HK1070567B - Spheroids based on plant extract adsorbates and method for preparing same - Google Patents

Description

Spheroids based on plant extract adsorbates and method for making same

The invention relates to formulations for rapidly dispersing spheroids based on low-substituted hydroxypropylated cellulose ethers, which can be filled with a large amount of active substance.

The invention also relates to a process for the preparation of these spheroids based on low-substituted hydroxypropylated cellulose ethers, which provides an adequate, very concentrated solution of the active substance, in particular of vegetable origin, to the spheroids.

The invention also relates to compositions of plants, minerals, vitamins or based on organic active ingredients, in the shape of such spheres.

Finally, the invention relates to the applications which are thus elicited by humans or animals, particularly in the fields of health, hygiene, diet, beauty, nutrition, agriculture, by oral or external application of these spheroids.

It is an object of the present invention to provide spheroids with a high active ingredient content.

It is another object of the present invention to provide a fast dispersing spherical body.

It is well known to prepare active solutions in liquid form, in particular solutions based on plant products obtained by extraction, maceration, infusion, decoction, digestion or lixiviation.

However, the direct use of these liquid extracts has a number of drawbacks, in particular their physical and chemical instability during storage, their low content of characteristic plant components and often a large amount of ethanol of varying degrees, which are generally undesirable, in particular for oral medicines.

In addition, this liquid form is also not practical for the user. The administration and dosing of the product is complicated, its transport is also difficult and it may be knocked over by chance.

For all these reasons, solid forms are highly desirable.

In fact, in order to turn these liquid extracts into dry extracts without any drawbacks, methods are used which require the supply of a large amount of heat, such as for example spraying, drying on a rotating cylinder or evaporation under reduced pressure.

If these methods allow to obtain more easily used, in particular orally administrable, pulverulent compounds, these methods use high temperatures, which may deteriorate unstable active ingredients, such as for example characteristic plant components.

Furthermore, these dry extracts tend to be very hygroscopic, which leads to clumping of the extract due to moisture absorption, and also to the risk of changing the physical and chemical stability, rendering and handling difficult.

Patent application FR 2721512 is also known, which describes a process for the absorption and adsorption of solutions of vegetable origin by pulverulent substances, generally of natural or synthetic polymer type, followed by extrusion and then spheronization of the moist agglomerate to form spheroids.

In this way, it is advantageous to obtain a simplified formulation, without thermal degradation, and therefore it is possible to administer the liquid preparation of plant origin in a dry form and to ensure physicochemical stability during the use of the active ingredient.

Polymers as described in this patent application as having suitable absorption and adsorption properties are microcrystalline cellulose, micro-fine cellulose, starch, modified starch and polysaccharides, with microcrystalline cellulose being preferred. These process excipients have satisfactory plastic characteristics and suitable absorption and adsorption properties.

However, to produce more concentrated active ingredient spheroids, it is particularly advantageous to improve these properties.

In fact, it is also possible to fill smaller dispenser systems with more active ingredient. For example, in the oral context, it is therefore possible to reduce the number of times a day is taken or to reduce the volume of composition swallowed.

These objects are achieved by the formulations and methods of the present invention.

To this end, according to an essential characteristic of the invention, the use of a specific and surprising process excipient, the absorption of which as active ingredient is at the same time particularly advantageous with respect to the adsorption matrix and its compatibility with the spheronization extrusion process.

The spheroids of the invention are prepared using at least one active substance absorbed and/or adsorbed onto a homogeneous dry process mixture of a low-substituted hydroxypropylated cellulose polymer, which spheroids are obtained using a spheronization extrusion process.

The method for producing a spherical body containing a highly active ingredient of the present invention comprises the steps of:

providing a very concentrated active solution or powder;

providing a homogeneous dry process mixture of low-substituted hydroxypropylated cellulose polymer having very high absorption and adsorption properties;

wetting the dry mixture with the active solution or with another liquid, aqueous or non-aqueous;

extruding;

forming spherical bodies by spheronization of the extruded product;

drying;

checking the dry composition size in order to form a spherical multiparticulate system of controlled particle size.

The method of the invention may comprise a supplementary step of:

coating these multiparticulate systems, for example to protect the components or to improve their release in the organism.

The method of the invention can provide any liquid active botanical composition, particularly liquid extracts, solutions, suspensions, or solid active botanical compositions, such as single or composite powders, dry extracts, etc., on spheroids of controlled particle size.

Preferably, an alcoholic or aqueous-alcoholic extract of one or more plant materials is used. However, any other active solution or powder containing one or more active ingredients, for example based on vitamins, minerals and/or organic constituents, is also suitable.

One of the features of the present invention for the dry process mixture is the utilization of the specific physico-chemical properties of the low substituted hydroxypropylated cellulose ether at the beta-O-glucopyranoside ring group. Preferably, such compounds are characterized by a substitution rate (hydroxypropyl groups) of about 10%, such as about 11%, and preferably are further characterized by a percentage of water soluble moieties of about 5%, such as about 4.29%.

These compounds have the plasticity, adsorption and absorption properties of liquids, and are compatible with extrusion and spheronization processes. Furthermore, such compounds make it possible to produce spheroids containing more concentrated ingredients than spheroids prepared using relatively common process excipients, specifically, microcrystalline cellulose, for example, and using the same method.

This assertion can be demonstrated, for example, by the following method of practice, in which the water absorption capacity of excipients of different properties is tested for the same mass (100 g):

excipients absorb water per 100 grams of excipient

Lactose 15 g

Starch 60 g

Microcrystalline cellulose 120 g

Low-substituted hydroxypropylated cellulose ether (LHPC) to 350 g

In the case of active powders, the dry hydroxypropylated cellulose polymer is moistened with a wetting liquid, which may be an active solution or other aqueous or non-aqueous liquid, until a homogeneous, malleable paste is obtained, which can be subjected to the subsequent steps of the process, i.e., extrusion and spheronization.

In the micro-cavities of the hydroxypropylated cellulose polymer, this wetting liquid acts as a carrier for the transport and acceptance of the active substance up to the core of the absorption and adsorption of the substance.

This manufacturing process is followed by extruding the wet mass through a die having calibrated orifices and then spheronizing (spheronizing) the extruded product.

During extrusion, the wetted mass is compacted and then drawn to a compacted filament, generally cylindrical in cross-section, referred to as the "extrudate".

To obtain spheroids, these "extrudates" are placed in a cylindrical device called a "spheronizer" with a controlled variable speed rotating disc in its lower part. These "extrudates" are regularly cut into segments under the centrifugal force exerted by the rotation of the rotating disk and then transformed into spheres by a roll-mixing action.

It has been observed that the possibility of transforming the extrudate into spheroids of uniform sphericity, of predetermined uniform size, depends on the plastic characteristics of the extrudate and therefore of the wetted mass, and also on the characteristics associated with the strictly balling operation, i.e. the rotation speed of the rotating disc and its rotation time.

According to a feature of the invention, the mass of wetting liquid is preferably 3-5 times the mass of hydroxypropylated cellulose polymer used in order to achieve suitable plasticity compatible with the technique of extrusion followed by spheronization.

A particular feature of the invention is, for example, the preparation of spheroids having a particle size of 350-1250 μm in a yield of at least 95% of the mass of spheroids produced.

In this case, the die of the extruder had holes with a hole diameter of 1000 microns and a length of 1000 microns (die thickness). The extrusion speed of the twin-screw extruder apparatus or the like is 100 rpm.

The period of balling in a balling apparatus having a diameter of 25 cm at a rotation speed of 1040 rpm was 5 minutes.

These spheroids are then dried at a temperature of about 30-40 ℃.

They then pass through a size checking apparatus consisting of, for example, a set of sieves, in order to obtain a spherical multiparticulate system of controlled particle size.

The resulting spheroids were stable at the time and were easy to control and reproduce. Their use is simple and practical. These spheroids can be stored at will, without particular care, and they are also easy to transport, since they are relatively light, not bulky and not fragile.

The spheroids of the invention may be as such or coated and may be packaged in bulk, in a dispenser-dispenser, capsule, tablet, sachet or in any other suitable physical form or packaging.

Preferably, they are contained in capsules or capsules in an amount corresponding to the amount of active substance determined according to the usual dosage of the composition, it also being possible to make the unit dosage more convenient.

These multiparticulate systems may be film coated in a supplementary step of the process of the invention before they are packaged, for example in the form of capsules.

When these spheroids are intended for oral administration, this is in principle carried out by covering them with a tough coating film, which is able to protect active ingredient molecules that are sensitive, for example, to the acidic pH of the stomach, or that are degraded by enzymes in the intestinal lumen.

This manipulation also allows the release of the active ingredient in the organism to be modulated. The release of the active ingredients can be delayed to selectively release them at certain parts of the digestive system, for example, on and in the small intestine.

It is also possible to administer the composition once, with different coatings for the spheroids of the same capsule, and to release a plurality of doses of the active ingredient in succession.

According to an essential feature of the invention, the dried process mixture contains a low substituted hydroxypropylated cellulose ether at the beta-O-glucopyranoside ring group, preferably with a substitution rate of about 10%, e.g. about 11%, and a percentage of water soluble fraction of about 5%, e.g. 4.29%.

In addition to the liquid plasticity, absorption and adsorption properties, properties compatible with the extrusion-spheronization process of the present invention, this compound also has particularly advantageous swelling properties in water, thus catalyzing the dispersion of the absorbing and/or adsorbing active substances.

In fact, this swelling favours the entry of the liquid into the micro-cavities of the absorbing and adsorbing substance and the extraction of the active product carried by it by leaching.

Thus, it is possible for such compounds to disperse adsorbed and/or absorbed components in an aqueous solution by rapid exfoliation.

By this basic solution it is possible to achieve the other objects of the invention, namely the rapid dispersion of the spheroids in a liquid medium, such as water, with or without temperature. The resulting fluid is used by internal or external means to solve the problems mentioned in the introduction, in particular in the aforementioned field.

Thus, for example, after oral absorption of the product, these substances are rapidly released in the stomach, the gastric juice undergoing the necessary leaching.

All active ingredients are released very rapidly in a controlled and reproducible manner. This excellent bioavailability makes this original formulation a preventive and therapeutic drug with very high efficiency.

The process for producing rapidly dispersing spheroids according to the invention then comprises the following steps:

providing an active solution or powder;

providing a homogeneous dry process mixture of low-substituted hydroxypropylated cellulose polymer having absorption and adsorption properties compatible with extrusion and spheronization processes, and also possibly dispersing entrained ingredients by rapid leaching;

wetting the mixture with the active solution or with another liquid, aqueous or non-aqueous;

extruding;

forming spherical bodies by spheronization of the extruded product;

drying;

checking the dry composition size in order to form a spherical multiparticulate system of controlled particle size.

The method may also include a supplementary step of coating the multi-particle system with a film.

In order to improve this advantageous result of the rapid release and new properties of the spheroids even further, it is a feature of the invention to exploit the specific physico-chemical and pharmaceutical-technological properties of the excipients compatible with the preparation of the spheroids and their dispersing capacity in liquid media, in particular water, by rapid decomposition upon contact with fluids, complex solutions or any liquid compositions, high water content pastes or semi-paste like compositions.

According to a preferred embodiment of the invention, the hydroxypropylated cellulose ether can be compounded with commonly used pharmaceutical excipients having good water solubility, such as lactose or other derivatives, preferably in a proportion of substantially 20-50% of the total dry mass.

It may also be combined with disintegrating excipients having "flash" disintegrating properties, such as cross-linked sodium carboxymethyl cellulose, preferably in a proportion of about 5% of the total dry mass.

The compositions may also contain other excipients which confer them complementary properties commonly used in the art, such as binders, slip agents, lubricating compounds, surfactants, etc.

The following examples provide a better understanding of the invention.

Using the method of the invention and using the process excipients described above, spheroids based on plant-derived material (liquid extract), ethanol and different dry residues were prepared.

Example 1

Valerian liquid extract 350 ml

Ethanol content: 27%, dry residue: 9.1 percent of

100 g of low-substituted hydroxypropylated cellulose ether

Example 2

350 ml of red grape liquid extract

Ethanol content: 11%, dry residue: 9.5 percent

100 g of low-substituted hydroxypropylated cellulose ether

Example 3

300 ml of liquid extract of Dandelion

Ethanol content: 40%, dry residue: 21.0 percent

100 g of low-substituted hydroxypropylated cellulose ether

Claims (21)

1. Spheroids, characterised in that they are prepared using at least one active substance which is absorbed and/or adsorbed on a homogeneously dried technical mixture of low-substituted hydroxypropylated cellulose polymers, and in that these spheroids are obtained by extrusion and spheronization processes.

2. Spherical body according to claim 1, characterized in that the active substance is of plant origin.

3. Spheroids according to claim 2, characterised in that the active substance is initially derived from an alcoholic or hydroalcoholic extract of one or more plant materials.

4. Spheroids according to claim 1, characterised in that the process mixture contains hydroxypropylated cellulose ethers with low substitution at the β -O-glucopyranoside ring group.

5. Spheroids according to claim 4, characterized in that the substitution rate of hydroxypropylated cellulose ether is equal to 10%.

6. Spheroids according to claim 4 or 5, characterized in that the percentage of water-soluble fraction of hydroxypropylated cellulose ether is equal to 5%.

7. Spheroids according to claim 4, characterised in that the hydroxypropylated cellulose ether is complexed with at least one commonly used pharmaceutical excipient having good aqueous solubility.

8. The spherical body according to claim 7, characterized in that hydroxypropylated cellulose ether is complexed with lactose.

9. Spheroids according to claim 7 or 8, characterised in that the at least one excipient is substantially 20-50% of the total dry mass.

10. Spheroids according to claim 4, characterised in that hydroxypropylated cellulose ether is complexed with a disintegrating excipient having "flash release" disintegrating properties.

11. Spheroids according to claim 10, characterised in that hydroxypropylated cellulose ether is complexed with cross-linked sodium carboxymethylcellulose.

12. Spheroids according to claim 10 or 11, characterised in that the disintegrating excipient is 5% of the total dry mass.

13. Spherical bodies according to claim 1, characterised in that they are contained in a capsule or capsule.

14. Plant, mineral, vitamin composition or composition based on organic active ingredients, characterized in that it is in the form of a spheroid preparation according to claim 1.

15. A method for producing a spherical body containing a highly active component, characterized in that the method comprises the steps of:

providing a very concentrated active solution or powder;

providing a homogeneous dry process mixture of low-substituted hydroxypropylated cellulose polymer having very high absorption and adsorption properties;

wetting the mixture with the active solution or with another liquid, aqueous or non-aqueous;

extruding;

forming spherical bodies by spheronization of the extruded product;

drying;

checking the dry composition size in order to form a spherical multiparticulate system of controlled particle size.

16. A process for the production of rapidly dispersing spheroids, characterised in that it comprises the steps of:

providing an active solution or powder;

providing a homogeneous dry process mixture of low-substituted hydroxypropylated cellulose polymer having absorption and adsorption properties compatible with extrusion and spheronization processes, yet allowing dispersion of the carried ingredients by rapid leaching;

wetting the mixture with the active solution or with another liquid, aqueous or non-aqueous;

extruding;

forming spherical bodies by spheronization of the extruded product;

drying;

checking the dry composition size in order to form a spherical multiparticulate system of controlled particle size.

17. A spherical body production method according to claim 15 or 16, characterized in that it further comprises a step of coating the multiparticulate systems with a film.

18. A process for the production of spheroids according to claim 15 or 16, characterised in that the mass of wetting liquid is 3-5 times the mass of hydroxypropylated cellulose polymer used.

19. A method for producing spherical bodies according to claim 15 or 16, wherein the die of the extruder has holes having a hole diameter of 1000 μm and a length of 1000 μm, and the extrusion speed is 100 rpm.

20. A method for producing spherical bodies according to claim 15 or 16, characterized in that the spheronization cycle using a spheronization apparatus with a diameter of 25 cm is a time of 5 minutes at a rotational speed of 1040 revolutions per minute.

21. A method of producing spheroids according to claim 15 or 16, characterised in that the spheroids are dried at a temperature of 30-40 ℃.