INNOVATIVEOF FOOD SUPPLEMENTS

M

A NEW TECHNOLOGY

INNOVATIVE FORMS OF FOOD SUPPLEMENTS FOR

ORAL USE:

M.A.T.R.I.S.® A NEW TECHNOLOGY

FOR

CONTROLLED RELEASE OF ACTIVE INGREDIENTS

In some tombs of Egyptian pharaohs, small gold spheres were found containing plant substances, considered actual "capsules" intended for the oral administration of substances with therapeutic activity.

This seems to show the interest since ancient times with the purpose of prolonging the therapeutic activity of the active ingredients and obtaining, with the same a reduction in administration frequency (patient compliance).

Whilst there are legitimate doubts effectiveness of such "capsules", although presumably intended for repeated use, there is no doubt that these attempts would coincide of controlled release of active ingredients for oral use, although at the timewould have been limited to ease of administration.

Let us briefly see the main stages of the evolutioconcept and how the idea of therapeutic controlled release ingredients has developed over the centuries latest technological achievements of our times.

CONTROLLED RELEASE OF ACTIVE INGREDIENTS

Egyptian pharaohs, small gold spheres

"capsules" intended

therapeutic activity.

seems to show the interest since ancient times for oral forms

the purpose of prolonging the therapeutic activity of the active ingredients and thereby

, with the same efficacy, administration

(patient compliance).

there are legitimate doubts concerning effectiveness of such "capsules", although presumably intended for repeated use, there is no doubt that these attempts would coincide precisely with the modern concept of controlled release of active ingredients for oral use, although at the time, and for many centuries afterwards

limited to ease of administration.

Let us briefly see the main stages of the evolutioconcept and how the idea of therapeutic controlled release ingredients has developed over the centuries right up latest technological achievements of our times.

CONTROLLED RELEASE OF ACTIVE INGREDIENTS

concerning the effectiveness of such "capsules", although presumably intended for repeated use, there is no doubt that these

precisely with the modern concept of controlled release of active ingredients for oral use,

afterwards, this limited to ease of administration.

Let us briefly see the main stages of the evolution of this concept and how the idea of therapeutic controlled release

right up to the

PREMESSE

FOREWORD

First and foremost it is necessary to specify that all considerations below apply eqfood supplements, products in terms of method of administration (oral), behaviour of the recipient organism (metabolism) and criteria for evaluating

DEVELOPMENTS IN TECHNOLOGY

Despite several attempts over the centuries to make formulations of controlled release active form of tablets, pills,tabloids, mucilage,lollipops and medicinal chocolateproducts, in order to reduce the frequency of administration or for protection gastro-sensitive substances,a scientific basis only conjunction with two key events:

First and foremost it is necessary to specify that all considerations below apply equally well to both drugfood supplements, as the affinity of the two categories of products in terms of method of administration (oral), behaviour of the recipient organism (metabolism) and criteria for evaluating their therapeutic activity, is evident

DEVELOPMENTS IN TECHNOLOGY

Despite several attempts over the centuries to make formulations of controlled release active ingredients in the form of tablets, pills, granules, boluses, tabloids, mucilage, cachets, right up to lollipops and medicinal chocolate

roducts, in order to reduce the frequency of administration or for protection of

sensitive substances, the study on a scientific basis only began in

with two key events:

1. The birth of modern pharmacology (mid-nineteenth century) in particular of pharmacokinetics (what the body does to the drug: absorption, distribution, metabolism, excretion) and pharmacodynamics (what that the drug does to the body: biochemical and physioeffects of the drugs and their mechanism).

First and foremost it is necessary to specify that all the ually well to both drugs and

the affinity of the two categories of products in terms of method of administration (oral), the behaviour of the recipient organism (metabolism) and the

is evident.

The birth of modern pharmacology nineteenth century) in particular of

pharmacokinetics (what the body does to the drug: absorption, distribution, metabolism, excretion) and pharmaco-dynamics (what that the drug does to the body: biochemical and physiological

of the drugs and their action

PREMESSE

Thanks to these branches of pharmacologhas other things, the optimal characteristics of release of therapeutic

2. The discovery of suitable polymers, both natural and synthetic, designed to allow the release and absorption the chosen gastro

Thanks to these branches of pharmacologhas finally been possible to establish, among other things, the optimal characteristics of release of therapeutically active substances.

iscovery of suitable polymers, both natural and synthetic, designed to allow the release and absorption

gastro-intestinal tract and in the desired

Thanks to these branches of pharmacology, it possible to establish, among

other things, the optimal characteristics of active substances.

iscovery of suitable polymers, both natural and synthetic, designed to allow the release and absorption within

intestinal tract and in the desired manner.

TAPPE FONDAMENTALI

FUNDAMENTAL MILESTONES

CONTROLLED-RELEASE PRODUCTS BY DISSOLUTION

The first real discovery dates back to 1949, when the technician of a major US pharmaceutical industry saw a pack of small discs of chocolate in a supermarket. That led to capsules with neutral media in the form of granules, coated with active principles able to dissolve at different intervals, thanks to a membrane coating of the granules themselves, with a more or less rapid different thicknesses. This invention made it possible to quickly obtain the release of an initial dose of active ingredient (active uncovergranules), with the doses (thicker membrane granules) thus maintaining the therapeutic level for 8comfort and safer use (patient compliance). The first drug in this form was launcmarket in 1952.

The discovery, besides contributing to of the proposed advantages, actually more (Serendipity) than toxicity level of thconventional dosage forms, thanks to into numerous microobtaining a reduced concentration in a sbody, with fewer side

FONDAMENTALI FUNDAMENTAL MILESTONES

RELEASE PRODUCTS BY

The first real discovery dates back to 1949, when the technician of a major US pharmaceutical industry saw a pack of small discs of chocolate covered with white granules

That led to the idea of filling hard gelatine capsules with neutral media in the form of granules, coated with active principles able to dissolve at different intervals, thanks to a membrane coating of the granules themselves, with a more or less rapid dissolutiondifferent thicknesses.

This invention made it possible to quickly obtain the release of an initial dose of active ingredient (active uncover

the subsequent gradual releasedoses (thicker membrane granules) thus maintaining the therapeutic level for 8-10 hours, with undoubted increased comfort and safer use (patient compliance).

The first drug in this form was launched on the American

The discovery, besides contributing to an easier acceptance proposed therapy, also had other important

advantages, actually more the result of randomness of real research. In particular, a lower

toxicity level of the active ingredients compared withconventional dosage forms, thanks to dividing the total dose

numerous micro-doses (active granules) and therefore a reduced concentration in a specific point of the

body, with fewer side-effects.

The first real discovery dates back to 1949, when the technician of a major US pharmaceutical industry saw a

covered with white granules the idea of filling hard gelatine

capsules with neutral media in the form of granules, coated with active principles able to dissolve at different time intervals, thanks to a membrane coating of the granules

dissolution based on

This invention made it possible to quickly obtain the release of an initial dose of active ingredient (active uncovered

gradual release of small doses (thicker membrane granules) thus maintaining the

10 hours, with undoubted increased

hed on the American

acceptance , also had other important

the result of randomness of real research. In particular, a lower e active ingredients compared with

the total dose doses (active granules) and therefore

pecific point of the

However this formulation presented some drawbacks, the main one of which was the randomness of the releasedue to the unpredictable speed of disintegration of the membrane, since physiological variables which differ individual, and even in the same individual at different times, such as gastrofluids, the presence or absence of food.

Furthermore, a limited capacity of the capsules and swallowing difficulties, especially for geriatric and products.

CONTROLLED-RELEASE PRODUCTS BY

In the early 60s, the of release, still in the United States and in granules for hard gelatine capsules, was made possible by the availability of new polymers for the contained, instead of the coating.

In this case, an insoluble and permeable membraneused, which allowpores and the leakage of the active principle by phenomenon largely variables indicated above.

A much more reliable rbecame possible with this technologymentioned abovevirtually the only possible capacity and the swallowing difficulties.

his formulation presented some drawbacks, the of which was the randomness of the release

the unpredictable speed of disintegration of the membrane, since this depends on a number of physiological variables which differ from individual to

and even in the same individual at different times, such as gastro-intestinal motility, pH, amfluids, the presence or absence of food.

limited capacity of the capsules and swallowing difficulties, especially for geriatric and

RELEASE PRODUCTS BY DIFFUSION

In the early 60s, the discovery of a new and advanced form in the United States and in granules for hard

capsules, was made possible by the availability of new polymers for the diffusion of the active ingredients they contained, instead of the dissolution of the membrane

In this case, an insoluble and permeable membraneallows the entry of body fluids through its leakage of the active principle by diffusionlargely independent from the physiological

variables indicated above.

much more reliable release of the active ingredientbecame possible with this technology, but the drawbacks mentioned above remained: hard gelatine virtually the only possible dosage form, their

swallowing difficulties.

his formulation presented some drawbacks, the of which was the randomness of the release,

the unpredictable speed of disintegration of the mber of

from individual to and even in the same individual at different

intestinal motility, pH, amount of

limited capacity of the capsules and swallowing difficulties, especially for geriatric and paediatric

DIFFUSION

discovery of a new and advanced form in the United States and in granules for hard

capsules, was made possible by the availability of of the active ingredients they

of the membrane

In this case, an insoluble and permeable membrane is the entry of body fluids through its

diffusion, a independent from the physiological

elease of the active ingredient , but the drawbacks

capsules, their limited

OSMOTIC PUMP

The development of research in the field of release drugs for oral use, at the end of the 80ssubsequently led to the invention of drugs in the form of an osmotic pump, both for tablets and capsules: the first suitable for extended release formulations, the second for delayed or repeated release

In this case, the drug is mixed with an excipient (a soluble polymer) which constitutes the inner part of the system. The wall coating consists of an insoluble and semipermeable polymer membrane, in which made with a laser. The physiological fluids spread within the system through the membrane, forming a concentrated solution.The concentration difference between the inside and the outside of the system generates the leakage of the active ingredient from the hole.

The advantage of a more rational bioavailability of the active ingredient is accompanied by the usual limitation features of the previous systems

The development of research in the field of release drugs for oral use, at the end of the 80s

to the invention of drugs in the form of an osmotic pump, both for tablets and capsules: the first suitable for extended release formulations, the second for delayed or repeated release formulations.

In this case, the drug is mixed with an excipient (a polymer) which constitutes the inner part of the

system. The wall coating consists of an insoluble and semipermeable polymer membrane, in which a small hole is

The physiological fluids spread within the system through

membrane, forming a concentrated solution. The concentration difference between the inside and the outside of the system generates the leakage of the active

the hole.

he advantage of a more rational bioavailability of the active is accompanied by the usual limitation features of

the previous systems in this case also.

The development of research in the field of controlled-release drugs for oral use, at the end of the 80s

to the invention of drugs in the form of an osmotic pump, both for tablets and capsules: the first suitable for extended release formulations, the second for

In this case, the drug is mixed with an excipient (a water-polymer) which constitutes the inner part of the

system. The wall coating consists of an insoluble and a small hole is

The physiological fluids spread within the system through

The concentration difference between the inside and the outside of the system generates the leakage of the active

he advantage of a more rational bioavailability of the active is accompanied by the usual limitation features of

FINAL CONSIDERATIONS AND STATE OF THE ART TECHNOLOGY OF PRODUCTS.

Recalling the above and considering that the disadvantage due to the limited capacity of hard osmotic tablets is particularly relevant food supplements, normally in drugs, it is possible tmaintains all the positive aspects already seen showing the negative aspects of the forms indicated above.

This form exists and is the result of years of research and trials by I.P.S:

Multiform AdministratioIngredient

(Single systemcontrolled-release ingredients

FINAL CONSIDERATIONS AND STATE OF THE ART TECHNOLOGY OF CONTROLLED-RELEASE

Recalling the above and considering that the disadvantage due to the limited capacity of hard gelatine capsules and osmotic tablets is particularly relevant when administeringfood supplements, normally in higher doses than those of

it is possible to try to set up a dosage form that maintains all the positive aspects already seen

the negative aspects of the forms indicated above.

This form exists and is the result of years of research and

M.A.T.R.I.S.® Administration Timed ReleaseIngredients System

system for the administration of active release ingredients in different oral

FINAL CONSIDERATIONS AND STATE OF THE ART SE

Recalling the above and considering that the disadvantage capsules and

when administering doses than those of

try to set up a dosage form that maintains all the positive aspects already seen without

the negative aspects of the forms indicated above.

This form exists and is the result of years of research and

Release

for the administration of active oral forms)

Multiform Administration Timed ReleaseIngredients System

This technology is based onactive principle, sizeinsoluble and permeable membrane, without any use of inactive materials The characteristics of this technology, which the state of the art in the field of oral timeingredients, are the following 1. A homogeneous and maximum disperingredient over the whole area of the gastrointestinal tract, for a uniform absorption time. 2. Continuous release of the active calibrated over 8 irritation and of possible unwanted side effec 3. The possibility of gastro 4. The implementation of various forms of administration, such as: single dose single dose small tablets, as well as capsules and tablets in traditional form. 5. M.A.T.R.I.S. SmarTTabsdeveloped by IPS thanks to a unique technologyparticular interest.

M.A.T.R.I.S. Multiform Administration Timed Release

Ingredients System

is based on covering each particle of , sized between 200 and 800 µ

insoluble and permeable membrane, acting by diffusionwithout any use of inactive materials.

The characteristics of this technology, which represents e art in the field of oral time-release

ingredients, are the following:

omogeneous and maximum dispersion of the active the whole area of the gastrointestinal tract,

for a uniform absorption during the arranged period of

2. Continuous release of the active ingredient by diffusion, 8 - 10 hours, with a lower risk of local

possible unwanted side effects.

The possibility of gastro-resistant dosage forms.

mplementation of various forms of administration, single dose dispersible and orosoluble sachets,

single dose small bottles with dosing cap, highly soluble tablets, as well as capsules and tablets in traditional form.

SmarTTabs®: this type of MATRISdeveloped by IPS thanks to a unique technology,

.

Multiform Administration Timed Release

each particle of between 200 and 800 µ, with an

by diffusion,

represents released active

sion of the active the whole area of the gastrointestinal tract,

arranged period of

y diffusion, risk of local

forms.

mplementation of various forms of administration, soluble sachets, , highly soluble

tablets, as well as capsules and tablets in traditional form.

this type of MATRIS® tablet, , deserves

6. High dosage pertitle (> 80%) of the finished product in MATRISseveral grams per unit dose of the active ingredients including different ones (in single

7. Total maskingsubstances.

8. Elimination of swallowing problems.

9. Modern and attractive dosage foimproved adherence to the proposed treatment.

6. High dosage per single administration, through a high e (> 80%) of the finished product in MATRIS® form, up to

several grams per unit dose of the active ingredients different ones (in single-dose sachets).

masking of the unpleasant taste of some

8. Elimination of swallowing problems.

9. Modern and attractive dosage form, easy to use, for adherence to the proposed treatment.

single administration, through a high form, up to

several grams per unit dose of the active ingredients dose sachets).

of the unpleasant taste of some

to use, for

The preferred and mosttechnology is that ofdispersible, of which numerous MATRISare available on the market. As an example, thioctic acid (or alphafor the production, amongdose MATRIS® form sachets up to either as taste masked The MATRIS® form of this supplement has a titre of 800 mg/g, is perfectly tasteless and, in the retard form, gradually releases the active principle up to eight/ten hours after ingestion. The duration of the releaon the basis of the ratio between the immediate release product and the time

The preferred and most modern form made possible btechnology is that of single-dose sachets, orodispersible, of which numerous MATRIS® preparation forms

on the market.

As an example, thioctic acid (or alpha-lipoic acid) suitable for the production, amongst other dosage forms, of single

form sachets up to 800 mg. per unit dose, taste masked (fast) or as time-release (retard).

form of this supplement has a titre of 800 mg/g, is perfectly tasteless and, in the retard form, gradually releases the active principle up to eight/ten hours

The duration of the release, in its final form, can be varied on the basis of the ratio between the immediate release

the time release one.

modern form made possible by this orosoluble or

preparation forms

lipoic acid) suitable other dosage forms, of single-

800 mg. per unit dose, release (retard).

form of this supplement has a titre of 800 mg/g, is perfectly tasteless and, in the retard form, gradually releases the active principle up to eight/ten hours

se, in its final form, can be varied on the basis of the ratio between the immediate release