CA2175293A1 - Pharmaceutical preparations having controlled release of active compound and processes for their preparation - Google Patents
Pharmaceutical preparations having controlled release of active compound and processes for their preparationInfo
- Publication number
- CA2175293A1 CA2175293A1 CA 2175293 CA2175293A CA2175293A1 CA 2175293 A1 CA2175293 A1 CA 2175293A1 CA 2175293 CA2175293 CA 2175293 CA 2175293 A CA2175293 A CA 2175293A CA 2175293 A1 CA2175293 A1 CA 2175293A1
- Authority
- CA
- Canada
- Prior art keywords
- active compound
- weight
- parts
- pharmaceutical preparation
- solid pharmaceutical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Abstract
The invention relates to pharmaceutical preparations having controlled release of active compound and to processes for their preparation, in particular for poorly soluble active compounds having problematic bioavailability.
Description
2~ 7~293 Pharmaceutical Preparations Eaving Controlled ~elease of Active Compound and Processes for Their Preparation The invention relates to ~h~ eutical preparations having controlled release of active compound and to processes for their preparation, in particular for poorly soluble active compounds having problematic bioavallability.
Numerous pharmaceutically acti~e compounds with low water solubility are difficult to formulate into pharmaceutical formulations which are sufficiently stable on storage and have an adequate bioavallabllity to be of practical use. To achleve adequate bioavailability, poorly soluble active compounds, e.g.
dihydropyridines, are supplied as preparations which exhibit high release rates within a short time in order to obtain adequate plasma levels.
It is known that active compounds in amorphous or dissolved form often have a higher bioavailability than the corresponding crystalline active compounds. In particular, compounds having a tendency to recrystallize cause problems, as often their bioavailability is not reproducible or decreases significantly after relatively long storage times.
To improve safety and patient compliance, it is desirable, in particular for long-term treatments, to reduce the daily administration fre~uency, e.g. to once or twice daily.
The invention relates to an orally administrable solid, stable pharmaceutical preparation having high bioavail-ability and controlled, long-lasting release, comprising 1 part by weight of the active compound in amorphous form as a 217~293 copreclpitate in 0 . 5 to lO parts by weight of polyvinyl-pyrrolidone, preferably l . 0 to 5 . 0 parts by weight, having an average molecular weight of about l5,000 to l,000,000.
preferably up to lO0,000, and a release-delaying component consisting essentially of 0 . Ol to 15 . 0 parts by weight of a ~el-forming polymer and, if appropriate, other auxiliaries and f Lllers .
The unexpected iUl~)L(~V. t in the storage stability of active compound coprecipitates and controlled release pharmaceutical preparations comprising the latter was found as a general principle for poarly water-soluble active compounds .
Examples which may be mentioned are the dihydro-pyridines, such as nifedipine, nimodipine, nitrendipine, nisoldipine, felodipine or nicardipine, non-steroidal anti-inflammatory active compounds such as ketoprofen, ibuprofen or flurbiprofen or antibacterial active compounds, e.g. from the suphonamide, quinolone, tetracycline or macrolide classes.
Particularly typical representatives which may be mentioned are the active compounds nimodipine and nifedipine. Nimodipine and nifedipine have solubilities of only about l.0 and 7.0 mg/l, respectively. Nimodipine tablets currently on the market exhibit a rapid release of active compound and require administration three times daily in order to guarantee adequate plasma levels (DE 32 05 399). The n1r~ ;ne controlled-release tablets according to the invention exhibit a long-lasting action and require administration twice daily.
2~52~
Previous attempts to prepare a nimodipine delayed-release formulation on the basis of conventional technologies, e.g. using very finely ground nimodipine crystals, did not lead to success. All attempts with this poorly soluble active compound produced inadequate bioavailability.
The known method of dissolving active compounds in amorphous form in polymers which are liquef ied by heating (melt process or melt extrusion process) is very complicated and needs a relatively large proportion of auxiliary (compare EP 0 240 904 and EP-A-0 240 906) excipients.
Another method of increasing the release rate of poorly soluble active compounds is adsorption of the active compounds together with a pharmacologically inactive pharma-ceutical auxiliary on a crosslinked polymer. An essential component of all these adsorbates is the water-insoluble, crosslinked polymer. These adsorbates are mixed with swellable polymers to prepare controlled-release formulations (EP 0 429 187 and US 5 128 142).
Surprisingly, it has been found that delayed-release tablets containing poorly-soluble active compounds can be prepared even without the crosslinked polymers. The proportion of auxiliary materials in the tablet is thus distinctly reduced and a smaller, easier-to-swallow tablet can be prepared.
It also appears that thc controlled-release tablets prepared in this way exhibit a surprisingly high storage stability. When in-vitro tests are carrled out, they exhibit an almost linear release and crystalline active compound is no ~ 217~93 longer detectable by customary methods, e.g. a~-ray analysis, in the respecti~e coprecipitates or dosage ~orms.
The controlled-release preparations according to the invention can have a customary composition of active compounds and auxiliaries. They preferably contain 1 part by weight of active compound in amorphous form, 0 . 5 to 10 parts by weight, preferably 1 to 4 parts by weight, of the coprecipitate-forming polymer, in particular polyvinylpyrrolidone (PVP) having an average molecular weight of 15,000 to 1,000,000 and optionally 0.01 to 15.0 parts by weight, preferably 0.1 to 4 parts by weight, of a gel former, preferably hydroxypropylmethyl-cellulose (EIPMC). Further processing to give a controlled-release form is likewise carried out by customary methods, e.g.
if necessary by the additional use of one or more polymers which form gels in the presence of water. The total amount of ~he gel-forming polymers needed is ~PrPnrlPnt on the retardation effect desired and can be varied appropriately in a customary manner .
In the case of the active compound-polymer coprecipitate, organic solvents which simultaneously dissolve the active compound and the polymer are preferably employed.
Active compounds and polymers can also be dissolved separately in different solvents and the solutions then mixed. Particu-larly suitable solvents are the low molecular weight halogenated hydrocarbons, ketones and/or alcohols each having up to 6 C
atoms, in particular having up to 4 C atoms. Of particular interest are solvents which can be removed and recovered again in simple manner, such as acetone, methylene chloride, chloro-form, ethanol, methanol and isopropanol or their mixtures.
- 3a -2~
Le A 31 972-EQreiyn C~ rltries Suitable Cu~ );LdLe formers are the customary polymers, in particular PVP having an average molecular weight of 15,0û0 to 1,000,000, preferably the PVP types on themarket, including their copolymers, which are marketed under the names KOLLIDON
12PF, -17PF, -25, -30, -90 or-~,rArS4 5 Suitable gel formers are also the customary polymers, preferably the cellulose ethers having low, average or high viscosity such as l~yJ~w~ylllcthylcellulose, l~yJlu~yl,Lllyl-cellulose, hyJlu~y~lu~ylcellulose, l~yJ~ui~yl)u~ylcellulose, l~yJlu,~yLJIu~ ;llyl-cellulose, sodium l,d bu~y~ ylcellulose~ calcium carboxymethylcellulose, methylcellu-lose, ethylcellulose and/or polyethylene glycols. Cellulose ethers can be employed as 10 release-delaying ~ and also as ..c~ JiLdLe formers.
One possibility for the preparation of the uù~Jleui~J;Ldte~ is the dissolution of one part by weight of the active compound with 0.5 to 10 parts by weight, preferably I to4 parts by weight, of the ~,ople~ d~e-forming polymer (PVP) and optionally the cellulose ether in an amount of organic solvent in which both ,,ull.~ull~ dissolve or 15 separate solutions of active compound and polymer in different solvents and combination of these solutions to give one solution. This solution can be used directly for g,, 1l-l;"~ the 0.01 to 13 parts by weight, preferably 0.1 to 2 parts by weight, of gel former and/or other auxiliaries or alternatively the other auxiliaries/gel formers can be suspeEded in this solution and the organic solvent can then be removed. The 20 removal of the solvent is carried out by customary methods, e.g. at elevated ~e~ ,.aLu~us between 70 and 150C, preferably between 90 and 120C, under a pressure of 5 to 200 mbar. Customary spray-drying processes are also suitable for this purpose. If necessary, this drying can take place under a nitrogen atmosphere. The duration of the drying is determined by the nature and amount of the solvent and the 25 other ~.-.."~ and can be between 30 minutes and 3 days. Drying preferably takes place within 2 to 48 hours. In aclditicn, the d~ A~P cbtA~ned con be subjected to an cpt~nal cll y ccrrlpact~n step in order to i chieve, for example, i~ c~esired hlLlc vol~ne of A~out 1.5 to 3.5 rnl/g.
The ~,ulJlec;~iL~Le premixture thus obtained can be converted into finished 2~
Le A 31 072-~sreiL~n Cmlnfries "~ ;cal preparations either directiy or by addition of an additional release-delaying component or auxiliaries. When preparing controlled-release preparations, this is carried out, for example, by mixing I part by weight of premixture with up to10 parts by weight of a gel-forming polymer and, if appropriate, further auxiliaries.
S Additionai gel formers are only employed if required, i.e. the totai amount of gel former controls the release rate. This mixture is then further processed by customary methods to give tablets or other solid dosage forms.
Gel-forming polymers of the release-delaying ~- ," which may be mentioned are preferably lly~iluAy~lllylcellulose (HEC), Ly~ilu~yl~lu~ylcellulose (I{PC), 10 lly i~w~y~lu~yllllethylcellulose (HPMC), sodium carboxymethylcellulose (Na CMC), methylcellulose (MC) and ethylcellulose (EC). Parficularly suitable cellulose derivatives are those based on IIPMC. Other gel formers such as sodium aiginate, ~,alla~ all~, ort~mqnnzln agar-agar, gum arabic, guar gum, xanthan gum and cdli,u~y~ulyl..~li.ylene or derivatives of starches, pectins, chiùn, polyethylene glycol, polyvinyl alcohol, ~.ù~ulylll~ of acrylic and methacrylic acid esters and their mixtures can also be employed. Preferably those polymers are used which have a viscosity of a 2% w/w solution at 20C of at least IS mPa s~'.
The controlled-release preparations according to the invention ~ cd;~ 'y contain 10 to 400 mg of active compound per individual preparation. In the case of controlled-release preparations, the dose is 20 to 400 mg, preferably 30 to 120 mg of active compound per individuai dose.
The controlled-release preparations according to the invention produce positive effects especially if the residual solvent content in the ~UlJlt~ d,t~:: is not too high. Preferabiy, the residuai solvent content should be not greater than I % by weight, based on the weight of the CU~ d~, preferably less than 0.8% by weight.
The controlled-release Cu,lJlt~ui~J;id~: tablets according to the invention, which contain, for example, 9û mg of amorphous nimodipine, exhibit extremely good stûrage stability.
With knowledge of the prior art, it was not to be expected that a stable and small 2~7~293 Le A 31 Q72-~orei~n ~rlln~ri.qc delayed-release ~ " tablet having satisfactory bioavailability for poorly soluble active compounds such as nimodipine or nifedipine can be prepared without water-insoluble crosslinked polymers (see EP O 429 187 and US 5 128 142).
In the case of light ,.~~ iV~ active ,Olllpl ' such as nifedipine and nin~ irir~, the S control~ed-release tablets must then be provided with a light-protective coating in order that the active compound is not degraded by the light. The coating is carried out, for exarnple, by spraying an aqueous suspension consisting of: E~PC (film former), PEG
(plasticizer), titanium dioxide and iron oxide (light-scattering and absorbing pigments).
During the coating procedure, hot air is blown onto the tablet bed.
10 The follo~-ving working examples illustrate the subject of the invention without restricting it.
2~7~g3 Le ~ 31 Q72-For~i~n C~n~ries = .
P~ of active ComG~ o, c ' ' /i ' Example ~
I kg of nimo~iri~ is dissolved together with 2.5 kg of PVP (MW 29,000) in sufficient acetone, The acetone is then removed at elevated ~~ and reduced pressure 5 down to a residual solvent content of less than 0.6%, The dried ~UIJle~ JikiLe iS
screened and the fine powder obtained can be further processed by customary methods to give tablets, E~amPle 2 In analogy to Example 1, a ~ contairling 1 part of nimo~irinr and 2.5 parts 10 of PVP and I part of HPMC 50 CP is prepared. Instead of acetone,the solvent isopropanol is employed.
E~:ample 3 In analogy to Example 2, instead of HPMC 50 CP,the polymer HPMC 1500 CP is employed.
15 ExamPle 4 In analogy to Example 2, instead of HPMC 50 CP,the polymer HPMC 4000 CP is employed.
ExamPle 5 ,~
In analogy to Example 1, 2.5 kg of PVP of average molecular weight 45,000 are 20 employed, E~cample 6 In analogy to Example 2, 1.5 kg of PVP of molecular weight 1,000,000 are employed and also, instead of isopropanol, the solvent ethanol is employed, The ethanolicsolution of nimodipine and PVP is clear before HPMC 50 CP is added, , . _ .. . . .. .. . .. . .... . . .......
2~ 93 Le A 31 07~-Porei~n C~l~nt~ie~ 8 -ExamPle 7 Composition is as in Example 4. Nimodipine and PVP are dissolved in acetone or nimo~lirine iS separately dissolved in acetone and PVP in ethanol and the solutions are then mixed This clear solution is used for granulation with HPMC 4000 CP The 5 solvent is then removed by customary methods.
E2~ample X
In analogy to Example 7, instead of nimodipine the active compound nifedipine isemployed Example 9 In analogy to Example 8, 1.5 kg of PVP of molecular weight 1,000,000 are employed.
Example 10 In analogy to Example 8, instead of HMPC 4,000 CP,the polymer HPMC 100,000 CP
is employed 3.0 kg of PVP (MW 29,000) are employed Example 11 15 In analogy to Example 8, instead of PVP,the copolymer Copolyvidon/ICollidon V~ 64 is employed.
ExamPle 12 In analogy to Example 1, instead of acetone,the solvent ethanol is employed and instead of PVP the polymer HPMC 15,000 CP is employed.
20 Example 13 In analogy to Example 1, instead of acetone,the solvent isopropanol is employed Example 14 In analogy to Example 1, instead of acetone, the solvent methylene chloride is employed.
~1 ~52~3 Le A ~ I QZ2-Porei~z~ Collntries ExamPle 15 T~le ~iu~ dL~ which was obtained analogous to Example ~ is prepared under reduced pressure (<300 mbar) in a fluidized-bed granulator by spray ~r~n~ tinn at lp~l~ul~s between 60 and 120C
S Examl~le 16 In analogy to Example 1, instead of ,\."u.l.~ r.,the active compound nifedipine and 2.0 kg of PVP (MW 29,000) are employed.
Example 17 In analogy to Example 1, instead of ~,i.l.~..l;l"l.f~the active compound ketoprofen is 10 employed.
Example 18 In analogy to Example 1, 1.5 kg of PVP of average molecular weight 1,000,000 areemployed. Instead of ~rPtnnP,Pth~nnl is employed.
Example 19 _ .
15 In analogy to Example 12, instead of HPMC,the polymer l~yd~u~y~!~u~Jylcellulose (HPC) is employed.
Example 20 In analogy to Example 19, instead of HPC,the polymer methylcellulose (MC) is employed.
20 Exam~le 21 In analogy to Example 20, instead of MC,the polymer l~yd~u~yc Ll~lcellulose (HEC) is employed).
Exam~le 22 In analogy to Example ~, instead of nimodipine,the active compound nifedipine is25 employed.
~ ~1 7~2~3 Le A ~1 0~2-Foreign ~mlntries Example 23 In analogy to Example 5, instead of nimo~irin~the active compound nifedipine is employed.
Example 24 5 In analogy to Example 12, instead of ~ l;r;~ r~th~ active compound nifedipine is employed.
E~ample 25 In analogy to Example 19, instead of 1..~....1;l,;". ,the actiYe compound nifedipine is employed.
10 Exam~le 26 In analogy to Example 20, instead of ";"~n~ ,th~ active compound nifedipine is employed.
Examl~le 27 In analogy to Example 21, instead of nimn~lirinl~the active compound nifedipine i~
15 employed.
2 1 75~g3 Le A, 31 ~7~-FQ~ei~n Cf~l~ntri~
' r and/or p ' ' ' r of the release-delaYin~ ~ r and further processin~ as a solid, ' ~ ' ~' dosaEe form E~ample 28 75.76 parts by weight of the G~l~,;pi~dl~ powder, obtained according to Example 1, S are mixed with 24.05 parts by weight of HPMC-4000 CP and then mixed with 0.19 parts by weight of m~ m stearate and afterwards ~;ou.p.~,;,.,~J to give tablets, each containing 90 mg of nimt~l1irir~ The tablets obtained are then coated.
Example 29 74.12 parts by weight of the u~ Jildl~ powder, obtained according to Example 1, are mixed with 21.74 parts by weight of HPMC-4000 CP, 3.95 parts by weight of HPMC-I500 CP and 0.19 part by weight of m~r~illm stearate and afterwards ~,uu~ cJ to give tablets, each containing 90 mg of nimn~1irine The tablets obtained are coated in analogy to Example 28.
E~amPle 30 67.15 parts by weight of the ~ lr~ci~;ldl~ powder, obtained according to Example 18, are mixed with 32.6 parts by weight of HPMC 1500 CP and 0.25 part by weight of magnesium stearate and afterwards c~,uu~ ,J to give tablets, each containing 90 mg of nim~(lirine The tablets obtained are coated in analogy to Example 28.
E~ample 31 84.2 parts by weight of the Co~llr~ dl~ powder, obtained according to Example 2, are mixed with 15.6 parts by weight of HPMC-4000 CP, compacted in dry form, screenedand then mixed with 0.2 part by weight of m~nP~ m stearate and afterwards C~ d to give tablets The tablets obtained are then coated.
E~amPle 32 53.8 parts by weight of the ~,~pl~Ci~ild~ powder, obtained according to Example 23, are mixed with 41 parts by weight of HPMC-4000 CP and 5 parts by weight of lactose and 0.2 part by weight of magnesium stearate and afterwards compressed to give ~ ~7~g3 Le A 31 97~-Forei~n Count~ies tablets. The tablets obtained are then coated.
E~amr)le 33 49.9 parts by weight of tne cu~"~u;~ ,L~ powder, obtained according to Example 16, are mixed with the same amount of HPMC-IS,000 CP and 0.2 part by weight of S IIIA~ 11 stearate and afterwards cul~ ,J to give tablets. The tablets obtained are then coated.
E~amr~le 34 88 parts by weight of the ,U~lt~ J;LdL~ powder, obtained according to Example 10, are mixed with 11.7 parts by weight of HPMC 100,000 CP and 0.3 part by weight of 10 mAgnPeillm stearate and afterwards cull.~ ,l to give tablets. The tablets obtained are then coated.
Numerous pharmaceutically acti~e compounds with low water solubility are difficult to formulate into pharmaceutical formulations which are sufficiently stable on storage and have an adequate bioavallabllity to be of practical use. To achleve adequate bioavailability, poorly soluble active compounds, e.g.
dihydropyridines, are supplied as preparations which exhibit high release rates within a short time in order to obtain adequate plasma levels.
It is known that active compounds in amorphous or dissolved form often have a higher bioavailability than the corresponding crystalline active compounds. In particular, compounds having a tendency to recrystallize cause problems, as often their bioavailability is not reproducible or decreases significantly after relatively long storage times.
To improve safety and patient compliance, it is desirable, in particular for long-term treatments, to reduce the daily administration fre~uency, e.g. to once or twice daily.
The invention relates to an orally administrable solid, stable pharmaceutical preparation having high bioavail-ability and controlled, long-lasting release, comprising 1 part by weight of the active compound in amorphous form as a 217~293 copreclpitate in 0 . 5 to lO parts by weight of polyvinyl-pyrrolidone, preferably l . 0 to 5 . 0 parts by weight, having an average molecular weight of about l5,000 to l,000,000.
preferably up to lO0,000, and a release-delaying component consisting essentially of 0 . Ol to 15 . 0 parts by weight of a ~el-forming polymer and, if appropriate, other auxiliaries and f Lllers .
The unexpected iUl~)L(~V. t in the storage stability of active compound coprecipitates and controlled release pharmaceutical preparations comprising the latter was found as a general principle for poarly water-soluble active compounds .
Examples which may be mentioned are the dihydro-pyridines, such as nifedipine, nimodipine, nitrendipine, nisoldipine, felodipine or nicardipine, non-steroidal anti-inflammatory active compounds such as ketoprofen, ibuprofen or flurbiprofen or antibacterial active compounds, e.g. from the suphonamide, quinolone, tetracycline or macrolide classes.
Particularly typical representatives which may be mentioned are the active compounds nimodipine and nifedipine. Nimodipine and nifedipine have solubilities of only about l.0 and 7.0 mg/l, respectively. Nimodipine tablets currently on the market exhibit a rapid release of active compound and require administration three times daily in order to guarantee adequate plasma levels (DE 32 05 399). The n1r~ ;ne controlled-release tablets according to the invention exhibit a long-lasting action and require administration twice daily.
2~52~
Previous attempts to prepare a nimodipine delayed-release formulation on the basis of conventional technologies, e.g. using very finely ground nimodipine crystals, did not lead to success. All attempts with this poorly soluble active compound produced inadequate bioavailability.
The known method of dissolving active compounds in amorphous form in polymers which are liquef ied by heating (melt process or melt extrusion process) is very complicated and needs a relatively large proportion of auxiliary (compare EP 0 240 904 and EP-A-0 240 906) excipients.
Another method of increasing the release rate of poorly soluble active compounds is adsorption of the active compounds together with a pharmacologically inactive pharma-ceutical auxiliary on a crosslinked polymer. An essential component of all these adsorbates is the water-insoluble, crosslinked polymer. These adsorbates are mixed with swellable polymers to prepare controlled-release formulations (EP 0 429 187 and US 5 128 142).
Surprisingly, it has been found that delayed-release tablets containing poorly-soluble active compounds can be prepared even without the crosslinked polymers. The proportion of auxiliary materials in the tablet is thus distinctly reduced and a smaller, easier-to-swallow tablet can be prepared.
It also appears that thc controlled-release tablets prepared in this way exhibit a surprisingly high storage stability. When in-vitro tests are carrled out, they exhibit an almost linear release and crystalline active compound is no ~ 217~93 longer detectable by customary methods, e.g. a~-ray analysis, in the respecti~e coprecipitates or dosage ~orms.
The controlled-release preparations according to the invention can have a customary composition of active compounds and auxiliaries. They preferably contain 1 part by weight of active compound in amorphous form, 0 . 5 to 10 parts by weight, preferably 1 to 4 parts by weight, of the coprecipitate-forming polymer, in particular polyvinylpyrrolidone (PVP) having an average molecular weight of 15,000 to 1,000,000 and optionally 0.01 to 15.0 parts by weight, preferably 0.1 to 4 parts by weight, of a gel former, preferably hydroxypropylmethyl-cellulose (EIPMC). Further processing to give a controlled-release form is likewise carried out by customary methods, e.g.
if necessary by the additional use of one or more polymers which form gels in the presence of water. The total amount of ~he gel-forming polymers needed is ~PrPnrlPnt on the retardation effect desired and can be varied appropriately in a customary manner .
In the case of the active compound-polymer coprecipitate, organic solvents which simultaneously dissolve the active compound and the polymer are preferably employed.
Active compounds and polymers can also be dissolved separately in different solvents and the solutions then mixed. Particu-larly suitable solvents are the low molecular weight halogenated hydrocarbons, ketones and/or alcohols each having up to 6 C
atoms, in particular having up to 4 C atoms. Of particular interest are solvents which can be removed and recovered again in simple manner, such as acetone, methylene chloride, chloro-form, ethanol, methanol and isopropanol or their mixtures.
- 3a -2~
Le A 31 972-EQreiyn C~ rltries Suitable Cu~ );LdLe formers are the customary polymers, in particular PVP having an average molecular weight of 15,0û0 to 1,000,000, preferably the PVP types on themarket, including their copolymers, which are marketed under the names KOLLIDON
12PF, -17PF, -25, -30, -90 or-~,rArS4 5 Suitable gel formers are also the customary polymers, preferably the cellulose ethers having low, average or high viscosity such as l~yJ~w~ylllcthylcellulose, l~yJlu~yl,Lllyl-cellulose, hyJlu~y~lu~ylcellulose, l~yJ~ui~yl)u~ylcellulose, l~yJlu,~yLJIu~ ;llyl-cellulose, sodium l,d bu~y~ ylcellulose~ calcium carboxymethylcellulose, methylcellu-lose, ethylcellulose and/or polyethylene glycols. Cellulose ethers can be employed as 10 release-delaying ~ and also as ..c~ JiLdLe formers.
One possibility for the preparation of the uù~Jleui~J;Ldte~ is the dissolution of one part by weight of the active compound with 0.5 to 10 parts by weight, preferably I to4 parts by weight, of the ~,ople~ d~e-forming polymer (PVP) and optionally the cellulose ether in an amount of organic solvent in which both ,,ull.~ull~ dissolve or 15 separate solutions of active compound and polymer in different solvents and combination of these solutions to give one solution. This solution can be used directly for g,, 1l-l;"~ the 0.01 to 13 parts by weight, preferably 0.1 to 2 parts by weight, of gel former and/or other auxiliaries or alternatively the other auxiliaries/gel formers can be suspeEded in this solution and the organic solvent can then be removed. The 20 removal of the solvent is carried out by customary methods, e.g. at elevated ~e~ ,.aLu~us between 70 and 150C, preferably between 90 and 120C, under a pressure of 5 to 200 mbar. Customary spray-drying processes are also suitable for this purpose. If necessary, this drying can take place under a nitrogen atmosphere. The duration of the drying is determined by the nature and amount of the solvent and the 25 other ~.-.."~ and can be between 30 minutes and 3 days. Drying preferably takes place within 2 to 48 hours. In aclditicn, the d~ A~P cbtA~ned con be subjected to an cpt~nal cll y ccrrlpact~n step in order to i chieve, for example, i~ c~esired hlLlc vol~ne of A~out 1.5 to 3.5 rnl/g.
The ~,ulJlec;~iL~Le premixture thus obtained can be converted into finished 2~
Le A 31 072-~sreiL~n Cmlnfries "~ ;cal preparations either directiy or by addition of an additional release-delaying component or auxiliaries. When preparing controlled-release preparations, this is carried out, for example, by mixing I part by weight of premixture with up to10 parts by weight of a gel-forming polymer and, if appropriate, further auxiliaries.
S Additionai gel formers are only employed if required, i.e. the totai amount of gel former controls the release rate. This mixture is then further processed by customary methods to give tablets or other solid dosage forms.
Gel-forming polymers of the release-delaying ~- ," which may be mentioned are preferably lly~iluAy~lllylcellulose (HEC), Ly~ilu~yl~lu~ylcellulose (I{PC), 10 lly i~w~y~lu~yllllethylcellulose (HPMC), sodium carboxymethylcellulose (Na CMC), methylcellulose (MC) and ethylcellulose (EC). Parficularly suitable cellulose derivatives are those based on IIPMC. Other gel formers such as sodium aiginate, ~,alla~ all~, ort~mqnnzln agar-agar, gum arabic, guar gum, xanthan gum and cdli,u~y~ulyl..~li.ylene or derivatives of starches, pectins, chiùn, polyethylene glycol, polyvinyl alcohol, ~.ù~ulylll~ of acrylic and methacrylic acid esters and their mixtures can also be employed. Preferably those polymers are used which have a viscosity of a 2% w/w solution at 20C of at least IS mPa s~'.
The controlled-release preparations according to the invention ~ cd;~ 'y contain 10 to 400 mg of active compound per individual preparation. In the case of controlled-release preparations, the dose is 20 to 400 mg, preferably 30 to 120 mg of active compound per individuai dose.
The controlled-release preparations according to the invention produce positive effects especially if the residual solvent content in the ~UlJlt~ d,t~:: is not too high. Preferabiy, the residuai solvent content should be not greater than I % by weight, based on the weight of the CU~ d~, preferably less than 0.8% by weight.
The controlled-release Cu,lJlt~ui~J;id~: tablets according to the invention, which contain, for example, 9û mg of amorphous nimodipine, exhibit extremely good stûrage stability.
With knowledge of the prior art, it was not to be expected that a stable and small 2~7~293 Le A 31 Q72-~orei~n ~rlln~ri.qc delayed-release ~ " tablet having satisfactory bioavailability for poorly soluble active compounds such as nimodipine or nifedipine can be prepared without water-insoluble crosslinked polymers (see EP O 429 187 and US 5 128 142).
In the case of light ,.~~ iV~ active ,Olllpl ' such as nifedipine and nin~ irir~, the S control~ed-release tablets must then be provided with a light-protective coating in order that the active compound is not degraded by the light. The coating is carried out, for exarnple, by spraying an aqueous suspension consisting of: E~PC (film former), PEG
(plasticizer), titanium dioxide and iron oxide (light-scattering and absorbing pigments).
During the coating procedure, hot air is blown onto the tablet bed.
10 The follo~-ving working examples illustrate the subject of the invention without restricting it.
2~7~g3 Le ~ 31 Q72-For~i~n C~n~ries = .
P~ of active ComG~ o, c ' ' /i ' Example ~
I kg of nimo~iri~ is dissolved together with 2.5 kg of PVP (MW 29,000) in sufficient acetone, The acetone is then removed at elevated ~~ and reduced pressure 5 down to a residual solvent content of less than 0.6%, The dried ~UIJle~ JikiLe iS
screened and the fine powder obtained can be further processed by customary methods to give tablets, E~amPle 2 In analogy to Example 1, a ~ contairling 1 part of nimo~irinr and 2.5 parts 10 of PVP and I part of HPMC 50 CP is prepared. Instead of acetone,the solvent isopropanol is employed.
E~:ample 3 In analogy to Example 2, instead of HPMC 50 CP,the polymer HPMC 1500 CP is employed.
15 ExamPle 4 In analogy to Example 2, instead of HPMC 50 CP,the polymer HPMC 4000 CP is employed.
ExamPle 5 ,~
In analogy to Example 1, 2.5 kg of PVP of average molecular weight 45,000 are 20 employed, E~cample 6 In analogy to Example 2, 1.5 kg of PVP of molecular weight 1,000,000 are employed and also, instead of isopropanol, the solvent ethanol is employed, The ethanolicsolution of nimodipine and PVP is clear before HPMC 50 CP is added, , . _ .. . . .. .. . .. . .... . . .......
2~ 93 Le A 31 07~-Porei~n C~l~nt~ie~ 8 -ExamPle 7 Composition is as in Example 4. Nimodipine and PVP are dissolved in acetone or nimo~lirine iS separately dissolved in acetone and PVP in ethanol and the solutions are then mixed This clear solution is used for granulation with HPMC 4000 CP The 5 solvent is then removed by customary methods.
E2~ample X
In analogy to Example 7, instead of nimodipine the active compound nifedipine isemployed Example 9 In analogy to Example 8, 1.5 kg of PVP of molecular weight 1,000,000 are employed.
Example 10 In analogy to Example 8, instead of HMPC 4,000 CP,the polymer HPMC 100,000 CP
is employed 3.0 kg of PVP (MW 29,000) are employed Example 11 15 In analogy to Example 8, instead of PVP,the copolymer Copolyvidon/ICollidon V~ 64 is employed.
ExamPle 12 In analogy to Example 1, instead of acetone,the solvent ethanol is employed and instead of PVP the polymer HPMC 15,000 CP is employed.
20 Example 13 In analogy to Example 1, instead of acetone,the solvent isopropanol is employed Example 14 In analogy to Example 1, instead of acetone, the solvent methylene chloride is employed.
~1 ~52~3 Le A ~ I QZ2-Porei~z~ Collntries ExamPle 15 T~le ~iu~ dL~ which was obtained analogous to Example ~ is prepared under reduced pressure (<300 mbar) in a fluidized-bed granulator by spray ~r~n~ tinn at lp~l~ul~s between 60 and 120C
S Examl~le 16 In analogy to Example 1, instead of ,\."u.l.~ r.,the active compound nifedipine and 2.0 kg of PVP (MW 29,000) are employed.
Example 17 In analogy to Example 1, instead of ~,i.l.~..l;l"l.f~the active compound ketoprofen is 10 employed.
Example 18 In analogy to Example 1, 1.5 kg of PVP of average molecular weight 1,000,000 areemployed. Instead of ~rPtnnP,Pth~nnl is employed.
Example 19 _ .
15 In analogy to Example 12, instead of HPMC,the polymer l~yd~u~y~!~u~Jylcellulose (HPC) is employed.
Example 20 In analogy to Example 19, instead of HPC,the polymer methylcellulose (MC) is employed.
20 Exam~le 21 In analogy to Example 20, instead of MC,the polymer l~yd~u~yc Ll~lcellulose (HEC) is employed).
Exam~le 22 In analogy to Example ~, instead of nimodipine,the active compound nifedipine is25 employed.
~ ~1 7~2~3 Le A ~1 0~2-Foreign ~mlntries Example 23 In analogy to Example 5, instead of nimo~irin~the active compound nifedipine is employed.
Example 24 5 In analogy to Example 12, instead of ~ l;r;~ r~th~ active compound nifedipine is employed.
E~ample 25 In analogy to Example 19, instead of 1..~....1;l,;". ,the actiYe compound nifedipine is employed.
10 Exam~le 26 In analogy to Example 20, instead of ";"~n~ ,th~ active compound nifedipine is employed.
Examl~le 27 In analogy to Example 21, instead of nimn~lirinl~the active compound nifedipine i~
15 employed.
2 1 75~g3 Le A, 31 ~7~-FQ~ei~n Cf~l~ntri~
' r and/or p ' ' ' r of the release-delaYin~ ~ r and further processin~ as a solid, ' ~ ' ~' dosaEe form E~ample 28 75.76 parts by weight of the G~l~,;pi~dl~ powder, obtained according to Example 1, S are mixed with 24.05 parts by weight of HPMC-4000 CP and then mixed with 0.19 parts by weight of m~ m stearate and afterwards ~;ou.p.~,;,.,~J to give tablets, each containing 90 mg of nimt~l1irir~ The tablets obtained are then coated.
Example 29 74.12 parts by weight of the u~ Jildl~ powder, obtained according to Example 1, are mixed with 21.74 parts by weight of HPMC-4000 CP, 3.95 parts by weight of HPMC-I500 CP and 0.19 part by weight of m~r~illm stearate and afterwards ~,uu~ cJ to give tablets, each containing 90 mg of nimn~1irine The tablets obtained are coated in analogy to Example 28.
E~amPle 30 67.15 parts by weight of the ~ lr~ci~;ldl~ powder, obtained according to Example 18, are mixed with 32.6 parts by weight of HPMC 1500 CP and 0.25 part by weight of magnesium stearate and afterwards c~,uu~ ,J to give tablets, each containing 90 mg of nim~(lirine The tablets obtained are coated in analogy to Example 28.
E~ample 31 84.2 parts by weight of the Co~llr~ dl~ powder, obtained according to Example 2, are mixed with 15.6 parts by weight of HPMC-4000 CP, compacted in dry form, screenedand then mixed with 0.2 part by weight of m~nP~ m stearate and afterwards C~ d to give tablets The tablets obtained are then coated.
E~amPle 32 53.8 parts by weight of the ~,~pl~Ci~ild~ powder, obtained according to Example 23, are mixed with 41 parts by weight of HPMC-4000 CP and 5 parts by weight of lactose and 0.2 part by weight of magnesium stearate and afterwards compressed to give ~ ~7~g3 Le A 31 97~-Forei~n Count~ies tablets. The tablets obtained are then coated.
E~amr)le 33 49.9 parts by weight of tne cu~"~u;~ ,L~ powder, obtained according to Example 16, are mixed with the same amount of HPMC-IS,000 CP and 0.2 part by weight of S IIIA~ 11 stearate and afterwards cul~ ,J to give tablets. The tablets obtained are then coated.
E~amr~le 34 88 parts by weight of the ,U~lt~ J;LdL~ powder, obtained according to Example 10, are mixed with 11.7 parts by weight of HPMC 100,000 CP and 0.3 part by weight of 10 mAgnPeillm stearate and afterwards cull.~ ,l to give tablets. The tablets obtained are then coated.
Claims (14)
1. Orally administrable solid pharmaceutical preparation having long-lasting controlled release and high storage stability, comprising 1 part by weight of the active compound in amorphous form as a coprecipitate in 0.5 to 10 parts by weight of polyvinylpyrrolidone having an average molecular weight of about 15,000 to 1,000,000 or other coprecipitate forming polymer.
2. Orally administrable solid pharmaceutical preparation according to claim 1, characterized in that the active compound is present in amorphous form as a coprecipitate with 1.0 to 4 parts by weight of polyvinylpyrrolidone having an average molecular weight of about 15,000 to 100,000.
3. orally administrable solid pharmaceutical preparation according to claim 1, that also includes a release-delaying component consisting essentially of 0.01 to 15 parts by weight of a gel-forming polymer.
4. Orally administrable solid pharmaceutical preparation according to claim 3, characterized in that, as release-delaying component, it contains 0.1 to 10 parts by weight of gel-forming cellulose ethers.
5. Orally administrable solid pharmaceutical preparation according to claim 1, characterized in that it contains as active compound a pharmaceutically active dihydropyridine.
6. Orally administrable solid pharmaceutical preparation according to claim 1, characterized in that it contains the active compound nimodipine.
7. Orally administrable solid pharmaceutical preparation according to claim 1, characterized in that it contains the active compound nifedipine.
8. Orally administrable solid pharmaceutical preparation according to claim 1, characterized in that it contains the active compound ketoprofen.
9. A process for the production of a pharmaceutical preparation according to claim 1, which includes the step of dissolving 0.5 to 10 parts by weight of polyvinylpyrrolidone of molecular weight 15,000 to 1,000,000 and 1 part by weight of pharmaceutically active compound in a suitable organic solvent and coprecipitating the active compound and the PVP
therefrom.
therefrom.
10, A process according to claim 9, wherein both the PVP
and the pharmaceutically active compound are dissolved in the same solvent.
and the pharmaceutically active compound are dissolved in the same solvent.
11. A process according to claim 9, wherein the PVP and the pharmaceutically active compound are dissolved in different solvents which are then admixed.
12. A process according to claim 9, 10 or 11, wherein the coprecipitation is caused by removal of the solvent.
13. A process according to claim 9, 10, 11 or 12, wherein the solvent is selected from the group consisting of a low molecular weight halogenated hydrocarbon, ketone and alcohol .
14. A process according to any one of claims 9 to 13, wherein 0.01 to 15 parts by weight of a gel-forming polymer is also dissolved in the organic solvent and coprecipitated with PVP and active compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19515972.1 | 1995-05-02 | ||
| DE1995115972 DE19515972A1 (en) | 1995-05-02 | 1995-05-02 | Controlled release pharmaceutical preparations and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2175293A1 true CA2175293A1 (en) | 1996-11-03 |
Family
ID=7760805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2175293 Abandoned CA2175293A1 (en) | 1995-05-02 | 1996-04-29 | Pharmaceutical preparations having controlled release of active compound and processes for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0740934A1 (en) |
| JP (1) | JPH08301789A (en) |
| CA (1) | CA2175293A1 (en) |
| DE (1) | DE19515972A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294201B1 (en) | 1997-10-12 | 2001-09-25 | Bayer Aktiengesellschaft | Osmotic medicament releasing system |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1284604B1 (en) * | 1996-09-27 | 1998-05-21 | Roberto Valducci | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION CONTAINING NIFEDIPINE AS THE ACTIVE SUBSTANCE |
| HN1998000115A (en) * | 1997-08-21 | 1999-06-02 | Warner Lambert Co | SOLID PHARMACEUTICAL DOSAGE FORMS |
| ES2310164T3 (en) * | 1999-02-10 | 2009-01-01 | Pfizer Products Inc. | LIBERATION DEVICE CONTROLLED BY THE MATRIX. |
| IL154370A0 (en) * | 2003-02-10 | 2003-09-17 | Chemagis Ltd | Solid amorphous mixtures, processes for the preparation thereof and pharmaceutical compositions containing the same |
| JP4391475B2 (en) * | 2003-06-20 | 2009-12-24 | 明治製菓株式会社 | Method for producing coprecipitate of poorly water-soluble substance and water-soluble polymer |
| KR20070083679A (en) | 2004-09-29 | 2007-08-24 | 케마지스 리미티드 | Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride |
| US20080107725A1 (en) * | 2006-10-13 | 2008-05-08 | Albano Antonio A | Pharmaceutical Solid Dosage Forms Comprising Amorphous Compounds Micro-Embedded in Ionic Water-Insoluble Polymers |
| DE102007048705A1 (en) * | 2007-10-11 | 2009-04-16 | Bayer Healthcare Ag | Amorphous formulation |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3142853A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | Solid pharmaceutical compositions containing nifedipine and process for their production |
| DE3270785D1 (en) * | 1981-10-29 | 1986-05-28 | Bayer Ag | Process for preparing solid fast-releasing drug formulations of dihydropyridines |
| DE3205399A1 (en) * | 1982-02-16 | 1983-08-25 | Bayer Ag, 5090 Leverkusen | Solid, rapid-release pharmaceutical compositions with dihydropyridines and process for their production |
| JPS57206612A (en) * | 1982-04-16 | 1982-12-18 | Bayer Ag | Collapsible absorptive compressed mold article of hard soluble medicine |
| IT1187750B (en) * | 1985-10-15 | 1987-12-23 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF TABLETS, EVEN OF PROLONGED RELEASE, OF ISCSORBIDE-5-MONONITRATE STABILIZED AND FORMULATIONS SO OBTAINED |
| IE59540B1 (en) * | 1987-01-09 | 1994-03-09 | Elan Corp | Sustained release capsule or tablet formulation |
| US5015479A (en) * | 1987-02-02 | 1991-05-14 | Seamus Mulligan | Sustained release capsule or tablet formulation comprising a pharmaceutically acceptable dihydropyridine |
| US5340591A (en) * | 1992-01-24 | 1994-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine |
-
1995
- 1995-05-02 DE DE1995115972 patent/DE19515972A1/en not_active Withdrawn
-
1996
- 1996-04-19 EP EP96106143A patent/EP0740934A1/en not_active Withdrawn
- 1996-04-29 CA CA 2175293 patent/CA2175293A1/en not_active Abandoned
- 1996-05-01 JP JP8132548A patent/JPH08301789A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294201B1 (en) | 1997-10-12 | 2001-09-25 | Bayer Aktiengesellschaft | Osmotic medicament releasing system |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08301789A (en) | 1996-11-19 |
| EP0740934A1 (en) | 1996-11-06 |
| DE19515972A1 (en) | 1996-11-07 |
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