CS276556B6 - Pharmaceutical with a controllable bio-disposal of active component - Google Patents

Description

The invention relates to a pharmaceutical composition with a controlled bioavailability of an orally administrable medicament contained therein. This agent is a drug which belongs to the group of calcium inhibitors.

BACKGROUND OF THE INVENTION

One of these drugs are dihydropyridine derivatives having excellent cardiovascular properties, but their utility is limited by their solubility problems in vivo, i.e. in an aqueous environment.

Attempts have therefore been made to obtain a special galenic form which would enable the in vivo release of such active substances to be achieved to achieve plasma values sufficient for the daily dose, whatever the solubility of the active substances.

It is known to associate the active ingredient with a crystalline water-soluble substrate, such as polyethylene glycol or polyvinylpyrrolidone, as a dispersing agent to obtain retarded forms, as described, for example, in French Patent No. 2,565,822. However, the dispersion thus obtained, converted into tablets or capsules with conventional excipients, as indicated in the French patent, exhibits rapid drug release during its gastric process unless it is protected by a fatty acid ester with glycerol or an enteric coating for gastrointestinal absorption. This rapid release generally results in secondary effects such as headaches, red spots on the skin, etc.

Experience has shown that the formation of such dispersions, under known physicochemical conditions, generally results in a product in the form of hard, difficult to crush pieces. Since crushing is associated with heating, the active ingredient becomes unstable and can at least partially decompose. In other cases, sticky substances are formed and are difficult to handle and are industrially difficult to manufacture (see Stability problems under special consideration of solid dispersion of drugs, S.T.P.

Pharms 1 (7), pp. 660-655 (1985)).

Numerous solutions suggested in the literature have not yet resulted in a solution that would meet the conditions of absorption and provide immediate drug packaging upon ingestion and for a further 24 hours.

The purpose of the invention is to propose an oral form of such medicaments which provides a permanent blanket for 24 hours at a single daily dose even when these compounds are poorly soluble or completely insoluble in water. Controlling biodisponibility involves slowing or accelerating diffusion as needed, particularly the ability to make it regular.

SUMMARY OF THE INVENTION

The object of the invention is to select a specific protein substrate to achieve this goal.

The example below illustrates this in more detail.

OXODIPINE which mathylethylester of l, 4-dihydro-2,6-dimethyl-4- (2 ^', 3'-msthylendioxyfenyl) -3,5-pyridinecarboxylic acid, as described in French Patent No. ·. No. 2,562,069, has a high calcium inhibitory effect, making it suitable for administration in the treatment of cardiovascular disorders such as high blood pressure. Nevertheless, its low water solubility seemed to limit the possibilities of its use in pharmaceutical compositions.

However, the use of conventional solubilizers, such as non-aqueous solvents (eg ethanol), or the addition of surfactants is not always compatible with the administration of the drug in vivo.

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Examination of the in vitro dissolution kinetics, both in distilled water and in the intestinal fluid, shows that it is already improved by using oxodipine-polyvinylpyrrolidone coprecipitate compared to using only oxodipine, which dissolves slow and limited, resulting in slow and limited absorption in vivo.

However, this solid dispersion has the drawbacks already mentioned in the prior art that it releases almost all of the active ingredient very rapidly and violently, which does not allow good control of biodispersibility throughout the day.

Figure 1 shows the in vivo rate of intestinal dissolution in the human body of two oxodipine formulations administered orally: pure oxodipine powder and solid oxodipine solution in polyvinylpyrrolidine, compared to a reference aqueous-alcoholic solution administered orally giving 100% absorption each containing 20 mg of active ingredient. It can be seen from the graph that the powder form releases at most 20% of the 20 mg administered, while the solid solution releases 100% of the active ingredient almost immediately, which amount is perfectly absorbed.

Further research has found that combining a solid solution of oxodipine (e.g., polyvinylpyrrolidone) with proteins makes it possible to obtain a therapeutically effective system ensuring regulation of absorption and bioavailability. Specifically, two of these proteins have been selected which make it possible to achieve ¹ within said association; the following objectives:

- to convert insoluble substances into solution,

- to regulate the release of soluble substances,

- provide the body with a quick dose (from a tablet or capsule fill) and a controlled dose,

- improve the in vivo solubility, absorption and bioavailability of the human body.

These natural proteins are obtained by the extraction of fresh, de-fat milk and are commercially available under the designations PROSÓBEL L 85 and PROSOBEL L 60.

Accordingly, the present invention provides a pharmaceutical composition with controllable bioavailability of the active ingredient, characterized in that it comprises a dihydropyridine derivative as a calcium inhibitor, 20 to 60% by weight. % of conventional vehicles and 30 to 60 wt. of concentrated milk proteins PROSOBEL.

The Oako dihydropyridine derivative comprises the composition of the invention oxodipine in the form of a co-precipitate of oxodipine with polyvinylpyrrolidone, or nifedipine.

The composition of the invention is preferably contained in a capsule representing a single daily dose or in the form of a tablet containing a single daily dose.

The tablet preferably consists of two layers, the first containing a dose of the rapidly releasing filler, while the second layer releasing slowly.

DETAILED DESCRIPTION OF THE INVENTION

Tablets and capsules were prepared with oxodipine or other dihydropyridines as the active ingredient. They were administered orally to healthy volunteers; the plasma values of the active substance were measured at regular intervals.

Example 1

Preparation of oxodipine coprecipitate with polyvinylpyrrolidone

A 20 L reactor was charged with 5800 mL of anhydrous ethanol and then, while stirring in portions, a total of 2600 g of polyvinylpyrrolidone. The reaction mixture is heated up to about 30 ° C to completely dissolve the polyvinylpyrrolidone, then 650 g of oxodipine are added. The mixture is gently heated to about 80 ° C to give a clear solution which is allowed to stand.

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Several crystals reappear on the reactor walls, 1 liter of ethanol is added and the mixture is reheated to 80 ° C; to dissolve these crystals. After dissolution of the reaction mixture, it is allowed to stand at room temperature (about 20 ° C) for 24 hours, then the solution is evaporated. The resulting product was dried at 80 ° C for several hours; and then ground and sieved through a 400 µm sieve.

The following composition (350 nm) of oxodipine t19-9% polyvinylpyrrolidone: 77.6% residual ethanol: 1200 ppm was determined by ultraviolet ray analysis.

Example 2.

Preparation of capsules containing 10 mg of oxodipine

Into the flask of the Turbula ss mixer, components (A) nes are introduced which are then mixed for 10 minutes to form a homogeneous mixture. The resulting mixture is blended with lubricants (B) and this mixture is filled with capsule # 1,

Capsules F (A) Oxodipine co-precipitate 0.150 g (containing 20% i.e. 10 mg oxodipine) hydroxypropyl methylcellulose 0.018 g

PROSOBEL L 60 'O,' 113 g maize starch 0,014 g lactose Oj‘O32 g

0,227 g (B) talc (2301-2A) 0,0022 g magnesium stearate (2493-SW) 0,0022 g

Content of one capsule 0.2314 g

Tobolka G

It will use the same amounts and the same ingredients but PROSOBEL L 60 will be replaced by PROSOBEL L 85.

Example 3

A two-layer tablet is formed, formed by physically joining two sub-tablets; (C) rapid release and (O) slow release containing the active ingredient mixed with conventional scales, and 3 with PROSOBEL L 85 or L 60 (which provide similar results).

The whole forms a therapeutic system that allows controlled release doses from the cartridge and its sustained release.

Preferred compositions of these sub-tablets are:

Partial tablet (C) (in percent by weight).

Oxodipine co-precipitate 23.4 ELGEMA - G 250 70.1 PRIMOOEL (carboxymethyl starch) 6.5

100 ALIGN!

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Partial tablet (0) in percent by weight)

Oxodipine coprecipite PROSOBEL (L 85 or L 60) hydroxypropyl ethylcellulose starch lactose

COMPŘXTOL talc magnesium stearate

100 ALIGN!

The sub-tablet (C) contains, for example, 5 mg of oxodipine and the sub-tablet (0) of 10, 15, 20 mg of oxodipine, allowing the unit doses to contain 15, 20 and 25 mg of oxodipine.

The novel pharmaceutical farms of the invention have been tested in vitro and in vivo.

In Fig. 1 (Kinetics of intestinal dissolution in vivo in human organism of two forms of oxodipine - φ o powder, + solid solution, 20% ni; X-axis from time of application, Y-axis percent dissolved substance: results are mean values found in 6 The percentages of active ingredient absorbed by the human body (intestinal fluid), pure oxodipine powder and solid solution of co-precipitate oxodipine with polyvinylpyrrolidone (containing 20% oxodipine) are shown at the same dose. It can be seen that in the case of a solid solution there is an immediate and powerful release of oxodipine (resulting in the aforementioned secondary reactions of the organism), whereas in the case of pure oxodipine the absorption does not exceed 20%) which is not sufficient.

Capsules F and G (according to Example 2) were administered to 6 healthy volunteers and the oxodipine plasma values as well as the percentage absorbed oxodipine were monitored for 24 hours. The results were compared with those obtained with conventional pharmaceutical forms (aqueous-alcoholic solution) (coprecipite) (pure oxodipine powder).

In Fig. 2 (Oxodipine 10 mg; coprecipite +) solution = 0; capsule F and g) capsule G = O) shows results (mean value achieved after 3 hours) representing maximum concentrations that are half that of the coprecipitate.

From Fig. 3 (In vivo dissolution kinetics (average values) for solid solution *, for FX and G β forms of Example 2 and for powdered oxodipine Φ; X axis »hours after application, Y axis» amount absorbed in vivo in% top right corner: Summary of dissolved a and undissolved Q fractions - (a) oxodipine powder; capsule F, capsule G, b) a solid solution) it is evident) that the percentages absorbed from PROSOBEL-containing capsules lie in the middle between too rapid absorption (coprecipite) and too slow absorption (powder), indicating better control of absorption with PROSOBEL.

It is also evident from Figure 3 that the type of PROSOBEL selected (L 60 or L 85) does not affect in vivo results in the human body.

The tablets of Example 3 containing 15, 20 and 25 mg oxodipine were administered to 6 healthy volunteers. Fig. 4 (Oxodipine - mean value for determination in 6 persons; plasma; tablet containing 25 mg = 4) tablet containing 20 mg = O - tablet containing 15 mg = Φ) and Table X shows the development of plasma concentrations monitored for 24 hours. The results are compared with those obtained after oral administration of oxodipine powder and coprecipitate.

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Table I

Ooba elapsed since the application Tablet with content 15 mg Tablet and contents 20 mg Tablet with content 25 mg (h) concentration (ng.ml ¹ ) concentration (ng.ml ¹ ) concentration (ng.ml ^-1 ) 0.00 0.0 0.0 0.0 0.17 2,0 1,8 2.9 0.33 10.0 11.9 12.0 0.50 19.5 17.2 16.1 0.66 19, '9 18.1 17.0 0.83 17.8 17.1 18.6 l; oo 17.0 16.2 15.7 1,25 18.2 14.2 14.4 1.50 16.4 12.8 14.3 2.00 16, ^ř 0 13.3 12.0 3.00 12.2 13.8 14.4 4.00 8.0 12.5 14.7 6.00 3.7 8.4 9.3 8.00 2,0 4.2 5.5 10.00 1.7 3.4 4.3 12.00 1.6 2.8 3.2 14.00 0.9 2.1 2.8 24,00 - 1.0 1.3 28,00 - 0.6 o; e

Plasma concentrations observed after single administration of 15, 20, 25 mg oxodipine tablets to 6 healthy subjects (mean).

An example of a tablet containing 20 mg is compared to the same dose contained in known forms (Table II and Fig. 5 -Oxidipine- mean value from 6 persons in plasma: co-precipitate = JL, tablet 20 mg = ·, powdered oxodipine · »· 20 mg).

Table II

Ooba gone by powdered oxodipine coprecipitate tablet from the app 20 mg 20 mg 20 mg (h) concentration concentration concentration (ng.ml ¹ ) (ng.ml ¹ ) (ng.ml ¹ ) 0.00 0.00 0.00 0.00 0.17 1,2 1.4 1,8

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Table IX - continued

Time elapsed powdered oxodipine coprecipitate tablet from the app 20 mg 20 mg 20 mg (h) concentration concentration concentration (ng.ml ¹ ) (ng.ml ¹ ) (ng.ml ¹ ) 0.33 1.4 28.9 11.9 0.50 2.7 76.3 17.2 0.66 4.2 95.5 18.1 0.83 5.0 93.4 17.1 1.00 6.0 75.8 16.2 1,25 θ, 8 55.7 14.2 1.50 6.5 43.4 12.8 2.00 6.2 28.2 13.3 3.00 5.1 15.7 13.8 4.00 4.0 10.5 12.5 6.00 2.4 5.0 '8,4 8.00 1.6 3.0 4.2 10.00 1.4 2.2 3.4 12.00 1.2 1.9 2.8 14.00 1.0 1.4 2.1 24,00 1,2 1.0 1.0 28,00 - - 0.6

Plasma concentrations observed after a single oral administration of three forms of oxodipine to 6 healthy subjects (mean).

This comparison shows that the values achieved with controlled release lie practically between the values found in the two known forms (FIG. 5) and are perfectly controlled over a 24 hour period. In particular, it is evident that in less than one hour, the blood co-precipitate induces a serum concentration of 95 ng.ml ^-1 and that, for technical reasons, the corresponding curve is only shown from 1 hour 5 minutes (43 ng.ml -1).

Analysis of the results confirms (Fig. 6 - Oxodipine: mean value from 6 persons; co-precipitate = M, 20 mg tablet, powdered oxodipine = ·) good controllability of dissolution-absorption of the active substance from the tablet.

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Table III

% of the dose infiltrated into organism after absorption and passage through the liver time from application (h) powdered oxodipine 20 mg kopreclpitát tablet λ · 15 mg tablet 20 mg tablet 25 mg 0.00 - - - - - 0.17 2.5 32 2.4 2.1 5.9 0.33 1.6 60 12.6 12.1 15 Dec 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 31.0 30.5 1.50 11.4 97 50.2 33 32.8 2.00 14.0 97 59.0 41.1 39.2 3.00 16.6 100 ALIGN! 68.7 51.0 48.1 4.00 18 100 ALIGN! 72.7 61.7 53.7 6.0 19.8 íoo 74.5 71.1 61.0 8.00 21.2 100 ALIGN! 75.6 74.8 63.8 10.00 22.6 íoo 77.2 78.5 66.6 12.00 23.8 100 ALIGN! 79.2 81.1 68.2 Relative bioavailability relative to solution 31% 100% 86% 92% 88%

The results shown in Table III show that the bioavailability of each of these forms is complete for co-precipitate (100%), low for oxodipine powder (31%) and excellent for tablets (86-92%) after 12 hours.

These results were compared with those obtained with other dihydropyridines, especially nifadipine.

From the diagram in Figure 7 (In vitro dissolution kinetics of identical formulations of oxodipine (-) and nifedipine (---) associated with and without PROSOBEL (bottom): X-axis = time, Y-axis =% solubility of oxodipine and nifedipine. The dissolution rates, very fast for both of these dihydropyridines (raw state for nifedipine, very soluble in water, and coprecipitated state for oxodipine), are controlled by the addition of PROSOBEL, in the same formulations as in Examples 2 and 3.

From this it can be concluded that PROSOBEL slows down, which is very surprising for the person skilled in the art, the dissolution of dihydropyridines in an aqueous medium and makes it possible to prepare new and original pharmaceutical forms of dihydropyridines with adjustable bioavailability.

Of course, the invention is not limited to the examples given; it is perfectly usable and effective whether the composition comprising PROSOBEL is in the form of granules, capsules or any solid or semi-solid form suitable for oral administration, such as mucoadhesive or pasty, or even a suspension. Experience has shown that the addition of 10 to 70% of PROSOBEL allows the drug's bioavailability to be adjusted to the required plasma levels, depending on the type of form or the water solubility of the active ingredient used.

Claims (6)

CLAIMS 1. A pharmaceutical composition with controllable bioavailability of an active ingredient, comprising a dihydropyridine derivative as a calcium inhibitor, 20 to 60% by weight. % of conventional vehicles and 30 to 60 wt. of concentrated milk proteins PROSOBEL. A pharmaceutical composition according to claim 1. characterized in that it comprises as the dihydropyridine derivative oxodipine in the form of a co-precipitate of oxodipine with polyvinylpyrrolidone. Pharmaceutical composition according to claim 1, characterized in that it contains nifedipine as the dihydropyridine derivative. Pharmaceutical composition according to claims 1 to 3, characterized in that it is contained in a capsule representing a single daily dose. Pharmaceutical composition according to claims 1 to 3, characterized in that it is in the form of a tablet containing a single daily dose. Pharmaceutical composition according to claim 5, characterized in that the tablet consists of two layers, the first of which contains a dose of a rapidly releasing filling, while the second of the layers is released slowly.