EP2129387A2

EP2129387A2 - Capsule containing plant preparations

Info

Publication number: EP2129387A2
Application number: EP08717491A
Authority: EP
Inventors: Dieter Wolfgang Engel
Original assignee: Swiss Caps Rechte und Lizenzen AG
Current assignee: Swiss Caps Rechte und Lizenzen AG
Priority date: 2007-03-26
Filing date: 2008-03-07
Publication date: 2009-12-09
Also published as: US20100098784A1; WO2008116737A2; WO2008116737A3; CA2679796A1; CH704033B1

Abstract

The invention relates to a composition containing a lipophilic extract of Vitellaria paradoxa and at least one amino sugar or a pharmaceutically acceptable salt thereof, in addition to a capsule containing said composition.

Description

Capsules containing plant preparations

The present invention relates to capsules containing a combination of pharmacologically active substances from Vitellaria paradoxa extracts and amino sugar derivatives, their preparation and use for the prophylaxis and treatment of inflammatory degenerative joint diseases.

Glucosamine and its salts, as well as chondroitin and its salts, have long been proposed for dietetic treatment and prevention of joint problems. This is understandable against the background that the cartilage and synovial fluid mainly consist of mucopolysaccharides, which in turn consist of the two most important acetylated amino sugars N-acetylglucosamine and N-acetylgalactosamine.

These amino sugars are obtained from special tissues of the vertebrates or chitin from crustaceans and administered as hydrochloride or sulfate salts in tablets and capsules for human use. Amino sugars and their acetylates are highly soluble in water. As a rule, the dosage in the form of a soft capsule requires the use of high proportions of mono- and di-triglycerides and waxes (beeswax) in order to obtain a flowable, sufficiently lipophilic mass which does not submerge with the capsule shell containing water during the encapsulation Discoloration or embrittlement.

However, as a result, conventional formulations containing amino sugars as the pharmacological ingredient are relatively bulky, with a substantial portion of the volume of carrier material being taken without pharmacological activity. The sheaf tree, also called shea butter tree (shea butter tree), is a tropical tree of 10-15 m in height, which are mainly native to Sudan and Niger. The plum-shaped fruits of the family Sapotaceae belonging Karitebaums (botanical name: Vitellaria Paradoxa, alternative botanical name: Butylospermium parkii) contain fruit seeds as seeds

(Nuts) which are High in Fats (Wissebach, H. (1969), Plant and Animal Fats, Handbook of Food Chemistry, KGD Acker, L .; Bergner, W .; Heimann, W .; Kiermeir, F .; Schormüller, J ; Souci, SW ;, Springer Verlag Berlin. IV Fats and lipids

(lipids): 41 ff.).

By breaking up the nuts and hot extraction, it is possible to obtain a fat which is available for refining (bleaching, deodorization) for food purposes and for cosmetics in world trade, which in many cases is today able to replace the much more expensive cocoa butter. This shea butter usually contains 3-15% unsaponifiable ingredients, of which about 70% are hydrocarbons, 7% squalene, 7% triterpene alcohols, and 8% phytosterols (Massera, AMF, E. Proserpio, G.; Rivista Italiana Essence Pro fumi 60 (7) (1978): 414-421; Nowak, GA (1984). The cosmetic preparations, Verlag für Chem. Industrie H. Zielkowsky KG, Augsburg). The shea butter has also been used to reduce the metabolically useful fat content in the diet (US-A-6, 149, 961).

The pharmaceutical use of leaves or extracts of the seeds of the sheaf tree is already known from traditional medicine. However, the carriers of the pharmacological action in Vitellaria extracts have not yet been identified in detail, although attention has been drawn to interesting substances at an early stage (Somorin, 0. "Preliminary studies on the physiological effects of extracts from the roots of Shea butter tree . " J. Clin. Pharmacol. 13: 178 (1973); Di Vincenzo, DM, Steve; Serraiocco, Arnaldo; Vito, Raffaella; Wiesman, Zeev; Bianchi, Giorgio. Journal of Agricultural and Food Chemistry 53 (19) (2005): 7473-7479). It may be phytosterols and polycyclic triterpene alcohols and their acetic and cinnamic acid esters with pronounced anti-inflammatory, or anti-arthritic effect.

WO 2004/002504 describes the isolation of triterpenoids or saponins from components of the sheaf tree, which have been made water-soluble by saponification, and the production of tablets containing these substances for the reduction of serum cholesterol and for the treatment of inflammatory diseases.

Semi-solid cosmetic or pharmaceutical preparations often make use of the shea butter as a viscosity-enhancing carrier without the use of the pharmacologically active substances which may be present in the shea butter (see, for example, EP-1 392 335). For this application, the shea butter is highly purified and refined. Most of the pharmacologically active ingredients are separated and discarded. The remaining high-purity shea butter no longer has any pharmacological activity.

On the other hand, the formulation of lipophilic Vitellaria extracts in solid form and in particular in tablet form is in principle very difficult or even impossible for technical reasons.

It was the object of the present invention to provide a compact as possible dosage form containing amino sugar as a pharmacological ingredient and also a higher pharmacological activity than conventional amino-based preparations.

Surprisingly, it has been found according to the present invention that when using a lipophilic Vitellaria extract for the preparation of an amino sugar-containing pharmaceutical capsule preparation, the above object is achieved.

This is mainly due to the following reasons:

- The combination of liquid Vitellaria extracts with solid aminosugars and their salts, the dosage form can be kept much smaller and thus space-saving, since the active ingredient Vitellaria extract is also the "carrier matrix" for the solid amino sugar compounds.

- In one capsule pharmacologically active lipophilic liquid Vitellaria extracts can be used, which are difficult to achieve in other solid oral dosage forms.

- The lipophilic liquid Vitellaria extracts can be prepared with emulsifiers and solubilizers as capsule contents so that they can mix quickly with aqueous biological media such as saliva, gastric juice or intestinal environment or emulsified in these. This increases their pharmacological activity;

- Correspondingly prepared lipophilic Vitellaria extracts may be provided in a capsule in liquid, emulsified or dispersed form.

It is thus possible to provide all carriers of the pharmacological activity of Vitellaria species (hydrophilic and lipophilic components) and amino sugars in combination in one capsule. put. For the above reasons, this is not possible, for example, in tablets.

The present invention does not use pharmacologically inactive carriers for the amino sugars, but rather Vitellaria extracts which themselves have a corresponding pharmacological activity which synergistically complements the activity of the amino sugars. In contrast to the conventional voluminous carrier matrices for amino sugars, the Vitellaria extract used according to the invention is compact, pharmacologically active and no "dead" volume.

The present invention thus also relates to a composition comprising a lipophilic extract of Vitellaria paraodixa and at least one amino sugar or a pharmaceutically acceptable salt thereof. This composition is particularly suitable as a filling material for capsules.

Capsules are established dosage forms for pharmaceuticals and nutritional supplements. They are designed as a core-shell structure, i. an ingredient of any consistency (the core) is surrounded by a shell of suitable shell material. A distinction is made in particular hard capsules and soft capsules.

For hard capsules, the shell material consists of a rather thin film (with a thickness of up to 200 microns), which is still dimensionally stable. In general, the shell of two complementary and joinable parts (body and cap) is constructed. The finished capsule is obtained by filling a part and joining both parts together. Usually used as film material are gelatin, cellulose derivatives, gums, PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone) and other synthetic and natural polymers or mixtures of polymers with other substances. det. Hard capsules are usually filled with powdery or particulate (pellets) products, but can also be filled with liquid, pasty products.

For soft capsules, the shell is usually thicker (with a thickness over 200 microns). The shell material selected from the group consisting of gelatin, starch, gums (hydrophilic biopolymers such as carrageenan, guar, alginate, etc.) or other natural or synthetic polymers or mixtures thereof and generally contains a plasticizer. As a result of the manufacturing process, soft capsules usually consist of one-part films (in the case of production via a drop, ring extrusion, injection molding (injection molding), co-injection molding process) or of two films welded together (in the case of US Pat of the ro- tary die method). Soft capsules are usually charged with liquid or pasty products, but can also be filled with powdery or particulate (pellets) contents.

Preferably, since hardly any interactions between the hydrophilic shell and the filling material occur, lipophilic liquid fillers are alone or as a carrier matrix for a suspension of crystalline water-soluble substances in a lipophilic matrix. Melt-solidified melts of lipophilic substances and highly viscous suspensions of water-soluble particles in lipophilic matrix are also suitable for filling hard capsules or for filling soft capsules whose shell is produced by melt-extrusion technology. This is described in EP-I 103 254 and EP-I 586 436, to the relevant contents of which reference is expressly made.

Capsules and methods for their preparation are well known (eg Stanley, JP "Soft gelatin capsules" in: Lachman et al. (Ed.) "The theory and practice of industrial pharmacy", Philadelphia, Lea & Febiger, 3rd edition (1986); Hofer et al., In: Fahrig, W .; Hofer, U. (ed.) "The Capsule", Wiss. Verlagsgesellschaft mbH, Stuttgart; Paperback APV Volume 7, Edition, 1981; Gennadios A, "Soft gelatin capsules," in Gennadios A. ed., Protein-based Films and Coatings, CRC Press, Boca Raton, 2002, ISBN1 -58716-107-9).

The lipophilic Vitellaria extracts which can be used in the composition according to the present invention are preferably obtained from the Upper Irish Vitellaria plant parts, e.g. from flowers, fruits, leaves or bark. Particularly preferred is the extract from the berries, especially from the seeds, the so-called shea nuts. According to the invention, the extracts can be obtained from Vitellaria species selected from the group consisting of Vitellaria Gaertn.f. , Vitellaria campechiana, Vitellaria mammosa (L.), Vitellaria mammosa (L.), Vitellaria nervosa (DC), Vitellaria paradoxa Gaertn., Vitellaria paradoxa subsp. Nilotica.

The extraction from the corresponding plant parts of the shea butter tree is carried out in a manner known to the person skilled in the art. Depending on whether hydrophilic or lipophilic components are to be extracted, the plant parts are treated with an appropriate solvent. In the case of the hydrophilic extracts, water or a polar solvent such as methanol or ethanol may be used. In the case of lipophilic extracts, apolar solvents such as hydrocarbons may be used accordingly. Of course, corresponding polar or apolar solvent mixtures can be combined or used successively. The extraction conditions are familiar to the person skilled in the art. It can be extracted at room temperature. Often, however, it is preferred to extract at elevated temperatures (to the boiling point of the particular solvent or solvent mixture), for example in a Soxhlet apparatus. If necessary, the extraction can be carried out several times (also with different solvents).

The extract obtained in this way may optionally be subjected to further purification steps or separation steps.

Extracts are understood to mean all extracts from plant material of any plant constituents, with the partial omission of primary plant constituents, such as cellulose, saccharides, proteins, triglycerides. The purpose of these extracts is to enrich certain secondary phytochemicals, especially those with desirable pharmacological properties.

In particular, lipophilic extracts can be obtained by extracting the naturally occurring oils / fats or fat-soluble fractions in the plant tissue. The naturally occurring triglycerides / waxes / hydrocarbons can also play the role of extraction solvent. These can not be evaporated off due to a lack of volatility, but must be further treated with a solvent or by methods such as countercurrent extraction, supercritical extraction, chromatographic methods, (steam or vacuum) distillation or other separation methods for further enrichment of secondary plant ingredients.

Lipophilic extracts are also readily available by extraction with a lipophilic low molecular weight solvent such as high preferably ethanol, acetone, ethyl acetate, hexane, chloroform, etc. or supercritical carbon dioxide which can be evaporated. The term "lipophilic" describes technically substances with a partition coefficient (log p) in octane / water or octane / saline solution of greater than 1.

The person skilled in the art is well aware of the comminution of the plant material, the disruption of the plant cells by grinding, heating, ultrasound treatment, and extraction, enrichment by evaporation of the solvent and cleaning.

Similarly, water-soluble extracts can be obtained by stripping with more hydrophilic solvents or by chemically reacting (e.g., saponifying the secondary plant ingredients) from lipophilic pulled-out fractions.

The term "amino sugar" is a collective term for monosaccharides in which one hydroxyl group has been replaced by an amino group, which may be a primary amino group or a secondary or tertiary amino group, for example glucosamine, preferably D-glucosamine, Galac - tosamine, preferably D-galactosamine, chondroitin or neuraminic acid, and the corresponding N-acetylated derivatives N-acetylglucosamine and N-acetylgalactosamine, hyaluronic acid, dermatan, keratan, heparin and their pharmaceutically acceptable salts mentioned in the composition according to the present invention In the invention, the amino sugars may be in free form or in the form of their pharmaceutically acceptable salts (for example, the corresponding halides or sulfates).

Due to their anti-inflammatory and antidegenerative activity Vitellaria extracts can be used in the prevention and treatment of rheumatic diseases. Under the rheumatic form of the diseases should be understood here in particular: polyarthritis of unknown origin (especially rheumatoid arthritis) and osteoarthritis (osteoarthritis)). According to the invention, it is thus particularly appropriate to use the antiinflammatory effect of Vitellaria extracts together with aminosugars for the biogenic structure of the To provide mucopolysaccharides in the joints.

For this purpose, it is preferable to design the capsules in such a way that the smallest possible number of capsules necessary for the dosage is possible with the highest possible bioavailability. This is done by suspending the amino sugars in a matrix which can be pumped at 25-35 ° C. and which does not sediment on standing, from biophilic vitamins extracts and / or fatty oils from vitellaria.

The Vitellaria extract can be depending on the proportion of unverseif- Barem ingredients, or by the proportion of C18: set to a solidification or melting range of 20-45 ⁰ C 0- fatty acids in the triglyceride content. In particular, the proportion of lower or higher melting fractions can be controlled by freezing (winterization). More preferably, the extract is adjusted to a dropping point of 25 to 40 ⁰ C, more preferably for soft gelatin capsules on a dropping point of 20 to 30 ° C, and for hard capsules, cachets and capsules produced with the Meitner extrusion method on a drop point of 30 -45 ⁰ C.

According to a preferred embodiment, the capsules according to the invention are thus formulated with a filling made of vitellaria extract or fatty oils of vitellaria and with aminosugars or their salts in such a way that at temperatures above +40 ° C pumpable filling material which is solidified at temperatures below + 35 ° C and filled into suitable capsules.

According to a further embodiment of the present invention, the capsule to be taken orally can be designed such that it emulsifies on contact with the gastric fluid itself, forms an emulsion. Such capsules are known in principle (e.g., EP 0 637 715, C.W. Pouton, Advanced Drug Delivery Reviews, 25: 47-58 (1997)).

For this purpose, one or more emulsifiers may be added or the lipid matrix saponified to free fatty acids or soaps (fatty acid alkali salt) (with the aid of mono- and distearates) or the extracts in the form of partially hydrolyzed (amphoteric) extracts (containing unsaponifiable components , Mono- and di-glycerides and fatty acid alkali salts) are introduced. Emulsifiers and solubilizers which can be used according to the invention are well known to the person skilled in the art and need not be explained in more detail here. By way of example, the following may be mentioned as solubilizers / cosolvents: caprylic acid monoglyceride, free fatty acids or fatty acid esters (eg oleic acid, fish oil ethyl ester (in various forms).) Emulsifiers may be mentioned by way of example: lecithin, span (sorbitan fatty acid esters), tweens (polysorbates), Polyglycerol ester.

The amounts of Vitellaria extract and amino sugar contained in the composition are not essential. According to the invention, however, vitellaria extract and amino sugar are preferably used in a ratio of 60:40 to 40:60.

In addition, the composition according to the invention may also contain other active substances selected from the group consisting of cysteine, taurine and its salts, glutathione and its salts, Glycine, glutamic acid, tocopherols, tocotrienols, rosemary extract or its ingredients, carnosine and rosmarinic acid.

The present invention will be further explained below by way of non-limiting examples.

Example 1:

Extract prepared from mashed fruit kernels (nuts) from Vitellaria paradoxa:

The nuts were mashed. The gray greasy mass was boiled with 1N potassium hydroxide solution for 60 min, neutralized with IN HCl and extracted with ethyl acetate. The solution was dried with sodium sulfate and the solvent was evaporated. The residue was melted at 70 ⁰ C and purified over a cellulose-packed column (at 70 ⁰ C). The extract contained about 50% tri-, di- and monoglycerides and about 50% sterols, triterpene alcohols and their esters.

Example 2:

Lipophilic extract of fruit kernels (nuts) of Vitellaria paradoxa:

The fruit kernels were tamped, the mixture heated and filtered hot or extracted with hexane. The faction was traded as raw shea butter. This was deacidified by standard methods of fatty chemistry, bleached and fractionated in Shea stearin and Shea olein. The Shea olein fraction was dekaritiniert, and washed successively with sodium hydroxide solution, sodium chloride solution and water, bleached, transesterified and hydrogenated. Renewed fractionation yielded a product with approx. 50% unsaponifiable part. This extract was further stabilized with 0.1% β, δ-tocopherols.

The product contained about 25% triterpene alcohol ester and sterol ester, and about 2-5% cinnamic acid ester.

Example 3:

A refined, shea butter (shea butter) with a high triglyceride content was used. The proportion of unsaponifiable components was 5-8%, again consisting of 75% triterpene alcohols, 18% hydrocarbons, 5% sterols and 2% methyl sterols (iodine number: 55-71, peroxide number <5 meq, melting point 32-40 ⁰ C). The product contained more than 40% of C18: 0 (stearic acid) and C18: l (mostly oleic acid) fatty acids.

Example 4:

Soft capsules with Vitellaria extract and glucosamine

A soft capsule was made from about 270 mg of a capsule shell (tapioca starch, maltitol, sorbitol, glycerol, glycerol monostearate, iron oxide red) and charged with the following contents:

Glucosamine sulphate 2 KCL 400.00 mg

Fish oil triglyceride (30% EPA + DHA) 200.00 mg

Vitellaria extract (Example 2) 100.00 mg

Lecithin (60% phosphatides) 20.00 mg (filling weight 720 mg)

The contents were filled after mixing, rolling (homogenization) and deaerating at about 30 ⁰ C in soft gelatin capsules. The capsule was immediately cooled intensively with air (10 ⁰ C) for about 5 min and dried in a stream of air (20 ⁰ C, 20% RH).

Example 5:

Soft capsules with Vitellaria extract, glucosamine and chondroitin:

A soft capsule was made from about 500 mg of a soft gelatin capsule shell (gelatin, glycerol, water, iron oxide brown) and charged with the following contents:

Glucosamine sulphate 2 KCL 667.00 mg

Chondroitin sulfate 40.00 mg

Fish Oil Ethyl Ester Form with 55% EPA + DHA 300.00 mg

Vitellaria extract (Example 3) 450.00 mg

Lecithin (60% phosphatides) 20.00 mg (filling weight 1477 mg)

The contents were filled after mixing, rolling (homogenization) and deaerating at about 30 ⁰ C in soft gelatin capsules. The capsule was immediately cooled intensively with air (10 ⁰ C) for about 5 min and dried in a stream of air (20 ° C, 20% RH).

Example 6:

Soft capsules with glucosamine and shea butter

Glucosamine sulfate 2 KCL 400.00 mg

Vitellaria extract (Example 1) 300.00 mg Tween 80 4.00 mg (Filling weight 704 mg)

The contents were filled after mixing, rolling (homogenizing) and venting at about 40 ⁰ C in the capsules.

Example 7:

Soft capsules with glucosamine and shea butter

A soft capsule was made from about 200 mg of a soft gelatin capsule shell (gelatin, glycerol, sorbitol, water, iron oxide brown) and charged with the following contents:

Glucosamine sulphate 2 KCL 350.00 mg

Vitellaria extract (Example 1) 190.00 mg Capmul MCM C8

(caprylic acid monoglycerides)

(Abitec Corp.) 40.00 mg

Tween 80 20.00 mg

(Filling weight 600 mg)

The contents were filled after mixing, rolling (homogenizing) and venting at about 30 ⁰ C in the capsules. The capsule was immediately cooled intensively with air (10 ⁰ C) for about 5 min and dried in a stream of air (20 ° C, 20% RH).

In a USP / EP release device (paddle, 900 ml, 0. IN HCL, 100 rpm), the capsules formed an emulsion which was stable over 1 h (opening of the capsules) for at least 15 min (opening of the capsules).

Claims

claims

A composition comprising a lipophilic extract of tellaria paradoxa and at least one amino sugar or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, characterized in that further comprises a hydrophilic extract of Vitellaria paradoxa.

3. Composition according to claim 1 or 2, characterized in that the at least one amino sugar is selected from the group consisting of D-glucosamine, N-acetylglucosamine, hyaluronic acid, D-galactosamine, N-acetylgalactosamine, chondroitin, dermatan, Keratan, heparin and their pharmaceutically acceptable salts.

4. The composition according to any one of the preceding claims, characterized in that the lipophilic Vitellaria extract contains at least 50% triglycerides or at least 50% Triterpenal- koholester.

5. Composition according to one of the preceding claims, characterized in that the extracts are obtained from Vitellaria species selected from the group consisting of Vitellaria Gaertn.f. , Vitellaria campechiana, Vitellaria mammosa (L.), Vitellaria mammosa (L.), Vitellaria nervosa (DC), Vitellaria paradoxa Gaertn., Vitellaria parodoxa subsp. Nilotica.

6. A composition according to any one of the preceding claims, characterized in that the composition is a Room temperature solidified melt is pasty at a temperature above 35 ° C.

7. Composition according to one of the preceding claims, characterized in that the Vitellaria extract has a solidification or melting range of 20 to 45 ° C.

8. The composition according to any one of the preceding claims, characterized in that the Vitellaria extract has a dropping point of 25 to 40 ⁰ C.

9. capsule containing a composition according to any one of claims 1 to 8 as a filling.

10. Capsule according to claim 9, characterized in that it is a soft capsule.

11. Capsule according to claim 9 or 10, characterized in that it forms an emulsion on contact with the gastric fluid.

12. A method for producing a capsule according to any one of claims 9 to 11, characterized in that it is filled with a composition according to any one of claims 1 to 8.

13. The method according to claim 12, characterized in that the capsule is produced in the rotary die process.

14. Use of a composition according to any one of claims 1 to 8 for the preparation of a capsule.

15. Use of a lipophilic Vitellaria extract for the preparation of an amino sugar-containing pharmaceutical or dietetic capsule preparation for the prophylaxis and treatment of rheumatic diseases.

16. Use of a capsule according to any one of claims 9 to 11 for the prophylaxis and treatment of rheumatic diseases.