HUT64217A - Process for producing solide dosing forms of almocalant - Google Patents

Description

The present invention relates to solid dosage forms of the anti-arrhythmic almokalant (p-INN) formulated as immediate release (IR) tablets and as extended release (ER extended release) tablets and a process for their preparation.

More particularly, the present invention relates to the use of polystyrene sulfonate complex of lime melant in solid dosage forms.

No solid dosage forms containing the polystyrene sulfonate complex of almokalant have been reported so far. The polystyrene sulfonate complex of almokalant is disclosed in European Patent Application EP 90850242.0, which was not available to the public when the original patent application was filed in Sweden, shortly thereafter.

Almokalant (p-INN), 4- [3- {ethyl- [3- (propylsulfinyl) -propyl] -amino) -2-hydroxypropoxy] -benzonitrile free base, is a viscous, sticky substance that is highly treated causes problems in the preparation of solid dosage forms. It is characterized by the fact that it produces a decomposition product with an unpleasant odor, which smells like that of old standing onions.

A number of different methods have been tried to produce a solid dosage form of lalmital. Commonly used methods have the following disadvantages.

Due to the instability of the base and the tendency to degrade the binding properties of the tablet, it is very difficult to prepare solid dosage forms of the free base. See Annex III for details. reference example.

Tablets prepared by conventional methods, in which lime melantan is dissolved in an acid granulation solution, have poorer stability and an unpleasant onion-like odor. Further details are given in Annexes I and III. Reference examples are provided.

Pharmaceutical compositions using complexes of the active compounds with ion exchange resins have been described previously. Amsei et al., Describe a process for preparing a controlled release suspension containing codeine (Amsei, LP et al., Unique Clock Controlled Release Systems: Invoice Drug Release Pattern, pp. 83-93), comprising complexing a codeine and an ion exchange resin with a diffusion membrane. and then converted into a suspension dosage form. In addition, the Pennwalt Corporation has published a series of patent applications describing the use of ion exchange resins that are pharmacological! Binding active substances and thus can be used in controlled release pharmaceutical compositions either alone or with additional diffusion membrane coating (U.S. Patent No. 4,221,778, EP 0 171 528 and EP 0 254 811). Other possible uses of complexes of ion-exchange resins in drug formulations are described, for example, in Raghunathan et al., J. Pharm. Sci.

• · ··· · ♦ · · · · · · · · · · · ································································ ((1981)].

FIELD OF THE INVENTION The present invention relates to solid dosage forms containing the antiarrhythmic lutalanthal, which are IR tablets and ER tablets with improved stability and odor. ER tablets may be formulated according to a variety of pharmaceutical formulations, such as hydrophilic gel matrix tablets, matrix tablets, membrane diffusion-controlled formulations, osmotic pressure-controlled dosage forms, and the like.

Since the use of solids in the tablet formulation process is generally advantageous and facilitates the manufacture, various methods of preparing solid dosage forms have been investigated.

Since it has been found that the almokalant compound alone has good stability in acidic solutions, so that it can be autoclaved without any significant degradation, the effect of adding acidic compounds was investigated.

The complex binding of viscous, unstable, pharmacologically active compounds to ion exchange resins to form a stable solid complex suitable for pharmaceutical processing has not been described previously, and this possibility has been investigated for almokalant.

Thus, the use of polystyrene sulfonate complex of almokalant in the preparation of dosage forms has been studied. Surprisingly, it has been found that the polystyrene sulfonate complex (A-PSS) of almokalant is much more stable, has a less unpleasant odor, and is much easier to handle during the process of tabletting.

For the preparation of ER tablets, the resulting complex must be mixed with, for example, a hydrophilic matrix. Hydroxypropyl methylcellulose (HPMC) is particularly preferred as a gelling agent. Even more preferred is the use of an HPMC blend containing both low and high molecular weight HPMC.

The use of different HPMC blends, according to known methods (Journal of Controlled Release 5, 159172 (1987)), provides different release rates of the active ingredient, lalmitalant.

The invention is further illustrated by the following examples.

Example 1

Immediate release lime calanthate tablets were prepared by mixing 90 parts of A-PSS, 85 parts of lactose, 91 parts of microcrystalline cellulose and 27 parts of polyvinylpyrrolidone, and the resulting mixture was granulated with purified water.

After drying, the granulate was milled, then mixed with sodium stearyl fumarate and compressed into tablets.

A reference preparation was prepared by dissolving the free base in 2M hydrochloric acid and using this solution to granulate the binders.

·· ♦ «· · • ♦« ··· · »·

A-PSS tablets

Reference I

1. A-PSS suitable for litter-almond

almokalant

2. Lactose, powdered

Anhydrous lactose crossAvicel ^R PH 101

Povidone ^R K-25

Poly (vinylpyrrolidone), bonded

Aerosil ^R

3. Water, purified

M hydrochloric acid solution (HCl content)

4. Sodium stearyl fumarate

Magnesium stearate

talc

Example 1 example 50.0 - - 50.0 84.5 - - 106.8 91.3 114.0 26.8 -

7.1

3.6

105

71.2 (5.2)

5.8

2.9

11.5

Poly (vinylpyrrolidone), cross-linked

5.7

The A-PSS tablet was prepared by first mixing ingredients 1 and 2. The mixture was then granulated with Component 3. After drying and milling, component 4 was mixed and compressed into tablets using a Korsch Pharmapress 100 device.

The reference tablet (Reference Example I) was prepared by preparing a granulation solution of ingredients 1 and 3 ······. The powders in component 2 were then mixed and granulated with the solution already prepared. After drying and grinding, the lubricant, lubricant and disintegrant in component 4 were mixed and tablets were compressed on the above apparatus.

A-PSS tablets

Reference I

Example 1 Example

Size of the stamp: 9 mm 10 mm Tablet weight: 298 mg 307 mg Hardness: 7.5 kP 6.7 kP Disintegration: 1-2 minutes 1-2 minutes

A-PSS tablets

Reference I

Example 1 Example

Stability data when stored in glass bottles. The degradation is measured by HPLC for by-products

system because its area was based on its definition.

month month, 25 ° C month, 50 ° C

3.5 months at 25 ° C

0.81 2.11 0.88 2.83 1.82 3.41 0.88 2.87

·· * ····

Example 2

Immediate release lime calanthan tablets were prepared by blending 90 slurry A-PSS, 85 parts lactose, 91 parts microcrystalline cellulose and 27 parts polyvinylpyrrolidone, and the resulting mixture was granulated with purified water.

After drying, the granulate was ground and then mixed with sodium stearyl fumarate lubricant and compressed into tablets.

Reference preparation (Reference Example II) was prepared by adding the free base to an aqueous solution of tartaric acid.

This solution was used to granulate the binders. A-PSS tablet II. reference Example 2 example First A-PSS for littermates 50.0 - almokalant - 50.0 Second Lactose, powdered 84.5 - Anhydrous lactose - 110.7 Avicel ^R PH 101 91.3 114.3 Polyvidone ^R K-25 26.8 - Third Water, purified 105 57.1 Tartaric acid - 21.5 4th Sodium stearyl fumarate 5.8 6.0 talc - 12.0 Poly (vinylpyrrolidone), bo

cross- linked

12.0

Size of the stamp 9 mm 10 mm Tablet weight: 298 mg 331 mg Hardness: 7.5 kp 5.9 kp Disintegration: 1-2 minute 8 minutes

A-PSS tablets were prepared by first mixing ingredients 1 and 2. The mixture was then granulated with Component 3. After drying and milling, component 4 was mixed and compressed into tablets using a Korsch Pharmapress 100 device.

The reference tablet (Reference Example II) was prepared by mixing ingredients 1 and 3 into a granulation solution, then mixing the powders in component 2 and granulating with the solution already prepared. After drying and milling, the lubricant, lubricant and disintegrant in component 4 were mixed and tablets were compressed on the above apparatus.

The odor intensities of the two formulations were compared immediately after preparation and after storage for 1 month in glass bottles.

····

Odor intensity

A-PSS tablets

II.

reference

Example 2 Example

Fresh after ++ months (some onion odor) (certain but not long lasting (pronounced onion odor +++ (strong onion odor))

Example 3

Immediate release of lime alfalfa tablets can be prepared at the appropriate potency.

Examples 1 and 2 described 50 mg formulations. 70 mg and 1.8 mg formulations are shown below.

3 / a. example 7 0 mg 3 / b. example 1.8 mg First A-PSS 127 3.3 AvICel ^R PH 101 148 29 Polyvidone ^R K-90 35 - Second Polyvidone ^R K-90 10 - Polyvidone ^R K-25 - 4.7 Water, purified 161 19

• · * * ·· · · «. ·. ···· * ·. r ···· ··· * ··

3. Avicel ^R PH102

coarse grained - 107 Poly (vinylpyrrolidone), - 4.3 crosslinked Sodium stearyl fumarate 1.6 1.4

A-PSS tablets were prepared by first mixing ingredients 1. The mixture was then granulated with a solution containing the ingredients 2. After drying and grinding, the ingredients were mixed and then compressed into tablets using a Korsch Pharmapress 100 device.

Size of the stamp: 10 mm 5 5 x 10.5 mm Tablet weight: 322 mg 150 mg Hardness: 9-10 kP 9-10 kP Disintegration (without reels): 0.6-1.0 minute 0.2-0.4 min

Example 4

Prolonged release lime calanthal tablets were prepared by mixing 95 parts of A-PSS, 40 parts of 50 cP (hydroxypropyl) methylcellulose (HPMC), 160 parts of 10,000 cP of HPMC and hydroxypropyl cellulose (HPC) and then the mixture was granulated with 99.5% ethanol. After drying, the granulate was milled, mixed with sodium stearyl furarate and finally compressed into tablets.

Reference Preparation (Reference Example III) was prepared by dissolving the free base (99.5%) in ethanol and using this solution to granulate the dry binders, otherwise it was prepared as described above.

III. reference Example 4 example Component mg / tablet mg / tablet First A-PSS for littermates 50.0 - almokalant - 50.0 Second HPMC 50 cP (Metolose ^R 60SH50) 40.0 40.0 Third HPMC 10,000 cP (Methocel ^R E10MCR) 160.0 160.0 4th HPC LF (Klucel ^R LF) 50.0 50.0 5th Ethanol 99.5% 261 235 6th Sodium stearyl fumarate (Pruv ^R ) 3.3 3.3

1-4. ingredients. The mixture was then granulated with ethanol. After drying and milling, the granulate was mixed with component 6.

The tablets were extruded using a Korsch Pharmapress 100 using an 11 mm round stamp. The tabletting machine was equipped with an instrument for recording compression force.

Tablet weight: 348 mg 303 mg Tablet pressing force: 8.6 kN 12.3 kN Tablet hardness: 5.5 kp 3.7 kp

The trigger properties of the free base were worse.

Odor intensity

A-PSS tablet (Example 4)

Freshly prepared (some but not pillsReference tablets (Example III.ref) +++ (strong onion odor) onion odor)

The release rate of 6 different tablets was determined using a USP 2 dissolution device at 100 rpm by placing the tablet in a resting basket placed above a minute rotating blade and 500 ml of pH 6.8 as the dissolving medium. buffer, which was kept at 37 ° C.

A-PSS tablets

Reference (4.

Example 1) Tablet (Example III.ref)

Cumulative emissions

Cumulative emissions

hours % % average (min-max) average (min-max) 2 15 (14-15) 28 (28-29) 4 24 (23-25) 43 (42-43) 6 34 (33-35) 55 (54-56) 10 51 (48-52) 74 (72-75) 24 91 (87-93) 102 (100-105)

• ·

.example

Prolonged-release lozalantan tablets can be prepared at the appropriate potency and at various release rates.

Example 4 describes a formulation containing 50 mg of active ingredient. The following are examples of 10 mg and 100 mg tablets.

mg 100 mg

Example 5a Example 5b

Ingredient mg / tablet

First A-PSS for littermates 10.0 100.0 Second Lactose, powdered 100.0 40.0 HPMC 50 cP (Metolose ^R 60SH50) 27.6 39.2 HPMC 10,000 cP (Methocel ^R E10MCR) 110.4 146.4 HPC LF (Klucel ^R LF) 25.0 - Third Polyethylene glycol 20 M 30.0 - (Carbowax ^R 20 M) Polyethylene glycol 6000 - 42.0 (Carbowax ^R 20 M) 4th Water, purified 70.0 98.1 5th Sodium stearyl fumarate (Pruv ^R ) 1.6 2.3

Ingredients 1 and 2 are mixed together. The mixture is then granulated with a solution of ingredients 3 and 4. After drying and milling, the granulate is mixed with component 5. Compressed into tablets Korsch Pharma15 · Press 100. The tabletting machine is equipped with an instrument for recording the compression force.

Size of the stamp

diameter: 10 mm 11 mm Tablet weight: 314 mg 459 mg Tablet compression force (kN): 11.0 11.4 Tablet hardness (kP): 8.2 5.4

The release rate was determined for 6 different tablets using a USP 2 dissolution device at 100 rpm blade rotation speed by placing the tablet in a resting basket placed above the blade and dissolving 500 ml.

A buffer solution of pH 6.8 was used and kept at 37 ° C.

10 mg prolonged release 100 mg prolonged release release release (ER) tablets (ER) tablets Example 5a Example 5b cumulative emissions cumulative emissions hours % % average (min-max) average (min-max) 2 27 (27-28) 17 (17-18) 3 44 (43-45) 28 (26-29) 6 37 (35-39)

(70-75)

______ 55 (52-60)

105 (96-109) ______ ______ 91 (84-95) ______ 100 (99-101)

6-7. example

Controlled release tablets were prepared by providing 54.3 parts of active ingredient, 30.0 parts of mannitol, 154 parts of HPMC 50 cP, 221 parts of HPMC 10,000 cP,

37.5 parts HPC, 0.3 parts propyl gallate were granulated with a solution containing 45 parts PEG 20,000 (Example 6) or PVP Κ-25 (Example 7) dissolved in 105 parts water. The dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate.

Example 6

Example 7

Ingredient mg / tablet

First A-PSS for littermates 30.0 30.0 Second Mannit, powdered 30.0 30.0 Third HPMC (Metolose ^R 60SH50) 154.0 154.0 4th HPMC (Methocel ^R E10MCR) 221.0 221.0 5. HPC (Klucel ^R LF) 37.5 37.5 6th Propyl gallate 0.3 0.3 7th PEG (Carbowax ^R 20M) 45.0 - PVP (Povidone ^R K-25) - 45.0 8th Water 105.0 105.0 9th Sodium stearyl fumarate (Pruv ^R ) 2.7 2.7

• · • ♦

1-6. The ingredients were blended and this mixture was granulated with a solution of ingredients 7 and 8. After drying, the granulate was mixed with component 9.

The tablets were extruded using a Korsch Pharmapress 100 machine with an 11 mm round stamp. The tabletting machine also included a device for recording compression force.

Example 6

Example 7

Tablet weight: 545 mg 545 mg Pressing force (kN): 20 19 Tablet hardness (kP): 7.7 12.2

The release rate was determined using a USP 2 dissolution device at 100 rpm blade rotation speed by placing the tablet in a resting basket placed above the blade and using 500 mL of pH 6.8 buffer as the dissolution medium, which was kept at 37 ° C.

Cumulative emissions% average (min-max)

Example 6

Example 7 Clock (17-18) (17-18) Clock (28-29) (28-29) · · • ···· · · ♦ ·

- 18 - '···. ·····

6 hours 38 (38-39) 38 (37-39) 10 am 55 (54-56) 54 (53-56) 16 o'clock 74 (73-76) 73 (71-74)

The examples show that PEG 20,000 and PVP K-25 are both useful in the process.

It is evident from the examples that the use of lime almond free base in the preparation of pharmaceutical compositions, apart from the difficult handling of the sticky viscous material, leads to dosage forms which have lower stability, taste and technical properties. The use of the polystyrene sulfonate complex of almokalant in the preparation of the pharmaceutical composition facilitates handling and provides more stable and better-tasting dosage forms.

To the best of our knowledge, the most preferred embodiment of the process of the invention is shown in Figures 6-7. The process for the preparation of the pharmaceutical compositions according to Examples 1 to 4.

Claims (7)

PATENT CLAIMS A pharmaceutical dosage form of almokalant, characterized in that it contains a polystyrene sulfone complex, optionally mixed with pharmaceutical excipients, and represents a solid dosage form for oral administration. The dosage form of claim 1, wherein the pharmaceutical excipients comprise a hydrophilic matrix. 3. The dosage form of claim 2, wherein the hydrophilic matrix is hydroxypropyl methylcellulose. The dosage form of claim 3, wherein the hydroxypropyl methylcellulose comprises both low and high molecular weight hydroxypropyl methylcellulose. A process for preparing a solid dosage form according to claim 1, characterized in that: a) reacting the apple melantalant with a polystyrene sulfonic acid complex; b) mixing the complex with suitable pharmaceutical excipients and converting it into a solid oral dosage form by any known method. 6. The process of claim 5, wherein the pharmaceutical excipients comprise a hydrophilic matrix. 7. The process of claim 6, wherein the hydrophilic matrix used is hydroxypropyl methylcellulose.