IE52959B1

IE52959B1 - Pharmaceutical preparations for treatment of diabetes

Info

Publication number: IE52959B1
Application number: IE810/82A
Authority: IE
Original assignee: Science Union & Cie
Priority date: 1981-04-07
Filing date: 1982-04-06
Publication date: 1988-04-27
Also published as: GB2099299B; IT8248180A0; IT1148161B; NZ200248A; CA1186997A; ZA822176B; GB2099299A; PH17582A; BE892781A; IE820810L; AU551033B2; LU84069A1; FR2502952A1; AU8238782A; CH653551A5; FR2502952B1

Abstract

Pharmaceutical preparations e.g. tablets, dragees or capsules of prolonged effect for the treatment of pathological manifestations connected with diabetes, which contain benfluorex hydrochloride as active ingredient, e.g. the benfluorex hydrochloride may be included in a digestible hydrophobic matrix and then dispersed in compressible excipients forming a hydrophilic network and a pharmaceutical combination which comprises a rapid release component of benfluorex hydrochloride and slow release component of benfluorex hydrochloride, these are usually present together in the same formulation and the slow release component may be composed in the same way as a single-component preparation.

Description

The present invention relates to pharmaceutical preparations and packs for the treatment of pathological manifestations connected with diabetes.

French Patent No. 6564M(UK Patent No. 1.175.516) discloses various phenylaminopropane derivatives and their use as anorexigenic agents and as analgesic, anticonvulsant and lipid metabolism-regulating agents in doses of from 10 to 200 mg.

It has been found that one such derivative, benfluorex, can be used for the treatment of diabetic patients: amounts of active ingredient higher than those disclosed in the above Patent are to be used, i.e. more than 200 mg.

Suitably, benfluorex is in the form of a physio15 logically tolerable salt, and benfluorex hydrochloride has proved advantageous.

More especially, the active ingredient has been found useful in the form of a preparation having prolonged effect, in particular where the active ingredient is present with one or more pharmaceutically suitable carriers in a preparation adapted for obtaining a progressive and prolonged release inside the digestive tract. - 2a Thus, the present invention provides pharmaceutical preparations of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises benfluorex hydrochloride together with one or more pharmaceutically suitable carriers, wherein the preparation is in unit dosage form, containing from 300 to 500 mg of benfluorex hydrochloride per unit dosage, and is adapted for obtaining a progressive and prolonged release inside the digestive tract, at least part of the benfluorex hydrochloride being in a digestible hydrophobic matrix comprising glyceryl trimyristate. - 3 In one such preparation the benfluorex hydrochloride is included in the hydrophobic matrix and then dispersed in a suitable excipient forming a hydrophilic network. For example, for a preparation in tablet form, benfluorex hydrochloride is in a digestible hydrophobic matrix comprising glyceryl trimyristate, then dispersed in a compressible excipient (s) . Preferably, the preparation is covered with a protective pellicle.

The present invention also provides a pharmaceutical combination of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises (i) a rapid release component of benfluorex hydrochloride and (ii) a slow release component of benfluorex hydrochloride in a hydrophobic matrix comprising glyceryl trimyristate, the combination being in unit dosage form containing from 300 to 500 mg of benfluorex hydrochloride per unit dosage. The proportion of these two components is suitably determined by the required result. The components of the combination may be present in a single formulation or, for example, in separate formulations associated together in a pack.

The slow release benfluorex hydrochloride component comprises benfluorex hydrochloride in the hydrophobic matrix and may, for example, then be dispersed in a suitable excipient forming a hydrophilic network. - 4 According to the present invention, the active ingredient is in a unit dosage of from 300 to 500 ng. This dose is noticeably higher than that previously mentioned in the French patent no. 6564 M (UK patent no. 1,175,516). This quantity of active ingredient may be present in its entirity in the delayed-action pharmaceutical form constituted by the single-component slow release formulation of the active ingredient, or divided between the rapid release component and the slow release component of the combination.

In these delayed-action pharmaceutical combinations using the two components, the distribution of the active ingredient between each component is determined by the release speed required for the active ingred15 ient, and thus by the bioavailability of the active ingredient. There should especially be mentioned combinations in which, per unit dosage, the weight of active ingredient in the slow release component (which, for simplification, is called the slow component) is double that in the rapid release component (which, for simplification, is called the rapid component). - 5 It is especially advantageous that the pharmaceutical combination contains per unit dosage: 200 mg of benfluorex hydrochloride in the alow component and 100 mg of benfluorex hydrochloride in the rapid component.

The usual dosage is two dosages per day but it can be reduced to one per day depending on the biological results.

An advantage of the pharmaceutical formulations 10 according to the invention lies -in the fact that the maximum plasma peak obtained is considerably lower than that obtained with an equivalent quantity of active ingredient administered in the form of classic pharmaceutical compositions. This means that the effect produced is milder, equally rapid in appearance, and much more prolonged. The pharmacokinetic curve still shows the presence of active ingredient at the end of fifty hours after administration of the formulations of the invention, while the administration of the same dose in a conventional, drinkable, form leads to barely detectable blood levels after twenty hours.

The formulations according to the invention exhibit hypoglycemic, hypolipidemic and hypo-uricemic properties They therefore allow the manifestations of diabetes to be treated effectively with a simple posology. They are effective against hyperglycemia. They induce a significant fall in and a normalisation of the plasma levels S28K9 — 6 — throughout the nychthemeron without substantial variation.

Furthermore, they induce a significant fall in the plasma levels of the triglycerides and cholesterol with a significant, favourable, action on the level of high density lipoproteins (BDL).

They have the further advantage of being safe medicines, with good acceptability, and generally are not likely to cause hypoglycemia or lactic acidosis.

In addition the incidence of gastro-intestinal disorders or effects on the central nervous system is minimal.

They are therefore suitable for the treatment of maturity-onset diabetes with or without overweight, isolated or associated with lipid anomalies.

They are equally useful in the treatment of hyperlipidemia (hypertriglyceridemia and/or hypercholesterolemia) and in the treatment of metabolic overloads.

The pharmaceutical preparations of the invention may be in one of the forms suitable for oral administration such as tablets, dragees, or gelatine capsules.

The content of active ingredient is from 300 to 500 mg per unit dosage form, more especially substantially 300 mg per dosage unit form. Two such unit dosages may, for example, be taken per day, although one may also be sufficient. - 7 The single-component delayed-action pharmaceutical preparation of the invention may be obtained, for example, by incorporating the active ingredient in the crystalline structure of a digestible hydrophobic matrix comprising glyceryl trimyristate, dividing this by extrusion, mixing the resulting vermicelli with one or more suitable, usually compressible, excipients forming a hydrophilic network, compressing the mixture obtained on a press fitted with punches, an3, if desired, coating the tablets formed with a coating suspension and then with a waxing solution.

The digestible hydrophobic matrix comprises glyceryl trimyristate; this is sold under the trademark Dynasan 114 by the Nobel Dynamite Co.. The matrix may also comprise glyceryl palmityl stearate, sold under the trademark Softisan by the Nobel Dynamite Co., which is made up of a mixture of glyceryl palmitate and glyceryl stearate. The nature of this matrix is chosen in such a way that it possesses a melting point higher 2C than 50°C, enabling it to be extruded without liquefying, and that it is suitable for being hydrolysed by the lipase enzymes in the digestive tract.

Suitable compressible excipients are, for example, disintegrating agents, binding agents and diluting agents. Suitable disintegrating agents are, for example carboxymethyl starch, polyvinyl pyrrolidone and Primojel. Suitable binding agents are, for example. - 7a modified cellulose, such ss, foe example, one sold under the trademark AVICEL PH 102. Suitable diluting agents are, for example, colloidal silica and cellulose.

Suitable coating agents are, for example, hydroxypropyl cellulose associated or not with a surface tension agent, a plasticiser and/or a lubricating agent.

Suitable waxing agents are, for example, high molecular weight polymers of ethylene glycol (i.e. those having a molecular weight > 6000).

The delay effect is obtained essentially by the - e dispersion of the digestable fatty hydrophobic matrix after extrusion in the excipient. The same unextruded hydrophobic mass does not appear to exhibit the same delay in the release of the active ingredient.

The formulations so obtained may also contain an agent to make them opaque or coloured.

The outer layer may further be coated with a skin of plastic film, for example by dispersion of a cellulose ester or of a poorly digested protein such, for example, as keratin.

The rates of disintegration from one batch to another have been found to be very constant. The release of the active ingredient measured by Poste's method (Biopharmaceutics and relevant pharmaco-kinetics, 1st edition, p. 112) is greater than eight hours.

The combination of the present invention may be a double release pharmaceutical preparation which comprises a rapid release benfluorex hydrochloride component and a slow release benfluorex hydrochloride component or, alternatively, the combination may be in the form of a pack comprising a separate slow release component and rapid release component.

The double release preparation, comprising a mixture of the two components, one of slow release and one of rapid release, of the same active ingredient, may, for example, be obtained by enclosing the mixture of slow release pellets and rapid release pellets of the - β active ingredient in an outer layer of one or acre suitable excipients, the unit then being formulated, e.g. compressed on a rotary press, into the mass required for the dosage unit. The dosage units thus obtained may then be coated with a film as shota in the following examples. Suitable excipients which can be used to form the outer layer are, for example, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate and colloidal silica.

The slow release pellets may be prepared as indicated above for the single-component delayed-action pharmaceutical preparation.

The rapid release pellets may be prepared by a conventional method: for example, the active ingredient and the excipient(s) are mixed in a stainless steel granulator mixer, the mixture is then wetted with an aqueous alcoholic solution and granulated, and the wet pellets are dried and then, once dry, cut up into the required length, generally from 1 to 1.5 mm.

Conveniently sanples may be taken during manufacture, the release time of the active ingredient of the samples determined and the result corrected by adding to the corresponding batch an appropriate amount of the rapid release component or alow release component, according to the difference established between the result obtained from the sample and the required result.

The present invention also provides a pack conprising - 10 (i) the rapid release benfluorex hydrochloride component comprising benfluorex hydrochloride formulated as, or in a form suitable for making up into, a rapid release preparation, and (ii) the slow release benfluorex hydrochloride component comprising benfluorex hydrochloride in a formulation comprising the active ingredient in a hyrophobic matrix comprising glyceryl trimyristate, the formulations being arranged in or on a container or other support member together with indications and/or instructions to indicate and facilitate administration of the two components of the specified combination simultaneously or at close intervals.

The content of active ingredient in each formulaT5 tion is set so that administration of an integral number of dosage units of each component will give the required result. Usually, there is one dosage unit of each component to be taken together and the indications and/or instructions will make this clear.

Preferably, the slow release dosage unit is composed as indicated above for the single-component delayed-action pharmaceutical preparation with suitable modification of amount of active ingredient, and may be prepared by the general method indicated above.

The rapid release dosage unit may, for example, be prepared conventionally, for example as described above.

The following Examples illustrate the invention. - 11 Example 1 Preparation of single-component delay tablets with 300 mg of active ingredient: Quantity for 10,000 tablets: Benfluorex hydrochloride Sodium salt of carboxymethyl starch Microcryatalline cellulose Glyceryl trimyristate Glycerol Hydroxypropyl cellulose Sodium lauryl sulphate Mineral colourants Mineral opacifiants Polyethylene glycol 6000 Polyvinylpyrrolidone Colloidal silica Magnesium stearate Talc Hater (for the coating suspension) Hater (for the waxing solution) 3,450 g 230 g 2.300 g 3,450 g 9.7 g 250 g 1.2 g 9.6 g g 8.2 g 371.45 g 8.05 g 15 g 195.5 g 17,702 g 100 g The glyceryl trimyristate waa weighed and put into a planetary mixer with a heated bowl and heated up to about 60°C to make it melt completely. Then benfluorex hydrochloride was introduced in small quantities into the melted glyceride and the «Aide was mixed while a temperature of about 45°C was maintained. - 12 10 The suspension obtained was extruded on an extruder having a grille with orifices of 1.1 mm in diameter.

The extrusion unit was kept at a temperature of the order of 40 to 45°C. The extruder operated with frontal or radial extrusion. The granules obtained, cooled to about 20°C, were gauged on an oscillating granulator, having a grille having a mesh size of 2.5 mm.

The grains obtained were mixed with colloidal silica, and then with the compressible excipients (cellulose, carboxymethyl starch, polyvinylpyrrolidone and talc). The mixture so obtained was compressed on a press provided with punches in the form of short rods (19 x 8 mm) to form tablets finishing with a mean weight of 0.87 g.

The tablets were then coated with 3 kg of the coating suspension so as to obtain a mean unit weight of 0.89 g. Finally, the coated tablets were waxed with 0.150 litre of the waxing solution. The tablets so formed, covered with a pellicle, had a mean weight of 0.895 g after drying.

The disaggregation time was about two minutes.

The disintegration of the active ingredient at various times was as follows: minutes 28.0 - 30 % 120 240 480 34.0 - 37 % 42.6 - 46.5 % 52.8 - 58 % 66.0 - 71 % - 13 The compositions according to Example 1 have been the subject of a multi-centre clinical trial on diabetic obese pereona, via-a-via placebo, two people, unknown, being placed on placebo. It was established that, for the same alimentary regime the loss of weight was about the same for the subjects treated as for those receiving the placebo, but that normalisation of the glycemia only occurred in the subjects receiving the preparation of the present invention. Bo significant variation in the glycemia of the subjects receiving the placebo was observed. λ conparative blood kinetic study waa carried out in man after oral administration of a single dose of: - one delayed-action tablet of 300 mg of benfluorex hydrochloride. - two standard tablets of 150 mg of benfluorex hydrochloride, and - 5 ml of a drinkable solution of benfluorex hydrochloride (i.e. 300 mg).

The results obtained were plotted on the graph shown in Fig. 1 of the accompanying drawings.

Statistical interpretation by variable analysis of the area under the blood graphs shows that the profiles differ in the peak blood concentration level and the half-elimination time; this gives the delayed-action tablet a prolonged effect which the standard forms do not possess.

Example 2 Preparation of delayed-action tablets using a mixture of two sorts of pellets: Por a coated tablet of 0,790 g 1. Core {of about 0.770 g): 1.1. Slow component: Benfluorex hydrochloride Semi-synthetic solid glycerides (Glyceryl trimyristate) 1.2. Rapid component: Benfluorex hydrochloride Lactose Maize starch Polyvinylpyrrolidone 1.3. Outer layer: Hydrogenated castor oil Polyvinylpyrroli done Magnesium stearate Colloidal silica 2. Coating: Glycerol Hydroxypropylmethyl cellulose Sodium laurylsulphate Iron oxide Polyoxyethylene glycol 6000 Titanium oxide Magnesium stearate 0.200 g approx. 0.200 g 0.100 g approx. 0.120 g 0.065 g 0.015 g 0.014 g 0.0425 g 0.0035 g 0.010 g approx. 0.000851 g 0.0141902 g 0.0000645 g 0.0005446 g 0.0007753 g 0.0027234 g 0.000851 g - 15 The Blow component was prepared by Belting the solid semi-synthetic glycerides in s stainless steel mixer st 60 to 70°C, and then incorporating the benfluorex hydrochloride. After being nixed for 15 to 30 minutes, the temperature of the mass was lowered to 40 to 50°C. Then this mass was extruded to form vermicelli of about 1 nm in diameter. The vermicelli, cooled to atmospheric temperature (20 + 5°C), were cut up into lengths of 1.5 to 2,5 nm to form the slow pellets.

The rapid component was prepared by first nixing the constituents in a stainless steel granulator mixer. The mixture was then wetted with an aqueous alcoholic solution and granulated. The wet pellets were dried and the dry pellets cut up into lengths of 1 to 1.5 nm.

The castor oil. the polyvinylpyrrolidone, the magnesium stearate and the colloidal silica were added as an outer layer to the slow pellets and the rapid pellets previously obtained. The mixture was compressed on a rotary press into the mass indicated in the detailed unit formula above, i.e. 0.770 g.

The tablets thus obtained were coated with a film having the composition indicated above .

Claims

1. A pharmaceutical preparation of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises benfluorex hydrochloride together with one or more pharmaceutically suitable carriers, wherein the preparation is in unit dosage form, containing from 300 to 500 mg of benfluorex hydrochloride per unit dosage, and is adapted for obtaining a progressive and prolonged release inside the digestive tract, at least part of the benfluorex hydrochloride being in a digestible hydrophobic matrix comprising glyceryl trimyristate.

2. A pharmaceutical preparation of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises benfluorex hydrochloride in a hydrophobic matrix comprising glyceryl trimyristate, dispersed in one or more suitable carriers, forming a hydrophilic network, the preparation being in unit dosage form containing from 300 to 500 mg of benfluorex hydrochloride per unit dosage.

3. A pharmaceutical combination of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises (i) a rapid release component of benfluorex hydrochloride and (ii) a slow release component of benfluorex hydrochloride in a hydrophobic matrix comprising glyceryl trimyristate, the combination being in unit dosage form containing - 17 from 300 to 500 mg of benfluorex hydrochloride per unit dosage.

4. A combination as claimed in claim 3, wherein the slow release component and the rapid release component are present together in the same, double release, formulation.

5. A combination as claimed in claim 3, wherein the slow release component and the rapid release component are present in separate formulations in a pack comprising (i) the rapid release benfluorex hydrochloride component comprising benfluorex hydrochloride formulated as a rapid release preparation, and (ii) the slow release benfluorex hydrochloride component comprising benfluorex hydrochloride in a formulation comprising the active ingredient in a hydrophobic matrix comprising glyceryl trimyristate, the formulations being arranged in or on a container or other support member together with indications and/or instructions, to indicate and facilitate administration of the two components of the specified combination simultaneously or at close intervals.

6. A combination as claimed in any one of claims 3 to 5, wherein the ratio of benfluorex hydrochloride in the slow release component to benfluorex hydrochloride in the rapid release component is substantially 2:1 by weight. - 18

7. A preparation or combination as claimed in any one of claims 2 to 6, wherein the hydrophobic matrix containing benfluorex hydrochloride is dispersed in one or more compressible carriers, forming a hydro5 philic network.

8. A preparation or combination as claimed in claim 7, wherein the compressible carrier(s) comprise a disintegrating agent, binding agent or diluting agent or two or more such agents.

9. 10 9. A preparation or combination as claimed in any one of claims 1 to 8, wherein the benfluorex hydrochloride is in the form of tablets, capsules or dragees. 10. A preparation or combination as claimed in 15 claim 9, wherein the dosage units have a protective pellicle.

10. 11. A preparation or combination as claimed in any one of claims 1 to 10, wherein the amount of benfluorex hydrochloride per unit dosage is 300 mg. 20

11. 12. A combination as claimed in claim 11, wherein the unit dosage is divided into substantially 200 mg of benfluorex hydrochloride in the slow release component and substantially 100 mg of benfluorex hydrochloride in the rapid release component. 25

12. 13. A preparation or combination as claimed in any one of claims 1 to 3, of prolonged effect for the treatment of pathological manifestations connected with - IS diabetes, substantially as herein described.

13. 14. A preparation or combination of prolonged effect for the treatment of pathological manifestations connected with diabetes, substantially as described in Example 1 or Example 2 herein.

14. 15. A process for the preparation of a pharmaceutical preparation of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises incorporating benfluorex hydrochloride in the crystalline structure of a digestible hydrophobic matrix comprising glyceryl trimyristate, extruding this mass and dispersing the extruded mass with one or more suitable carriers, forming a hydrophilic network, the preparation being formulated in unit dosage form containing 300 to 500 mg of benfluorex hydrochloride per unit dosage.

15. 16. A process as claimed in claim 15, wherein the mass of benfluorex hydrochloride incorporated in a matrix of glyceryl trimyristate is divided by hot extrusion, the resulting vermicelli are mixed with one or more compressible carriers forming a hydrophilic network and the mixture obtained is compressed on a press provided with punches. 16. 17. A process as claimed in claim 15 or claim 16, wherein the tablets are coated with a coating suspension and then with a waxing solution.

16. A process for the preparation of a pharma52959 - 20 ceutical preparation as claimed in claim 1, of prolonged effect for the treatment of pathological manifestations connected with diabetes, carried out substantially as described herein. 5 19. A process for the preparation of a pharmaceutical preparation of prolonged effect for the treat ment of pathological manifestations connected with diabetes, carried out substantially as described in Example 1 herein. 10 20. A process for the preparation of a combination of prolonged effect for the treatment of pathological manifestations connected with diabetes, which comprises formulating (i) a slow release benfluorex hydrochloride component 15 comprising the active ingredient in a hydrophobic matrix comprising glyceryl trimyristate, and (ii) a rapid benfluorex hydrochloride component, into a single formulation containing 300 to 500 mg of active ingredient surrounded by an outer layer of one

17. 20 or more pharmaceutically suitable carriers.

18. 21. A process as claimed in claim 20, wherein a mixture of slow release and rapid release pellets of the active ingredient is surrounded by an outer layer of one or more suitable carriers and the whole unit is 25 compressed on a rotary press to the required mass.

19. 22. A process as claimed in claim 20 or claim 21 wherein the slow release component is prepared by a - 21 process as specified in any one of claims 15, 15, 18 and 19.

20. 23. A process as claimed in any one of claims 20 to 22, wherein the outer layer comprises hydrogenated 5 castor oil, polyvinylpyrrolidone, magnesium stearate or colloidal silica or two or more of these carriers.

21. 24. A process as claimed in any one of claims 20 to 23, wherein the outer layer is coated with a film.

22. 25. A process for the preparation of a combina10 tion as claimed in any one of claims 1 to 3, of prolonged effect for the treatment of pathological manifestations connected with diabetes, carried out substantially as described herein.

23. 26. A process for the preparation of a combina15 tion of prolonged effect for the treatment of pathological manifestations connected with diabetes, carried out substantially as described in Example 2 herein.

24. 27. A pharmaceutical preparation or combination of prolonged effect for the treatment of pathological 20 manifestations connected with diabetes, which has been prepared by a process as claimed in any one of claims 15 to 26.