CA2097178A1 - Solid dosage forms of almokalant and processes for manufacture thereof - Google Patents
Solid dosage forms of almokalant and processes for manufacture thereofInfo
- Publication number
- CA2097178A1 CA2097178A1 CA002097178A CA2097178A CA2097178A1 CA 2097178 A1 CA2097178 A1 CA 2097178A1 CA 002097178 A CA002097178 A CA 002097178A CA 2097178 A CA2097178 A CA 2097178A CA 2097178 A1 CA2097178 A1 CA 2097178A1
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- almokalant
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- tablet
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/795—Polymers containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- General Chemical & Material Sciences (AREA)
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- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Chemical Treatment Of Metals (AREA)
Abstract
Solid oral pharmaceutical dosage forms containing a complex of almokalant as well as processes for their manufacture.
Description
--. W092/101/2 2 ~ 9 717 ~ PCT/SE91/00#15 SOLID DOSAGE FORMS OF ALMOKALANT AND PROCESSES FOR
MANUFACTURE THEREOF
Field of the invention This invention relates to solid dosage forms of the antiar~hytnmic drug almokalant (p-INN) formulated as immedlate release ( IR) tablets and extended release (ER) tablets as well as processes for manufacture thereof.
Specif~ 5.~11y the invention relates to the use of the polystyrene sulphonate complex of almokalant in solid i~ dosage forms.
Backqround of the invention No solid dosage f orms containing the polystyrene sulphonate complex of almokalant have been reported. The polystyrene sulphonate complex of almokalant is described in the European patent application E~ 90850242.0 (our ref.
H 1020-1), which is not publically available at the time of filing the basic application in Sweden, but will be so shortly thereafter.
Almokalant (p-INN), 4-~3-~ethyl~3-(propylsulfinyl)-propyl]amino~-2-hydroxypropoxy]-benzonitrile free base is a viscous, sticky substance, problematic to handle in the manufacture of solid dosage forms. It has a pronounced tendency to give a repellent odorous degradation product with a smell resembling old onions.
Several different ways were tested in order to prepare a solid dosage form of almoka!an~. Commonly used methods had the followin~ disadvan~ages.
Due to che lnstablli~y o- ~ne _ase and its tendency to WO92/l0l72 2 ~19 71 7 ~ 2 PCT/SE9l/00~lC-worsen tablet binding properties, solid dosage ~orms of the free base are difficult to produce. See further reference example III.
Tablets prepared by conventional technique, w1th almokalant dissolved in an acidic sranulatln~ solulion, have inferior stabilit~ prover-i-s ~rc devel~ ~ -epe'llng onion-like odour. See further reference examples I and III.
The use of complexes of drug substances with ion exchange resins in pharmaceutical formulat~on is described previously. A way to obtai-. a ^cn~-ollQd r-leas2 suspension containing codelne is des-.lbed by ~ms21 L.~.
et al "Unique Oral Controlled ~elease Systems": In-Vivo Drug Release Pattern pp 83-93 where a complex between codeine and an ion exchange resin is coated with a diffusion membrane and then formulated into a suspension.
In addition, Pennwalt Corporation has published a series of patents describing the use of ion exchange resins having pharmacologically active substances absorbed thereon for use in controlled release preparations either as such or further coated with diffusion membranes (US
Pat 4,221,778, EP 0171 528, EP 0 254 811). Other uses of ion exchange resin complexes with drugs in phar~aceutical formulation is for example summarized by Raghunathan et al. J Pharm Sci 1981, 70, ~No 4), 379-384.
Descri~tion of the invention The aim of the present invention is to provide solid dosage forms of the antiarrhythmic drug almokalant, formulated as IR-tablets and ER-tablets with improved stability and minimal odour. E~-tablets can be formulated by a variety of formulation principles, such as for instance hydrophilic gel-m2 ~i:~ t~l'ts, m2t-i~ t~_l_'s membrane dirfusion controlled rormuia.ions, osmollc pressure controlled dosaae -orms etc.
-:- WO 92/1017~ 2 ~ 9 717 ~ PCT/SE91/OOXl5 As the use of solid substances in tablet manufacture in general is advantageous and facilitates the production different ways to prepare solid dosage forms were investigated.
As it had been noticed that the ccmpound almokal~c 25 such in acidic solutions has a good stability, which makes it possible to autoclave it without noteworthy degradation, the addition of acid compounds were tested.
Although complex-binding to ion-e~change resins of viscous, unstable, pharmaoologic~1ly ac~fYe asen~S, ~o form a stabile solid comple~ suit~ie for pnarmaceut cal li processing has not been previousl~ described, this was tested with almokalant.
Thus, it was tested to use the polystyrene sulfonate complex of almokalant in the formulation of pharmaceutical dosage forms. It was then unexpectedly found that almokalant polystyrene sulphonate complex (A-PSS), had a much better stability, less repelling odour and was much easier to handle in tablet manufacture.
To form ER tablets it is necessary to mix the formed complex with e.g. a hydrophilic matrix. It is especially preferable to use hydroxypropyl methylcellulose as the gel forming substance. It is further preferred to use a mixture of HPMC containing both low and high molecular weight HPMC.
The use of different mixtures of HPMC gi~es according to known technics (Journal of Controlled release, S (1987) 159-172), different release rates of the active ingredient almokalant.
WO92/1017~ 4 PCT/SE91/OOX1C
EXAMPLES
Exam~le 1 Immediate release tablets of almokalant were prepared by mi~lns A-~SS 90 parts, lactose 85 parts, microcrystalline cellulos~ 9l parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
After drying the granulate was milled and then mixed with sodium stearyl fumarate and compressed to tablets.
A refe~enc2 pre?aration was produced by dissolving the free base in 2 2M hydrochloric acid solution and using this solution to granulate the excipients.
A-PSS tablet Ref.
Ex l Ex I
1. A-PSS corresp. to almokalant 50.0 Almokalant - 50.0 2. Lactose pwd 84.5 Lactose anhydrous - 106.8 Avicel~ PH lOl 9l.3 114.0 Povidone~ K-25 26.8 Polyvinyl pyrrolidone, cross-linked - 7.l Aerosil~ - 3.6 3. Water, purified 105 Hydrochloric acid 2M - 71.2 (corresp. to HCl) - (5.2) 4. Sodium stearyl fumarate 5.8 Magnesium stearate - 2.9 Talcum - ll.5 Pol w inyl pvrrolidone, cross-linked - 5.7 The .~-~SS ~blet wa3 ?r~pared by firs~ mi~ing ingredients l and 2. The mixture was g-anulated with 3. After drying and milling 4 was admixec, whereupon compression to WO92/10172 2 f~ 3 7 1 7 ,~ PCT/SE91/00815 tablets was performed on a Korsch Pharmapress lO0.
The reference tablet (Ref. ex. I) was prepared by maklng a granulating solution of the ingredients l and 3. The powders in 2 were mixed and then granulated with the prepared solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets compressed on the same machine.
A-PSS tablet.Ref.ex. I
Ex. l Punches: 9 mm lO mm Tablet weight: 298 mg307 mg Hardness: 7.5 kP6.7 kP
lS 2isintegration: 1-2 min.1-2 min.
Ex. l Ref.
A-PSS tabletEx. I
20 Stability data of storage in glass bottles. Degradation measured as area sum of byproducts in a HPLC-system 0 month 0.81 2.ll 2S l month in 2SC 0.88 2.83 l month in 50C l.82 3.41 3.5 months in 25C 0.88 2.87 Exam~le 2 Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 8S parts, microcrystalline cellulose 9l parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
After drying the granulate was milled and then mixed with the lubric3nt sodlum stear l fumarate whereupon compression to tablets was done.
2 o 9 !7 1 7 ~
A reference preparation (Ref. ex. II) was produced by dissolving the free base in an aqueous tartaric acid solution and using this solution to granulate the excipients.
A-~SS tablet P~e~. tabl t _ T
l. A-PSS corresp. to almoXalant 50.0 -Almokalant - 50.0 2. Lactose pwd 84.;
Lactose anhydrous - llO.7 Avicel~ PX lOl C'.3 ll-.3 Polyvidone K-25 25.8 li 3. Water, purified l3~ ;7.1 Tartaric acid - 21.5 4. Sodium stearyl fumarate 5.8 6.0 Talcum - 12.0 Polyvinyl pyrrolidone, cross-linked - 12.0 Punches: 9 mm lOmm Tablet weight: 298 mg 331mg Hardness: 7.5 kP 5.9kP
Disintegration: 1-2 min. 8min.
The A-PSS tablets were prepared by first mixing ingredients l and 2. The mixture was granulated with 3.
After drying and milling 4 was admixed, whereupon compression to tablets were performed on a Korsch Pharmapress lO0.
The reference tablet (Ref. ex. II) was prepared by making a granulating solution of l and 3. The powders 2 were mixed and granulated with the solution. After drving and milling the lubricant, glldant and disintegrant in 4 were admixed and tablets we~e csmo-essed on the ~me machl?e.
The odour intensitv of the two formulatlons were com~a-ed '~
':
2~717g immediately after manufacturing and after l month of storage in glass bottles.
Odour intensit~
A-PSS ta~lets Re~.
E:~. 2 Freshly prepared + ++
(some smell, but (pronounced smell not of onions.) of onions.) l month + ++
(some smell, but (stron~ s",ell of not of onions.) of onions) ExamPle 3 Immediate release tablets of almokalant can be prepared in suitable strengths.
In Ex. l and 2 a 50 mg preparation was described. Below are examples of 70 mg and l.8 mg preparations shown.
Ex 3a 70 mg Ex 3b l.8 mg l. A-PSS 127 3.3 Avicel~ PH l0l 148 29 Polyvidone~ K-90 35 2. Polyvidone~ g-90 l0 Polyvidone~ K-25 - 4.7 Water, purified 161 l9 3. Avicel~ PHl02 coarse grade - l07 Polyvinyl pyrrolidone, cross-lin~ed - 1 3 Sodium stearyl fumarate 1.6 i.4 . .
. :
WO92/101/2 ~ ~71 7 ~ 8 PCT/SE91/0081!
The A-PSS tablets were prepared by first mixing the ingredients l..The mixture was granulated with a solution made of ingredients 2. After drying and milling ingredients 3 were admixed, whereupon compression to S tablets were performed on a Korsch Pharmapress lO0.
Punches: lO mm 5.5xlO.5 mm Tablet weight: 322 mg 150 mg Hardness: 9-lO kP 9-lO kP
Disintegration (without discs): 0.6-l.0 min. 0.2-0.4 min.
l; ExamDle 4 Extended release tablets of almokalant were prepared by mixing A-PSS 95 parts, hydroxypropyl methylcellulose (HPMC) 50 cps 40 parts, HPMC lO000 cps 160 parts and hydroxypropyl cellulose (HPC) 50 parts and then granulating the mixture with ethanol 99.5%. After drying the granulate was milled and then mixed with sodium stearyl fumarate whereupon compression to tablets was done.
A reference preparation (Ref. ex. III) was made by dissolving the free base in ethanol ~99.5%) and using this solution to granulate the dry excipients, and otherwise following the same way of production.
Example 4 Ref.ex. III
Ingredient mg/tabletmg/tablet l. A-?SS cor-~sp. to ~lmokalan-50.0 ~lmokalant - 50.0 2. H~MC 50 C25 (Metolose~ 60SH50) 40.0 40.0 W092/10172 2 0 9 717 ~ PCT/SE91/00815 3. HPMC 10000 cps (Methocel0 ElOMCR) 160.0 160.0 4. H~C LF (Klucel~ LF) 50.0 50.0 5. Ethanol 99.5% 261 235 6. Sodium stearyl fumarate (Pruv~) 3.3 3.3 s Ingredients 1 to 4 were mixed. The mixture was granulated wi~h ethanol. ~fter dryin~ and millins the granulate was mixed with 6.
Compression to tablets was performed on a Korsch Pharmapress 100 with 11 mm circular punches. The tablet machine was e~uipped with compression force registration.
Tablet weight: 348 mg 303 mg " compression force: 8.6 kN 12.3 kN
" hardness: 5.5 kP 3.7 kP
Tablets made using the free base have inferior binding properties.
Odour intensitv A-PSS Reference tablets tablet (Ex. 4) ~Ref.ex. III) Freshly prepared + +++
~some smell, but tstrong smell not of onions.) of onions.) The release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/mln and the tablet placed in a stationary basket above the paddle, 500 ml buffer solution pH 6.~ kept at 37C was use~ as dissolu~ion medium.
-: , , ::
,: . ` . ,. :
wos2~10l72 2 0 9 717 ~ lo PCT/SE91/0~
A-PSS tablet Ref. tablet (Ex. 4) (Ref.ex. III) cumulative cumulative 5 hours % released % released average (min-max) aYe.age (min-m~) 2 15 (14-15) 2~ (28-29) 4 24 t23-2;) ~3 (~ 3) 6 34 (33-35) 55 (54-56) 51 (48-52) 71 (72-75) 24 91 (87-93) 102(100-'05) ExamPle 5 Extended release tablets of almokalant can be prepared in suitable strengths and with different release rates.
In Ex. 4 a preparation with 50 mg strength is described.
Below follows examples o$ 10 mg and 100 mg.
10 mg 100 mg Ex. 5a Ex. 5b Ingredient mg/tablet 1. A-PSS corresp. to almokalant10.0 100.0 2. Lactose pwd 100.0 40.0 HPMC 50 cps ~Metolose~ 60SXSO) 27.6 39.2 HPMC lOOOOcps ~Methocel~ ElOMCR) 110.4 146.4 HPC LF (~lucel LF) 25.0 3. Polyethylene glycol 20M
~Carbowax~ 20M) 10.0 Polyethylene glycol 6000 (Carbowax~ 6000) 4. Water, puri~ied 70.0 ~8.1 5. Sodium stearyl fumara-s (Pr~ ) 1.5 ~.3 . ~
: ` :
.
, .^ WO92/10172 2 ~ .~ 717 8 PCT/SE91/00815 1 and 2 were mixed. The mixture was granulated with a solution made of 3 and 4. After drying and milling the granulate was mixed with 5.
Compression to tablets was ~erf~rmed on a Korsch Pharmapress 100. The tablel machine was s~u~p~ed w'th compression force registration.
Punches, diameter: 10 mm 11 mm Tablet weight: 314 mg 459 mg compression force (XN): 11.0 11.4 " hardness (1~) 8.2 5.4 The release rate was de.erm ned .~om 6 individual .ablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary bas~et above the paddle. 500 ml buffer solution pH 6.8 ~ept at 37C was used as dissolution medium.
10 mg ER tablet 100 mg ER tablet Ex. 5aEx. 5b cumulative cumulative 25 hours % released ~ released average (min-max) average ~min-max) 2 27 (27-28) 17 ~17-18) 4 44 (43-45) 28 (26-29) 6 - - - - - 37 (35-39) 8 72 ~70-75) - - - - -- - - - - 55 ~52-60) 12 105 (96-109) - - - - -- - - - - 91 (84-95) 35 24 - - - - - 100(99-101) : , :' .' ' ' ~
;
2~71 73 W092/10t7~ 12 PCT/SE91/0081~--Exam~les 6-7 Controlled release tablets were prepared by granulating 54.3 parts active substance, 30.0 parts mannitol, 154 parts HP~.C 50 cps, 221 parts HPMC 10,000 cps, 37.5 parts HPC, 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Ex. 6) or PVP ~-25 (Ex. 7) dissolved in 105 parts of water. The dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate.
Example 6 E~mple 7 Inqredient mg/tablet 1. A-PSS corresp. to almokalant 30.0 30.O
2. Mannitol pwd 30.0 30.0 3. HPMC (Metolose0 60SH50)154.0 154.0 4. HPMC (Methocel0 ElOMCR)221.0 221.0 5. HPC (glucel~ LF) 37.5 37,5 6. Propyl gallate 0.3 0.3 7. PEG (Carbowax~ 20M) 45.0 PVP (Povidone~ R-25) - 4s.O
MANUFACTURE THEREOF
Field of the invention This invention relates to solid dosage forms of the antiar~hytnmic drug almokalant (p-INN) formulated as immedlate release ( IR) tablets and extended release (ER) tablets as well as processes for manufacture thereof.
Specif~ 5.~11y the invention relates to the use of the polystyrene sulphonate complex of almokalant in solid i~ dosage forms.
Backqround of the invention No solid dosage f orms containing the polystyrene sulphonate complex of almokalant have been reported. The polystyrene sulphonate complex of almokalant is described in the European patent application E~ 90850242.0 (our ref.
H 1020-1), which is not publically available at the time of filing the basic application in Sweden, but will be so shortly thereafter.
Almokalant (p-INN), 4-~3-~ethyl~3-(propylsulfinyl)-propyl]amino~-2-hydroxypropoxy]-benzonitrile free base is a viscous, sticky substance, problematic to handle in the manufacture of solid dosage forms. It has a pronounced tendency to give a repellent odorous degradation product with a smell resembling old onions.
Several different ways were tested in order to prepare a solid dosage form of almoka!an~. Commonly used methods had the followin~ disadvan~ages.
Due to che lnstablli~y o- ~ne _ase and its tendency to WO92/l0l72 2 ~19 71 7 ~ 2 PCT/SE9l/00~lC-worsen tablet binding properties, solid dosage ~orms of the free base are difficult to produce. See further reference example III.
Tablets prepared by conventional technique, w1th almokalant dissolved in an acidic sranulatln~ solulion, have inferior stabilit~ prover-i-s ~rc devel~ ~ -epe'llng onion-like odour. See further reference examples I and III.
The use of complexes of drug substances with ion exchange resins in pharmaceutical formulat~on is described previously. A way to obtai-. a ^cn~-ollQd r-leas2 suspension containing codelne is des-.lbed by ~ms21 L.~.
et al "Unique Oral Controlled ~elease Systems": In-Vivo Drug Release Pattern pp 83-93 where a complex between codeine and an ion exchange resin is coated with a diffusion membrane and then formulated into a suspension.
In addition, Pennwalt Corporation has published a series of patents describing the use of ion exchange resins having pharmacologically active substances absorbed thereon for use in controlled release preparations either as such or further coated with diffusion membranes (US
Pat 4,221,778, EP 0171 528, EP 0 254 811). Other uses of ion exchange resin complexes with drugs in phar~aceutical formulation is for example summarized by Raghunathan et al. J Pharm Sci 1981, 70, ~No 4), 379-384.
Descri~tion of the invention The aim of the present invention is to provide solid dosage forms of the antiarrhythmic drug almokalant, formulated as IR-tablets and ER-tablets with improved stability and minimal odour. E~-tablets can be formulated by a variety of formulation principles, such as for instance hydrophilic gel-m2 ~i:~ t~l'ts, m2t-i~ t~_l_'s membrane dirfusion controlled rormuia.ions, osmollc pressure controlled dosaae -orms etc.
-:- WO 92/1017~ 2 ~ 9 717 ~ PCT/SE91/OOXl5 As the use of solid substances in tablet manufacture in general is advantageous and facilitates the production different ways to prepare solid dosage forms were investigated.
As it had been noticed that the ccmpound almokal~c 25 such in acidic solutions has a good stability, which makes it possible to autoclave it without noteworthy degradation, the addition of acid compounds were tested.
Although complex-binding to ion-e~change resins of viscous, unstable, pharmaoologic~1ly ac~fYe asen~S, ~o form a stabile solid comple~ suit~ie for pnarmaceut cal li processing has not been previousl~ described, this was tested with almokalant.
Thus, it was tested to use the polystyrene sulfonate complex of almokalant in the formulation of pharmaceutical dosage forms. It was then unexpectedly found that almokalant polystyrene sulphonate complex (A-PSS), had a much better stability, less repelling odour and was much easier to handle in tablet manufacture.
To form ER tablets it is necessary to mix the formed complex with e.g. a hydrophilic matrix. It is especially preferable to use hydroxypropyl methylcellulose as the gel forming substance. It is further preferred to use a mixture of HPMC containing both low and high molecular weight HPMC.
The use of different mixtures of HPMC gi~es according to known technics (Journal of Controlled release, S (1987) 159-172), different release rates of the active ingredient almokalant.
WO92/1017~ 4 PCT/SE91/OOX1C
EXAMPLES
Exam~le 1 Immediate release tablets of almokalant were prepared by mi~lns A-~SS 90 parts, lactose 85 parts, microcrystalline cellulos~ 9l parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
After drying the granulate was milled and then mixed with sodium stearyl fumarate and compressed to tablets.
A refe~enc2 pre?aration was produced by dissolving the free base in 2 2M hydrochloric acid solution and using this solution to granulate the excipients.
A-PSS tablet Ref.
Ex l Ex I
1. A-PSS corresp. to almokalant 50.0 Almokalant - 50.0 2. Lactose pwd 84.5 Lactose anhydrous - 106.8 Avicel~ PH lOl 9l.3 114.0 Povidone~ K-25 26.8 Polyvinyl pyrrolidone, cross-linked - 7.l Aerosil~ - 3.6 3. Water, purified 105 Hydrochloric acid 2M - 71.2 (corresp. to HCl) - (5.2) 4. Sodium stearyl fumarate 5.8 Magnesium stearate - 2.9 Talcum - ll.5 Pol w inyl pvrrolidone, cross-linked - 5.7 The .~-~SS ~blet wa3 ?r~pared by firs~ mi~ing ingredients l and 2. The mixture was g-anulated with 3. After drying and milling 4 was admixec, whereupon compression to WO92/10172 2 f~ 3 7 1 7 ,~ PCT/SE91/00815 tablets was performed on a Korsch Pharmapress lO0.
The reference tablet (Ref. ex. I) was prepared by maklng a granulating solution of the ingredients l and 3. The powders in 2 were mixed and then granulated with the prepared solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets compressed on the same machine.
A-PSS tablet.Ref.ex. I
Ex. l Punches: 9 mm lO mm Tablet weight: 298 mg307 mg Hardness: 7.5 kP6.7 kP
lS 2isintegration: 1-2 min.1-2 min.
Ex. l Ref.
A-PSS tabletEx. I
20 Stability data of storage in glass bottles. Degradation measured as area sum of byproducts in a HPLC-system 0 month 0.81 2.ll 2S l month in 2SC 0.88 2.83 l month in 50C l.82 3.41 3.5 months in 25C 0.88 2.87 Exam~le 2 Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 8S parts, microcrystalline cellulose 9l parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
After drying the granulate was milled and then mixed with the lubric3nt sodlum stear l fumarate whereupon compression to tablets was done.
2 o 9 !7 1 7 ~
A reference preparation (Ref. ex. II) was produced by dissolving the free base in an aqueous tartaric acid solution and using this solution to granulate the excipients.
A-~SS tablet P~e~. tabl t _ T
l. A-PSS corresp. to almoXalant 50.0 -Almokalant - 50.0 2. Lactose pwd 84.;
Lactose anhydrous - llO.7 Avicel~ PX lOl C'.3 ll-.3 Polyvidone K-25 25.8 li 3. Water, purified l3~ ;7.1 Tartaric acid - 21.5 4. Sodium stearyl fumarate 5.8 6.0 Talcum - 12.0 Polyvinyl pyrrolidone, cross-linked - 12.0 Punches: 9 mm lOmm Tablet weight: 298 mg 331mg Hardness: 7.5 kP 5.9kP
Disintegration: 1-2 min. 8min.
The A-PSS tablets were prepared by first mixing ingredients l and 2. The mixture was granulated with 3.
After drying and milling 4 was admixed, whereupon compression to tablets were performed on a Korsch Pharmapress lO0.
The reference tablet (Ref. ex. II) was prepared by making a granulating solution of l and 3. The powders 2 were mixed and granulated with the solution. After drving and milling the lubricant, glldant and disintegrant in 4 were admixed and tablets we~e csmo-essed on the ~me machl?e.
The odour intensitv of the two formulatlons were com~a-ed '~
':
2~717g immediately after manufacturing and after l month of storage in glass bottles.
Odour intensit~
A-PSS ta~lets Re~.
E:~. 2 Freshly prepared + ++
(some smell, but (pronounced smell not of onions.) of onions.) l month + ++
(some smell, but (stron~ s",ell of not of onions.) of onions) ExamPle 3 Immediate release tablets of almokalant can be prepared in suitable strengths.
In Ex. l and 2 a 50 mg preparation was described. Below are examples of 70 mg and l.8 mg preparations shown.
Ex 3a 70 mg Ex 3b l.8 mg l. A-PSS 127 3.3 Avicel~ PH l0l 148 29 Polyvidone~ K-90 35 2. Polyvidone~ g-90 l0 Polyvidone~ K-25 - 4.7 Water, purified 161 l9 3. Avicel~ PHl02 coarse grade - l07 Polyvinyl pyrrolidone, cross-lin~ed - 1 3 Sodium stearyl fumarate 1.6 i.4 . .
. :
WO92/101/2 ~ ~71 7 ~ 8 PCT/SE91/0081!
The A-PSS tablets were prepared by first mixing the ingredients l..The mixture was granulated with a solution made of ingredients 2. After drying and milling ingredients 3 were admixed, whereupon compression to S tablets were performed on a Korsch Pharmapress lO0.
Punches: lO mm 5.5xlO.5 mm Tablet weight: 322 mg 150 mg Hardness: 9-lO kP 9-lO kP
Disintegration (without discs): 0.6-l.0 min. 0.2-0.4 min.
l; ExamDle 4 Extended release tablets of almokalant were prepared by mixing A-PSS 95 parts, hydroxypropyl methylcellulose (HPMC) 50 cps 40 parts, HPMC lO000 cps 160 parts and hydroxypropyl cellulose (HPC) 50 parts and then granulating the mixture with ethanol 99.5%. After drying the granulate was milled and then mixed with sodium stearyl fumarate whereupon compression to tablets was done.
A reference preparation (Ref. ex. III) was made by dissolving the free base in ethanol ~99.5%) and using this solution to granulate the dry excipients, and otherwise following the same way of production.
Example 4 Ref.ex. III
Ingredient mg/tabletmg/tablet l. A-?SS cor-~sp. to ~lmokalan-50.0 ~lmokalant - 50.0 2. H~MC 50 C25 (Metolose~ 60SH50) 40.0 40.0 W092/10172 2 0 9 717 ~ PCT/SE91/00815 3. HPMC 10000 cps (Methocel0 ElOMCR) 160.0 160.0 4. H~C LF (Klucel~ LF) 50.0 50.0 5. Ethanol 99.5% 261 235 6. Sodium stearyl fumarate (Pruv~) 3.3 3.3 s Ingredients 1 to 4 were mixed. The mixture was granulated wi~h ethanol. ~fter dryin~ and millins the granulate was mixed with 6.
Compression to tablets was performed on a Korsch Pharmapress 100 with 11 mm circular punches. The tablet machine was e~uipped with compression force registration.
Tablet weight: 348 mg 303 mg " compression force: 8.6 kN 12.3 kN
" hardness: 5.5 kP 3.7 kP
Tablets made using the free base have inferior binding properties.
Odour intensitv A-PSS Reference tablets tablet (Ex. 4) ~Ref.ex. III) Freshly prepared + +++
~some smell, but tstrong smell not of onions.) of onions.) The release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/mln and the tablet placed in a stationary basket above the paddle, 500 ml buffer solution pH 6.~ kept at 37C was use~ as dissolu~ion medium.
-: , , ::
,: . ` . ,. :
wos2~10l72 2 0 9 717 ~ lo PCT/SE91/0~
A-PSS tablet Ref. tablet (Ex. 4) (Ref.ex. III) cumulative cumulative 5 hours % released % released average (min-max) aYe.age (min-m~) 2 15 (14-15) 2~ (28-29) 4 24 t23-2;) ~3 (~ 3) 6 34 (33-35) 55 (54-56) 51 (48-52) 71 (72-75) 24 91 (87-93) 102(100-'05) ExamPle 5 Extended release tablets of almokalant can be prepared in suitable strengths and with different release rates.
In Ex. 4 a preparation with 50 mg strength is described.
Below follows examples o$ 10 mg and 100 mg.
10 mg 100 mg Ex. 5a Ex. 5b Ingredient mg/tablet 1. A-PSS corresp. to almokalant10.0 100.0 2. Lactose pwd 100.0 40.0 HPMC 50 cps ~Metolose~ 60SXSO) 27.6 39.2 HPMC lOOOOcps ~Methocel~ ElOMCR) 110.4 146.4 HPC LF (~lucel LF) 25.0 3. Polyethylene glycol 20M
~Carbowax~ 20M) 10.0 Polyethylene glycol 6000 (Carbowax~ 6000) 4. Water, puri~ied 70.0 ~8.1 5. Sodium stearyl fumara-s (Pr~ ) 1.5 ~.3 . ~
: ` :
.
, .^ WO92/10172 2 ~ .~ 717 8 PCT/SE91/00815 1 and 2 were mixed. The mixture was granulated with a solution made of 3 and 4. After drying and milling the granulate was mixed with 5.
Compression to tablets was ~erf~rmed on a Korsch Pharmapress 100. The tablel machine was s~u~p~ed w'th compression force registration.
Punches, diameter: 10 mm 11 mm Tablet weight: 314 mg 459 mg compression force (XN): 11.0 11.4 " hardness (1~) 8.2 5.4 The release rate was de.erm ned .~om 6 individual .ablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary bas~et above the paddle. 500 ml buffer solution pH 6.8 ~ept at 37C was used as dissolution medium.
10 mg ER tablet 100 mg ER tablet Ex. 5aEx. 5b cumulative cumulative 25 hours % released ~ released average (min-max) average ~min-max) 2 27 (27-28) 17 ~17-18) 4 44 (43-45) 28 (26-29) 6 - - - - - 37 (35-39) 8 72 ~70-75) - - - - -- - - - - 55 ~52-60) 12 105 (96-109) - - - - -- - - - - 91 (84-95) 35 24 - - - - - 100(99-101) : , :' .' ' ' ~
;
2~71 73 W092/10t7~ 12 PCT/SE91/0081~--Exam~les 6-7 Controlled release tablets were prepared by granulating 54.3 parts active substance, 30.0 parts mannitol, 154 parts HP~.C 50 cps, 221 parts HPMC 10,000 cps, 37.5 parts HPC, 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Ex. 6) or PVP ~-25 (Ex. 7) dissolved in 105 parts of water. The dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate.
Example 6 E~mple 7 Inqredient mg/tablet 1. A-PSS corresp. to almokalant 30.0 30.O
2. Mannitol pwd 30.0 30.0 3. HPMC (Metolose0 60SH50)154.0 154.0 4. HPMC (Methocel0 ElOMCR)221.0 221.0 5. HPC (glucel~ LF) 37.5 37,5 6. Propyl gallate 0.3 0.3 7. PEG (Carbowax~ 20M) 45.0 PVP (Povidone~ R-25) - 4s.O
8. Water 105.0 105.0 9. Sodium stearyl fumarate (Pruv~) 2.7 2.7 Ingredients 1 to 6 were mixed. The mixture was granulated with a solution made of 7 and 8. After drying the granulate was mixed with 9.
Compression to tablets were performed on a ~orsch Pharmapress 100 with ll mm circular punches. The tablet machine was equipped with compression force registration .
E.c~m21~ 6 Exam~le 7 Tablet weight: 545 mg 54; ma :. .
. .
2~397178 compression force (kN): 20 19 tablet hardness (kP): 7.7 12.2 The release rate was determined i~ USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buf~er solution pH 6.8 Xept at 37C was used as dissolution medium.
Cumulative % released Average (min-max) E.Yam~1e 5 Exam~le 7 15 2h 17(17-18) 18(17-18) 4h 28(28-29) 28(28-29l 6h 38(38-39) 38(37-39) lOh 55(54-56) 54(53-56) 16h 74(73-76) 73(71-74) The examples show that PEG 20000 and PVP K-25 both function in the process.
Discussion From the examples it is quite obvious that the use of almokalant free base in pharmaceutical formulation - apart from the inconvenience of handling a sticky, viscous substance - results in dosage forms with inferior stability and palatability as well as in inferior technical properties. The use of almokalant polystyrene sulphonate complex in pharmaceutical formulation eases the handling and results in more stabile and more palatable dosage f orms.
The best mode of carrying out the invention known at present is to prepare the -ormulation according to E~ampies 6-7.
.
: ` , ..
,
Compression to tablets were performed on a ~orsch Pharmapress 100 with ll mm circular punches. The tablet machine was equipped with compression force registration .
E.c~m21~ 6 Exam~le 7 Tablet weight: 545 mg 54; ma :. .
. .
2~397178 compression force (kN): 20 19 tablet hardness (kP): 7.7 12.2 The release rate was determined i~ USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buf~er solution pH 6.8 Xept at 37C was used as dissolution medium.
Cumulative % released Average (min-max) E.Yam~1e 5 Exam~le 7 15 2h 17(17-18) 18(17-18) 4h 28(28-29) 28(28-29l 6h 38(38-39) 38(37-39) lOh 55(54-56) 54(53-56) 16h 74(73-76) 73(71-74) The examples show that PEG 20000 and PVP K-25 both function in the process.
Discussion From the examples it is quite obvious that the use of almokalant free base in pharmaceutical formulation - apart from the inconvenience of handling a sticky, viscous substance - results in dosage forms with inferior stability and palatability as well as in inferior technical properties. The use of almokalant polystyrene sulphonate complex in pharmaceutical formulation eases the handling and results in more stabile and more palatable dosage f orms.
The best mode of carrying out the invention known at present is to prepare the -ormulation according to E~ampies 6-7.
.
: ` , ..
,
Claims (7)
Claims
1. A pharmaceutical dosage form of almokalant wherein said almokalant in the form of a complex with polystyrene sulphonate optionally mixed with pharmaceutical excipients forms an oral solid dosage form.
2. A dosage form according to claim 1 wherein the pharmaceutical excipients contain a hydrophilic matrix.
3. A dosage form according to claim 2 wherein the hydrophilic matrix is hydroxypropyl methylcellulose.
4. A dosage form according to claim 3 wherein the hydroxypropyl methylcellulose contains both low and high molecular weight hydroxypropyl methylcellulose.
5. A process for the manufacture of a solid dosage form according to claim 1 wherein a) almokalant is reacted with polystyrene sulphonic acid to form a complex b) the complex is mixed with pharmaceutical excipients and an oral solid dosage form is prepared according to any known method.
6. A process according to claim 5, wherein the pharmaceutical excipients contain a hydrophilic matrix.
7. A process according to claim 6, wherein the hydrophilic matrix is hydroxypropyl methylcellulose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9003902-5 | 1990-12-07 | ||
| SE9003902A SE9003902D0 (en) | 1990-12-07 | 1990-12-07 | SOLID DOSAGE FORMS OF A DRUG |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2097178A1 true CA2097178A1 (en) | 1992-06-08 |
Family
ID=20381121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002097178A Abandoned CA2097178A1 (en) | 1990-12-07 | 1991-12-03 | Solid dosage forms of almokalant and processes for manufacture thereof |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0560821A1 (en) |
| JP (1) | JPH06503312A (en) |
| CN (1) | CN1063039A (en) |
| AP (1) | AP258A (en) |
| AU (1) | AU8930791A (en) |
| BG (1) | BG97851A (en) |
| CA (1) | CA2097178A1 (en) |
| CZ (1) | CZ103793A3 (en) |
| FI (1) | FI932554A (en) |
| HU (1) | HUT64217A (en) |
| IE (1) | IE914137A1 (en) |
| IL (1) | IL100150A0 (en) |
| IS (1) | IS3788A7 (en) |
| LT (1) | LTIP1717A (en) |
| MA (1) | MA22355A1 (en) |
| MX (1) | MX9102325A (en) |
| MY (1) | MY106776A (en) |
| NZ (1) | NZ240731A (en) |
| PT (1) | PT99719A (en) |
| SE (1) | SE9003902D0 (en) |
| SK (1) | SK55693A3 (en) |
| TN (1) | TNSN91117A1 (en) |
| TW (1) | TW215057B (en) |
| WO (1) | WO1992010172A1 (en) |
| YU (1) | YU186891A (en) |
| ZA (1) | ZA919264B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19602757A1 (en) | 1996-01-26 | 1997-07-31 | Boehringer Mannheim Gmbh | Solid instant release dosage forms and processes for their manufacture |
| GB9611328D0 (en) * | 1996-05-31 | 1996-08-07 | Zeneca Ltd | Pharmaceutical compositions |
| US6024981A (en) * | 1997-04-16 | 2000-02-15 | Cima Labs Inc. | Rapidly dissolving robust dosage form |
| JP4504467B2 (en) * | 1998-07-30 | 2010-07-14 | 佐藤製薬株式会社 | Orally disintegrating tablets |
| JP7426685B2 (en) * | 2018-06-14 | 2024-02-02 | 株式会社東洋新薬 | tablet |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8705150D0 (en) * | 1987-12-23 | 1987-12-23 | Haessle Ab | NOVEL ANTIARRHYTHMIC AGENTS |
| IL90245A (en) * | 1988-05-11 | 1994-04-12 | Glaxo Group Ltd | Resin adsorbate comprising ranitidine together with a synthetic cation exchange resin, its preparation and pharmaceutical compositions containing it |
| SE8902236D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL POLYSTYRENESULPHONATE |
-
1990
- 1990-12-07 SE SE9003902A patent/SE9003902D0/en unknown
-
1991
- 1991-11-22 ZA ZA919264A patent/ZA919264B/en unknown
- 1991-11-25 IL IL100150A patent/IL100150A0/en unknown
- 1991-11-25 TW TW080109239A patent/TW215057B/zh active
- 1991-11-26 NZ NZ240731A patent/NZ240731A/en unknown
- 1991-11-27 YU YU186891A patent/YU186891A/en unknown
- 1991-11-28 IE IE413791A patent/IE914137A1/en unknown
- 1991-12-02 AP APAP/P/1991/000338A patent/AP258A/en active
- 1991-12-02 MX MX9102325A patent/MX9102325A/en unknown
- 1991-12-03 WO PCT/SE1991/000815 patent/WO1992010172A1/en not_active Application Discontinuation
- 1991-12-03 MA MA22639A patent/MA22355A1/en unknown
- 1991-12-03 CA CA002097178A patent/CA2097178A1/en not_active Abandoned
- 1991-12-03 AU AU89307/91A patent/AU8930791A/en not_active Abandoned
- 1991-12-03 EP EP91920708A patent/EP0560821A1/en not_active Withdrawn
- 1991-12-03 CZ CS931037A patent/CZ103793A3/en unknown
- 1991-12-03 SK SK55693A patent/SK55693A3/en unknown
- 1991-12-03 JP JP4500117A patent/JPH06503312A/en active Pending
- 1991-12-03 HU HU9301670A patent/HUT64217A/en unknown
- 1991-12-06 IS IS3788A patent/IS3788A7/en unknown
- 1991-12-06 PT PT99719A patent/PT99719A/en not_active Application Discontinuation
- 1991-12-06 MY MYPI91002267A patent/MY106776A/en unknown
- 1991-12-06 TN TNTNSN91117A patent/TNSN91117A1/en unknown
- 1991-12-07 CN CN91112789A patent/CN1063039A/en active Pending
-
1993
- 1993-06-04 FI FI932554A patent/FI932554A/en not_active Application Discontinuation
- 1993-06-04 BG BG97851A patent/BG97851A/en unknown
- 1993-12-30 LT LTIP1717A patent/LTIP1717A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI932554A (en) | 1993-06-08 |
| MY106776A (en) | 1995-07-31 |
| NZ240731A (en) | 1993-10-26 |
| EP0560821A1 (en) | 1993-09-22 |
| ZA919264B (en) | 1992-08-26 |
| PT99719A (en) | 1992-10-30 |
| MX9102325A (en) | 1992-06-01 |
| HU9301670D0 (en) | 1993-09-28 |
| SE9003902D0 (en) | 1990-12-07 |
| SK55693A3 (en) | 1993-10-06 |
| LTIP1717A (en) | 1995-07-25 |
| CN1063039A (en) | 1992-07-29 |
| TNSN91117A1 (en) | 1992-10-25 |
| JPH06503312A (en) | 1994-04-14 |
| HUT64217A (en) | 1993-12-28 |
| AP258A (en) | 1993-06-03 |
| YU186891A (en) | 1994-04-05 |
| MA22355A1 (en) | 1992-07-01 |
| AP9100338A0 (en) | 1992-01-31 |
| TW215057B (en) | 1993-10-21 |
| WO1992010172A1 (en) | 1992-06-25 |
| CZ103793A3 (en) | 1994-02-16 |
| BG97851A (en) | 1994-04-29 |
| IS3788A7 (en) | 1992-06-08 |
| IL100150A0 (en) | 1992-08-18 |
| FI932554A0 (en) | 1993-06-04 |
| IE914137A1 (en) | 1992-06-17 |
| AU8930791A (en) | 1992-07-08 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |