WO2024063537A1 - Pharmaceutical composition comprising sacubitril valsartan calcium salt - Google Patents
Pharmaceutical composition comprising sacubitril valsartan calcium salt Download PDFInfo
- Publication number
- WO2024063537A1 WO2024063537A1 PCT/KR2023/014295 KR2023014295W WO2024063537A1 WO 2024063537 A1 WO2024063537 A1 WO 2024063537A1 KR 2023014295 W KR2023014295 W KR 2023014295W WO 2024063537 A1 WO2024063537 A1 WO 2024063537A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sacubitril
- pharmaceutical composition
- valsartan
- calcium salt
- dissolution
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 55
- 229960003953 sacubitril Drugs 0.000 title claims description 44
- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims description 42
- 229960004699 valsartan Drugs 0.000 title claims description 40
- -1 sacubitril valsartan calcium salt Chemical class 0.000 title description 7
- 238000004090 dissolution Methods 0.000 claims abstract description 84
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 41
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- 159000000003 magnesium salts Chemical class 0.000 claims abstract description 19
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 claims description 42
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 33
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Images
Classifications
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- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt and colloidal silicon dioxide, with improved drug dissolution.
- Korean Patent No. 10-2149125 suggested a novel sacubitril calcium salt/valsartan co-amorphous form overcoming the problems of sacubitril ⁇ valsartan sodium 2.5 hydrate, but had a new problem caused by strong hygroscopicity thereof.
- Korean Patent Laid-Open Publication No. 10-2022-0012821 which is a related art patent filed by the present applicant, suggested a novel sacubitril ⁇ valsartan calcium salt that solved the problem of hygroscopicity of sacubitril ⁇ valsartan sodium 2.5 hydrate and sacubitril ⁇ valsartan sodium 3 hydrate, but still had a problem with poor solubility and absorption rate in the body.
- An object of the present invention is to provide a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt that is stable with improved hygroscopicity and has an improved dissolution rate as compared to conventional sacubitril ⁇ valsartan sodium salt.
- an object of the present invention is to provide a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt and colloidal silicon dioxide, with improved drug dissolution.
- Another object of the present invention is to provide a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt, colloidal silicon dioxide, and inorganic magnesium salt, with improved drug dissolution.
- the present invention provides a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt and colloidal silicon dioxide.
- the sacubitril ⁇ valsartan calcium salt of the present invention refers to a calcium salt of a compound in which sacubitril and valsartan are combined.
- the sacubitril ⁇ valsartan calcium salt of the present invention refers to sacubitril ⁇ valsartan calcium salt hydrate described in Korean Patent Laid-Open Publication No. 10-2022-0012821, which was invented and filed by the present applicant.
- sacubitril ⁇ valsartan calcium salt referred to in the present invention may be a sacubitril ⁇ valsartan calcium salt hydrate represented by the following Chemical Formula 1:
- n is 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.
- the sacubitril ⁇ valsartan calcium salt hydrate of the present invention may be 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, 2.5 hydrate, 3 hydrate, 3.5 hydrate or 4 hydrate.
- sacubitril ⁇ valsartan calcium salt hydrate of the present invention may be crystalline.
- n may be 4.
- the sacubitril ⁇ valsartan calcium salt of the present invention may be sacubitril ⁇ valsartan calcium salt tetrahydrate.
- the sacubitril ⁇ valsartan calcium salt may be prepared, for example, according to a method for preparing sacubitril ⁇ valsartan calcium salt hydrate described in Korean Patent Laid-Open Publication No. 10-2022-0012821, or may be prepared by using other methods known to those skilled in the art.
- the sacubitril ⁇ valsartan calcium salt of the present invention overcomes the disadvantage of sacubitril, i.e., low stability, by forming a complex, and has excellent physical and chemical properties compared to the conventional sacubitril ⁇ valsartan sodium salt in terms of hygroscopicity, thereby making it possible to be usefully utilized as an active ingredient of a pharmaceutical composition.
- the present inventors have found that the sacubitril ⁇ valsartan calcium salt had a problem of a low absorption rate in the body due to low solubility, and have studied and made efforts to solve the problem, and as a result, they have confirmed that the drug release could be dramatically improved by adding colloidal silicon dioxide to the composition or selectively further adding inorganic magnesium salt to thereby increase the dispersing power of the active ingredient.
- sacubitril ⁇ valsartan sodium salt 2.5 hydrate and sacubitril ⁇ valsartan sodium salt trihydrate according to the related art was compared for sacubitril ⁇ valsartan calcium salt tetrahydrate according to the present invention.
- sacubitril ⁇ valsartan calcium salt had about 10 times lower solubility of sacubitril as compared to sacubitril ⁇ valsartan sodium salts (Experimental Example 1).
- a solubilizer or a disintegrant is used to increase the release of an active ingredient in a pharmaceutical composition such as a tablet.
- the present invention is characterized by providing a pharmaceutical composition comprising sacubitril ⁇ valsartan calcium salt with well dispersion of an active ingredient and a significantly increased release rate by comprising colloidal silicon dioxide in the pharmaceutical composition and selectively adding inorganic magnesium salt thereto without using the above conventional means for improving release.
- the colloidal silicon dioxide contained in the pharmaceutical composition of the present invention dramatically increases the dissolution rate of sacubitril and valsartan, wherein the colloidal silicon dioxide included therein preferably has an amount of 5 to 15 wt% based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the colloidal silicon dioxide may be contained in an amount of 7 to 13 wt% based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the amount of the colloidal silicon dioxide is small to the level of the amount of the lubricant or glidant used when designing conventional oral solid dosage forms, i.e., when the amount of the colloidal silicon dioxide is less than 5 wt% based on the weight of sacubitril ⁇ valsartan calcium salt, it is not possible to achieve the effect of improving the dissolution rate, which is the object of the present invention.
- the colloidal silicon dioxide is included in an amount of more than 15 wt% based on the weight of sacubitril ⁇ valsartan calcium salt, the density of the composition is lowered, which is disadvantageous for mass production.
- Example 1 a comparative dissolution test was performed between Comparative Example 1 containing sacubitril ⁇ valsartan calcium salt as the main component and colloidal silicon dioxide in an amount of about 2 mg, which is the desired amount of the conventional lubricant or glidant, and Example 1 containing sacubitril ⁇ valsartan calcium salt as the main component and the colloidal silicon dioxide in an amount of 20 mg, i.e., a 10-fold increase of the above desired amount.
- the dissolution rates of both sacubitril and valsartan of Example 1 was significantly increased at pH 1.2 and pH 4.5 compared to those of Comparative Example 1 (Experimental Example 3).
- Example 2 a comparative dissolution test was performed on Example 2 containing sacubitril ⁇ valsartan calcium salt as a main component and 30 mg of colloidal silicon dioxide, which is 15 times the usual amount of 2 mg of colloidal silicon dioxide.
- the dissolution rates of both sacubitril and valsartan at pH 1.2 and pH 4.5 were further increased compared to those of Example 1, which were improved to the same as or similar level to the reference drug (Entresto film-coated tablet 200 mg) (Experimental Example 5).
- the pharmaceutical composition of the present invention may further comprise an inorganic magnesium salt in addition to colloidal silicon dioxide.
- the present inventors studied the additional introduction of an alkalizing agent to improve the release of the sacubitril ⁇ valsartan calcium salt composition by focusing on the fact that the solubility of sacubitril ⁇ valsartan increases at higher pH than at low pH.
- the inorganic magnesium salt of the present invention is preferably contained in 10 to 30 wt% based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the inorganic magnesium salt may be contained in 15 to 20 wt% based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the inorganic magnesium salt of the present invention may be magnesium oxide or magnesium carbonate.
- the inorganic magnesium salt of the present invention may be magnesium oxide.
- the pharmaceutical composition of the present invention comprises all of sacubitril ⁇ valsartan calcium salt and colloidal silicon dioxide and inorganic magnesium salt.
- the colloidal silicon dioxide may be contained in the pharmaceutical composition of the present invention in an amount of 5 to 15 wt%, and the inorganic magnesium salt may be contained therein in an amount of 10 to 30 wt%, based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the colloidal silicon dioxide may be contained in the pharmaceutical composition of the present invention in an amount of 7 to 13 wt%, and the inorganic magnesium salt may be contained therein in an amount of 15 to 20 wt%, based on the weight of the sacubitril ⁇ valsartan calcium salt.
- the pharmaceutical composition of the present invention is characterized in that 85% or more of sacubitril and valsartan are dissolved after 30 minutes from the onset of dissolution, respectively, during the dissolution test under the conditions of 37 ⁇ 0.5 °C, pH 4.5 test solution, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of General Test Method of the Korean Pharmacopoeia.
- Example 4 the animal PK test was performed on Example 1 showing a lower dissolution rate than the reference drug (Entresto film-coated tablet 200 mg) only at pH 4.5, and as a result, the unequal results were shown in bioavailability (Experimental Example 4).
- the dissolution rate at 30 minutes from the onset of dissolution at pH 4.5 is very important to secure the bioequivalence of the sacubitril ⁇ valsartan calcium salt composition, and in order to achieve the desired bioavailability, it is required to show a dissolution rate of at least 85% or higher, which is similar to the dissolution rate of the reference drug, i.e., about 95% at a minimum pH of 4.5.
- the pharmaceutical composition of the present invention is characterized in that dissolution rates of sacubitril and valsartan therein are equivalent to dissolution rates of sacubitril and valsartan in Entresto film-coated tablet TM having the same active ingredient dose.
- the pharmaceutical composition is characterized to show the area under the blood concentration-time curve (AUC) and maximum blood concentration (C max ) that are biologically equivalent to Entresto film-coated tablet TM having the same active ingredient dose.
- AUC blood concentration-time curve
- C max maximum blood concentration
- the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive commonly contained in oral solid dosage forms.
- the additive may further comprise, for example, any one or more selected from the group consisting of excipients, disintegrants, binders, lubricants, and coating agents, and is not limited thereto as long as the present invention has the desired effect.
- the excipient usable in the present invention may be, for example, microcrystalline cellulose, lactose, corn starch, potato starch, wheat starch, sucrose, glucose, fructose, D-mannitol, synthetic aluminum silicate, calcium monohydrogen phosphate, dextrin, sodium alginate, methyl cellulose, carboxymethyl cellulose sodium, kaolin, colloidal silica gel, hydroxypropyl starch, dextrin, dextrose, or a mixture thereof, but is not limited thereto.
- the disintegrant usable in the present invention may be, for example, at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, pregelatinized starch, sodium croscarboxymethylcellulose, and a mixture thereof, but is not limited thereto.
- the binder usable in the present invention may be, for example, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, pregelatinized starch, or a mixture thereof, but is not limited thereto.
- the lubricant usable in the present invention may be, for example, colloidal silicon dioxide, talc, magnesium stearate, magnesium aluminometasilicate, glyceryl behenate, calcium stearate, stearic acid, sodium stearyl fumarate, or a mixture thereof, but is not limited thereto.
- the coating agent usable in the present invention may be, for example, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the like, or trade name Opadry ® or a mixture thereof, but is not limited thereto.
- composition of the present invention may be administered in various forms, for example, granules, tablets, capsules, dry syrup, and the like.
- the pharmaceutical composition of the present invention may be in tablet form.
- the method of preparation may be performed according to the methods described in Examples of the present invention or any method known in the art of the present invention.
- the pharmaceutical composition of the present invention may additionally include a coating layer on the outside.
- the coating layer may be formed according to a method for forming a film coating layer commonly used on the surface of a plain tablet.
- composition of the present invention may be significantly useful for preventing or treating heart failure.
- the preventive and therapeutic effects of sacubitril and valsartan on heart failure and pharmacological mechanisms thereof are well known in the art.
- the present invention provides a method for treating or preventing heart failure, comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof.
- the subject may be a mammal, including a human.
- terapéuticaally effective amount refers to an amount of the pharmaceutical composition effective for the treatment or prevention of heart failure.
- pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level may be determined depending on the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field.
- the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a commercially available therapeutic agent.
- the pharmaceutical composition of the present invention may be administered singly or in multiple doses. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with the minimum amount without side effects, which may be easily determined by those skilled in the art.
- the administration dose of the pharmaceutical composition of the present invention may be determined by specialists according to various factors such as the patient's condition, age, sex, complications, and the like.
- the present invention provides a use of the pharmaceutical composition for use in the manufacture of a medicament for use in the treatment or prevention of heart failure.
- the above-described pharmaceutical composition for the manufacture of a medicament may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation together with other active agents to have a synergistic action of the active ingredients.
- the pharmaceutical composition comprising the sacubitril ⁇ valsartan calcium salt of the present invention may have excellent dissolution rate and bioavailability while having low hygroscopicity compared to conventional sacubitril ⁇ valsartan sodium salt.
- FIG. 1 shows the results of animal Pharmacokinetics (PK) tests for sacubitril of the reference drug, Test Drug 1 (Comparative Example 1), and Test Drug 2 (Example 1).
- PK Pharmacokinetics
- FIG. 2 shows the results of animal Pharmacokinetics (PK) tests for valsartan of the reference drug, Test Drug 1 (Comparative Example 1), and Test Drug 2 (Example 1).
- PK Pharmacokinetics
- Sacubitril ⁇ valsartan calcium salt tetrahydrate was synthesized and used according to the method described in Preparation Examples 1, 2 and Example 1 of Korean Patent Publication No. 10-2022-0012821.
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- the solubility test results are HPLC analysis results at 24 hours, which are shown in Table 1 below.
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- sacubitril ⁇ valsartan sodium salt trihydrate showed dissolution rates of about 100% for both sacubitril and valsartan from 5 minutes after the onset of dissolution.
- sacubitril ⁇ valsartan calcium salt tetrahydrate showed significantly low dissolution rates of about 30% for sacubitril and about 50% for valsartan at 30 minutes from the onset of dissolution, and even after 1 hour from the onset of dissolution and stirring at 200 rpm for 15 minutes, sacubitril showed about 50% dissolution rate and valsartan showed about 70% dissolution rate, confirming that the final dissolution rates of sacubitril ⁇ valsartan calcium salt tetrahydrate were lower than those of sacubitril ⁇ valsartan sodium salt.
- Example 1 having a higher colloidal silicon dioxide content than Comparative Example 1 was prepared.
- sacubitril ⁇ valsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, and a binder in the amounts shown in Table 3 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient, a disintegrant, and a binder were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed. Comparative Example 1 and Example 1 were prepared by tableting and coating the final mixtures.
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- Example 1 As a result, as shown in Table 4, it could be confirmed that in Comparative Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of sacubitril in pH 6.8 and purified water were similar to those of the reference drug, but the dissolution rates of sacubitril at pH 1.2 and pH 4.5 were significantly lower than those of the reference drug. In addition, it could be confirmed that in Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of sacubitril in pH 1.2, pH 6.8, and purified water were similar to those of the reference drug, and the dissolution rate of sacubitril at pH 4.5 was increased by about 2 times compared to Comparative Example 1, but the dissolution rate thereof was reduced by about 30% compared to the reference drug.
- Test Drug 1 Comparative Example 1
- Test Drug 2 Example 1
- Blood collection points blank, 0.083, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24 hr (14 points)
- Example 1 showed that the dissolution rates of sacubitril and valsartan in pH 1.2, pH 6.8, and purified water were equal or similar to those of the reference drug, but there was a difference in dissolution rate at pH 4.5 from the reference drug at 30 minutes from the onset of dissolution.
- Comparative Example 1 and Example 1 showed as results of in vivo animal PK tests that the 90% confidence intervals of AUC and C max were out of the range of 0.8 to 1.25, and all of the T/R ratios also showed biologically non-equivalent results except for the valsartan AUC value of Comparative Example 1.
- the dissolution rate at 30 minutes from the onset of dissolution at a minimum pH of 4.5 should be at least 85% or more, which is similar to the dissolution rate of the reference drug of about 95%.
- Comparative Example 2 which did not contain colloidal silicon dioxide at all, and Example 2, in which the amount of colloidal silicon dioxide was further increased compared to Example 1, were prepared.
- sacubitril ⁇ valsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, and a binder in the amounts shown in Table 7 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient, a disintegrant, and a binder were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed.
- Comparative Example 2 and Example 2 were prepared by tableting and coating the final mixtures.
- dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Comparative Example 2 and Example 2.
- the reference drug, Comparative Example 2, and Example 2 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ⁇ 0.5 °C, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia.
- the HPLC analysis conditions were as follows:
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- compositions of Examples 3 to 7 containing various alkalizing agents were prepared to confirm the degree of improvement in the release rate according to the use of the alkalizing agent. Specifically, sacubitril ⁇ valsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient and an alkalizing agent in the amount shown in Table 10 below. Then, a binder solution was added to prepare granules, followed by granulation and drying. An excipient and a disintegrant were added to the dried sized product and mixed, and then a lubricant was added thereto and finally mixed. Examples 3 to 7 were prepared by tableting and coating the final mixtures.
- dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Examples 3 to 7. Specifically, the reference drug, and Examples 3 to 7 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ⁇ 0.5 °C, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia.
- the HPLC analysis conditions were as follows:
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- Example 6 containing sodium carbonate was hardly dissolved with a dissolution rate of less than 10% at 30 minutes from the onset of dissolution
- Examples 4 and 5 containing calcium carbonate or sodium bicarbonate also showed the sacubitril dissolution rate of about 30%.
- Examples 3 and 7 containing inorganic magnesium salts showed the sacubitril dissolution rate of about 60%, which was about 5 to 7 times greater than that of Example 6 and about 2 times greater than that of Examples 4 and 5.
- Example 6 containing sodium carbonate was hardly dissolved with a dissolution rate of 16.4% at 30 minutes from the onset of dissolution, and Examples 4 and 5 containing calcium carbonate or sodium bicarbonate also showed the valsartan dissolution rate of about 60%. Meanwhile, Examples 3 and 7 containing inorganic magnesium salts showed the valsartan dissolution rate of 70% or more at 30 minutes from the onset of dissolution, and in particular, Example 3 showed the valsartan dissolution rate of 95% or more, confirming that the dissolution rate was very similar to that of the reference drug.
- sacubitril ⁇ valsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, a binder, and an alkalizing agent in the amounts shown in Table 13 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient and a disintegrant were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed.
- Example 8 was prepared by tableting and coating the final mixture.
- Mobile phase A Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
- Mobile phase B Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
- Example 8 showed that as compared to the reference drug, all the T/R values of sacubitril, sacubitrilat which is sacubitril's active metabolite, and valsartan were close to 1, which was confirmed to have a bioequivalence level to the reference drug.
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Abstract
The pharmaceutical composition containing the sacubitrilㆍvalsartan calcium salt of the present invention comprises colloidal silicon dioxide and optionally further comprises inorganic magnesium salt to have excellent dissolution rate and bioavailability while having low hygroscopicity compared to conventional sacubitrilㆍvalsartan sodium salt.
Description
The present invention relates to a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt and colloidal silicon dioxide, with improved drug dissolution.
Novartis' sacubitrilㆍvalsartan co-crystal, marketed under the trade name Entresto, has been effectively used in the treatment of chronic heart failure. Entresto is a dual-acting compound of valsartan, an angiotensin receptor blocker (ARB), and sacubitril, a neprilysin inhibitor (NEPi). However, it has been reported that sacubitrilㆍvalsartan sodium 2.5 hydrate, the main ingredient of Entresto, has poor stability and significantly poor ease of formulation.
Accordingly, Korean Patent No. 10-2149125 suggested a novel sacubitril calcium salt/valsartan co-amorphous form overcoming the problems of sacubitrilㆍvalsartan sodium 2.5 hydrate, but had a new problem caused by strong hygroscopicity thereof.
In addition, Korean Patent Laid-Open Publication No. 10-2022-0012821, which is a related art patent filed by the present applicant, suggested a novel sacubitrilㆍvalsartan calcium salt that solved the problem of hygroscopicity of sacubitrilㆍvalsartan sodium 2.5 hydrate and sacubitrilㆍvalsartan sodium 3 hydrate, but still had a problem with poor solubility and absorption rate in the body.
Therefore, it is necessary to develop a novel sacubitrilㆍvalsartan formulation having excellent dissolution and bioavailability while solving the problem of hygroscopicity of the sacubitrilㆍvalsartan formulation.
An object of the present invention is to provide a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt that is stable with improved hygroscopicity and has an improved dissolution rate as compared to conventional sacubitrilㆍvalsartan sodium salt.
Specifically, an object of the present invention is to provide a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt and colloidal silicon dioxide, with improved drug dissolution.
Further, another object of the present invention is to provide a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt, colloidal silicon dioxide, and inorganic magnesium salt, with improved drug dissolution.
In one general aspect, the present invention provides a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt and colloidal silicon dioxide.
The sacubitrilㆍvalsartan calcium salt of the present invention refers to a calcium salt of a compound in which sacubitril and valsartan are combined.
Specifically, the sacubitrilㆍvalsartan calcium salt of the present invention refers to sacubitrilㆍvalsartan calcium salt hydrate described in Korean Patent Laid-Open Publication No. 10-2022-0012821, which was invented and filed by the present applicant.
More specifically, the sacubitrilㆍvalsartan calcium salt referred to in the present invention may be a sacubitrilㆍvalsartan calcium salt hydrate represented by the following Chemical Formula 1:
[Chemical Formula 1]
in Chemical Formula 1 above, n is 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4.
The sacubitrilㆍvalsartan calcium salt hydrate of the present invention may be 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, 2.5 hydrate, 3 hydrate, 3.5 hydrate or 4 hydrate.
In addition, the sacubitrilㆍvalsartan calcium salt hydrate of the present invention may be crystalline.
Preferably, in Chemical Formula 1 above, n may be 4.
Specifically, the sacubitrilㆍvalsartan calcium salt of the present invention may be sacubitrilㆍvalsartan calcium salt tetrahydrate.
The sacubitrilㆍvalsartan calcium salt may be prepared, for example, according to a method for preparing sacubitrilㆍvalsartan calcium salt hydrate described in Korean Patent Laid-Open Publication No. 10-2022-0012821, or may be prepared by using other methods known to those skilled in the art.
The sacubitrilㆍvalsartan calcium salt of the present invention overcomes the disadvantage of sacubitril, i.e., low stability, by forming a complex, and has excellent physical and chemical properties compared to the conventional sacubitrilㆍvalsartan sodium salt in terms of hygroscopicity, thereby making it possible to be usefully utilized as an active ingredient of a pharmaceutical composition.
However, the present inventors have found that the sacubitrilㆍvalsartan calcium salt had a problem of a low absorption rate in the body due to low solubility, and have studied and made efforts to solve the problem, and as a result, they have confirmed that the drug release could be dramatically improved by adding colloidal silicon dioxide to the composition or selectively further adding inorganic magnesium salt to thereby increase the dispersing power of the active ingredient.
Specifically, the solubility in purified water was compared for sacubitrilㆍvalsartan sodium salt 2.5 hydrate and sacubitrilㆍvalsartan sodium salt trihydrate according to the related art, and sacubitrilㆍvalsartan calcium salt tetrahydrate according to the present invention. As a result, it could be confirmed that sacubitrilㆍvalsartan calcium salt had about 10 times lower solubility of sacubitril as compared to sacubitrilㆍvalsartan sodium salts (Experimental Example 1).
It could be confirmed that this low water solubility of sacubitrilㆍvalsartan calcium salt had a significant effect on the dissolution of the main component, and thus the dissolution rates of sacubitril and valsartan in sacubitrilㆍvalsartan calcium salt were significantly lower than those of sacubitrilㆍvalsartan sodium salt (Experimental Example 2).
In general, a solubilizer or a disintegrant is used to increase the release of an active ingredient in a pharmaceutical composition such as a tablet.
Meanwhile, the present invention is characterized by providing a pharmaceutical composition comprising sacubitrilㆍvalsartan calcium salt with well dispersion of an active ingredient and a significantly increased release rate by comprising colloidal silicon dioxide in the pharmaceutical composition and selectively adding inorganic magnesium salt thereto without using the above conventional means for improving release.
The colloidal silicon dioxide contained in the pharmaceutical composition of the present invention dramatically increases the dissolution rate of sacubitril and valsartan, wherein the colloidal silicon dioxide included therein preferably has an amount of 5 to 15 wt% based on the weight of the sacubitrilㆍvalsartan calcium salt.
Further, more preferably, the colloidal silicon dioxide may be contained in an amount of 7 to 13 wt% based on the weight of the sacubitrilㆍvalsartan calcium salt.
When the amount of the colloidal silicon dioxide is small to the level of the amount of the lubricant or glidant used when designing conventional oral solid dosage forms, i.e., when the amount of the colloidal silicon dioxide is less than 5 wt% based on the weight of sacubitrilㆍvalsartan calcium salt, it is not possible to achieve the effect of improving the dissolution rate, which is the object of the present invention. When the colloidal silicon dioxide is included in an amount of more than 15 wt% based on the weight of sacubitrilㆍvalsartan calcium salt, the density of the composition is lowered, which is disadvantageous for mass production.
In a specific Experimental Example, a comparative dissolution test was performed between Comparative Example 1 containing sacubitrilㆍvalsartan calcium salt as the main component and colloidal silicon dioxide in an amount of about 2 mg, which is the desired amount of the conventional lubricant or glidant, and Example 1 containing sacubitrilㆍvalsartan calcium salt as the main component and the colloidal silicon dioxide in an amount of 20 mg, i.e., a 10-fold increase of the above desired amount. As a result, it could be confirmed that the dissolution rates of both sacubitril and valsartan of Example 1 was significantly increased at pH 1.2 and pH 4.5 compared to those of Comparative Example 1 (Experimental Example 3).
In addition, in another specific Experimental Example, a comparative dissolution test was performed on Example 2 containing sacubitrilㆍvalsartan calcium salt as a main component and 30 mg of colloidal silicon dioxide, which is 15 times the usual amount of 2 mg of colloidal silicon dioxide. As a result, it could be confirmed that the dissolution rates of both sacubitril and valsartan at pH 1.2 and pH 4.5 were further increased compared to those of Example 1, which were improved to the same as or similar level to the reference drug (Entresto film-coated tablet 200 mg) (Experimental Example 5).
Preferably, the pharmaceutical composition of the present invention may further comprise an inorganic magnesium salt in addition to colloidal silicon dioxide.
The present inventors studied the additional introduction of an alkalizing agent to improve the release of the sacubitrilㆍvalsartan calcium salt composition by focusing on the fact that the solubility of sacubitrilㆍvalsartan increases at higher pH than at low pH.
In a specific Experimental Example, a comparative dissolution test was performed on Examples containing sacubitrilㆍvalsartan calcium salt as a main component and various alkalizing agents. As a result, even though all of the included excipients were alkalizing agents, it could be confirmed that the effects on the dissolution of the main component were very different, and the dissolution rates of Examples containing the inorganic magnesium salt were significantly superior to those of Examples containing other alkalizing agents (Experimental Example 6).
The inorganic magnesium salt of the present invention is preferably contained in 10 to 30 wt% based on the weight of the sacubitrilㆍvalsartan calcium salt.
More preferably, the inorganic magnesium salt may be contained in 15 to 20 wt% based on the weight of the sacubitrilㆍvalsartan calcium salt.
The inorganic magnesium salt of the present invention may be magnesium oxide or magnesium carbonate.
Preferably, the inorganic magnesium salt of the present invention may be magnesium oxide.
Most preferably, the pharmaceutical composition of the present invention comprises all of sacubitrilㆍvalsartan calcium salt and colloidal silicon dioxide and inorganic magnesium salt. Here, the colloidal silicon dioxide may be contained in the pharmaceutical composition of the present invention in an amount of 5 to 15 wt%, and the inorganic magnesium salt may be contained therein in an amount of 10 to 30 wt%, based on the weight of the sacubitrilㆍvalsartan calcium salt. Further, more preferably, the colloidal silicon dioxide may be contained in the pharmaceutical composition of the present invention in an amount of 7 to 13 wt%, and the inorganic magnesium salt may be contained therein in an amount of 15 to 20 wt%, based on the weight of the sacubitrilㆍvalsartan calcium salt.
Preferably, the pharmaceutical composition of the present invention is characterized in that 85% or more of sacubitril and valsartan are dissolved after 30 minutes from the onset of dissolution, respectively, during the dissolution test under the conditions of 37 ± 0.5 ℃, pH 4.5 test solution, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of General Test Method of the Korean Pharmacopoeia.
In a specific Experimental Example, the animal PK test was performed on Example 1 showing a lower dissolution rate than the reference drug (Entresto film-coated tablet 200 mg) only at pH 4.5, and as a result, the unequal results were shown in bioavailability (Experimental Example 4). Through this, it may be appreciated that the dissolution rate at 30 minutes from the onset of dissolution at pH 4.5 is very important to secure the bioequivalence of the sacubitrilㆍvalsartan calcium salt composition, and in order to achieve the desired bioavailability, it is required to show a dissolution rate of at least 85% or higher, which is similar to the dissolution rate of the reference drug, i.e., about 95% at a minimum pH of 4.5.
In addition, preferably, the pharmaceutical composition of the present invention is characterized in that dissolution rates of sacubitril and valsartan therein are equivalent to dissolution rates of sacubitril and valsartan in Entresto film-coated tabletTM having the same active ingredient dose.
Further, the pharmaceutical composition is characterized to show the area under the blood concentration-time curve (AUC) and maximum blood concentration (Cmax) that are biologically equivalent to Entresto film-coated tabletTM having the same active ingredient dose.
In specific Experimental Examples, a comparative dissolution test and a clinical test were performed on Examples containing sacubitrilㆍvalsartan calcium salt as a main component and colloidal silicon dioxide and magnesium oxide. As a result, as described above, it was confirmed that the pharmaceutical composition of the present invention achieved a dissolution rate of 85% or more at pH 4.5 at 30 minutes from the onset of dissolution (Experimental Example 7), which was improved to a level similar to that of the reference drug (Entresto film-coated tablet 200 mg), and showed the area under the blood concentration-time curve (AUC) and maximum blood concentration (Cmax) that are biologically equivalent to the reference drug even in a clinical trial involving 24 subjects (Experimental Example 8).
The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive commonly contained in oral solid dosage forms. The additive may further comprise, for example, any one or more selected from the group consisting of excipients, disintegrants, binders, lubricants, and coating agents, and is not limited thereto as long as the present invention has the desired effect.
The excipient usable in the present invention may be, for example, microcrystalline cellulose, lactose, corn starch, potato starch, wheat starch, sucrose, glucose, fructose, D-mannitol, synthetic aluminum silicate, calcium monohydrogen phosphate, dextrin, sodium alginate, methyl cellulose, carboxymethyl cellulose sodium, kaolin, colloidal silica gel, hydroxypropyl starch, dextrin, dextrose, or a mixture thereof, but is not limited thereto.
The disintegrant usable in the present invention may be, for example, at least one disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, pregelatinized starch, sodium croscarboxymethylcellulose, and a mixture thereof, but is not limited thereto.
The binder usable in the present invention may be, for example, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, pregelatinized starch, or a mixture thereof, but is not limited thereto.
The lubricant usable in the present invention may be, for example, colloidal silicon dioxide, talc, magnesium stearate, magnesium aluminometasilicate, glyceryl behenate, calcium stearate, stearic acid, sodium stearyl fumarate, or a mixture thereof, but is not limited thereto.
The coating agent usable in the present invention may be, for example, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the like, or trade name Opadry® or a mixture thereof, but is not limited thereto.
The pharmaceutical composition of the present invention may be administered in various forms, for example, granules, tablets, capsules, dry syrup, and the like.
Preferably, the pharmaceutical composition of the present invention may be in tablet form.
The method of preparation may be performed according to the methods described in Examples of the present invention or any method known in the art of the present invention.
If the pharmaceutical composition of the present invention is a tablet, the pharmaceutical composition may additionally include a coating layer on the outside. The coating layer may be formed according to a method for forming a film coating layer commonly used on the surface of a plain tablet.
In addition, the pharmaceutical composition of the present invention may be significantly useful for preventing or treating heart failure. The preventive and therapeutic effects of sacubitril and valsartan on heart failure and pharmacological mechanisms thereof are well known in the art.
Further, the present invention provides a method for treating or preventing heart failure, comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof. The subject may be a mammal, including a human.
The term "therapeutically effective amount" as used herein refers to an amount of the pharmaceutical composition effective for the treatment or prevention of heart failure. Specifically, the "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level may be determined depending on the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a commercially available therapeutic agent. In addition, the pharmaceutical composition of the present invention may be administered singly or in multiple doses. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with the minimum amount without side effects, which may be easily determined by those skilled in the art. The administration dose of the pharmaceutical composition of the present invention may be determined by specialists according to various factors such as the patient's condition, age, sex, complications, and the like.
In addition, the present invention provides a use of the pharmaceutical composition for use in the manufacture of a medicament for use in the treatment or prevention of heart failure. The above-described pharmaceutical composition for the manufacture of a medicament may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared as a combined preparation together with other active agents to have a synergistic action of the active ingredients.
Matters described in the use, composition, and treatment method of the pharmaceutical composition of the present invention are equally applied unless they contradict each other.
The pharmaceutical composition comprising the sacubitrilㆍvalsartan calcium salt of the present invention may have excellent dissolution rate and bioavailability while having low hygroscopicity compared to conventional sacubitrilㆍvalsartan sodium salt.
FIG. 1 shows the results of animal Pharmacokinetics (PK) tests for sacubitril of the reference drug, Test Drug 1 (Comparative Example 1), and Test Drug 2 (Example 1).
FIG. 2 shows the results of animal Pharmacokinetics (PK) tests for valsartan of the reference drug, Test Drug 1 (Comparative Example 1), and Test Drug 2 (Example 1).
Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are only provided for illustrative purposes to facilitate understanding of the present invention, and the scope of the present invention is not limited by the following Examples.
Preparation Example 1: Synthesis of sacubitril
ㆍ
valsartan calcium salt hydrate
Sacubitrilㆍvalsartan calcium salt tetrahydrate was synthesized and used according to the method described in Preparation Examples 1, 2 and Example 1 of Korean Patent Publication No. 10-2022-0012821.
Experimental Example 1: Comparative solubility experiment of sacubitril
ㆍ
valsartan calcium salt hydrate
In order to confirm the solubility of sacubitrilㆍvalsartan calcium salt hydrate, a solubility test was performed using the sacubitril-valsartan calcium salt tetrahydrate of Preparation Example 1 as a representative example. In detail, for comparison of solubility among sacubitrilㆍvalsartan calcium salt tetrahydrate, the conventional sacubitrilㆍvalsartan sodium salt 2.5 hydrate, and sacubitrilㆍvalsartan sodium salt trihydrate, 500 mg of each sample was dissolved in 50 mL of purified water at room temperature (25 ℃) (10,000 ppm), taken for 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours while stirring at 300 rpm, and analyzed by HPLC. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A : Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 minutes
The solubility test results are HPLC analysis results at 24 hours, which are shown in Table 1 below.
[Table 1]
As a result, as could be confirmed in Table 1 above, the solubility of sacubitril in sacubitrilㆍvalsartan calcium salt tetrahydrate was about 10 times lower than that of sacubitrilㆍvalsartan sodium salt 2.5 hydrate or sacubitrilㆍvalsartan sodium salt trihydrate.
Experimental Example 2: Comparative dissolution test of sacubitril
ㆍ
valsartan calcium salt hydrate
In order to confirm the dissolution rate of sacubitrilㆍvalsartan calcium salt hydrate, a dissolution test was performed in an Agilent dissolution tester using the sacubitrilㆍvalsartan calcium salt tetrahydrate of Preparation Example 1 as a representative example. Specifically, for comparison of dissolution between sacubitrilㆍvalsartan calcium salt tetrahydrate and the conventional sacubitrilㆍvalsartan sodium salt trihydrate, 200 mg of sacubitrilㆍvalsartan was weighed for each sample, and then subjected to the dissolution test under the following conditions: Dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia, 37 ± 0.5 ℃, pH 4.5, 900 mL, and for 1 hour at 50 rpm + 15 minutes at 200 rpm. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A : Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 minutes
Results thereof are shown in Table 2 below.
[Table 2]
As a result, as could be confirmed in Table 2, sacubitrilㆍvalsartan sodium salt trihydrate showed dissolution rates of about 100% for both sacubitril and valsartan from 5 minutes after the onset of dissolution. On the other hand, sacubitrilㆍvalsartan calcium salt tetrahydrate showed significantly low dissolution rates of about 30% for sacubitril and about 50% for valsartan at 30 minutes from the onset of dissolution, and even after 1 hour from the onset of dissolution and stirring at 200 rpm for 15 minutes, sacubitril showed about 50% dissolution rate and valsartan showed about 70% dissolution rate, confirming that the final dissolution rates of sacubitrilㆍvalsartan calcium salt tetrahydrate were lower than those of sacubitrilㆍvalsartan sodium salt.
Comparative Example 1 and Example 1: Preparation of sacubitril
ㆍ
valsartan calcium salt composition
In order to improve the solubility and dissolution rate of sacubitrilㆍvalsartan calcium salt hydrate, a similar prescription to the reference drug (Entresto film-coated tablet 200 mg, Novartis) was set as Comparative Example 1, and Example 1 having a higher colloidal silicon dioxide content than Comparative Example 1 was prepared. Specifically, sacubitrilㆍvalsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, and a binder in the amounts shown in Table 3 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient, a disintegrant, and a binder were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed. Comparative Example 1 and Example 1 were prepared by tableting and coating the final mixtures.
[Table 3]
Experimental Example 3: Comparative dissolution test of Comparative Example 1 and Example 1
In order to confirm the dissolution rate of the sacubitrilㆍvalsartan calcium salt hydrate composition, dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Comparative Example 1 and Example 1, which are similar prescriptions to the reference drug. Specifically, the reference drug, Comparative Example 1, and Example 1 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ± 0.5 ℃, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A: Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 min
Results thereof are shown in Tables 4 and 5 below.
[Table 4]
[Table 5]
As a result, as shown in Table 4, it could be confirmed that in Comparative Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of sacubitril in pH 6.8 and purified water were similar to those of the reference drug, but the dissolution rates of sacubitril at pH 1.2 and pH 4.5 were significantly lower than those of the reference drug. In addition, it could be confirmed that in Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of sacubitril in pH 1.2, pH 6.8, and purified water were similar to those of the reference drug, and the dissolution rate of sacubitril at pH 4.5 was increased by about 2 times compared to Comparative Example 1, but the dissolution rate thereof was reduced by about 30% compared to the reference drug.
In addition, as shown in Table 5, it could be confirmed that in Comparative Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of valsartan in pH 6.8 and purified water were similar to those of the reference drug, but the dissolution rates of valsartan at pH 1.2 and pH 4.5 were significantly lower than those of the reference drug. In addition, it could be confirmed that in Example 1 at 30 minutes from the onset of dissolution, the dissolution rates of sacubitril in pH 1.2, pH 6.8, and purified water were similar to those of the reference drug, and the dissolution rate of sacubitril at pH 4.5 was increased by about 30% compared to Comparative Example 1, but the dissolution rate thereof was reduced by about 20% compared to the reference drug.
Experimental Example 4: Animal Pharmacokinetics (PK) comparison test of Comparative Example 1 and Example 1
In order to confirm the in-vivo bioavailability of sacubitrilㆍvalsartan calcium salt hydrate composition, animal PK tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis), and the compositions of Comparative Example 1 and Example 1, which are similar prescriptions to the reference drug. The animal test design was as follows:
1) Number of groups: 12 Beagle Dogs, 3 X 3 (n=4), Wash-out : 1 week
2) Test drug information:
Reference drug: Entresto film-coated tablet 200 mg (Novartis)
Test Drug 1 : Comparative Example 1
Test Drug 2 : Example 1
3) Dosage: 1 tablet once
4) Blood collection points: blank, 0.083, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24 hr (14 points)
Results thereof are shown in FIGS. 1 and 2 and Table 6 below.
[Table 6]
In the comparative dissolution test of Experimental Example 3, Example 1 showed that the dissolution rates of sacubitril and valsartan in pH 1.2, pH 6.8, and purified water were equal or similar to those of the reference drug, but there was a difference in dissolution rate at pH 4.5 from the reference drug at 30 minutes from the onset of dissolution.
As could be confirmed in FIGS. 1 and 2 and Table 6, Comparative Example 1 and Example 1 showed as results of in vivo animal PK tests that the 90% confidence intervals of AUC and Cmax were out of the range of 0.8 to 1.25, and all of the T/R ratios also showed biologically non-equivalent results except for the valsartan AUC value of Comparative Example 1.
It could be appreciated from the above results that in order to achieve the desired bioavailability, the dissolution rate at 30 minutes from the onset of dissolution at a minimum pH of 4.5 should be at least 85% or more, which is similar to the dissolution rate of the reference drug of about 95%.
Comparative Example 2 and Example 2: Preparation of sacubitril
ㆍ
valsartan calcium salt composition
It was confirmed from the dissolution test study of Comparative Example 1 and Example 1 previously performed, the release rate of the drug was improved when the amount of colloidal silicon dioxide was increased. In order to more accurately confirm whether the improvement in drug release rate was caused by colloidal silicon dioxide, Comparative Example 2, which did not contain colloidal silicon dioxide at all, and Example 2, in which the amount of colloidal silicon dioxide was further increased compared to Example 1, were prepared. Specifically, sacubitrilㆍvalsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, and a binder in the amounts shown in Table 7 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient, a disintegrant, and a binder were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed. Comparative Example 2 and Example 2 were prepared by tableting and coating the final mixtures.
[Table 7]
Experimental Example 5: Comparative dissolution test of Comparative Example 2 and Example 2
In order to confirm the dissolution rate of the sacubitrilㆍvalsartan calcium salt hydrate composition, dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Comparative Example 2 and Example 2. Specifically, the reference drug, Comparative Example 2, and Example 2 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ± 0.5 ℃, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A: Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 min
Results thereof are shown in Tables 8 and 9 below.
[Table 8]
[Table 9]
As a result, as shown in Tables 8 and 9, it could be confirmed that in Comparative Example 2, the dissolution rates of sacubitril and valsartan at pH 1.2 and pH 4.5 were significantly lower than those of the reference drug. On the other hand, in Example 2, the dissolution rates of sacubitril and valsartan at pH 1.2 and pH 4.5 were equal to or improved than those of the reference drug.
Examples 3 to 7: Preparation of sacubitril
ㆍ
valsartan calcium salt composition
Compositions of Examples 3 to 7 containing various alkalizing agents were prepared to confirm the degree of improvement in the release rate according to the use of the alkalizing agent. Specifically, sacubitrilㆍvalsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient and an alkalizing agent in the amount shown in Table 10 below. Then, a binder solution was added to prepare granules, followed by granulation and drying. An excipient and a disintegrant were added to the dried sized product and mixed, and then a lubricant was added thereto and finally mixed. Examples 3 to 7 were prepared by tableting and coating the final mixtures.
[Table 10]
Experimental Example 6: Comparative dissolution test of Examples 3 to 7
In order to confirm the dissolution rate of the sacubitrilㆍvalsartan calcium salt hydrate composition according to the type of alkalizing agent, dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Examples 3 to 7. Specifically, the reference drug, and Examples 3 to 7 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ± 0.5 ℃, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A: Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 min
Results thereof are shown in Tables 11 and 12 below.
[Table 11]
[Table 12]
As a result, as shown in Tables 11 and 12, Examples 3 and 7 containing inorganic magnesium salts at pH 4.5 exhibited significantly better dissolution rate improvement effect compared to Examples 4 to 6 containing other alkalizing agents.
Specifically, as to sacubitril, Example 6 containing sodium carbonate was hardly dissolved with a dissolution rate of less than 10% at 30 minutes from the onset of dissolution, and Examples 4 and 5 containing calcium carbonate or sodium bicarbonate also showed the sacubitril dissolution rate of about 30%. Meanwhile, Examples 3 and 7 containing inorganic magnesium salts showed the sacubitril dissolution rate of about 60%, which was about 5 to 7 times greater than that of Example 6 and about 2 times greater than that of Examples 4 and 5.
Further, as to valsartan, Example 6 containing sodium carbonate was hardly dissolved with a dissolution rate of 16.4% at 30 minutes from the onset of dissolution, and Examples 4 and 5 containing calcium carbonate or sodium bicarbonate also showed the valsartan dissolution rate of about 60%. Meanwhile, Examples 3 and 7 containing inorganic magnesium salts showed the valsartan dissolution rate of 70% or more at 30 minutes from the onset of dissolution, and in particular, Example 3 showed the valsartan dissolution rate of 95% or more, confirming that the dissolution rate was very similar to that of the reference drug.
Example 8: Preparation of sacubitril
ㆍ
valsartan calcium salt composition
Specifically, sacubitrilㆍvalsartan calcium salt tetrahydrate of Preparation Example 1 was mixed with an excipient, a disintegrant, a binder, and an alkalizing agent in the amounts shown in Table 13 below, and then sieved. Then, a lubricant was added, mixed, and then pounded to establish size. An excipient and a disintegrant were added to the sized product and mixed, and then a lubricant was added thereto and finally mixed. Example 8 was prepared by tableting and coating the final mixture.
[Table 13]
Experimental Example 7: Comparative dissolution test of Example 8
In order to confirm the dissolution rate of the sacubitrilㆍvalsartan calcium salt hydrate composition, dissolution tests were performed on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the compositions of Comparative Example 1 and Example 8 prepared above. Specifically, the reference drug, Comparative Example 1, and Example 8 were subjected to a dissolution test in an Agilent dissolution tester under the conditions of 37 ± 0.5 ℃, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of the Korean Pharmacopoeia. The HPLC analysis conditions were as follows:
① Detector : Ultraviolet absorption photometer (measurement wavelength : 254 nm)
② Column : X-Bridge C18 (4.6*150 mm, 5 ㎛)
③ Flow rate : 1.0 mL/min
④ Column temperature : Constant temperature around 45 ℃
⑤ Sample solution temperature : Constant temperature around 10 ℃
⑥ Mobile phase : Mixed solution of mobile phase A and mobile phase B (5 : 5)
Mobile phase A: Mixed solution of purified water, acetonitrile, and trifluoroacetic acid (950 : 50 : 1)
Mobile phase B : Mixed solution of acetonitrile and trifluoroacetic acid (1000 : 1)
⑦ Analysis time : 7 min
Results thereof are shown in Tables 14 and 15 below.
[Table 14]
[Table 15]
As a result, it could be confirmed that as shown in Table 14, the dissolution rates of sacubitril of Example 8 in all of pH 1.2, pH 4.5, pH 6.8 and purified water were equivalent to those of the reference drug, and as shown in Table 15, the dissolution rates of valsartan of Example 8 in all of pH 1.2, pH 4.5, pH 6.8 and purified water were equivalent to those of the reference drug.
Experimental Example 8: Clinical trial of Example 8
In order to confirm the bioavailability of the sacubitrilㆍvalsartan calcium salt hydrate composition, clinical trials were conducted on the reference drug (Entresto film-coated tablet 200 mg, Novartis) and the composition of Example 8. The clinical trial design is shown in Table 16 below:
[Table 16]
Results thereof are shown in Table 17 below.
[Table 17]
As shown in Table 17, Example 8 showed that as compared to the reference drug, all the T/R values of sacubitril, sacubitrilat which is sacubitril's active metabolite, and valsartan were close to 1, which was confirmed to have a bioequivalence level to the reference drug.
Claims (15)
- A pharmaceutical composition comprising: sacubitrilㆍvalsartan calcium salt, and colloidal silicon dioxide.
- The pharmaceutical composition of claim 1, wherein the sacubitrilㆍvalsartan calcium salt is a sacubitrilㆍvalsartan calcium salt hydrate represented by the following Chemical Formula 1:[Chemical Formula 1]
in Chemical Formula 1 above, n is 0.5, 1, 1.5, 2, 2.5, 3, 3.5 or 4. - The pharmaceutical composition of claim 2, wherein n is 4.
- The pharmaceutical composition of claim 1, wherein the colloidal silicon dioxide is contained in 5 to 15 wt% based on the weight of sacubitrilㆍvalsartan calcium salt.
- The pharmaceutical composition of claim 1, wherein the colloidal silicon dioxide is contained in 7 to 13 wt% based on the weight of sacubitrilㆍvalsartan calcium salt.
- The pharmaceutical composition of claim 1, further comprising an inorganic magnesium salt.
- The pharmaceutical composition of claim 6, wherein the inorganic magnesium salt is contained in 10 to 30 wt% based on the weight of the sacubitrilㆍvalsartan calcium salt.
- The pharmaceutical composition of claim 6, wherein the inorganic magnesium salt is magnesium oxide or magnesium carbonate.
- The pharmaceutical composition of claim 1, further comprising at least one selected from the group consisting of an excipient, a disintegrant, a binder, a lubricant, and a coating agent.
- The pharmaceutical composition of claim 1, wherein 85% or more of sacubitril and valsartan in the pharmaceutical composition are dissolved after 30 minutes from the onset of dissolution, respectively, during the dissolution test under the conditions of 37 ± 0.5 ℃, pH 4.5 test solution, 900 mL, and 50 rpm according to the dissolution test Method 2 (paddle method) of General Test Method of the Korean Pharmacopoeia.
- The pharmaceutical composition of claim 1, wherein dissolution rates of sacubitril and valsartan are equivalent to dissolution rates of sacubitril and valsartan of Entresto film-coated tabletTM having the same active ingredient dose.
- The pharmaceutical composition of claim 1, wherein the pharmaceutical composition shows the area under the blood concentration-time curve (AUC) and maximum blood concentration (Cmax) that are biologically equivalent to Entresto film-coated tabletTM having the same active ingredient dose.
- The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of a tablet.
- The pharmaceutical composition of claim 13, wherein the tablet is in the form of a coated tablet that additionally includes a coating layer on the outside.
- The pharmaceutical composition of any one of claims 1 to 14, wherein the pharmaceutical composition is for preventing or treating heart failure.
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| KR10-2022-0119359 | 2022-09-21 | ||
| KR1020220119359A KR20240040407A (en) | 2022-09-21 | 2022-09-21 | Pharmaceutical composition comprising sacubitril valsartan calcium salt |
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| WO (1) | WO2024063537A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100990223B1 (en) * | 2008-02-21 | 2010-10-29 | 주식회사 중외제약 | Pharmaceutical composition for improving dissolution rate of cefdinir |
| KR101632079B1 (en) * | 2007-07-23 | 2016-06-20 | 파마덴 에스.에이. | Pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof |
| CN106074421A (en) * | 2015-07-11 | 2016-11-09 | 凌莉 | A kind of pharmaceutical composition improving stability |
| KR20220012821A (en) * | 2020-07-23 | 2022-02-04 | 주식회사 종근당 | Polymorphs of double acting compound and preparation method thereof |
| KR20220091767A (en) * | 2020-12-24 | 2022-07-01 | 주식회사 보령 | Pharmaceutical composition comprising sacubitril valsartan hybrid compound or pharmaceutical salts thereof as an active ingredient |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102149125B1 (en) | 2020-02-05 | 2020-08-28 | 유니셀랩 주식회사 | A novel co-amorphous of sacubitril calcium / valsartan |
-
2022
- 2022-09-21 KR KR1020220119359A patent/KR20240040407A/en unknown
-
2023
- 2023-09-20 WO PCT/KR2023/014295 patent/WO2024063537A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101632079B1 (en) * | 2007-07-23 | 2016-06-20 | 파마덴 에스.에이. | Pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof |
| KR100990223B1 (en) * | 2008-02-21 | 2010-10-29 | 주식회사 중외제약 | Pharmaceutical composition for improving dissolution rate of cefdinir |
| CN106074421A (en) * | 2015-07-11 | 2016-11-09 | 凌莉 | A kind of pharmaceutical composition improving stability |
| KR20220012821A (en) * | 2020-07-23 | 2022-02-04 | 주식회사 종근당 | Polymorphs of double acting compound and preparation method thereof |
| KR20220091767A (en) * | 2020-12-24 | 2022-07-01 | 주식회사 보령 | Pharmaceutical composition comprising sacubitril valsartan hybrid compound or pharmaceutical salts thereof as an active ingredient |
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| Publication number | Publication date |
|---|---|
| KR20240040407A (en) | 2024-03-28 |
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