Link:  Pharm/Biotech Resources

Title:  Chitosan-xanthan based polyionic hydrogels for stabilization and controlled release of vitamins

United States Patent:  6,964,772

Issued:  November 15, 2005

Inventors:  Chornet; Esteban (Sherbrooke, CA); Dumitriu; Severian (Sherbrooke, CA)

Assignee:  Kemestrie Inc. (Sherbrooke, CA)

Appl. No.:  301670

Filed:  April 28, 1999

A thermo- and photo stable composition comprising a chitosan/xanthan hydrogel including at least one thermo- or photo-sensitive substance chosen among the following: vitamins, amino-acids, nucleic acids, and polypeptides. The hydrogel can be adapted to release the thermo- or photo-sensible substances in either a human or an animal. The present invention also discloses a method of making these hydrogel composition. Additionally, the present invention presents a method of using these hydrogel composition in dermatology or as a food supplement.

FIELD OF THE INVENTION

The present invention relates to chitosan/xanthan based hydrogels. More specifically, the present invention deals with chitosan/xanthan based hydrogels used in dermatology and as food additives, where such hydrogels are used as carrier for active compounds such as vitamins, amino-acids, nucleic acids, polypeptides, etc.

BACKGROUND OF THE INVENTION

The production of chitosan/xanthan hydrogels is known. U.S. Pat. Nos. 5,620,706 and 5,648,252 describe such hydrogels as inert supports for enzyme immobilisation or for the controlled release of specific antibiotics or anticancer agents. However, the application of such hydrogels as supports, stabilisation and subsequent controlled release of vitamins, amino-acids, nucleic acids and polypeptides has not been proposed yet.

One of the key aspects in the preparation of food additives and dermatological preparations is the preservation of active ingredients prone to degradation, such as vitamins, amino-acids, nucleic acids and polypeptides. Exposure of such ingredients to heat or light accelerates their degradation.

Given the importance of the active ingredients mentioned above, several excipients, such as tablets, capsules, gellules, gels, lotions, ointments, emulsions and simple solutions, have been developed with a view to protect the active ingredients against degradation or simply to render them hydrophobic. However, several drawbacks of these synthetic devices have been identified. In particular their irritation potential and toxicity were put forward.

Due to the inherent limitations of conventional excipients, the use of synthetic polycations was recently proposed. As an example, European patent application # 504 066 A1, 1992, to L'Oréal (France) proposes cosmetic compositions comprising a dispersion of active solid particles coated with a cationic polymer. The aim of the polymeric coating being to increase the stability of the overall composition in addition to preventing degradation of the active ingredient.

Yet an important objective remains unfulfilled. Indeed, there remains an important need to develop new excipients capable of being used in food and dermatological preparations to stabilise thermo- or photo sensitive active ingredients, such as vitamins, nucleic acids, amino-acids and polypeptides.

OBJECTS OF THE INVENTION

An object of the present invention is therefore to provide a hydrogel preparation for use as a delivery device for food or dermatological preparations with a concurrent objects of providing stabilization of thermo- and photo sensitive active ingredients and avoiding any irritation or toxicity potentials. A further object of the present invention is to disclose a method of dispersion of the active ingredient within the hydrogel matrix.

SUMMARY OF THE INVENTION

Generally, in accordance with the present invention, there is provided a preparation which stabilises thermo- and photo sensitive bioactive molecules. The preparation comprises a hydrogel made of a complex of chitosan and xanthan. Within the hydrogel there is lodged at least one thermo- or photo sensitive substance chosen among the following: vitamins, amino-acids, nucleic acids and polypeptides. The hydrogel configuration and structure is prepared so as to release, in a controlled way, the thermo- or photo sensitive ingredients either in a human or animal subjects.

The present invention also discloses a method of making these hydrogels. The present invention also teaches the use of these hydrogels in dermatology or as a food additive vehicle.

Other objects, advantages and features of the present invention will become more apparent upon reading of the following non restrictive description of preferred embodiments thereof, given by way of example only with reference to the accompanying drawings.

Those specialised in the area covered by this invention will certainly be able to apply modifications or adaptations to the details described in the preferred embodiment while being constrained within the framework of the current invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The detailed description reveals compositions for food and dermatological applications comprising one or several active ingredients that are either prone to thermo- or photo degradation. These compositions are based on a polyionic hydrogels obtained by a chitosan/ xanthan complexing which incorporates therein the active ingredients thereby protecting them from thermo- or photo induced degradation while controlling their release thus enhancing their activity and the duration of this activity.

Also described are two methods of incorporation of the active ingredients in the hydrogel depending on the nature of the active ingredients. In a first method, liposoluble active ingredients are introduced in the hydrogel during the making of the hydrogel. In a second method, hydrosoluble active ingredients are introduced by diffusion in the already made hydrogel. Both methods can be used in sequence.

The present invention thus reveals a novel and surprising way of introducing various vitamins and other ingredients such as amino-acids, nucleic acids and polypeptides in hydrogels and of controlling the release of those ingredients in various drug delivery vehicles such as: capsules or gelcaps for oral ingestion, rectal suppositories, creams and ointments, gels, solutions and cutaneous patches.

The present invention further reveals a method of introducing in the same hydrogel liposoluble and hydrosoluble active ingredients.

Finally, the present invention further discloses methods of making food additives and dermatological creams incorporating the hydrogel.

It is to be noted that the terms "dermatologic" and "dermatological" are used in their widest sense thus covering both the dermatological and cosmetic applications. Furthermore, these terms are meant to cover direct skin treatments or treatment through nails or hair.

The term "food additive" is also to be understood in its widest sense including thus all food preparations where the additive has a nutritional or therapeutic function as well as simple mechanical functions such as that of a texturizing agent, filler or viscosity control agent.

The preparations covered by the present invention focus mainly on humans although they may be used in the veterinary field.

On FIG. 1 (see Original Patent), it is shown how the hydrogel of the present invention is an ionic complex between chitosan, a cationic natural polymer, and xanthan, an anionic natural polymer. A method of making of the hydrogel has been described in U.S. Pat. No. 5,720,206 granted to the same assignee as in the present application and is incorporated herein by reference. As shown in FIG. 1, xanthan and chitosan form a complex, i.e. a network of ionic linkages between these two polymer molecules. The complex is a highly hydrophilic hydrogel.

(a) Inclusion of liposoluble vitamins in the chitosan-xanthan hydrogel

Vitamin A, also called Retinol, is a molecule extremely sensitive to light and oxygen. As a consequence, this vitamin may not be used in a cream unless it is being stabilised to counteract the negative effects of light and oxygen (from ambient air). The method of the present invention consists in stabilising Vitamin A in a hydrogel made of xanthan and chitosan complex. The xanthan and chitosan complex being described in U.S. Pat. No. 5,620,706.

EXAMPLE 1

Inclusion of Vitamin A when making the hydrogel

A solution (100 ml) of Vitamin A (10-20 w/v %) in ethanol is first prepared. This solution is added, under intense agitation, to 500 ml of a xanthan solution, 0.65 w/v %. The final solution has a Vitamin A concentration between 1.66 and 3.33 w/v %. The solution is kept at 3° C. It is subsequently sprayed, via a nozzle, into 800 ml of a 0.65 w/v % chitosan solution. The complexation reaction is conducted during 30 minutes. The gel formed is then filtered and rinsed with water to a pH of 6.8. In order to increase the hydrogel stability, a final washing with a sodium bicarbonate solution, 1 w/v %, brings the gel to a pH of 7.5. The gel is then frozen and freeze-dried. All these operations, including the freeze drying, are best conducted in the absence of light and oxygen.

EXAMPLE 2

Inclusion of Vitamin A by diffusion

Using a previously prepared xanthan-chitosan hydrogel with a swelling index (α) of at least 2000%, it is possible to introduce the Vitamin A by diffusion. The swelling index (α) is defined as follows:

Under these conditions, the time for the experiment is decreased thereby preventing the molecule's degradation. The method involves dissolving 0.07 g of Vitamin A in 1 ml of ethanol (96%) and adding 1.5 g of the freeze dried xanthan-chitosan complex having α=2500%. Slight agitation allows the obtention of a homogeneous paste. 2 ml of ethanol, and 200 μl of water are then added under slight agitation and the mixture is kept at 4° C. for 24 hours in absence of light. The alcohol is then evaporated, at 4° C. The final product can be freeze dried and has 46 mg of Vitamin A per g of freeze dried xanthan-chitosan complex.

EXAMPLE 3

Inclusion of Vitamin E

The method (a) developed for Vitamin A is also applied for the inclusion of Vitamin E. The concentration of Vitamin E in the freeze dried hydrogel can reach 20 wt %.

EXAMPLE 4

Inclusion of Vitamin K

The method (a) developed for Vitamin A is also applied for the inclusion of Vitamin K. The concentration of Vitamin K in the freeze dried hydrogel can reach 20 wt %.

(b) Inclusion of hydrosoluble vitamins in the chitosan-xanthan hydrogel

For bioactive hydrosoluble ingredients, it is preferable to use the diffusion method in the freeze dried hydrogel to avoid loss of ingredients that would otherwise occur during the reaction between xanthan and chitosan. In this method, the xanthan-chitosan hydrogel must have a swelling index of at least 2000%.

EXAMPLE 5

Inclusion of Vitamin C

Given the redox character of Vitamin C with regards to chitosan, a new method of inclusion has been developed. This method involves 2 steps:

Step 1: Preparation of the xanthan-chitosan complex (CHITOXAN™), i.e. the polyonic hydrogel;

Step 2: Incorporation of Vitamin C.

Step 1- Preparation of the xanthan-chitosan complex

Step 1 follows the method described in U.S. Pat. No. 5,620,706. Chitosan used has typically a molecular weight comprised between 250,000 and 350,000 and the hydrogel produced a swelling index of α>2000%. The CHITOXAN™ thus produced is milled to obtain a fine powder of particles comprised between 250 and 500 μm.

Step 2 - Incorporation of Vitamin C

This step can be carried out via two different approaches:

The previous method (2a) is used replacing the three amino-acids with a tripeptide having sulfur-containing functionalities. To 10 ml of water, g of Vitamin C and 0.002 g of glutathione are added. After 5 minutes of agitation, 1 g of CHITOXAN™ is added. The mixture is kept in slight agitation until a homogeneous paste is obtained. The mixture is left to stand for 2 hours to reach the equilibrium hydration. The paste is then frozen and freeze-dried. All operations preferably require absence of light.

Claim 1 of 9 Claims

1. A dermatological cream comprising a controlled release composition comprising up to 25 wt % of a thermal or photosensitive active ingredient selected from vitamins, amino acids, nucleic acids, peptides and mixtures thereof, and comprising a chitosan-xanthan hydrogel, and comprising a stabilizing agent having a protective thermal and photo effect on said thermal or photosensitive ingredient, said hydrogel comprising 24-40% wt chitosan and 60-76% wt xanthan.

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