WO2002058673A1

WO2002058673A1 - Method of preparing pharmaceutical or dietary compositions for conveying labile substances into the intestine

Info

Publication number: WO2002058673A1
Application number: PCT/EP2002/000515
Authority: WO
Inventors: Sergio Cecchetti; Valter Gatti
Original assignee: Giuliani SpA
Current assignee: Giuliani SpA
Priority date: 2001-01-26
Filing date: 2002-01-17
Publication date: 2002-08-01
Anticipated expiration: 2003-07-26
Also published as: ITMI20010141A1; WO2002058673A8

Abstract

Method of preparation of pharmaceutical or dietary compositions comprising a polysaccharide, a phospholipid and an active principle, characterized in that it comprises the following stages: a) dry mixing of the said polysaccharide, phospholipid and active principle; b) adding an aqueous solution containing a pH buffer, in a smaller amount by weight relative to the dry mixture obtained in the said stage a) and in a ratio not greater than 1:3, thus forming moist granules; c) drying of the said moist granules, thus obtaining the said compositions in the form of powder.

Description

"METHOD OF PREPARING PHARMACEUTICAL OR DIETARY COMPOSITIONS FOR CONVEYING LABILE

SUBSTANCES INTO THE INTESTINE"

* * * * * * * Published application WO 00/43036 describes lipoprotein complexes comprising a lipase-inhibiting protein component, an amylase-inhibiting protein component and a phospholipid component, compositions containing these complexes in combination with a polysaccharide component, pharmaceutical formulations and foodstuffs containing these complexes or compositions, methods for preparing the aforesaid complexes and compositions that are able to reduce the weight increase resulting from hypercaloric diets and to exert a cholesterol- lowering, triglyceride-lowering and antioxidant action.

That patent describes the preparation of the said complexes starting in every case from dilute solutions of the active substance and with the use of inert supports if necessary. In these methods, the active substance, dissolved in a dilute aqueous solution or in an organic solvent, is combined with the phospholipid, which may be deposited on the surface of a support, and is then isolated by concentration and successive evaporation of the solvent, by spray-drying. In some cases an inert support is also used as temporary medium for depositing the phospholipid, and this support must subsequently be removed by filtration or centrifugation.

The known preparative procedures of the type described above therefore involve complex and expensive apparatus, large volumes of solutions, the use of flammable organic solvents, very long times for completing the production cycle, expenditure of considerable quantities of energy, and hence, in conclusion, high product cost.

To solve these problems, the present invention proposes a method for the preparation of pharmaceutical or dietary compositions that include a polysaccharide selected from amides, cellulose, edible fibres, chitins, chitosans, pectins, inulins, lignins and derivatives, cyclodextrins and derivatives, and their mixtures; a phospholipid selected from lecithins, phosphatidylcholine, phosphatidylethanolamine, monodimethylphosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and derivatives, phosphatidylglycerol, cardiolipins, lysophospholipids, and their mixtures; an active principle selected from lipase-inhibiting peptides, amylase-inhibiting peptides, caseinphosphopeptides, lactoferrins, S-adenosylmethionine, peptides with antidepressant activity, and their mixtures, characterized in that it comprises the following stages: a) dry mixing of the said polysaccharide, phospholipid and active principle; b) adding an aqueous solution containing a pH buffer, in a lower quantity by weight relative to the dry mixture obtained in the said stage a), and in a ratio not greater than 1 :3, thus forming moist granules; c) drying of the said moist granules, thus obtaining the said compositions in the form of solid powder. Commercial soya lecithins can be used as a source of phospholipids suitable for the purposes of the present invention. The compositions according to the present invention can also include other active ingredients, for example vitamins and mineral salts, yeast, maltodextrins and the like, all being mixed dry in the said stage a) according to a basic characteristic of the invention.

The compositions thus prepared are then formulated for the end use in various galenical forms such as: packets, tablets, effervescent tablets, coated tablets, soft capsules, hard capsules, dragees, sweets, solutions, syrups, suspensions, pills in general, etc. For better understanding of the characteristics and advantages of the invention, non-limiting examples of practical application thereof are described below.

EXAMPLE 1 Production of packets with lipase-inhibiting active principle (using

Lodige type mixer and fluidized-bed drying; ratio of aqueous buffer solution to dry mixture 1 :9 w/w).

Equipment High-speed mixer/granulator of the Lodige type or equivalent with a horizontal mixing shaft with variable-speed blades and with 2 fixed- speed choppers; spraying system with pneumatic pump and 2 nozzles positioned above the choppers. Fluidized-bed dryer

Oscillating-arm granulator equipped with steel screen - Automatic line for making packets

Method a) Introduce the following into the high-speed mixer/granulator after first passing through a suitable sieve: oat fibre (approx. 100 kg), hydrolysed protein (approx. 60 kg), vitamin E 50% (approx. 2 kg), beta-carotene 10% (approx. 1 kg), chromium-containing yeast

(approx. 0.3 kg), maltodextrins (approx. 50 kg), soya lecithin (approx. 50 kg), and mix with the mixer until the mixture is homogeneous. b) Soak (a) with approx. 30 litres of an aqueous buffer solution (e.g. of citric acid/sodium citrate) at pH = 4-5, using both the mixer at a speed of approx. 80 rpm and the choppers. Knead with the mixer and the choppers for a few minutes. c) Transfer the moist granules to the appropriate container of the fluidized-bed dryer and dry to residual moisture content of 2-4%. d) Add the flavourings, sweeteners, silicon dioxide (3-4%) to the dried powder, and mix. e) Standardize the granulometry of the powder with an oscillating-arm granulator. f) Distribute the granules thus obtained in packets on a suitable automatic packing line.

EXAMPLE 2 Production of chewable tablets with amylase-inhibiting active principle (with Colette mixer and fluidized-bed drying; ratio of aqueous buffer solution to dry mixture 1 :15 w/w).

Equipment High-speed mixer/granulator of the Colette type or equivalent with a horizontal stirrer and chopper; equipped with a spraying system with peristaltic pump and nozzles. - Fluidized-bed dryer.

Oscillating-arm granulator equipped with steel screen. Rotary tableting machine equipped with stainless-steel dies. Automatic machine for making blister packs. Line for packing in boxes. Method a) Introduce the following into the high-speed mixer/granulator after first passing through a suitable sieve: oat fibre (approx. 50 kg), amylase-inhibiting bean protein (approx. 50 kg), maltodextrins (approx. 30 kg), soya lecithin (approx. 20 kg), and mix at high speed until the mixture is homogeneous. b) Soak (a) with approx. 10 litres of a buffer solution at pH = 6-7, using both the high-speed mixer and the chopper and knead for a few minutes. Continue to soak mixture (a) with a small quantity of purified water using the mixer and knead for a few minutes. c) Transfer the moist granules to the appropriate container of the fluidized-bed dryer and dry to a residual moisture content of 2-4%. d) Add the flavourings, sweeteners, silicon dioxide, rice starch and magnesium stearate to the dried powder and mix. e) Standardize the granulometry of the powder with an oscillating-arm granulator. f) Distribute the granules thus obtained in tablets by means of a rotary tableting machine equipped with stainless-steel dies of suitable dimensions. g) Pack in blister packs on an automatic blister-packing machine, h) Pack in boxes on a suitable packing line.

EXAMPLE 3 Production of capsules with caseinphosphopeptide (with Colette mixer and drying under vacuum; ratio of aqueous buffer solution to dry mixture 1 :5 w/w).

Equipment High-speed mixer/granulator of the Colette type or equivalent with a horizontal shaft and chopper; equipped with a spraying system with peristaltic pump and nozzles. - Rotary vacuum dryer.

High-speed granulator, type Glatt TR-160 or equivalent. Automatic capsuling machine MG-2 or equivalent for filling capsules.

Method a) Introduce the following into the high-speed mixer/granulator after first passing through a suitable sieve: edible fibre (approx. 100 kg), caseinphosphopeptide (approx. 100 kg), soya lecithin (approx. 100 kg), starch (approx. 30 kg), and mix at high speed until the mixture is homogeneous. b) Soak (a) with approx. 60 litres of a buffer solution at physiological pH, using both the high-speed mixer and the chopper and knead for a few minutes. c) Transfer the moist granules into the rotary vacuum dryer and dry to residual moisture content below 1 %. d) Break up the lumps by passing through the type TR-160 rotary granulator, standardizing the granulometry of the powder with a screen with clear hole size of 0.8 mm. e) Distribute the granules thus obtained in capsules using a suitable automatic machine.

EXAMPLE 4 Production of tablets with lactoferrin (with "Roto" type of granulator and static drying; ratio of aqueous buffer solution to dry mixture 1 :4 w/w). Equipment

High-speed mixer/granulator of the "Roto" Zanchetta type or equivalent equipped with a pump spraying system and nozzles, working under vacuum. Static dryer. - Oscillating-arm granulator equipped with steel screen.

Rotary tableting machine equipped with stainless-steel dies.

Method a) Introduce the following into the high-speed mixer/granulator after first passing through a suitable sieve: edible fibre (approx. 50 kg), starch (approx. 50 kg), lactoferrin (approx. 50 kg), soya lecithin

(approx. 60 kg), and mix at high speed until the mixture is homogeneous. b) Soak (a) with approx. 50 litres of a buffer solution at pH 4.7 and knead until there is complete granulation of the moist mass. c) Apply vacuum to the apparatus and continue mixing the mass until a residual moisture content of 4-6% is reached. d) Transfer the granules into the appropriate containers and place them in the static dryer. Carry out drying at approx. 60°C until a relative moisture content of 1-2% is reached. e) Add the flavourings, sweeteners and lubricants to the dried powder, and mix. f) Standardize the granulometry of the powder using an oscillating- arm granulator. g) Distribute the granules thus obtained in tablets by means of a rotary tableting machine equipped with stainless-steel dies of suitable dimensions. With the method of the present invention, in the final composition obtained, the active principle is contained in a kind of shell consisting of the said phospholipid and polysaccharide, which protects it against attack by gastric juices. The result is that substances of pharmaceutical or dietary interest can be released in the intestines, which would otherwise be inactivated by gastric digestion.

The said pharmaceutical, dietary or nutritional compositions are suitable for various applications, such as: control of body weight, restriction of the absorption of carbohydrates, lowering of blood levels of triglycerides and cholesterol, improvement of calcium absorption and fixation in the bones, probiotic treatments, supply of sulphurated precursors, etc. GASTROPROTECTION IN VITRO

The following tests were carried out with the aim of demonstrating that compositions prepared by the method of the invention described here are effective in protecting the active fraction against attack by gastric juices. In an "in vitro" laboratory model with simulated gastric juices as described in the literature, the following were treated and compared: The active principle as such (five different active principles as specified below)

The polysaccharide as such (oat fibre) The phospholipid as such (soya lecithin) The composition consisting of the ternary complex of the said components obtained by the method of the invention. In each case, the concentration in solution of free amino acids derived from digestion of the active substance was measured over time.

The results of these tests are shown by way of example in Tables 1 to 5 below, and in the graphs in Figs. 1 to 5 in the appended drawings. Each table from 1 to 5 corresponds to a different active principle as specified below. The graph in Fig. 1 corresponds to Table 1 , Fig. 2 to Table 2, and so on.

TABLE 1 Li ase-inhibitin oli o e tides

TABLE 5 Derivatives of amino acids: S-adenosylmethionine (SAMe)

As can be seen, the substantial effect of the composition prepared according to the method of the invention is to cause a marked reduction in release of the active principle at gastric pH, measured from the concentration of amino acids released in vitro, which in the case of the invention is reduced considerably relative to the use of the unmodified active principle.

With regard to the other advantages of the method of the invention, it permits the use of production equipment that is widely used in the pharmaceutical and food industry, which constitutes the main sector for application of the complexes in question; the use of very restricted volumes of reagents, as the work is carried out in the solid phase; moreover, no use of flammable and hazardous organic solvents is envisaged; finally, the rapidity of the production cycle and the limited expenditure of energy keep down the cost of the final product.

Claims

1. A method of preparation of pharmaceutical or dietary compositions comprising a polysaccharide selected from amides, cellulose, edible fibres, chitins, chitosans, pectins, inulins, lignins and derivatives, cyclodextrins and derivatives, and their mixtures; a phospholipid selected from lecithins, phosphatidylcholine, phosphatidylethanolamine, monodimethylphosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and derivatives, phosphatidylglycerol, cardiolipins, lysophospholipids, and their mixtures; an active principle selected from lipase-inhibiting peptides, amylase-inhibiting peptides, caseinphosphopeptide, lactoferrins, S- adenosylmethionine, peptides with antidepressant activity, and their mixtures, characterized in that it comprises the following stages: a) dry mixing of the said polysaccharide, phospholipid and active principle; b) adding an aqueous solution containing a pH buffer, in a lower quantity by weight relative to the dry mixture obtained in the said stage a), and in a ratio not greater than 1 :3, thus forming moist granules; c) drying of the said moist granules, thus obtaining the said compositions in the form of solid powder.

2. A method according to Claim 1 , characterized in that additional active ingredients such as vitamins, mineral salts, yeast, maltodextrins etc. are dry mixed in the said stage a).

3. A method according to Claim 1 , characterized in that the said drying stage c) is conducted in a fluidized bed.

4. A method according to Claim 1 , characterized in that, in the said stage b), the pH of the said buffer solution is between approx. 4 and 7. method according to Claim 1 , characterized in that at the end of the said drying stage c), the residual moisture content of the composition is at most 4% w/w.