HK1162959A1 - Pharmaceutical compositions comprising dronedarone - Google Patents
Pharmaceutical compositions comprising dronedarone Download PDFInfo
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- HK1162959A1 HK1162959A1 HK12103681.4A HK12103681A HK1162959A1 HK 1162959 A1 HK1162959 A1 HK 1162959A1 HK 12103681 A HK12103681 A HK 12103681A HK 1162959 A1 HK1162959 A1 HK 1162959A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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Abstract
Pharmaceutical compositions used for treating arrhythmia, preparative methods and uses thereof are disclosed in the present invention. Said pharmaceutical compositions comprise dronedarone or pharmaceutically acceptable salts thereof as active ingredients, pharmaceutically acceptable amphiphilic lipid surfactants and phospholipids, optionally one or more pharmaceutical additives.
Description
Technical Field
The invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, an amphiphilic lipid surfactant and a phospholipid.
Background
Dronedarone (Dronedarone) chemical name 2-n-butyl-3 [4- (3-di-n-butyl-aminopropoxy) benzoyl]-5-methylsulfanylbenzofuran of formula C31H44N2O5S, molecular weight 556.765.
Dronedarone hydrochloride is a drug for the treatment of arrhythmias which is newly developed by the company senofil-formerly danabao (Sanofi-Synthelabo). The product is a benzofuran derivative without iodine, has a structure and characteristics similar to amiodarone, but is low in lipophilicity because of no iodine contained in dronedarone, so that the curative effect of amiodarone is kept, no extra-cardiac adverse reaction of amiodarone is caused, the half-life period is 1-2 days, and the drug dosage is convenient to adjust.
Dronedarone hydrochloride has a very low solubility in aqueous media, in particular its solubility is pH dependent at room temperature, it has a very high solubility in the pH range 3-5, about 1-2mg/ml, and it has a very low solubility at pH about 6-7, since it has only 10 μ g/ml at pH 7.
Due to the characteristic of low solubility of dronedarone hydrochloride, the bioavailability of dronedarone hydrochloride for gastrointestinal administration is low, because the process from stomach to intestinal tract is a process of gradually increasing pH, which means that the solubility of dronedarone hydrochloride is gradually reduced, so that dronedarone hydrochloride cannot be dissolved out from a solid preparation or the dissolution rate of dronedarone hydrochloride is low under the environment of higher pH of intestinal tract. In order to improve the bioavailability of dronedarone hydrochloride, a way for improving the dissolution rate of dronedarone hydrochloride must be found.
US20040044070 discloses injection of dronedarone hydrochloride. The beta-cyclodextrin derivative is added into a buffer system (the pH value ranges from 3 to 5), so that the solubility of the effective components is improved. However, the method for improving the solubility of dronedarone hydrochloride has complex manufacturing process and may have poor stability.
The invention discloses a solid pharmaceutical composition containing benzofuran derivatives, which is disclosed in the patent ZL98808158.X, and discovers that a nonionic surfactant, especially a poloxamer nonionic surfactant, can keep an active ingredient dissolved in a solution with the pH of about 4.5 in a pH6-7 solution after being diluted by a high-pH solution, and basically cannot precipitate under the influence of the increase of the pH, so that the bioavailability of dronedarone hydrochloride in an empty stomach is improved. The screening process described in this patent specification shows that although a series of nonionic surfactants can improve the retention capacity of dronedarone hydrochloride in the solution, only poloxamer 407 in a small amount can show a significant effect. While other types of surfactants require larger amounts.
In addition, according to incomplete statistics, about 40% of new drugs have the problem of low solubility, and the oral administration of the drugs often has the problems of low bioavailability, large individual difference and the like. In order to solve this problem, in recent years, it has become a hot spot in the pharmaceutical field to improve the bioavailability of poorly soluble drugs by using lipid matrices, particularly amphiphilic lipid surfactants having self-emulsifying ability. However, in practical applications, the amount of such amphiphilic lipid surfactants is often large, which limits the applications to some extent.
Based on past experience, through a great deal of experimental research, the invention surprisingly discovers that the solubility of dronedarone hydrochloride can be greatly improved by adding phospholipid into the formula in the presence of the amphiphilic lipid surfactant.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, the invention aims to provide a pharmaceutical composition which is characterized by comprising dronedarone or pharmaceutically acceptable salts thereof as an active ingredient, one or more pharmaceutically acceptable amphiphilic lipid surfactants, one or more phospholipids, and one or more pharmaceutically acceptable additives. It has antiarrhythmic activity and is used clinically in treating arrhythmia.
Dronedarone pharmaceutically acceptable salts including but not limited to hydrochloride, sulphate, nitrate, citrate, maleate, tartrate, mesylate and fumarate, preferably hydrochloride.
The amphiphilic lipid surfactant used in the pharmaceutical composition of the present invention includes, but is not limited to, lauric acid macrogol glyceride, stearic acid macrogol glyceride, oleic acid macrogol glyceride, caprylic/capric acid triglyceride, polyglycerol fatty acid ester, vitamin E succinate, and the like.
The phospholipid as a core part of the present invention includes, but is not limited to, soybean phospholipid, egg yolk phospholipid, polyene phosphatidylcholine, hydrogenated soybean phospholipid, and the like.
The pharmaceutical composition of the present invention is any solid pharmaceutical composition suitable for oral administration, and basically is considered to be a pharmaceutical composition formed by a solid component in a powdered or granular form, and the composition can be made into granules, tablets and capsules at normal temperature.
A further subject of the present invention is therefore the above-mentioned pharmaceutical composition in the form of tablets, capsules, granules or powders.
The pharmaceutical composition of the present invention contains an active ingredient, an amphiphilic lipid surfactant, a phospholipid and an excipient.
In general, dronedarone or a pharmaceutically acceptable salt thereof, such as the hydrochloride, of the pharmaceutical composition according to the invention can be contained in an amount ranging from 50mg to 500mg, preferably from 200mg to 400mg, per elementary administration unit, such as per tablet or per capsule, or per packet of granules.
Typically, the proportion of amphoteric lipid surfactant in the pharmaceutical compositions of the present invention is from 1.25 to 50% by weight of the active ingredient in the dosage form. In the form of an orally administered dosage form such as a tablet, capsule, granule, etc., the proportion of the amphiphilic lipid surfactant is 1.5 to 20%, preferably 2 to 10%, by weight of the active ingredient in the dosage form.
Typically, the phospholipid is present in the pharmaceutical composition in a proportion of 0.5 to 15% by weight of the active ingredient in the dosage form. In the form of oral dosage forms such as tablet, capsule, granule, etc., the phospholipid is 1-10%, preferably 2-7.5% by weight of the active ingredient in the dosage form
In addition to the amphiphilic surfactant and phospholipid, the pharmaceutical composition of the present invention may contain other pharmaceutical excipients commonly used in oral pharmaceutical research, development, and manufacture, such as microcrystalline cellulose, aerosil, croscarmellose sodium, methylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, polyethylene glycols (e.g., polyethylene glycol 6000), vinylpyrrolidone polymers or copolymers (e.g., polyvinylpyrrolidone), magnesium stearate, and the like.
The pharmaceutical composition of the invention can be prepared by a suitable process method:
a) dissolving an active ingredient, an amphiphilic lipid surfactant and a phospholipid in an organic solvent or an aqueous solution thereof, wherein the organic solvent is selected from ethanol, methanol, dichloromethane and acetone;
b) adding excipient, absorbing solvent, and stirring for granulating, wherein the excipient is selected from one or more of silicon oxide, aluminum oxide or cellulose derivative for preparing pharmaceutical tablet or capsule;
if necessary, a disintegrant, a lubricant, or the like may be further used, and the resulting material may be further compressed into tablets, coated or filled into capsules.
Through a large number of researches and experiments, the researchers of the invention surprisingly find that the solubility of the medicine can be greatly improved and the dissolution rate of the solid preparation can be improved on the original basis by adding a proper amount of phospholipid into the dronedarone hydrochloride formula in the presence of the amphiphilic lipid surfactant, so that the bioavailability of the medicine is improved. The invention has the beneficial effects that the phospholipid is added into the pharmaceutical composition, so that the problem of the solubility of the dronedarone hydrochloride is solved while the dosage of the amphiphilic lipid surfactant is reduced.
Detailed Description
In order to better explain the present invention, the present invention is explained below by way of specific embodiments. The following examples, experimental examples, are given solely for the purpose of illustrating the invention and are not intended to be construed as limitations of the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Example 1
Screening for amphiphilic lipid surfactants
Retention assay in phosphate buffer at pH6.7
With hydrogen phosphate (NaH) at pH4.52PO4) Buffer, 2mg/ml dronedarone hydrochloride solution was prepared at 37 degrees celsius over 2 hours. The solution was then placed in a neutral phosphate medium (Na)2HPO4+NaH2PO4) Diluted to 1/10 and the final solution had a pH of 6.7. After 2 hours at 37 degrees C, the solution is filtered through a 5.0um glass fiber filter and the active components in the solution are measured with an ultraviolet spectrophotometer.
The results are shown in the following table:
and (4) conclusion: under the condition of existence of amphiphilic lipid surfactant, the percentage of dronedarone in the solution with higher pH value can be increased, and the percentage of dronedarone hydrochloride in the solution is increased more remarkably after phospholipid is added.
Example 2:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
according to the proportion of the prescription, dronedarone hydrochloride (synthesized by Jiangsu Henry medicine Co., Ltd.), lauric acid macrogol glyceride and phospholipid are weighed. Adding ethanol with the amount of 50 percent of the active ingredient calculated by dronedarone, and heating in a water bath at 50 ℃ until the ethanol is dissolved. Adding microcrystalline cellulose, silica gel micropowder and croscarmellose sodium according to the proportion of the prescription, absorbing the solvent, stirring and granulating, drying at 50 ℃, sieving the granules with a 20-mesh sieve for granulation, adding magnesium stearate according to the proportion of the prescription, mixing and tabletting.
Specifically, the following description is provided: or adopting the prescription process, and finally filling the granules into capsules or directly packaging the granules to prepare capsules or granules. The following examples can also be made into capsules or granules by similar methods, and are not repeated.
Example 3:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 4:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 5:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 6:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 7:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 8:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 9:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 10:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 11:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 12:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Example 13:
dronedarone hydrochloride tablet
Prescription:
the process comprises the following steps:
the same as in example 2.
Comparative example
Dronedarone hydrochloride tablet
The dronedarone hydrochloride tablets are prepared according to the formula process of the patent ZL98808158.X, example 1.
Experimental example 1: retention assay in phosphate buffer at pH6.7
1) Dronedarone hydrochloride tablets (equivalent to dronedarone hydrochloride 426mg) were dissolved and made to volume by adding phosphate buffer solution of ph4.5 to a 200ml measuring flask, and kept at 37 ℃ for 2 hours.
2) This solution was diluted to 1/10 with neutral phosphate medium (Na2HPO4+ NaH2PO4) and the pH of the final solution was 6.7. After 2 hours at 37 ℃ the solution was filtered through a 5.0um glass fibre filter and the active ingredient in the solution was measured with a UV spectrophotometer at a wavelength of 291 nm.
And (4) conclusion: compared with the preparation in examples 2 and 8 (without phospholipid), the preparation containing phospholipid (examples 3-7, 9-13) has significantly improved solubility of dronedarone hydrochloride. Compared with the comparative example, the prescription containing the amphiphilic lipid surfactant and the phospholipid can more remarkably improve the retention capacity of the dronedarone hydrochloride in the high-pH solution.
Experimental example 2: dissolution determination
Referring to the appendix XC of the 2005 edition of Chinese pharmacopoeia, a paddle method is adopted, 900ml of phosphate buffer solution with the temperature of 37 +/-0.5 ℃ and the pH of 6.7 is taken as a medium, sampling is carried out for 45 minutes, the value A is measured by an ultraviolet spectrophotometry, and the cumulative dissolution percentage is calculated.
And (4) conclusion: compared with the formulations of examples 2 and 8 (without phospholipid), the dissolution rate of dronedarone hydrochloride in the formulations containing phospholipid (examples 3-7, 9-13) in a medium with higher pH is obviously improved, and is generally higher than that of the comparative examples.
Experimental example 3: bioavailability assay
Collecting blood plasma: 39 beagle dogs in each experimental example 3, experimental examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, the formulation of the comparative example, the dose administered: taking 2.0ml of blood from forelimb veins after 30mg/kg of dronedarone hydrochloride and 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 16.0, 18.0, 20.0, 22.0 and 24.0h after administration, placing the blood in a heparinized test tube, centrifuging at 3000rpm for 10min, separating plasma, and storing at-20 ℃ for testing.
Determination of plasma samples: after liquid-liquid extraction, the dog plasma samples were determined by LC/MS.
And (4) conclusion: compared with the preparation in examples 2 and 8 (without phospholipid), the bioavailability of dronedarone hydrochloride in the prescription containing phospholipid (examples 3-7 and 9-13) is obviously improved. Compared with the comparative example, the bioavailability of dronedarone hydrochloride can be more remarkably improved by the formula containing the amphiphilic lipid surfactant and the phospholipid.
Claims (19)
1. A pharmaceutical composition characterized in that it comprises dronedarone or a pharmaceutically acceptable salt thereof, as active ingredient, one or more pharmaceutically acceptable amphiphilic lipid surfactants, one or more phospholipids, in association with one or more pharmaceutical excipients.
2. The pharmaceutical composition according to claim 1, characterized in that said pharmaceutically acceptable salt of dronedarone is selected from the group consisting of hydrochloride, sulfate, nitrate, citrate, maleate or tartrate.
3. The pharmaceutical composition according to claim 1, characterized in that said pharmaceutically acceptable salt of dronedarone is the hydrochloride salt.
4. The pharmaceutical composition according to claim 1, characterized in that the amphiphilic lipid surfactant is selected from the group consisting of macrogolglycerides of lauric acid, stearic acid, oleic acid, caprylic/capric acid, triglycerides, polyglycerol fatty esters, or vitamin E succinate.
5. The pharmaceutical composition according to claim 1, characterized in that said phospholipid is selected from the group consisting of soybean phospholipids, egg yolk phospholipids, polyene phosphatidylcholine and hydrogenated soybean phospholipids.
6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an oral dosage form.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet, capsule or granule.
8. Pharmaceutical composition according to claim 6, characterized in that the proportion of amphiphilic lipid surfactant is from 1.25% to 50% by weight of active ingredient in the dosage form.
9. Pharmaceutical composition according to claim 6, characterized in that the proportion of amphiphilic lipid surfactant is from 1.5% to 20% by weight of active ingredient in the dosage form.
10. Pharmaceutical composition according to claim 6, characterized in that the proportion of amphiphilic lipid surfactant is from 2% to 10% by weight of active ingredient in the dosage form.
11. Pharmaceutical composition according to claim 6, characterized in that the proportion of phospholipids is between 0.5 and 15% by weight of the active ingredient in the dosage form.
12. Pharmaceutical composition according to claim 6, characterized in that the proportion of phospholipids is between 1 and 10% by weight of the active ingredient in the dosage form.
13. Pharmaceutical composition according to claim 6, characterized in that the proportion of phospholipids is between 2% and 7.5% by weight of the active ingredient in the dosage form.
14. Pharmaceutical composition according to any one of claims 1 to 13, characterized in that it contains 50 to 500mg of active ingredient per administration unit.
15. Pharmaceutical composition according to claim 14, characterized in that it contains 200 to 400mg of active ingredient per administration unit.
16. Pharmaceutical composition according to claim 1, characterized in that it contains 200 to 400mg of active ingredient in the dosage form per administration unit, and 2-10% of amphiphilic lipid surfactant and 2-7.5% of phospholipids relative to the active ingredient in the dosage form.
17. A process for preparing a pharmaceutical composition according to claim 1, characterized by comprising the steps of:
a) dissolving an active ingredient, an amphiphilic lipid surfactant and phospholipid in an organic solvent or a mixed solution of the organic solvent and water, wherein the organic solvent is selected from ethanol, methanol, dichloromethane and acetone;
b) adding excipient selected from one or more of silicon oxide, aluminum oxide or cellulose derivative for preparing pharmaceutical tablet or capsule, absorbing solvent, and granulating under stirring.
18. The method of claim 17, further comprising the step of coating, encapsulating, or compressing the tablet.
19. The production method according to claim 17 or 18, characterized in that a disintegrant, a lubricant and a binder are further used.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010131414.X | 2010-03-19 | ||
| CN201010131414XA CN102188417A (en) | 2010-03-19 | 2010-03-19 | Dronedarone medicinal composition |
| PCT/CN2011/071285 WO2011113320A1 (en) | 2010-03-19 | 2011-02-25 | Pharmaceutical compositions comprising dronedarone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1162959A1 true HK1162959A1 (en) | 2012-09-07 |
| HK1162959B HK1162959B (en) | 2014-05-23 |
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Also Published As
| Publication number | Publication date |
|---|---|
| CN102188417A (en) | 2011-09-21 |
| WO2011113320A1 (en) | 2011-09-22 |
| CN102470121A (en) | 2012-05-23 |
| CN102470121B (en) | 2013-10-16 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PC | Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee) |
Effective date: 20220219 |