Field of Art

The present invention relates to a manufacturing method of oral dosage form containing berberine, enabling easy manipulation and processing, such as dry granulation, homogenization, compression and capsule filling of mixtures containing berberine. The present invention also relates to a composition of a mixture containing berberine, suitable for dry granulation, homogenization, tabletting and capsule filling, as well as to the use thereof.

Background Art

Berberine is a plant isoquinoline alkaloid chemically described as 5,6-dihydro-9,10- dimethoxybenzo[g]-l,3-benzodioxolo[5,6-a]quinolizinium. This compound has a long history of medicinal use in both Chinese and Ayurvedic medicine. Berberine is present in many plants such as Hydrastis canadensis (goldenseal), Coptis chinensis (coptis or goldenthread), Phellodendron, Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree tumeric).

Beberin has broad antibacterial activities. Berberine has been proven to have also other pharmacological effects including blood glucose-lowering, high cholesterol control, hypertension treatment, weight control, heart disease treatment, anti-aging, immune challenges and antiinflammatory properties. Moreover, there is increasing research on the regulation of cancer cell metabolism by berberine hydrochloride. Berberine has been shown to be effective against bacteria, protozoa and fungi.

At present, there are many oral food supplements containing berberine on the market world-wide mostly in form of capsule. As the compound has a short half-life, three times a day is generally recommended to take in oral dosage forms. Commonly recommended dose to take is 500 mg three times a day for a total of 1,500 mg per day.

Different types of oral dosage forms were described in the prior art documents. Generally and most preferably berberine is formulated in solid dosage forms. Oral liquid formulations comprising berberine are described in EP2937077 Al patent application and EP 0227108 A2.

Berberine has some important physical properties which should be taken into account when formulating the dosage forms. The compound extreme bitterness should be masked by inactive ingredients and manufacturing process, e.g. by coating. Other undesirable property is high water content, approximately 14 % (w/w) which makes the manufacturing of dry, physically stable pills difficult, as described in WO 2013063271 Al patent application.

Generally water content both water in the active substance itself and water as a binder added during dosage form manufacturing make formulation very challenging because mixture of berberine and water is strongly sticking on any surfaces of manufacturing equipment. Other undesirable property is very poor flow of the active substance which is connected to very fine particles needed for demanded pharmaceutical effect. Therefore usage of conventional manufacturing method such as direct compression, wet granulation but also dry granulation is very difficult. All the above mentioned disadvantages make the manufacturing process very expensive due to big losses of the material and in some cases technologically even impossible.

Disclosure of the Invention The present invention relates to a manufacturing method of oral solid dosage form containing berberine. The method overcomes manufacturing challenges mentioned in background prior art, i.e. undesirable physical properties of berberine substance such as poor flow properties and sticking problems, which cause severe difficulties during dosage form maufacturing, e.g. direct compression, wet granulation and even dry granulation processes, and therefore great loss of material during the manufacturing process. Surprisingly, it was found that berberine particles, when pre-mixed with a glidant or with a glidant with up to 20 wt % of a filler in the first homogenization step, show significantly improved physical properties such as powder flow and non-sticking behaviour. Using this procedure, berberine particles are covered by the glidant particles which are very small thus have a large surface area in total. A mixture obtained is then easily processed by the above mentioned conventional technology of direct tabletting or dry granulation.

The term "berberine" as used herein includes free berberine and pharmaceutically acceptable salts thereof. The subject of the present invention is a manufacturing method of oral dosage form containing berberine, which contains the following steps:

(i) homogenization of berberine with at least one glidant, the glidant optionally containing up to 20 wt% of a filler, to obtain a homogenous mixture A, wherein the particle size of at least 90 % of all berberine particles is preferably smaller than 500 μπι, more preferably smaller than 50 μπι, most preferably smaller than 10 μπι with mean particle size of c. 5 μπι; Preferably, the glidant specific surface area is in the range of from 100 to 400 m ² /g, more preferably in the range of from 150 to 250 m ² /g.

(ii) homogenization of the homogenous mixture A from step (i) with at least one filler to obtain a homogenous mixture B ;

(iii) homogenization of the product from step (ii) (mixture B) with at least one lubricant to obtain a homogenous mixture C;

(iv) dry granulation and sieving of the homogenous mixture C from step (iii) to obtain a granulated mixture C;

(v) homogenization of the granulated mixture C from step (iv) with at least one disintegrant to obtain a homogenous mixture D;

(vi) preparation of oral dosage form selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules using the homogenized mixture from step (v). Conventional methods are used for oral dosage form preparation in step (vii), and a person skilled in the art would know which method should be used.

Preferably, mixture D from step (v) is homogenized with at least one lubricant to obtain a homogenous mixture E before entering into step (vi).

The resulting homogenous mixture from step (vi) contains preferably from 100 to 1000 mg of berberine, from 2 to 100 mg of a glidant, from 50 to 1000 mg of a filler, from 5 to 70 mg of a lubricant and from 5 to 30 mg of a disintegrant. All ingredient amounts herein and hereafter are calculated per one dosage unit of the final dosage form (e.g. tablet or capsule). In a preferred embodiment, the resulting homogenous mixture from step (vi) contains 500 mg of berberine, 27 mg of a glidant, 332.5 mg of a filler, 22.5 mg of a lubricant and 9 mg of a disintegrant. In the most preferred embodiment, the resulting homogenous mixture from step (vi) contains 500 mg of berberine, 27 mg of colloidal anhydrous silica, 332.5 mg of microcrystalline silicified cellulose, 22.5 mg of magnesium stearate and 9 mg of sodium croscarmellose.

Homogenization

Generally, homogenization processes are used in order to make a homogenous mixture of an active substance and excipients, which would be further suitable for following manufacturing steps such as granulation, compression, encapsulation and others. In the present invention, homogenization comprises several blending steps. The first step is pre-mixing of the active substance (berberine) with a glidant or pre-mixing of the active substance with a glidant and a filler or pre-mixing of the active substance with a glidant, a filler, a lubricant and a disintegrant. Various manufacturing equipment can be used for homogenization process, e.g. low speed blenders. A person skilled in the art would be familiar with conventional homogenization methods. Dry granulation and sieving

Dry granulation process is employed to form granules without using a liquid solution. Homogenized powder mixture is dry granulated using roller compator or tablet press. Powder is squeezed between two rotating rollers to produce a continuous ribbon of materials in case of roller compaction. Powder is filled into the dies and compressed to tablets in case of tablet compression. Compressed material both ribbon or tablet is then milled to get granules with desired particle size. The desired particle size in step (iv) of the present invention corresponds to sieve sizes from 0.5 mm to 3.0 mm. used for milling. Final granules are used for following processing such as homogenization, compression, encapsulation, sachet filling and coating. A person skilled in the art would be familiar with conventional dry granulation and sieving methods.

In one prefered embodiment, the manufacturing method according to the present invention contains berberine and the glidant in step (i) in weight ratio from 500 : 1 to 5 : 1. In one embodiment, the glidant is selected from colloidal anhydrous silica, talc and/or calcium silicate. Preferably, the glidant specific surface area is in the range of from 100 to 400 m ² /g, more preferably in the range of from 150 to 250 m ² /g.

In one embodiment, the filler is selected from microcrystalline silicified cellulose, microcrystalline cellulose, mannitol, sorbitol, lactose, calcium hydrogen phosphate, starch and pregelatinized starch.

In one prefered embodiment, the manufacturing method according to the present invention contains berberine and the filler in step (ii) in weight ratio from 20 : 1 to 1 : 10. In one embodiment, the lubricant is selected from magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, glycerol behenate, glycerol distearate.

In one prefered embodiment, the manufacturing method according to the present invention contains berberine and the lubricant are in weight ratio from 200: 1 to 5 : 1

In one embodiment of the manufacturing method according to the present invention, the dry granulation and sieving in step (iv) takes place using pressure in the range of from 10 bar to 150 bar (corresponding to the range of from 1 MPa to 15 MPa), roller gap in the range of from 0.5 to 5.0 mm and sieve size in the range of from 3.0 to 0.5 mm. In one embodiment, the disintegrant is selected from sodium croscarmellose, croslinked polyvinylpyrrolidon and sodium salt of carboxymethylstarch.

In one embodiment, oral dosage forms from the step (vii) are further coated with a coating material. Preferably, the content of the coating material in the oral dosage form is from 3 to 5 % (w/w), more preferably 4 % (w/w), of the total oral dosage form weight.

The coating materials are preferably selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, PEG (polyethylene glycol of molecular mass in the range of from 400 to 8000), TEG (triethylene glycol), propylenglycol, polyvinylalcohol, poly dextrose, titanium dioxide, talc, maltodextrin, triglycerides, colourants.

In one prefered embodiment, the manufacturing method of oral dosage form containing berberine contains the following steps:

(i) homogenization of 100 to 1000 weight units of berberine with particle size smaller than 50 μπι, preferably 500 weight units of berberine with particle size smaller than 50 μπι, with 2 to 100 weight units of a glidant, preferably from 20 to 35 weight units of a glidant, most preferably the glidant is colloidal anhydrous silica, to obtain a homogenous mixture A;

(ii) homogenization of the homogenous mixture A from step (i) with 50 to 1000 weight units of a filler, preferably from 250 to 500 weight units of a filler, most preferably the filler is silicified microcrystalline cellulose, to obtain a homogenous mixture B ;

(iii) homogenization of the product from step (ii) (mixture B) with 2 to 35 weight units of a lubricant, preferably from 5 to 15 weight units of a lubricant, most preferably the lubricant is magnesium stearate, to obtain a homogenous mixture C;

(iv) dry granulation and sieving of the homogenous mixture C to obtain a granulated mixture C;

(v) homogenization of the granulated mixture C from step (iv) with 5 to 30 weight units of a disintegrant, preferably from 5 to 15 weight units of a disintegrant, most preferably the disintegrant is sodium croscarmellose, to obtain a homogenous mixture D;

(vi) homogenization of the mixture D from step (v) with 2 to 35 weight units of a lubricant, preferably from 5 to 15 weight units of a lubricant, most preferably the lubricant is magnesium stearate, to obtain a homogenous mixture E;

(vii) preparation of oral dosage form selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules using the homogenized mixture from step (vi). The preparation of the above mentioned oral dosage forms includes processing, such as dry granulation, homogenization, compression and capsule filling, obvious to the person skilled in the art. The resulting homogenous mixture from step (vi) contains from 100 to 1000 mg of berberine, from 2 to 100 mg of a glidant, from 50 to 1000 mg of a filler, from 5 to 70 mg of a lubricant and from 5 to 30 mg of a disintegrant. All ingredient amounts herein and hereafter are calculated per one dosage unit of the final dosage form (e.g. tablet or capsule).

The resulting oral dosage forms might be further coated with a coating material selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, PVA (polyvinylalcohol), PEG (polyethylene glycol of molecular mass in the range of from 400 to 8000), TEG (triethylene glycol), propylenglycol, polyvinylalcohol, polydextrose, titanium dioxide, talc, maltodextrin, medium chain triglycerides, colourants. In the most prefered embodiment, the manufacturing method of oral dosage form containing berberine contains the following steps:

(i) homogenization of 500 weight units of berberine with particle size smaller than 50 μπι with 27 weight units of colloidal anhydrous silica, to obtain a homogenous mixture A;

(ii) homogenization of the homogenous mixture A from step (i) with 332.5 weight units of silicified microcrystalline cellulose, to obtain a homogenous mixture B ;

(iii) homogenization of mixture B from step (ii) with 11.25 weight units of magnesium stearate, to obtain a homogenous mixture C;

(iv) dry granulation and sieving of the homogenous mixture C to obtain a granulated mixture C;

(v) homogenization of the granulated mixture C from step (iv) with 9 weight units of sodium croscarmellose, to obtain a homogenous mixture D;

(vi) homogenization of the mixture D from step (v) with 11.25 weight units of magnesium stearate, to obtain a homogenous mixture E;

(vii) preparation of oral dosage form selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules using the homogenized mixture from step (vi). The preparation of the above mentioned oral dosage forms includes processing, such as dry granulation, homogenization, compression and capsule filling, obvious to the person skilled in the art. The resulting homogenous mixture from step (vi) therefore contains 500 mg of berberine, 27 mg of colloidal anhydrous silica, 332.5 mg of silicified microcrystalline cellulose, 22.5 mg of magnesium stearate and 9 mg of sodium croscarmellose. All ingredient amounts herein and hereafter are calculated per one dosage unit of the final dosage form (e.g. tablet or capsule). The resulting oral dosage forms might be further coated with a coating material selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, PEG (polyethylene glycol of molecular mass in the range of from 400 to 8000), TEG (triethylene glycol), propylenglycol, polyvinylalcohol, polydextrose, titanium dioxide, talc, maltodextrin, medium chain triglycerides, colourants. The subject of the present invention is also an oral dosage form containing berberine, which contains from 100 to 1000 mg of berberine (in a form of free berberine and/or a pharmaceutically acceptable salt thereof); from 2 to 100 mg of a glidant, selected from colloidal anhydrous silica, talc and/or calcium silicate; from 50 to 1000 mg of a filler, selected from microcrystalline silicified cellulose, microcrystalline cellulose, mannitol, lactose, starch and pregelatinized starch; from 5 to 70 mg of a lubricant, selected from magnesium stearate, talc, calcium stearate and stearic acid; and from 5 to 30 mg of a disintegrant, selected from sodium croscarmellose, polyvinylpyrrolidon and sodium salt of carboxymethylstarch. The oral dosage form is selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules.

In one prefered embodiment, the oral dosage form of the present invention is obtainable by the manufacturing method of oral dosage form containing berberine of the present invention as described above. In one prefered embodiment, the oral dosage form containing berberine contains 500 mg of berberine (in a form of free berberine and/or a pharmaceutically acceptable salt thereof); 27 mg of a glidant, selected from colloidal anhydrous silica, talc and/or calcium silicate; 332.5 mg of a filler, selected from microcrystalline silicified cellulose, microcrystalline cellulose, mannitol, lactose, starch and pregelatinized starch; 22.50 mg of a lubricant, selected from magnesium stearate, talc, calcium stearate and stearic acid; and 9 mg of a disintegrant, selected from sodium croscarmellose, polyvinylpyrrolidon and sodium salt of carboxymethylstarch. The oral dosage form is selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules.

In the most prefered embodiment, the oral dosage form containing berberine, selected from tablets, coated tablets, pills, orally disintegrating tablets, capsules, powders and/or granules, contains 500 mg of berberine (in a form of free berberine and/or a pharmaceutically acceptable salt thereof); 27 mg of colloidal anhydrous silica; 332.5 mg of microcrystalline silicified cellulose; 22.50 mg of magnesium stearate; and 9 mg of sodium croscarmellose. The subject of the present invention is also the oral dosage form containing berberine according to the present invention for use as a medicament.

The subject of the present invention is also the oral dosage form containing berberine according to the present invention for use in the treatment of metabolic syndrome, diabetes, prediabetes, dyslipidemia, hypertension, non-alcoholic fatty liver disease, obesity, gastrointestinal and other infections, diarrhoea including traveler's diarrhoea, irritable bowel syndrome, inflammatory bowel disease, polycystic ovary syndrome, heart diseases, cancers, neurodegenerative diseases.

The subject of the present invention is also use of the oral dosage form containing berberine according to the present invention as a food supplement, preferably as a food supplement for blood glucose and lipids normalization, blood pressure normalization, weight reduction, normalization of intestinal functions including diarrhoea improvement, modulation of biochemical processes in the body. Examples

The invention is further illustrated by the following examples, which should not be construed as limiting the claimed scope.

Examples 1, 6, 8 and partially 4 and 5 present prefered embodiments of the invention. Examples 2, 3 and 9 do not present embodiments of the present invention, they illustrate inconvenient embodiments in order to compare the present invention with conventional methods used in the state of the art.

Example 1: Preparation of oral dosage form of berberine using dry granulation - roller compaction

The contents of the resulting mixture are described in Table 1.

Example 1 presents an optimal composition and manufacturing process according to the present invention.

Table 1 : Composition of the oral dosage form of berberine according to the present invention

Composition Theory 1 pc (mg) % Function

Berberine 500.00 53.4 Active substance

Cellulose, Silicified Microcrystalline Filler

332.5 35.5

(SMCC 90)

Silica, colloidal anhydrous (Aerosil) 27.00 2.9 Glidant

Croscarmellose sodium 18.00 2.0 Disintegrant

Magnesium stearate 22.50 2.4 Lubricant

Core 900.0

Opadry II 57220037 yellow 36.0 3.8 Coating

Coated tablet 936.00 100.0 Manufacturing process:

The oral dosage form of berberine according to the present invention was prepared as follows:

Sieving: Magnesium stearate through sieve of 0.5 mm

Silica, colloidal anhydrous through sieve of 1.0 mm

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose (homogenized mixture B). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of B and ½ of total amount of magnesium stearate (homogenized mixture C). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (roller compaction) and sieving of the homogenous mixture C from step (iii) to obtain a granulated mixture C.

Compaction process parameters:

Pressuse 30 bar

Roller gap 1.6 mm

Sieves sizes 1.6 mm (1st sieve) + 0.8 mm (2nd sieve)

Homogenization of granules, disintegrant and lubricant

4) Homogenization of granulated mixture C and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a homogenized mixture D)

5) Homogenization of homogenized mixture D and ½ of total amount of magnesium stearate. Low speed blender used at 15 RPM for 5 mins. (homogenized mixture E - final mixture ready for compression). Evaluated parameters of the final mixture are in Table 2.

Compression (Tabletting)

Tablet core parameters: oblong 19 mm x 9 mm. Evaluated parameters of the tablet core are in Table 3.

Tablet press: common rotary tabletting machine.

Coating of tablet cores

Coating equipment: common coater for solid dosage forms such as tablets. Coating : 15% coating suspension Evaluation

Manufacturing process and composition of Example 1 presents the most advantageous and preferable example of the invention. All physical evaluated parameters mentioned below in Tables 2, 3 and 4 are very good.

Table 2: Evaluated parameters of the final homogenized mixture E

Table 3: Evaluated parameters of the final tablet core

Table 4: Evaluation of yield an losses during manufacturing

Yield 95 % and more shows very low sticking or non-sticking problem during manufacture.

Example 2 (not part of the present invention) Preparation of oral dosage form of berberine using wet granulation - high shear

Table 5: Composition of the oral dosage form of berberine according to batch nb. 04-070916

Composition Theory 1 pc (mg) % Function

Berberine 500.00 66.7 Active substance

Croscarmellose sodium 7.50 1.0 Disintegrant

Cellulose, Silicified 26.3 Filler

197.50

Microcrystalline (SMCC 90) Magnesium stearate 20.00 2.7 Lubricant

Povidon 25 7.50 1.0 Granulation aid

Glycerin 7.50 1.0 Granulation aid

Silica, colloidal anhydrous 1.3 Glidant

10.00

(Aerosil)

Weight of core: 750.00 100.0

Manufacturing process:

The oral dosage form of berberine according to batch nb. 04-070916 was prepared as follows:

Wet granulation:

1) mixing berberine and SMCC 90 (mixture A)

2) granulation of mixture A with povidone 25/glycerine/water solution

Evaluation

Mixture containing berberine and excipients was stuck on surfaces of granulation vessel and following manufacturing steps such as drying, sieving, compression and coating were impossible to be done. There was 100% of real losses.

Example 3 (not part of the present invention) Preparation of oral dosage form of berberine using wet granulation - high shear with higher amount of glidant

Table 6: Composition of the oral dosage form of berberine according to batch nb. 06-200916

Manufacturing process:

The oral dosage form of berberine according to batch nb. 06-200916 was prepared as follows: Wet granulation

1) mixing berberine and SMCC 90 and silica (mixture A)

2) granulation of mixture A with povidone 25/glycerine/water solution

Evaluation

Mixture containing berberine and excipients was stuck on surfaces of granulation vessel and following manufacturing steps such as drying, sieving, compression and coating were impossible to be done. There was 100% of real losses.

Example 4 (not part of the present invention) Preparation of oral dosage form of berberine using of direct compressing of homogenous mixture

Table 7: Composition of the oral dosage form of berberine according to batch nb. 07-200916

Manufacturing process:

The oral dosage form of berberine according to batch nb. 07-200916 was prepared as follows:

Sieving: Silica, colloidal anhydrous through sieve of 1.0 mm

magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm)

Homogenization of starting materials for briquttes:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose and croscarmellose sodium (homogenized mixture A with filler and disintegrant). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of previous mixture and magnesium stearate (final mixture). Low speed blender used at 15 RPM for 5 mins. Compression (Tabletting)

Tablet core parameters: oblong 20 mm x 10 mm. Evaluated parameters of the tablet core are in Table 9.

Tablet press: common rotary tabletting machine.

Evaluation

Low content of the disintegrant is responsible for poor material flow and corresponding insufficient dosing of the mixture into dies of tabletting machine. The final tablet shape (oblong 20x10 mm) is quite big for patient compliance. On the other hand all other physical evaluated parameters mentioned below in Tables 8 and 9 are acceptable.

Table 8: Evaluated parameters of the final homogenized mixture C

Table 9 Evaluated parameters of the final tablet core

Table 10: Evaluation of yield an losses during manufacturing

Yield 95 % and more shows very low sticking or non-sticking problem during manufacture. Example 5 (not part of the present invention) Preparation of oral dosage form of berberine by dry granulation using tablet press

Table 11 : Content of the oral dosage form of berberine according to batch nb. 11-071016 Composition Theory 1 pc (mg) % Function

Berberine 500.00 55.5 Active substance

Cellulose, Silicified Microcrystalline 38.0 Filler

341.50

(SMCC 90)

Silica, colloidal anhydrous (Aerosil) 27.00 3.0 Glidant

Croscarmellose sodium 9.00 1.0 Disintegrant

Magnesium stearate 22.50 2.5 Lubricant

Weight of core: 900.00 100.0

Manufacturing process:

The oral dosage form of berberine according to batch nb. 11-071016 was prepared as follows:

Sieving: Silica, colloidal anhydrous through sieve of 1.0 mm

magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm)

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose and croscarmellose sodium (homogenized mixture for next step). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of previously obtained mixture and ½ of total amount of magnesium stearate (homogenized mixture D). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (by tablet press)

Briquette/tablet parameters: round flat shape , diameter 12 mm, hardness 100N Briquette/tablet press: common rotary tabletting machine.

Milling of briquettes/tablets to obtain granulated mixture D

Through grater sieve of 1.5 mm

Homogenization of sieved mixture D, disintegrant and lubricant 4) Homogenization of screened mixture D and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a homogenized mixture D with disintegrant)

5) Homogenization of homogenized mixture D with disintegrant and ½ of total amount of magnesium stearate. Low speed blender used at 15 RPM for 5 mins. (homogenized mixture E - final mixture ready for compression). Evaluated parameters of the final mixture are in Table 12.

Compression (Tabletting) of mixture E

Tablet core parameters : oblong 20x10 mm. Evaluated parameters of tablet cores are in table 13.

Tablet press: common rotary tabletting machine.

Coating of tablet cores:

Coating equipment: common coater for solid dosage forms such as tablets. Coating : 15% coating suspension

Evaluation

Manufacturing process and composition of Example 5 present time-consuming process. Because of a poor flow the mixture before dry granulation needs to be filled into the tabletting machine manually. This final tablet shape (oblong 20x10 mm) is quite big for patient compliance. On the other hand all other physical evaluated parameters mentioned below in Tables 12and 13 are acceptable.

Table 12: Evaluated parameters of the final homogenized mixture E (after dry granulation)

Physical tests of final mixture E batch 11-071116

Bulk density 0.6116 g/ml

Flow angle 85.0°

Flowability 11.46 g/s

Table 13: Evaluated parameters of the final tablet cores

Physical tests of cores batch 11-071116

Weight 899.5 mg

Friability 0.13 %

Hardness 131 N

Shape 20x10 mm Table 14: Evaluation of yield an losses during manufacturing

Yield 95 % and more shows very low sticking or non-sticking problem during manufacture. Example 6 Preparation of oral dosage form of berberine by dry granulation - roller compaction of mixture containing low amount of silica colloidal anhydrous

Table 15: Composition of the oral dosage form of berberine according to batch nb. 15-160517

Manufacturing process:

The oral dosage form of berberine according to batch nb. 15-160517 was prepared as follows:

Sieving: Silica, colloidal anhydrous through sieve of 1.0 mm

magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm)

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose (homogenized mixture B). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of B and ½ of total amount of magnesium stearate (homogenized mixture C). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (roller compaction) and sieving of the homogenous mixture C from step 3 to obtain a granulated mixture C.

Compaction process parameters:

Pressuse 30 bar

Roller gap 1.6 mm

Sieves sizes 1.6 mm (1st sieve) + 0.8 mm (2nd sieve)

Homogenization of granules, disintegrant and lubricant

4) Homogenization of granulated mixture C and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a homogenized mixture D) 5) Homogenization of homogenized mixture D and ½ of total amount of magnesium stearate. Low speed blender used at 15 RPM for 5 mins. (homogenized mixture E - final mixture ready for compression). Evaluated parameters of the final mixture are in Table 16. Compression (Tabletting)

Tablet core parameters: oblong 19 mm x 9 mm. Evaluated parameters of the tablet core are in Table 17.

Tablet press: common rotary tabletting machine. Evaluation

Technological test of low amount of silica colloidal anhydrous in the mixture to show for patent variability. All physical evaluated parameters mentioned below in Tables 16 and 17 are acceptable.

Table 16: Evaluated parameters of the final homogenized mixture E

Physical tests of final mixture E batch 15-160517

Bulk density 0.5935 g/ml

Flow angle 84.90°

Flowability 11.13 g/s

Table 17: Evaluated parameters of the final tablet cores

Physical tests of cores batch 15-160517

Weight 881.1 mg

Friability 0.0 %

Hardness 125 N

Shape 19x9 mm Table 18: Evaluation of yield an losses during manufacturing

Yield 95 % and more shows very low sticking or non-sticking problem during manufacture.

Example 7 Preparation of oral dosage form of berberine by dry granulation - roller compaction - high hydraulic pressure during compaction

Table 19: Composition of the oral dosage form of berberine according to batch nb. 16-160517/A

Manufacturing process:

The oral dosage form of berberine according to batch nb. 16-160517/A was prepared as follows:

Sieving: Silica, colloidal anhydrous through sieve of 1.0 mm

magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm)

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose (homogenized mixture B). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of B and ½ of total amount of magnesium stearate (homogenized mixture C). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (roller compaction) and sieving of the homogenous mixture C from step 3) to obtain a granulated mixture C. Compaction process parameters:

Pressuse 100 bar

Roller gap 1.6 mm

Sieves sizes 1.6 mm (1st sieve) + 0.8 mm (2nd sieve)

Homogenization of granules, disintegrant and lubricant

4) Homogenization of granulated mixture C and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a homogenized mixture D)

5) Homogenization of homogenized mixture D and ½ of total amount of magnesium stearate. Low speed blender used at 15 RPM for 5 mins. (homogenized mixture E - final mixture ready for compression). Evaluated parameters of the final mixture are in Table 20.

Compression (Tabletting)

Tablet core parameters: oblong 19 mm x 9 mm. Evaluated parameters of the tablet core are in Table 21.

Tablet press: common rotary tabletting machine.

Evaluation

Due to a high hydraulic pressure during roller compaction, compressibility of material is exhausted and is insufficient for tablet core production. Tablet cores have very low hardness and high friability. All physical evaluated parameters are mentioned below in Tables 20 and 21.

Table 20: Evaluated parameters of the final homogenized mixture E

Physical tests of final mixture E batch 16-1605111 A

Bulk density 0.6849 g/ml

Flow angle 86.60°

Flowability 16.60 g/s

Table 21 : Evaluated parameters of the final tablet cores

Physical tests of cores batch 16-160517/A

Weight 909.2 mg

Friability 4.1 %

Hardness 41 N

Shape 19x9 mm Table 22: Evaluation of yield an losses during manufacturing

Yield 95 % and more shows very low sticking or non-sticking problem during manufacture.

Example 8 Preparation of oral dosage form of berberine by dry granulation - roller compaction - low amount of lubricant

Table 23: Contents of the oral dosage form of berberine according to batch nb. 16-160517/B

Manufacturing process:

The oral dosage form of berberine according to batch nb. 16-160517/B was prepared as follows:

Sieving: Silica, colloidal anhydrous through sieve of 1.0 mm

magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and silica, (homogenized mixture A).

Low speed blender used at 15 RPM for 10 mins.

2) Homogenization of A and silicified microcrystalline cellulose (homogenized mixture B). Low speed blender used at 15 RPM for 10 mins.

3) Homogenization of B and ½ of total amount of magnesium stearate (homogenized mixture C). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (roller compaction) and sieving of the homogenous mixture C from step 3 to obtain a granulated mixture C. Compaction process parameters:

Pressuse 30 bar

Roller gap 1.6 mm

Sieves sizes 1.6 mm (1st sieve) + 0.8 mm (2nd sieve)

Homogenization of granules, disintegrant and lubricant

4) Homogenization of granulated mixture C and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a final mixture D)

Evaluated parameters of the final mixture are in Table 24.

Compression (Tabletting)

Tablet core parameters: oblong 19 mm x 9 mm. Evaluated parameters of the tablet core are in Table 25.

Tablet press: common rotary tabletting machine.

Evaluation

Technological test of low amount of magnesium stearate for patent variability. All physical evaluated parameters are mentioned below in Tables 24 and 25.

Table 24: Evaluated parameters of the final homogenized mixture D

Physical tests of final mixture D batch 16-160517/B

Bulk density 0.6116 g/ml

Flow angle 84.90°

Flowability 11.24 g/s

Table 25: Evaluated parameters of the final tablet cores

Physical tests of cores batch 16-160517/B

Weight 891.4 mg

Friability 0.0 %

Hardness 121 N

Shape 19x9 mm

Table 26: Evaluation of yield an losses during manufacturing

Evaluation of yield an losses during Real yield Real losses manufacturing (% w/w of theoretical 100% yield) (% w/w)

Yield of final mixture manufacturing* 95 % 5 %

Yield of tablet cores manufacturing* 95 % 5 % *Yield 95 % and more shows very low sticking or complete removal of the sticking problem during manufacture.

Example 9 (comparative example) Preparation of oral dosage form of berberine by dry granulation - roller compaction - composition without gtidant (silica)

Table 27: Composition of the oral dosage form of berberine according to batch nb. 17-220517

Manufacturing process:

The oral dosage form of berberine according to batch nb. 17-220517 was prepared as follows:

Sieving: magnesium stearate through sieve of 0.5 mm

(all other ingredients if needed through sieve 1.0 mm)

Homogenization of starting materials:

1) Homogenization (pre-mixing) of berberine and microcrystalline cellulose (homogenized mixture A). Low speed blender used at 15 RPM for 15 mins.

2) Homogenization of A and ½ of total amount of magnesium stearate (homogenized mixture B). Low speed blender used at 15 RPM for 5 mins.

Dry granulation (roller compaction) and sieving of the homogenous mixture B from step 2 to obtain a granulated mixture C.

Compaction process parameters:

Pressuse 30 bar

Roller gap 1.6 mm

Sieves sizes 1.6 mm (1st sieve) + 0.8 mm (2nd sieve)

Homogenization of granules, disintegrant and lubricant 3) Homogenization of granulated mixture C and croscarmellose sodium. Low speed blender used at 15 RPM for 10 mins. (resulting in a homogenized mixture D)

4) Homogenization of homogenized mixture D and ½ of total amount of magnesium stearate. Low speed blender used at 15 RPM for 5 mins. (homogenized mixture E - final mixture ready for compression). Evaluated parameters of the final mixture are in Table 28.

Compression (Tabletting)

Tablet core parameters: oblong 19 mm x 9 mm. Evaluated parameters of the tablet core are in Table 29.

Tablet press: common rotary tabletting machine.

Evaluation

This technological test contains no glidant and MCC without silica as a filler. Homogenised mixture B has a very poor flow quality. Dry granulated mixture C could not be prepared without manually added mixture into the dies of tablet press. All physical evaluated parameters are mentioned below in Tables 28 and 29.

Table 28: Evaluated parameters of the final homogenized mixture D

Physical tests of final mixture D batch 17-220517

Bulk density 0.5747 g/ml

Flow angle 84.70°

Flowability 10.87 g/s

Table 29: Evaluated parameters of the final tablet cores

Physical tests of cores batch 17-220517

Weight 904.2 mg

Friability 0.0 %

Hardness 144 N

Shape 19x9 mm

Table 30: Evaluation of yield an losses during manufacturing

Evaluation of yield an losses during Real yield Real losses manufacturing (% w/w of theoretical 100% yield) (% w/w)

Yield of final mixture manufacturing* 88 % 12 %

Yield of tablet cores manufacturing* 94 % 6 % *Yield 95 % and more shows very low sticking or removal of the sticking problem during manufacture.

Tablet cores can be prepred only by manually added mixture into the dies of tablet press. For commercial production this process is not feasible.