Delayed release microtablet of .beta.-phenylpropiophenone derivatives

A cylindrical delayed release tablet with a convex or flat upper side and lower side is provided, along with a method for its production and a gelatin capsule containing 3-200 tablets of the same having identical or different release rates, wherein the tablet if made of .beta.-phenylpropiophenone derivatives of the formula I as active ingredient ##STR1## where R is n-propyl or 1,1-dimethylpropyl, and their pharmacologically acceptable salts, wherein the tablet has a height and diameter that are both, independently of one another, 1-3 mm, the active ingredient content is in the range from 81-99.9% of the weight of the microtablet, (but not taking into account the weight of any coating which is present, the active ingredient density is greater than 1, the release of active ingredient in the USP paddle method at 50 rpm is 80% as a maximum after 3 hours and as a minimum after 24 hours, the release rate is virtually independent of the pressure when compressing the tablets, and the tablet contains no release-delaying ancillary substance but can contain 0.1-5% by weight of a lubricant and 0-18.9% by weight of other conventional ancillary substances.

This application is a 35USC371 of PCT/EP94/00949 filed Mar. 24, 1994. 
BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to cylindrical microtablets of 
.beta.-phenylpropiophenone derivatives with a high content and density of 
active ingredient and a delayed release which is independent of the 
compressive force, with no release-delaying ancillary substances. 
2. Discussion of the Background 
Reference to .beta.-phenylpropiophenone derivatives hereinbefore and 
hereinafter always includes and particularly means their physiologically 
acceptable salts, preferably the hydrochloride. 
In the prior art the release of active ingredient from tablets is delayed 
either by a release-delaying matrix in which the active ingredient is 
embedded, or by a release-delaying coating through which the digestive 
fluid diffuses in and the active ingredient diffuses out. 
Both principles have considerable disadvantages. For example, matrix 
tablets contain relatively large amounts of ancillary substances so that 
the volume of the tablet for a given dose of active ingredient is 
relatively large, which is unpleasant for the patient. On the other hand, 
film-coated tablets are elaborate to produce and, in particular, 
mechanically sensitive. The slightest damage to the lacquer film leads to 
the risk of sudden release of the entire content of active ingredient 
(dose dumping), which is extremely undesirable (local and temporal 
overdose with adverse side effects; short total action time). 
Both matrix and film-coated delayed release tablets normally have diameters 
of about 6 to 12 mm or more and are therefore unable to pass through the 
closed pylorus. The release and absorption of their total content of 
active ingredient concentrated at one site in the gastrointestinal tract 
depends on the conditions prevailing at this site, which results in wide 
interindividual and intraindividual variation in the plasma level. 
This variation is less with multiple unit delayed release forms because the 
units are distributed uniformly along the gastrointestinal tract and can 
also pass through the closed pylorus. Usually employed as multiple unit 
forms are pellets with a diffusion lacquer packed into hard gelatin 
capsules. It is possible to produce matrix pellets only with very low 
doses of medicinal substances because, owing to the large surface area, 
even more matrix substance would be required than for the bolus delayed d 
release tablet. 
For example, the Patent Applications GB 2 176 999 and WO 92/04013 disclose 
small matrix delayed release tablets which likewise contain relatively 
large amounts of release-delaying ancillary substances. The Patent 
Application EP 22 17 32 claims delayed release tablets of active 
ingredients with low solubility, which contain 60-80% active ingredient in 
addition to at least four auxiliaries. The release from these bolus forms 
is, as described in the patent, highly dependent on the granulation 
process and the equipment used for manufacture. 
It is furthermore generally known that an increase in the compressive force 
in tablet production is associated with a slowing of the release of active 
ingredient. This applies both to fast release tablets and to delayed 
release tablets (Patent Application WO 92/00064). Since the compressive 
forces fluctuate, despite the most up to date machine engineering, the 
resulting release rates vary. An additional factor is the variation 
between batches in the compression properties, which derives from the 
variability in the granules to be compressed. Differences in the particle 
size, porosity, surface structure, wettability etc. may have a large 
effect on the compression properties and the delaying of release. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to overcome the disadvantages of 
the prior art, ie. to develop propafenone and diprafenone tablets with a 
small size, high content and density of active ingredient and release of 
active ingredient which is independent of the compressive force and 
uniform over a lengthy period. 
We have found that this object is achieved by the microtablets of the 
present invention. This is because it has been found, surprisingly, that 
it is possible in the present case to produce delayed release tablets 
without release-delaying ancillary substances. This is all the more 
surprising because other medicinal substances with a water solubility 
similar to that of propafenone hydrochloride (0.7%), for example 
cimetidine hydrochloride or paracetamol, are 90% released in 1 hour from 
the same preparation. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
By comparison with other substances, propafenone HCl is extremely difficult 
to compress. A bolus tablet with commercial dosages of 150-300 mg and an 
active ingredient content above 80% cannot be produced under production 
conditions. By contrast, the microtablets according to the invention can, 
surprisingly, be produced at a relatively high machine speed without 
problems concerning friability and hardness, and specifically with active 
ingredient contents in the range from 81 to 99.9, preferably 85 to 99.5, % 
by weight and with an active ingredient density above 1. Such high 
contents of active ingredients of this type in tablets have not previously 
been reached. 
The microtablets according to the invention are cylindrical with a flat or 
convex upper side and lower side and with a diameter and height which are 
preferably approximately equal and, independently of one another, from 1 
to 3, preferably 1.5 to 2.5 mm. 
It was furthermore not predictable that the release of active ingredient 
is, in contrast to usual experience, virtually independent of the pressure 
when compressing the tablets and, moreover, over a wide range of pH of the 
medium. "Virtually independent" means that the effect can be neglected for 
practical purposes. This ensures release at a constant rate. It is 
adjusted via the size of the tablet and possibly by additives which 
increase the release rate so that the release of active ingredient after 
3, preferably 5, hours is not more than 80 and after 24, preferably 15, 
hours is not less than 80%. Surprisingly, the microtablets according to 
the invention also display distinct advantages in vivo unlike conventional 
delayed release forms such as a bolus delayed release form with similar in 
vitro release. Despite the short half-life, a pronounced blood level 
plateau develops (FIG. 11). The fluctuations in the blood level are 
considerably less with the microtablets. This is evident from the 
t.sub.75% (period in the dosage interval during which the plasma levels 
are at least 75% of the maximum level), which is 8 to 9 hours with the 
microtablets according to the invention compared with 5 to 6 hours with 
the bolus delayed release form, and from the PTF (peak to trough 
fluctuation; cf. H. P. Koch and W. A. Ritschel, Synopsis der Biopharmazie 
und Pharmakokinetik, Ecomed-Verlagsgesellschaft mbH, Landsberg und 
Munchen, 1986) 
##EQU1## 
for the AUC, cf. J. K. Aronson et al., Europ. J. of Clinical Pharmacology 
35 (1988), 1-7. 
which has a value for the microtablets which is only about half that for 
the bolus forms, in particular less than 75, preferably less than 60, %. 
The microtablets accordingly increase therapeutic safety because excessive 
peaks of plasma levels and the side effects caused thereby do not occur, 
the plasma level does not fall below the minimum effective level, and the 
bioavailability of this form is unaffected by food intake, in contrast to 
the bolus delayed release form. 
The AUC found for the bolus delayed release form is 50% higher when 
fasting. 
In general, the microtablets show smaller intra- and inter-individual 
differences by comparison with the bolus delayed release form. 
The microtablets according to the invention furthermore have the advantage 
that when introduced into gastric or intestinal fluid they show no 
tendency to stick or adhere. This ensures that they pass as individual 
articles through the gastrointestinal tract and, moreover, do not become 
attached to the wall of the stomach or intestine and induce irritation. 
Sticking or adhesion properties of this type are displayed, for example, 
by small articles with hydrophilic release-delaying polymers (cf. WO 
92/04013). 
The production of delayed release forms with hydrophilic release-delaying 
polymers often requires the use of organic solvents during granulation so 
that swelling does not start even during this process. It is possible 
entirely to dispense with this in the production of the microtablets 
according to the invention. 
Presentations with hydrophilic release-delaying polymers additionally have 
the disadvantage that, because of the tendency to sorption and swelling, 
they are sensitive to a change in humidity during storage. These 
formulations are damaged by high humidities in particular. The 
microtablets according to the invention are stable even at relatively high 
humidities because of the insensitivity of the materials used. Even after 
storage at 93% rel. humidity for 21 days the water uptake is less than 1%, 
and no visible change is detectable. 
The microtablets according to the invention are produced in conventional 
pharmaceutical equipment by the following steps: granulation, drying, 
mixing, tabletting. 
The particle size of the active ingredient is, within the conventional 
pharmaceutical range, of only minor or no importance in the production of 
the microtablets according to the invention, against all expectations. 
This means that it is possible to convert propafenone hydrochloride and 
diprafenone hydrochloride of different particle sizes into products of the 
same quality. 
Granulation and drying are preferably carried out in a fluidized bed. 
However, the agglomeration can also be carried out in a horizontal or 
vertical mixer. 
After the wet granules have been passed through a screen of suitable mesh 
width they are dried either in a circulating air dryer or in a fluidized 
bed. The particle size of the granules should be below 1 mm, preferably 
below 0.8 mm. 
It is possible to employ all conventional binders or adhesives for the 
agglomeration, eg. polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate 
copolymers, gelatin, hydroxypropylmethylcellulose, hydroxypropylcellulose, 
polymers of methacrylic acid and its esters. It is possible to dispense 
with the use of a binder by using a solution of active ingredient as 
granulation liquid. Water without additives is preferred as granulation 
liquid. 
After the granules have been dried to the defined water content, 0.1-5, 
preferably 0.3-2, % by weight of a lubricant for the tabletting are mixed 
in homogeneously. It is likewise possible to use for this purpose all 
conventional substances such as talc, magnesium stearate, calcium 
stearate, stearic acid, calcium behenate, glycerin palmitostearate, sodium 
acetate, polyethylene glycol, sodium stearate sic! fumarate. In addition, 
up to 18.9% by weight of other conventional ancillary substances can be 
added, for example colorants, stabilizers, fillers, wetting agents, flow 
regulators but no release-delaying agents. 
The tabletting takes place in a suitable tabletting machine equipped with 
multiple microtablet punches. The resulting microtablets have a 
cylindrical shape with flat or convex surface sic!. The height and the 
diameter can be varied independently of one another. It is often 
expedient, to increase the apparent density and improve flowability, to 
match the height of the microtablets to the diameter. 
Another element in the control of release besides the size of the 
microtablets is the addition of wetting agents which increase the rate of 
dissolution. Wetting agents which can be used are, on the one hand, 
surfactants such as polyoxyethylene fatty acid esters, polyoxyethylene 
fatty alcohol ethers, fatty acid salts, bile acid salts, alkyl sulfates or 
ethylene oxide/propylene oxide block copolymers or, on the other hand, 
genuinely water-soluble substances such as polyethylene glycols, urea, 
sodium chloride, sorbitol, mannitol, glycine, nicotinamide, or salts of 
citric acid, tartaric acid or phosphoric acid. In this case the rate of 
release increases in parallel with the rise in the wetting agent 
concentration. 
The wetting agent can have been incorporated into the granules or else be 
subsequently mixed in together with the lubricant. This is, of course, 
possible only with solid wetting agents. The wetting agent concentration 
is 0.1-15, as a rule 1-10, % of the total mass. 
To increase the rate of erosion of the active ingredient from the tablet 
surface, and thus the release of active ingredient, it is also possible to 
use disintegrants in concentrations of 0.001-0.5, preferably 0.01-0.1, %, 
which are far below the conventional concentrations. 
As a rule, the microtablets can be packed into gelatin capsules directly 
using conventional filling machines. It may occasionally be advantageous 
for the microtablets, before the packing, to be provided with a readily 
soluble film coating which does not influence the release. 
In addition, it is in many cases expedient to combine delayed release with 
instant release or not so delayed release microtablets. This results in 
release of an initial dose at once, followed by the slow release of the 
maintenance dose. Modern capsule filling machines are able to meter two 
products into one capsule without problems. 
The instant release microtablet differs from the delayed release 
microtablet in that it contains conventional amounts of disintegrant, 
swelling agent, pore former, which bring about rapid disintegration of the 
microtablet into small fragments and rapid dissolution of the active 
ingredient. 
The microtablets of the examples always had a diameter and height each of 2 
mm, and the density of active ingredient was always more than 1.

EXAMPLES 
Example 1 (FIG. 1) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 6.25 mg (96%) 
Hydroxypropylmethylcellulose 
0.20 mg 
Magnesium stearate 0.05 mg 
Total weight 6.50 mg 
______________________________________ 
30kg of propafenone HCl were granulated with 10 kg of a 10% strength 
hydroxypropylmethylcellulose solution (Pharmacoat.RTM. 603) and dried in a 
fluidized bed granulator. The granules were passed through a screen of 
suitable mesh width and then mixed in a plowshare mixer with the stated 
amount of magnesium stearate. 
The microtablets were produced in a rotary tabletting machine equipped with 
multiple microtablet punches. 
The number of microtablets corresponding to the dose to be administered was 
packed into hard gelatin capsules using a suitable capsule filling 
machine. 
TABLE 1 
______________________________________ 
Results of studies on volunteers with propafenone HCl 
microtablets of Example 1 and a bolus delayed release form 
according to the comparative test (n = 18, dose: 400 mg of 
propafenone HCl, repeated administration) 
Bolus delayed release 
Microtablets form 
fasting non-fasting 
fasting 
non-fasting 
______________________________________ 
AUC ng .multidot. h 
5 500 5 500 6 900 4 700 
ml 
t.sub.75% 
(h) 8-9 8-9 5-6 5-6 
PTF (%) 52 56 88 106 
______________________________________ 
n = number of volunteers 
ng = nanogram 
h = hours 
Example 2 (FIG. 2) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 5.92 mg (91%) 
Hydroxypropylmethylcellulose 
0.20 mg 
Poloxamer 188 (USP) 0.33 mg 
Magnesium stearate 0.05 mg 
Total weight 6.5 mg 
______________________________________ 
Production took place as in Example 1. The required amount of poloxamer 188 
together with the magnesium stearate were mixed with the granules in a 
plowshare mixer. 
Example 3 (FIG. 3) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 5.61 mg (86%) 
Hydroxypropylmethylcellulose 
0.19 mg 
Poloxamer 188 0.65 mg 
Magnesium stearate 0.05 mg 
Total weight 6.5 mg 
______________________________________ 
Production took place as in Example 2. 
Example 4 (FIG. 4) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 6.0 mg (86%) 
Hydroxypropylmethylcellulose 
0.2 mg 
Calcium hydrogen phosphate 
0.613 mg 
Monoglyceride (Myvatox .RTM.) 
0.15 mg 
Crosslinked polyvinylpyrrolidone 
0.007 mg 
Magnesium stearate 0.03 mg 
Total weight 7.0 mg 
______________________________________ 
Production took place as in Example 2. 
Example 5 (FIG. 5) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 5.70 mg (81%) 
Gelatin 0.18 mg 
Calcium hydrogen phosphate 
0.38 mg 
NaCl 0.70 mg 
Magnesium stearate 0.04 mg 
Total weight 7.0 mg 
______________________________________ 
Production took place as in Example 1. A 10% strength gelatin solution was 
used as granulating agent. The amount of NaCl was mixed in with the 
magnesium stearate. 
Example 6 (FIG. 6) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 5.83 mg (83%) 
Hydroxypropylmethylcellulose 
0.17 mg 
.beta.-Cyclodextrin 0.9 mg 
Magnesium stearate 0.1 mg 
Total weight 7.0 mg 
______________________________________ 
Production took place as in Example 2. 
Example 7 (FIG. 7) 
Gelatin capsules with propafenone delayed release microtablets and 
propafenone instant release microtablets 
To achieve a higher initial release, 14 instant release microtablets and 55 
delayed release microtablets were packed into hard gelatin capsules in a 
suitable capsule filling machine. 
______________________________________ 
Composition of the instant release microtablets 
______________________________________ 
Propafenone HCl 6.05 mg (93%) 
Hydroxypropylmethylcellulose 
0.20 mg 
Sodium carboxymethylstarch 
0.20 mg 
Magnesium stearate 0.05 mg 
Total weight 6.5 mg 
______________________________________ 
The instant release microtablets were produced as in Example 2. 
The delayed release microtablets were produced as in Example 1. 
Example 8 (FIG. 8) 
Propafenone delayed release microtablets 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 6.48 mg (99.7%) 
Magnesium stearate 0.02 mg 
Total weight 6.50 mg 
______________________________________ 
Propafenone hydrochloride and magnesium stearate were mixed in a plowshare 
mixer and subsequently compressed to microtablets. 
The in vitro release plots (FIGS. 1 to 10) were determined using a USP 
paddle apparatus with 0.08 molar HCl in the first two hours and then 
phosphate buffer pH 6.8. The paddle rotated at 50 rpm. 
Comparative test 
Propafenone delayed release bolus film-coated tablet 
______________________________________ 
Composition 
______________________________________ 
Propafenone HCl 450.0 mg 
Sodium alginate 112.0 mg 
Microcrystalline cellulose 
37.0 mg 
type PH 101 
Copolymers of acrylic and 
15.0 mg 
methacrylic esters with a small 
content of quaternary ammonium 
groups (Eudragit .RTM. RS) 
Gelatin 55.0 mg 
Magnesium stearate 3.5 mg 
Microcrystalline cellulose 
12.5 mg 
type PH 102 
Readily soluble film coating 
15.0 mg 
Total weight 700.0 mg 
______________________________________ 
Propafenone hydrochloride, sodium alginate, microcrystalline cellulose 
(type PH 101) and Eudragit RS were mixed in a vertical mixer and 
granulated with 20% strength gelatin solution. The wet granules were dried 
in a fluidized bed dryer with inlet air at 60.degree. C. After passing 
through a screen of suitable mesh width, magnesium stearate and 
microcrystalline cellulose (type PH 102) were admixed in a horizontal 
mixer and subsequently the mixture was compressed to oblong tablets 
(dimensions 18.times.8.7 mm) in a rotary tabletting machine. The readily 
soluble coating was applied in a horizontal coater. 
Determination of in vitro release in a paddle apparatus at 50 rpm produced 
the following results (in %): 
______________________________________ 
1st hour 
3.8 
2nd hour 
5.5 
3rd hour 
23.7 
4th hour 
43.0 
6th hour 
75.4 
8th hour 
89.5 
______________________________________ 
The in vitro release from the delayed release bolus film-coated tablet is 
thus similar to that of the delayed release microtablets according to the 
invention. Nevertheless, the in vivo release is entirely different and, in 
fact, better according to the invention, cf. drug levels shown in FIG. 11.