CA1255597A - Solid medicament formulations containing dihydropyridines and a process for their preparation - Google Patents
Solid medicament formulations containing dihydropyridines and a process for their preparationInfo
- Publication number
- CA1255597A CA1255597A CA000486160A CA486160A CA1255597A CA 1255597 A CA1255597 A CA 1255597A CA 000486160 A CA000486160 A CA 000486160A CA 486160 A CA486160 A CA 486160A CA 1255597 A CA1255597 A CA 1255597A
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- dihydropyridine
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- solid medicament
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- 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
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines Containing Plant Substances (AREA)
- Jellies, Jams, And Syrups (AREA)
Abstract
Solid medicament formulations containing dihydropyridines and a process for their preparation ABSTRACT
A solid, rapidly absorbable composition by weight comprising 1 ? 0.015 part of a dihydropyridine, 0.01 to 1.5 parts of PVP with an average molecular weight of 15,000 to 50,000 and 1 to 12 parts by weight of crosslinked insoluble PVPP.
A solid, rapidly absorbable composition by weight comprising 1 ? 0.015 part of a dihydropyridine, 0.01 to 1.5 parts of PVP with an average molecular weight of 15,000 to 50,000 and 1 to 12 parts by weight of crosslinked insoluble PVPP.
Description
1~S~5~7 -. 1 - ';
The present invention relates to particular rap;dly absorbable solid medicament formulations conta;n-ing ~ihydropyridines, polyvinylpyrrolidone snd cross-linked polyvinylpyrrolidone, and a process for their preparation~
Dihydropyridines and their calcium-antagonistic action are kno~n ~compare Brit;sh Patent 1,173,862 and Br;tish Patent 1,358,951)~ Mar-y representatives of th;s class of substance are very sensitive to li~ht and have an extremeLy lo~ solubility in aqueous media~ For example, the uater-solubil;ty of nifedipine is onLy 10 mg per litre, and the ~ater-solubil;ty of nimod;pine is only
The present invention relates to particular rap;dly absorbable solid medicament formulations conta;n-ing ~ihydropyridines, polyvinylpyrrolidone snd cross-linked polyvinylpyrrolidone, and a process for their preparation~
Dihydropyridines and their calcium-antagonistic action are kno~n ~compare Brit;sh Patent 1,173,862 and Br;tish Patent 1,358,951)~ Mar-y representatives of th;s class of substance are very sensitive to li~ht and have an extremeLy lo~ solubility in aqueous media~ For example, the uater-solubil;ty of nifedipine is onLy 10 mg per litre, and the ~ater-solubil;ty of nimod;pine is only
2 mg per litre. ~ecause of these particular properties, a number of d;ff;cult;es occur in formulating galenical preparations, as can be seen from numerous patent appl;cat;ons for part;cular formulat;ons of ~hese active compounds~
U~S. Patent 3,784,6840 for example~ relates to particular bitable gelatine capsuies ~hich contain nife~
d;pine in d;ssolved form ;n order to ut;l;se the coronary action of nifed;pine advantageously. ~ritish Patent 1,456,618 descr;bes and claims solid ~edicament formula-tions ~hich are said to ensure a good b;oava~lability of the dihydropyrid;nes~
DT-O~ ~German Publ;shed Specification) 2~8Z2,882 l;ke~;se describes col;d ~edicament formulations, in wh;ch the sparing solub;lity of dihydropyr;dines is said to be compensated by using certain solubiLisins agents and surface-active substances.
The absorbab;l;ty of n;fed;p;ne is also sa;d, in EP-OS (European Publ;shed Specification 1,247, to be ;mproved by using polyethylene glycol (PEG~ and certain porous carrier substances. This Application also states that the poor solub;lity of n;fedipine can be compensated Le A 23 1SO
~2SSS9~7 by forming co-precip-tates from nifedipin~ and polyvinyl-pyrrolidone ~PVP), in which the nifedipine 1s present ;n amorphous form as a solid solut~on.
These co-precipitates are prepared by dissolving nifedipine and PVP in organic solvents, ~ith subsequent evaporation of the solvent ;n order to obtain a vitreous composition ~compare DT-OS (Ger0an Published Specifica-t;on) 2,82Z,882). Such evaporaition of the or~anic sol-vent can be carried out industrialLy only ~ith ~reat expen-d;ture, since the PVP composition strongly b;nds the or~anic solvent and becomes very viscous shortly before dry-in~. A volum;nous foamy composiition forms and, shortly before the 0nd of drying, is very viscous, can no lon~er be stirred and can be further processed only ~ith diffi-culty. Complete removal of the solvent from the co-precipitate is virtually impossible. Another disadvan tage in using a nifed;pine-PVP co-precipitate in the pro-duction of tablets is the fact that aLthough this co-precipitate can be mixed ~ith other auxiliaries, it cannot be granulated ~ith aqueous solut;ons. Ho~ever, such a simple mixture bet~een the PYP co-precipitate and other auxiliaries tends to demix dur;ng further mechanical process;ng, for example to form tablets or during fill;ng of capsules. In the end effect, this çan lead to medic~-ment formulations with a very different content of activecompound in indiv;dual tablets or capsules tdeficient "content un;formity"), which is extremeLy undesirable ~ith a highly active substance such as n;fedipine. More-over, the add;tional auxiliaries ~hich are available for selection are very l;mited, especially for the production of tablets, because PVP acts at the same time as a binder, and the disintegration of the tablets or capsules is prevented by the presence of relatively large amounts of PVP (30 to 100 mg per tablet or capsule)u Accord;ng to DE-OS (German Published Specifica-tion) 3,1420853, the disadvantages mentioned above are Le A 23 160 5~';' eliminatecl by using a larger amount of auxiliaries for absorption of the solution containing dihydropyridine and polyvinylpyrroli-done/acetone. Such formulations are acceptable if the active compounds are to be used only in low dosages.
However, if higher dosages, for e~ample 30 or 100 mg of active compound, are to be used, this method has the disadvantage that the ratio of active compound to auxiliary must remain constant and very large formulation forms are thus obtained, which the patients find difficult to take (for example tablets weighing 2 g).
The present invention relates to new solid dihydropyri-dine formulations with a rapid absorbability and a uniform content of active compound, the relative standard deviation of which is at most 1.5%, containing 1 part by weight of dihydropyridine as active substance, 0.01 to 1.5 parts by weight of polyvinylpyrrolidone (PVP) with an average molecular weight of 15,000 to 50,000 and as stabilizer 1 to 12 parts by weight of crosslinked insoluble poly-vinylpyrrolidone (PVPP) as adsorbant and as desintigrant, and, if appropriate, other customary auxiliaries.
Medicament formulations which contain the dihydropyridine active compound in a dosage of 1 to 100 mg, in particular 5 to 70 mg, may be mentioned as ~referred, Preferred dihydropyridines which may be are compounds of the general formula I
S5~
R400C ~ OORl 1 (I) ~1 in which R represents phenyl, which is substituted by one or two identical or different substituents selected from the group consisting of nitro, chlorine, CF3, OCHF2 and =N-0-N=, Rl and ~4 are identical or different and each Le A 23 160 - 3a -~St~S~7 represent alkyl (1 - 10 C atoms), ~hich is option-ally substituted by Dlkoxy ~ 4 C atoms)~
fluortne, chlorine or an N-methyl-N-benzyl ~roup, and S R2 and R3 are identical or d;fferent 3nd each represent alkyl (1 - 4 C atoms)O which is option-alLy substituted by hydroxyl, or repre~ent cyano.
Those formulation forms which contaln a dihydro-pyrid;ne from the group comprising ni~edipine, ni~odipine~
n;trendipine, nisoldipine, nicardipine and felodipine are of particular importance.
Those formuLation forms ~hich conta;n 0.05 to 1.5 parts by ~eight, in particular 0.1 to 1 part by ueight, o~ PVP and 2 to 8 parts by ~eight, in particular 2 to 6 parts by weight~ of PVPP per part by ueight of dihydropyridine are to be singled out.
Preferred aux;liar;es uhich may be mentioned are:
~ett;ny agents, such as, for example, ssdium lauryl-sulphate and T~een~R), these wetting agents being employed in a maximum amount of 1 part by ~eight. There may also be ment;oned: lubricants, such as, for example, magnesium stearate. The presence of fillers, such as sugars, for example lactose and mannitol, ~lycocol~
calcium carbonate, maize starch and Avicel, may also be , ~
advantageous~ If appropriate, the tablets can also addi-t;onally contain disinte~rating agents or can be subse-quently provided ~ith a customary lacquering in order to achieve, in the formul3tion accordin~ to the invention, immediate soLubility~ retardation or resistance to ~as-tric juice. The formuLations according to the invention,in particular the granuLes, can furthermore be eombined with other galenical forms contain;ng the same or differ-ent active coMpounds.
The soLid formuLation according to the invention is prepared by a procedure in which 1 part by ~ei~ht o~
dihydropyridine and 0.01 to 1.5 parts by ~eight of PVP
Le A 23 160 ~ r~
.
~2S559~
are dissolved in a corresponding amount of or~anic sol-vents in ~hich the t~o solid constituents can be dis-solved, a wetting ayent is suspended or dissolved therein, if appropriate, and this solution is ~ranulated with 1 to 12 parts by weight of PYPP and the resultin~ ~ranules are further processed to solid med;cament formulations, if appropriate after add;tion of further auxiliari~sO
Preferred solid medicament formulations ~hich may be mentioned are: tablets, pills, dragees, ~ranules, powders, capsuLes, sachets and pellets.
Preferred organic solvents which may be ~entioned are: ethanol, methanol, acetone, ~ethyLene chloride and chloroform and mixtures of these ~olvents. They are preferably employed in amounts of 6 ~o 50, ;n particular 8 to 20, parts by ~ei~ht, based on the dihydropyridine.
It could not be predicted that the medicament formulations thus obtained retain a very sood bioavail-ability and at the same time a good çontent unifor~ity.
The granules consisting of the PVPP ~etted ~ith dihydro-pyridine-PVP solution ~hich are obtained by the process according to the invention can be dried, sieved, further processed, mixed uith other auxiliaries and compressed to form tablets without problems. The bioavailability of the formulatisns accordin~ to the invention is at least equivalent to that of the for~ulations known hitherto in respect of speed and level~ It moreover has the advantage tha~ the process can be carried out ~ith very little energy and in a short time. The easy drying and the shorter dryiny time associated thereuith (a~ most 20X of the conventional drying time) should be particularLy emphasised. The solid ~ormulations obtained are very small and, in spite of their high con-tent of active compound, ran also be taken by the pat;ent ~ithout trouble.
Due to the lo~ PVP content, drying of the moist ~ranules is effected in a considerably shorter time Le A 23 160 ~LZ5~5~7 (max;mun of 20X of the convent;onal drying t;me). For the same reasonO no lumps occur durin~ dryin~.
In ~ontrast to kno~n formulatlons, ~hich are pre-pared by granulation ~ith oraanic solvents~ the residual solvent contents are so greatly reduced by the present invention that they are belo~ 0.05X and thus virtually can no longer be detected by conventional analytical methods. This reduction ;n residual solvent contents is advantageous from the toxicological point of view, especially for long~term treatments.
Tablets produced in th;s manner have dis;ntegra-tion times of less than 5 minutes. Auxiliaries are saved by the process according to the ;nvention, and not only is oral administration thereby facilitated but at the same time the production costs are also reduçed.
Example 1 30 ~ of nimodipines and 17 9 of PVP 25 are dis~
solved in 500 9 of acetone, and 0Y5 ~ of sodium lauryl-sulphate is suspended in the solution. 107 9 of cross-linked PVPP is granulated with this solution in agranulating apparatus. The ~ranules are dried and sieved.
After admixing 1.5 9 of magnesium stearate, the granules are compressed to form tablets ~e;gh;ng 156 mg and each containing 30 m~ of nimodipine. The tablets are distin-guished by a lo~ ueight, ~ood disintegra~ion times andadvantageous release.
Example 2 The ~ranules obtained in Example 1 are compressed to form tablets ~eigh;ng 520 mg and each containing 100 mg of nimodipine.
Example 3 30 9 of nimodipine and 4 g of PVP 25 are dissolved in ~00 9 of acetone, and 0.5 9 of sodium lauryl sulphate is suspended in the so~ution. 180 9 of crosslinked PVPP
are granulated ~ith this solution in a granulatin3 apparatus. The granules are dried~ sieved and, after Ee A Z3 160 3l~S55~
admixing 2.0 9 of magnesium suLphate, compressed to ~orm tab-lets weighiny 216 mg and each contain;n~ 30 ~9 of nimodipine.
Example 4 30 9 of nimodipine, 45 9 of PVP 25 are dis-solved in 500 9 of acetone, and 0.5 9 of sodium lauryl-sulphate is suspended in the solution. 120 9 of cross-linked PVPP are granulated ~ith this solution in a granulating apparatus. The granules are dried, s;eved and, after admixing 1.5 9 of magnesium stearate, pressed to tablets ~eighing 197 mg and each containing 30 mg of nimod;p;ne.
Example 5 rhe granules ~rom Example 1 are ~illed or bri-quetted and capsules or sachet~ are filled ~ith the granules obta;ned after sieving.
Example 6 The solvent acetone described ;n Example 1 is replaced by the same amount of ~ethylene chloride or chloroform or a mixture thereof.
Example 7 20 9 of nitrendipine, 15 9 of PVP Z5 and 1.5 9 of T~een 80 are dissolved in acetone. 110 9 of crosslinked PVPP are granulated with this solution in a granulating apparatus. The ~ranules are dried and sieved. A mixture 25 of 20 9 of Avicel, 10 9 of maize starch and 1.5 9 of magnesium stearate is added as an af~er~mixture. The mixture is pressed to tablets weighing 178 mg and each containing 20 mg of n;trendipine.
Example 8 This example is as Example 7, but instead of the after-m;xture, granu~es obtained from 30 9 of ~actose, 20 9 of ~vicel and 5 9 of maize starch by aqueous granu-lation are added. The t~o granules are mixed, lubricated ~ith 1.5 9 of magnesium stearate and pressed to tablets ~e;ghing 203 mg.
Le A 23 160 12SS5~
Example 9 10 ~ of nifedipine and 5 y of PVP are dissolved in 100 9 of acetone. 80 9 of crossl;nked PYPP are 0ranulated ~;th th;s solution in a ~ranulating ~pparatus.
S The granuLes are dried and sieved. After admixing 1.0 9 of nagnesium stearate, the 0ranules are co~pressed to form tablets ~e;ghing 96 Mg. The 10 mg nifedipine tablets are distinsuished by ~ood disintegrat;on, lo~ wei~ht and advantageous release.
ExampLe 10 10 9 of nifedipine and 5 9 of PVP are dissolved in a mixture of 100 g of acetone and 4 9 of ethanol. A
~ixture of 80 0 of crosslinked PVPP, 19 9 of Avicel and 15 9 of maize starch is granulated ~ith the soLution in a granulatin~ apparatus. The granules are dried, sieved and m;xed ~ith an after-mixture consist;n0 of 10 9 of AviceL, 10 9 of crossLinked PVPP and 1 9 of magnesium stearate and compressed to form tablets ~eighin~ 150 mg and each containing 10 mg of nifedipine.
Example 11 This example is as Example 9, ~ith the addition of 1~0 9 of T~een 80tR), givin~ 10 m9 nifedipine tablets ~eigh;ng 151 mg.
Le A 23 160
U~S. Patent 3,784,6840 for example~ relates to particular bitable gelatine capsuies ~hich contain nife~
d;pine in d;ssolved form ;n order to ut;l;se the coronary action of nifed;pine advantageously. ~ritish Patent 1,456,618 descr;bes and claims solid ~edicament formula-tions ~hich are said to ensure a good b;oava~lability of the dihydropyrid;nes~
DT-O~ ~German Publ;shed Specification) 2~8Z2,882 l;ke~;se describes col;d ~edicament formulations, in wh;ch the sparing solub;lity of dihydropyr;dines is said to be compensated by using certain solubiLisins agents and surface-active substances.
The absorbab;l;ty of n;fed;p;ne is also sa;d, in EP-OS (European Publ;shed Specification 1,247, to be ;mproved by using polyethylene glycol (PEG~ and certain porous carrier substances. This Application also states that the poor solub;lity of n;fedipine can be compensated Le A 23 1SO
~2SSS9~7 by forming co-precip-tates from nifedipin~ and polyvinyl-pyrrolidone ~PVP), in which the nifedipine 1s present ;n amorphous form as a solid solut~on.
These co-precipitates are prepared by dissolving nifedipine and PVP in organic solvents, ~ith subsequent evaporation of the solvent ;n order to obtain a vitreous composition ~compare DT-OS (Ger0an Published Specifica-t;on) 2,82Z,882). Such evaporaition of the or~anic sol-vent can be carried out industrialLy only ~ith ~reat expen-d;ture, since the PVP composition strongly b;nds the or~anic solvent and becomes very viscous shortly before dry-in~. A volum;nous foamy composiition forms and, shortly before the 0nd of drying, is very viscous, can no lon~er be stirred and can be further processed only ~ith diffi-culty. Complete removal of the solvent from the co-precipitate is virtually impossible. Another disadvan tage in using a nifed;pine-PVP co-precipitate in the pro-duction of tablets is the fact that aLthough this co-precipitate can be mixed ~ith other auxiliaries, it cannot be granulated ~ith aqueous solut;ons. Ho~ever, such a simple mixture bet~een the PYP co-precipitate and other auxiliaries tends to demix dur;ng further mechanical process;ng, for example to form tablets or during fill;ng of capsules. In the end effect, this çan lead to medic~-ment formulations with a very different content of activecompound in indiv;dual tablets or capsules tdeficient "content un;formity"), which is extremeLy undesirable ~ith a highly active substance such as n;fedipine. More-over, the add;tional auxiliaries ~hich are available for selection are very l;mited, especially for the production of tablets, because PVP acts at the same time as a binder, and the disintegration of the tablets or capsules is prevented by the presence of relatively large amounts of PVP (30 to 100 mg per tablet or capsule)u Accord;ng to DE-OS (German Published Specifica-tion) 3,1420853, the disadvantages mentioned above are Le A 23 160 5~';' eliminatecl by using a larger amount of auxiliaries for absorption of the solution containing dihydropyridine and polyvinylpyrroli-done/acetone. Such formulations are acceptable if the active compounds are to be used only in low dosages.
However, if higher dosages, for e~ample 30 or 100 mg of active compound, are to be used, this method has the disadvantage that the ratio of active compound to auxiliary must remain constant and very large formulation forms are thus obtained, which the patients find difficult to take (for example tablets weighing 2 g).
The present invention relates to new solid dihydropyri-dine formulations with a rapid absorbability and a uniform content of active compound, the relative standard deviation of which is at most 1.5%, containing 1 part by weight of dihydropyridine as active substance, 0.01 to 1.5 parts by weight of polyvinylpyrrolidone (PVP) with an average molecular weight of 15,000 to 50,000 and as stabilizer 1 to 12 parts by weight of crosslinked insoluble poly-vinylpyrrolidone (PVPP) as adsorbant and as desintigrant, and, if appropriate, other customary auxiliaries.
Medicament formulations which contain the dihydropyridine active compound in a dosage of 1 to 100 mg, in particular 5 to 70 mg, may be mentioned as ~referred, Preferred dihydropyridines which may be are compounds of the general formula I
S5~
R400C ~ OORl 1 (I) ~1 in which R represents phenyl, which is substituted by one or two identical or different substituents selected from the group consisting of nitro, chlorine, CF3, OCHF2 and =N-0-N=, Rl and ~4 are identical or different and each Le A 23 160 - 3a -~St~S~7 represent alkyl (1 - 10 C atoms), ~hich is option-ally substituted by Dlkoxy ~ 4 C atoms)~
fluortne, chlorine or an N-methyl-N-benzyl ~roup, and S R2 and R3 are identical or d;fferent 3nd each represent alkyl (1 - 4 C atoms)O which is option-alLy substituted by hydroxyl, or repre~ent cyano.
Those formulation forms which contaln a dihydro-pyrid;ne from the group comprising ni~edipine, ni~odipine~
n;trendipine, nisoldipine, nicardipine and felodipine are of particular importance.
Those formuLation forms ~hich conta;n 0.05 to 1.5 parts by ~eight, in particular 0.1 to 1 part by ueight, o~ PVP and 2 to 8 parts by ~eight, in particular 2 to 6 parts by weight~ of PVPP per part by ueight of dihydropyridine are to be singled out.
Preferred aux;liar;es uhich may be mentioned are:
~ett;ny agents, such as, for example, ssdium lauryl-sulphate and T~een~R), these wetting agents being employed in a maximum amount of 1 part by ~eight. There may also be ment;oned: lubricants, such as, for example, magnesium stearate. The presence of fillers, such as sugars, for example lactose and mannitol, ~lycocol~
calcium carbonate, maize starch and Avicel, may also be , ~
advantageous~ If appropriate, the tablets can also addi-t;onally contain disinte~rating agents or can be subse-quently provided ~ith a customary lacquering in order to achieve, in the formul3tion accordin~ to the invention, immediate soLubility~ retardation or resistance to ~as-tric juice. The formuLations according to the invention,in particular the granuLes, can furthermore be eombined with other galenical forms contain;ng the same or differ-ent active coMpounds.
The soLid formuLation according to the invention is prepared by a procedure in which 1 part by ~ei~ht o~
dihydropyridine and 0.01 to 1.5 parts by ~eight of PVP
Le A 23 160 ~ r~
.
~2S559~
are dissolved in a corresponding amount of or~anic sol-vents in ~hich the t~o solid constituents can be dis-solved, a wetting ayent is suspended or dissolved therein, if appropriate, and this solution is ~ranulated with 1 to 12 parts by weight of PYPP and the resultin~ ~ranules are further processed to solid med;cament formulations, if appropriate after add;tion of further auxiliari~sO
Preferred solid medicament formulations ~hich may be mentioned are: tablets, pills, dragees, ~ranules, powders, capsuLes, sachets and pellets.
Preferred organic solvents which may be ~entioned are: ethanol, methanol, acetone, ~ethyLene chloride and chloroform and mixtures of these ~olvents. They are preferably employed in amounts of 6 ~o 50, ;n particular 8 to 20, parts by ~ei~ht, based on the dihydropyridine.
It could not be predicted that the medicament formulations thus obtained retain a very sood bioavail-ability and at the same time a good çontent unifor~ity.
The granules consisting of the PVPP ~etted ~ith dihydro-pyridine-PVP solution ~hich are obtained by the process according to the invention can be dried, sieved, further processed, mixed uith other auxiliaries and compressed to form tablets without problems. The bioavailability of the formulatisns accordin~ to the invention is at least equivalent to that of the for~ulations known hitherto in respect of speed and level~ It moreover has the advantage tha~ the process can be carried out ~ith very little energy and in a short time. The easy drying and the shorter dryiny time associated thereuith (a~ most 20X of the conventional drying time) should be particularLy emphasised. The solid ~ormulations obtained are very small and, in spite of their high con-tent of active compound, ran also be taken by the pat;ent ~ithout trouble.
Due to the lo~ PVP content, drying of the moist ~ranules is effected in a considerably shorter time Le A 23 160 ~LZ5~5~7 (max;mun of 20X of the convent;onal drying t;me). For the same reasonO no lumps occur durin~ dryin~.
In ~ontrast to kno~n formulatlons, ~hich are pre-pared by granulation ~ith oraanic solvents~ the residual solvent contents are so greatly reduced by the present invention that they are belo~ 0.05X and thus virtually can no longer be detected by conventional analytical methods. This reduction ;n residual solvent contents is advantageous from the toxicological point of view, especially for long~term treatments.
Tablets produced in th;s manner have dis;ntegra-tion times of less than 5 minutes. Auxiliaries are saved by the process according to the ;nvention, and not only is oral administration thereby facilitated but at the same time the production costs are also reduçed.
Example 1 30 ~ of nimodipines and 17 9 of PVP 25 are dis~
solved in 500 9 of acetone, and 0Y5 ~ of sodium lauryl-sulphate is suspended in the solution. 107 9 of cross-linked PVPP is granulated with this solution in agranulating apparatus. The ~ranules are dried and sieved.
After admixing 1.5 9 of magnesium stearate, the granules are compressed to form tablets ~e;gh;ng 156 mg and each containing 30 m~ of nimodipine. The tablets are distin-guished by a lo~ ueight, ~ood disintegra~ion times andadvantageous release.
Example 2 The ~ranules obtained in Example 1 are compressed to form tablets ~eigh;ng 520 mg and each containing 100 mg of nimodipine.
Example 3 30 9 of nimodipine and 4 g of PVP 25 are dissolved in ~00 9 of acetone, and 0.5 9 of sodium lauryl sulphate is suspended in the so~ution. 180 9 of crosslinked PVPP
are granulated ~ith this solution in a granulatin3 apparatus. The granules are dried~ sieved and, after Ee A Z3 160 3l~S55~
admixing 2.0 9 of magnesium suLphate, compressed to ~orm tab-lets weighiny 216 mg and each contain;n~ 30 ~9 of nimodipine.
Example 4 30 9 of nimodipine, 45 9 of PVP 25 are dis-solved in 500 9 of acetone, and 0.5 9 of sodium lauryl-sulphate is suspended in the solution. 120 9 of cross-linked PVPP are granulated ~ith this solution in a granulating apparatus. The granules are dried, s;eved and, after admixing 1.5 9 of magnesium stearate, pressed to tablets ~eighing 197 mg and each containing 30 mg of nimod;p;ne.
Example 5 rhe granules ~rom Example 1 are ~illed or bri-quetted and capsules or sachet~ are filled ~ith the granules obta;ned after sieving.
Example 6 The solvent acetone described ;n Example 1 is replaced by the same amount of ~ethylene chloride or chloroform or a mixture thereof.
Example 7 20 9 of nitrendipine, 15 9 of PVP Z5 and 1.5 9 of T~een 80 are dissolved in acetone. 110 9 of crosslinked PVPP are granulated with this solution in a granulating apparatus. The ~ranules are dried and sieved. A mixture 25 of 20 9 of Avicel, 10 9 of maize starch and 1.5 9 of magnesium stearate is added as an af~er~mixture. The mixture is pressed to tablets weighing 178 mg and each containing 20 mg of n;trendipine.
Example 8 This example is as Example 7, but instead of the after-m;xture, granu~es obtained from 30 9 of ~actose, 20 9 of ~vicel and 5 9 of maize starch by aqueous granu-lation are added. The t~o granules are mixed, lubricated ~ith 1.5 9 of magnesium stearate and pressed to tablets ~e;ghing 203 mg.
Le A 23 160 12SS5~
Example 9 10 ~ of nifedipine and 5 y of PVP are dissolved in 100 9 of acetone. 80 9 of crossl;nked PYPP are 0ranulated ~;th th;s solution in a ~ranulating ~pparatus.
S The granuLes are dried and sieved. After admixing 1.0 9 of nagnesium stearate, the 0ranules are co~pressed to form tablets ~e;ghing 96 Mg. The 10 mg nifedipine tablets are distinsuished by ~ood disintegrat;on, lo~ wei~ht and advantageous release.
ExampLe 10 10 9 of nifedipine and 5 9 of PVP are dissolved in a mixture of 100 g of acetone and 4 9 of ethanol. A
~ixture of 80 0 of crosslinked PVPP, 19 9 of Avicel and 15 9 of maize starch is granulated ~ith the soLution in a granulatin~ apparatus. The granules are dried, sieved and m;xed ~ith an after-mixture consist;n0 of 10 9 of AviceL, 10 9 of crossLinked PVPP and 1 9 of magnesium stearate and compressed to form tablets ~eighin~ 150 mg and each containing 10 mg of nifedipine.
Example 11 This example is as Example 9, ~ith the addition of 1~0 9 of T~een 80tR), givin~ 10 m9 nifedipine tablets ~eigh;ng 151 mg.
Le A 23 160
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A solid, rapidly absorbable medicament formulation without a test solvent content and with a maximum standard deviation of the active compound content of 1.5%, containing 1 part by weight of dihydropyridine, 0.01 to 1.5 parts by weight of PVP
with an average molecular weight of 15,000 to 50,000 and 1 to 12 parts by weight of crosslinked insoluble PVPP.
with an average molecular weight of 15,000 to 50,000 and 1 to 12 parts by weight of crosslinked insoluble PVPP.
2. A solid medicament formulation according to Claim 1, containing 0.05 to 1.5 parts by weight of PVP and 2 to 8 parts by weight of PVPP.
3. A solid medicament formulation according to Claim 1, containing 0.1 to 1 part by weight of PVP and 2 to 6 parts by weight of PVPP.
4. A solid medicament formulation according to Claims 1, 2 or 3, containing a dihydropyridine of the general formula I
(I) in which R represents phenyl, which is substituted by one or two identical or different substituents selected from the group consist-ing of nitro, chlorine, CF3, OCHF2 and =N-O-N=, R1 and R4 are identical or different and each represent alkyl (1-10 C atoms), which is optionally substituted by alkoxy (1-4 C atoms), fluorine, chlorine or an N-methyl-N-benzyl group, and R2 and R3 are identical or different and each represent alkyl (1-4 C atoms), which is optionally substituted by hydroxy, or represent cyano.
(I) in which R represents phenyl, which is substituted by one or two identical or different substituents selected from the group consist-ing of nitro, chlorine, CF3, OCHF2 and =N-O-N=, R1 and R4 are identical or different and each represent alkyl (1-10 C atoms), which is optionally substituted by alkoxy (1-4 C atoms), fluorine, chlorine or an N-methyl-N-benzyl group, and R2 and R3 are identical or different and each represent alkyl (1-4 C atoms), which is optionally substituted by hydroxy, or represent cyano.
5. A solid medicament formulation according to Claim 1, 2 or 3 containing a dihydropyridine selected from the group consist-ing of nifedipine, nimodipine, nitrendipine, nisoldipine, nicardi-pine and felodipine.
6. A solid medicament formulation according to Claim 1, 2 or 3, containing a wetting agent or lubricant.
7. A solid medicament formulation according to Claim 1, 2 or 3, in the form of granules, powder, tablet or dragee.
8. A process for the preparation of a solid medicament formulation as defined in Claim 1, comprising dissolving 1 part by weight of dihydropyridine and 0.01 to 1.5 parts by weight of PVP
in a corresponding amount of organic solvent and granulating this solution with 1 to 12 parts by weight of PVPP and further processing the resulting granules to a solid medicament formulation.
in a corresponding amount of organic solvent and granulating this solution with 1 to 12 parts by weight of PVPP and further processing the resulting granules to a solid medicament formulation.
9. A process according to Claim 8, wherein methanol, ethanol, acetone, methylene chloride or chloroform or a mixture thereof is used as the organic solvent in an amount of 6 to 50 parts by weight, based on the dihydropyridine.
10. A solid medicament formulation according to Claim 1, 2 or 3 in dosage unit form containing from 5 to 70 mg of the dihydropyridine per dosage unit.
11. A solid medicament formulation according to Claim 1, 2 or 3 in dosage unit form containing from 5 to 70 mg of the dihydropyridine per dosage unit wherein the dihydropyridine is selected from the group consisting of nifedipine, nimodipine, nitrendipine, nisoldipine, nicardipine and felodipine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3424553.7 | 1984-07-04 | ||
| DE19843424553 DE3424553A1 (en) | 1984-07-04 | 1984-07-04 | SOLID DRUG PREPARATIONS WITH DIHYDROPYRIDINE AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1255597A true CA1255597A (en) | 1989-06-13 |
Family
ID=6239792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000486160A Expired CA1255597A (en) | 1984-07-04 | 1985-06-28 | Solid medicament formulations containing dihydropyridines and a process for their preparation |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0167909B2 (en) |
| JP (1) | JPH0665644B2 (en) |
| KR (1) | KR920006908B1 (en) |
| AT (1) | ATE71297T1 (en) |
| AU (1) | AU570328B2 (en) |
| CA (1) | CA1255597A (en) |
| DE (2) | DE3424553A1 (en) |
| DK (1) | DK304485A (en) |
| ES (1) | ES8607018A1 (en) |
| FI (1) | FI852610L (en) |
| GR (1) | GR851617B (en) |
| HU (1) | HU197844B (en) |
| IL (1) | IL75686A (en) |
| PT (1) | PT80752B (en) |
| ZA (1) | ZA855017B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE63321B1 (en) * | 1986-02-03 | 1995-04-05 | Elan Corp Plc | Drug delivery system |
| 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 |
| US5001139A (en) * | 1987-06-12 | 1991-03-19 | American Cyanamid Company | Enchancers for the transdermal flux of nivadipine |
| US5045553A (en) * | 1987-06-24 | 1991-09-03 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutical composition for percutaneous drug absorption and percutaneous drug absorption promoter |
| US4797405A (en) * | 1987-10-26 | 1989-01-10 | Eli Lilly And Company | Stabilized pergolide compositions |
| GB8903328D0 (en) * | 1989-02-14 | 1989-04-05 | Ethical Pharma Ltd | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
| HU203041B (en) * | 1989-03-14 | 1991-05-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing pharmaceutical compositions of controlled releasing factor containing nifedipin |
| DE4130173A1 (en) * | 1991-09-11 | 1993-03-18 | Bayer Ag | PHARMACEUTICAL PREPARATIONS WITH A SPECIAL CRYSTAL MODIFICATION OF 1,4-DIHYDRO-2,6-DIMETHYL-4- (3-NITROPHENYL) -3,5-PYRIDINDICARBONIC ACID ISOPROPYL- (2-METHOXYETHYL) ESTER |
| GB9200607D0 (en) * | 1992-01-13 | 1992-03-11 | Ethical Pharma Ltd | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
| EP0818195B1 (en) * | 1995-03-29 | 2003-11-26 | Shionogi & Co., Ltd. | Gelatin capsule with adjusted water activity |
| CO4771151A1 (en) * | 1996-01-19 | 1999-04-30 | Rachitzky Falicman Pablo Alberto | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING NIFEDIPINE AND THE PHARMACEUTICAL PREPARATION OBTAINED THROUGH THE SAME |
| JP4334869B2 (en) | 2000-12-01 | 2009-09-30 | 協和発酵キリン株式会社 | Compositions with improved solubility or oral absorption |
| DE10117049A1 (en) * | 2001-04-05 | 2002-10-17 | Novartis Ag | New pharmaceutical composition useful for preparing solid and liquid dosage forms, e.g. ophthalmic solutions, comprises an anionic surfactant with a basic polymer or a cationic surfactant with acidic polymer, and an active ingredient |
| JP5072748B2 (en) * | 2007-07-10 | 2012-11-14 | 株式会社 メドレックス | Amlodipine stable solution and jelly |
| IE20100799A1 (en) * | 2010-12-22 | 2012-08-01 | Eurand Pharmaceuticals Ltd | Pharmaceutical composites of poorly water soluble drugs and polymers |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| 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 |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| JPS6038322A (en) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | Easily soluble solid preparation containing dihydropyridine-a substance |
| ATE33348T1 (en) * | 1983-11-30 | 1988-04-15 | Siegfried Ag | CORONAR THERAPY IN THE FORM OF SOFT GELATIN CAPSULES. |
| DE3427402A1 (en) * | 1984-07-25 | 1986-01-30 | Bayer Ag, 5090 Leverkusen | NEW COMBINATION DEVICE, METHOD FOR THE PRODUCTION THEREOF AND ITS USE AS A MEDICINAL PRODUCT |
-
1984
- 1984-07-04 DE DE19843424553 patent/DE3424553A1/en not_active Withdrawn
-
1985
- 1985-06-22 EP EP85107733A patent/EP0167909B2/en not_active Expired - Lifetime
- 1985-06-22 DE DE8585107733T patent/DE3585107D1/en not_active Expired - Lifetime
- 1985-06-22 AT AT85107733T patent/ATE71297T1/en active
- 1985-06-28 AU AU44298/85A patent/AU570328B2/en not_active Ceased
- 1985-06-28 CA CA000486160A patent/CA1255597A/en not_active Expired
- 1985-07-01 IL IL75686A patent/IL75686A/en not_active IP Right Cessation
- 1985-07-02 PT PT80752A patent/PT80752B/en not_active IP Right Cessation
- 1985-07-02 FI FI852610A patent/FI852610L/en not_active Application Discontinuation
- 1985-07-02 ES ES544787A patent/ES8607018A1/en not_active Expired
- 1985-07-02 KR KR1019850004730A patent/KR920006908B1/en not_active IP Right Cessation
- 1985-07-02 GR GR851617A patent/GR851617B/el unknown
- 1985-07-03 JP JP60144846A patent/JPH0665644B2/en not_active Expired - Lifetime
- 1985-07-03 ZA ZA855017A patent/ZA855017B/en unknown
- 1985-07-03 DK DK304485A patent/DK304485A/en not_active Application Discontinuation
- 1985-07-04 HU HU852604A patent/HU197844B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR860000864A (en) | 1986-02-20 |
| EP0167909B2 (en) | 1994-10-19 |
| FI852610L (en) | 1986-01-05 |
| ATE71297T1 (en) | 1992-01-15 |
| ES544787A0 (en) | 1986-06-16 |
| AU4429885A (en) | 1986-01-09 |
| IL75686A0 (en) | 1985-11-29 |
| IL75686A (en) | 1988-11-30 |
| FI852610A0 (en) | 1985-07-02 |
| ZA855017B (en) | 1986-02-26 |
| JPS6118725A (en) | 1986-01-27 |
| EP0167909A3 (en) | 1987-10-14 |
| PT80752B (en) | 1987-10-20 |
| KR920006908B1 (en) | 1992-08-22 |
| GR851617B (en) | 1985-11-26 |
| DE3424553A1 (en) | 1986-01-09 |
| DK304485A (en) | 1986-01-05 |
| PT80752A (en) | 1985-08-01 |
| JPH0665644B2 (en) | 1994-08-24 |
| EP0167909B1 (en) | 1992-01-08 |
| HU197844B (en) | 1989-06-28 |
| EP0167909A2 (en) | 1986-01-15 |
| ES8607018A1 (en) | 1986-06-16 |
| DE3585107D1 (en) | 1992-02-20 |
| DK304485D0 (en) | 1985-07-03 |
| AU570328B2 (en) | 1988-03-10 |
| HUT41259A (en) | 1987-04-28 |
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