WO2018219369A1

WO2018219369A1 - A dosage unit with ppis (proton pump inhibitors)

Info

Publication number: WO2018219369A1
Application number: PCT/CZ2018/000025
Authority: WO
Inventors: Katarina PUCHLA; Pavel Sebek
Original assignee: Zentiva, K.S.
Priority date: 2017-06-02
Filing date: 2018-05-30
Publication date: 2018-12-06
Also published as: EP3630075A1; CZ2017315A3

Abstract

The present invention relates to a dosage unit with the active ingredient PPI in a quantity of 15 to 85% by weight. In this case, the active ingredient is processed with at least one pharmaceutically acceptable substance into the form of a pellet that is provided with insulating and acid resistant coating. The active ingredient is selected from the group comprising lansoprazole, pantoprazole, racemic omeprazole or one of its enantiomers.

Description

A dosage unit with PPIs (proton pump inhibitors) Background Art Many literary data deal with pharmaceutical formulations of PPIs as omeprazole or lansoprazole.

So e.g. the publication EP247983A, in Example 2, describes preparation of a pharmaceutical formulation of omeprazole in capsules. First, pellets with the active ingredient omeprazole based on the filler mannitol are prepared by extrusion and spheronization. These pellets are further coated twice, namely with an insulating and then an acid resistant layer. Then, capsules are filled with these pellets. Every capsule was filled with 225 mg of these pellets with the content of 20 mg of the active ingredient omeprazole. Thus, the matter contained in a capsule (capsule matter) contained approx. 8.88% of omeprazole.

Another publication, WO9501783, in Example 4, describes a similar formulation where the active ingredient omeprazole magnesium salt is comprised in a mannitol-based pellet. The pellets are filled into a capsule. The filling of the capsule comprises approx. 9.4% of the magnesium salt of omeprazole. In another publication, EP277741 A, in Example 2, neutral pellets are coated with the active ingredient, lansoprazole. On the layer with the active ingredient, an insulating layer is applied and then an acid resistant layer. The pellets are filled into capsules. The content of lansoprazole in the capsuled matter is approx. 7.11%. In the publication EP1010423, in Example 1, neutral pellets were coated with lansoprazole and subsequently with a layer comprising acid resistant coating. The content of lansoprazole in the pellets was approx. 6.5%.

In all the described examples with capsules that are filled with pellets with acid resistant coating, the filling of the capsule comprises less than 10% of the active ingredient, i.e. more than 90% of inactive excipients. Naturally, this limits the performance and consequently the capacity of the equipment and leads to high production costs. The production equipment must process a ten times higher quantity of matter to achieve the required quantity of the active ingredient. Thus, increasing the capacity of the production equipment represents a problem.

It is true that pellets with a higher quantity of the active ingredient have also been described. However they were not filled into capsules, but tablets were made from them (called MUPS). However, tabletting of ready-made pellets required addition of other excipients.

In Example 1 of EP 723436, pellets were prepared comprising 15.9% of omeprazole Mg salt. Before tabletting, 200 g of these pellets were mixed with 299 g of microcrystalline cellulose and 1.2 g of sodium lauryl sulphate. Thus, the final tablet only contains 6.36% of the active ingredient. Similarly, in Example 3, the produced pellets are further mixed with microcrystalline cellulose (no weight ratios are mentioned). In Example 1 of EP 723437, pellets with acid resistant coating are prepared containing 21% of lansoprazole. However, before tabletting, 82 g of these pellets are mixed with 191 g of microcrystalline cellulose. It means that the final tablet only contains 6.3% of the active ingredient.

Other excipients are added to the pellets to ensure flow properties. However, in a similar way, flow properties of pellets designed for further processing must also be provided. The higher the concentration of the active ingredient in pellets is, the fewer pellets are inserted into one dosage form as e.g. capsules or tablets, and the bigger problems related to uneven weight can be expected. This results in deviations of the contents and uniformity of the content of the active ingredient in the filling of a capsule or tablet.

The present invention provides tablets that can be loaded into a capsule or tablet even with a high content of the active ingredient, by addition of a minimal quantity of excipients. This makes it possible to produce pellets with a PPI content of 15 to 85%, which will significantly increase the production capacity of the equipment. Pellets with a PPI concentration of 15 to 85% can be filled into capsules of a small size, which will at the same time contribute to better compliance of the patient.

Disclosure of the Invention

Description of principal features

The invention provides a dosage unit with the active ingredient PPI in a quantity of 15 to 85%. More specifically the PPI can be loaded between 20 to 40% or still more specifically between 28 to 38%. Other embodiments of the invention constitute the loading 40 to 66% or 45 to 55%.

According to the invention, the active ingredient is processed with at least one pharmaceutically acceptable substance into the form of a pellet that is provided with insulating and acid resistant coating.

In a preferred embodiment, the ratio of the acid resistant coating to the pellet core comprising the active ingredient coated with an insulating layer is 1:1 to 1:5

Another aspect of the invention is a preparation method of the concerned dosage form consisting in coating of a neutral core with a layer of the active ingredient in connection with a suitable binder. Coating of the layer with the active ingredient with an inert polymer, and subsequently it is coated with an acid resistant layer. This acid resistant coating can be possibly coated with another neutral layer. To improve the flow properties, the pellet can be further dusted with a suitable glidant.

It is further the size of a pellet that is important for the inventive solution. It varies in the range from 0.2 to 2 mm. To achieve a high concentration of PPI, small pellets are more convenient, i.e. approx. 0.3 to 0.6 mm. The number of the pellets in the dosing unit according to the invention should vary between 200 to 600 or 200 to 450. Detailed description of the Invention

Definitions

PPI is the abbreviation of a Protone Pump Inhibitor. These are well-known drugs used to treat stomach disorders related to its over-acidification. These substances are used e.g. to treat peptic ulcers or gastroesophageal reflux. These substances comprise racemic omeprazole or its enantiomer, lansoprazole, pantoprazole or rabeprazole.

Unless otherwise specified, all the percentages refer to weight, i.e. ratios are specified as percent by weight.

The term dosage unit refers to a part of the product that comprises a quantity of the active ingredient intended for one dose, each dosage unit being separated from the others. In this example, dosage unit are mainly represented by tablets or capsules.

According to the invention, these dosage units consist of individual pellets. The most preferred dosage unit with the active ingredient PPI according to the invention is in the form of pellets that are filled into hard gelatin capsules or are used for the preparation of tablets.

The pellets consist of:

a) a core comprising the active ingredient, PPI

b) a separating layer

c) an enteric layer

d) a possible outer surface protecting layer Tablets made of enteric-coated pellets consisting of:

a) a core comprising the active ingredient, PPI

b) a separating layer

c) an enteric layer

d) an outer surface protecting layer

Pellets according to the invention

l. CORE

The core is prepared by application of a layer of the active ingredient PPI on inert particles of starch, sucrose or other pharmaceutically acceptable substances as e.g. microcrystalline cellulose, or is prepared by extrusion and spheronization. The size of particles comprising PPI may be in the range of 0.2 to 2.0 mm.

The application of the layer of the active ingredient from a solution or suspension onto inert particles is carried out in a fluidized bed apparatus with the use of water and/or organic solvents.

Besides the active ingredient PPI, the active layer also comprises other ingredients from the group of stabilizers, fillers, disintegrants, binders, solubilizers or other pharmaceutically acceptable excipients.

If extrusion is used, a mixture of the active ingredient and ingredients from the group of stabilizers, fillers, disintegrants, binders, solubilizers or other pharmaceutically acceptable excipients enters an extruder.

A polymer based on polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC) is used as the binder. 2. INSULATING LAYER

The core containing PPI must be insulated from the enteric layer comprising free carboxylic groups. Otherwise, PPI might get degraded during the spraying and/or storage period.

The insulating layer comprises a polymer based on polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, or possibly other excipients as plasticizers, colorants, pigments, fillers, glidants.

The insulating layer is applied onto the core containing the active ingredient in a fluidized bed apparatus with the use of water and/or organic solvents. 3. ENTERIC LAYER

One or more polymers from the group of copolymers of methacrylic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate or other polymers suitable for the preparation of an acid resistant layer can be used for the preparation of the enteric layer.

To achieve the desired mechanical properties of the film as elasticity and strength, the ehterosolvent layer can comprise plasticizers: triacetin, citric acid esters, dibutyl sebacate, polyethylene glycols, polysorbates, or possible other ingredients as colorants, pigments, or ahti-foaming agents. The quantity of the plasticizer usually amounts to 10 - 50% of the weight of the polymer.

The enteric layer is applied onto the core containing PPI coated with the separating layer in a fluidized bed apparatus with the use of water and/or organic solvents.

4. OUTER SURFACE PROTECTING LAYER

One or more outer protecting layers can be applied onto the enteric-coated pellets. The outer protecting layer is applied onto the enteric-coated pellets in a fluidized bed apparatus with the use of water and/or organic solvents.

The outer protecting layer comprises a polymer based on polyvinyl alcohol (PVA), HPMC or HPC, or possibly other excipients as plasticizers, colorants, pigments, fillers, glidants.

The outer protecting layer can protect the enteric layer from cracking during the tabletting of the pellets. To achieve the desired mechanical properties, mainly elasticity and strength, the outer protecting layer comprises pharmaceutically acceptable plasticizers as triacetin, citric acid ester, dibutyl sebacate, polyethylene glycols, polysorbates, cetyl alcohol, stearyl alcohol and others. The quantity of the plasticizer usually represents 10 - 50% of the weight of the material forming the outer layer. Capsules according to the invention

These are hard capsules, usually made of gelatin. If necessary, the capsules may consist of another polymer, e.g. hydroxypropyl methyleellulose (HPMC). For the invention, commercially available capsules of size 5 to 0 can be used.

Tablets according to the invention

According to the invention, the enteric-coated pellets can be used for the preparation of tablets.

For this purpose, enteric-coated tablets comprising an outer protective layer are compressed into tablets together with excipients from a group comprising fillers, binders, disintegrants, glidants and other pharmaceutically acceptable excipients.

A tablet comprises:

a) enteric-coated pellets containing PPI

b) a mixture of at least two fillers or possibly another pharmaceutically acceptable excipient According to the invention, a tablet comprises enteric-coated tablets compressed together with at least two fillers, which differ from each other by the particle size and are smaller than the size of the enteric-coated pellets, most preferably, one of the fillers is 2x smaller than the size of the enteric-coated pellets.

The size of the enteric-coated pellets can be 200 - 2000 μηι, more preferably 500 - 1000 μπι. According to the invention, a tablet comprises 70 - 30% by weight of tabletting ingredients as fillers, glidants and anti-adhesive agents and/or disintegrants and or plasticizers.

According to the invention, a tablet comprises enteric-coated tablets compressed together with at least two fillers, which differ from each other by the particle size and are smaller than the size of the enteric-coated pellets.

According to the invention, a tablet comprises two fillers having a different particle size where at least one of them is a filler with a bigger particle size and at least one of them is a filler with a smaller particle size.

According to the invention, the particles of the filler with a bigger particle size are 1-20 times smaller, preferably 2.5- 10 times smaller than the size of the enteric-coated tablets.

According to the invention, the particles of the filler with a smaller particle size are 4-100 times smaller, preferably 10-50 times smaller than the size of the enteric-coated tablets. The quantity of the filler with a bigger particle size is in a ratio to the total quantity of the tabletting ingredients in the tablet of approx. 39-80% by weight. The quantity of the filler with a smaller particle size is in a ratio to the total quantity of the tabletting ingredients in the tablet of approx. 19-60% by weight.

According to the invention, the filler used for the preparation of tablets can be microcrystalline cellulose, lactose, sucrose, polyalcohols, calcium monohydrogen phosphate dihydrate, anhydrous calcium phosphate, calcium phosphate or other available fillers suitable for direct compression.

According to the invention, the filler with a bigger particle size is preferably a filler with a particle size in the range of 100 - 200 μιη. According to the invention, the filler with a bigger particle size is preferably microcrystalline cellulose with a particle size in the range of 100 - 200 μιη.

According to the invention, the tablet may contain disintegrants in a quantity of 0 - 5% of the total quantity of the tabletting ingredients, glidants and anti-adhesive substances in a quantity of 0.5 - 2% of the total quantity of the tabletting ingredients and plasticizers in a quantity of 0 - 20% of the total quantity of tabletting ingredients.

According to the invention, magnesium stearate, stearic acid, calcium stearate and others can be used in the tablet as the glidant / lubricant, most preferably magnesium stearate and sodium stearyl fumarate.

According to the invention, the tablets are prepared by mixing of enteric-coated tablets containing omeprazole and/or its salts, fillers, or possibly disintegrant, glidant and other tabletting ingredients and by being compressed on a rotary tabletting press.

The diameter of the pellets varies in the range of 0.2 to 2 mm, more preferably from 0.3 to 0.6 mm.

In one of embodiments of the invention, the pellets consist of a neutral core with several coating layers one of which comprises the active ingredients. The neutral core may consist of sucrose and a suitable binder as e.g. PVP, HPMC, HPC. The size of the neutral core may be in the range of 0.1 - 1.5 mm, preferably 0.2 - 0.4 mm.

The first principal problem of the design of the pellet according to the invention is the coating comprising the active ingredient. The coating must be designed in such a way to comprise up to 90% of the active ingredient. For this purpose, a binder is selected that can be based on polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC).

The insulating layer must meet the requirements for being completely inert with respect to the active ingredient. This holds good especially for high concentrations of the active ingredient when higher sensitivity to this selection can be expected. The acid resistant layer comprises the acid resistant polymer itself on the one hand, and it may further comprise a softener that should ensure its elasticity. The weight proportion of the acid resistant coating with respect to the whole pellet is selected in such a way to maintain the same dissolution properties as in the case of a lower content of the active ingredient. The selection of a suitable composition and quantity of the acid resistant coating is another principal problem solved by the present invention.

Another optional neutral layer can further improve the mechanical characteristics of the pellet. It is selected in such a way as not to affect the dissolution rate of the active ingredient on the one hand and to improve the mechanical and flow characteristics of the pellets on the other hand.

A specific embodiment of the invention might be defined as a dosing unit containing a PPI as an active ingredient in the amount of 20 to 40% (w/w) in the form of pellets, which are present in the amount of 200 to 600.

A high loaded dosing unit with the PPI amount of 40 to 66% (w/w) or preferably 45 to 55% (w/w)

Method

The production method of the pellets is based on preparation of the pellets by:

a) applying multiple layers in a fluidized bed apparatus onto a neutral core

i) active layer

ii) insulating layer

iii) enteric layer

iv) optional protecting layer b) applying multiple layers in a fluidized bed apparatus onto pellets comprising the active ingredient prepared by extrusion and spheronization

i) insulating layer

ii) enteric layer

iii) optional protecting layer

The dosing unit according to the invention enables better use of manufacturing capacity, using a smaller dosing unit and thus improving the patient's compliance. But surprisingly, the dosing unit exhibits considerable better chemical stability, that the known one. The total amount of impurities formed in the dosage unit can be smaller than the disregard limit, which is 0.05%. The exceptional product stability enables to use a cheaper packaging; the dosing unit does not need the packaging which would be completely isolated from atmosphere.

Examples

Example 1

Lansoprazole

A suspension of the active ingredient is prepared from lansoprazole, HPMC, talc, polysorbate 80 and purified water. The suspension prepared this way is layered onto neutral sugar pellets in a fluidized bed apparatus with the use of the "bottom spray technique". An insulating layer comprising HPC, talc and magnesium stearate is applied onto dried pellets with a layer of the active ingredient in a fluidized bed apparatus with the use of the "bottom spray technique"

An enteric layer in the form of a suspension prepared from the copolymer of methacrylic acid and ethyl acrylate (Eudragit L-30 D-55), triethyl citrate, glycerol monostearate, polysorbate 80 and purified water is applied onto dried pellets with the insulating layer in a fluidized bed apparatus with the use of the "bottom spray technique". The spraying is followed by drying in the same equipment. Example 2

Esomeprazole

Ingredient Quantitative Quantitative

composition per layer composition per capsule

Core

Magnesium esomeprazole 64.7% 44.6%

Sugar pellets 18.9% 13.0%

Hydroxypropyl methylcellulose 14.5% 10.0%

Talc 1.1% 0.75%

Polysorbate 80 0.9% 0.6%

Insulating layer

Core with a layer of the active ingredient 86.5% -

Hydroxypropyl cellulose 6.3% 5.0%

Talc 6.3% 5.0%

Magnesium stearate 0.9% 0.75%

Enteric layer

Pellets with an insulating layer 79.7% -

Copolymer of methacrylic acid and ethyl 18.0% 18.0%

acrylate

Triethyl citrate 1.8% 1.8%

Glycerol monostearate 0.3% 0.3%

Polysorbate 80 0.2% 0.2% A suspension of the active ingredient is prepared from magnesium esomeprazole, HPMC, talc, polysorbate 80 and purified water. The suspension prepared this way is layered onto neutral sugar pellets in a fluidized bed apparatus with the use of the "bottom spray technique". An insulating layer comprising HPC, talc and magnesium stearate is applied onto dried pellets with a layer of the active ingredient in a fluidized bed apparatus with the use of the "bottom spray technique"

An enteric layer in the form of a suspension prepared from the copolymer of methacrylic acid and ethyl acrylate (Eudragit L-30 D-55), triethyl citrate, glycerol monostearate, polysorbate 80 and purified water is applied onto dried pellets with the insulating layer in a fluidized bed apparatus with the use of the "bottom spray technique". The spraying is followed by drying in the same equipment

Example 3

Omeprazole (racemate)

Ingredient Quantitative Quantitative

composition per layer composition per capsule

Core

Omeprazole 75.0% 50.0%

Mannitol 15.0% 10.0%

Disodium phosphate 5.6% 3.75%

Hydroxypropyl methylcellulose 3.8% 2.5%

Polysorbate 80 0.6% 0.375%

Insulating layer

Core with a layer of the active ingredient 87.6% -

Hydroxypropyl cellulose 5.8% 4.375%

Talc 5.8% 4.375%

Magnesium stearate 0.8% 0.625%

Enteric layer

Pellets with an insulating layer 76.0% -

Copolymer of methacrylic acid and ethyl 21.2% 21.25% aery late

Triethyl citrate 2.1% 2.125%

Glycerol monostearate 0.4% 0.375%

Polysorbate 80 0.3% 0.25%

The pellets are prepared by wet granulation of a dry mixture, spheronization of the granulated matter and coating of the pellet cores with an insulating and enteric layer.

A mixture of omeprazole, mannitol, disodium phosphate, hydroxypropyl methylcellulose and polysorbate 80 is moistened with water in a high-speed granulator. The wet mixture is extruded through a perforated opening of the extruder and subsequently spheronized. The prepared pellets containing omeprazole are dried in a fluid drier.

An insulating layer comprising HPC, talc and magnesium stearate is applied onto the dried pellets comprising omeprazole in a fluidized bed apparatus with the use of the "bottom spray technique".

An enteric layer in the form of a suspension prepared from the copolymer of methacrylic acid and ethyl acrylate (Eudragit L-30 D-55), triethyl citrate, glycerol monostearate, polysorbate 80 and purified water is applied onto dried pellets with the insulating layer in a fluidized bed apparatus with the use of the "bottom spray technique". The spraying is followed by drying in the same equipment.

Example 4

Esomeprazole delayed release pellets containing an active layer, an isolation layer consisting of hydroxypropylcellulose and enterosolvent layer based on methacrylic acid copolymer. Each film coating suspension was made and sprayed over the preceding layer in a fluidized bed apparatus. The components of each coating layer are summarized in the following table:

Coat component mg per 40 mg dose

Nucleus Inert beads 20,0

Esomeprazole

44,6

Active layer magnesium trihydrate

Methocel E5 20,0

Talc 1,5 Tween 80 1,2

Isolation layer Hydroxypropylcellulose 20,0

Talc 34,0

Magnesium stearate 3,0

Eudragit L30D55, dry

80,0

content

Enterosolvent layer Triethylcitrate 8,0

Glycerolmonostearate 4,0

Tween 80 1,6

Total - 237,9

Example 5

Coat component mg per 40 mg dose

Nucleus Inert beads 10,0

Esomeprazole

44,6

Active layer magnesium trihydrate

Methocel E5 20,0

Talc 1,5

Tween 80 1,2

Isolation layer Hydroxypropylcellulose 20,0

Talc 34,0

Magnesium stearate 3,0

Enterosolvent layer Eudragit L30D55, dry 80,0 content

Triethylcitrate 8,0

Glycerolmonostearate 4,0

Tween 80 1,6

Total - 227,9

Example 6

Coat component mg per 40 mg dose

Nucleus Inert beads 7,0

Esomeprazole

44,6

Active layer magnesium trihydrate

Methocel E5 20,0

Talc 1,5

Tween 80 1,2

Isolation layer Hydroxypropylcellulose 20,0

Talc 34,0

Magnesium stearate 3,0

Eudragit L30D55, dry

44,0

content

Enterosolvent layer Triethylcitrate 4,4

Glycerolmonostearate 2,2

Tween 80 0,9

Total - 182,8

Claims

1. A dosage unit with an active ingredient consisting of PPI (proton pump inhibitor) processed in the form of pellets, characterized in that it comprises 15 to 85% by weight of the active ingredient.

2. A dosage unit in accordance with claim 1, characterized in that PPI is selected from the group comprising lansoprazole, pantoprazole, racemic omeprazole or one of its enantiomers.

3. A dosage unit in accordance with claims 1 and 2, characterized in that it comprises 15 to 35% by weight of the active ingredient.

4. A dosage unit in accordance with claim 3, characterized in that the active ingredient PPI is lansoprazole.

5. A dosage unit in accordance with claim 3, characterized in that the active ingredient PPI is pantoprazole.

6. A dosage unit in accordance with claim 3, characterized in that the active ingredient PPI is racemic omeprazole or one of its enantiomers.

7. A dosage unit in accordance with claims 1 or 2, characterized in that it comprises 40 to 66% by weight of the active ingredient.

8. A dosage unit in accordance with claim 7, characterized in that the active ingredient PPI is lansoprazole.

9. A dosage unit in accordance with claim 7, characterized in that the active ingredient PPI is pantoprazole.

10. A dosage unit in accordance with claim 7, characterized in that the active ingredient PPI is racemic omeprazole or one of its enantiomers.

11. A dosage form in accordance with claims 1 or 2, characterized in that it comprises 70 to 85% by weight of the active ingredient.

12. A dosage unit in accordance with claim 11, characterized in that the active ingredient PPI is lansoprazole.

13. A dosage unit in accordance with claim 11, characterized in that the active ingredient PPI is pantoprazole

14. A dosage unit in accordance with claim 11, characterized in that the active ingredient PPI is racemic omeprazole or one of its enantiomers.

15. A dosage unit in accordance with any one of the preceding claims, characterized in that the active ingredient is contained in the coating of individual pellets that are used in the respective dosage form.

16. A dosage unit in accordance with any one of the preceding claims, characterized in that the active ingredient is contained in the pellet core, the pellets being used in hard capsules or tablets.