CA1180277A - Solid medicament formulations containing nifedipine, and processes for their preparation - Google Patents
Solid medicament formulations containing nifedipine, and processes for their preparationInfo
- Publication number
- CA1180277A CA1180277A CA000385365A CA385365A CA1180277A CA 1180277 A CA1180277 A CA 1180277A CA 000385365 A CA000385365 A CA 000385365A CA 385365 A CA385365 A CA 385365A CA 1180277 A CA1180277 A CA 1180277A
- Authority
- CA
- Canada
- Prior art keywords
- nifedipine
- surface area
- specific surface
- solid
- medicament
- 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.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Solid medicament formulations containing nifedipine and processes for their preparation ABSTRACT OF THE DISCLOSURE
The invention is directed to the provision of solid pharmaceutical compositions (and methods for their preparation) containing nifedipine crystals with a specific surface area of 0.5 to 6 m.2/g., in admixture with a solid diluent. The said compositions overcome the deficiencies of prior art compositions containing which is known to have effect as a coronary vasodilator.
The invention is directed to the provision of solid pharmaceutical compositions (and methods for their preparation) containing nifedipine crystals with a specific surface area of 0.5 to 6 m.2/g., in admixture with a solid diluent. The said compositions overcome the deficiencies of prior art compositions containing which is known to have effect as a coronary vasodilator.
Description
t) 2 7 7 The prese.nt inve.ntion relates. to novel p-arti.cular solid medicament formulations containin~ the known compound nifedipine, which has an action on the circulation, and to processes for their production.
It has already been disclosed that the compound nifedipine has very po~-erful actions which influence khe circulat.ion ~s.ee. British Pate.nt Specification 1,173,862).
Because nifedipine is sensiti.ve to light and sparingly soluble, a number of difficulties. occur in the galenical formulation of medicamental specialities~ as is seen from ~ ' numerous pakents an/~patént applications for special .~- formulations. of this act.ive co~pound. Thus, for example, . U.S. Patent Specificat.ion 3,784,684- relates to particular gelatin capsules for chewing which contain nifedipine and as a result of which the:coronary action of nifedipine can be.advantageously utilised. Furthermore, British Patent Specification lg456,618 describes and claims solid medic-ament formulations which likewi'se ensure a good bio-availability of nifedipine. Solid medicament forms in which khe poor solubility of ni~edipine is said to be compensated by using certain solubilising agents and surface-active substances are also described in DT-OS
(German Published Specification) 2,822,882. The ease of absorption of nifedipine as a result of using polyethylene glycol and certain porous excipient substances is also said to be improved in European Published Patent Applicaticn 1,247.
All previous attempts to compensate the poor solubility of nifedipine by .certain measures and at the same time. to ensure good bio-availability have a number of disadvantages. The 'use of surface-active substances, solubilising agents and ce.rtain excipient substances which h~ave a particular surface, for example are porous, frequently leads to administration forms in which the preparations are undesirably large in size. In order to faci1ik.ate swallowing, such:'tab.Iets or capsules are freq'uently converted into particular shapes, such as, .. ....
' ~e A'2~'4~47 ellipsoids or elongate shapes, but this no longer leads to satisfactory results in the case of preparations weighing over 400 mg. More frequent inta~e of smaller preparatlons also does not provide a satisfactory solution.
For medicament formulations, both the number and the amount of auxiliaries and excipients should be kept as low as possibIe. On comparison of two medicamentous specialities, ~ha~ preparation which, in addition to the active compound, contains as few auxiliaries and additives as possible is always preferred, in order largely to avoid undesired biological actions.
A further disadvantage cf the nifedipine-containing preparations which have been known hi~herto is the e~pensive process for producing them, this disadvantage applying, in particular, to liquid formulations and capsule preparations.
The high sensitivity of nifedipine to light and its poor solubility result in expensive process measures which, especially in the case of liquid formulations, require~ as protection from light, exclusion of daylight and the use of sodium light.
According to the present invention we provide a solid pharmaceutical composition containing as the active ingredient nifedipine crystals with a specific surface area of 0.5 to 6 m2/g, in admi~ture-with a solid diluent.
The invention also provide~ a solid'medicament in dosage unit form comprising nifedipine crystals with a specific surface area of 0.5 to 6m2!g.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, sachet or multi-phase preparations, such as two-layer tablets comprising nifedipine cry'stals wi~h a specific surf'ace area o~ 0.5 ~o 6m /g.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dos~ge unit lorm" as used in this Specification means physically discrete coherent units suitabIe for medical administration ~e A 20 447 .. ..
~ ~027~
each containing a daily dose or a multiple (up to four tlmes) or submultiple (down to a fartieth) of a daily dose of the compour.d of the invention in association with a carrier and/or enclosed within an envelope.
Whether the medicament contains a daily dose or, for example, a halfJ a third or a quarter of a daily dose will depend on whe~her the medicament-is to be administered once or, for example, twice, three times or ~our times a day respectively.
The diluents to be used in pharmaceutical compositions (e,g. granula~es) adapted to be formed into tablets, dragees~ capsules and pills include the following:
(a) fillers and extenders, e.g. starch; sugars, manni~ol, and silicic acid; (b~ binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelat;ne and polyvinyl pyrrolidone, (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol mono-stearate; (h) adsorptive carriers, e.g. kaolin and benton-ite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
m e tablets, dragees, capsules and pills-f~rmed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably 3o in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, o~ polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dl.luent s .
~e A 20 447 .
Pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g~ saccharin).
In addition to the ni~edipine crystals of stated surface areg the pharmaceutical compositions and medicaments according to the invention can also contain other pharm-aceutically active compounds.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
The discrete coherent portions constituting the medicarnent according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills~ dragees, capsules, sachets and multI- ~
phase preparations, such as two-layer tablets. Some of these forms may be made up for delayed release of the active ingredient Some, such as capsulès, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
Those solid medicaments and pharmaceutical compositions which contain nifedipine crystals wikh a specific surface area of 1 to 4 m?/g are particularly advantageous.
The nifedipine crystals which have a specific surface area of 0.5 to 6 m2!g and are used according to the invention are prepared by grinding the crystal mixtures obtained from the synthesis of nifedipine. Grinding can be effected~
for example, with pin disc mills or ha~mer mills.
Nifedipine with the desired surface area can be obtained by varying the speed of the mill, the amount of product fed in and/or the grinding périod.
Le A 20 4~7 1 ~8~
If a product wi'th'a reIatIvely high specific surface area (for example 5 m2/g) is desired~ it is advantageous to carry out grinding with air jet mills.
Crystals with a lower specific surface area (for example 0.5 m /g) are advàntageously to be prepared by sieving in very fine sieves, preferably with mesh wi.d~hs of 0.1 to 0.2 mm. In all casesj it is also possible to obtain a product with the desired specific surface area by mixing nifedipine crystals o~ different specific surface areas.
Accordingly the present invention also provides a process for the production of pharmaceutic compositions of the present invention in which nifedipine crystals obtained , from the synthesis are converted in a crystal mixture with a speci~ic surface area of 0.5 to 6 m2!~ by grinding or si.eving and the solid pharmaceutical compositions are fo'rmulated from these nifedipine crystals using one or more solid auxiliaries and/or excipients.
The specific sur~ace area is measured by the gas adsorption method (BET method; see S. Brunauer:
The Adsorp,tion of Gases and Vapours, Princeton (1945)).
Surprislngly,-the solid-formulations according to the invention have an une~pectedly high bio-availability.
In the publication by I. Sugimoto et al, Drug Development and Industrial Pharmacy, 6(2~, 137-160 (1980)g it is particularly emphàsised (see page 1~9) that, when administ-ered orally, crystalline nifedipine is poorly absorbed and has only a very low bio-availability. It could thus not be expected that, after oral administration of the formul-ation according to the invention, whic,h contains crystal-line nifedipine, the plasma concentration rises rapidly andremains at a high value for many hours. In cases in whi~h nifedipine must be taken over relatively long periods, it is sufficient, on the basis ,of this, very high period of action, to administer 1 or 2 tablets daily. Another 35 . considerable advantage is that. very small tablets with a high .,co.ntent,,of.active.,comp,ound can be p.repared, since ,solubïlising agents, surf,ace~acti,ve s.ub.stances and ',~e A 20''447 ~ 1802~77 and additional auxiliaries can largely be dispensed wi.th.
The smallness of the tab.Iets and the surprisingly long period of action of the formulation according to the invention enable ni~edipine to be used for the treatment of coronary illnesses over relatively long periods, and also prophylactically, and furthermore,. this formulation presents the possibility of employing the ~potensive action o~ nifedipine for the treatment of hypertonia.
The long-las-ting blood level of the active compound which is obtainable by the formulation according to the invention represents an extension of the possibilities for using nifedipine in practice, and at the same time mean relief for the patients.
From the knowledge of the state of the art, from which it can be seen that the experts h.ave for years been concerned with finding useful formulation forms for the active compound nifedipine, which is difficult to formulate 3 it is to be described as exceptionally surprising that a very simple and effective principle for galenical processing has been found by choosing a quite definite specific surface area of the active compound. - .
The solid formulation forms according to the invention represent relief for the patient during administ-ration, and at the same kime increase the reliability of the patient's treatment.
To demonstrate the advantageous action of the medicament formulations according to the invention, the plasma concentration of each of 8 persons was determined for several hours after the administration. The values can be seen from the following table:
Le A 20 447 ~T, :3L ~3 ;~ ~ 7 ~able __.
Time (hours) 1 2 3 4 6 8 10 25.5 Plasma concen-tration3 ~g/l after peroral administrat-ion of the 105.8 86.1 65.3 63.9 43.1 46.7 11.8 10.8 tablets from - -~xample 1 (20 mg) ditto, after peroral admin-istration of the table~s 52.1 66.3 60.4 51.3 32.4 25 18.~ 11.4 from Example
It has already been disclosed that the compound nifedipine has very po~-erful actions which influence khe circulat.ion ~s.ee. British Pate.nt Specification 1,173,862).
Because nifedipine is sensiti.ve to light and sparingly soluble, a number of difficulties. occur in the galenical formulation of medicamental specialities~ as is seen from ~ ' numerous pakents an/~patént applications for special .~- formulations. of this act.ive co~pound. Thus, for example, . U.S. Patent Specificat.ion 3,784,684- relates to particular gelatin capsules for chewing which contain nifedipine and as a result of which the:coronary action of nifedipine can be.advantageously utilised. Furthermore, British Patent Specification lg456,618 describes and claims solid medic-ament formulations which likewi'se ensure a good bio-availability of nifedipine. Solid medicament forms in which khe poor solubility of ni~edipine is said to be compensated by using certain solubilising agents and surface-active substances are also described in DT-OS
(German Published Specification) 2,822,882. The ease of absorption of nifedipine as a result of using polyethylene glycol and certain porous excipient substances is also said to be improved in European Published Patent Applicaticn 1,247.
All previous attempts to compensate the poor solubility of nifedipine by .certain measures and at the same time. to ensure good bio-availability have a number of disadvantages. The 'use of surface-active substances, solubilising agents and ce.rtain excipient substances which h~ave a particular surface, for example are porous, frequently leads to administration forms in which the preparations are undesirably large in size. In order to faci1ik.ate swallowing, such:'tab.Iets or capsules are freq'uently converted into particular shapes, such as, .. ....
' ~e A'2~'4~47 ellipsoids or elongate shapes, but this no longer leads to satisfactory results in the case of preparations weighing over 400 mg. More frequent inta~e of smaller preparatlons also does not provide a satisfactory solution.
For medicament formulations, both the number and the amount of auxiliaries and excipients should be kept as low as possibIe. On comparison of two medicamentous specialities, ~ha~ preparation which, in addition to the active compound, contains as few auxiliaries and additives as possible is always preferred, in order largely to avoid undesired biological actions.
A further disadvantage cf the nifedipine-containing preparations which have been known hi~herto is the e~pensive process for producing them, this disadvantage applying, in particular, to liquid formulations and capsule preparations.
The high sensitivity of nifedipine to light and its poor solubility result in expensive process measures which, especially in the case of liquid formulations, require~ as protection from light, exclusion of daylight and the use of sodium light.
According to the present invention we provide a solid pharmaceutical composition containing as the active ingredient nifedipine crystals with a specific surface area of 0.5 to 6 m2/g, in admi~ture-with a solid diluent.
The invention also provide~ a solid'medicament in dosage unit form comprising nifedipine crystals with a specific surface area of 0.5 to 6m2!g.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, sachet or multi-phase preparations, such as two-layer tablets comprising nifedipine cry'stals wi~h a specific surf'ace area o~ 0.5 ~o 6m /g.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dos~ge unit lorm" as used in this Specification means physically discrete coherent units suitabIe for medical administration ~e A 20 447 .. ..
~ ~027~
each containing a daily dose or a multiple (up to four tlmes) or submultiple (down to a fartieth) of a daily dose of the compour.d of the invention in association with a carrier and/or enclosed within an envelope.
Whether the medicament contains a daily dose or, for example, a halfJ a third or a quarter of a daily dose will depend on whe~her the medicament-is to be administered once or, for example, twice, three times or ~our times a day respectively.
The diluents to be used in pharmaceutical compositions (e,g. granula~es) adapted to be formed into tablets, dragees~ capsules and pills include the following:
(a) fillers and extenders, e.g. starch; sugars, manni~ol, and silicic acid; (b~ binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelat;ne and polyvinyl pyrrolidone, (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol mono-stearate; (h) adsorptive carriers, e.g. kaolin and benton-ite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
m e tablets, dragees, capsules and pills-f~rmed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably 3o in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, o~ polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dl.luent s .
~e A 20 447 .
Pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g~ saccharin).
In addition to the ni~edipine crystals of stated surface areg the pharmaceutical compositions and medicaments according to the invention can also contain other pharm-aceutically active compounds.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
The discrete coherent portions constituting the medicarnent according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills~ dragees, capsules, sachets and multI- ~
phase preparations, such as two-layer tablets. Some of these forms may be made up for delayed release of the active ingredient Some, such as capsulès, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
Those solid medicaments and pharmaceutical compositions which contain nifedipine crystals wikh a specific surface area of 1 to 4 m?/g are particularly advantageous.
The nifedipine crystals which have a specific surface area of 0.5 to 6 m2!g and are used according to the invention are prepared by grinding the crystal mixtures obtained from the synthesis of nifedipine. Grinding can be effected~
for example, with pin disc mills or ha~mer mills.
Nifedipine with the desired surface area can be obtained by varying the speed of the mill, the amount of product fed in and/or the grinding périod.
Le A 20 4~7 1 ~8~
If a product wi'th'a reIatIvely high specific surface area (for example 5 m2/g) is desired~ it is advantageous to carry out grinding with air jet mills.
Crystals with a lower specific surface area (for example 0.5 m /g) are advàntageously to be prepared by sieving in very fine sieves, preferably with mesh wi.d~hs of 0.1 to 0.2 mm. In all casesj it is also possible to obtain a product with the desired specific surface area by mixing nifedipine crystals o~ different specific surface areas.
Accordingly the present invention also provides a process for the production of pharmaceutic compositions of the present invention in which nifedipine crystals obtained , from the synthesis are converted in a crystal mixture with a speci~ic surface area of 0.5 to 6 m2!~ by grinding or si.eving and the solid pharmaceutical compositions are fo'rmulated from these nifedipine crystals using one or more solid auxiliaries and/or excipients.
The specific sur~ace area is measured by the gas adsorption method (BET method; see S. Brunauer:
The Adsorp,tion of Gases and Vapours, Princeton (1945)).
Surprislngly,-the solid-formulations according to the invention have an une~pectedly high bio-availability.
In the publication by I. Sugimoto et al, Drug Development and Industrial Pharmacy, 6(2~, 137-160 (1980)g it is particularly emphàsised (see page 1~9) that, when administ-ered orally, crystalline nifedipine is poorly absorbed and has only a very low bio-availability. It could thus not be expected that, after oral administration of the formul-ation according to the invention, whic,h contains crystal-line nifedipine, the plasma concentration rises rapidly andremains at a high value for many hours. In cases in whi~h nifedipine must be taken over relatively long periods, it is sufficient, on the basis ,of this, very high period of action, to administer 1 or 2 tablets daily. Another 35 . considerable advantage is that. very small tablets with a high .,co.ntent,,of.active.,comp,ound can be p.repared, since ,solubïlising agents, surf,ace~acti,ve s.ub.stances and ',~e A 20''447 ~ 1802~77 and additional auxiliaries can largely be dispensed wi.th.
The smallness of the tab.Iets and the surprisingly long period of action of the formulation according to the invention enable ni~edipine to be used for the treatment of coronary illnesses over relatively long periods, and also prophylactically, and furthermore,. this formulation presents the possibility of employing the ~potensive action o~ nifedipine for the treatment of hypertonia.
The long-las-ting blood level of the active compound which is obtainable by the formulation according to the invention represents an extension of the possibilities for using nifedipine in practice, and at the same time mean relief for the patients.
From the knowledge of the state of the art, from which it can be seen that the experts h.ave for years been concerned with finding useful formulation forms for the active compound nifedipine, which is difficult to formulate 3 it is to be described as exceptionally surprising that a very simple and effective principle for galenical processing has been found by choosing a quite definite specific surface area of the active compound. - .
The solid formulation forms according to the invention represent relief for the patient during administ-ration, and at the same kime increase the reliability of the patient's treatment.
To demonstrate the advantageous action of the medicament formulations according to the invention, the plasma concentration of each of 8 persons was determined for several hours after the administration. The values can be seen from the following table:
Le A 20 447 ~T, :3L ~3 ;~ ~ 7 ~able __.
Time (hours) 1 2 3 4 6 8 10 25.5 Plasma concen-tration3 ~g/l after peroral administrat-ion of the 105.8 86.1 65.3 63.9 43.1 46.7 11.8 10.8 tablets from - -~xample 1 (20 mg) ditto, after peroral admin-istration of the table~s 52.1 66.3 60.4 51.3 32.4 25 18.~ 11.4 from Example
2 (20 mg) The following Examples illustrate processes for the production of solid medicament formulations according to the invention.
Example 1 200 g o~ nifedipine crystals with a specific surface area of 4 m tg were mixed with 348 g of micro~
crystalline cellulose, 100 g of lactose, 10 g of "Tween" 80, (Trada Mark), 70 g of sta~ch and 2 g of magnesium stearate.
A paste was prepared from a further 70 g of starch with water and, in the custo~ary manner, the past~ was granulated with the abovementioned mixture and the mixture was dried and then pressed to tablets which individually weighed 80mg.
These tablets were then labelled; they had a diameter of 6 mm.
A suspension of 18 g of hydroxypropylmethyl-cellulose, 6 g of polyethylene glycol, 5.4 g of titanium dioxide, 0.6 g of iron oxide and 370 g of water or ethanol was used to lacquer 800 g of tablets.
Example 2 200 g of nifedipine crystals with a specific surface area of 1 m?!g wexe pressed to 80 mg tablets with - a di'ameter of 6 mm and filmcoated analogously to Example 1.
Le A 20~447 `7 xamE~ ~
2CO g of nifedipine with a specific surface area of 1.2 m2/g were mixed with 800 g of lactose, 960 g of starch and 40 g o, magnesium stearate. 100 mg portions of the mixture were filled into si~e 3 hard gelatin -capsules. Each capsule then contain.ed 10 mg of nifed-iplne. Capsules containing various dosages, for example between 5 mg and 40 mg of active compound per capsule, could be prepared by varying the capsule size and the weight Or contents.
~xample 4 Two-layer tablets were p.repared. One layer consisted of 7.5 mg of nifedipine with a specific surface area of 6 m2!g, 7.5 mg of lactose, 30 mg of starch, 3 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate (100 mg in total), and the second layer had the same composition~ but the nifedipine had a specific surface area of 0.6 m2!g. The compressed two-layer tablets weighing a total of 200 mg could be provided with a break-ing groo~e in order to provide an individual dosage forthe patient.
.
Le A 2~ 447
Example 1 200 g o~ nifedipine crystals with a specific surface area of 4 m tg were mixed with 348 g of micro~
crystalline cellulose, 100 g of lactose, 10 g of "Tween" 80, (Trada Mark), 70 g of sta~ch and 2 g of magnesium stearate.
A paste was prepared from a further 70 g of starch with water and, in the custo~ary manner, the past~ was granulated with the abovementioned mixture and the mixture was dried and then pressed to tablets which individually weighed 80mg.
These tablets were then labelled; they had a diameter of 6 mm.
A suspension of 18 g of hydroxypropylmethyl-cellulose, 6 g of polyethylene glycol, 5.4 g of titanium dioxide, 0.6 g of iron oxide and 370 g of water or ethanol was used to lacquer 800 g of tablets.
Example 2 200 g of nifedipine crystals with a specific surface area of 1 m?!g wexe pressed to 80 mg tablets with - a di'ameter of 6 mm and filmcoated analogously to Example 1.
Le A 20~447 `7 xamE~ ~
2CO g of nifedipine with a specific surface area of 1.2 m2/g were mixed with 800 g of lactose, 960 g of starch and 40 g o, magnesium stearate. 100 mg portions of the mixture were filled into si~e 3 hard gelatin -capsules. Each capsule then contain.ed 10 mg of nifed-iplne. Capsules containing various dosages, for example between 5 mg and 40 mg of active compound per capsule, could be prepared by varying the capsule size and the weight Or contents.
~xample 4 Two-layer tablets were p.repared. One layer consisted of 7.5 mg of nifedipine with a specific surface area of 6 m2!g, 7.5 mg of lactose, 30 mg of starch, 3 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate (100 mg in total), and the second layer had the same composition~ but the nifedipine had a specific surface area of 0.6 m2!g. The compressed two-layer tablets weighing a total of 200 mg could be provided with a break-ing groo~e in order to provide an individual dosage forthe patient.
.
Le A 2~ 447
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A solid pharmaceutical composition containing as the active ingredient nifedipine crystals having a specific surface area of 0.5 to 6 m2/g, in admixture with a solid diluent.
2. A solid medicament in dosage unit form comprising nifedipine crystals with a specific surface area of 0.5 to 6 m2/g.
3. A medicament in the form of tablets, pills, dragees, capsules, suppositories, sachets or two-layer tablets comprising nifedipine crystals with a specific surface area of 0.5 to 6 m2/g.
4. A pharmaceutical composition according to claim 1 or medicament according to claim 2 or 3 in which the nifedipine crystals have a specific surface area of 1 to 4 m2/g.
5. A process for the preparation of a solid pharmaceutical composition in which nifedipine crystals obtained from the synthesis of this substance are converted into a crystal mixture having a specific surface area of 0.5 to 6 m2/g by grinding or sieving, and the resulting crystal mixture is formulated into a solid pharmaceutical composition using a solid auxiliary and/or excipient.
6. A process for the preparation of a solid medicament in dosage unit form, in which nifedipine crystals obtained from the synthesis of this sub-stance are converted into a crystal mixture having a specific surface area of 0.5 to 6 m2/g, and the resulting crystal mixture is formulated into a medicament in dosage unit form.
7. A process according to claim 5 or 6 wherein the crystals are converted to a crystal mixture having a specific surface area of 1 to 4 m2/g.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3033919.6 | 1980-09-09 | ||
| DE19803033919 DE3033919A1 (en) | 1980-09-09 | 1980-09-09 | SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1180277A true CA1180277A (en) | 1985-01-02 |
Family
ID=6111496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000385365A Expired CA1180277A (en) | 1980-09-09 | 1981-09-08 | Solid medicament formulations containing nifedipine, and processes for their preparation |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0047899B2 (en) |
| JP (1) | JPS5914446B2 (en) |
| AR (1) | AR226377A1 (en) |
| AT (1) | ATE5761T1 (en) |
| AU (1) | AU558331B2 (en) |
| CA (1) | CA1180277A (en) |
| DD (1) | DD201974A5 (en) |
| DE (2) | DE3033919A1 (en) |
| DK (1) | DK154326C (en) |
| FI (1) | FI72648B (en) |
| GR (1) | GR78237B (en) |
| HU (1) | HU184879B (en) |
| IE (1) | IE51549B1 (en) |
| IL (1) | IL63749A (en) |
| NO (1) | NO157368B (en) |
| NZ (1) | NZ198285A (en) |
| PH (1) | PH24097A (en) |
| PL (1) | PL232951A1 (en) |
| PT (1) | PT73603B (en) |
| ZA (1) | ZA816213B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880623A (en) * | 1985-10-15 | 1989-11-14 | Eurand Italia S.P.A. | Process for the preparation of solid nifedipine formulations of high bioavailability and with sustained effect, and formulations thus obtained |
| US4940556A (en) * | 1986-01-30 | 1990-07-10 | Syntex (U.S.A.) Inc. | Method of preparing long acting formulation |
| US4942040A (en) * | 1987-10-08 | 1990-07-17 | Aktiebolaget Hassle | Pharmaceutical preparation and a process for its preparation |
| US5145683A (en) * | 1989-02-14 | 1992-09-08 | Ethical Pharmaceuticals, Ltd. | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
| US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
| US5594013A (en) * | 1992-01-13 | 1997-01-14 | Ethical Pharmaceuticals Limited | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264446A (en) * | 1980-09-09 | 1993-11-23 | Bayer Aktiengesellschaft | Solid medicament formulations containing nifedipine, and processes for their preparation |
| JPS5846019A (en) * | 1981-09-14 | 1983-03-17 | Kanebo Ltd | Nifedipine preparation with prolonged action |
| DE3222367A1 (en) * | 1982-06-15 | 1983-12-15 | Bayer Ag, 5090 Leverkusen | Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof |
| JPS59101423A (en) * | 1982-12-02 | 1984-06-12 | Takada Seiyaku Kk | Novel solid pharmaceutical preparation of nifedipine |
| US4529733A (en) * | 1983-04-06 | 1985-07-16 | Merrell Dow Pharmaceuticals Inc. | Antihypertensive 3-furoyl-1,4-dihydropyridines |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| NL194389C (en) * | 1984-06-14 | 2002-03-04 | Novartis Ag | Process for preparing a solid dispersion of a pharmaceutically active agent that has low water solubility in a solid matrix of a water-soluble polyalkylene glycol as a carrier. |
| IT1178511B (en) * | 1984-09-14 | 1987-09-09 | Pharmatec Spa | PROCEDURE FOR THE PREPARATION OF A SOLID FORM FOR ORAL USE BASED ON NIFEDIPINE WITH RELEASE |
| CH673947A5 (en) * | 1986-09-23 | 1990-04-30 | Sandoz Ag | |
| JPS6464659A (en) * | 1987-09-03 | 1989-03-10 | Kenbi Kogaku Kenkyusho Kk | Preparation of safe and effective powder formulation |
| DE3814532A1 (en) * | 1988-04-29 | 1989-11-09 | Bayer Ag | DHP-RETARD-PREPARATION |
| JPH0298550U (en) * | 1989-01-25 | 1990-08-06 | ||
| US5271944A (en) * | 1991-04-05 | 1993-12-21 | Biofor, Ltd. | Pharmacologically enhanced formulations |
| 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 |
| US6726930B1 (en) | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5773025A (en) | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| US5543099A (en) * | 1994-09-29 | 1996-08-06 | Hallmark Pharmaceutical, Inc. | Process to manufacture micronized nifedipine granules for sustained release medicaments |
| DK0800392T3 (en) * | 1994-12-29 | 2002-03-18 | Shire Deutschland Gmbh & Co Kg | Pharmaceutical compositions containing nifedipine and its method of preparation |
| JP3220373B2 (en) | 1995-11-28 | 2001-10-22 | バイエル薬品株式会社 | Long-acting nifedipine preparation |
| WO1998001117A1 (en) | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
| IT1284604B1 (en) * | 1996-09-27 | 1998-05-21 | Roberto Valducci | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION CONTAINING NIFEDIPINE AS THE ACTIVE SUBSTANCE |
| US6056977A (en) * | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| IL143375A0 (en) | 1999-09-30 | 2002-04-21 | Penwest Pharmaceuticals Co | Sustained release matrix systems for highly soluble drugs |
| EP1737847B1 (en) | 2004-07-30 | 2008-06-04 | Torrent Pharmaceuticals Ltd | Nebivolol and its pharmaceutically acceptable salts, process for preparation and pharmaceutical compositions of nebivolol |
| DE102004062475A1 (en) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Solid, orally administrable, modified release pharmaceutical dosage forms |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3330727A (en) * | 1960-04-19 | 1967-07-11 | Glaxo Lab Ltd | Griseofulvin with high specific surface area |
| US3401221A (en) * | 1964-08-25 | 1968-09-10 | Norwich Pharma Co | Treatment of urinary tract infection |
| DE2348334C2 (en) * | 1973-09-26 | 1982-11-11 | Boehringer Mannheim Gmbh, 6800 Mannheim | New form of preparation of N-4- [2- (5-chloro-2-methoxybenzamido) ethyl] -phenyl-sulfonyl-N'-cyclohexylurea |
| DE2400819C2 (en) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Process for the production of solid preparations of poorly soluble active pharmaceutical ingredients in extremely fine distribution |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| JPS55129221A (en) * | 1979-03-29 | 1980-10-06 | Kaken Pharmaceut Co Ltd | Preparation of oral preparation containing hardly soluble medicine |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
-
1980
- 1980-09-09 DE DE19803033919 patent/DE3033919A1/en not_active Ceased
- 1980-12-27 JP JP55185148A patent/JPS5914446B2/en not_active Expired
-
1981
- 1981-08-25 NO NO812879A patent/NO157368B/en unknown
- 1981-08-28 AT AT81106729T patent/ATE5761T1/en not_active IP Right Cessation
- 1981-08-28 EP EP81106729A patent/EP0047899B2/en not_active Expired - Lifetime
- 1981-08-28 DE DE8181106729T patent/DE3161838D1/en not_active Expired
- 1981-08-31 PT PT73603A patent/PT73603B/en unknown
- 1981-08-31 PH PH26121A patent/PH24097A/en unknown
- 1981-09-01 DD DD81232939A patent/DD201974A5/en not_active IP Right Cessation
- 1981-09-07 GR GR65968A patent/GR78237B/el unknown
- 1981-09-07 NZ NZ198285A patent/NZ198285A/en unknown
- 1981-09-07 FI FI812758A patent/FI72648B/en not_active Application Discontinuation
- 1981-09-07 IL IL63749A patent/IL63749A/en not_active IP Right Cessation
- 1981-09-08 DK DK396381A patent/DK154326C/en not_active IP Right Cessation
- 1981-09-08 CA CA000385365A patent/CA1180277A/en not_active Expired
- 1981-09-08 PL PL23295181A patent/PL232951A1/xx unknown
- 1981-09-08 AU AU75063/81A patent/AU558331B2/en not_active Expired
- 1981-09-08 ZA ZA816213A patent/ZA816213B/en unknown
- 1981-09-08 IE IE2075/81A patent/IE51549B1/en not_active IP Right Cessation
- 1981-09-08 AR AR286686A patent/AR226377A1/en active
- 1981-09-09 HU HU812594A patent/HU184879B/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880623A (en) * | 1985-10-15 | 1989-11-14 | Eurand Italia S.P.A. | Process for the preparation of solid nifedipine formulations of high bioavailability and with sustained effect, and formulations thus obtained |
| US4940556A (en) * | 1986-01-30 | 1990-07-10 | Syntex (U.S.A.) Inc. | Method of preparing long acting formulation |
| US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
| US4942040A (en) * | 1987-10-08 | 1990-07-17 | Aktiebolaget Hassle | Pharmaceutical preparation and a process for its preparation |
| US5145683A (en) * | 1989-02-14 | 1992-09-08 | Ethical Pharmaceuticals, Ltd. | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
| US5594013A (en) * | 1992-01-13 | 1997-01-14 | Ethical Pharmaceuticals Limited | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU558331B2 (en) | 1987-01-29 |
| IL63749A (en) | 1984-06-29 |
| ZA816213B (en) | 1982-09-29 |
| DD201974A5 (en) | 1983-08-24 |
| IE812075L (en) | 1982-03-09 |
| IL63749A0 (en) | 1981-12-31 |
| DK154326B (en) | 1988-11-07 |
| IE51549B1 (en) | 1987-01-07 |
| EP0047899B2 (en) | 1996-02-28 |
| ATE5761T1 (en) | 1984-01-15 |
| FI72648B (en) | 1987-03-31 |
| DK154326C (en) | 1995-03-13 |
| NO812879L (en) | 1982-03-10 |
| GR78237B (en) | 1984-09-26 |
| AU7506381A (en) | 1982-03-18 |
| AR226377A1 (en) | 1982-06-30 |
| EP0047899A1 (en) | 1982-03-24 |
| PH24097A (en) | 1990-03-05 |
| DK396381A (en) | 1982-03-10 |
| PT73603A (en) | 1981-09-01 |
| PL232951A1 (en) | 1982-10-11 |
| DE3033919A1 (en) | 1982-04-22 |
| JPS5750913A (en) | 1982-03-25 |
| NZ198285A (en) | 1984-04-27 |
| DE3161838D1 (en) | 1984-02-09 |
| FI812758L (en) | 1982-03-10 |
| PT73603B (en) | 1982-11-10 |
| EP0047899B1 (en) | 1984-01-04 |
| JPS5914446B2 (en) | 1984-04-04 |
| HU184879B (en) | 1984-10-29 |
| NO157368B (en) | 1987-11-30 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |