DE102010021688A1 - Process for the preparation of a micellar active substance concentrate - Google Patents

Abstract

The invention relates to a method for producing an active ingredient concentrate from micellar nanoparticles without the use of chemical auxiliaries for taking up fat- or water-soluble active ingredients. Furthermore, the invention relates to the use of this micellar active ingredient concentrate, in particular based on naturally occurring active ingredients. It is provided according to the invention to produce a fat-soluble active ingredient suspension which has micelles with a micelle size of up to 1000 nm, to crush the micelles of the active ingredient suspension by means of high pressure application and to separate the micelles from the fat-soluble active ingredient suspension by means of ultra-centrifugation , Furthermore, the use of these micellar active ingredient concentrates and the composition of the active ingredient suspension of individual process steps are encompassed by the invention.

Description

The invention relates to a process for the preparation of a micellar nanoparticin active ingredient concentrate without the use of chemical excipients for the absorption of fat- or water-soluble active ingredients. Furthermore, the invention relates to the use of this micellar active substance concentrate, in particular based on naturally occurring active ingredients.

Micellar drug complexes are known in the art. Especially in the field of pharmaceutics, dietetics but also cosmetics, there is a great need to formulate long-term stable active substances or combinations of active substances and substances of a group of active substances which are sensitive to decomposition. At the same time, physiological compatibility of the overall formulation must be ensured as a boundary condition. As a problem, it has been found that the compositions used in the preparation have components which are to promote the formation and maintenance of the micelles in the manufacturing process and develop or have disturbing or undesirable properties during later processing or application.

Technologically, emulsions are currently required for the preparation of micellar active complexes. As a rule, so-called fine or nano-emulsions of the O / W emulsion type are required, energy is supplied to the underlying mixture, either in the form of mechanical energy, to fragment the dispersed phase into fine droplets, or in the form of thermal energy by performing a phase change method with temperature (80 ° C), such as the systems manufactured according to the PET technique ("Phase Inversion Temperature"). These systems are well known and today make it possible to provide fine emulsions.

With the method of mechanical energy supply fine emulsions can be obtained, which are referred to as nanoemulsions and, for example, in the publications EP-A-728 460 . EP-A-780 114 . EP-A-780 115 . EP-A-879 589 . EP-A-1,010,413 . EP-A-1,010,414 . EP-A-1,010,415 . EP-A-1,010,416 . EP-A-1,013,338 . EP-A-1,016,453 . EP-A-1,018,363 . EP-A-1,020,219 . EP-A-1,025,898 . EP-A-1,120,102 . EP-A-1,120,101 . EP-A-1,160,005 . EP-A-1,172,077 and EP-A-1,353,629 are described. The oil droplets of the nanoemulsions have a mean size below 100 nm. The disadvantage of these nanoemulsions is the necessity of supplying voluminous quantities of mechanical energy.

Incidentally, the PIT technique is well known to those skilled in the art and has been particularly noted in the documents WO 89/11907 . DE-A-4318171 . EP-A-815 846 and EP-A-1,297,824 described. However, this technique for producing fine emulsions has the following disadvantages: The high temperature of the PIT process results in formulation limitations. It is therefore difficult to apply this technique to thermosensitive molecules, and this method is therefore limited to molecules that are not sensitive to heat. This limits the type and number of raw materials that can be used, or the procedure must be adapted to the formulation depending on the raw materials used, and the preparation of these emulsions then becomes more complex and expensive. Therefore, this method excludes or at least limits the use of volatile compounds such as volatile lipophilic compounds, particularly volatile oils, for example volatile silicones, and certain active or plant extracts which are heat sensitive. The preparation of micelles by this method is therefore coupled to chemical additives for stabilization or otherwise excluded because the micelle structure would be destroyed.

The EP 1 616 552 B1 on the other hand describes a process for the preparation and a composition of a fine emulsion for topical application, which is in the form of a fine oil-in-water emulsion. Their manufacturing process is largely implemented without energy input. Variants of these fine emulsions can be used as a basis for micelle formation, provided that certain substances are inhibited that inhibit micelle formation.

The composition described in this publication consists of an oil-in-water type (O / W) emulsion in the form of a carrier consisting of a dispersing continuous aqueous phase and a dispersed discontinuous oil phase. In-oil type (W / O) consist of a dispersing continuous fat phase and a discontinuous dispersed aqueous phase.

The EP 1 616 552 B1 thus describes to produce fine emulsions without mechanical or thermal energy input which can be prepared entirely at ambient temperature due to the particular choice of surfactants, the particular choice of oils, and due to a particular ratio of oils / surfactants.

The processes described in the publication make use of chemical substances, in particular the anionic surface-active substances, which can occur in considerable amounts in the emulsion in a manner which is disadvantageous for micelle production.

Furthermore, the emulsifier system may also contain so-called cosurfactants, which are surfactants. Both the oil phase and the aqueous phase are formed with substances which, as chemical auxiliaries, are to assist the dispersion of the constituents in the emulsion.

In addition, further chemical auxiliaries are provided, which may have water-soluble or fat-soluble character and may be contained in the respective corresponding phases. Thus, in particular, nonionic or ionic thickeners, antioxidants, emollients, cosmetic or dermatological agents, perfumes, preservatives, fillers, masking agents, pigments, colorants or any other ingredients commonly used in the fields considered may be included.

Incidentally, in the prior art, transparent microemulsions are known. In contrast to nanoemulsions, these microemulsions are not emulsions in the true sense. They are transparent solutions of oil-swollen micelles, and otherwise solubilized by the co-presence of a large amount of surfactants and cosurfactants that form the micelles. The size of the swollen micelles is small because of the small amount of oil they can solubilize.

In the WO 2001/094002 describes how micelles are formed in emulsions. This publication relates to emulsions of nano- to micrometer size and a process for their preparation and their use. More particularly, this publication relates to emulsified droplets of a liquid material that is substantially insoluble in water, and wherein the stabilizing interface has incorporated therein surfactants, thereby forming an interface having a number of advantages.

The main disadvantage of these known production processes for fine emulsions or microemulsions, which could be used for the preparation of micelles, which can form spontaneously in an emulsion, is the high content of chemical auxiliaries, in particular surfactants, in comparison with the fat-soluble phase. which can cause incompatibilities. Cotensides also have a disadvantageous effect on the versatility of use of a desired micellar product.

The object of the invention is therefore to provide a method which is suitable for the simple production of micellar active substance concentrates and which makes it possible to produce a high micelle concentration without addition of chemical auxiliaries and with low mechanical and thermal energy input and into a stable state hold.

Furthermore, it is an object of the invention to provide a composition which forms an optimized basis for the production process. Finally, it is an object of the invention to provide uses of the micellar active substance concentrates obtained.

With the invention it has been recognized that the preparation of micellar drug concentrates is simplified with emulsions which are counted among the fine or nanoemulsions whose droplet size can range up to about 1500 nm. The choice of suitable droplet size depends on the desired field of use and on the active substances or combinations of active substances to be solubilized.

The invention has further recognized that it is possible to dispense with undesired or harmful chemical auxiliaries which would be required on the one hand for stabilizing the emulsions or on the other hand would be required for stabilizing the micelles in an emulsion.

The invention has also recognized that the quality of the micellar active substance concentrate obtained is improved if the individual process steps follow one another directly and are preferably carried out in a protective atmosphere.

Surprisingly, it has been found with the invention that this makes it possible to dispense with chemical auxiliaries, in particular release agents, film formers, cosurfactants and surface-active substances.

Surprisingly good results in the production of micelles can be achieved by producing a fat-soluble active substance suspension which has micelles with a micelle size of up to 1000 nm, micronizing them by high-pressure application, and micelles by ultra-centrifugation from the fat-soluble Drug suspension are divorced.

The micelles are produced in the fat-soluble active ingredient suspension itself, which as In the ultra-centrifugation, the unnecessary components of the carrier substrate are separated from the micelle-containing constituents of the carrier substrate.

• a. Herstellen einer flüssigen Voremulsion, umfassend Glycerol und Phosphatidylcholin;
• b. Einmischen von bidestilliertem Wasser in die Emulsion;
• c. Einmischen eines Öl-Wirkstoffgemischs;
• d. Rühren der Wirkstoff-Suspension mit einer Drehzahl zwischen 100 s–1 und 400 s–1 für eine Dauer von 3 bis 10 Minuten.

For this purpose, the fat-soluble active ingredient suspension is prepared in a first process section. It is envisaged that the fat-soluble active ingredient suspension is prepared in the order of the following steps:

• a. Preparing a liquid pre-emulsion comprising glycerol and phosphatidylcholine;
• b. Mixing bidistilled water into the emulsion;
• c. Mixing in an oil-active substance mixture;
• d. Stir the active ingredient suspension at a speed between 100 s-1 and 400 s-1 for a period of 3 to 10 minutes.

The pre-emulsion is generated with a radial acceleration of 85 G, where G corresponds to the acceleration due to gravity. An aqueous phase is introduced into the pre-emulsion. The aqueous phase contains bidistilled water. The resulting mixture is then fed to a fat-soluble phase. The fat-soluble phase consists of an oil and a drug absorbed therein, which form the oil-drug mixture. The mixture thus formed, which contains all constituents of the carrier substrate and the active ingredients to be solubilized by the micelles, is then stirred while introducing high shear forces, after which the micelles are present in a size of about 1000 nm in the resulting fat-soluble active ingredient suspension.

The size range of the available micelles can vary according to the invention between 750 nm and 1250 nm, which is essentially controlled by the energy input during stirring. In the process, the macromicelles formed spontaneously during mixing of the carrier substrate disintegrate into micelles of smaller sizes.

• a.) zu der Gruppe der Spurenelemente, Metalle, Mineralstoffe und Vitamine für den menschlichen und tierischen Bedarf zugeordnet sind;
• b.) zu der Gruppe der folgenden fettlöslichen Wirkstoffe zugeordnet sind: Coenzym Q10, RRR-alpha-Tocopherol, Gamma-Tocopherol, Beta-Tocopherol, Delta-Tocopherol, Lycopen, spezifische Fettsäuren;
• c.) zu der Gruppe der folgenden wasserlöslichen Wirkstoffe zugeordnet sind: Eisen, Magnesium, Pflanzenextrakte, Chondroitinsulfat, Glucosamin, Zink, wasserlösliche Vitamine;
• d.) zu der Gruppe der natürlichen Antioxidantien zugeordnet sind.

In order to increase the entry of the active ingredients solubilized by the micelles, it is provided that complementary water-soluble active substances and / or fat-soluble active substances which supplement the oil-active substance mixture are dissolved in the double-distilled water prior to mixing into the pre-emulsion. As active ingredients according to the invention all known in the art solubilizable agents are provided. In particular, however, it is provided that the complementary soluble active ingredients

• a.) are assigned to the group of trace elements, metals, minerals and vitamins for human and animal use;
• b.) are assigned to the group of the following fat-soluble active substances: coenzyme Q10, RRR-alpha-tocopherol, gamma-tocopherol, beta-tocopherol, delta-tocopherol, lycopene, specific fatty acids;
• c.) are assigned to the group of the following water-soluble active substances: iron, magnesium, plant extracts, chondroitin sulfate, glucosamine, zinc, water-soluble vitamins;
• d.) are assigned to the group of natural antioxidants.

• a.) der Emulgator enthält Glycerol im Mengenbereich zwischen 40 und 60 Gew.-% und Phosphatidylcholin im Mengenbereich zwischen 5 und 15 Gew.-%;
• b.) das bidestillierte Wasser umfasst 38 bis 50 Gew.-%;
• c.) das Öl-Wirkstoffgemisch umfasst bis zu 5 Gew.-%.

It has proven to be advantageous that the water-soluble active ingredients have an active substance-dependent proportion of between 3 and 10 wt .-% based on the total amount of the active ingredient suspension. It has been recognized with the invention that for the preparation of the micellar active substance concentrate, a predetermined quantity composition or quantity distribution in the carrier substrate containing the active substances can be advantageous. This is provided by the fact that the active ingredient suspension has the following quantitative composition based on the total amount:

• a.) The emulsifier contains glycerol in the amount range between 40 and 60 wt .-% and phosphatidylcholine in the range between 5 and 15 wt .-%;
• b.) the bidistilled water comprises 38 to 50 wt .-%;
• c.) the oil-active substance mixture comprises up to 5 wt .-%.

A suitable composition is thereby provided by mixing the oil / active substance mixture of 3 parts of oil constituents and 1 part of active ingredient constituents. In this case, the proportion of bidistilled water is adjusted in proportion to the proportion of the active ingredient.

Furthermore, it has been recognized with the invention that natural oils are particularly suitable for the preparation of the micellar active substance concentrate, since these are prone to surfactant formation, which supports micelle formation and, moreover, the compatibility with human or veterinary application is particularly favorable is. According to the invention this is ensured by the fact that the oil-active substance mixture contains vegetable oil, which preferably comprises one or more of the oils from the following group: germ oils, nut oils, seed oils and seed oils. (Claim 8) According to the invention, these include in particular: thistle oil, sweet almond oil, avocado oil, castor oil, olive oil, sesame oil, peanut oil, grapeseed oil, rapeseed oil, coprabi, hazelnut oil, shea butter oil, palm oil, apricot kernel oil, calophyllum oil, rice bran oil, corn germ oil, wheat germ oil, soybean oil, sunflower oil, Evening primrose oil, safflower oil, passion flower oil and rye oil.

The success of the invention, in particular to obtain a substance whose micelles on a have been reduced in size, is achieved by the fact that the micelles of the active ingredient suspension are comminuted by the high pressure application in the ratio 1: 8 to 1:12, preferably in the ratio 1:10. The actual size of the micelles is determined inter alia by the pre-comminution in the first part of the process.

In the high-pressure application, the active ingredient suspension is subjected to pressure after its preparation, which leads to further comminution of the micelles and to a finer dispersion. The most favorable results are provided according to the invention in that the active ingredient suspension is exposed to a pressure in the range from 350 to 450 bar, preferably a pressure of 400 bar.

It has been recognized with the invention that the stability of the micellar active substance concentrate can be achieved in that an oily micelle paste is eliminated by means of the ultra-centrifugation from the active substance suspension.

The micelle paste is then freed from water and glycerol. There are separated by centrifugation two phases from the active ingredient suspension. Of which one phase contains the glycerol and the water and the other phase forms the micelles containing oily micelle paste. The glycerol and the water-containing phase can be attributed to the production of new active ingredient suspension.

• a.) einer Radialbeschleunigung von 1,0 × 10⁵ G bis 1,5 × 10⁵ G ausgesetzt wird, wobei G die Erdbeschleunigung ist;
• b.) in einem Temperaturbereich zwischen 5°C und 40°C temperiert wird;
• c.) für die Dauer von 5 bis 60 Minuten zentrifugiert wird.

It is provided according to the invention that the active ingredient suspension in the ultra-centrifugation

• a.) is subjected to a radial acceleration of 1.0 × 10 ⁵ G to 1.5 × 10 ⁵ G, G being the gravitational acceleration;
• b.) Is tempered in a temperature range between 5 ° C and 40 ° C;
• c.) is centrifuged for a period of 5 to 60 minutes.

The oily micelle paste obtained by the ultra-centrifugation can be processed further, whereby a higher stability and more favorable mixing or solubility properties can be achieved. This is achieved by solidifying the micelle paste by depositing oil components.

Depending on the intended use, the oily or solidified micelle paste can be stored and further processed as a micellar active substance concentrate. Also, the immediate use of the micellar drug concentrate is advantageously encompassed by the invention.

• a.) als Bestandteil einer Füllung in licht-, luft- und keimdichten Sachets oder Kapseln;
• b.) als Zusatz in Tropfen, Gels, Cremes, Salben, Emulsionen, vorzugsweise zur Aufbringung auf die Haut, auf Schleimhäute oder zur Applikation in die Augen;
• c.) als Zusatz in Mitteln zur oralen Aufnahme, vorzugsweise Pasten, Pillen, Kapseln oder Dragees;
• d.) als Zusatz in Mitteln zur rektalen Aufnahme, vorzugsweise Zäpfchen;
• e.) als Resuspension in Flüssigkeiten;
• f.) als Präparat für diätischen, pharmazeutische, kosmetische, medizinische Zwecke zur Anwendung beim Menschen und beim Tier.

Application examples are in particular the use

• a.) as part of a filling in light, air and germ-proof sachets or capsules;
• b.) as an additive in drops, gels, creams, ointments, emulsions, preferably for application to the skin, on mucous membranes or for application in the eyes;
• c.) as an additive in oral ingestion agents, preferably pastes, pills, capsules or dragees;
• d.) as an additive in rectal uptake agents, preferably suppositories;
• e.) as resuspension in liquids;
• f.) as a preparation for dietary, pharmaceutical, cosmetic, medical purposes for use in humans and animals.

The examples of use mentioned here are not exhaustive enumeration according to the invention but are examples of the applications according to the invention.

Furthermore, the use of these micellar active substance concentrates as well as the composition of the active substance suspension of individual process steps is encompassed by the invention.

An advantage of the method according to the invention is that the particle size of the micelles present can be further reduced by the ultra-centrifugation, but on the other components of the premix of the active ingredient suspension can be eliminated, which in the further course of processing and portioning and in the Packaging could have adverse effects.

Another advantage is that the active ingredient concentrate is present after the ultra-centrifugation in the form of an oily paste, which is largely protected in terms of contamination with germs and thus the durability is improved, compared to known methods in which the micelle substance is present in an environment chemically reactive molecules which can influence, for example, oxidation and permeability.

Furthermore, an advantage of the invention is that the drying of the active ingredient concentrate can be carried out by separation of the oil components from the oily paste, so that the dried micelle concentrate is present without chemical auxiliaries and can be used in any hydro- or lipophilic environments.

Another advantage is the cost-efficient and ecological production method, which makes it possible to return some of the substances used in the production process to multiple uses.

Another advantage of the invention is the fact that simultaneously water-soluble and fat-soluble active ingredients can be processed and present in the micellar active substance concentrate after completion of the process. Thus, a variety of drug combinations for this method is possible.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 728460A [0004]
• EP 780114A [0004]
• EP 780115 A [0004]
• EP 879589 A [0004]
• EP1010413A [0004]
• EP 1010414 A [0004]
• EP 1010415 A [0004]
• EP 1010416 A [0004]
• EP 1013338A [0004]
• EP 1016453 A [0004]
• EP 1018363 A [0004]
• EP 1020219 A [0004]
• EP 1025898A [0004]
• EP 1120102 A [0004]
• EP 1120101 A [0004]
• EP 1160005 A [0004]
• EP 1172077 A [0004]
• EP 1353629 A [0004]
• WO 89/11907 A [0005]
• DE 4318171 A [0005]
• EP 815846 A [0005]
• EP 1297824A [0005]
• EP 1616552 B1 [0006, 0008]
• WO 2001/094002 [0013]

Claims (14)

A process for the preparation of a drug concentrate from micellar nanoparticles without the use of chemical excipients for receiving natural fat or water-soluble drugs, characterized in that a fat-soluble active ingredient suspension is produced, which micelles having a micelle size of up to 1000 nm that the Micelles are crushed by high-pressure application and that the micelles are separated by ultra-centrifugation from the fat-soluble drug suspension. Process for the preparation of a micellar active substance concentrate according to claim 1, characterized in that the fat-soluble active substance suspension is prepared in the order of the following steps: a. Preparing a liquid pre-emulsion comprising glycerol and phosphatidylcholine; b. Mixing bidistilled water into the emulsion; c. Mixing in an oil-active substance mixture; d. Stir the active ingredient suspension at a speed between 100 s-1 and 400 s-1 for a period of 3 to 10 minutes. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 and 2, characterized in that complementary water-soluble active substances and / or fat-soluble active substances which supplement the oil-active substance mixture are dissolved in the bidistilled water before mixing into the pre-emulsion. Process for the preparation of a micellar active substance concentrate according to claim 3, characterized in that the complementary soluble active substances a.) are assigned to the group of trace elements, metals, minerals and vitamins for human and animal use; b.) are assigned to the group of the following fat-soluble active substances: coenzyme Q10, RRR-alpha-tocopherol, gamma-tocopherol, beta-tocopherol, delta-tocopherol, lycopene, specific fatty acids; c.) are assigned to the group of the following water-soluble active substances: iron, magnesium, plant extracts, chondroitin sulfate, glucosamine, zinc, water-soluble vitamins; d.) are assigned to the group of natural antioxidants. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 3 and 4, characterized in that the water-soluble active ingredients have an active substance-dependent proportion of between 3 and 10% by weight, based on the total amount of active ingredient suspension. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 to 5, characterized in that the active substance suspension has the following quantitative composition, based on the total amount: a.) The emulsifier contains glycerol in the amount range between 40 and 60 wt .-% and phosphatidylcholine in the range between 5 and 15 wt .-%; b.) the bidistilled water comprises 38 to 50 wt .-%; c.) the oil-active substance mixture comprises up to 5 wt .-%. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 to 6, characterized in that the oil / active substance mixture is mixed with 3 parts of oil constituents and 1 part of active ingredient constituents. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 to 7, characterized in that the oil / active substance mixture contains vegetable oil which preferably comprises one or more of the oils from the following group: germ oils, nut oils, seed oils and seed oils. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 to 8, characterized in that the micelles of the active substance suspension are comminuted by the high-pressure application in a ratio of 1: 8 to 1:12, preferably 1:10. Process for the preparation of a micellar active ingredient concentrate according to claim 9, characterized in that the active substance suspension is exposed to a pressure in the range of 350 to 450 bar, preferably a pressure of 400 bar. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 1 to 10, characterized in that an oily micelle paste is eliminated by means of the ultra-centrifugation from the active substance suspension. A process for the preparation of a micellar active substance concentrate according to one or more of claims 1 to 11, characterized in that the active substance suspension in the ultra-centrifugation a.) A radial acceleration of 1.0 × 10 ⁵ G to 1.5 × 10 ⁵ G where G is the gravitational acceleration; b.) Is tempered in a temperature range between 5 ° C and 40 ° C; c.) is centrifuged for a period of 5 to 60 minutes. Process for the preparation of a micellar active substance concentrate according to one or more of Claims 11 and 12, characterized in that the micelle paste is solidified by precipitation of oil constituents. Use of a micellar active substance concentrate prepared according to one or more of claims 1 to 13 a.) as part of a filling in light, air and germ-proof sachets or capsules; b.) as an additive in drops, gels, creams, ointments, emulsions, preferably for application to the skin, on mucous membranes or for application in the eyes; c.) as an additive in oral ingestion agents, preferably pastes, pills, capsules or dragees; d.) as an additive in rectal uptake agents, preferably suppositories; e.) as resuspension in liquids; f.) as a preparation for dietary, pharmaceutical, cosmetic, medical purposes for use in humans and animals.