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 .
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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.
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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.
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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.
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