WO2016128386A1

WO2016128386A1 - Multiparticulate formulation comprising herbal extracts

Info

Publication number: WO2016128386A1
Application number: PCT/EP2016/052704
Authority: WO
Inventors: Jose VEREEKEN
Original assignee: Vereeken Jose
Priority date: 2015-02-09
Filing date: 2016-02-09
Publication date: 2016-08-18
Also published as: EP3256141A1

Abstract

The present invention relates to multiparticulate formulations comprising herbal extracts, in particular spray-dried herbal extracts, said multiparticulate formulations being prepared by extrusion-spheronization. In particular, said multiparticulate formulations comprise colloidal silicon dioxide at a total concentration of about 1 % w/w to about 5% w/w. Furthermore, the present invention relates to the use of such formulations in human or veterinary medicine as well as methods for preparing such formulations.

Description

MULTIPARTICULATE FORMULATION COMPRISING HERBAL EXTRACTS

FIELD OF THE INVENTION

BACKGROUND TO THE INVENTION

Formulations comprising herbal extracts are frequently used in traditional Chinese medicine and also gain more and more interest in the Western Civilization. For example, Zingiberis, Gentian and/or Matricaria extracts are suitable for use in the treatment of gastro-intestinal complaints/disorders, including flatulence, motion sickness, travel sickness, loss of appetite, ... These extracts are mostly formulated in powder form or tablets, which need to be swallowed with water. However, in case of quickly upcoming nausea or motion sickness, water may not always be available to the patient (eg. while driving a car), and it may thus be difficult to administer such powders or tablets to the patient in need thereof.

Hence, it is advantageous to formulate such herbal extracts in a different form, which can be quickly administered to the patient, even in the absence of water. A possible solution for this problem is to formulate the herbal extracts in a multiparticulate formulation, comprising small particles. These particles can easily be administered to a patient and due to their small size, they can be swallowed without the need of water. Furthermore, such particles can be coated in order to mask the bad taste of the included herbal extracts without the addition of taste masking agents, in contrast to formulations provided in powder form. A multiparticulate formulation comprising ginger extracts is for example known from Deol et al., 2013. Said formulation is prepared by entrapping alginate beads with ginger extracts followed by Eudragit S100 coating. Calcium alginate beads are water-insoluble gelatinous beads prepared by addition of aqueous calcium chloride to aqueous sodium alginate, and they are often used for entrapping macromolecules such as enzymes. However, due to the rather insolubility of these alginate beads, the entrapped active ingredient is only very slowly released (e.g. less than 0% in the first 5 h, see Deol et al). Therefore, this type of formulation is not suitable for use in indications in which a very fast relief of symptoms is desired such as for example in case of nausea or motion sickness. Alternatively, multiparticulate herbal formulations prepared by extrusion-spheronization can be used (e.g. Beringhs et al., 2013 or Araujo-Junior et al., 2013). These formulations in general dissolve much faster and are thus suitable for use in indications in which a very fast relief of symptoms is desired. As evident from these publications, such formulations are generally prepared using freeze-dried or solvent-evaporated herbal extracts as a starting material, followed by mixing said herbal extracts with microcrystalline cellulose and other ingredients. Although, freeze-drying and solvent-evaporation techniques are commonly used on laboratory scale, they have a low potential for industrial use due to high costs for large-scale productions. Hence, other herbal preparation techniques such as spray-drying are preferable in that these are easy to upscale for industrial use.

In that regard, US2003206978 discloses solid dosage forms comprising an active agent, such as a spray dried plant extract; WO03047551 discloses agglomerated particles including spray- dried herbal extract; Soares et al., 2005 discloses tablets comprising spray-dried plant extracts; and WO03048666 discloses spray-drying processes for preparing agglomerated particles containing an herbal extract. However, none of these publications discloses said formulations to be in the form of extrudates, or extrusion-spheronization processes for preparing such formulation. However, it was an object of the present invention to provide a multiparticulate formulation of spray-dried herbal extracts prepared by extrusion- spheronization; i.e. that is in the form of an extrudate. Nevertheless, the inventors found that the mere replacement of freeze-dried or solvent-evaporated extracts by spray-dried extracts in the known formulations resulted in an extrudate with excessive surface irregulaties, commonly referred to as 'sharkskin' which significantly reduced the yield during the spheronisaton step. Hence, the formulations disclosed in these earlier publications were not suitable for the preparation of a multiparticulate formulation of spray-dried herbal extracts prepared by extrusion-spheronization. In contrast, the inventors have surprisingly found that the addition of a small amount of colloidal silicon dioxide (about 1 % w/w to about 5% w/w) to the spray-dried herbal extracts before the extrusion-spheronization step, avoids such shark skiming and significantly increases the yield, thereby resulting in a herbal extract preparation suitable for extrusion-spheronization.

Low amounts of colloidal silicon dioxide (0.1 to 0.5% by weight) are often used in tablets and capsules as a glidant. In contrast, large amounts (up to about 40%) of colloidal silicon dioxide, in combination with a surfactant and/or a plasticizer were used during extrusion-spheronization of a (non-herbal extract) formulation, in order to replace the classically used microcrystalline cellulose as an excipient (WO2008001 140). However, in said instance such large amounts of colloidal silicon dioxide were needed in combination with a surfactant and/or a plasticizer, in order for the formulations to be suitable for extrusion-spheronization. These formulations have the major disadvantage that the total amount of active ingredient to be incorporated in the final product is significantly reduced due to the high amounts of colloidal silicon dioxide.

In contrast, the inventors have now found that the addition of a moderate amount (about 1 % w/w to about 5% w/w) of silicon dioxide, before the extrusion-spheronization process, is very suitable for the preparation of multiparticulates comprising significant amounts of spray-dried herbal extracts, even in the absence of surfactants or plasticizers.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a multiparticulate pharmaceutical dosage form, wherein each particle comprises:

- one or more spray-dried herbal extracts,

- colloidal silicon dioxide (Si0₂),

- an extrusion spheronization aid, and

- a disintegrant

characterized in that said Si0₂ is present at a total concentration of about 1 % w/w to about 5% w/w; and in that the pharmaceutical dosage form is an extrudate. In a particular embodiment, the dosage form according to this invention comprises a combination of at least 2 or more spray-dried herbal extracts.

In another particular embodiment, said spray-dried herbal extracts are selected from the list comprising Zingiberis extracts, Gentian extracts, and Matricaria extracts.

In yet a further embodiment, said extrusion spheronization aid is selected from the list comprising microcrystalline cellulose, celluloses, starch and derivatives thereof, chitosan, K- Carrageenan, pectin ic-acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, and cross-linked PVP.

In yet a further embodiment, said disintegrant is a superdisintegrant selected from the list comprising cross-linked cellulose, cross-linked polyvinylpyrrolidone (PVPP), cross-linked starch or cross-linked alginic acid; more in particular PVPP. In a particular embodiment the dosage form core, (i.e. before application of an optional coating layer), does not contain a surfactant or a plasticizer. ln yet a further embodiment, the dosage form, i.e. the multiparticulates, according to this invention is coated. Said coating is preferably a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.

In a specific embodiment, the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Gentian Extract. In another specific embodiment, the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Matricaria Extract.

In a further aspect, the present invention provides the dosage form according to this invention for use in human or veterinary medicine, more in particular for use in the treatment and/or prevention of gastro-intestinal disorders; such as for example in the treatment and/or prevention of spasmodic gastrointestinal complaints including bloating and flatulence, motion sickness, travel sickness, mild dyspeptic/gastrointestinal disorders, temporary loss of apetite, gastro-intestinal complaints such as minor spasm, or epigastric distension. In yet a further aspect, the present invention provides a method for the preparation of a solid multiparticulate pharmaceutical dosage form according to this invention comprising the steps of:

- preparing a spray-dried formulation of one or more herbal extracts,

- mixing said formulation with about 1 % w/w to about 5% w/w of Si0₂, a spheronization aid and a disintegrant,

- wet granulation of said formulation,

- cold extrusion of said formulation, and

- spheronisation of said formulation to obtain a multiparticulate dosage form

- drying of said multiparticulate dosage form

In a further embodiment, the method according to this invention may further comprise the step of coating said multiparticulate dosage form, with a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers. DETAILED DESCRIPTION OF THE INVENTION

- one or more spray-dried herbal extracts,

- colloidal silicon dioxide (Si0₂),

- an extrusion spheronization aid, and

- a disintegrant

characterized in that said Si0₂ is present at a total concentration of about 1 % w/w to about 5% w/w; and in that the pharmaceutical dosage form is an extrudate.

In the context of the present invention the term 'multiparticulate' is meant to be a plurality of pellets (particles), which are in particular substantially spheroidal. By way of example each particle may have a diameter of from about 0.1 mm to about 5.0 mm, e.g. from about 0.5 mm to about 5.0 mm, in particular from about 0.5 mm to about 2.5mm, more particularly from about 0.5 mm to about 1 .0 mm, more in particular about 0.75 mm. These particles may subsequently be formulated in sachets or capsules for easy dosing and administration.

In the context of the present invention, the multiparticulate pharmaceutical dosage form comprises an agent to facilitate the extrusion spheronization process (i.e. extrusion spheronization aid). Although microcrystalline cellulose (CMC) is the most widely used extrusion spheronization aid, and is also preferred in the formulations according to the invention, other suitable extrusion spheronization aids may also be used such as for example celluloses, starch and derivatives thereof, chitosan, K-Carrageenan, pectinic-acid, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, polyethylene oxide, and cross-linked PVP.

The extrusion/spheronization process in general comprises 5 steps including dry mixing, wet granulation, extrusion, spheronization and drying. First, the materials are dry mixed to achieve a homogeneous powder dispersion and then wet granulated to produce a sufficiently plastic wet mass. The wet mass is extruded to form rod-shaped particles of uniform diameter that are charged into a spheronizer and rounded off into spherical particles. The spherical particles are then dried to achieve the desired moisture content. The resulting end products of such an extrusion/spheronization process according to the present invention, are termed 'extrudates'. Hence, the pharmaceutical dosage form of the present invention is characterized in being an extrudate, by being produced using the described extrusion/spheronization process. ln the context of the present invention, the multiparticulate pharmaceutical dosage form comprises an agent to facilitate disintegration (disintegrant) after administration to the patient. Disintegrants expand when wetted, causing the particles to break apart in the digestive tract, and thereby releasing the active ingredient(s).

In the formulations according to this invention, the disintegrant is preferably a superdisintegrant. These substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. Upon contact with water, superdisintegrants swell, hydrate, change volume or form, and produce a disruptive change in the particles. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs. Superdisintegrants, suitable in the formulations according to this invention, may be selected from the list comprising cross-linked cellulose, cross-linked polyvinylpyrrolidone (PVPP), cross- linked starch or cross-linked alginic acid; more in particular PVPP.

In the context of the present invention, the multiparticulate pharmaceutical dosage form comprises colloidal silicon dioxide (CSD), which is a very fine particulate (colloidal) form of silicon dioxide (Si0₂). Although colloidal silicon dioxide may or may not be used during the preparation of the herbal extracts, it is essential in the context of the present invention, that colloidal silicon dioxide is added to the herbal extracts, before the extrusion-spheronization thereof.

The formulations of the current invention in particular comprise one or more spray-dried herbal extracts. Spray-drying is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. A spray dryer takes a liquid stream and separates the solute or suspension as a solid and the solvent into a vapor. The liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporised. Solids form as moisture quickly leaves the droplets. The solid is usually collected in a drum or cyclone. A nozzle is usually used to make the droplets as small as possible, maximising heat transfer and the rate of water vaporisation. Droplet sizes can range from 10 to 500 μιτι depending on the nozzle. Spray dryers can dry a product very quickly compared to other methods of drying. They also turn a solution, or slurry into a dried powder in a single step, which can be advantageous for profit maximization and process simplification. During the spray-drying process, a carrier can be used such as for example maltodextrin, gum arabic or waxy starch. In the context of the present invention, spray-dried herbal extracts prepared using maltodextrin as a carrier are preferred.

To allow high amounts of active ingredient to be incorporated in the dosage form according to this invention, it preferably does not comprise other ingredients than the ones listed above. In particular, the dosage form according to this invention, preferably does not contain a surfactant or a plasticizer in the core of the particles. Evidently, an optional coating, which does not affect the loading of the active ingredient, may further comprise a surfactant or plasticizer.

In contrast to the (non-herbal extract containing) formulations described in WO2008001 140, we found no need for the presence of high amounts of CSD or the presence of surfactants or plasticizers for suitably formulating spray dried herbal extracts for extrusion spheronization. This difference is most likely due to the type of starting material, and hence the formulations of the current invention are particularly suitable for spray-dried herbal extracts.

As already indicated herein before, the multiparticulates according to this invention may optionally be coated. Such a coating is advantageous in for example masking the bad taste of the herbal extracts. However, and in order to quickly relief a patients' symptoms, this coating is preferably a fast-dissolving coating. Hence, the optional coating is preferably a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.

In a specific embodiment, the spray-dried herbal extracts may be selected from the list comprising Zingiberis extracts, Gentian extracts, and Matricaria extracts. These extracts are generally known to be particularly suitable for treating or relieving the gastro-intestinal disorders or complaints according to this invention. However, any other suitable type of spray- dried herbal extracts may be used in the formulations according to the present invention.

It is also an object of the present invention to provide combinations of herbal extracts. Hence, in a particular embodiment, the dosage form according to this invention may comprises a combination of at least 2 spray-dried herbal extracts, such as for example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 spray-dried herbal extracts.

In a specific embodiment, the dosage form according to this invention comprises a combination of spray-dried Zingiberis Extract and spray-dried Gentian Extract; or a combination of spray-dried Zingiberis Extract and spray-dried Matricaria Extract.

Zingiberis extracts are generally known for the symptomatic treatment of mild, spasmodic gastrointestinal complaints including bloating and flatulence or for the symptomatic relief of motion sickness. Gentian extracts may be used for the symptomatic treatment of mild dyspeptic/gastrointestinal disorders, and/or in temporary loss of appetite. Matricaria extracts may in turn be used for the relief of gastrointestinal complaints such as minor spasm, epigastric distension, or travel sickness. Therefore, in a further aspect, the present invention provides the dosage forms according to this invention for use in human or veterinary medicine, more in particular for use in the treatment and/or prevention of gastro-intestinal disorders; such as for example in the treatment and/or prevention of spasmodic gastrointestinal complaints including bloating and flatulence, motion sickness, travel sickness, mild dyspeptic/gastrointestinal disorders, temporary loss of apetite, gastro-intestinal complaints such as minor spasm, or epigastric distension.

In a further aspect, the present invention provides a method for the preparation of a solid multiparticulate pharmaceutical dosage form (i.e. extrudate) according to this invention comprising the steps of:

- preparing a spray-dried formulation of one or more herbal extracts,

- wet granulation of said formulation,

- cold extrusion of said formulation, and

- spheronisation of said formulation to obtain a multiparticulate dosage form

- drying of said multiparticulate dosage form

In a further embodiment, the method according to this invention may further comprise the step of coating said multiparticulate dosage form, with a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.

EXAMPLES

Materials and Methods

Avicel PH 101 (microcrystalline cellulose), Kollidon XL, Zingiberis spray-dried extract (Zingiberis officinale Roscoe, Roots), Gentian spray-dried extract (Gentiana Lutea L, Roots and Rhizomes), Matricaria Chamomille spray-dried extract (Matricaria ecutita L. , Petals), colloidal silicium dioxide. The spray-dried herbal extracts were prepared using maltodextrin as a carrier for the spray-drying process. Composition of the mixtures:

Preparation of the formulations

Avicel PH 101 , Kollidon XL, the dry extracts and the colloidal silicon dioxide were dry blended in a planetary mixer using a K-shaped arm. Next the water was added (10 g per 100 g for formule 1 and 40 g per 100 g for formule 2). In each case a 1 kg batch was prepared.

Extrusion

- The wet granulated mass was extruded in dome shaped extruder (Fuji Paudale).

- Next the extrudates were processed in a spheronizer (model 15, Caleva Ltd) for 5 minutes at 1000 rpm.

- Next the spheres were air dried (can also be dried at 40-50° C in fluid bed dryer).

- Finally, the dry pellets were coated in a fluid bed coater with Eudragit E dispersion

(Eudragit EPO-Evonik 85,7 g, sodium laurylsulphate 8,6 g , stearic acid 12,9 g , talc 42, 8 g , water 850 g)

- A 20% weight gain was put as target.

Result

Wet granulation of the power blends was impossible without the addition of extra silicon dioxide in the power blend. Without addition of silicon dioxide, the distribution of the granulation liquid (water) is not adequate and the extrudates are of poor quality, and results in shark skining, which in term significantly reduces the yield of pellets during the spheronisaton step.

In contrast, the addition of moderate amounts (1 -5%) of CSD before the extrusion step resulted in extrudates of good quality and a high yield of pellets after the spheronisation step. REFERENCES

Araujo-Junior et al., 2013: Preparation of pellets containing Pothomorphe umbellate extracts by extrusion-spheronization: improvement of 4-nerolidylcatechol photostability. Revista Brasileira de Farmacognosia 23(1 ): Jan/Feb. 2013: 169-174.

Beringhs et al., 2013: Technical development of Cecpropia glaziovi extract pellets by extrusion-spheronization. Revista Brasileira de Farmacognosia 23(1 ): Jan/Feb. 2013: 160- 168.

Deol et al., 2013: Improving the therapeutic efficiency of ginger extract for treatment of colon cancer using a suitably designed multiparticulate system. J. Drug Target; Nov 21 (9) 2013: 855-65. Soares et al., 2005: Dry Granulation and Compression of Spray-Dried Plant Extracts. AAPS PharmSciTech; Oct, 14 2005; 6(3) Art. 45

Claims

1 . A multiparticulate pharmaceutical dosage form, wherein each particle comprises:

- one or more spray-dried herbal extracts,

- colloidal silicon dioxide (Si0₂),

- an extrusion spheronization aid, and

- a disintegrant

2. The dosage form according to claim 1 , comprising a combination of at least 2 or more spray-dried herbal extracts.

3. The dosage form according to anyone of claims 1 or 2, wherein said spray-dried herbal extracts are selected from the list comprising Zingiberis extracts, Gentian extracts, and

Matricaria extracts.

4. The dosage form according to anyone of claims 1 to 3; wherein said extrusion spheronization aid is selected from the list comprising microcrystalline cellulose, celluloses, starch and derivatives thereof, chitosan, K-Carrageenan, pectinic-acid, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyethylene oxide, and cross-linked PVP.

5. The dosage form according to anyone of claims 1 to 4; wherein said disintegrant is a superdisintegrant selected from the list comprising cross-linked cellulose, cross-linked polyvinylpyrrolidone (PVPP), cross-linked starch or cross-linked alginic acid; more in particular PVPP.

6. The dosage form according to anyone of claims 1 to 5; wherein said dosage form does not contain a surfactant or a plasticizer.

7. The dosage form according to anyone of claims 1 to 6; wherein said multiparticulates are coated .

8. The dosage form according to anyone of claims 1 to 7; wherein said multiparticulates are coated with a coating composition selected from the list comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.

9. The dosage form according to anyone of claims 1 to 8 comprising a combination of spray- dried Zingiberis Extract and spray-dried Gentian Extract.

10. The dosage form according to anyone of claims 1 to 8 comprising a combination of spray- dried Zingiberis Extract and spray-dried Matricaria Extract.

1 1 . The dosage form according to anyone of claims 1 to 1 1 for use in human or veterinary medicine.

12. The dosage form according to anyone of claims 9 or 10 for use in the treatment and/or prevention of gastro-intestinal disorders.

13. The dosage form according to anyone of claims 9 or 10 for use in the treatment and/or prevention of spasmodic gastrointestinal complaints including bloating and flatulence, motion sickness, travel sickness, mild dyspeptic/gastrointestinal disorders, temporary loss of apetite, gastro-intestinal complaints such as minor spasm, or epigastric distension.

14. A method for the preparation of a solid multiparticulate pharmaceutical dosage form according to anyone of claims 1 to 13 comprising the steps of:

- preparing a spray-dried formulation of one or more herbal extracts,

- wet granulation of said formulation,

- cold extrusion of said formulation, and

- spheronisation of said formulation to obtain a multiparticulate dosage form

- drying of said multiparticulate dosage form

15. The method according to claim 14 further comprising the step of coating said multiparticulate dosage form, with a coating composition comprising a copolymer of dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate (Eudragit EPO®), hydroxypropylmethyl cellulose, a graft copolymer of PVA and PEG (Kollicoat IR), shellac, ethylcellulose, polyvinylacetate, cellulose-esters and ethers.