FR2532177A1 - Material for supplementing nutrition or admin. of pharmaceutical - Google Patents

Abstract

Agglomerated substance for absorption through the gastro-intestinal tract comprises at least 2 agglomerate units (10,12) of different active ingredients. The 1st unit (10) consists of a 1st active ingredient (14) coated with an inactive layer (16) which after a chosen period of time corresponding to the pH changes encountered, will dissolve and thus liberate (14) in high conentration in the target area in the gastrointestinal tract. The 2nd unit (12) consists of a 2nd active ingredient (18) located with a 2nd inactive layer (20) which after a chosen period of time (different to that above) corresp. to the pH changes encountered will dissolve to liberate (18) in high concentration in the target area of the gastrointestinal tract. The invention allows the release of individual active ingredients at different position in the gastrointestinal tract, and can be used for the release of nutrients or of medicines.

Description

 The subject of the present invention is ingestible tablets or capsules containing nutritional supplements or medicaments in which an almost complete release of the individual ingredients is carried out at various locations along the gastrointestinal route corresponding to the targeted zones chosen beforehand on the route and where the maximum absorption takes place.

 It is known according to the prior art tablets or capsules made so that a single active ingredient can be absorbed on the gastrointestinal tract during a period of immersed time. This is achieved by forming microgells comprising "grains" of active ingredients coated with different coatings which slowly dissolve at low concentrations at different times after ingestion so that sustained release of the single ingredient can be achieved .

Another approach is to form elements of the single ingredient in which each element comprises a series of layers of active ingredients and interposed coating layers. This allows the active ingredient to undergo sustained release as the successive layers of the coating material dissolve on the gastrointestinal tract.

 Although the prior art allows a sustained release action for the continuous absorption of a single ingredient on the gastrointestinal tract, it does not allow a maximum effectiveness according to which several ingredients would be introduced in high concentrations on the route, the different ingredients are better absorbed in different areas of the path so that maximum efficiency can be achieved.

 According to the invention, a tablet or a capsule is produced containing an agglomerate of several active ingredients such as nutritional supplements or medicaments for human or animal application, tablets or capsules in which each agglomerate element comprises at least one active ingredient covered with a coating which dissolves on the gastrointestinal tract after changes in pH variations have been encountered corresponding to a predetermined period of time after ingestion. This produces a substantially complete release (high concentration) of the active ingredient in a targeted area chosen beforehand on the route and where maximum effectiveness of this particular ingredient can be obtained.

 The manufacturing process for the agglomerated ingredients includes the preparation, in separate batches, of individual active ingredients coated with the respective inactive coating. These are intended to dissolve at different points in time following the appearance of various changes in ph. Thus, after ingestion, specific target areas on the gastrointestinal tract are reached so that the absorption of the particular ingredients provides the maximum effectiveness mentioned. Individually coated active ingredient particles are mixed together in a final step of the process to form tablets or capsules.

 Thus, as will be understood, the present invention relates to the release in target regions separated from each of the different active ingredients contained within an agglomerate of several ingredients.

Inactive coatings isolate the active ingredients intended for various target regions, so that they are protected from changes in pH of the intestinal fluids encountered which would cause their early dissolution and make them inactive when they reach the intended target areas. This is in marked contradiction with the release for an extended period of time of a single ingredient on the basis of a continuous low concentration on the gastrointestinal path obtainable according to the prior art mentioned above.

 Whatever the following description of the invention is made in terms of nutritional or food supplements, it should be understood that the invention can also be used just as well for pharmaceutical products and medicaments administered to humans or animals.

Above-mentioned objects and advantages of the invention will appear more clearly with the aid of the description which follows and by means of the appended drawings in which
FIG. 1A is a schematic representation of an agglomerate of individual elements designed according to the invention,
- Figure 1B is a schematic illustration showing a layered construction of active ingredients and coatings according to the prior art.

 - Figure 2 is a flow diagram of a method of manufacturing the structure in tablets or capsules of the invention.

 In order to allow the reader a greater understanding of the invention, reference is made to FIG. 1A which schematically illustrates two adjacent elementary agglomerates 10 and 12 which can be studied microscopically without taking account of the agglomeration of elements located at the neighborhood and adhering to it that will form the volume of a tablet or capsule.

 As can be seen, a first active ingredient 14, indicated as active product A is covered with a coating layer 16 indicated in the figure as an inactive ingredient B. An adjacent agglomerate element 12 comprises an ingredient different active ingredient 18 indicated in the figure as active ingredient C, which is coated with a coating layer 20 indicated in the figure as inactive ingredient D. The material of the inactive ingredient D forming the coating layer 20 is different from that of the material inactive B forming the coating layer 16. The inactive materials of the coating layers are intended to have different dissolution times in response to different ph levels encountered along the gastrointestinal tract, so that their corresponding active ingredients are substantially completely released at different times after ingestion.

This is in opposition to an element formed in layers 22 constituting the prior art as illustrated in FIG. 1B. As indicated in this figure, the active ingredient indicated in A constitutes the central layer of the core 24 and the layer 26, these layers are separated by an inactive coating layer 28 indicated in
B. A second similar inactive coating forming the layer 30 covers the outer surface of the active ingredient layer 26. The circular line in dashed lines 32 shows a succession of such alternating active and inactive layers.

 After ingestion of the element of the prior art illustrated in FIG. 1B, the digestive juices will successively dissolve the coating layers and the layers of active ingredient. As long as each active layer comprises the same ingredient and as long as each coating layer comprises the same inactive coating material, the release of the active ingredient after ingestion occurs for a continuous period of time established over an extended period of time along the gastrointestinal tract.

 On the contrary, in accordance with the invention as described in FIG. 1A, there is provision for selective release of various ingredients at high concentration in targeted areas on the gastrointestinal tract where the absorption of particular ingredients causes a superior efficiency. Such release in a targeted area cannot be obtained according to the prior art mentioned.

On the contrary, ingestion of the elements of the prior art produces a release for an extended time of the same ingredient at low concentration and over a long length of the gastrointestinal tract.

 In FIG. 2, a circulation diagram has been illustrated to explain the process for implementing the invention.

The left branch of the circulation diagram indicates the basic steps necessary to form a first granulation I which is stored as an intermediate mixture of one or more active ingredients which are intended for the same targeted release zone. Similarly, the granulation In indicates the steps necessary for the formation of a second intermediate product comprising different active ingredients intended to be absorbed in a second targeted region of the digestive tract.

 Considering granulation I, the active ingredients which must be absorbed by a first targeted region are mixed together as indicated in step 34 so as to be homogeneous. An inactive material is granulated with the active ingredients as indicated in step 36, causing the coating or covering of all the active ingredient granules. The resulting granule is dried as indicated in step 38 and then reduced as indicated in step 40 so as to form a stable granule which can be stored appropriately as indicated in 42.

 The second granulation stage II corresponds to a sequence of stages marked 44 to 52 which correspond directly to the various stages previously described 34 to 42. The two intermediate granulations I and II can then be extracted from the storage facilities for mixing as indicated in step 54 until the mixture is homogeneous.

 After which, the resulting mixture can either undergo a capsule setting process as indicated in step 58, or can be formed into tablets as indicated in step 56.

 Example.

 A nutritional supplement comprising amino acids, vitamins and minerals is manufactured so that they are absorbed on the gastrointestinal route to various target areas, and this in the following manner. It should be noted that it is not the ingredients indicated which in themselves are new, but rather the structure of the resulting tablet or capsule, as well as the complete process allowing their manufacture, which constitutes the invention.

First of all, the following amino acids and an ETHOCEL powder are introduced into a mixer as indicated in step 34 of FIG. 2, which requires approximately 10 minutes in order to obtain homogeneity
Ingredients kg g
METHIONINE POWDER 5,000
CYSTEINE HCl POWDER 2,597
HISTIDINE POWDER 1000
L-TRYPTOPHANE POWDER 1000
LEUCINE POWDER 1000
ISOLEUCIN POWDER 1000
CYSTINE POWDER 2,000
L-LYSINE MONOHYDROCHLORIDE POWDER 1,250
PHENYLALANINE POWDER 1000
THREONINE POWDER 1000
VALINE POWDER 1000
ETHOCEL N-10 2 948
A typical satisfactory mixer is the Marion Mixer manufactured by the Marion Company of Grand Rapids, Iowa (USA). The mixer can operate at 60 rpm
(average speed)
Next, the amino acids are granulated as shown in step 36 of Figure 2 with inactive ingredients including
ETHOCEL SOLUTION (0.06 kg / l) 2,948
Use approximately 49.2 liters of methanol solution (as granulating agents).

 After careful granulation, the drying step can be undertaken at 43.50C for approximately 6 hours.

Then, the resulting aggregate is reduced as indicated in step 40 of FIG. 2 by passing through a suitable sieve, in particular a 2B sieve operating at medium speed with knives in front. This reducer mold can operate at a speed of 1,750 rpm. The resulting product can then be placed in multi-coating drums for storage as indicated in step 42 in FIG. 2.

 The characteristics of the granulate II manufacturing process as illustrated in Figure 2 are as follows.

Next B complex vitamins, minerals and powder
PVP are added to a mixer to achieve homogeneity
Ingredients Kg g
PYRIDOXINE HC1 POWDER 4,010
PANTOTHENATE OF CALCIUM POWDER 2,716
AMINO CHELATE 10% COPPER ACID 4,000 SELENIUM YEAST (2000 micrograms / g 20,000
POLYVINYL PYRROLIDONE POWDER 1,361
The mixing corresponding to step 44 of FIG. 2 can be carried out in a pony mixer manufactured by the company Day Mixer, Inc. of Cincinnati, Ohio (USA). The mixer can operate at 70 revolutions per minute. The ingredients must be mixed for approximately 5 minutes in order to ensure homogeneity. Then, step 46 of FIG. 2 is carried out by granulating the above-mentioned mixture with a solution of polyvinyl pyrrolidone (0.12 kg / l) using approximately 11.35 liters of solution in methanol. Granulation should be done slowly and carefully.

 Next, the drying step 48 of Figure 2 should be carried out at a temperature of 43.5 ° C for approximately 6 hours.

 Then, the reduction step 50 of FIG. 2 is carried out through a suitable screen, for example a screen 2B operating at medium speed and with knives directed towards the front. The reducing screen can rotate at 1750 revolutions / minute.

 The storage step 52 of FIG. 2 is carried out by storing the material after reduction in suitable containers such as. poly-coated drums.

The final mixing step 54 of Figure 2 is achieved by mixing the stored materials from processes 42 and 52 for about 15 minutes. A suitable mixing machine is the Bush mixer manufactured by
Bush Machines, Inc. of Brooklyn (New York) USA operating at 60 rpm (medium speed). The resulting mixed material can then be put. in conventional capsules as indicated in step 58 or be formed into tablets using a conventional tablet press as indicated in step 56.

 If the product is presented as a tablet, a suitable coating material can be added to improve the odor, taste and facilitate swallowing.

Typically, orange oil and pharmaceutical frosting are used.

Considering the release qualities in the targeted areas of the products of the invention, the aggregate
I will include inactive coating materials associated therewith which will dissolve approximately 3 hours after ingestion. This allows the active ingredients of granulate 1 to be substantially absorbed in their entirety shortly after the passage of a duration of 3 hours. This corresponds to a predetermined target region located on the gastrointestinal path where the amino acids of granulate 1 are absorbed most efficiently and are used by the body. The complex B vitamins and minerals included in the ingredients of granulate II become available and can be absorbed 1 hour after ingestion. This occurs after the inactive coating material of granulate II has dissolved on the gastrointestinal tract after a period of about 1 hour, whereby substantially all of the vitamins and minerals contained therein are released in a predetermined region correspondent chosen along the gastrointestinal tract.

In the previous example, in order to simplify the explanation, the inclusion of antioxidants and preservatives was not mentioned. The need to use such products is well known in the art of nutritional supplements. Thus, in aggregate 1, suitable antioxidants and preservatives can be added as indicated below.
Ingredients Kg g
SUPEROXIDE DISMUTASE 10,000
BHA (HYDROXYANISOLE BUTYLE POWDER) 1,080
BHT (HYDROOXYTOLUENE BUTYLE POWDER) 1,080
In the case where certain active ingredients are to be absorbed immediately after ingestion, they can be introduced during step 54 of FIG. 2 without a clean coating, so that they can be immediately dissolved on the gastrointestinal tract.

 It should also be noted that, although the foregoing description of the invention relates to nutritional supplements, the. structure of the resulting capsule or tablet and the corresponding inventive processes are equally applicable to a drug or a pharmaceutical product.

 Furthermore, whatever the invention has been described in relation to a tablet or a capsule, the resulting granulated powder mixtures obtained after step 54 can be mixed with liquid carriers so as to be drunk immediately before all the coatings inactive have been dissolved by the liquid carrier vehicle.

 As a consequence of the foregoing discussion, it appears that the invention offers a process for the release of a nutritional supplement, of a drug or of a pharmaceutical product which allows the release of an ingredient not on the basis of a low sustained concentration without discrimination, but rather at a high concentration in a specific, predetermined target area of the gastrointestinal tract where the ingredient is most effectively absorbed.

 It is understood that the invention is not limited to the exact details of implementation illustrated and described below, including all the obvious modifications which appear to the field of the skilled person.

Claims (7)

 1. Agglomerate for absorption on the gastrointestinal tract comprising at least two agglomerate elements of different active ingredients, the first element (10) comprising  - a first active element (A) covered with a first inactive coating (B) which dissolves after a predetermined period of time corresponding to changes encountered in the Ph following ingestion, whereby the first ingredient is released active at high concentration in a specified region of the route  - a second element (12) comprising a second active ingredient (C) coated with a second inactive coating (D) which dissolves after a second predetermined period of time corresponding to modifications of the encountered Ph appearing after ingestion, thanks to what, the second active ingredient is released in high concentration in a corresponding chosen area of the path  2. A means for delivering various ingredients forming a nutritional supplement in order to separate predetermined selected areas along the gastrointestinal path where each individual ingredient is most effectively absorbed, said means being characterized in that it comprises an agglomerate of various elements in which each comprises at least one active ingredient covered with a respective inactive coating which dissolves in a corresponding chosen region allowing the release of a high concentration of the active ingredient in this said region.  3. A means for delivering various drug-forming ingredients to separate selected predetermined areas along the gastrointestinal tract where each individual ingredient is most effectively absorbed, said means being characterized in that it comprises agglomerates various elements in which each comprises at least one active ingredient covered with a respective inactive coating which dissolves in a corresponding chosen region allowing the release of a high concentration of the active ingredient in this said region.  4. A method of manufacturing an agglomerate composed of a plurality of active ingredients in particular for the implementation of any one of the preceding claims, wherein each of the ingredients is more effectively absorbed in various selected areas along the gastrointestinal path, said method being characterized in that it comprises the following stages  a) the active ingredients having the same targeted action zone are mixed;  b) the ingredients mixed with inactive materials are granulated  c) the granulated mixture is dried,  d) the dried granulated mixture is reduced so that the active ingredients are reduced to particles covered with inactive material to form a first granulation  e) repeating steps a) to d) for the other active ingredients having different targeted regions of action so as to form a plurality of granulations different from the first; and  f) the resulting granulations are mixed  5. Method according to claim 4, characterized in that the resulting granulations are compressed so as to form tablets.  6. Method according to claim 4, characterized in that the resulting granulations are placed in capsules.  7. Method according to claim 4, characterized in that the resulting granulations are mixed in a liquid vector carrier which can be swallowed.