Composition containing pyrrolizidine-alkaloid-free petasites

p0001The present invention relates to the use of a pharmaceutical composition based on petasitic extract, without hepatotoxic, carcinogenic, cytostatic and / or mutagenic effects, as well as processes for their preparation.

p0002Petasitic extracts are isolated from the roots of the butterbur and have a krampösende and analgesic effect. Hippocrates, Galen, and Paracelsus were already familiar with this effect. The currently used pharmaceutical preparations from petasitic extract are, in particular, viscous extracts of Rhizoma petasites, ie extracts from the rootstock of the butterbur, which produce an unpleasant, Bitter taste, are not readily absorbable, and thus have a slightly delayed pharmaceutical effect after administration.

p0003In addition to the sesquiterpenes, the erythema also contains eremophilanes and pyrrolizidinal alkaloids. The pyrrolizidine alkaloids are common to the pyrrolizidine skeleton. They are common in higher plants worldwide. Thus, pyrrolidizine alkaloids and their N-oxides are found, among others, in the genera of the petasites. The pyrrolidizine alkaloids present in the plant parts of the genus Petasites are characterized by considerable hepatotoxic, carcinogenic and mutagenic as well as cytostatic properties. The toxicity of the pyrrolizidine alkaloids is linked to certain structural groups which have the following structural features:<ul><li>Double bonds in the 1,2-position of the pyrrolizidine ring;</li><li>Esterification of at least the primary hydroxymethyl group with a C₅ or C₆carboxylic acid;</li><li>Branching of the alkyl side chain with at least one of the necic acids.</li></ul>The highest toxicity and carcinogenicity are the cyclic diesters. The pyrrolizidine alkaloids are absorbed rapidly after peroral absorption, their N-oxides are absorbed only after reduction through the intestinal flora. In metabolism in the liver, the pyrrolidizine alkaloids are converted by highly functional oxidases into very toxic pyrrole derivatives. These are highly reactive and alkylating nucleophilic groups of DNA, such as amino, thiol and hydroxy groups, under physiological conditions.

p0004In phytotherapy, pyrrolidizine alkaloid-containing medicinal plants have long been used as a natural remedy. Since the Federal Health Office (BGA) classified all medicinal plants and their preparations containing toxic pyrrolizidine alkaloids as potentially harmful to the health and potentially cause cancer, intensive efforts have been made to provide pharmaceutical petasitic extracts which have a markedly reduced content of pyrrolizidine alkaloids.

p0005Thus, in the <patcit id="pcit0001" dnum="DE3910831"><text>DE 39 10 831</text></patcit>, <patcit id="pcit0002" dnum="DE4111141"><text>DE 41 11 141</text></patcit>, <patcit id="pcit0003" dnum="DE4141749"><text>DE 41 41 749</text></patcit> Which can be used to reduce the content of pyrrolizidine alkaloids in the extract to less than 5 ppm, or even to less than 0.1 ppm, but no real pyrrolizidine alkaloid-free petasitic extract can be obtained by these methods.

p0006It is an object of the present invention to provide the use of pharmaceutical compositions based on petasitic extract without hepatotoxic, carcinogenic, cytotostatic and / or mutagenic effects.

p0007A further object of the invention is to provide methods for the preparation of pharmaceutical compositions based on petasitic extract without hepatotoxic, carcinogenic, cytotostatic and / or mutagenic effects.

p0008A further object of the invention is to provide the use of pharmaceutical compositions for the preparation of petasite preparations without a hepatotoxic, carcinogenic, cytostatic and / or mutagenic effect with a rapid and / or improved effect.

p0009The object of the present invention is achieved by the use of a pharmaceutical composition based on petasitic extract according to claim 1 wherein the petasitic extract is obtained from the plant and / or plant parts of the genus petasites for the manufacture of a medicament for the treatment, eczema and / or of psoriasis , The petasitic extract is free from pyrrolizidine alkaloids, and magnesium and / or further pharmaceutically and / or physiologically active substances are optionally added to this pharmaceutical composition.

p0010The process-related object of the invention is achieved by an extraction process according to claims 12 and 13, wherein the crude extract is subjected to a subsequent aftertreatment in the aqueous medium with a pH value of &lt;7, preferably ≤ 4.

p0011Further embodiments according to the invention are given in the subclaims and in the examples.

p0012In the prior art, the petasitic extract has so far been obtained from the rootstock of the butterbur. It has now proved to be advantageous to obtain the extract from plants and / or plant parts of petasites hybridus, petasites albus, petasites japonicus, petasites paradoxus, and / or petasites spurius, the underground plant parts preferably being used for producing the extract. The use of not only the subterranean plant parts for producing the extract but also other plant parts has the advantage that a substantially higher yield of petasitic extract relative to the entire plant is obtained.

p0013In addition to the already known destruction methods with supercritical CO₂, As for example in the <patcit id="pcit0004" dnum="EP0392504A"><text>EP 0 392 504</text></patcit> and the <patcit id="pcit0005" dnum="EP0547465A"><text>EP 0 547 465</text></patcit> Petasitic extracts according to the invention can also be produced with other means of destroying. Because of the temperature sensitivity of the natural product extracts, such solvents are to be selected which can already be converted into the supercritical state at temperatures below 100 ° C., preferably at ≤ 50 ° C., and which have a sufficient solubility for lipophilic petasite active ingredients. Suitable gases include, for example, ethylene (critical temperature: 9.95 ° C) and ethane (critical temperature: 32.25 ° C). Suitable conditions for the precipitation with petasine ethylene and ethane from butterbur plant parts are at pressures of 1-50 MPa, preferably 8-30 MPa, and temperatures of 10-50 ° C. The raw petasite extracts obtained by these processes contain up to 30% of water, depending on the degree of predrying of the starting material, which must subsequently be separated off. If desired, the crude extract can be treated with one to ten times the amount of water, preferably with a pH of 7 7, and subsequently dried by conventional methods.

p0014Alternatively, good alkaloid depletions could also be achieved by injecting water into the compressed solvent-extract mixture in the separator region of the extraction plant. For this purpose, approx. 10-50% by weight of water are pressed into the separating device of the extraction system, before the decompression of the solvent-extract mixture, relative to the quantity of extract to be separated and then decompressed. After separation of the water phase, the extracts obtained in this way had pyrrolizidine alkaloid contents below 0.1 ppm.

p0015Surprisingly, it has now also been found that, instead of destructions with gases in the supercritical state, suitable crude extracts of petasites are also obtained by extraction with high-pressure liquefied gases under subcritical conditions.

p0016Compressed-liquefied propane has proven to be particularly suitable for petasitic extraction under subcritical conditions. Propane (critical temperature: 97 ° C) can be liquefied at room temperature under high pressure (critical pressure: approx. 42 MPa). In appropriate autoclave reactors, crushed petasite plant material is subjected to a solids extraction with liquefied propane by conventional methods. Here, too, the targeted enrichment of the extraction material with up to 40% by weight of water can be advantageously used for improved pyrrolizidinal-caloid separation, as is the subsequent compression of water into the compressed propane extract mixture.

p0017The propane extraction process can be carried out in the temperature range of 15-40 ° C., preferably at 20-30 ° C., and particularly preferably at room temperature. The extraction pressures used are in the range from 5 to 20 MPa, preferably 10 to 15 MPa, and more preferably approximately 14 MPa, ie usually well below typical distraction pressures. The crude extracts obtained after evaporation of the solvent contain a partially emulsified residual water content of up to 20% and surprisingly have a very small proportion of pyrrolizidine alkaloids which is significantly depleted in contrast to the starting material. Excess water can be separated by skimming or decanting. The small amounts of water-soluble pyrrolizidine alkaloids in the crude extract can be completely separated off by aqueous aftertreatment, preferably pH &lt;7 and subsequent phase separation, as described below. Furthermore, the extract can be dried and freed from emulsified water by means of customary drying agents such as, for example, sodium sulfate, magnesium sulfate, as well as molecular sieves and the like.

p0018The advantage of this process according to the invention lies in the possible application of lower temperatures, for example extraction at room temperature, and the lower pressures, which ensure both cost-effective and gentle extraction of the sensitive petasitic extracts.

p0019A further advantage, in particular, compared to the conventional supercritical CO₂-draction method, is due to the more favorable solution properties of the liquid propane. Since propane as the hydrocarbon is able to dissolve the lipophilic petasins much better than the hydrophilic pyrrolizidine alkaloids, the separation of both components is better and the depletion of the undesired alkaloids from the petasites material is clearly more complete. The crude extracts obtained by subcritical propane extraction are as a rule a residual alkaloid content of well below 0.1 ppm. Furthermore, the overall yields of crude extract obtainable under comparable conditions are higher overall.

p0020The subcritical propane extraction according to the invention can be carried out batchwise or semi-continuously in conventional autoclave reactors, which can be designed as single-body or multi-body extraction systems. Reactors with continuous extract separation with return of the propane into the extraction autoclave are preferred for reasons of cost and environmental considerations. In addition, the extraction can also be carried out in simple pressure reactors in one or more successive steps.

p0021The water-containing extract can also be treated directly with a conventional drying agent, preferably Na.sub.2₂SO₄, Dry without shaking the extract with water. For this purpose, excess water is separated off and the drying agent is added to the extract in the required amount. The drying agent is then separated according to conventional methods, for example by means of filtration or centrifugation.

p0022The extract can be treated with a 0.01-10 fold, preferably 0.1-10 fold, amount of water, based on the extract, in a continuous or discontinuous extraction process to remove, for example, pyrrolizidine alkaloids.

p0023Optionally, the extract is shaken off at least once with the 0.1 to 10-fold amount of water having a pH of &lt;7, preferably ≤ 4, particularly preferably pH≤1, the acid phase is separated off and the extract is adjusted to a pH by repeated washing Value of 3-7. The acid used is preferably a mineral acid, particularly sulfuric acid with a normality of from 0.0001 to 1, preferably from 0.1 to 1.

p0024With the aid of a drying agent, preferably Na₂SO₄, And / or a centrifuge, the water content of the petasitic extract can be lowered to well below 1% by weight.

p0025Alternatively or additionally, the crude extracts can be taken up with a suitable adsorbent such as, for example, silica gel, aluminum oxide, aluminosilicate, zeolite, zirconium oxide, titanium oxide and molecular sieve, and optionally extracted again with distillation or extraction conditions with the addition of water, preferably water vapor. Subsequently, as described above, water is drained or water is separated from the extract, for example, by carefully draining the extract, the protruding aqueous phase subsequently being discarded. Advantageously, phase separation of water / extract can be effected by means of ultrasound. The accelerated formation of a sharp phase boundary is made possible by the action of ultrasound.

p0026Thus obtained extracts have a pyrrolizidine alkaloid content of ≤ 0.1 ppm when the content in the crude extract is up to 0.5 ppm. In a further post-treatment step, the extract is mixed at least 2 times, preferably 4 to 6 times, in the ratio of 1 part of extract and 2 parts of bidistilled water at a water temperature of at least 40 ° C. The phases are then separated and the residual water emulsified in the last step is bound by the addition of conventional drying agents, preferably sodium sulfate. The water-laden drying agent is centrifuged off.

p0027An ELISA can be used to determine the pyrrolizidine alkaloid content in the trace region, which is usually more sensitive by a factor of 1000 compared to GC-MS coupling. In petasite extracts prepared according to the invention no pyrrolizidine alkaloids could be found.

p0028The petasites produced according to the invention comprise about 40% petasines (calculated as isopetasin) and can without further Aufbereitun be used g in pharmaceutical compositions.

p0029An advantageous embodiment of the invention comprises the use of pharmaceutical compositions based on petasitic extract containing magnesium, preferably With a content of> 0-500 mg, particularly preferably 10-250 mg, and more preferably 50-100 mg, based on the total composition.

p0030It has been found that the antifungal and analgesic effects of a pharmaceutical composition which can be used according to the invention, based on petasitic extract with a magnesium content, is substantially more effective than the magnesium-free composition. Thus, in the treatment of migraine in patients, a markedly faster and longer lasting effect of the petasin-containing composition according to the invention with magnesium than with magnesium-free petasin-containing compositions could be observed.

p0031The pharmaceutical effect of petasin-containing compositions has surprisingly also been achieved by the addition of at least one pharmaceutically and / or physiologically active substance comprising at least one antiphlogistic or analgesic, preferably extracts of Chamomilla recutita, Rhizoma Curcumae longae, Rhizoma Curcumae xanthorrhizae, Curcumae xanthorrhiza, Cortex Salicis , Salicis purpurea, Salicis daphenoides and / or Tanacetum parthenium; At least one trace element, preferably iron, cobalt, chromium, iodine, copper, manganese, zinc and / or selenium; At least one secretolytic or secretion motor, preferably extracts of the sweet-pickled root, thyme herb and / or peppermint oil; At least one bronchospasmolytic, preferably extracts of ivy leaves; And / or vitamin, preferably vitamin A, B, C, D and / or E, can be increased.

p0032Moreover, it has been found that the resorption of the pharmaceutical composition containing petasites according to the invention can be increased in the gastrointestinal tract when at least one emulsifier such as sodium alkylsulfate, alkylsulfonate, alkylcarboxylate, alkyl alcoholate, preferably with an alkyl chain length of C, is used₁₂-C₁₈; At least one ester, and ethers of polyethylene glycol with higher fatty acids or fatty alcohols and / or polyethylene glycol stearate, particularly preferably cetylstearyl alcohol and / or glycerol-polyethylene glycol ricinoleate, lecithin, soya oil or polysorbates.

p0033Another embodiment which is advantageous according to the invention comprises the use of a composition containing petasites, in which the absorption in the gastrointestinal tract is retarded.

p0034The use of such a composition has the advantage that one can administer a greater amount of petasitic extract per dosage unit, which is then resorbed over a prolonged period of time. This makes it possible to achieve a petasite active agent blood plasma level of the pharmaceutically active main active ingredients of the petasitic extract over a period of at least 12-48 hours, preferably 24 hours, which allows for a twice, preferably one-time administration of the pharmaceutical petasites per day.

p0035Suitable substances for this purpose include the delaying substances generally known for absorption in the gastrointestinal tract for the release of lipophilic active substances. The substance which retards the absorption is preferably selected from the group of the paraffins, preferably a paraffin which is solid at room temperature, particularly preferably a hard paraffin.

p0036In addition, an orally administrable petasitic extract according to the invention can be coated with a gastric juice-resistant and / or absorption-retarding layer.

p0037A particular drawback of the petasitic extract is its unpleasant, bitter taste. Consequently, a dosage form that partially or completely releases the active ingredient in the mouth / throat area is not possible, since the taste of the petasitic extract is perceived as unpleasant by the patients and sometimes causes immediate nausea.

p0038It has now been found that the bitter, extremely unpleasant taste of petasites or petasitic extracts can be effectively masked by the addition of at least one taste-masking substance, the taste masking material preferably comprising essential oils, essences, aromatic waters, oil sugars, fruit aromas such as strawberries,

p0039Lemon, vanilla, and the like, aromatic drug extracts, artificial flavorings, sugars, sweetened polyols, neutral-tasting thickeners, cyclodextrins, and / or mixtures thereof.

p0040By adding a taste-improving substance, petasitic extracts containing teas, chewing tablets, juices and the like can be administered.

p0041The pharmaceutical composition containing petasitic extract which can be used according to the invention can be present in a liquid, solid or liposomal administration form. According to the invention, it is advantageous if the dosage form is a spray, an aerosol, a foam, an inhalate, a powder, a tablet, a capsule, a soft gelatine capsule, a chewing tablet, an ointment, a cream, a gel, a suppository or an injection solution . It is particularly preferred if the pharmaceutical composition containing petasitic extract which can be used according to the invention is designed as a tablet, capsule or chewing tablet comprising the active ingredient in the form of microcapsules.

p0042Possible further plant substances for a petasite cream which can be used according to the invention are, in particular, calendula (tinctura / extraction), viola (tinctura / extraction) and / or vitamins, preferably vitamin E.

p0043It is advantageous according to the invention if the daily dose is preferably in the range from 5 to 600 mg of petasite extract, particularly preferably in the range from 5 to 250 mg of petasite extract.

p0044The pharmaceutical composition containing petasitic extract according to the invention is particularly suitable for the treatment of gastrointestinal disorders of all kinds, for example of endo- and exogenous disorders of the stomach and intestinal mucosa, gastrointestinal ulceration and gastritis of all kinds, Crohn's disease and ulcerative colitis, as well as cough Asthma, pollinosis, eczema, migraine, psoriasis, dysmenorrhea, hypertension or for use as a spasmolytic and analgesic.

p0045In addition, the pharmaceutical composition containing petasitic extract according to the invention is suitable for the preparation of a medicament for the treatment of eczema and / or of psoriasis.

p0046The following examples are intended to illustrate the invention in more detail without limiting it in any way:

Example 1:

Subcritical propane extraction of petasites

p0047500 g of comminuted butterbur drug from Rhizoma petasitidis with an average moisture content of 12.8% by weight, a petasin content of about 0.8% and a content of pyrrolizidine alkaloids of about 20-30 ppm were dissolved in an autoclave (25 l volume ) At a temperature of 24 ° C. under a pressure of 13.8 MPa with about 6 kg of propane in one step. The cloudy crude extract obtained after evaporation of the propane (about 17 g) contained about 10% of water and a pyrrolizidine alkaloid content of less than 0.1 ppm

Example 2:

Aqueous processing of the crude extract

p0048The extract is shaken out three times with a fifth amount of 0.1 normal sulfuric acid, the acid phase is separated off, the extract is brought to a pH value of 3-7 by repeated washing with bidistilled water and the extract is then re-adjusted to a water content of 1 wt. -%. The extract thus obtained does not contain any detectable pyrrolizidine alkaloids by GC-MS analysis. This extract is then shaken out 5 times in the ratio of 1 part of extract and 2 parts of bidistilled water, with a water temperature of at least 45 ° C. After each intermixing, the separation of the water phase from the lipophilic extract phase is awaited by standing, and then the excess water is carefully poured from above. In the last step, 20 g of sodium sulfate are added after decanting. The water sulfate sodium sulfate is centrifuged off. An ELISA was then carried out for the determination of the residual pyrrolidicide alkaloid content in the petasitic extract, in which case no pyrrolidicidal alkaloid could be detected. The detection limit of an ELISA for pyrrolizidine alkaloids is at least 1000 times more sensitive compared to GC-MS coupling.

Example 3:

Formulation for a retarded soft gelatine capsule

p0049<tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>Composition:</entry><entry rowsep="0">quality</entry><entry rowsep="0">amount</entry></row><row><entry>active substance</entry></row></thead><tbody><row><entry>Extract Petasitidis e radice 30: 1</entry><entry>25.0 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>excipients</entry></row></thead><tbody><row><entry>Medium chain triglycerides *</entry><entry>Ph. Eur</entry><entry>245.0 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>Capsule cover</entry></row></thead><tbody><row><entry>Glycerol 85%</entry><entry>Ph. Eur</entry><entry>23.52-27.60 mg</entry></row><row><entry>Dry substance from sorbitol solution 70% Non-crystalline</entry><entry>Ph. Eur</entry><entry>17.12-20.10 mg</entry></row><row><entry>gelatin</entry><entry>Ph. Eur</entry><entry>80.89-94.96 mg</entry></row><row><entry>Iron oxide red</entry><entry>E 172</entry><entry>0.47-0.55 mg</entry></row><row><entry>glycerol</entry><entry>Ph. Eur</entry><entry>1.60-1.88 mg</entry></row><row><entry>Iron oxide black</entry><entry>E 172</entry><entry>1.13-1.33 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>coating</entry></row></thead><tbody><row><entry>Eudragit RL (after Fiedler)</entry><entry>1.0-15.0 mg</entry></row></tbody></tgroup><tgroup cols="3" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><tbody><row><entry namest="col1" nameend="col3" align="justify">* Other lipoids in which the extract dissolves include: olive oil, corn oil, soybean oil. Therapeutic plasma concentration 1 to 100 mg / l.</entry></row></tbody></tgroup></table></tables>

Example 4:

Formulation for a gastric juice-resistant soft gelatine capsule

p0050<tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>Composition:</entry><entry rowsep="0">quality</entry><entry rowsep="0">amount</entry></row><row><entry>active substance</entry></row></thead><tbody><row><entry>Extract Petasitidis e radice 30: 1</entry><entry>25.0 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>excipients</entry></row></thead><tbody><row><entry>Medium chain triglycerides *</entry><entry>Ph. Eur</entry><entry>245.0 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>Capsule cover</entry></row></thead><tbody><row><entry>Glycerol 85%</entry><entry>Ph. Eur</entry><entry>23.52-27.60 mg</entry></row><row><entry>Dry substance from sorbitol solution 70% Non-crystalline</entry><entry>Ph. Eur</entry><entry>17.12-20.10 mg</entry></row><row><entry>gelatin</entry><entry>Ph. Eur</entry><entry>80.89-94.96 mg</entry></row><row><entry>Iron oxide red</entry><entry>E 172</entry><entry>0.47-0.55 mg</entry></row><row><entry>glycerol</entry><entry>Ph. Eur</entry><entry>1.60-1.88 mg</entry></row><row><entry>Iron oxide black</entry><entry>E 172</entry><entry>1.13-1.33 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><thead valign="top"><row><entry>coating</entry></row></thead><tbody><row><entry>cellulose acetate phthalate</entry><entry>1.0-15.0 mg</entry></row></tbody></tgroup><tgroup cols="3" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="84mm" /><colspec colnum="2" colname="col2" colwidth="23mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><tbody><row><entry namest="col1" nameend="col3" align="justify">* Other lipoids in which the extract dissolves include: olive oil, corn oil, soybean oil. Therapeutic plasma concentration 1 to 100 mg / l.</entry></row></tbody></tgroup></table></tables>

Example 5:

injection solution

p0051The petasitic extract is mixed 1:10 with highly purified soybean oil with the addition of 0.1-2% by weight of egg lecithin as emulsifier and the mixture is emulsified to 0.5 to 2.0% by weight in water for injection purposes. Therapeutic plasma concentration 1 to 100 μg / l.

Example 6:

Liposomal composition

p0052The liposomes are prepared from glycerophospholipids, cholesterol and stearylamine and at least one lipid derivative, the pestle extract being dissolved in the lipid phase of the liposomes. Therapeutic plasma concentration 1 to 100 mg / l.

Example 7:

Extract Petasites e rad. 30: 1 in liquid dosage form

p0053<tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="55mm" /><colspec colnum="2" colname="col2" colwidth="18mm" /><colspec colnum="3" colname="col3" colwidth="19mm" /><thead valign="top"><row><entry>Composition 100g contain:</entry><entry rowsep="0">quality</entry><entry rowsep="0">amount</entry></row><row><entry>active substance</entry></row></thead><tbody><row><entry>Extract Petasitidis e radice 30: 1</entry><entry>500 mg</entry></row></tbody></tgroup><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="55mm" /><colspec colnum="2" colname="col2" colwidth="18mm" /><colspec colnum="3" colname="col3" colwidth="19mm" /><thead valign="top"><row><entry>excipients</entry></row></thead><tbody><row><entry>Glycerol-polyethyleneglycolricinoleate</entry><entry>USP XXII</entry><entry>4500 mg</entry></row><row><entry>Ethanol 43%</entry><entry>HAB 1</entry><entry>95,000 g</entry></row><row><entry>100,000 g</entry></row></tbody></tgroup></table></tables>