO.
In Reference Example 1, creatinine and blood urea nitrogen were remarkably increased with a decrease in renal function, and an increase in blood Mg level was observed due to the migration of magnesium leaked from cells due to cell damage caused by cisplatin into the blood.

Example 6
(I) Test method Eight weeks old SD male rats were usually fed. Rats were orally administered 200 mg / kg of magnesium oxide. On the other hand, cisplatin 7.0 mg / kg was intraperitoneally administered and blood was collected to evaluate renal function. Magnesium oxide to be administered was suspended in 0.5% CMC-Na in 500 mg magnesium oxide tablet to 40 mg / mL, and then 5 mL / kg was orally administered to rats once a day. Oral administration of magnesium oxide was continued from 3 days before cisplatin administration to 1 day after administration. The time of blood collection was before cisplatin administration and 1, 3, 5, 7, 14, 21, and 28 days after administration, and renal function evaluation items were creatinine (Cre) and blood urea nitrogen (BUN).
(Ii) Magnesium oxide used In this evaluation, a magnesium oxide preparation in the form of a tablet containing 500 mg of magnesium oxide per tablet was used as the magnesium oxide preparation, and the suspension was disintegrated for administration to rats. . The magnesium oxide used consists of magnesium oxide particles having an average secondary particle size of 0.5 to 10 μm.

Reference example 2:
In Example 6, renal function was evaluated in the same manner as in Example 6 except that magnesium oxide was not orally administered.
The results of Example 6 and Reference Example 2 are collectively shown in Tables 7 and 8 below.

Results of Example 6

Result of Reference Example 2

Comparison of Evaluation between Example 6 and Reference Example 2 In Example 6, as compared with Reference Example 2, an increase in creatinine and an increase in blood urea nitrogen were suppressed, and it was shown that renal damage caused by cisplatin was reduced. In addition, no increase in blood magnesium level due to oral administration of magnesium oxide was observed, indicating the effectiveness of oral administration of magnesium oxide.
On the other hand, in Reference Example 2, creatinine and blood urea nitrogen significantly increased with a decrease in renal function.

Industrial applicability

The pharmaceutical preparation of the present invention can prevent or reduce renal damage caused by drugs, can greatly reduce the burden on patients treated with anticancer drugs, and improve the quality of life.

Claims

80% by mass or more of at least one magnesium compound selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate for prevention or treatment of renal damage caused by a platinum-containing chemical preparation Contains tablets or granules for oral administration.
The tablet or granule according to claim 1, wherein the magnesium compound is at least one selected from the group consisting of magnesium oxide, magnesium hydroxide, and magnesium citrate.
The tablet or granule according to claim 1, wherein the magnesium compound is magnesium oxide.
The tablet or granule according to claim 1, further comprising a binder, a disintegrant and a lubricant as additive components.
The tablet or granule according to claim 1, wherein the disintegration time measured in water does not exceed 30 seconds.
The platinum-containing chemical formulation includes cisplatin (cis-diamine dichloroplatinum), oxaliplatin (cis-1,2-cyclohexanediamine-oxalate platinum), carboplatin (cis-diamine-1,1-cyclobutanedicarboxalate platinum) and The tablet or granule according to claim 1, comprising at least one selected from the group consisting of nedaplatin (cis-diamine glycolate platinum) as an active ingredient.
Platinum-containing chemistry characterized by orally administering a tablet or granule containing 80% by mass or more of at least one magnesium compound selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate A method for preventing or treating renal damage caused by a pharmaceutical preparation.
80% by mass or more of (A) at least one magnesium compound selected from the group consisting of platinum-containing chemical preparations for cancer prevention or treatment and (B) magnesium oxide, magnesium hydroxide, magnesium silicate and magnesium citrate A pharmaceutical composition comprising a combination of tablets or granules for oral administration.