<div id="description" class="application article clearfix">
<p lang="en" class="printTableText">23 4 5 93 <br><br>
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23'APR i993"" <br><br>
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No.: Date: <br><br>
NEW ZEALAND <br><br>
PATENTS ACT, 1953 <br><br>
COMPLETE SPECIFICATION <br><br>
M=W ZEALAND <br><br>
PATENT office <br><br>
20 JUL WO <br><br>
received u <br><br>
NEW ORAL PHARMACEUTICAL DOSAGE FORM IMPROVING BIOAVAILABILITY <br><br>
k/We, LABORATOIRES DELAGRANGE, a French Company of 1, avenue Pierre Brossolette, 91380 Chilly-Mazarin, France hereby declare the invention for which Xk / we pray that a patent may be granted to HY&/\is, and the method by which it is to be performed, to be particularly described in and by the following statement: - <br><br>
- 1 - <br><br>
(followed by page la) <br><br>
- la - <br><br>
23 4593 <br><br>
The invention relates to a new pharmaceutical dosage form enabling the bioavailability of medicinal products, and especially those belonging to the category of calcium inhibitors, to be controlled. <br><br>
Among these inhibitors, dihydropyridine derivatives endowed with valuable cardiovascular properties are limited in their use by problems of dissolution in vivo, and consequently in an aqueous medium. <br><br>
The Applicant has hence endeavoured to obtain a special pharmaceutical dosage form to match the in vivo release of such active principles to the production of plasma levels sufficient for one daily dose, irrespective of the solubility of these active principles. <br><br>
The essence of the invention lies in the choice of a specific protein substrate enabling this objective to be attained. <br><br>
It is known to combine an active principle with a water-soluble crystalline substrate, such as polyethylene glycol or polyvinylpyrrolidone, in the form of a dispersant agent, to obtain sustained release forms as is described for example, in British Patent No. 2,lbG,I00. However, the resulting dispersion, converted into tablets or hard gelatin capsules with conventional excipients, undergoes, as stated in the abovementioned patent, "a rapid release of the medicinal product during passage through the stomach" unless protected by a fatty acid glyceryl ester, or by an enteric coating, for gastrointestinal absorption. This rapid release generally causes side effects such as headaches, blotches, and the like. <br><br>
Experience showed that the production of these dispersions under known physicochemical conditions generally led to a product in the form of solid lumps which were difficult to grind. Since grinding causes a heating effect, the active principle becomes unstable and runs the risk of an at least partial decomposition. In other cases, sticky substances, difficult to recover and hence incapable of industrial exploitation, are obtained ( "Stability Problems under special consideration of solid., dispersion of drugs", S.T.P. Pharma 1 (7) 660-665 <br><br>
234593 <br><br>
( 1985 ) ) . <br><br>
The many solutions proposed in the literature have not hitherto succeeded in satisfying the absorption conditions capable of offering immediate cover after ingestion of the medicinal product and of continuing regularly over 2 4 hours. <br><br>
The subject of this invention is to propose an oral dosage form of such medicinal products, offering constant cover over 24 hours with a single daily dose, <br><br>
even when these compounds are only sparingly soluble or insoluble in water. Control of bioavailability implies, depending on the case, slowing down or speeding up diffusion, but above all making it regular. <br><br>
The example which follows illustrates its practical importance. <br><br>
Oxodipine (or methyl ethyl 1,4-dihydro-2,6-dimethyl-4-(2,3-methylenedioxyphenyl)-3,5-pyridinedicarboxylate), described in New Zealand Patent Specification No. 211456, has evinced a potent calcium inhibitory activity capable of application in the treatment of cardiovascular disorders such as hypertension. However, its low solubility in water appeared to limit its possibilities of use in pharmaceutical compositions. <br><br>
Now, the use of common means of solubilization, <br><br>
such as non-aqueous solvents (ethanol, for example) or the addition of wetting agents, is not always compatible with an in vivo administration. <br><br>
A study of the kinetics of dissolution in vitro, <br><br>
carried out on the one hand in distilled water and on the other hand in intestinal juice, shows that an improvement was already obtained by using an oxodipine/polyvinyl-pyrrolidone coprecipitate, compared with pure oxodipine whose dissolution is slow and limited, thereby resulting in a slow and limited absorption in vivo. <br><br>
However, this solid dispersion has the deficiencies already emphasized in the prior art, that is to say it releases almost all of the active principle intensely and very rapidly, which does not permit good control of the bioavailability over the course of a day. <br><br>
3 - <br><br>
Figure 1 shows the kinetics of intestinal dissolution in vivo in man of two oxodipine preparations administered orally, namely "powder" of pure oxodipine and "solid solution" of oxodipine in polyvinylpyrrolidone, relative to a reference oral aqueous-alcoholic solution giving 100% absorption, each dosage fonn containing 20 mg of active principle. It is seen that the "powder" releases at most 20% of the 20 mg administered, <br><br>
while the "solid solution" releases 100% of it, which is totally absorbed, almost immediately. <br><br>
The Applicant discovered, continuing his investigations, that the combination of a solid solution (of oxodipine with polyvinylpyrrolidone, for example) and total milk protein extracts enabled a satisfactory therapeutic system, ensuring the control of absorption and bioavailability, to be obtained. <br><br>
The invention accordingly provides a pharmaceutical composition navir.g controlled bioavailability, comprising at least one active principle acting as a calcium inhibitor, as active principle, common excipients and total milk protein extracts. <br><br>
The insertion of total milk protein extracts into the formula brings about a controlled release of the active principle. It makes it possible to obtain single-dose forms applicable, in particular, to dihydropyridines possessing calcium-antagonist properties. These special dosage forms are useful for producing a daily therapeutic dose. <br><br>
Among the total milk protein extracts, two are specifically distinguished since they make it possible to attain, within this combination, the following objectives: <br><br>
bringing the insoluble matter into solution <br><br>
- controlling the release of the soluble matter <br><br>
- making available to the body a rapid (loading) <br><br>
dose and a controlled dose improving the dissolution, absorption and bioavailability in vivo in man. <br><br>
These two milk protein extracts, sold under the names PR0S0BEL I 60 and PR0S0BEL L 85, are obtained from fresh skimmed milk by pasteurization at low temperature, ultrafiltration, concentrating and drying and contain respectively 60% and 85.5% by weight of proteins. <br><br>
Tablets and hard gelatin capsules were made, with oxodipine or other dihydropyridines as the active principle. They were then administered orally to healthy volunteers; the plasma levels of active principle were monitored at regular intervals. <br><br>
Example 1 <br><br>
Preparation of an oxodipine/polwinvlpvrrolidone coore-cioitate <br><br>
5,800 ml of absolute ethanol were introduced into a 20-litre reactor, followed by the portionwise addition, <br><br>
with stirring, of 2,600 g of polyvinylpyrrolidone. The <br><br>
234593 <br><br>
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23 4 5 <br><br>
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mixture was heated to approximately 30"C to effect complete dissolution and 650 g of oxodipine were added. The mixture was heated gently to approximately 80"C so as to obtain a complete solution, and left to stand. 5 A few crystals reappeared on the walls of the flask. 1 litre of ethanol was added and the mixture was again brought to 80°C in order to dissolve the product. The mixture was left standing for 24 hours at room temperature (approximately 20°C) and the solution was 10 then evaporated. The product obtained was dried for several hours at 80°C and ground, then sieved through a 400^sieve. <br><br>
Assay by UV spectrometry gave the following results: <br><br>
15 (360 ran) OXODIPINE: 19.9% <br><br>
PVP : 77.6% <br><br>
Residual ethanol 1200 ppm <br><br>
Example 2 <br><br>
Preparation of hard gelatin capsules containing 10 ma of 20 Oxodipine <br><br>
The components (A) are introduced into the chamber of a "Turbula" mixer and homogenized for 10 minutes. <br><br>
The preparation is mixed with the lubricating 25 components (B) and No. 1 hard gelatin capsules are filled with this mixture. <br><br>
Reference capsules F <br><br>
(A) Oxodipine coprecipitate 0.050 g <br><br>
(containing 20% or 10 mg of oxodipine) 30 HPMC 15000 0.018 g <br><br>
(hydroxypropylmethylcellulose) <br><br>
PROSOBEL - L 60 0.113 g <br><br>
Maize starch 0.014 g <br><br>
Lactose 0.032 g <br><br>
35 <br><br>
0.227 g <br><br>
(B) Talc (2301 - ZA) 0.0022 g <br><br>
Mg stearate (2493-SW) 0.0022 g <br><br>
Per hard gelatin capsule containing 0.2314 g <br><br>
234593 <br><br>
- 5 - <br><br>
Reference capsule G <br><br>
The same quantities and the same components are taken, but PROSOBEL - L 60 is replaced by PROSOBEL - L 85. <br><br>
Example 3 <br><br>
A single double-layer tablet is produced, consisting of the physical combination (bonding) of two "sub-tablets", (C) rapid-release and (D) slow-release, containing the active principle combined with common excipients, and with PROSOBEL - L85 or - L60 (which give similar results). <br><br>
The whole constitutes a therapeutic system which permits the controlled release of loading and maintenance doses. <br><br>
The preferred proportions of these sub-tablets are: <br><br>
sub-tablet C (in percentage by weight) <br><br>
Oxodipine coprecipitate 23.4 <br><br>
ELCEMA - G250 70.1 <br><br>
PRIMOJEL (carboxymethylstarch) 6.5 <br><br>
100 <br><br>
sub-tablet D (in percentage by weight) <br><br>
Oxodipine coprecipitate 22 <br><br>
PROSOBEL (L85 or L60) 50 <br><br>
HPMC 8 <br><br>
Starch 6 <br><br>
Lactose 4 <br><br>
COMPRITOL 8 <br><br>
Talc 1 <br><br>
Mg stearate 1 <br><br>
100 <br><br>
By way of example, the sub-tablet C contains 5 mg of oxodipine and the sub-tablet D 10, 15 or 20 mg of oxodipine, which makes it possible to have unit dosages containing 15, 20 and 25 mg of oxodipine. <br><br>
The new pharmaceutical dosage forms according to the invention form the subject of in vitro and in vivo <br><br>
23 4 5 9 <br><br>
- 6 - <br><br>
studies. <br><br>
Figure 1 expresses, for the same dose, the percentage of active principle absorbed into the human body (intestinal juice) for pure oxodipine (powder) and oxodipine in a solid solution of oxodipine/polyvinylpyr-rolidone coprecipitate (containing 20% of oxodipine). It is seen that, in the case of the solid solution, there is immediate and massive release of oxodipine (which causes the side effects already described) while, in the case of pure oxodipine, a 20% absorption is not exceeded, which is insufficient. <br><br>
The hard gelatin capsules F and G (according to Example 2) were administered to 6 healthy volunteers, and the plasma oxodipine levels as well as the percentages of absorbed oxodipine were monitored throughout the twenty-four-hour period. <br><br>
The results were compared with those obtained with the known dosage forms <br><br>
( hydroalcohol ic solution, coprecipitate and powder of pure oxodipine). <br><br>
Figure 2 presents the results corresponding to 3 hours, and demonstrates maximum concentrations reduced by one half relative to the coprecipitate. <br><br>
Figure 3 shows that the percentages absorbed from the hard gelatin capsules containing PROSOBEL are intermediate between an excessively rapid (coprecipitate) or excessively slow (powder) absorption, evidence of an improved control of absorption with PROSOBEL. <br><br>
Furthermore, it is seen that the variety of PROSOBEL selected (L60 or L85) does not influence the result in vivo in man. <br><br>
Tablets according to Example 3, containing 15, 20 and 25 mg of oxodipine, were administered to 6 healthy volunteers. Figure 4 and Table I show the changes in the plasma concentrations, monitored throughout the twenty-four-hour period. The results are compared with those obtained after oral administration of the powder and of the coprecipitate. <br><br>
234593 <br><br>
D <br><br>
- 7 - <br><br>
Table I <br><br>
15-mg tablet <br><br>
2 0-mg tablet <br><br>
2 5-mg tablet <br><br>
5 <br><br>
Time (h) <br><br>
Concentration <br><br>
Concentration <br><br>
Concentration <br><br>
in ng/ml in ng/ml in ng/ml <br><br>
0.00 <br><br>
0.0 <br><br>
0.0 <br><br>
0.0 <br><br>
0.17 <br><br>
2.0 <br><br>
1.8 <br><br>
2.9 <br><br>
10 <br><br>
0.33 <br><br>
10.0 <br><br>
11.9 <br><br>
12.0 <br><br>
0.50 <br><br>
19.5 <br><br>
17.2 <br><br>
16.1 <br><br>
0.66 <br><br>
19.9 <br><br>
18.1 <br><br>
17, 0 <br><br>
0.83 <br><br>
17.8 <br><br>
17. 1 <br><br>
18.6 <br><br>
1.00 <br><br>
17.0 <br><br>
16.2 <br><br>
15.7 <br><br>
15 <br><br>
1. 25 <br><br>
18.2 <br><br>
14.2 <br><br>
14.4 <br><br>
1.50 <br><br>
16.4 <br><br>
12.8 <br><br>
14.3 <br><br>
2 . 00 <br><br>
16.0 <br><br>
13. 3 <br><br>
12.0 <br><br>
3.00 <br><br>
12.2 <br><br>
13.8 <br><br>
14.4 <br><br>
4.00 <br><br>
8.0 <br><br>
12.5 <br><br>
14.7 <br><br>
20 <br><br>
6.00 <br><br>
3.7 <br><br>
8.4 <br><br>
9.3 <br><br>
8.00 <br><br>
2.0 <br><br>
4.2 <br><br>
5.5 <br><br>
10.00 <br><br>
1.7 <br><br>
3.4 <br><br>
4.3 <br><br>
12.00 <br><br>
1.6 <br><br>
2.8 <br><br>
3.2 <br><br>
14.00 <br><br>
0.9 <br><br>
2.1 <br><br>
2.8 <br><br>
25 <br><br>
24.00 <br><br>
- <br><br>
1.0 <br><br>
1.3 <br><br>
28.00 <br><br>
— <br><br>
0.6 <br><br>
0.6 <br><br>
Plasma concentrations observed after single administration of the 15-, 20- and 25-mg tablets to 6 healthy 30 subjects (mean). <br><br>
The example of the 20-mg tablet is extended and compared to the same dose in the known dosage forms (Table II). <br><br>
23 4 5 <br><br>
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Table II <br><br>
20 mg powder <br><br>
20 mg coprecipitate <br><br>
20-mg tablet <br><br>
5 <br><br>
Time (h) <br><br>
Concentration <br><br>
Concentration <br><br>
Concentration <br><br>
in ng/ml in ng/ml in ng/ml <br><br>
0.00 <br><br>
0.0 <br><br>
0.0 <br><br>
0.0 <br><br>
10 <br><br>
0.17 <br><br>
1.2 <br><br>
1.4 <br><br>
1.8 <br><br>
0.33 <br><br>
1.4 <br><br>
28.9 <br><br>
11.9 <br><br>
0.50 <br><br>
2.7 <br><br>
76.3 <br><br>
17.2 <br><br>
0.66 <br><br>
4.2 <br><br>
95.5 <br><br>
18. 1 <br><br>
0. 83 <br><br>
5.0 <br><br>
93.4 <br><br>
17.1 <br><br>
15 <br><br>
1.00 <br><br>
6.0 <br><br>
75.8 <br><br>
16.2 <br><br>
1.25 <br><br>
6.8 <br><br>
55.7 <br><br>
14.2 <br><br>
1.50 <br><br>
6.5 <br><br>
43.4 <br><br>
12. 8 <br><br>
2. 00 <br><br>
6.2 <br><br>
28.2 <br><br>
13.3 <br><br>
3.00 <br><br>
5.1 <br><br>
15.7 <br><br>
13.8 <br><br>
20 <br><br>
4.00 <br><br>
4.0 <br><br>
10.5 <br><br>
12.5 <br><br>
6.00 <br><br>
2.4 <br><br>
5.0 <br><br>
8.4 <br><br>
8. 00 <br><br>
1.6 <br><br>
3.0 <br><br>
4.2 <br><br>
10. 00 <br><br>
1.4 <br><br>
2.2 <br><br>
3.4 <br><br>
12.00 <br><br>
1.2 <br><br>
1.9 <br><br>
2.8 <br><br>
25 <br><br>
14. 00 <br><br>
1.0 <br><br>
1.4 <br><br>
2.1 <br><br>
24.00 <br><br>
1.2 <br><br>
1.0 <br><br>
1.0 <br><br>
28.00 <br><br>
— <br><br>
— <br><br>
0.6 <br><br>
Plasma concentrations observed after single oral 30 administration of the three dosage forms of oxodipine in <br><br>
6 healthy subjects (mean). <br><br>
This comparison underlines the fact that the controlled levels achieved are truly intermediate between 35 those arising from the two known dosage forms (Figure 5), <br><br>
and are perfectly regulated during the 24-hour period. It will be noted, in particular, that, in less than one hour, the coprecipitate induces a blood concentration of 95 ng/ml of serum, and that the corresponding curve is <br><br>
2 3 4 5 9 <br><br>
- 9 - <br><br>
plotted in Figure 5 only from 1 h 50 min (43 ng/ml) for reasons of clarity of the drawing. <br><br>
Analysis of the results confirms (Figure 6) the good control of the dissolution/absorption of the active principle from the tablet dosage form. <br><br>
Table III <br><br>
% OF DOSE ENTERING THE BODY AFTER ABSORPTION AND PASSAGE THROUGH THE LIVER <br><br>
TIME <h) <br><br>
20 ms POWDEH | COPRECIPITATE <br><br>
1 <br><br>
15-mg TABLETj 20-o* TABLETj 25-ms TABLET ;! i ;0.00 ;- ;- ;- ;- ;- ;0.17 ;2.5 ;32 ;2.4 ;2.1 ;5.9 ;0.33 ;1.6 ;60 ;12.6 ;12.1 ;15 ;0.50 ;4.5 ;75 ;26.2 ;20.3 ;23.5 ;0.66 ;6.6 ;87 ;32.7 ;24.5 ;26 ;0.83 ;7.0 ;93 ;35.5 ;26 ;28.1 ;1.00 ;9.3 ;96 ;38.9 ;31.9 ;28.3 ;1.25 ;11 ;96 ;46.4 * <br><br>
31.0 <br><br>
30.5 <br><br>
1.50 <br><br>
11.4 <br><br>
97 <br><br>
50.2 <br><br>
33 <br><br>
32.8 <br><br>
2.00 <br><br>
14.0 <br><br>
97 <br><br>
59.0 <br><br>
41.1 <br><br>
39.2 <br><br>
3.00 <br><br>
16.6 <br><br>
100 <br><br>
68.7 <br><br>
51.0 <br><br>
48.1 <br><br>
4.00 <br><br>
18 <br><br>
100 <br><br>
72.7 <br><br>
61.7 <br><br>
53.7 <br><br>
6.00 <br><br>
19.8 <br><br>
100 <br><br>
74.5 <br><br>
71.1 <br><br>
61.0 <br><br>
8.00 <br><br>
21.2 <br><br>
100 <br><br>
75.6 <br><br>
74.8 <br><br>
63.8 <br><br>
10.00 <br><br>
22.6 <br><br>
100 <br><br>
77.2 <br><br>
78.5 <br><br>
66.6 <br><br>
12.00 <br><br>
23.8 <br><br>
100 <br><br>
79.2 <br><br>
81.1 <br><br>
68.2 <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
- <br><br>
REIATIVE BIOAVAILABILITY COMPARED WITH THE SOLUTION <br><br>
31% <br><br>
100 <br><br>
86% <br><br>
92% <br><br>
88% <br><br>
234593 <br><br>
- 10 - <br><br>
The results seen in Table III show that the bioavailability of each dosage form is total for the coprecipitate (100%), low for the powder of pure oxodipine (31%) and excellent for the tablets (86 to 92%) after 12 hours. <br><br>
These results were confirmed by those obtained by the Applicant with other dihydropyridines, and in particular NIFEDIPINE. <br><br>
Figure 7 shows the parallel behaviour between oxodipine and nifedipine. The kinetics of dissolution, very rapid for both of these dihydropyridines (in the crude state for nifedipine, which is very soluble in water, and in the state of a coprecipitate for oxodipine) , are controlled by the addition of PROSOBEL, in the same formulae as in Examples 2 and 3. <br><br>
It may be concluded from this that PROSOBEL, very unexpectedly from the standpoint of those skilled in the art, slows down the dissolution in an aqueous medium and enables new and original pharmaceutical dosage forms of dihydropyridines having controlled bioavailability to be obtained. <br><br>
Naturally, it is not the object of the examples given to limit the invention, the latter being perfectly applicable and efficacious when the mixture containing PROSOBEL is presented in the form of granules, capsules or any solid or semi-solid oral dosage form such as a muco-adhesive gel or a paste, or even a suspension. Depending on the dosage form in question or depending on the solubility in water of the active principle introduced, experience showed that the addition of 10 to 70% of PROSOBEL enabled the bioavailability of the medicinal product to be matched to the desired plasma levels. <br><br></p>
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