FR2761890A1 - New gel-type patch based on prolamine(s) is carrier of active agents - Google Patents

Abstract

Carrier formulated as biodegradable patch comprises a gliadin gel based on plant prolamines extracted from cereals, particularly wheat, the patch allowing optimisation of the adhesive and viscoelastic properties of the gel and its properties being modulated by variation of the physico-chemical parameters of extraction.

Description

 The present invention relates to the generation of a new type of biodegradable vector in the form of a transdermal or transmucosal system - hereinafter called gelpatch - based on prolamins of plant origin allowing the optimization of the bioavailability of the active ingredients contained in the formulations incorporating it, and the discovery of a topical system because of its adhesive and visco-elastic properties. I) e such systems would find their utility in the medical field as "vectors" of drugs for transdermal or transmucosal administration, as a mode of topical application of active principle or as a dressing.

The applicant has set itself the goal of developing a new biodegradable support in order to allow:
1) an increase in the adhesiveness of the associated formulations in these patches; the production of this patch, natural and of plant origin, will allow its use in the medical field, more particularly in dermatology, stomatology and gynecology;
2) an improvement in the delivery and / or bioavailability of active substances of the various active principles which may be associated with it (chemical substance, biological substance, active principle,
3) to play a mechanical protective role vis-à-vis external aggressions both in the skin and in the mucous membranes (mainly the oral mucosa).

Prolamines are reserve proteins found in cereals. These prolamins are accumulated in the starchy albumen of cereal grains such as wheat, barley, rye, oats, corn, rice .... These prolamins represent a real nitrogen storage, which will be used during germination. These proteins are very rich in proline and glutamine. They are classified into two main groups:
- monomeric gliadins
- polymeric glutenins
Gliadins include different forms of protein:
- low-sulfur gliadins or gliadins a, b and g which have molecular weights between 30 and 40 kD
- the gliadins w of higher molecular mass between 60 and 80 kD.

 A patch formed from at least one prolamine or a mixture of prolamines (gliadins and glutenins) in defined proportions, will have viscoelastic properties as well as adhesive properties which may possibly be reinforced by the addition of other adhesive agents. n could also be associated with a certain percentage of polar lipids. By acting on the homogeneous nature and the clarity of gelpatch, different applications can be envisaged with in particular the possibility of incorporating molecules of different chemical nature. gelpatch is a hydrophobic gel or film, a particularly interesting property in the mucosa.

Extraction:
Prolamins can be extracted from different cereal sources. By way of example (not limiting), we will describe here the extraction of wheat prolamins.

Example of extraction from wheat:
Gliadins are extracted from 1 kg of ground wheat. The ground material is dispersed with vigorous stirring in 5 ethanol liues whose titer is between 70 and 800, 2 hours, at a temperature between 35 and 400C. The solid and liquid phases are then separated by filtration. This filtrate contains gliadin at a concentration of around 6%.

 The filtrate is concentrated by evaporation of the ethanol under vacuum at low temperature. An aqueous solution is then obtained in which the gliadin precipitates. This gliadin can be dehydrated to obtain a dry powder.

Example of extraction from fresh gluten:
1 kg of fresh gluten is dispersed in the quantity of absolute ethanol necessary to obtain a degree of alcohol of between 70 and 80 (depending on the hydration level of fresh gluten). After stirring for 2 hours at a temperature between 35 and 400C, treatments identical to those described above are carried out.

 It should be noted that the origin of the raw materials used as well as the degree of alcohol used and the extraction temperature will largely influence the texture of the patch as well as its appearance (clarity, color). It is therefore possible to adapt the extractions according to the nature of the desired patch. By varying the physicochemical parameters (temperature, source of extraction, alcoholic degree), it is possible to extract different proportions of gliadins and glutenins and to keep a certain percentage of lipids (essentially polar lipids) which will make it possible to achieve patches of different quality and whose adhesive power may vary. Viscosity is attributed to gliadins while elasticity is attributed rather to glutenins.

Preparation of a prolamine-based patch (gelpatch):
A prolamine-based patch includes:
1) at least one prolamine of plant origin (18 to 36% of prolamins in powder)
2) at least one plasticizer chosen from carbohydrates, preferably glycerol or sorbitol
3) 46 to 73% of a 50/50 water / alcohol mixture (alcohol: preferably ethanol)
4) possibly other adhesive agents (such as carhoxymethylcellulose)
In order to make the most of the manufacturing properties of the patches with prolamins, these prolamins must be dissolved in the water / ethanol mixture at 400C with stirring, preferably mechanical until the mixture is completely homogenized. Due to the viscosity of the mixture obtained, it is preferable to use teflon or polypropylene containers. Then the plasticizers at a concentration of 5 to 18% are added to the preparation in order to obtain a flexible and resistant finished product. The plasticizers are added in the following proportions: 30% glycerol and 70% sorbitol. This last step is also carried out at 400C with stirring until the mixture is homogenized. The viscosity, color and clarity of the mixture obtained can be varied.

 The possible incorporation of an active principle is carried out at the end of the preparation of the prolamine gel, as well as the possible incorporation of another adhesive agent of the carboxymethylcellulose type.

 The realization of a gelpatch is obtained by spreading and drying for 20 hours, preferably in the open air, or a shorter time thanks to a suitable drying system (gas stream, heat, radiation such as infrared, micro -onde ...), preferably on teflon or polypropylene plates. It is necessary to optimize this spreading in order to obtain a uniform and controlled thickness of the patch. For patches for stomatological purposes, the natural taste of gliadin can be masked by different aromas (such as strawberry, lemon, caramel, essence of mint).

 In addition to the foregoing arrangements, the invention also comprises other arrangements, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention. It should be understood that these examples are given by way of illustration of the subject of the invention and do not in any way constitute a limitation.

Example of resistance to dissolution of a gelpatch in a moist environment such as the oral mucosa:
The adhesiveness of this patch was carried out in an ex vivo survival maintenance system of human oral mucosa.

Preparation of the oral mucous membranes
Fragments of the oral mucosa are deposited in an insert itself positioned on a culture well. A prolamine-containing patch is deposited on the epithelium (after a precise weighing of it) and is covered with artificial saliva. The whole is maintained in organ culture at 37 ° C. during the time of the adhesion experiment, the culture medium (antibiotics, SVF) being deposited in the bottom of the wells.

 The patch is removed over time and weighed (5, 15, 30 minutes, 1, 2 and 3 hours).

Results:
50% of the prolamine-based patch is still dosable after 1 hour of application to the surface of the oral mucosa.

Example of release of a hormone (4-pregnene-3,20 dione) from a gelpatch:
The aim is to analyze the release kinetics of an active ingredient, progesterone (0.7%), contained in a prolamine patch as a function of time (0, 10, 20, 30 minutes, 1, 2, 3 , 4 hours).

 The patches are placed in a physiological saline solution with constant stirring at 370C. Physiological saline samples are taken regularly and the absorbances are measured using a UV spectrophotometer at a wavelength of 240 nm.

Results:
11OJo of progesterone are released after 2 hours.

APPLICATIONS:
We are seeking to develop the use of prolamins of plant origin for medical applications, mainly odonto-stomatological and dermatological.

I. Applications in odonto-stomatology
The gelpatch could solve the difficulties encountered with the application of topicals to the level of the oral mucosa: difficulty of adhesion, dilution of active principles by saliva, mechanical movements which prevent the maintenance of the active principle at the level of the oral mucosa.

1) Traling of tartaric gingivitis and periodontopathies
During tartaric gingivitis, the release of free radicals by the inflammatory elements is responsible for major damage to the gingival tissue, which can go as far as loss of the attached gum and the formation of periodontal pockets. Topical application of a gelpatch with the incorporation of a free radical scavenger or SOD (superoxide dismutase) preferably of plant origin makes it possible to prevent gingivitis. The incorporation of an antiseptic (such as chlorhexidine) or a non-steroidal anti-inflammatory into gelpatch also makes it possible to act as a curative or a preventive on gingivitis.

2! Oral mucosal surgery
The use of prolamine would allow the progressive release of the analgesic thus allowing a better treatment of the pain. The development of a prolamine-based patch in which a viscous xylocaine-type contact anesthetic is incorporated can play an analgesic role immediately after surgery.

3) Healing agent
In the treatment of mouth ulcers, traumatic ulcers, erosive stomatitis and post-operatively, the production of a patch based on prolamines for healing purposes incorporating vitamins, amino acids or growth factors has demonstrated an interest that "classic" forms do not allow to obtain.

4) Treatment of white lesions of the oral cavity (smoking leukoplakias. Lichen planus!
As part of the treatment of precancerous lesions and the prevention of cancer of the oral cavity, a patch has been developed based on prolamins incorporating:
- either an anti-radical or a superoxide dismutase preferably of plant origin possibly combined with a keratolytic agent (salicylic acid type);
- either retinoic acid (acid form or aldehyde form);
- either combination with vitamins (such as vitamin E, B carotene).

5) Dermatological disorders of the oral mucosa
A product combining a gelpatch and a steroidal anti-inflammatory drug (class I to IV) has been envisaged for the treatment of bullous stomatitis such as erosive lichen, bullous pemphigoid, pemphigus.

6) infections
For the treatment of various infections, the preparation of a product associating a gelpatch with an antifungal, antiviral or antibacterial agent has been considered.

7) Oral dental support
A candy based on a progressive disintegrating gelpatch allows its application in the prevention of dental plaque after incorporation of fluorine. We can add a synthetic sugar or polyol. A patchgel can also intervene in the protection of aromas (chewing gum) and serve as a support for the composition of toothpastes.

8) Prevention of radiodermltes and radlomucltes
Realization of a gelpatch in which a superoxide dismutase or anti-radical substances is incorporated: this patch is applied in contact with the oral mucosa or on the skin side before radiotherapy in order to avoid radiodermatitis.

II. Applications in dermatology and gvnecology (vulvar mucosa)
The production of a gliadin-based gel incorporating an active principle has been envisaged in order to increase its duration of application and therefore its effectiveness and its adaptability to its function.

As an example, we can cite:
- steroidal anti-inflammatory
- healing agent
- analgesic
- antiviral agent
- antiseptic
- keratolytic agent
- immunomodulator
- anti-acne
III. Applications in the medical field
A gelpatch can be used as a drug vector for transdermal administration. Mention may be made, in a non-exhaustive manner, of its use as a support for hormone replacement therapy for menopause.

IV. Dressings
lt has been considered the interest of a gelpatch as a dressing at the level of the skin or at the level of the oral mucosa (canker sore).

V. Cosmetological applications
The realization of gelpatchs incorporating products has been envisaged. They advantageously have a higher efficiency than conventional products, especially for applications:
- for moisturizing purposes
- anti-aging (combining free radical scavengers and active oxygen species, preferably vegetable SOD, vitamins, trace elements, minerals ...)
- with anti-redness aim
- for slimming purposes
- etc

Claims (8)

CLAIMS:  1) Vector presented in biodegradable patch comprising a gliadin gel based on vegetable prolamins extracted from cereals, in particular wheat, the so-called gliadin patch allowing the optimization of the adhesive and viscoelastic properties of the gels incorporating it, its properties being modular by varying the physico-chemical parameters of its extraction.  2) Vector according to claim l, characterized in that the gliadin patch contains a prolamine or a mixture of prolamins (gliadins and glutenins).  3) Vector according to one of claims 1 or 2 containing in addition to vitamins, SOD preferably of plant origin, antioxidants, trace elements, growth factors, skin care products and skin appendages, substances pharmacologically active such as anti-inflammatory, antimicrobial (antifungal, antiviral, antiparasitic or antibacterial ...), anesthetics, analgesics, sedatives, immunomodulators, immunosuppressants, antihistamines, antiallergics, antispasmodics, cytolytics and cytostats, vasoregulators, venotonics, venotonics, venotonics, antiseborrhoeic, antipririgneux, kératolyques, pigmentation modifiers, photosensitivity modifiers, cicatrizers.  4) Use of a vector according to claim 3 for the manufacture of a cosmetic or pharmaceutical composition.  5) Use of a vector according to claim 3 for the manufacture of a pharmaceutical composition, more particularly of a transdermal system (systemic route).  6) Use of a vector according to claim 3 for the manufacture of a cosmetic or pharmaceutical composition, more particularly of occlusive dressing.  7) Use of a vector according to claim 3 for the manufacture of a pharmaceutical composition,  Used in odontostomatology:  - for the treatment of tartar gingivitis and periodontopathies,  - for surgery of the oral mucosa,  - as a healing agent,  - for the treatment of white lesions of the oral cavity,  - for dermatological affections of the oral mucosa,  - for infections,  - as a support for oral hygiene,  - for the prevention of radiodermatitis and radiomucitis,  Or used in dermatology and gynecology:  - as an anti-inflammatory,  - as a healing agent,  - as analgesics,  - as an antiviral agent,  - as an antiseptic,  as a keratolytic agent,  - as an immunomodulator.  8) Use of a vector according to claim 3 for the manufacture of a cosmetic composition:  - for moisturizing purposes,  - for anti-aging purposes,  - with anti-redness aim,  - for slimming purposes.