WO1996033694A1 - Pectic preparations used as medicament carriers - Google Patents

Abstract

The invention concerns pectic preparations which comprise at least one pectin associated with a complex composition comprising firstly an effervescent pair which easily disperses the pectin in water and hydrates it and regulates the gellification process irrespective of the hardness of the water used for the suspension, and secondly a mixture of compounds which provide the calcium ions necessary for the formation of the gel in an acid medium, together with magnesium ions regulating the kinetics of the calcium availability.

Description

 PECTIC PREPARATIONS FOR USE AS MEDICATION MEDICINE

The invention relates to pectic preparations which can be used as a medicament support intended to be administered to humans by the oral route in the form of a stable extemporaneous suspension which can easily be produced in drinking water and which forms a gel in the stomach.

It is known that a product having the consistency of a semi-solid gel can be obtained by the action of hydrochloric acid on certain hydrocolloids: document US-A-4,717,713 uses this property (essentially from gum xanthan, sodium alginate, gelatin, carrageenan, methylcellulose) to produce an excipient allowing, after oral administration in humans, a controlled availability of certain therapeutic active ingredients, in particular theophylline.

It is also known that an effect of covering an acid surface can be obtained by association of pectins with certain complexes of aluminum salts: the document JP-A-52 083 964 uses this property to propose an excipient with a view to administration to humans of anti-inflammatory therapeutic agents.

Document EP-A-0 286 085 describes an antacid composition using a very small amount of pectin to form a floating network in the stomach. This pectin is generally present in the form of pectin salt, or pectate, demethoxylated, not very structured and not very viscous. In this composition, CO ₂ is released on contact with the acidic environment of the stomach and makes the floating network foam.

With regard more generally to pectins, it is known: - that some of them, highly methoxylated (HM), form gels after hot acidification in a sweet medium, - while others, weakly methoxylated (LM or LM amidates), immediately form gels of varying qualities by simple interaction with the calcium ions present in the medium.

It is also known that the dispersion in water of pectins, whatever their nature (HM or LM or LM amidates) requires the use of significant mechanical means to avoid the formation of lumps very difficult to destroy. For weakly methoxylated pectins (LM and / or amidated LM), it is known that their dispersion in water can only be carried out in a medium free of calcium ions.

An object of the present invention is to provide pectic preparations capable of being easily dispersed in drinking water and of constituting therein a stable suspension, itself capable of being ingested and of constituting a gel in the stomach acid medium. .

The subject of the invention is pectic preparations which can be used as a drug carrier, intended to be administered orally in the form of an extem¬ poranous suspension stable in water and capable of forming a gel in an acid medium, characterized in that they contain at least one pectin, associated with a complex composition comprising:

- on the one hand, an effervescent couple ensuring at the same time:

• easy dispersion in water and hydration of pectin, and

• regulation of the gelling process whatever the hardness of the water used for the suspension, - on the other hand, a mixture of compounds providing:

• the calcium ions necessary for the formation of the gel in an acid medium,

• in association with magnesium ions ensuring the regulation of the kinetics of calcium availability.

According to other characteristics of the invention: - the pectins used are non-amidated pectins having a degree of methoxylation greater than 15%;

- at least one of these pectins with a degree of methoxylation of less than 50%;

- The pectins used are amidated pectins having:

• a degree of methoxylation greater than 15%, • a degree of amidation less than 35%;

• at least one of these pectins with a degree of methoxylation of less than 50%;

- the effervescent couple consists of a mineral or organic acid or a salt of these acids, and an alkali carbonate or bicarbonate or a sodium or potassium glycine carbonate; - the mineral acid salt is sodium or potassium monosodium phosphate or dihydrogen phosphate;

- the organic acid is fumaric acid; the organic acid salt is sodium fumarate;

- the organic acid is citric acid;

the organic acid salt is monosodium citrate;

- the alkaline carbonate is sodium bicarbonate; - the quantity of effervescent couple used, expressed in stoichiometric couple, is between 20 and 120% of the weight of pectin;

- the calcium ions are provided in the form of hydroxides or insoluble salts;

- the insoluble calcium salt is calcium carbonate;

- the amount of calcium supplied is less than or equal to 250 mg of calcium per gram of pectin;

- the magnesium ions are provided in the form of hydroxides or insoluble salts;

- the magnesium salts used are magnesium hydrocarbonate or magnesium trisilicate;

- the quantity of magnesium provided is less than or equal to 250 mg of magnesium per gram of pectin.

According to the invention, the pectic preparations, in the form of powder or granules, contain pectic products and a complex composition containing, in association, an effervescent couple and polyvalent and preferably bivalent cations.

Pectic products are pectins of fruit origin from the apple and citrus groups. They are weakly methoxylated, their degree of methoxylation preferably being less than 50%. They can be amidated or non-amidated, but preferably amidated, their degree of amidation being less than 35%.

Sparkling couples are based on mineral or organic acids or their salts, and alkali carbonates or bicarbonate, or sodium or potassium glycine carbonates.

Preferably, the mineral acids are in the form of sodium or potassium salts, such as sodium or potassium dihydrogen phosphate.

The organic acids are preferably citric acid or fumaric acid or are in the form of sodium salts. By way of example, an effervescent couple preferably consists of monosodium citrate and sodium bicarbonate and / or sodium glycine carbonate. The amount of effervescent couple expressed in stoichiometric couple is between 20% and 120% of the weight of pectin.

The ions provided by the mixture of compounds are polyvalent and preferably bivalent cations, being in the form of calcium or magnesium salts or hydroxides, insoluble or practically insoluble in water. Preferably, the salts used are calcium carbonate, tricalcium citrate, di- or tricalcium phosphates, magnesium hydroxy carbonate and magnesium trisilicate.

The amounts of calcium salts present, expressed in the form of calcium, are preferably less than 250 mg per gram of pectin. The amounts of magnesium salts present expressed in the form of magnesium are preferably less than 250 mg per gram of pectin.

The powder, or the granules, containing the pectic products and the association of an effervescent couple and of polyvalent cations, are diluted in water and stirred to obtain a dispersion capable of being ingested. This dispersion should not gel prematurely before ingestion.

When the powdered pectic preparations must be presented in the form of granules, they are treated, for example, by granulation with an excipient which is preferably a hydrolyzed gelatin.

The pectic preparations according to the invention, after extemporaneous dilution in drinking water, are ingested, and the gelation occurs only in the stomach, in the presence of the gastric acid medium.

The pectic preparations according to the invention can be used in compositions for therapeutic purposes with local action, such as compositions with antacid properties or compositions capable of acting locally on the gastric mucosa, for example on Helicobacter pylori. They can also be used in compositions for which it is desired to modify the conditions of release of the active principle (s). Thus, the gel that forms in the stomach can retain an active product which is released gradually or with delay. These pharmaceutical compositions contain at least one drug. Preferably the active principle is chosen from one or more components of the group formed from acceptable pharmaceutical bismuth compounds, for example colloidal bismuth sub-citrate, and anti-infectives: beta-lactam antibiotics, such as penicillins (for example Arnoxicillin and Ampicillin) and cephalosporins (e.g. cephalexin, cephradine, cephaclor, cefuroxime-axetil, cefamandol and ceftazidime), macrolides (e.g. josamycin and erythromycin), tetracyclines (e.g. doxycycline) , lincosamides, nitrofurantoins, quinolones (for example ciprofloxacin), furazolidones and / or imidazoles and nitroimidazoles such as metronidazol and tinidazol. Advantageously also anti-inflammatory drugs such as 5- or 4- aminosalicylic acid, corticosteroids, such as beclomethasone, and retinoids are incorporated in the pectic compositions according to the invention.

In addition, pectic preparations can be used in dietetics as a support for a low-calorie diet. On the one hand the gel gives an impression of saturation, on the other hand it protects the gastric mucosa and retains products which only become assimilated with delay and prolongs the duration of suppression of the feeling of hunger. The following examples illustrate the invention more clearly.

EXAMPLE 1

In the tank of a cubic mixer of suitable capacity, we introduce:

- a part by weight of pectin of apple origin, idea with a degree of methoxylation of 28% and a degree of amidation of 18.3%;

- 0.240 parts by weight of anhydrous monosodium citrate powder;

- 0.180 part by weight of sodium bicarbonate;

- 0.060 part by weight of calcium carbonate and

- 0.100 part of magnesium carbonate (hydrocarbonate). After 20 minutes of stirring, a homogeneous mixture is obtained.

1.58 g of this mixture gives, with 60 ml of drinking water after slight stirring, a suspension of low viscosity (around 45 mPa.s) which remains unchanged for at least 30 minutes.

By adding 30 ml of 0.1 N hydrochloric acid, the suspension is transformed into a consistent gel.

EXAMPLE 2

In the tank of a cubic mixer of suitable capacity, the following are introduced: - a portion by weight of pectin of apple origin, not amidated with a degree of methoxylation of 32.5%;

- 0.320 parts by weight of anhydrous monosodium citrate powder;

- 0.240 part of sodium bicarbonate;

- 0.030 part of calcium carbonate and - part of magnesium trisilicate.

After 20 minutes of stirring, a homogeneous mixture is obtained.

2.5 g of this mixture give, with 60 ml of drinking water after light stirring, a suspension of low viscosity (close to 37 mPa.s) which remains unchanged for at least 30 minutes. By adding 30 ml of 0.1 N hydrochloric acid, the suspension becomes a firm gel. EXAMPLE 3

In the tank of a cubic mixer of suitable capacity, we introduce:

• a part by weight of pectin of apple origin, amidated, with a degree of methoxylation of 29.1% and a degree of amidation of 18.0%;

• 0.240 parts of powdered sodium citrate;

• 0.220 part of sodium glycine carbonate;

• 0.060 part of calcium carbonate and

• 0.500 part of magnesium trisilicate. After 20 minutes of stirring, a homogeneous mixture is obtained.

2.02 g of this mixture gives, with 60 ml of drinking water, a homogeneous suspension after light stirring, of low viscosity (around 42 mPa.s) which remains unchanged for at least 30 minutes.

By adding 30 ml of 0.1 N hydrochloric acid, the suspension becomes a firm gel.

EXAMPLE 4

In the tank of a cubic mixer of suitable capacity, the following are introduced: • a portion by weight of pectin of apple origin, amidated, with a degree of methoxylation of 28.0% and a degree of amidation of 18.3 %;

• 0.240 parts by weight of anhydrous monosodium citrate, previously passed through a 0.5 mm sieve;

• 0.220 part by weight of sodium glycine carbonate, previously passed through a 0.5 mm sieve;

• 0.060 part by weight of calcium carbonate, previously passed through a 0.16 mm sieve;

• 0.5 part by weight of magnesium trisilicate, previously passed through a 0.25 mm sieve and • 0.25 part by weight of sorbitol powder.

After 20 minutes of stirring, a homogeneous mixture is obtained. 2.27 g of this mixture gives, with 60 ml of drinking water, after light stirring, a suspension of low viscosity (close to 50 mPa.s) which remains unchanged for at least 30 minutes.

At ordinary temperature as at 37 ° C., the addition of 0.1 N hydrochloric acid at a rate of 1 ml per minute to the suspension causes the formation of a gel consisting of 25 ml or more.

At 37 ° C, the gel obtained after total addition of 70 ml of 0.1 N hydrochloric acid at a rate of 1 ml per minute and poured over a 40 μm sieve placed on a funnel (all kept at 37 ° C) is retained in its entirety on the sieve (absence of syneresis phenomenon).

After addition of 100 ml of 0.1 N hydrochloric acid to the 60 ml of suspension, no syneresis phenomenon is observed. At 20 ° C, the gel obtained is retained in its entirety on the 40 μm sieve.

EXAMPLE 5

Granulated powder for extemporaneous suspension. Unit formula:

• Pectin (*) 1,000 g

• Anhydrous monosodium citrate 0.240 g

• Sodium glycine carbonate 0.220 g

• Light calcium carbonate 0.080 g

• Magnesium trisilicate 0.500 g

• Sorbitol powder 0.300 g

• Caramel flavor 0.070 g

• Orange flavor 0.050 g

• Aspartame 0.010 g

• Colloidal silica 0.0025 g (*) apple origin - degree of methoxylation 28.0%

- degree of amidation 18.3%

Method of preparation:

Granulation of magnesium trisilicate / light calcium carbonate: In the tank of a planetary mixer of satisfactory capacity, introduce all of the magnesium trisilicate, calcium carbonate previously passed through a 0.25 mm sieve and powdered sorbitol previously passed through a 630 μm sieve.

Mix for 10 minutes on speed 1. Moisten with stirring on speed 1 using approximately 12.5% (m / m) of purified water until satisfactory consistency for passage on a 2.5 mm opening grid of mesh.

Granulate on a 2.5 mm stainless steel grid.

Dry in a fluidized air bed at 50 - 60 ° C.

Calibrate on a 630 μm grid. Mixture for extemporaneous suspension.

In the tank of a cubic mixer, of suitable capacity, we introduce:

• half of the calcium carbonate / trisilicate / sorbitol grain;

• all of the anhydrous monosodium citrate previously passed through a 0.5 mm sieve;

• all of the sodium glycine carbonate previously passed through a 0.5 mm sieve; "Pectin;

• the flavors and the sweetener and

• the rest of the calcium carbonate / trisilicate / sorbitol grain. Mix for 10 minutes.

Add the colloidal silica previously passed through a 0.16 mm sieve. After 25 minutes of stirring (total) a mixture of homogeneous appearance is obtained.

2.4725 g of this mixture gives, with 60 ml of drinking water after light stirring, a suspension of low viscosity (close to 45 mPa.s) which remains unchanged for at least 30 minutes.

At ordinary temperature as at 37 ° C., the addition of 0.1 N hydrochloric acid at a rate of 1 ml per minute to the suspension causes the formation of a gel consisting of 25 ml or more.

At 37 ° C, the gel obtained after the total addition of 70 ml of 0.1 N hydrochloric acid at a rate of 1 ml per minute poured over a 40 μm sieve placed on a funnel (all kept at 37 ° C) is retained entirely on the sieve (absence of syneresis phenomenon). After addition of 100 ml of 0.1 N hydrochloric acid to 60 ml of suspension, no syneresis phenomenon is observed. At 20 ° C., the gel obtained is completely retained on the sieve. EXAMPLE 6

By repeating Example 4 but after replacing the pectin with a pectin of citrus origin with a degree of methoxylation of 27.0% and a degree of amidation of 19.0%, it was observed that:

The viscosity of the suspension is close to 56 mPa.s, it remains unchanged for at least 30 minutes and

• the results of the other tests are identical to those of Example 4.

EXAMPLE 7

By repeating Example 4 but after replacing the pectin with a pectin of apple origin with a degree of methoxylation of 30.3% and a degree of amidation of 17.4%, it was observed that:

The viscosity of the suspension is close to 60 mPa.s, it remains unchanged for at least 30 minutes and

• the results of the other tests are identical to those of Example 4.

EXAMPLE 8

Powder for extemporaneous suspension. Unit formula:

• Red pectin NA-ND 0.800 g • Heavy calcium carbonate 0.150 g

• Sodium glycine carbonate 0.140 g

• Anhydrous monosodium phosphate 0.450 g

• Magnesium trisilicate 0.010 g

• Aspartame 0.015 g • Apricot flavor 0.045 g

• Vanilla flavor 0.005 g The red pectin NA-ND has a degree of methoxylation of 32.0%. EXAMPLE 9

Unit formula:

• Red pectin NA-ND 0.800 g • Heavy calcium carbonate 0.150 g

• Sodium glycine carbonate 0.280 g

• Magnesium trisilicate 0.010 g

• Sodium fumarate 0.200 g

NA-ND red pectin has a methoxylation level of 32.0%. A sweetener and flavors are included in the formula.

EXAMPLE 10

Colloidal bismuth sub citrate 0.606 g

Red pectin NA-ND 0.800 g

Sodium glycine carbonate 0.280 g

Anhydrous monosodium citrate 0.400 g

Heavy calcium carbonate 0.150 g

Magnesium trisilicate qs

Flavorings and sweeteners qs

EXAMPLE 11

Colloidal bismuth sub citrate 0.606 g

Red pectin NA-ND 0.800 g

Heavy calcium carbonate 0.150 g

Sodium glycine carbonate 0.140 g

Anhydrous monosodium phosphate 0.450 g

Magnesium trisilicate 0.010 g

Aspartame 0.015 g

Apricot flavor 0.045 g

Vanilla flavor 0.005 g EXAMPLE 12

The viscosity stability of the extemporaneous suspension in 60 ml of drinking water for 30 minutes for different pectins and under the following conditions was determined:

Formulas studied:

• Pectin * 1 g and 1.2 g

• Citric acid 0.1 g

• Sodium glycine carbonate 0.4 g • Calcium carbonate 0.060 g

• Magnesium hydrocarbon 0.100 g

(*) Table 1 shows the characteristics of the different pectins

Methodology: Measurement of viscosity of the suspension after 5 minutes, 15 minutes, 30 minutes.

BROOKFIELD viscometer:

• Module 1

• Speed 50 rpm

• Measurement after 30 seconds of stirring at 20 ° C

TABLE NO. 1

Pectin Concentration Viscosity (mPa.s) of the used in 60 ml suspension after: origin drinking water apples 5 minutes 15 minutes 30 minutes

degree of methoxylation 25% 1 g 52 52 52 and degree of amidation 22.7%

red NH-ND 1.20 g 74 74 75

degree of methoxylation 33% 1 g 44 43 42 and not amidated

red NA-ND 1.20 g 59 57 57

degree of methoxylation 29.2% l g 41 41.4 41 and degree of amidation 20.8%

PH 320 NH 1.20 g 57 57.4 59

degree of methoxylation 37% l g 35 36 35 and not amidated

27 NA-ND 1.20 g 45 45 45

Table no. 2 shows the influence of the dilution on the viscosity of the extemporaneous suspension in drinking water. Pectin used:

• 25% degree of methoxylation

• degree of amidation 22.7% (red reference NH-ND) TABLE NO, 2

Viscosity (mPa.s) Concentration after 1.2 g g 1.2 g in 50 ml in 60 ml in 70 ml

5 minutes 108 74 55

15 minutes 108 74 55

30 minutes 109 75 55.4

The viscosity varies according to the dilution, but it remains stable over time for each dilution.

Claims

1. Pectic preparations usable as a drug carrier, intended to be administered orally in the form of an extemporaneous suspension stable in water and capable of forming a gel in an acid medium, characterized in that they comprise at least one pectin, associated to a complex composition comprising - on the one hand, an effervescent couple ensuring at the same time: • easy dispersion in water and hydration of pectin, and "regulation of the gelling process regardless of the hardness of the water used for suspension, - and on the other hand a mixture of compounds providing: • the calcium ions necessary for the formation of the gel in an acid medium, • in association with magnesium ions ensuring the regulation of the kinetics of calcium availability. 2. Pectic preparations according to claim 1, characterized in that the pectins used are non-amidated pectins having a degree of methoxylation greater than 15%. 3. Pectic preparations according to claim 2, characterized in that at least one of these pectins with a degree of methoxylation of less than 50%. 4. Pectic preparations according to claim 1, characterized in that the pectins used are amidated pectins having: • a degree of methoxylation less than 15%, • a degree of amidation less than 35%. 5. Pectic preparations according to claim 4, characterized in that at least one of these pectins with a degree of methoxylation of less than 50%. 6. Pectic preparations according to claim 1, characterized in that the effervescent couple consists of a mineral or organic acid or a salt of these acids, and an alkali carbonate or a sodium glycine carbonate. 7. Pectic preparations according to claim 6, characterized in that the mineral acid salt is monosodium phosphate or sodium dihydrogen phosphate. 8. Pectic preparations according to claim 6, characterized in that the organic acid is fumaric acid. 9. Pectic preparations according to claim 6, characterized in that the organic acid salt is sodium fumarate. 10. Pectic preparations according to claim 6, characterized in that the organic acid is citric acid. 11. Pectic preparations according to claim 6, characterized in that the organic acid salt is monosodium citrate. 12. Pectic preparations according to claim 6, characterized in that the alkali carbonate is sodium bicarbonate. 13. Pectic preparations according to claim 6, characterized in that the quantity of effervescent couple used, expressed in stoichiometric couple, is between 20 and 120% of the weight of pectin. 14. Pectic preparations according to claim 1, characterized in that the calcium ions are provided in the form of hydroxides or salts insoluble in water. 15. Pectic preparations according to claim 14, characterized in that the insoluble calcium salt is calcium carbonate. 16. Pectic preparations according to claim 14, characterized in that the amount of calcium supplied is less than or equal to 250 mg of calcium per gram of pectin. 17. Pectic preparations according to claim 1, characterized in that the magnesium ions are provided in the form of hydroxides or salts insoluble in water. 18. Pectic preparations according to claim 17, characterized in that the magnesium salts used are magnesium hydrocarbonate or magnesium trisilicate. 19. Pectic preparations according to claim 17, characterized in that the quantity of magnesium supplied is less than or equal to 250 mg of magnesium per gram of pectin. 20. Compositions for therapeutic purposes, characterized in that they contain the pectic preparations according to any one of claims 1 - 19 and at least one medicament.