HK1057333B - Flavone-containing plant extract solutions having improved storage and heat stability - Google Patents

Description

The invention relates to sterile, flavonated plant extract solutions for injection with high storage and thermal stability in terms of their content of pharmaceutically relevant ingredients (in particular flavones and/or terpenes), the medicinal products for injection containing these and the methods of their manufacture.

Extracts of plant parts containing flavones are used as solutions for injection to treat various conditions, for example, brain disorders (ginkgo extract), venous diseases (aesculus extract) and decreased cardiac function (crataegus extract).

However, these injectable extract solutions have a problem of unsatisfactory storage stability, both due to chemical instabilities, i.e. a decrease in the concentration of the active ingredients, and physical instabilities, i.e. precipitation, flocculation, etc. Another problem is that these injectable extract solutions are sterilized most simply and reliably by heat treatment, but this is where the risk of degradation of the relevant ingredients is particularly high.

DE-2117429-A reveals solutions for injection containing ginkgo extract.

The present invention is intended to provide injectable flavonated plant extract solutions (flavonated plant extract injection preparations) with improved storage and thermal stability and to provide injectable medicinal products containing such flavonated plant extract solutions with improved storage stability.

A solution to this problem is to provide a flavone-containing plant extract solution for injection from Gingko biloba and/or Aesculus spec., preferably from its leaves and/or flowers, characterised by: that the flavonated plant extracts are dissolved in water in an aqueous alcoholic solvent of 2-40% m/m, preferably 10-25% m/m alcohol, that the pH of the solution is in the acid range of pH 2 to pH 6, preferably pH 3 to pH 4, that the solution is evaporated, after 15 minutes of steam sterilisation at 121°C and 2 bar, the flavon and terpene content is reduced by a maximum of 10% m/m.

The alcohols used are ethanol and/or propylene glycol.

The pH of the plant extract solution is preferably set by adding a pharmaceutically acceptable acid, i.e. one commonly used in medicinal products, in particular hydrochloric acid, or phosphoric acid and/or acetic acid, instead of or in addition to hydrochloric acid.

The plant extract solutions of the invention are surprisingly stable to heat treatment, in particular to heat or steam sterilisation (autoclave), and to long-term storage. Their content of pharmaceutically relevant ingredients, in particular flavones and/or terpenes, is reduced after steam sterilisation, especially at 121°C, at 2 bar for 15 minutes, from the level before steam sterilisation by a maximum of 10 per cent m/m. In the case of ginkgo extract solutions, such steam or heat sterilisation has been shown to significantly alter the composition and composition of neither the flavonglycosides nor the terlactones (biloba, ginkgolide) (see example 1).

When stored in containers (e.g. ampoules or chambers of a multi-chamber system), such vapourised or heat-sterilised plant extract solutions shall, even after 12 months of storage under standard conditions (25°C room temperature and 60% relative humidity), have a maximum of 10% m/m reduction in their content of pharmaceutically relevant ingredients compared to the content before or at the beginning of storage.

To further address this problem, a medicinal product containing flavonated extract solutions of plant parts is proposed, which is injectable (i.e. can be administered by injection) and has a high storage and thermal stability in relation to its content of pharmaceutically relevant active substances, and which is characterised by being composed entirely or almost exclusively of the two components (A), namely a plant extract solution according to one of claims 1 to 4 and (B), namely a sterile buffer solution (i.e. a buffer solution consisting of one or more buffer salts) with air-permeable, i.e. highly resistant to air, i.e. suitable for use in medicinal products of a buffer composition, whereby these components (A and B) are stored separately in two or more chambers (for example, two or more chambers) for up to 12 months (approximately 10% of the volume of the application) and whereby the two components are kept in separate storage (for more than one application) and are intended for use in a single application (i.e. at a maximum of 10 or more chambers) and at a temperature of 12°C. These components are used in two or more applications (i.e. at a maximum of 10 or more) months, and are intended for use in a single application and at a maximum of two or more applications (more than one) months.

A phosphoric acid/sodium phosphate solution, which may also contain isotonic agents such as table salt or sugar alcohols, is preferred as a buffer solution (with appropriate pH and osmolarity).

To further increase the thermal and storage stability of the medicinal product of the invention, the components (A) and/or (B) may also contain ascorbic acid and/or at least one other pharmaceutically acceptable excipient commonly used in medicinal products.

The direct-applicable medicinal product of the invention, namely the physiologically compatible direct-applicable pharmaceutical solution for injection with the components (A) and (B), has as its principal liquid components water and alcohol by volume and its pH is in the neutral to slightly acidic range, preferably in the pH range 6 to pH 8, particularly preferably in the pH range 6.5 to pH 7.5.

The method of preparation of a sterile plant extract solution for injection, containing flavones, is characterised by the fact that a plant extract traditionally obtained from gingko biloba and/or Aesculus spec., preferably from leaves and/or flowers, is dissolved in an aqueous alcohol medium of 2-40% m/m, preferably 10-25 m/m alcohol (preferably ethanol) in water, the resulting solution being dissolved in a pH range of 2 to 6, and the solution is preferably made by heating and dissolving the solution in a temperature range of pH 3 to pH 4 and preferably by heating and dissolving it in a solvent.Other The method of preparation of a medicinal product for injection containing plant extracts containing flavones according to the present invention is characterized by dissolving, for component (A), a conventionally obtained plant extract of Gingko biloba and/or Aesculus spec., preferably from its leaves and/or flowers, in an aqueous alcoholic medium of 2 to 40%, preferably 10 to 25% alcohol (preferably ethanol) in water, adjusting the resulting solution to an acid pH in the range of pH 2 to pH 6, preferably pH 3 to pH 4, and dissolving this acid solution by acidification under standard conditions, in particular at 121°C, preferably at standard temperature.The first step is to ensure that the product is sterilized at a temperature of 2 bar and for 15 minutes, that a buffer solution is provided for component (B) with a physiologically compatible composition, i.e. with an appropriate pH and osmolarity, that the two components (A) and (B) are stored between manufacture and application/injection/injection in separate containers, such as two ampoules or two chambers of a multi-chamber syringe or other multi-chamber system, and that they are mixed together for the intended (soon to be) injection use.

The pH of the component (A) is preferably set by the addition of an acid, in particular hydrochloric acid.

For component (B), all buffer solutions commonly used in or for the manufacture of medicinal products are suitable as buffer solutions according to the invention. A phosphoric acid/sodium phosphate solution is particularly preferred.

The buffer solution may contain at least one isotonic agent, in particular table salt and/or sugar alcohol.

The following is a detailed explanation of the invention by means of examples of embodiments.

Example 1: Manufacture of a solution containing gingko extract by the method of the invention

Zutaten:	Menge [% m/m]:
Ginkgo Extrakt	0,916
Sorbit	4,985
Ethanol 96 %	19,940
Salzsäure 1 N	0,474
Wasser für Injektionszwecke	73,685

Manufacture:

The extract is added and dissolved by stirring, adding hydrochloric acid to a pH of 3.0 and then adding the remaining water to 100% by weight. This solution is filtered in the usual way for preparations for injection through a 0,22 μm membrane filter, filled with sterile nitrogen in ampoules and vaporised under standard conditions in the final container (15 min, 121 °C; European Pharmacopoeia 1997).

The refrigerated solution is clear and free of precipitation. A determination of the flavonglycoside and terpene lactone content of the extract solution in the vials before and after steam or heat sterilisation shows by comparison that the flavonglycoside content has decreased by only 2.0% and the terpene lactone content by only 3.8%.

Mixing 2 ml of this sterilised extract solution with 2 ml of an appropriate buffer solution results in a physiologically acceptable pH of 6.8.

Example 2: Manufacture of a solution containing gingko extract by the method of the invention

Zutaten:	Menge [% m/m]:
Ginkgo Extrakt	0,916
Sorbit	4,985
Propylenglykol 100 %	19,940
Salzsäure 1 N	0,474
Wasser für Injektionszwecke	73,685

Manufacture:

As described in example 1, except that propylene glycol is used instead of ethanol.

Example 3: Preparation of a solution containing Aesculus spec. extract by the method of the invention

Zutaten:	Menge [% m/m]:
Aesculus Extrakt	0,916
Sorbit	4,985
Ethanol 96 %	19,940
Salzsäure 1 N	0,474
Wasser für Injektionszwecke	73,685

Manufacture:

As described in example 1, except that Aesculus extract is used instead of ginkgo extract.

Example 4: Comparative example Ingredients and quantities [% w/w]:

as in example 1, but using only 0.2-0.4% hydrochloric acid.

Manufacture:

As described in example 1, except that a pH of 4.0 is set instead of pH 3.0.

The determination of the flavonglycoside and terpene lactone content of the extract solution in the ampoules before and after steam and heat sterilisation shows a comparative reduction of 21.3% in the terpene lactone content (a decrease in bilobalid of up to 45.2%) following the heat sterilisation.

If a higher pH is set, the thermal sterilization will further reduce the terpene lactone content and may eventually result in complete degradation of the terpene lactones

Example 5: Comparative example

Zutaten:	Menge [% m/m]:
Ginkgo Extrakt	0,916
Sorbit	4,985
Ethanol 96 %	9,940
Salzsäure 1 N	0,474
Wasser für Injektionszwecke	83,685

Manufacture:

As described in example 1.

A comparison of the extract solution in the ampoules before and after steam and/or heat sterilisation shows that heat sterilisation leads to a significant increase in the cloudiness of the extract solution, i.e. the precipitation of extract components which do not dissolve when cooled.

Claims (10)

1. An injectable, flavone-containing plant extract solution from Ginkgo biloba and/or Aesculus spec., preferably from their leaves and/or flowers characterised in

   - that the flavone-containing plant extracts are dissolved in an aqueous alcoholic solvent with a content of 2 - 40 % m/m, preferably 10 - 25 % m/m alcohol in water,

   - that the pH of the solution is in the acidic range of pH 2 to pH 6, preferably pH 3 to pH 4,

   - and that the solution has been sterilized by steam sterilization, whereby after steam sterilization at 121 °C and 2 bar for the duration of 15 minutes, the content of flavones and terpens is reduced by max. 10% m/m.
2. The plant extract solution according to claim 1, characterised in that ethanol and/or propylene glycol are used as the alcohol.
3. The plant extract solution according to claim 1, characterised in that the solution for adjustment of the pH contains a pharmaceutically acceptable acid, particularly hydrochloric acid.
4. The plant extract solution according to one of the claims 1 to 3, characterised in that the content of flavones and terpens is reduced by max. 10 % m/m after 12 months of storage at 25°C and 60% relative humidity.
5. An injectable drug containing flavone-containing plant extract solutions with high storage and heat stability regarding its content of pharmaceutically relevant ingredients , characterised in

   - that it consists of the two components (A), that is a plant extract solution according to one of the claims 1 to 4, and (B), that is a sterile buffer salt solution with physiologically tolerable composition, which are mixed together for the application,

   - that these two components (A) and (B) are prepared separately and are storeable separately in individual containers until the application,

   - and that after 12 months of storage at 25°C and 60% relative humidity the content of flavones and terpens of component A is reduced by max. 10% m/m.
6. The drug according to claim 5, characterised in that the buffer solution is a phosphoric acid/sodium phosphate buffer solution.
7. The drug according to claims 5 or 6, characterised in that the buffer solution contains at least one isotonising agent, particularly table salt and/or sugar alcohol(s).
8. The drug according to one of the claims 5 to 7, characterised in that the component(s) (A) and/or (B) contain ascorbic acid and/or at least one other pharmaceutical adjuvant.
9. A method for preparation of a sterile injectable flavone-containing plant extract solution according to claim 1, characterised in

   - that a plant extract, extracted in a conventional way from Ginkgo biloba and/or Aesculus spec., preferably from their leaves and/or flowers, is dissolved in aqueous alcoholic medium of 2 - 40 % m/m, preferably 10 - 25 % m/m alcohol in water,

   - that the solution obtained in this way is adjusted to an acidic pH in the range of pH 2 to pH 6, preferably pH 3 to pH 4,

   - and that this acidic solution is sterilised by heat sterilisation, that is steam sterilisation at 121 °C and 2 bar for the duration of 15 minutes.
10. A method for preparation of an injectable flavone-containing plant extract-containing drug according to claim 5, characterised in

    - that a plant extract, extracted in a conventional way, is dissolved in aqueous alcoholic medium of 2 - 40 % m/m, preferably 10 - 25 % m/m alcohol in water for the component (A),

    - that the solution obtained in this way is adjusted to an acidic pH in the range of pH 2 to pH 6, preferably pH 3 to pH 4,

    - that this acidic solution is sterilised by heat sterilisation, that is steam sterilisation at 121 °C and 2 bar for the duration of 15 minutes,

    - that a buffer solution with physiologically tolerable substance composition is provided for component (B),

    - that both components (A) and (B) are stored filled in individual containers for the time between preparation and application/injection/injecting,

    - and that they are mixed together for use as injection.