CA2304493A1 - Flavonolignan preparations, especially silymarin preparations - Google Patents
Flavonolignan preparations, especially silymarin preparations Download PDFInfo
- Publication number
- CA2304493A1 CA2304493A1 CA002304493A CA2304493A CA2304493A1 CA 2304493 A1 CA2304493 A1 CA 2304493A1 CA 002304493 A CA002304493 A CA 002304493A CA 2304493 A CA2304493 A CA 2304493A CA 2304493 A1 CA2304493 A1 CA 2304493A1
- Authority
- CA
- Canada
- Prior art keywords
- peg
- silymarin
- preparations
- preparation according
- polyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Abstract
The invention relates to flavonolignan preparations, especially silymarin preparations, which dissolve more easily than pure flavonoids or pure silymarin, to medicaments which contain these preparations and which are used for treating and preventing liver disease, and to a method for producing the preparations without using additional support materials. The inventive flavonolignan preparations are characterised in that they consist of a homogenous liquid mixture of milk thistle extract (Carduus extract) with a high silymarin content, in polyethylene glycol (PEG).
Description
Flavonolignan Preparations, especially Silymarin Preparations DESCRIPTION
The invention relates to flavonolignan preparations, especially silymarin preparations, which dissolve more easily than do pure flavonoids or pure silymarin, i.e., which have an especially improved release rate and subsequently improved absorption and bio-availability in animal or human bodies; to medicines containing these that are used for the treatment and prevention of liver ailments; and to a process for manufacturing the preparations.
Among the medicines used for the treatment and prevention of liver ailments, those based on milk thistle extracts (Carduus extracts) are playing an ever more significant role. An effective component of the milk thistle extract preparation is silymarin, which consists of the four flavonoid isomers (flavonolignan isomers), silibinin, isosilibinin, silicristin, and silidianin. Since silymarin, or flavonoids, in water are only minimally soluble (the solubility of pure silymarin in a pH 6.9 buffer lies at ca.
0.08 mg/ml), all of these medicines have the problem that their absorption, and thereby their bio-availability, in human or animal bodies, is often only unsatisfactorily low.
Furthermore, the flavonoid isomers tend to form agglomerates that do not dissolve easily with many of the common galenic inactive ingredients. In order to improve the water solubility, attempts have already been made to convert, with special chemical agents, the flavonoid isomers of silymarin into derivatives (adducts, complex compounds, ester inclusion compounds) that exhibit better water solubility and a higher release rate. A basic disadvantage of these derivatives is the fact that, in principle, one is dealing with new active substances, and the agents coupled to the flavonoid isomers can often cause undesirable physiological side effects and/or also impair the effectiveness of the flavonoid isomers. These disadvantages in many ways outweigh the advantage of the improved water solubility. Basically, a biopharmaceutical influence of the absorption and bio-availability via the optimization of the pharmaceutical composition is always preferable.
Another method of improving the dissolution reaction, release rate, and bio-availability is described in the publication EP 0 722 719. Accordingly, the flavonoid isomers are dissolved with pharmaceutically acceptable carrier materials and wetting agents in an aqueous alcoholic medium, and this solution is concentrated, filtered, vacuum-dried, and pulverized to form a co-precipitate. The silymarin co-precipitates resulting from this method exhibit a significantly higher release rate (of 95 - 100 %) and bio-availability when compared to the pure active substance, and they are very easily absorbed into human or animal bodies and develop the desired and expected physiological effect. This manufacturing process is, however, technically very complex and results in relatively high costs, above all caused by the fact that (1) several inactive ingredients are needed, that (2) solvents are used that must later be removed, that (3) grinding is necessary, and that (4) the active substance is exposed to thermal stress. Heating the initial solution to the boiling point results in the disadvantage that under such thermal stress, the probability of chemical alterations is increased.
A very similar solution to the problem has also already been described in DE 27 19 581 A1. In the process shown there, the active substance polyhydoxyphenl-chromanone taken from Silybum marianum is dissolved together with polyvinylpyrrolidone in an aqueous-organic solvent, and this solution is lyophylized, wherein a surface-active substance can be added.
A process for manufacturing a plant extract preparation, in which one expressly abstains from drying and grinding, is already known from EP 0 496 705. This publication recommends the manufacturing of a mass made from a liquid partial- or full-extract of fresh and/or dried plant(particles) and at least one carrier material, e.g., polyethylene glycol or polysorbate, in a mass ratio between 20:1 and 200:1. In the list of plants that may be used for the plant extract, Silybum marianum or Carduus or milk thistle are not listed, however; and the problem of the poor dissolution, the release rate, and the bio-availability of flavonoids is also nowhere touched upon in this publication. Furthermore, the crude or primary plant extract described therein still basically contains significant residues of the solvents) used for its manufacture; and also, following the final concentration, the end product that is to be made into capsules still contains solvent residues. In the end, none of the manufactured preparations described therein contains the plant extract in a completely or even largely dissolved form.
The object of the present invention is therefore the preparation of a silymarin preparation in which the flavonoid isomers are left largely in their natural state, i.e., especially do not exist bonded to other chemical substances; and exhibit a high silymarin release rate, i.e., a very good silymarin dissolution behavior and thereby the prerequisite for a good absorption and high bio-availability of the flavonoid isomers in human or animal bodies. The inactive ingredients necessary for the preparation should be completely physiologically harmless and substantially limited in number, i.e., the least possible number of different inactive ingredients. should be used.
The invention relates to flavonolignan preparations, especially silymarin preparations, which dissolve more easily than do pure flavonoids or pure silymarin, i.e., which have an especially improved release rate and subsequently improved absorption and bio-availability in animal or human bodies; to medicines containing these that are used for the treatment and prevention of liver ailments; and to a process for manufacturing the preparations.
Among the medicines used for the treatment and prevention of liver ailments, those based on milk thistle extracts (Carduus extracts) are playing an ever more significant role. An effective component of the milk thistle extract preparation is silymarin, which consists of the four flavonoid isomers (flavonolignan isomers), silibinin, isosilibinin, silicristin, and silidianin. Since silymarin, or flavonoids, in water are only minimally soluble (the solubility of pure silymarin in a pH 6.9 buffer lies at ca.
0.08 mg/ml), all of these medicines have the problem that their absorption, and thereby their bio-availability, in human or animal bodies, is often only unsatisfactorily low.
Furthermore, the flavonoid isomers tend to form agglomerates that do not dissolve easily with many of the common galenic inactive ingredients. In order to improve the water solubility, attempts have already been made to convert, with special chemical agents, the flavonoid isomers of silymarin into derivatives (adducts, complex compounds, ester inclusion compounds) that exhibit better water solubility and a higher release rate. A basic disadvantage of these derivatives is the fact that, in principle, one is dealing with new active substances, and the agents coupled to the flavonoid isomers can often cause undesirable physiological side effects and/or also impair the effectiveness of the flavonoid isomers. These disadvantages in many ways outweigh the advantage of the improved water solubility. Basically, a biopharmaceutical influence of the absorption and bio-availability via the optimization of the pharmaceutical composition is always preferable.
Another method of improving the dissolution reaction, release rate, and bio-availability is described in the publication EP 0 722 719. Accordingly, the flavonoid isomers are dissolved with pharmaceutically acceptable carrier materials and wetting agents in an aqueous alcoholic medium, and this solution is concentrated, filtered, vacuum-dried, and pulverized to form a co-precipitate. The silymarin co-precipitates resulting from this method exhibit a significantly higher release rate (of 95 - 100 %) and bio-availability when compared to the pure active substance, and they are very easily absorbed into human or animal bodies and develop the desired and expected physiological effect. This manufacturing process is, however, technically very complex and results in relatively high costs, above all caused by the fact that (1) several inactive ingredients are needed, that (2) solvents are used that must later be removed, that (3) grinding is necessary, and that (4) the active substance is exposed to thermal stress. Heating the initial solution to the boiling point results in the disadvantage that under such thermal stress, the probability of chemical alterations is increased.
A very similar solution to the problem has also already been described in DE 27 19 581 A1. In the process shown there, the active substance polyhydoxyphenl-chromanone taken from Silybum marianum is dissolved together with polyvinylpyrrolidone in an aqueous-organic solvent, and this solution is lyophylized, wherein a surface-active substance can be added.
A process for manufacturing a plant extract preparation, in which one expressly abstains from drying and grinding, is already known from EP 0 496 705. This publication recommends the manufacturing of a mass made from a liquid partial- or full-extract of fresh and/or dried plant(particles) and at least one carrier material, e.g., polyethylene glycol or polysorbate, in a mass ratio between 20:1 and 200:1. In the list of plants that may be used for the plant extract, Silybum marianum or Carduus or milk thistle are not listed, however; and the problem of the poor dissolution, the release rate, and the bio-availability of flavonoids is also nowhere touched upon in this publication. Furthermore, the crude or primary plant extract described therein still basically contains significant residues of the solvents) used for its manufacture; and also, following the final concentration, the end product that is to be made into capsules still contains solvent residues. In the end, none of the manufactured preparations described therein contains the plant extract in a completely or even largely dissolved form.
The object of the present invention is therefore the preparation of a silymarin preparation in which the flavonoid isomers are left largely in their natural state, i.e., especially do not exist bonded to other chemical substances; and exhibit a high silymarin release rate, i.e., a very good silymarin dissolution behavior and thereby the prerequisite for a good absorption and high bio-availability of the flavonoid isomers in human or animal bodies. The inactive ingredients necessary for the preparation should be completely physiologically harmless and substantially limited in number, i.e., the least possible number of different inactive ingredients. should be used.
A solution for this object lies in the preparation of flavonolignan or silymarin preparations of the initially described type, which consist exclusively, or almost exclusively,. of an almost or completely homogenous liquid mixture of dry milk thistle extract (Carduus extract) with high silymarin content in polyethylene glycol (PEG) -without using additional carrier materials. Surprisingly, it was namely discovered that as sole solvent for the dry milk thistle extract, PEG results in the technically simplest method for obtaining a milk thistle extract that exhibits a practically equally good dissolution behavior as do the co-precipitates described in EP 0 722 719 A1 and the tested and evaluated medicines found in the publication by H.-U. Schulz et. al., "Untersuchungen zum Freisetzungsverhalten and zur Bioaquivalenz von Silymarin-Praparaten" (Investigations of the Release Rate Behavior and Bioequivalence of Silymarin Preparations), Arzneim.-Forsch./Drug Res. 45(I), No. 1, 1995.
The preparation according to the invention has the advantage that it disperses very well in water and that it releases the active substance silymarin at a comparatively high rate. The established values for the in-vitro release rate are at least equivalent to those of co-precipitate preparations (see Table 2). In contrast to this known preparation, the preparation according to the invention can, however, be manufactured with considerably less technical effort and more reasonable expense. In particular, there is an elimination of the grinding and those manufacturing steps that use special solvents that must later be removed and disposed of, or reprocessed, as waste.
The preferred forms of polyethylene glycol used are PEG
200, PEG 300, PEG 400, or PEG 600.
In a preferred variation of the preparation according to the invention, the ratio of dry milk thistle extract to polyethylene glycol (PEG) lies in the range between 1:10 and 1:1.5, preferably between 1:5 and 1:2. This preparation exhibits an extraordinarily good dissolution, both in comparison to the values named in EP 0 722 719, as well as to the values of diverse silymarin preparations mentioned in the publication by H.-U. Schulz et. al., "Untersuchungen zum Freisetzungsverhalten and zur Bioaquivalenz von Silymarin-Praparaten", Arzneim.-Forsch./Drug Res. 45(I), No. 1, 1995. A preparation with these kinds of extraordinarily good characteristics contains the dry milk thistle extract (Carduus extract) in polyethylene glycol 400 in a mass ratio of 1:3.
Depending upon the ratio of extract to solvent, either a clear, colored extract solution is present, or a suspension in which the extract is largely dissolved.
The preparation according to the invention can contain additives of pharmaceutically commonly accepted inactive ingredients and co-solvents. The addition of co-solvents is particularly advantageous if the preparation is intended for manufacture as soft gelatine capsules. Propylene glycol, anhydrous glycerin or glycerin 85 % may be used as co-solvents. Preferred co-solvents are glycerin or propylene glycol.
Further additives, e.g., surfactants, especially polysorbate 80 (Tween 80), can also be added.
For the manufacture of the preparations according to the invention, a process is recommended that is characterized by the number and sequence of the following procedural steps:
(a) Heating of liquid polyethylene glycol, preferably to ca. 50 °C, (b) Mixing a conventionally obtained dry milk thistle extract into the heated solution, and intensive homogenization, (c) Addition of co-solvents and/or inactive ingredients, (d) Homogenization with intensive stirring until an almost completely or completely homogenized liquid mixture has been obtained, wherein method steps (a), (b), and (d) are necessary, while method step (c) is performed only when required, i.e., when the addition of co-solvents and/or inactive ingredients is necessary, and is omitted when the preparations are free of co-solvents and inactive ingredients.
The data of a preferred preparation according to the invention are listed below:
dry milk thistle extract approx. 25 weight with high silymarin content (ca. 80 % m/m) liquid polyethylene glycol approx. 60 weight if necessary, polysorbate 80 approx. 5 weight o (Tween 80) if necessary, glycerin or approx. 15 weight o propylene glycol whereby the o by weight given always relates to the total weight of dry milk thistle extract and polyethylene glycol.
The preparation according to the invention is especially suitable for filling into gelatin capsules, preferably soft gelatin capsules, manufactured from normal gelatin or succinylated gelatin. For this purpose, it is recommended that the preparation be manufactured according to the presently described method with the addition of co-solvents and inactive ingredients.
The invention is explained in more detail in the following, by using manufacturing examples and in-vitro test results.
Example 1: Manufacture of a milk thistle extract-polyethylene glycol preparation A dry extract with a silymarin content of ca. 80 0 (photometric assay) is manufactured from milk thistle fruits (Cardui mariae fructus) according to a conventional method. This extract is stirred into polyethylene glycol 400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a homogeneous, liquid mixture is obtained, i.e, according to experience, about 5 minutes.
Example 2: Manufacture of a milk thistle extract-polyethylene glycol preparation for filling into soft gelatin capsules A dry extract with a silymarin content of ca. 80 0 (photometric assay) is manufactured from milk thistle fruits (Cardui mariae fructus) according to conventional methods. This extract is stirred into polyethylene glycol 400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a homogeneous, liquid mixture has been obtained. Anhydrous glycerin and, if necessary, other additions, such as, polysorbate 80, are added to this mixture. Finally, it is further homogenized (ca. 1 min.). The liquid mixture so obtained can, when constantly stirred, be filled directly into soft gelatin capsules.
_ g _ Example 3: Testing of the silymarin release rate of milk thistle extract-polyethylene glycol preparations The active substance release of the milk thistle extract-polyethylene glycol preparations produced according to Examples 1 and 2 were tested in a release apparatus (standard conditions, Paddle model, according to DAB 10, 900 ml:. phosphate buffer pH 7.5 according to DAB 10). On the basis of the minimal solubility of the active substance, 1/ of the normal single dosage, corresponding to ca. 35 mg. silymarin, was used. The quantitative determination of the dissolved silymarin amount was performed photometrically (photometer of manufacturer Perkin Elmer, type Lambda 14) at 288 nm (calculation of the concentration by means of comparison with correspondingly produced comparative solutions). The results are presented in the following Table 1.
Silymarin-polyethylene glycol Released portion (in o) of preparations the utilized amount of silymarin after 60 minutes (photometrically determined at 288 nm) according to Example 1 98.3 according to Example 2 83.2 The rapid and most complete dissolution or release possible guarantees good absorption and high bio-availability of the active substance.
Table 2:
Release of silymarin from milk thistle extract preparations (silymarin content ca. 80 o m/m) in 900 ml. phosphate buffer pH 7.4 R according to DAB 10, photometric determination. Total weight of extract 43.9 mg./release container, corresponding to 1/ of the normal single dosage.
Preparation Released Portion of Silymarin (o) after 60 Minutes Liquid mixture according to the 98.3 invention made from milk thistle extract and PEG 400/polysorbate 80 Ground co-precipitate, produced 85.0 analogous EP 0722719A1; particle size 99 0 < 40 ~m Commercial medicine, containing 84.0 milk thistle extract
The preparation according to the invention has the advantage that it disperses very well in water and that it releases the active substance silymarin at a comparatively high rate. The established values for the in-vitro release rate are at least equivalent to those of co-precipitate preparations (see Table 2). In contrast to this known preparation, the preparation according to the invention can, however, be manufactured with considerably less technical effort and more reasonable expense. In particular, there is an elimination of the grinding and those manufacturing steps that use special solvents that must later be removed and disposed of, or reprocessed, as waste.
The preferred forms of polyethylene glycol used are PEG
200, PEG 300, PEG 400, or PEG 600.
In a preferred variation of the preparation according to the invention, the ratio of dry milk thistle extract to polyethylene glycol (PEG) lies in the range between 1:10 and 1:1.5, preferably between 1:5 and 1:2. This preparation exhibits an extraordinarily good dissolution, both in comparison to the values named in EP 0 722 719, as well as to the values of diverse silymarin preparations mentioned in the publication by H.-U. Schulz et. al., "Untersuchungen zum Freisetzungsverhalten and zur Bioaquivalenz von Silymarin-Praparaten", Arzneim.-Forsch./Drug Res. 45(I), No. 1, 1995. A preparation with these kinds of extraordinarily good characteristics contains the dry milk thistle extract (Carduus extract) in polyethylene glycol 400 in a mass ratio of 1:3.
Depending upon the ratio of extract to solvent, either a clear, colored extract solution is present, or a suspension in which the extract is largely dissolved.
The preparation according to the invention can contain additives of pharmaceutically commonly accepted inactive ingredients and co-solvents. The addition of co-solvents is particularly advantageous if the preparation is intended for manufacture as soft gelatine capsules. Propylene glycol, anhydrous glycerin or glycerin 85 % may be used as co-solvents. Preferred co-solvents are glycerin or propylene glycol.
Further additives, e.g., surfactants, especially polysorbate 80 (Tween 80), can also be added.
For the manufacture of the preparations according to the invention, a process is recommended that is characterized by the number and sequence of the following procedural steps:
(a) Heating of liquid polyethylene glycol, preferably to ca. 50 °C, (b) Mixing a conventionally obtained dry milk thistle extract into the heated solution, and intensive homogenization, (c) Addition of co-solvents and/or inactive ingredients, (d) Homogenization with intensive stirring until an almost completely or completely homogenized liquid mixture has been obtained, wherein method steps (a), (b), and (d) are necessary, while method step (c) is performed only when required, i.e., when the addition of co-solvents and/or inactive ingredients is necessary, and is omitted when the preparations are free of co-solvents and inactive ingredients.
The data of a preferred preparation according to the invention are listed below:
dry milk thistle extract approx. 25 weight with high silymarin content (ca. 80 % m/m) liquid polyethylene glycol approx. 60 weight if necessary, polysorbate 80 approx. 5 weight o (Tween 80) if necessary, glycerin or approx. 15 weight o propylene glycol whereby the o by weight given always relates to the total weight of dry milk thistle extract and polyethylene glycol.
The preparation according to the invention is especially suitable for filling into gelatin capsules, preferably soft gelatin capsules, manufactured from normal gelatin or succinylated gelatin. For this purpose, it is recommended that the preparation be manufactured according to the presently described method with the addition of co-solvents and inactive ingredients.
The invention is explained in more detail in the following, by using manufacturing examples and in-vitro test results.
Example 1: Manufacture of a milk thistle extract-polyethylene glycol preparation A dry extract with a silymarin content of ca. 80 0 (photometric assay) is manufactured from milk thistle fruits (Cardui mariae fructus) according to a conventional method. This extract is stirred into polyethylene glycol 400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a homogeneous, liquid mixture is obtained, i.e, according to experience, about 5 minutes.
Example 2: Manufacture of a milk thistle extract-polyethylene glycol preparation for filling into soft gelatin capsules A dry extract with a silymarin content of ca. 80 0 (photometric assay) is manufactured from milk thistle fruits (Cardui mariae fructus) according to conventional methods. This extract is stirred into polyethylene glycol 400, which has been heated to ca. 50 °C for this purpose.
This mixture is intensively homogenized until a homogeneous, liquid mixture has been obtained. Anhydrous glycerin and, if necessary, other additions, such as, polysorbate 80, are added to this mixture. Finally, it is further homogenized (ca. 1 min.). The liquid mixture so obtained can, when constantly stirred, be filled directly into soft gelatin capsules.
_ g _ Example 3: Testing of the silymarin release rate of milk thistle extract-polyethylene glycol preparations The active substance release of the milk thistle extract-polyethylene glycol preparations produced according to Examples 1 and 2 were tested in a release apparatus (standard conditions, Paddle model, according to DAB 10, 900 ml:. phosphate buffer pH 7.5 according to DAB 10). On the basis of the minimal solubility of the active substance, 1/ of the normal single dosage, corresponding to ca. 35 mg. silymarin, was used. The quantitative determination of the dissolved silymarin amount was performed photometrically (photometer of manufacturer Perkin Elmer, type Lambda 14) at 288 nm (calculation of the concentration by means of comparison with correspondingly produced comparative solutions). The results are presented in the following Table 1.
Silymarin-polyethylene glycol Released portion (in o) of preparations the utilized amount of silymarin after 60 minutes (photometrically determined at 288 nm) according to Example 1 98.3 according to Example 2 83.2 The rapid and most complete dissolution or release possible guarantees good absorption and high bio-availability of the active substance.
Table 2:
Release of silymarin from milk thistle extract preparations (silymarin content ca. 80 o m/m) in 900 ml. phosphate buffer pH 7.4 R according to DAB 10, photometric determination. Total weight of extract 43.9 mg./release container, corresponding to 1/ of the normal single dosage.
Preparation Released Portion of Silymarin (o) after 60 Minutes Liquid mixture according to the 98.3 invention made from milk thistle extract and PEG 400/polysorbate 80 Ground co-precipitate, produced 85.0 analogous EP 0722719A1; particle size 99 0 < 40 ~m Commercial medicine, containing 84.0 milk thistle extract
Claims (10)
1. Flavonolignan preparations, especially silymarin preparations, with improved dissolution behavior compared to pure flavonoids or pure silymarin, characterized in that the preparation consists exclusively or almost exclusively of an almost or completely homogeneous liquid mixture of milk thistle extract in polyethylene glycol (PEG).
2. Preparation according to claim 1, characterized in that the polyethylene glycol (PEG) is PEG 200, PEG
300, PEG 400, or PEG 600.
300, PEG 400, or PEG 600.
3. Preparation according to claim 1 or 2, characterized in that the weight ratio of milk thistle extract to polyethylene glycol (PEG) lies in the range between 1:10 and 1:1.5, preferably between 1:5 and 1:2.
4. Preparation according to one of the claims 1 to 3, characterized in that the liquid mixture consists of dry milk thistle extract and PEG in a weight ratio of 1:3.
5. Preparation according to one of the claims 1 to 4, characterized in that the additions of pharmaceutically accepted co-solvents and/or inactive ingredients are provided.
6. Preparation according to claim 5, characterized in that the co-solvent is anhydrous glycerin or propylene glycol.
7. Preparation according to one of the claims 3 to 6, characterized in that the inactive ingredient(s) is/are surfactant(s), in particular polysorbate 80 (Tween 80).
8. Manufacturing process of a preparation according to one of the claims 1 to 7, characterized by the number and sequence of the method steps:
(a) Heating of liquid polyethylene glycol, preferably to ca. 50 °C, (b) Mixing of a dry milk thistle extract into this heated solution and intensive homogenization, (c) Addition of co-solvents and/or inactive ingredient(s), (d) Homogenization of the mixture until an almost or completely homogenous fluid mixture has been obtained, wherein procedural step (c) is eliminated if the preparation is free of co-solvents and inactive ingredients.
(a) Heating of liquid polyethylene glycol, preferably to ca. 50 °C, (b) Mixing of a dry milk thistle extract into this heated solution and intensive homogenization, (c) Addition of co-solvents and/or inactive ingredient(s), (d) Homogenization of the mixture until an almost or completely homogenous fluid mixture has been obtained, wherein procedural step (c) is eliminated if the preparation is free of co-solvents and inactive ingredients.
9. Medicine for the treatment and prevention of liver ailments containing at least one silymarin preparation according to one of the claims 1 to 7.
10. Manufacturing method of a medicine according to claim 9, characterized in that a preparation according to claim 8 is produced, with the addition of co-solvents and inactive ingredients, and is filled into gelatin capsules, preferably soft gelatin capsules, made of normal gelatin or succinylated gelatin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19744459.8 | 1997-10-08 | ||
| DE19744459A DE19744459A1 (en) | 1997-10-08 | 1997-10-08 | Solubilised silymarin formulation |
| PCT/DE1998/002943 WO1999018985A1 (en) | 1997-10-08 | 1998-09-29 | Flavonolignan preparations, especially silymarin preparations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2304493A1 true CA2304493A1 (en) | 1999-04-22 |
Family
ID=7844948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002304493A Abandoned CA2304493A1 (en) | 1997-10-08 | 1998-09-29 | Flavonolignan preparations, especially silymarin preparations |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1021198B1 (en) |
| AT (1) | ATE213640T1 (en) |
| CA (1) | CA2304493A1 (en) |
| DE (2) | DE19744459A1 (en) |
| WO (1) | WO1999018985A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI610692B (en) * | 2012-03-28 | 2018-01-11 | 大幸藥品股份有限公司 | Pharmaceutical composition and soft capsule containing the composition sealed therein |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100342942B1 (en) * | 1999-07-05 | 2002-07-02 | 민경윤 | Oral micro-emulsion composition comprising Carduus marianus extract or silybin isolated therefrom |
| IT1317062B1 (en) * | 2000-07-14 | 2003-05-26 | Sigma Tau Healthscience Spa | FOOD SUPPLEMENT USEFUL TO PREVENT EBILARY HEPATIC DYSFUNCTIONS INCLUDING AN ALCANOIL L-CARNITINE. |
| KR100385366B1 (en) * | 2001-03-05 | 2003-05-27 | 부광약품 주식회사 | Compositions and preparations of silymarin complex with the improved bioavailability |
| CZ292832B6 (en) | 2001-08-30 | 2003-12-17 | Ivax Pharmaceuticals S.R.O. | Process for preparing silymarin exhibiting increased solubility |
| US6913769B2 (en) | 2003-02-18 | 2005-07-05 | Brian Douglas Oslick | Compositions for prevention and treatment of symptoms associated with ethyl alcohol consumption |
| DE102008039271A1 (en) * | 2007-12-23 | 2009-06-25 | Euromed Sa | New milk thistle extract, method of preparation and use |
| ES2593858T3 (en) | 2009-05-14 | 2016-12-13 | Madaus Gmbh | Method to prepare amorphous silibinin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2017789A1 (en) * | 1970-04-09 | 1971-10-21 | Klosa, Josef, Dipl.-Chem. Dr.Rer. Nat., 1000 Berlin | Carduus marianus seed extraction and sily-marine isolation |
| DE3869442D1 (en) * | 1987-01-19 | 1992-04-30 | Rochas Parfums | COSMETIC OR DERMATOLOGICAL PREPARATIONS CONTAINING AN EXTRACT OF THE FRUIT OF THE SILYBUM MARIANUM WITH A HIGH SYLIMARINE CONTENT WITH ESSENTIAL FATTY ACIDS. |
| IT1222012B (en) * | 1987-07-10 | 1990-08-31 | Indena Spa | PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING COMPLEX FLAVONOLIGNANS WITH PHOSPHOLIPIDS |
-
1997
- 1997-10-08 DE DE19744459A patent/DE19744459A1/en not_active Withdrawn
-
1998
- 1998-09-29 CA CA002304493A patent/CA2304493A1/en not_active Abandoned
- 1998-09-29 EP EP98958807A patent/EP1021198B1/en not_active Expired - Lifetime
- 1998-09-29 WO PCT/DE1998/002943 patent/WO1999018985A1/en active IP Right Grant
- 1998-09-29 DE DE59803223T patent/DE59803223D1/en not_active Expired - Fee Related
- 1998-09-29 AT AT98958807T patent/ATE213640T1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI610692B (en) * | 2012-03-28 | 2018-01-11 | 大幸藥品股份有限公司 | Pharmaceutical composition and soft capsule containing the composition sealed therein |
| US11617794B2 (en) | 2012-03-28 | 2023-04-04 | Taiko Pharmaceutical Co., Ltd. | Drug composition and soft capsule drug sealing the drug composition |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59803223D1 (en) | 2002-04-04 |
| EP1021198A1 (en) | 2000-07-26 |
| EP1021198B1 (en) | 2002-02-27 |
| ATE213640T1 (en) | 2002-03-15 |
| DE19744459A1 (en) | 1999-04-15 |
| WO1999018985A1 (en) | 1999-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101778576B (en) | Stabilized anthocyanin compositions | |
| CN102470103B (en) | Pharmaceutical composition as hcv protease inhibitors | |
| FI80589C (en) | Process for Preparing a Dry Powder for a Pharmaceutical Mixture Preparation, which Powder Contains Microencapsulated Bacampicillin Hydrochloride | |
| FI96095C (en) | A method of preparing a sustained release medicament | |
| EP0142561A1 (en) | Long-acting nifedipine preparation | |
| WO1988006457A1 (en) | Medicinal composition containing albumin as carrier and process for its preparation | |
| CN102228506A (en) | Composition of malaytea scurfpea extract as well as preparation method and use thereof | |
| JP2011525498A (en) | Flavonolignan-based compositions and methods for their preparation | |
| RU2219907C2 (en) | Porous hydroxyapatite particles as drug carriers | |
| RU2157225C2 (en) | Flavane-lignan composition and drug based on thereof | |
| CA2304493A1 (en) | Flavonolignan preparations, especially silymarin preparations | |
| CZ20013153A3 (en) | Process for preparing silymarin exhibiting enhanced solubility | |
| CA3133582A1 (en) | Carrier system for preparing herbaceous extracts | |
| CN1981779B (en) | Xanthosine composition and its production method | |
| JP3995202B2 (en) | Turmeric composition for oral use | |
| Eraga et al. | Some physical properties of Vernonia amygdalina and Garcinia kola microspheres prepared with high molecular weight polyethylene glycols | |
| EP2934590A1 (en) | Magnesium hydroxide carbonate as excipient in pharmaceutical preparations, having improved release of active ingredient | |
| Mohammad et al. | Efficacious formulation of anti-malarial dry suspension for pediatric use | |
| JPS62221633A (en) | Drug for gill disease of sweetfish | |
| JPH07196525A (en) | Preventing and therapeutic agent for gastritis, gastric and duodenal ulcer | |
| CN1732926B (en) | Medicine contained soft capsule | |
| Mupparaju et al. | Formulation and evaluation of dolutegravir sodium solid dispersions and fast dissolving tablets using poloxamer-188 and jackfruit seed starch as excipients | |
| JP2008074838A (en) | Glucosyl hesperidin-containing composition | |
| KR970011272B1 (en) | A process for the preparation of guiryungwon formulations | |
| JPH01238526A (en) | Vitamin e absorption-improving preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |