WO2016009314A1 - "amorphous mixture of ivabradine and chrysin" - Google Patents
"amorphous mixture of ivabradine and chrysin" Download PDFInfo
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- WO2016009314A1 WO2016009314A1 PCT/IB2015/055224 IB2015055224W WO2016009314A1 WO 2016009314 A1 WO2016009314 A1 WO 2016009314A1 IB 2015055224 W IB2015055224 W IB 2015055224W WO 2016009314 A1 WO2016009314 A1 WO 2016009314A1
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- ivabradine
- amorphous compound
- chrysin
- solid
- mixture
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
Definitions
- Subject-matter of the present invention is a novel amorphous compound comprising ivabradine, in particular a solid amorphous compound consisting of ivabradine and chrysin.
- Subject-matter of the invention is also a process for the preparation of said amorphous compound, its use in therapy and the pharmaceutical compositions comprising it.
- Patent EP 0 534 859 in the name of Adir/Servier.
- Ivabradine free base is a yellowish, very viscous oil that is hardly to treat and to formulate.
- ivabradine base has not been considered convenient for preparing pharmaceutical compositions to be used in therapy and it has been preferred to formulate pharmaceutical compositions containing ivabradine in a salified form, in particular as the hydrochloride salt, presenting as a solid and therefore being more suitable to the industrial processing.
- the dispersion of such a small amount of solid active ingredient in the solid matrix of excipients is not an easy, industrial process.
- An object of the invention is to provide a novel solid compound comprising ivabradine allowing its easier industrial processing and which could be easily formulated in pharmaceutical compositions.
- a further object of the invention is to provide pharmaceutical compositions comprising the novel solid compound comprising ivabradine and their use in therapy.
- a further object of the invention is to provide a process for the preparation of the novel solid compound of ivabradine.
- a subject-matter of the invention is a novel solid compound comprising ivabradine which is an amorphous compound consisting of ivabradine and chrysin.
- the amorphous compound consisting of ivabradine and chrysin is solid.
- Ivabradine has the following structural formula (I)
- amorphous compound is meant to define a mixture of ivabradine and chrysin under the form of an amorphous substance, i.e. not crystallized, consisting of an intimate aggregate of ivabradine and chrysin.
- said amorphous compound is a solid amorphous compound.
- a subject-matter of the invention is a process for the preparation of the novel amorphous compound of the invention which comprises: a. adding a mixture of ivabradine and chrysin to a suitable solvent, up to saturation;
- the ivabradine used in step (a) is ivabradine free base.
- ivabradine and chrysin are used in 1/1 to 10/1 molar ratio, preferably 3/1 to 7/1 ratio, advantageously in a 5/1 ratio.
- Appropriate solvents for the process of the invention include lower alcohols, water and mixtures thereof.
- lower alcohols are herein meant alcohols having 1 to 4 carbon atoms, as methanol, ethanol, isopropanol and butanol, for example.
- Preferred solvents according to the invention are the lower alcohols, in particular ethanol and water. More preferred solvents are ethanol and mixtures of ethanol/water. An advantageous mixture of ethanol/water is the mixture containing 95% ethanol and 5% water (v/v).
- step (b) the reaction mixture is preferably, but not necessarily, heated to a temperature between 30°C and the boiling temperature of the mixture, advantageously between 40°C and 60°C, for example around 50°C.
- step (b) can also be carried out in an ultrasound bath.
- step (c) The same temperatures can be used for the evaporation of the solvent in step (c).
- novel, preferably solid, amorphous compound obtainable and/or obtained by the above described process, is a further subject-matter of the invention.
- novel, preferably solid, amorphous compound of ivabradine and chrysin in particular the compound in the 5/1 molar ratio, showed a good stability, remaining stable at 0°C and room temperature for a long time.
- Obtaining the novel amorphous compound of ivabradine and chrysin is not obvious at all.
- the present Applicant made tests for the preparation of compound of ivabradine with a number of other substances but none of tested substances provided satisfactory results. Therefore, the novel solid amorphous compound represents a remarkable and unexpected technical progress.
- the novel amorphous compound presents as a glassy solid, which can be mashed, for example micronized, for its formulation in pharmaceutical compositions.
- the solid amorphous compound of the invention allows to obtain a powder containing ivabradine in the base form, i.e. not salified, perfectly stable and workable, that can be used for preparing solid pharmaceutical compositions, suspensions and suppositories, but also buccal patches or even transdermal patches, preferably in addition to one or more conventional pharmaceutically acceptable excipients.
- compositions comprising the preferably solid, amorphous compound of ivabradine and chrysin are a further subject-matter of the invention, such as also the use in therapy of the amorphous compound of ivabradine and chrysin and pharmaceutical compositions containing them, in particular in the treatment of heart failure, hypertension, angina and in the post-infarction treatment.
- the invention also comprises a method of treating heart failure, hypertension, angina and post-infarction condition which comprises administering, to a subject in the need thereof, an effective amount of the preferably solid, amorphous compound of ivabradine and chrysin, advantageously in the form of a pharmaceutical composition of the invention.
- compositions of the invention are particularly suitable for oral administration.
- compositions can be in the form of tablets, capsules or granulates and are prepared according to conventional methods with pharmaceutically acceptable excipients such as binding agents, bulking agents, lubricants, disintegrants, wetting agents, flavoring agents, etc. Tablets can also be coated by methods well known in the art.
- each dosage unit according to the invention comprises an amount of ivabradine (calculated as ivabradine free base) from 1 to 10 mg, for example 4 to 8 mg, advantageously 5 mg and 7.5 mg, together with conventional excipients and additives well known to the person skilled in the art.
- ivabradine calculated as ivabradine free base
- the preferably solid, amorphous compound of ivabradine and chrysin can be formulated in combination with additional active ingredients.
- the preferably solid, amorphous compound of ivabradine and chrysin is formulated as the only active ingredient. It is evident from the above that thanks to the invention it is possible to use ivabradine base which, as mentioned, is an oil difficult to process, directly as active ingredient, with the additional advantage of being able to formulate the preferably solid, amorphous compound in a simple and industrially convenient way, thereby obtaining pharmaceutical compositions wherein the active ingredient is homogeneously dispersed.
- ivabradine and 6.7 mg chrysin are added to 3.5 ml ethanol; the container was closed and the mixture was heated to 50°C in an ultrasound bath for 30 minutes. The suspension was then filtrated on a Whatman Rezist 13 0.2 PTFE preheated filter (0.2 micron), then the solvent was evaporated at a temperature of 50°C.
- 61.61 g of solid amorphous compound of ivabradine/chrysin, in a 5/1 molar ratio were obtained as a yellow glassy solid.
- the solid amorphous compound obtained with the example 1 was subjected to stability assays at 25°C, 0% and 25% humidity for 27 days. In these conditions the solid amorphous compound showed to be stable.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Subject-matter of the present invention is a novel amorphous compound comprising ivabradine, in particular a solid amorphous compound consisting of ivabradine and chrysin. Subject-matter of the invention is also a process for the preparation of said solid amorphous compound, its use in therapy and the pharmaceutical compositions comprising it.
Description
AMORPHOUS MIXTURE OF IVABRADINE AND CHRYSIN
Summary of the Invention
Subject-matter of the present invention is a novel amorphous compound comprising ivabradine, in particular a solid amorphous compound consisting of ivabradine and chrysin. Subject-matter of the invention is also a process for the preparation of said amorphous compound, its use in therapy and the pharmaceutical compositions comprising it.
Technical Background
Ivabradine or 3-[3-( {[(75)-3,4-dimethoxybicycle[4.2.0]octa-l }3,5-trien'7- yl]methyl} (methyl)amino) propyl]-7,8-dimethoxy- 1 ,3 ,4,5-tetrahydro-2H-3- benzazepin-2-one, having the following formula
is used in cardiology against heart failure, hypertension, angina and post-infarction treatment and has been described for the first time in Patent EP 0 534 859 in the name of Adir/Servier.
Ivabradine free base is a yellowish, very viscous oil that is hardly to treat and to formulate. For this reason ivabradine base has not been considered convenient for preparing pharmaceutical compositions to be used in therapy and it has been preferred to formulate pharmaceutical compositions containing ivabradine in a salified form, in particular as the hydrochloride salt, presenting as a solid and therefore being more suitable to the industrial processing.
However, considering the low dose of active ingredient present in the ivabradine formulations (for example tablets comprising only 5 mg of ivabradine), the dispersion of such a small amount of solid active ingredient in the solid matrix of excipients, with the purpose of obtaining a highly homogeneous dispersion, is not an easy, industrial process.
Thus there is the need for a solid form of ivabradine allowing a homogeneous
dispersion thereof in the pharmaceutical composition, even when used in low dosage, without this leading to difficulties in industrial processing.
Objects of the Invention
An object of the invention is to provide a novel solid compound comprising ivabradine allowing its easier industrial processing and which could be easily formulated in pharmaceutical compositions.
A further object of the invention is to provide pharmaceutical compositions comprising the novel solid compound comprising ivabradine and their use in therapy.
A further object of the invention is to provide a process for the preparation of the novel solid compound of ivabradine.
Description of the Invention
According to one of its aspects, a subject-matter of the invention is a novel solid compound comprising ivabradine which is an amorphous compound consisting of ivabradine and chrysin.
According to a preferred embodiment, the amorphous compound consisting of ivabradine and chrysin is solid.
Ivabradine has the following structural formula (I)
has the followin structural formula (II)
According to the invention, the term "amorphous compound" is meant to define a mixture of ivabradine and chrysin under the form of an amorphous substance, i.e. not crystallized, consisting of an intimate aggregate of ivabradine and chrysin. Preferably,
said amorphous compound is a solid amorphous compound.
According to a preferred embodiment in the advantageously solid, amorphous compound of the invention, the ivabradine/chrysin molar ratio is between 1/1 and 10/1, included 1/1 and 10/1 ratios, preferably 3/1 to 7/1, advantageously the ratio is 5/1. According to another of its aspects, a subject-matter of the invention is a process for the preparation of the novel amorphous compound of the invention which comprises: a. adding a mixture of ivabradine and chrysin to a suitable solvent, up to saturation;
b. optionally heating the mixture;
c. evaporating the solvent from the mixture to isolate said amorphous compound.
The ivabradine used in step (a) is ivabradine free base.
According to a preferred embodiment, in step (a) ivabradine and chrysin are used in 1/1 to 10/1 molar ratio, preferably 3/1 to 7/1 ratio, advantageously in a 5/1 ratio. Appropriate solvents for the process of the invention include lower alcohols, water and mixtures thereof.
By "lower alcohols" are herein meant alcohols having 1 to 4 carbon atoms, as methanol, ethanol, isopropanol and butanol, for example.
Preferred solvents according to the invention are the lower alcohols, in particular ethanol and water. More preferred solvents are ethanol and mixtures of ethanol/water. An advantageous mixture of ethanol/water is the mixture containing 95% ethanol and 5% water (v/v).
In step (b) the reaction mixture is preferably, but not necessarily, heated to a temperature between 30°C and the boiling temperature of the mixture, advantageously between 40°C and 60°C, for example around 50°C.
The heating of step (b) can also be carried out in an ultrasound bath.
The same temperatures can be used for the evaporation of the solvent in step (c).
The novel, preferably solid, amorphous compound, obtainable and/or obtained by the above described process, is a further subject-matter of the invention.
The novel, preferably solid, amorphous compound of ivabradine and chrysin, in particular the compound in the 5/1 molar ratio, showed a good stability, remaining stable at 0°C and room temperature for a long time.
Obtaining the novel amorphous compound of ivabradine and chrysin is not obvious at all. The present Applicant made tests for the preparation of compound of ivabradine with a number of other substances but none of tested substances provided satisfactory results. Therefore, the novel solid amorphous compound represents a remarkable and unexpected technical progress.
The novel amorphous compound presents as a glassy solid, which can be mashed, for example micronized, for its formulation in pharmaceutical compositions.
Therefore the solid amorphous compound of the invention allows to obtain a powder containing ivabradine in the base form, i.e. not salified, perfectly stable and workable, that can be used for preparing solid pharmaceutical compositions, suspensions and suppositories, but also buccal patches or even transdermal patches, preferably in addition to one or more conventional pharmaceutically acceptable excipients.
Pharmaceutical compositions comprising the preferably solid, amorphous compound of ivabradine and chrysin are a further subject-matter of the invention, such as also the use in therapy of the amorphous compound of ivabradine and chrysin and pharmaceutical compositions containing them, in particular in the treatment of heart failure, hypertension, angina and in the post-infarction treatment.
The invention also comprises a method of treating heart failure, hypertension, angina and post-infarction condition which comprises administering, to a subject in the need thereof, an effective amount of the preferably solid, amorphous compound of ivabradine and chrysin, advantageously in the form of a pharmaceutical composition of the invention.
Pharmaceutical compositions of the invention are particularly suitable for oral administration.
For oral administration, said compositions can be in the form of tablets, capsules or granulates and are prepared according to conventional methods with pharmaceutically acceptable excipients such as binding agents, bulking agents, lubricants, disintegrants, wetting agents, flavoring agents, etc. Tablets can also be coated by methods well known in the art.
The compositions of the invention are advantageously in the form of dosage units. Preferably, each dosage unit according to the invention comprises an amount of
ivabradine (calculated as ivabradine free base) from 1 to 10 mg, for example 4 to 8 mg, advantageously 5 mg and 7.5 mg, together with conventional excipients and additives well known to the person skilled in the art.
Thanks to its stability, in the compositions according to the invention, the preferably solid, amorphous compound of ivabradine and chrysin can be formulated in combination with additional active ingredients. According to a preferred embodiment, in the compositions according to the invention the preferably solid, amorphous compound of ivabradine and chrysin is formulated as the only active ingredient. It is evident from the above that thanks to the invention it is possible to use ivabradine base which, as mentioned, is an oil difficult to process, directly as active ingredient, with the additional advantage of being able to formulate the preferably solid, amorphous compound in a simple and industrially convenient way, thereby obtaining pharmaceutical compositions wherein the active ingredient is homogeneously dispersed.
Experimental Section
Example 1
Preparation of the amorphous compound of ivabradine and chrysin
In a container, 60.3 mg ivabradine and 6.7 mg chrysin are added to 3.5 ml ethanol; the container was closed and the mixture was heated to 50°C in an ultrasound bath for 30 minutes. The suspension was then filtrated on a Whatman Rezist 13 0.2 PTFE preheated filter (0.2 micron), then the solvent was evaporated at a temperature of 50°C. Thus 61.61 g of solid amorphous compound of ivabradine/chrysin, in a 5/1 molar ratio, were obtained as a yellow glassy solid.
Example 2
Preparation of the amorphous compound of ivabradine and chrysin
The process of example 1 was repeated using 60.8 mg ivabradine and 3.4 mg chrysin. 58.23 g of solid amorphous compound of ivabradine/chrysin, in a 10/1 molar ratio, were obtained as a yellow glassy solid.
Example 3
Preparation of the amorphous compound of ivabradine and chrysin
The process of example 1 was repeated using 60.3 mg ivabradine and 10.9 mg chrysin.
64.41 g of solid amorphous compound of ivabradine/chrysin, in a 3/1 molar ratio, were obtained as a yellow glassy solid.
Example 4
Preparation of the amorphous compound of ivabradine and chrysin
The process of example 1 was repeated using 30.4 mg ivabradine and 16.8 mg chrysin by replacing ethanol with a mixture of 95/5 ethanol/water (v/v). 39.93 g of solid amorphous compound of ivabradine/chrysin, in a 1/1 molar ratio, were obtained as a yellow glassy solid.
Example 5
Stability assays
The solid amorphous compound obtained with the example 1 was subjected to stability assays at 25°C, 0% and 25% humidity for 27 days. In these conditions the solid amorphous compound showed to be stable.
Claims
1. Amorphous compound consisting of ivabradine and chrysin.
2. Amorphous compound according to claim 1, which is solid.
3. Amorphous compound according to claim 1 or 2, characterized in that ivabradine and chrysin are present in said amorphous compound in a molar ratio of from 1/1 to 10/1.
4. Amorphous compound according to claim 3, characterized in that said molar ratio is 5/1.
5. Process for the preparation of the amorphous compound according to any one of claims 1 to 4, which comprises:
a. adding a mixture of ivabradine and chrysin to a suitable solvent, up to saturation;
b. optionally heating the mixture;
c. evaporating the solvent from the mixture to isolate said amorphous compound.
6. Process according to claim 5, characterized in that in step (a) the molar ratio of ivabradine to chrysin is of 5/1.
7. Process according to any one of claims 5 or 6, characterized in that said solvent is selected from lower alcohols, water and mixtures thereof.
8. Process according to claim 7, characterized in that said solvent is selected from ethanol and a mixture of ethanol/water.
9. Solid amorphous compound consisting of ivabradine and chrysin obtainable according to the process of any one of claims 5 to 8.
10. Pharmaceutical composition which comprises the solid amorphous compound according to any one of claims 1 to 4 and 9.
11. Solid amorphous compound according to any one of claims 1 to 4 and 9, or composition according to claim 10, for use in therapy.
12. Solid amorphous compound according to any one of claims 1 to 4 and 9, or composition according to claim 10, for use in the treatment of heart failure, hypertension, angina and in the post-infarction treatment.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20141313 | 2014-07-18 | ||
| ITMI2014A001313 | 2014-07-18 |
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| WO2016009314A1 true WO2016009314A1 (en) | 2016-01-21 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (en) | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substituted 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases |
| WO2002013790A1 (en) * | 2000-08-18 | 2002-02-21 | Korea Research Institute Of Chemical Technology | Solid dispersion of ipriflavone for oral administration and its manufacturing methods |
| CN102451175A (en) * | 2010-11-01 | 2012-05-16 | 中国科学院大连化学物理研究所 | Resveratrol and bioflavonoid composition as well as preparation and application thereof |
| WO2013058751A1 (en) * | 2011-10-19 | 2013-04-25 | Virginia Tech Intellectual Properties, Inc. | Cellulose derivatives for enhancing bioavailability of flavonoids |
| WO2013150544A2 (en) * | 2012-04-02 | 2013-10-10 | Hetero Research Foundation | Ivabradine hydrochloride solid dispersion |
-
2015
- 2015-07-10 WO PCT/IB2015/055224 patent/WO2016009314A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534859A1 (en) | 1991-09-27 | 1993-03-31 | Adir Et Compagnie | Benzocyclobutyl- or indanyl-alkyl-amino-alkyl substituted 3-benzazepin-2-ones useful in the treatment of cardiovascular diseases |
| WO2002013790A1 (en) * | 2000-08-18 | 2002-02-21 | Korea Research Institute Of Chemical Technology | Solid dispersion of ipriflavone for oral administration and its manufacturing methods |
| CN102451175A (en) * | 2010-11-01 | 2012-05-16 | 中国科学院大连化学物理研究所 | Resveratrol and bioflavonoid composition as well as preparation and application thereof |
| WO2013058751A1 (en) * | 2011-10-19 | 2013-04-25 | Virginia Tech Intellectual Properties, Inc. | Cellulose derivatives for enhancing bioavailability of flavonoids |
| WO2013150544A2 (en) * | 2012-04-02 | 2013-10-10 | Hetero Research Foundation | Ivabradine hydrochloride solid dispersion |
Non-Patent Citations (2)
| Title |
|---|
| HUGHEY, JUSTIN R. ET AL: "The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus-based solid dispersions", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 48, no. 4-5, 2013, pages 758 - 766, XP002732910, DOI: 10.1016/J.EJPS.2013.01.004 * |
| KONNO TSUTOMU: "Physical and chemical changes of medicinals in mixtures with adsorbents in the solid state. IV. Study on reduced- pressure mixing for practical use of amorphous mixtures of flufenamic acid", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 38, no. 7, 1990, pages 2003 - 2007, XP008132274, ISSN: 0009-2363 * |
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