Title of Invention | METHOD FOR PREPARING A STORAGE-STABLE IVY LEAVES EXTRACT USING AN EXTRACTING AGENT |
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Abstract | This invention relates to a method for preparing a storage - stable ivy leaves extract using an extracting agent, with the extract comprising at least the constituents hederacoside C and α - hederin. The steps of comminuting a quantity of dried ivy leaves; steaming the comminuted quantity of dried ivy leaves with hot water vapor; extracting by adding the extracting agent, and optionally, drying the extract. |
Full Text | Method for preparing a storage stable ivy leaves extract and an extract prepared according to said method The present invention relates to a method for preparing a storage-stable ivy leaves extract using an extracting agent, with the extract at least comprising the constituents hederacoside C and α-hederin. Within the meaning of the present invention, the term "storage-stable" means that, whether it is determined by the natural composition of the extract or whether it is adjusted to the given value by selective measures, a particular hederacoside C/α-hederin ratio in the extract remains stable for long periods. Extracts from ivy leaves are nowadays successfully employed for treating respiratory tract diseases, in particular, since the extract exhibits spasmolytic, expectorant and antiobstructive effects. These effects are to be attributed, in particular, to the therapeutically important ivy leaves extract constituents which belong to the triterpene saponin class. In this connection, the main saponin is the bidesmosidic hederacoside C and the α-hederin which is formed from it by by ester hydrolysis. Another saponin which has been detected is hederagenin. Since ivy leaves extracts can be obtained by a variety of methods, these extracts frequently exhibit different degrees of efficiency. This stems from the fact that the proportions of the constituents depend not only on the natural constitution of the ivy leaves but also on the particular method used for preparing the extract. In addition to this, the applicant has recently demonstrated that α-hederin, in particular, is responsible for the spasmolytic effect of ivy leaves extracts since this active compound binds to P-adrenergic receptors, with this leading, in the smooth musculature of the bronchial systems, to relaxation by way of further cascades. A great variety of methods for preparing dry extracts from plant materials have been described in the field of pharmacy and. in particular in the field of pharmaceutical preparation. For example. DE 101 12 168 AI discloses a method lor preparing dry extracts from plant materials. The method disclosed in this document can allegedly be used to adjust the content of lipophilic and hydrophilic substances. In this method, the plant material is subjected to at least two extractions with solvents of differing lipophilicity and the extracts from these extractions are isolated separately. The extracts are dried separately from each other and then mixed in the desired ratio. This makes it possible to adjust the content of lipophilic and hydrophilic substances. The method is allegedly also suitable for obtaining dry extracts from ivy (Hedera helix). However, a disadvantage of this method is the circumstance that two separate extractions have to be carried out. thereby making the method as a whole very elaborate. In addition. DE 30 25 223 AI discloses a pharmaceutical preparation based on iv\ extracts and a method for producing it. in which method an ivy extract having a hederasaponin C content of 60 and. respectively, 90% is obtained using acetone and methanol. However, the hederacoside C content of the extract which is obtained from this method is not stable since experience shows that the hederacoside C in the extract is hydrolyzed to α-hederin. However, it is frequently necessary to keep the content of the constituents hederacoside C and α-hederin in ivy extracts stable and thereby storable. Only when stable quantity ratios are available it is possible, for example, to prepare mixed extracts having precisely adjusted concentration ratios. Such precisely adjusted concentration ratios make it easier to produce pharmaceuticals which comprise exactly reproducible contents of active compound and open up the possibility of influencing bioavailability. It is therefore object of the present invention to provide a method which can be used to obtain, in only a few steps and without great input, an ivy extract, in particular a dry extract, in which the content of the constituents hederacoside C and α-hederin is stable during storage. According to the initially mentioned method, the object underlying the invention is achieved bv the method comprising the following steps: a) comminuting a quantity of ivy leaves. b) steaming the comminuted quantity of ivy leaves with hot water vapor. c) extracting by adding the extracting agent, and d) where appropriate, drying the extract. The method according to the invention now makes it possible to obtain an ivy leaves extract which comprises the constituents hederacoside and α-hederin at a concentration which is stable during storage. There is no possibility of any undesirable hederacoside C/a-hederin conversion and consequently of any change in the hederacoside C/α-hederin ratio in the extract. In particular, this method makes it possible to prepare an extract which comprises at mo-1 the quantity of α-hederin which is already present in the original drug. Expressed in another wax. the method results in the isolation of an extract which has a high hederacoside C content which remains unchanged over relatively long periods. Such extracts are. for example, of great interest when they are to be used as the starting material for mixed extracts which comprise a specifically determinable and precisely fixed content of the active compounds hederacoside C and α-hederin. In particular, the step of steaming increases the extraction yield of hederacoside C since the steaming disrupts the cells in the ivy leaves and thereby largely inactivates the enzyme which catalyzes the conversion of hederacoside C to α-hederin. Accordingly, extracts having a high content of hederacoside C and a low content of a-hederin can be obtained by means of the method according to the invention, depending on the original drug employed or depending on the content of active compounds present in the original drug. The percentage content of a-hederin in the extract which is obtained by the method according to the invention does not exceed the percentage content within the leaves which are used. Accordingly, an extract which is, for example, isolated using leaf batches having a content of less than 0.5% a-hederin itself has a maximum content of 0.5% a-hederin. Such an extract can then advantageously be used, for example, for selectively preparing mixtures of extracts each of which comprises precisely determinable quantities of the particular active compounds, i.e. hederacoside C and a-hederin. with this then resulting in final extracts which comprise a concretely specified content of the two active compounds. This step of steaming also opens up the possibility of initially allowing a certain conversion of hederacoside C into a-hederin and then terminating this conversion. In the method according to the invention, preference is given to the ivy leaves being used as the dried drug. In pharmaceutical production, dried drugs have the advantage that they are sometimes easier to manipulate, with regard to stability, than are fresh drugs. However, the possibility of using fresh ivy leaves in the method according to the invention is not excluded. In the field of pharmaceutical technology, dried medicinal plants and medicinal plant parts are described bv, definition as being "drugs". In this connection, such medicinal plants, which are present as "drugs", are used either in unaltered form or in comminuted form. Preference is furthermore given to comminuting the ivy leaves down to ≤ 5 ≤ 5 mm in step a). Preference is furthermore given to the steaming being carried out over a period of from I to 30 seconds, in particular of from 1 to 10 seconds, and preferably for 5 seconds. This period proved to be effective for the extraction process since, on the one hand, the hydrolysis of hederacoside C to a-hederin is prevented and. at the same time, rapid implementation of the method is ensured. In this connection, preference is given to the steaming with water vapor taking place at a temperature of from approx. 90°C (where appropriate under negative pressure) to 140ºC. in particular at a temperature of from approx. 100 to I20°C. and preferably at 140ºC. Preference is furthermore given, in the method according to the invention, to the extracting agent being a mixture of alcohol and water components. Particular preference is given to the alcohol employed being 30% ethanol. Ethanol is a tried and tested pharmaceutical solvent and is frequently employed as an extracting agent in the field of pharmaceutical technology. However, it is possible to use other alcohols, for example propanol, isopropanol. etc.. that is any alcohols which can be employed as water/alcohol mixtures in connection with extracting for the purpose of preparing pharmaceuticals. In addition, preference is given to the extracting in step c) being carried out by means of preswelling and percolation and, in particular to a period of from approx. 1 hour to approx. 30 hours, preferably a period of 6 hours, being pro\ ided for the preswelling. Preswelling and percolation are customary methods in the prior art and. in particular, in the field of preparing pharmaceuticals from plants. An exhaustive extraction of the ivy leaves can be achieved b> means of the steps of preswelling and percolation. In this connection, preference is given to maintaining a process temperature of from 10 to 40°C. in particular of 30°C. Preference is given, in a development of the method according to the invention, to the drying in step d) being carried out by means of thin film vaporization and subsequent spray drying. Both methods are conventional drying methods, with thin film vaporization having proved to be a mild evaporation method in connection with preparing pharmaceuticals, just like spray drying, which can be used, as experience shows, to dry liquid preparations to give pulyerulent final products which are distinguished, in particular, by the fact that they can be readily mixed once again with water to gi\e ready-to-use preparations. In this connection, the thin film vaporization is. for example, carried out at from approx. 50 to 60°C and at from 130 to 180 mbar. and the spray drying is carried out at from 45 to 60°C. Preference is furthermore given to the method according to the invention being used to prepare an ivy leaves extract having an elevated content of hederacoside C. As described above. it is possible to use the method according to the invention to selectively increase the proportion of hederacoside C. with the content of α-hederin in the extract at the same time corresponding to at most the content of a-hederin in the original drug. One embodiment provides for at least a part of the hederacoside C being selectively converted into α-hederin prior to step b). that is the steaming. This opens up the possibility of selectively preparing (as it were "designing") extracts having a particular hederacoside C/α-hederin ratio and of only carrying out the steaming step, which then prevents any further conversion of hederacoside C into a-hederin, after a particular hederacoside C/a-hederin ratio has been reached. This is based on the applicant's finding that conversion of hederacoside C into a-hederin can be brought about by a fermentation step which is catalyzed by water. The invention furthermore relates to a storage-stable ivy leaves extract which is prepared using the method according to the invention. Extracts having a high content of hederacoside are advantageous, for example, when mixtures composed of extracts which comprise a determinable content of hederacoside are to be prepared. Even if, as explained above, α-hederin is the active constituent of the ivleaves as far as the bronchospasmolytic effect is concerned, extracts having a high content of hederacoside C are also advantageous since these extracts can. as mentioned above, be used for preparing selective mixtures. The invention furthermore relates to the use of the extract which is prepared in accordance with the invention, in particular the dry extract, for preparing a pharmaceutical and. in particular, for preparing a pharmaceutical for treating respiratory tract diseases. The pharmaceutical according to the invention can accordingly be used for treating respiratory tract diseases such as infectious and inflammatory respiratory tract diseases, such as pneumonia, tracheitis, bronchitis etc.. and also in connection with obstructive and restrictive lung diseases such as chronic bronchitis, bronchial asthma, bronchiectases, etc.. that is in connection with respiratory tract diseases in which relaxation of the weak musculature is desired. The invention furthermore relates to a pharmaceutical which comprises an extract which is prepared using the method according to the invention. In this connection, the pharmaceutical can be present in the form of capsules, tablets, coated tablets, suppositories, granules, powders, solutions, creams, emulsions, aerosols. ointments and oils. Oral administration forms arc particularly preferred in this connection. The pharmaceutical can comprise auxiliary substances which are conventionally used in pharmaceutical preparation. A number of suitable substances can be found, for example, in A. Kibbe, Handbook of Pharmaceutical Excipients, 3rd Ed.. 2000, American Pharmaceutical Association and Pharmaceutical Press. Other advantages ensue from the example and the attached figures. In the/figures Fig. 1a shows a graph of the influence of the drug steaming on the constituent spectrum of the extract Fig. 1b shows a graph of the influence of the drug steaming on the extraction yield of Hedera saponins. It will be understood that the features which arc mentioned above and which are still to be explained below can be used not only in the combination which is in each case specified but also in other combinations, or on their own. without departing from the scope of the present invention. Example: Preparing dry ivv leaves extracts having an elevated content of hederacoside C The basis for controlling the ratio of hederacoside C to α-hederin is to selectively prevent the elimination of the sugar in the C28 position of the hederacoside C during the extraction process. When selecting the drug batch, care should be taken 10 ensure that leaves batches having a low α-hederin content are used. It is advisable to specify that the content of a-hederin in the dried drug should be less man 0.5%. A homogeneous sample of ivy leaves gave the following analysis with regard to the content of the two saponins: hederacoside C: 6.37% a-hederin: 0.85% Starting from that drug, in each case three extractions were carried out twice in accordance with the following extraction protocols: Extraction protocol 1: 3 g of the drug, which had been dried and comminuted down to approx. 3x3 mm, were steamed with hot water vapor (approx. 100°C) for a few seconds. The drug which had been treated in this way was preswollen with 18 g of the extracting agent (30% ethanol (m/m)) for approx. 6 hours. After draining off the miscella. the remaining drug was percolated with a further 18 g of the extracting agent. This miscella was dried in a vacuum-drying oven. The extraction temperature is preferably between approx. 20 and approx. 40°C. in particular approx. 30°C. The ratio of drug to the extracting agent is. for example, 1:12. Alternative!y the drying can be carried out, for example, by means of thin film vaporization at. for example. 55°C and 150 mbar and then spray drying at 45-60ºC. Extraction protocol 2: The extraction protocol corresponds to extraction protocol 1 with the exception of the procedural step of steaming. After the resulting extracts have been analyzed, it was possible to document the results listed in table 1 below. In Figs. 1a and 1b, the results are explained by the two diagrams. The figures show clearly that there is a higher content of hederacoside C and a lower content of α-hederin in the extract prepared in accordance with extraction protocol I (with the steaming step) than in the extract which was prepared using a conventional method (without the steaming step) (see Fig. 1a). At the same time, it was possible to increase the extraction yield by using extraction protocol I (with the steaming step) as compared with using extraction protocol 2 (without the steaming step) (see Fig. 1b). The dry leaves extract which was prepared in accordance with this protocol therefore comprised the quantity of a-hederin which was maximally present in the leaves which were used. Therefore, extracts containing a high content of hederacoside C and a very low content of a-hederin were obtained. When leaves batches having a content of α-hederin of less than 0.5% are used, it can also be assumed that the resulting extract has a maximum content of 0.5% α-hederin. It is consequently possible, by selectively fixing different hederacoside-enriched extracts, to obtain an extract which is characterized by a specified content of hederacoside C and a maximum content or 0.5% a-hederin. These dry extracts were stoned and the hederacoside C/a-hederin ratio was determined once again after 3,6 and 9 moths. No significant change in the ratio was found in this connection. These stored extracts can be used without problems in connection with subsequent formulation to produce pharmaceuticals. Any undesirable conversion of hederacoside C into a-hederin can be ruled out, which means that it is possible to produce pharmaceuticals having a defined hederacoside C/α-hederin ratio in a selective and reproducible manner. DECLARATION UNDER 'BIO DIVERSITY ACT" "THE PROCESS ACCORDING TO THE INVENTION WAS CARRIED OUT WITHOUT USING ANY NATURAL BIOLOGICAL RESOURCES OF INDIA" We Claim 1. Method for preparing a storage - stable ivy leaves extract using an extracting agent, with the extract comprising at least the constituents hederacoside C and α - hederin, characterized by comprising the steps of:- a) comminuting a quantity of dried ivy leaves; b) steaming the comminuted quantity of dried ivy leaves with hot water vapor; c) extracting by adding the extracting agent, and d) optionally, drying the extract. 2. Method as claimed in claim 1, wherein the ivy leaves are comminuted down to ≤ 5 x 5 mm in step a). 3. Method as claimed in claims 1 or 2, wherein the steaming is carried out over a period of from 1 to 30 seconds. 4. Method as claimed in claim 3, wherein the steaming is carried out for a period of from 1 to 10 seconds, in particular for 5 seconds. 5. Method as claimed in anyone of claims 1 to 4, wherein the steaming with water vapor is carried out at a temperature of from approximately 90°C to 140°C. 6. Method as claimed in claim 5, wherein the steaming with water vapor is carried out at a temperature of from approximately 100°C to approximately 120°C, in particular of 110°C. 7. Method as claimed in anyone of claims 1 to 6, wherein the extracting agent employed is an alcohol/water mixture. 8. Method as claimed in claim 7, wherein the extracting agent employed is 30% ethanol (m/m). 9. Method as claimed in anyone of claims 1 to 8, wherein the extracting is carried out by means of preswelling and percolation. 10. Method as claimed in claim 9, wherein the preswelling is carried out for a period of from approximately 1 to approximately 30 hours. 11. Method as claimed in claim 10, wherein the preswelling is carried out for a period of approximately 6 hours. 12. Method as claimed in anyone of claims 1 to 11, wherein the drying is carried out by thin film vaporization and subsequently spray drying. 13. Method as claimed in anyone of claims 1 to 12 for preparing an ivy leaves extract having a content of a - hederin of ≤ 0.85%. 14. Method as claimed in anyone of claims 1 to 12, wherein at least a part of the hederacoside C is selectively converted into α-hederin prior to step b). 15. Ivy leaves extract, characterized in that it is prepared carrying-out the method as claimed in anyone of claims 1 to 14. 16. A pharmaceutical composition comprising an extract as claimed in claim 15 for treating of respiratory tract diseases. This invention relates to a method for preparing a storage - stable ivy leaves extract using an extracting agent, with the extract comprising at least the constituents hederacoside C and α - hederin. The steps of comminuting a quantity of dried ivy leaves; steaming the comminuted quantity of dried ivy leaves with hot water vapor; extracting by adding the extracting agent, and optionally, drying the extract. |
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491-KOLNP-2006-FORM 27-1.1.pdf
491-kolnp-2006-granted-abstract.pdf
491-kolnp-2006-granted-claims.pdf
491-kolnp-2006-granted-correspondence.pdf
491-kolnp-2006-granted-description (complete).pdf
491-kolnp-2006-granted-drawings.pdf
491-kolnp-2006-granted-examination report.pdf
491-kolnp-2006-granted-form 1.pdf
491-kolnp-2006-granted-form 18.pdf
491-kolnp-2006-granted-form 2.pdf
491-kolnp-2006-granted-form 26.pdf
491-kolnp-2006-granted-form 3.pdf
491-kolnp-2006-granted-form 5.pdf
491-kolnp-2006-granted-reply to examination report.pdf
491-kolnp-2006-granted-specification.pdf
491-kolnp-2006-granted-translated copy of priority document.pdf
Patent Number | 227624 | |||||||||||||||
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Indian Patent Application Number | 491/KOLNP/2006 | |||||||||||||||
PG Journal Number | 03/2009 | |||||||||||||||
Publication Date | 16-Jan-2009 | |||||||||||||||
Grant Date | 14-Jan-2009 | |||||||||||||||
Date of Filing | 02-Mar-2006 | |||||||||||||||
Name of Patentee | ENGELHARD ARZNEIMITTEL GMBH & CO. KG. | |||||||||||||||
Applicant Address | HERZBERGSTRASSE 3 61138 NIEDERDORFELDEN | |||||||||||||||
Inventors:
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PCT International Classification Number | A61P 11/00 | |||||||||||||||
PCT International Application Number | PCT/EP2004/010093 | |||||||||||||||
PCT International Filing date | 2004-09-10 | |||||||||||||||
PCT Conventions:
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