CZ103793A3 - Solid dosing forms of almocalant, and process for preparing thereof - Google Patents

Abstract

Solid oral pharmaceutical dosage forms containing a complex of almokalant as well as processes for their manufacture.

Description

Technical field

The present invention relates to solid dosage forms of the antiarrhythmic active ingredient almokalant (p-INN) formulated into immediate release (IR) and prolonged (prolonged) release (ER) tablets, as well as methods for their preparation.

In particular, the present invention relates to the use of a polystyrene sulfonate complex of almokalant in solid dosage forms.

BACKGROUND OF THE INVENTION

No solid dosage forms containing the polystyrene sulfonate complex of almokalant have been previously described. The polystyrene sulphonate complex of almokalant is described in European Patent Application No. 90 850 242.0 (Applicant's mark H 1020-1), which is not available as a publication at the time of filing the basic patent application in Sweden, but which will be published shortly thereafter.

The almokalant (p-INN), 4- [3- / ethyl- (3- (propylsulfinyl) propyl) amino] -2-hydroxypropoxy] benzonitrile free base is a viscous tacky substance which is difficult to handle in the preparation of solid dosage forms. This substance has an explicit tendency to produce a odor repellent product, with an odor reminiscent of old onions.

Several different routes have been tried to prepare a solid dosage form of almokalant. However, the generally used methods have disadvantages, which are listed below.

Due to the instability of the base and its tendency to impair the tablet binding properties, solid dosage forms of the free base are difficult to prepare, see data in Comparative Example III.

Tablets produced by conventional techniques with almokalant dissolved in an acidic solution for granulation have inferior stability and lead to the development of an onion-like odor repellent, see data given in Comparative Examples I and III.

The use of drug substance complexes with ion exchange resins in pharmaceutical compositions has already been described. The way to achieve controlled release of a codeine-containing suspension is described by L. P. Amsel et al. in Unique Oral Controlled Relase Systems: In-Vivo Drug Release Pattern, pp. 83-93, wherein the codeine-ion exchange resin complexes are coated with a diffuse membrane and then processed to a suspension. In addition, Pennwalt Corporation has published a number of patents which disclose the use of ion exchange resins containing pharmacologically active substances absorbed thereon for use in the controlled release of preparations either as such or further coated with diffusion membranes (U.S. Pat.

No. 221 778, European Patent No. 0 171 528, European Patent No. 5,156,519;

254 811). Other uses of drug exchange ion exchange resin complexes in a pharmaceutical composition are summarized, for example, by Raghunathan et al. in J. Pharm. Sci. 70, (No.4), 379-384 (1981).

SUMMARY OF THE INVENTION

The present invention provides solid dosage forms of the antiarrhythmic drug Almokalant, formulated as immediate release or sustained release tablets having

- 3 improved stability and minimal odor. Prolonged-release tablets may be formulated according to various basic formulation principles, such as instant hydrophilic tablets comprising a gel matrix, matrix tablets, membrane diffusion controlled formulations, osmotic pressure controlled dosage forms and the like.

Regarding the use of solids to prepare tablets, their use is generally preferred. Opportunities are being sought to facilitate various manufacturing processes that lead to the preparation of solid dosage forms.

As already mentioned, the compound almokalant as such in acidic solutions has good stability which allows its processing in an autoclave without any remarkable degradation. The addition of acidic compounds was tested.

Although the ion-exchange resin-binding complex of viscous unstable pharmacologically active formulations, forming a stable solid complex suitable for pharmaceutical processing, has not yet been described, this complex has been tested with an almokalant.

The use of polystyrene sulfonate almokalant complex was tested for the preparation of pharmaceutical dosage forms. Unexpectedly, the polystyrene sulfonate complex of almokalant (A-PSS) has been found to have much better stability, produce a less repellent odor and are easier to handle when preparing tablets.

In order to form sustained release tablets it is necessary to mix the treated complex with, for example, a hydrophilic matrix. It is particularly preferred to use hydroxy-4-propyl methylcellulose as the gel-forming active ingredient.

It is further preferred to use mixtures of hydroxypropyl methylcelluloses containing both low molecular weight and high molecular weight hydroxypropylmethylcellulose.

The use of various mixtures of hydroxypropyl methylcelluloses gives different almokalant release rates according to the prior art (Journal of Controlled Release, 5, 159-172 (1987)).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Almokalant immediate release tablets are prepared by mixing 90 parts of polystyrene sulfonate complex of almokalant, 85 parts of lactose, 91 parts of microcrystalline cellulose and 27 parts of polyvinylpyrrolidone and the mixture is then granulated with purified water.

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

A comparative formulation was prepared by dissolving the free base in 2M hydrochloric acid and using this solution to granulate excipients.

A-PSS tablets, Example 1

Comparative example

1 A-PSS corresponding to almokalant Almokalant 50.0 50.0 2 Lactose, powdered 84.5 - Lactose, anhydrous - 106.8 Avicel ^R PH 101 91.3 114.0 Povidone ^R K-25 26.8 - Polyvinylpyrrolidone, crosslinked - 7.1 Aerosil ^R - 3.6 3 Water, purified 105 - Hydrochloric acid, 2 molar - 71.2 (corresponds to HCl) - (5.2) 4 Sodium stearyl fumarate 5.8 - Magnesium stearate - 2.9 Talc - 11.5 Polyvinylpyrrolidone, cross-linked - 5.7

Tablets containing the polystyrene sulfonate complex of almokalant are prepared by first mixing components 1 and 2, granulating the mixture with component 3, adding, after drying and grinding, component 4, and then compressing them into tablets on a Korsch Pharmapress 100 press.

Comparative tablets (Comparative Example I) are prepared by making a granulating solution from components 1 and 3. The powders listed under component 2 are mixed and then granulated with the prepared solution. After drying and grinding, the lubricant, glidant and tablet disintegrating agent listed under 4 are added and tablets are compressed on the same machine.

Tablets

A-PSS, Example 1

Comparative example

Punch

Tablet weight

Hardness

Decay mm 298 mg

7.5 kp 1-2 min mm 307 mg

6.7 kp 1-2 min

A-PSS tablets, Example 1

Comparative example

Storage stability data in combined vials. Decay is measured as the sum of the area of the by-products in the high performance liquid chromatography system.

0 months 0.81 2.11 1 month at 25 ’C 0.88 2.83 1 month at 50 ° C 1.82 3.41 3.5 months at 25 C 0.88 2.87

Example 2

Immediate almokalant release tablets are prepared by mixing 90 parts polystyrene sulfonate complex of almokalant, 85 parts lactose, 91 parts microcrystalline cellulose and 27 parts polyvinylpyrrolidone and then granulating the mixture with purified water. After drying, the granulate is ground and then mixed with sodium stearyl fumarate as a lubricant and then compressed into tablets.

A comparative preparation (Comparative Example II) was prepared by dissolving the free base in an aqueous solution of tartaric acid and using it in this solution to granulate excipients.

Tablets A-PSS, Example 2 Comparative Example II 1 A-PSS corresponding to almokalant 50.0 - Almokalant - 50.0 Lactose, powdered 84.5 - Lactose, anhydrous - 110.7 Avicel ^R PH 101 91.3 114.0 Polyvidone ^R K-25 26.8 - 3 Purified water 105 57.1 Tartaric acid - 21.5 Sodium stearyl fumarate 5.8 6.0 Talc - 12.0 Polyvinylpyrrolidone, cross-linked - 12.0 Punch 9 mm 10 mm Tablet weight 298 mg 331 mg Hardness 7,5 kp 5,9 kp Disintegration 1-2 min 8 min

Tablets containing the polystyrene sulfonate complex of almokalant are prepared by first mixing components 1 and 2, granulating the obtained mixture with component 3, and then adding component 4 after drying and grinding. The tablets are then compressed into a Korsch Pharmapress 100 press.

Comparative tablets (Comparative Example II) were prepared by granulating a solution of components 1 and 3. The powders listed under component 2 were mixed and granulated with the solution. After drying and grinding, the lubricant, glidant and disintegrant listed in component 4 are added and the tablets are compressed on the same machine.

The odor intensity of the two formulations is compared immediately after preparation and after one month storage in glass bottles.

Odor intensity

Tablets Comparative

A-PSS, Example II Example 2

Freshly prepared

In 1 month +

(some odor, but not onion) +

(some odor but not onion) ++ (explicit onion odor) +++ (strong onion odor)

Example 3

Tablets can be prepared with immediate release almokalant of suitable weight.

Examples 1 and 2 describe the preparation of a formulation containing 50 mg of active ingredient. The following are examples where the formulations contain 70 mg and 1.8 mg of active ingredient.

Example 3a Example 3b

0 mg 1.8 mg

1 A-PSS 127 3.3 Avicel ^R PH 101 148 29 Polyvidone ^R K-90 35 - 2 Polyvidone ^R K-90 10 - Polyvidone ^R K-25 - 4.7 Water, purified 161 19 Dec 3 Avicel ^R PH 102, raw quality - 107 Polyvinylpyrrolidone, crosslinked - 4.3 Sodium stearyl fumarate 1.6 1.4

Tablets containing the polystyrene sulphonate complex of almokalant are prepared by first mixing the components 1, granulating them with a solution made of the components 2, adding the components 3 after drying and grinding, and then compressing them into tablets using a Korsch Pharmapress 100 press.

Example 3a Example 3b

Punch 10 mm 5,5x10,5 mm Tablet weight 22 mg 150 mg Hardness 9-10 kp 9-10 kp Disintegration 0.6-1.0 min 0.2-0.4 min

(without discs)

Example 4

Prolonged-release almokalant tablets are prepared by mixing 95 parts polystyrene sulfonate complex of almokalant, 40 parts hydroxypropylmethylcellulose 50 mPa.s (HPMC 50 cps), 160 parts hydroxypropyl methylcellulose 10 Pa.s (HPMC 10,000 cps) and 50 parts hydroxypropylcellulose (HPC) and blend. is then granulated with 99.5% ethanol. After drying, the granulate is ground, then mixed with sodium stearyl fumarate and then compressed into tablets.

The comparative preparation (Comparative Example III) was carried out by dissolving the free base in 99.5% ethanol and using this solution to granulate dry excipients. Otherwise, the same preparation method is used.

Component Example 4 mg / tablet Comparative Example III mg / tablet 1 A-PSS corresponding to almokalant 50.0 - Almokalant - 50.0 2 HPMC 50 cps (Metolose ^R 60SH50) 40.0 40.0 3 HPMC 10000 CPS (Methocel ^R E10MCR) 160.0 160.0 4 HPC LF (Klucel LF ^R) 50.0 50.0 5 Ethanol, 99.5% 261 235 6 Sodium stearyl fumarate (Pruv ^R ) 3.3 3.3

Components 1 to 4 are mixed and the mixture is granulated with ethanol. After drying and grinding, the granulate is mixed with component 6.

Compression into tablets is performed on a Korsch Pharmapress 100 press with a 11 mm diameter punch. The tabletting machine is equipped with a recording device for monitoring the pressing force.

Example 4 Comparative Example III

Tablet weight 348 mg 303 mg The power to compress the tablet 8.6 kN 12.3 kN Tablet hardness 5,5 kp 3.7 kp

Tablets made using the free base have deteriorated compression properties of the ingredients.

Odor intensity

Tablets

A-PSS (Example 4)

Comparative Tablets (Comparative Example III)

Freshly prepared + +++ (some odor, (strong odor but not after onion) onion)

The release rate is determined on six individual tablets using a USP dissolution apparatus 2, with a paddle rotating at 100 rpm and a tablet placed in a stationary basket above the paddle. 500 ml of a buffer solution having a pH of 6.8 is used as the dissolution medium and is maintained at 37 ° C.

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Tablets

A-PSS (Example 4)

Comparative Tablets (Comparative Example III) Cumulative Released% Average (min-max) Cumulative Released% Average (min-max)

2 15 Dec (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 5

Prolonged-release tablets of almokalant may be prepared with suitable weights and different release rates.

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

Component

Example 5a 10 mg mg / tablet

Example 5b 100 mg mg / tablet

1 A-PSS corresponding to almokalant 10.0 100.0 Lactose, powdered 100.0 40.0 HPMC 50 cps (Metolose ^R 60SH50) 27.6 39.2 HPMC 10000 cps (Methocel ^R E10MCR) 110.4 146.4 HPC LF (Klucel LF ^R) 25.0 - 3 Polyethylene glycol 20M Carbowax ^R 20M 30.0 - Polyethylene glycol 6000 Carbowax ^R 6000 - 42.0 4 Purified water 70.0 98.1 5 Sodium stearyl fumarate (Pruv ^R ) 1.6 2.3

Components 1 and 2 are mixed and the mixture is granulated with the solution prepared from components 3 and 4. After drying and grinding, the granulate is mixed with component 5.

Compression of the tablets is performed on a Korsch Pharmapress 100. The tableting machine is equipped with a recording device to monitor the compression force.

Example 5a

Example 5b

Punch, diameter 10 mm 11 mm Weight of the tablet 314 mg 459 mg The power to compress the tablet 11.0 kN 11.4 kN Tablet hardness 8,2 kp 5,4 kp Speed of release set at 6 individual

tablets using a USP dissolution apparatus 2 equipped with a 100 rpm blade and with a tablet placed in a stationary basket above the blade. 500 ml of a buffer solution having a pH of 6.8 is used as the dissolution medium and is maintained at 37 ° C.

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ER tablets 10 mg (Example 5a)

ER tablets 100 mg (Example 5b) cumulative released% mean (min-max) cumulative released% mean (min-max)

27 (27-28)

44 (43-45) 28 (26-29) _6-37 (35-39)

72 (70-75) - - - - 55

105 (96-109) - --- 20- - - 91 (84-95) - - - 100 (99-101)

Examples 6 to 7

Controlled release tablets are prepared by granulating 54.3 parts of active ingredient, 30.0 parts of mannitol, 154 parts of hydroxypropylmethylcellulose 50 mPa.s (HPMC 50 cps), 221 parts of hydroxypropyl methylcellulose 10 Pa.s (HPMC 10,000 cps), 37, 5 parts hydroxypropylcellulose (HPC) and 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Example 6) or PVP K-25 (Example 7) dissolved in 105 parts water. The dried granulate is lubricated with 2.7 parts of sodium stearyl fumarate.

Component Example 6 mg / tablet Example 7 mg / tablet 1 A-PSS corresponding to almokalant 30.0 30.0 2 Mannitol, powdered 30.0 30.0 2 HPMC (Metolose ^R 60SH50) 154.0 154.0 4 HPMC (Methocel ^R E10MCR) 221.0 221.0 4 HPC (Klucel ^R LF) 37.5 37.5 6 Propyl gallate 0.3 0.3 6 PEG (Carbowax ^R 20M) 45.0 - PVP (Povidone K-25 ^R) - 45.0 8 Water 105.0 105.0 9 Sodium stearyl fumarate (Pruv ^R ) 2.7 2.7 Components 1 to 6 are mixed and the mixture is granulated with flow made from components 7 and 8. After drying with granulate mixed with component 9. Compression into tablets is accomplished with press Korsch Pharmapress 100, which is the caregiver . round punch with diameter 11 mm. The tableting machine is equipped with a recording device for monitoring the pressing pressure. Example 6 Example 7 Tablet weight 545 mg 545 mg Pressing force 20 kN 10 kN Tablet hardness 7,7 kp 12,2 kp The rate of release of the active ingredient varies set on

a USP dissolution apparatus 2 with a 100 RPM blade and a tablet placed in a stationary basket above the blade. 500 ml of a buffer solution having a pH of 6.8, which is maintained at 37 ° C, is used as the dissolution medium.

Example 6

Example 7 hours cumulatively cumulatively released% released% average (min-max) average (min-max)

2 17 (17-18) 18 (17-18) 4 28 (28-29) 28 (28-29) 6 38 (38-39) 38 (37-39) 10 55 (54-56) 54 (53-56) 16 74 (73-76) 73 (71-74)

This example shows that PEG 20,000 and PVP K-25 both have the same function in this method.

Discussion

It is evident from the examples that the use of almokalant free base in pharmaceutical compositions - independently of the difficulty of handling a sticky viscous substance - results in dosage forms with inferior stability and inferior taste properties, as well as poor technical properties. The use of polystyrene sulfonate complexes of almokalant in a pharmaceutical composition facilitates handling and results in dosage forms with improved taste properties.

The best known embodiment of the present invention is to prepare the compositions of the Examples

Claims (7)

6 and 7. - 17 - PATEN T 0 V É Claims 1. Pharmaceutical batch the form of almokalant, v y tagging by that almokalant ve form The polystyrene sulfonate complex is optionally mixed with pharmaceutical excipients to form a solid dosage form for oral administration. 2. A dosage form according to claim 1 wherein the pharmaceutical excipients comprise a hydrophilic matrix. The dosage form of claim 2, wherein the hydrophilic matrix is hydroxypropylmethylcellulose. The dosage form of claim 3, wherein the hydroxypropylmethylcellulose comprises both low molecular weight hydroxypropylmethylcellulose and high molecular weight hydroxypropylmethylcellulose. A process for preparing a solid dosage form according to claim 1, characterized in that: (a) reacting the almokalant with polystyrenesulfonic acid to form a complex; and b) mixing the complex with pharmaceutical excipients and preparing the oral solid dosage form according to any of the known methods. The method of claim 5, wherein the pharmaceutical excipients comprise a hydrophilic matrix. í Γ '” The method of claim 6, wherein the hydrophilic matrix is hydroxypropylmethylcellulose.