FR2664814A1 - SOLID PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THEIR PREPARATION. - Google Patents

Abstract

The invention provides solid pharmaceutical compositions, preferably soft gelatin capsules, comprising a light-sensitive active component optionally barely soluble in water, preferably nifedipine [4- (2'-nitrophenyl) -2, 6-dimethyl-3,5-dimethoxycarbonyl 1,4-dihydropyridine], with conventional carriers and / or auxiliary agents, these compositions comprising a vegetable dye. In addition, the invention relates to the preparation of these compositions. The incorporation of a vegetable dye in the filler of the capsule and possibly in the wall of the capsule provides reliable protection against light during the manufacturing and filling operations and improves the solubility of nifedipine in certain carriers.

Description

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  SOLID PHAPHICACEUTICAL COMPOSITIONS

  The present invention relates to solid pharmaceutical compositions and to a process for their preparation. More particularly, it relates to solid pharmaceutical compositions comprising a light-sensitive active component which is optionally soluble in water, as well as a process for the production thereof.

preparation of these compositions.

  It is known that the preparation of pharmaceutical compositions comprising as an active ingredient a

  light-sensitive substance involves serious difficulties.

  Under the effect of light, decomposition products are formed which may be inactive or even therapeutically harmful. At the same time, the requirements of the pharmacopoeia regarding the quantity of decomposition products are becoming increasingly important. Severe It is also known that active components that do not dissolve easily in water, can be formulated at the cost of great difficulty On the one hand, poorly soluble components in water are hardly soluble in the media and additives used for the preparation of pharmaceutical compositions and on the other hand, due to the poor water solubility of the molecule, the release rate of the

active component is weak.

  The facts indicated above show that the formulation of active ingredients sensitive to light and hardly soluble in water in pharmaceutical compositions, is a delicate task for the specialists and represents at the same time an increasingly urgent need for the pharmaceutical industry. The above problems arise especially in the manufacture of pharmaceutical preparations from dihydropyridine derivatives, which are both light-sensitive and barely soluble in water. One of the most important representatives

  of these compounds is nifedipine 4- (2'-nitrophenyl)

  2,6-dimethyl-3,5-dimethoxycarbonyl-14-dihydropyridine, which is a widely used, extremely useful calcium antagonist -IV in the treatment of acute or chronic ischemic heart disease, hypertension, circulatory disorders

brain and peripheral.

  Nifedipine is known to be highly sensitive to light and does not readily dissolve in water (UIC Patent 1,362,671. Due to the high sensitivity to light of the molecule, decomposition products, in particular nitro derivatives and nitroso, are formed very rapidly The maximum tolerable amount of decomposition products is determined by strict regulations of the pharmacopoeia Thus, according to the conditions determined in USP XXII, the maximum permitted amount of nitro compound can not exceed 2.0% by weight , while in the case of a nitroso decomposition product, this value can not exceed 0.5% by weight Moreover, since it is not very soluble in water, nifedipine does not dissolve easily in the supports and auxiliary agents generally applied in the pharmaceutical industry for the preparation of solid pharmaceutical compositions, at the same time, given its low solubility in water, component release

  active is very weak, thus preventing proper absorption.

  Preferred representatives of the pharmaceutical compositions comprising nifedipine are soft gelatin capsules, but their preparation gives rise to difficulties because of the sensitivity to light and the low water solubility of the active component. Several methods have been published. for the preparation of soft gelatin capsules of this kind According to UKI Patent 1362627, one or more opacifiers, for example, titanium dioxide or calcium carbonate and optionally a synthetic dye absorbing light in a certain range of lengths of dye. wave (e.g., elborange, Erythrosin) are incorporated in the gelatin shell of the capsule The presence of the opacifier is mandatory,

  while that of the synthetic dye is only preferable.

  Colored opacifiers, for example, pigments based on iron oxide, impart an external appearance and aesthetic color to the envelope of the capsule These colored pigments are incorporated in the gelatin shell of the capsule at the rate of 2 at 3% by weight to provide the desired anti-weathering effect The amount of the opacifier can be reduced to about 0.5 to 1.5% by weight by adding a colorant to the composition, but its incorporation can not be omitted Synthetic dyes in themselves can not provide an infallible anti-tampering effect, but only when applied with an opacifier. However, the protection against light provided by the capsule wall involves serious disadvantages, namely that the anti-tampering effect is provided only by the ready-to-use capsule which already involves the filling solution containing the active component. The latter is absolutely not protected against light during manufacturing and filling processes, so that costly and cumbersome precautionary measures requiring strict technological and work disciplines must be taken to avoid light decomposition (for example, operations must be conducted under Neutral red lighting, etc.) Protection of the filling solution against the effect of light is particularly important when filtering the finished solution Light protection must be ensured during each encapsulation operation (eg black leaf

  special devices to exclude light, light filters, etc.).

  Another disadvantage of the light protection provided by the capsule wall is that the incorporation of the finely dispersed solid opacifier into the capsule wall

  requires a separate operation and separate instruments.

  The finely pulverized opacifier must be uniformly suspended in the viscous gelatin mass constituting the wall of the capsule, which is a long and painful process. During the manufacturing process, the possibility of accidental inhomogeneity can not be avoided. gelatin mass can form bubbles as a result of agitation, which can lead to the formation of inclusions and these can

  lack of homogeneity and weakness in the capsule wall.

  European Patent No. 143,857 discloses soft gelatin capsules comprising nifedipine as an active ingredient. The capsule wall comprises glycerol, one or more light-absorbing dyes in the desired wavelength range, and an opacifier. while the mixture constituting the filling mass of the capsule contains a solution of nifedipine in an organic solvent A characteristic aspect of this patent lies in that the filling weight of the capsule contains nifedipine and a polyvinylpyrrolidone (PVP) dissolved in a solution of a polyether alcohol in tetrahydrofurfuryl alcohol, and contains no glycerol at all the latter being present only in the wall of the capsule This method also involves the disadvantages indicated above Indeed, the opacifying agent is mixed exclusively with the material of the capsule wall and as a result, the filling weight of the capsule is not not protected against light during manufacturing and filling operations, moreover, the difficulties mentioned above resulting from the incorporation of the opacifier

  in the capsule wall must also be overcome.

  The object of the present invention is to provide a simple manufacturing method for the preparation of solid pharmaceutical compositions comprising as active component a light-sensitive substance possibly barely soluble in water which provides reliable protection against light and eliminates the disadvantages of known processes

until now.

  The object of the present invention is in particular to provide a process which is easy to implement and which provides reliable protection against light for the preparation of solid pharmaceutical compositions, in particular soft gelatin capsules containing nifedipine slightly soluble in

  water and light sensitive as an active component.

  The present invention is based on the finding that plant dyes themselves, i.e. without the presence of opacifying components, are capable of preventing photolysis of the light-sensitive active components. According to one aspect of the present invention, there is provided a process for the preparation of solid pharmaceutical compositions comprising a light-sensitive and optionally barely soluble water-active component with conventional carriers and / or auxiliaries, which comprises the incorporation of a

  vegetable dye in the composition.

  As plant dyes, it is preferable to use chlorophyll, caramel, saffron yellow or beet dye (Pote Beete, E Dragocoo). According to a preferred embodiment of the process of the invention, use is made of

  chlorophyll, the natural dye of green plants.

  The both lipophilic and hydrophilic forms of chlorophyll are suitable for accomplishing the process according to the present invention with the desired result. The lipophilic form of chlorophyll is extracted from nettle with an organic solvent. The lipophilic form of chlorophyll is a green product. dark-like honey-like Hydrophilic chlorophyll is a naturally occurring dye, in which the central magnesium atom of the molecule is exchanged with a copper atom, and the water-soluble sodium salt is obtained with water. sodium hydroxide The potassium salt can be prepared analogously with potassium hydroxide The hydrophilic chlorophyll is a

finely dispersed green powder.

  The vegetable dye can be used in a quantity

  from 0.1 to 10% by weight relative to the total weight of the product.

  According to his research, the Applicant has found that the light-sensitive compounds which may be poorly soluble in the following water may be used as active components for the solid pharmaceutical compositions according to the present invention: vitamins O, preferably colecalciferol ; vitamin A: imidazoline derivatives, preferably methynazol; piperazine derivatives, preferably tripolydin hydrochloride hydrazine; ergot and indole alkaloids, preferably dihydroergotoxin methanesulfonate or ergotamine tartrate; butyrophenone derivatives, preferably haloperidol, droperidol or benperidol; nitroglycerine; dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine; anabolic steroids, preferably phenoxymesterone; thyroid hormones, preferably levothyroxine; antimetabolites of folic acid analogues, preferably methotrexate; antimetabolites of purine analogs, preferably azathoprine; nitrofuran derivatives, preferably nitrofurantoin; antineoplastic methylhydroxines, preferably procarbazine; corticosteroids, preferably betamethasone; sodium nitroprusside; morphine derivatives, preferably morphine sulfate or papaverine hydrochloride; catecholamines, preferably dopemine or isoprenaline; estrognes, preferably hexosterol; sulfadiazine; alkaloids, preferably coichicin; derivatives of the profene, preferably ketoprofen; antibiotics, preferably mitomycin or bacitracin; tricyclic antidepressants, preferably carbamazepine; phenthiazines, preferably hibernal or trifluoperazine; nitrogen mustard; cocaine hydrochloride; ethylene diamine derivatives, preferably tripelinamine; or

  aminoquinoline derivatives, preferably chloroquine.

  According to a particularly preferred embodiment of the present invention, a light-sensitive, water-soluble dihydropyridine derivative such as vitamin A or nitroglycerin is used as the active component. According to another particularly preferred embodiment of the present invention, dihydropyridine derivatives having a solubility in water of not more than 20 g / liter at C are used as active components. Nifedipine, niludipine, nitrendipine, Nisoldipine, nimodipine, nicardipine and felodipine are particularly useful as

active components.

  According to the process of the present invention, active components sensitive to light and possibly barely soluble in water, can be formulated preferably in soft gelatin capsules, tablets, dragees or capsules of

  hard gelatin, especially soft gelatin capsules.

  When soft gelatin capsules are prepared, a plant dye, in particular chlorophyll, is incorporated in the capsule filling material. As a result, the filling mass containing the light-sensitive active component is already protected against light. during manufacturing and filling processes and not only after being enclosed in the capsules In this way, expensive and painstaking measures can be eliminated providing protection against light during the filling which encapsulates the

  active component sensitive to light.

  The lipophilic form of the chlorophyll is mixed with the filler in an amount of 1 to 10% by weight, preferably 1 to 5% by weight, more preferably 1.5 to 3.5% by weight. The hydrophilic colloid of the filling compound may vary between 0.5 and 10% by weight, preferably between 1 and 7% by weight, more preferably between 1.5 and 5% by weight. If nifedipine is used as the active component, the The active component content of the filling composition may vary between 0.5 and 7% by weight, preferably between 1 and 5% by weight and more.

  advantageously between 1.5 and 3% by weight.

  As another component, the filler may also contain a solvent suitable for oral administration and compatible with the wall material of the soft gelatin capsule. In this regard, the following solvents may be used as vegetable oils and aromatics (such as sunflower oil, gourd oil, olive oil, lemon oil, and nonionic surfactants (for example, polyoxyethylene sorbitol fatty acid esters, preferably a polyoxyethylene sorbitol monoleate), lecithin or polyethylene glycols (eg Carbowax 300 l The capsule filling weight may optionally contain aromas (eg perfumes or essential oils, also when using In the case of lipophilic chlorophyll, the filling weight of the capsule may contain, as a solvent, preferably a polyoxyethylene sorbitol fatty acid ester, in particular a polyoxyethylene sorbin monoleate. tol With hydrophilic chlorophyll, polyethylene glycols (e.g.

  Carbowax 3001 is preferably used as a solvent.

  The preparation of the capsule filling mass is carried out by standard methods of the pharmaceutical industry. The active component is preferably dissolved in a heated solvent at the appropriate temperature. The lipophilic or hydrophilic chlorophyll and the other components are added to this solution. when it is still hot, either after cooling and if necessary, the solution

  obtained is filtered through a sieve.

  The filler mass prepared in this way and containing a vegetable dye is then introduced into soft gelatin capsules. The capsule wall may contain plasticizers for the gelatin base (for example, glycerol or sorbitol) and a preservative (for example For example, Nipaginel A plant dye, preferably chlorophyll, can also be added to the capsule wall material as well. In this case, the chlorophyll content of the capsule wall is 0.1 to 5% by weight. preferably from 0.2 to 3% by weight, more preferably from 0.3 to 1.5% by weight. The capsule wall may contain the foam.

hydrophilic chlorophyll.

  The preparation of the plant dye-containing capsule wall is carried out as follows: the plasticizer (for example, glycerol or sorbitol) and the other optionally applied component (s) (for example, a polyvinylpyrrolidone or a preservative) are dissolved in

  Hot water (70-90 ° C) and gelatin is added to the solution.

  The mass thus obtained is treated under vacuum and with vigorous continuous stirring until a translucent mass resembling honey is obtained. The chlorophyll is dissolved separately in a portion of water and then mixed with the mass.

cooled ready.

  Encapsulation is carried out mechanically by methods known per se. Tablets, dragees and hard gelatin capsules may contain the following conventional carriers and / or auxiliary agents: disintegrating agents such as starch, modified starch, cellulose, cellulose derivatives, Crosslinked PVP (PVPP1), sodium alginate and colloidal silicon dioxide; binding materials such as gelatin, gum tragacanth, glucose syrup, starch, PVP, cellulose derivatives, polyethylene glycols (PES 1000-5000 l and alginates, lubricants such as magnesium stearate, stearic acid, paraffin, talc, vegetable or animal fats , oils and cines, silicones, polyethylene glycols (PEO 1000-5000 J; supports and fillers such as starch, cellulose, PVP, PVPP, colloidal silicon dioxide, lactose, magnesium stearate, calcium stearate; diluents such as lactose, mannitol, starch, crystalline cellulose;

  coloring and aromatic agents and conventional coatings.

  The pellet of the solid pharmaceutical compositions enumerated above may contain 0.1 to 5% by weight, preferably 0.5 to 3% by weight of a vegetable dye, while its coating may comprise 0.1 to 1% by weight. , preferably 0.3

  0.7% by weight of the same substance.

  The preparation of hard gelatin tablets, dragees and gelatin capsules according to the present invention is carried out according to

methods known per se.

  In another aspect of the present invention, there is provided solid pharmaceutical compositions comprising a light-sensitive active component which may be scarcely soluble in water with conventional carriers and / or auxiliaries, which compositions comprise a plant dye. The preferred forms of solid pharmaceutical compositions of the invention, the plant dyes, in addition to the light-sensitive and barely water-soluble components preferably used for the solid pharmaceutical compositions according to the invention, have already been indicated.

upper.

  According to a preferred aspect of the present invention, there are provided solid pharmaceutical compositions, particularly soft gelatin capsules, comprising nifedipine as

that active component.

  According to another preferred aspect of the present invention, there are provided solid pharmaceutical compositions comprising nifedipine as an active ingredient, wherein the filler and / or the capsule wall comprises a plant dye, preferably chlorophyll,

  in an amount of 0.1 to 10% by weight.

  The photolgetic decomposition of the active component in the soft gelatin capsules according to the present invention is studied by the so-called "sun" test for 4 hours. The results are given in Table I.

Table I

  Photolytic decomposition Echantiilon Concentration concentration of active ingredient decomposition products Initial example (wt% No (wt%) nitro nitroso other Filling solution

Example 2

98.50 1.00 0.23 0.27

Capsule wall

Example 4

Filling solution

Example 1

98.00 0.90 0.24 0.86

Capsule wall

Example 5

  According to USP XXII, the amount of nitro decomposition product can not exceed 2.0% by weight, while that of the nitroso compound can not exceed 0.5% by weight The data in Table 1 show that the soft gelatin capsules prepared according to the present invention contain the decomposition products in an amount substantially less than that which is tolerated. It is extremely remarkable to note that, even in the case of soft gelatin capsules containing a vegetable dye only in the filler mass, we obtain a protection against light satisfying the conditions of USP XXII without incorporation of a coloring agent in the wall of the capsule On the other hand, the wall

  capsule contains no opacifier.

  It has surprisingly been found that not only is adequate protection against light obtained by the process of the invention, but that vegetable dyes improve the solublility of nifedipine in certain carriers (for example, in vegetable oils). It is known that nifedipine is hardly soluble in vegetable oils. At the same time, because of their compatibility with the gelatin capsule wall, these are excellent carriers, but their applicability is hindered by the low solubility of nifedipine. The following experiment shows that vegetable dyes have the effect of improving both the solubility of nifedipine in different

  vegetable oils and its release.

  The release of the medicament from the capsules is determined in a rotating pallet equipment according to UISP XXII with distilled water as dissolution medium for 15 minutes, at a temperature of 37 + 0.50 C 1 (50 rpm). The results

  are gathered in Table II.

Table II

  Release of the active ingredient Plant oil Chlorine content Release of the component used phylle of the active solution from the capsule as filling in 15 minutes (% by weight) solvent (% by weight) (lrequest: 80%) Calabash oil 82 , 30 Calabash oil 1,5 92,40 Celebasse oil 3,0 97,02 Lemon oil 90, 76 Lemon oil 1,5 95,37 Lemon oil 3,0 100,14 Olive oil 86, 38 Olive oil 1.5 90.50 Olive oil 3.0 96.40 According to the conditions defined in USP XXII, the release rate of nifedipine must be at least 80%. that the release of nifedipine from the vegetable oils used as a solvent (gourd oil, lemon oil, olive lemon) considerably exceeds this value In addition, it is remarkable to observe that in the presence of chlorophyll, the release of nifedipine is significantly higher than that which is obtained with basically the same carrier, but without plant dyes The fact that plant dyes promote the release of the drug could not be expected and is therefore surprising. Other details illustrating the present invention are provided in the following nonlimiting examples.

Example 1

  A filling composition for the capsule having the following composition is prepared. Component Quantity,% by weight Nifedipine 3.00 Polyoxyethylene sorbitol monooleate 22.85 Lemon oil 14.65 Lecithin 57.00 Chlorophyll (lipophilel 2.50, 00

  Preparation: polyoxyethylene monooleate

  sorbitol is heated to about 70 O and nifedipine is dissolved in. The dissolution is complete, lecithin and lipophilic chlorophyll are added to the still hot solution, then the mixture is cooled to room temperature and lemon oil is introduced into the If necessary, the solution is filtered through a plastic screen (pore size: 120 mesh, 0.12 mm).

Example 2

  A filling composition for capsule having the following composition is prepared: Component Quantity,% by weight Nifedipine 2.80 Polyoxyethylene sorbitol monooleate 82.50 Calabash oil 11.50 Chlorophyll (lipophilic) 3.20, 00 Preparation: monooleate of the polyoxyethylenesorbitol is heated to about 700 C and the nifedipine is dissolved in. The dissolution is complete, the solution is cooled to about 45 C and added with gourd oil and lipophilic chlorophyll. If necessary, the solution is filtered through a sieve. plastic (pore size: 120 mesh, 0, 12 mm).

Example 3

  A filling composition for the following composition capsule is prepared: having the component Nifedipine Carbowax 300 Lemon oil Chlorophyll (hydrophilic) Amount,% by weight 4.00 88.00 3.00, 00.00 Preparation: the Carbowax 300 is heated to The dissolution is complete, the solution is cooled to about 25- 30 ° C. and lemon oil and hydrophilic chlorophyll are added. If necessary, the solution is filtered through a plastic screen (

pores: 120 mesh, 0.12 mm).

Example 4

  A capsule wall having the following composition is prepared: Component Selatin Glycerin Sorbitol 70% Distilled water Quantity, wt%, 00 27.00 6.00 1700 o, 00 Preparation: The water is heated to 80 o C and added The gelatin is then introduced into the mixture with vigorous stirring and the stirring continued under stirring.

  empty until the mixture forms a translucent mass resembling honey The latter is converted into capsules by mechanical means in a manner known per se.

Example 5

  A capsule wall having the following composition is prepared: Component Oelatin i 3 Lycerin Preservative Chlorophyll (hydrophilic) Distilled water Quantity% by weight, 00 36.30 0.20 0.50 18.00, 00 Preparation: the water is heated at 800 ° C and the preservative is dissolved in the gercerol is added to the solution, then the gelatin is introduced into it under vigorous stirring The stirring is continued under vacuum until the mixture forms a translucent mass resembling honey The chlorophyll is dissolved separately in a small portion of water and the aqueous solution is mixed with the mass obtained above cooled to 600 CG This is converted

  in capsules by mechanical means in a known manner per se.

Example 6

  A capsule wall having the following composition is prepared: Component Oelatin @ 1 Lycerin Polyvinylpyrrolidone Hydrophilic chlorophyll Distilled water Quantity,% by weight, 00 37.00, 00 1.00 12.00, 00 Preparation: the water is heated to 80 C. and the polyvinylpyrrolidone is dissolved therein and the glycerol is added to the solution. The gelatin is then introduced into the mixture under vigorous continuous stirring. The stirring is continued under vacuum until the mixture forms a translucent mass resembling honey. The chlorophyll is dissolved separately

  in a small portion of water and the aqueous solution is mixed with the mass obtained above it cooled to 80 o C The latter is converted into capsules by mechanical means in a known manner per se.

WEDNESDAY 1 CATIONS

  A solid pharmaceutical composition comprising an active component sensitive to light and possibly barely soluble in water with conventional carriers and / or auxiliaries, characterized in that this composition comprises a

vegetable dye.

  Process for the preparation of a solid pharmaceutical composition according to Claim 1, characterized in that it comprises the incorporation of a vegetable dye into the

composition.

  Process according to claim 2, characterized in that it comprises the use of chlorophyll, caramel, saffron yellow and red beet dye as vegetable dye. Process according to Claim 2 or Claim 3, characterized in that it comprises the use of chlorophyll in an amount of 0.1 to 10% by weight with respect to

total weight of the composition.

  Process according to any one of

  Claims 2 to 4, characterized in that it comprises the use

  as a light-sensitive and / or barely water-soluble component of a compound selected from the group consisting of: vitamin D, preferably colecalciferol; vitamin A derived from imidazoline, preferably methynazol; piperazine derivatives, preferably tripolydin hydrochloride hydrazine; ergot alkaloids and indole, preferably dihydroergotoxid methane sulfonate or ergotamine tartrate; butyrophenone derivatives, preferably haloperidol, droperidol or benperidol; nitroglycerine; dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine; anabolic steroids, preferably phenoxymesterone; thyroid hormones, preferably levothyroxine; antimetabolites of folic acid analogues, preferably methotrexate; antimetabolites of purine analogs, preferably azathoprine; nitrofuran derivatives, preferably nitrofurantoin; antineoplastic methylhydroxines, preferably procarbazine; corticosteroids, preferably betamethasone; sodium nitroprusside; morphine derivatives, preferably morphine sulfate or papaverine hydrochloride; catecholamines, preferably dopamine or isoprenaline; estrogens, preferably hexosterol; sulfadiazine; alkaloids, preferably coichicin; derivatives of the profene, preferably ketoprofen; antibiotics, preferably mitomycin or bacitracin; tricyclic antidepressants, preferably carbamazepine; phenthiazines, preferably hibernal or trifluoperazine; nitrogen mustard; cocaine hydrochloride; ethylene diamine derivatives, preferably tripelinamine; or

  aminoquinoline derivatives, preferably chloroquine.

  Process according to claim 5, characterized in that it comprises the use of a derivative of dihydropyridine, nitroglycerine or vitamin A as an active ingredient

  sensitive to light and possibly barely soluble in water.

  Process according to claim 6, characterized in that it comprises the use of nifedipine as a light-sensitive active component and possibly barely soluble in water, 8 Process according to any one of

  Claims 2 to 7, characterized in that it comprises the

  1 g preparation of soft gelatin capsules, 6 S candies or hard gelatin capsules as a solid pharmaceutical composition. Process according to Claim 7 for the preparation of soft gelatin capsules comprising nifedipine as active component, characterized in that it comprises the incorporation into the filling mass and / or the wall of the capsule of a dye The process according to claim 9 for the preparation of soft gelatin capsules comprising nifedipine as an active ingredient, characterized in that it comprises the introduction of a composition containing 5 to 7% by weight of nifedipine, a vegetable dye or a nonionic surfactant and 0.5 to 10% by weight, preferably 1 to 7% by weight, more preferably 1.5 to 5% by weight of chlorophyll, in a capsule having a wall comprising a plasticizer in the gelatin base, preferably glycerol or sorbitol, and optionally a preservative and optionally 0.1 to 5% by weight, preferably 0.2 to 3% by weight, more preferences beneficial 0.3

1.5% by weight of chlorophyll.