US20080274191A1

US20080274191A1 - Bioadhesive Composition With Programmed Release

Info

Publication number: US20080274191A1
Application number: US11/577,503
Authority: US
Inventors: Laurence Paris
Original assignee: Interpharm Development SA
Current assignee: Interpharm Development SA
Priority date: 2004-10-20
Filing date: 2005-10-19
Publication date: 2008-11-06
Also published as: JP5979466B2; CN101084017B; CN101084017A; DE602005008760D1; FR2876581B1; FR2876581A1; US10646435B2; WO2006043005A2; AU2005297009A1; PL1807114T3; JP2008517043A; EP1807114A2; ATE403441T1; PT1807114E; EP1807114B1; ES2314738T3; WO2006043005A3; US20160235715A1

Abstract

The invention relates to novel viscous liquid compositions for producing pasty forms having a prolonged action and/or release for local applications. These compositions are characterized in that the long-lasting action and/or the prolonged release of the active substance is obtained by the in-situ formation of a matrix film having an increased bioadhesive power and being more or less viscous and biodegradable. The invention also relates to a viscous liquid composition with an increased bioadhesive power for a local application in pasty form with a prolonged release of an active substance, whereby being characterized in that it contains at least one matrix agent, a medium for hydrating the matrix agent, and at least one active substance.

Description

The present invention relates to the pharmaceutical, cosmetic and nutraceutical field and more particularly to that of bio-adhesive systems with programmed release of active ingredients in the human body.
The human body is constituted by a certain number of cavities accessible from the exterior and covered with mucous membranes. These mucous membranes are the site of a certain number of diseases or local infections. This is the case of:

- the oral mucous membrane, which extends from the mouth to the esophagus by passing via the throat;
- the nasal mucous membrane, which extends from the nose to the rear throat
- the rectal mucous membrane covering the distal part of the large intestine
- the vaginal mucous membrane
- the ocular mucous membrane called the cornea.

These mucous membranes have the characteristic of being permanently moistened by liquids specific to the mucous membrane in question.
These secretions have two major roles concerning the mucous membrane:

- a role of protection for the latter vis-à-vis external stresses
- a role as lubricant.

It is thus in the case of lachrymal liquid, saliva, and vaginal secretions.
The accessibility of these mucous membranes via the exterior allows therefore a treatment known as local if necessary.
In fact, a certain number of products exist to treat local infections such as:

- suckable tablets for the treatments of mouth ulcers, stomatitis, gingivitis, glossitis, etc. . . .
- gels and creams for oral, vaginal, and rectal (hemorrhoids), and ocular treatments,
- liquids for the nasal route (nasal solutes) and for the ocular route (eye lotions).

However these products have a very short action duration from a therapeutic standpoint because of a perpetual “washing” of these mucous membranes by the secretions thus eliminating the active ingredient deposited in situ.
This thus requires repeated local administrations that in certain cases are not very agreeable for the patient. By way of example, we can cite the repeated administrations of eye lotion.
Furthermore, to ensure the remission of the infection, the local treatment is generally coupled with a systemic treatment.
By “systemic treatment” we mean the supply via the blood of an active ingredient to the inside of the entire organism. This supply can be carried out by direct administration in blood circulation (intravenous administration) or by oral administration.
As an example of a local treatment coupled with a systemic treatment, we can cite the case to acyclovir, active ingredient used in the treatment of herpes.
Herpes is caused by a virus that develops at the oral, vaginal and ocular area.
This affection is treated locally by creams. According to the seriousness of the affection, the local treatment is coupled with a systemic treatment. It is also thus for an ocular herpes. Local treatment requires 5 applications per day in the conjunctival cul-de-sac of the eye. The pulse therapy in the case of vaginal herpes is identical. In several cases of the two impairments, an oral administration (systemic administration) is coupled with the local treatment.
Thus it appears necessary, for the comfort of the patient, to have systems that make it possible to maintain a local action duration more substantial than simple creams, in order to reduce the number of applications per day.
Broadly speaking, any system that makes it possible to prolong the action of the active ingredient in the organism is called “form with prolonged or programmed release”.
To date such systems have been for the most part developed for the oral route. They are generally tablets or gelatin capsules containing microgranules. These forms with prolonged release or known as programmed are numerous and belong to different categories according to the excipients used to slow down the release of the active ingredients. They are:

- matrix forms. They are generally tablets from which the active ingredient is released, either
  - by erosion of the support, or
  - by diffusion through the network formed by the ingredients of the tablet
- coated forms. They are conventional tablets or microgranules, having undergone a coating with the aid of substances having certain properties enabling a slow liberation through the formed membrane.

Numerous patents have been awarded in this field and are related to the active ingredients used in this form.
Apart from the oral route few systems having prolonged release have been developed.
For the intravenous route, this type of system does not exist.
In the case of the intramuscular route, the prolongation of the action is obtained by injection of a suspension of particles intended to be solubilized gradually in the organism. The best-known example is that of insulin: intramuscular injection of particles of insulin for a 24 hours action minimum.
A second example is that of the administration of implants in the case of hormone therapy: deposit of small hormone (progestins) tablets under the skin that are intended to dissolve slowly.
Concerning the cutaneous route, a system with prolonged release has been developed for a systemic administration of active ingredients: they are the transdermal systems known as “patch”.
The best-known example is the nicotine patch for the weaning of smokers.
From the local standpoint, very few things exist.
The route that has received great attention in this field is the ocular route.
A certain number of products have been developed such as:

- soluble gels that slow down the release of the active ingredient because of their elevated viscosity. The viscosity prolongs the contact time of the active ingredient in the cornea and presence time in the conjunctival cul-de-sac. This intensification of the action is due to the slowing down of the elimination process in the lachrymal channel, due to the viscosity of the product.

These gels are generally based on water-soluble polymeric molecules such as polyvinyl alcohol, cellulose derivatives, and acrylic derivatives.
By way of example can be cited the works of:

- WANG and HAMMARLUNG (1) on gels of polyvinyl alcohol and of hydroxypropylmethyl cellulose containing homatropine hypobromite having a myotic effect
- HAAS and Coll. (2) on methylcellulose gels containing pilocarpine
- GOLBERG and Coll. (3) as well as those of MANDELL and Coll. (4) and MARCH and Coll. (5) on high viscosity acrylic gels containing pilocarpine hydrochlorate
- SCHOENWALD and Coll. (6) on Carbopol® gels containing prednisolone acetate

Other polymers can be used with the aim of delaying the release of the active ingredient such as alginic acid (Carteol® LP), and gellane gums (Timoptol®).
In certain cases, a certain bio-adhesion of the materials used would have been displayed, in the cornea. It could be the case of Carbopol® (HO-WAH HUI and Coll. [7]). But the bio-adhesion mechanism could not be perfectly established.

- emulsions or pseudo-latex. They are emulsions containing microballs based on cellulose acetophtalate or others such as polymetacrylic derivatives, on which the active ingredient is fixed. These suspended particles deposit themselves in the conjunctival cul-de-sac and gradually liberate the active ingredient.
- Inserts such as:
- pre-cast hydrophilic matrices or hydrophilic lenses, which are considered as reservoirs because they are capable of being hydrated to nearly 85%. However the re-release of active ingredient contained in this reservoir is rapid
- erodable soluble implants impregnated with active ingredients (oval plates or pellets). Placed in the conjunctival cul-de-sac, they saturate quickly with lachrymal liquid. The liberation of the active ingredient is done by progressive dissolution of the support. A concrete example of this system is the hydroxypropylcellulose-based product Lacrisert®.

In the present case, the emulsions or pseudo-latexes as well as the inserts, are not defined as bio-adhesive systems with prolonged release. Their prolonged activity comes from the fact they are maintained in place in the eye in the conjunctival cul-de-sac, which plays in this case the role of storing active ingredients. In this situation, no physical or chemical combination is used with one of the biological components of the eye.
Concerning the nasal mucous membrane few things have been explored because of the secondary effects that can be brought about by the application of substances which, generally in the case of the forms with prolonged action, are products:

- insoluble in aqueous medium such as celluloses;
- presenting viscosities non compatible with those of the organism.

Thus, a risk of passage of these substances in the respiratory tracts, having a potential for leading to an obstruction of the bronchi and bronchioles, is to be feared.
However studies have been conducted with Carbopol® (NAGAI and Coll. [8] and CHU and Coll. [9])). The bioavailability of the active ingredients would be augmented when administrated in the state:

- of powders: active ingredient/Carbopol® mixture
- and of hydrogels.

The American patent U.S. Pat. No. 4,226,848 refers to use of cellulose derivatives and acrylic polymers for a bio-adhesive nasal application.
Contrary to the ocular route or to the nasal route where in most cases the bio-adhesive preparations are introduced in the form of gel or creams. The forms known as bio-adhesives for the oral route could be mostly introduced in the form of tablets or patches. The ingredients known as bio-adhesives tested within this application framework are:

- Carbopol®
- hydroxypropylmethylcellulose
- chitosan
- and gum of acacia.

Some pasty forms exist, of which the principal bio-adhesive excipients used are:

- cellulose derivatives, carboxymethylcellulose among others
- very high purity glycerides that have the property of gelifying in contact with saliva
- and Carbopol®

However even if the tablets and the patches ensure a prolonged release of the active ingredient in the oral cavity, the maintenance during 8 hours of such a form in the mouth is not conceivable for a patient. Furthermore, the pasty forms do not resist the “washing” action of the mucous membrane by the saliva and thus are not maintained in situ on an 8 hours period.
In the case of the vaginal route the useable forms are identical to those of the oral route:

- tablets
- pasty forms

As previously the tablets can very well offer a prolonged release in situ.
However the administration of such a form is not practical for the patient and a rejection may occur after a certain time.
In the case of the pasty forms we find the same bio-adhesive excipients as for the oral or ocular route. However, as for the oral route, the vaginal secretions do not allow the maintenance in place of such preparations for a long action duration.
Apart from suppositories, the forms applied locally in the rectal area are generally creams or gels for the treatment of hemorrhoids. This route can also be used with the aim of a systemic action of the active ingredients which, administered by oral route, are quickly degraded hepatically. The rectal route avoids this problem.
To date very few forms with prolonged release have been developed for this route. Work has been realized by HOSNY and coll. (10) using, as bio-adhesive agent, Carbopol® for the rectal administration of indomethacine.
Thus, after a thorough study of the literature in the field of the forms with prolonged release, it has been unable to be demonstrated an effective solution for obtaining a form with prolonged release of long duration, greater than 2 hours, because of the phenomenon of washing of the mucous membranes by the local secretions.
Given this situation and to remedy it, the invention offers an original concept of viscous liquid compositions intended for the realization of pasty forms having prolonged action and/or release for local applications. These compositions are characterized in that long lasting and/or prolonged action and/or release of the active ingredient is obtained by the in situ formation of a matrix film having reinforced bio-adhesive capacity, more or less viscous and biodegradable. The aforementioned reinforced bio-adhesive character is obtained by a complexation reaction of the matrix agent with one of the components of the local secretions or of the mucous membrane, leading, under the effect of a permanent washing of the mucous membranes by the secretions, to an action and/or release, on a period greater than 2 hours, of the active ingredient previously dissolved or dispersed with the aid of a solvent, this action and/or release being changeable by incorporation of appropriate additives.
Thus, the purpose of the present invention is to realize in situ, after application of the preparation, a matrix film having reinforced and biodegradable bio-adhesive capacity, of which the action and/or release of the active ingredient is, as far as possible, independent of the pH and/or independent of the action of the secretions of the mucous membranes, depending on the excipients used to reinforce the solidity of the aforesaid bio-adhesive matrix film.
The reinforced bio-adhesion is such that it is quasi-instantaneous from the moment of application on the mucous membranes.
By “bio-adhesion” we mean the capacity that a biological or synthetic substance has to “stick” to a biological or mucous membrane.
By “reinforced” we mean the creation of supplemental bonds with the support represented by the mucous membrane, other than those observed with the conventional bio-adhesive excipients.
By “matrix film” we mean the formation of a three-dimensional network, more or less solid, more or less thick, and more or less porous, in which is included the active substance.
By “biodegradable” we mean the degradation of a support generated by a biological mechanism such as the action of enzymes but also by a mechanical erosion mechanism due to the “washing” secretions of the organism.
By “washing” we mean a repeated passage of a solution on the same support until total exhaustion of the latter.
This invention is applicable to the preparations intended for the oral mucous membrane, as well as the nasal, vaginal and rectal mucous membranes; and the cornea.
This invention is based on the fact that certain substances in the solid state or the liquid state have the property to complex with certain molecules of the mucous membranes when they are applied to the latter. Thus there is attachment of the matrix agent to the surface of the mucous membranes thus forming a three-dimensional network from which the action and/or from which the active ingredient diffuses gradually over time. The substances used are mostly materials of natural origin much used in the pharmaceutical, cosmetic and dietetic field.
By “complex” we mean the formation of a chemical bond other than the hydrogen bonds encountered with the majority of the other agents known as bio-adhesives. This bond is characterized in that energy is intermediate between the energy of a covalent bond and the energy of a hydrogen bond thus leading to a structure more resistant to the phenomenon of “washing”.
Thus, the invention has as the aim a viscous liquid composition with reinforced bio-adhesive capacity, for a local application in pasty form having prolonged release of an active ingredient, characterized in that it includes at least a matrix agent, a hydration medium of matrix agent and at least one active ingredient.
Obtaining of the aforesaid bio-adhesive matrix films having prolonged release being the subject of the present invention calls for substances known as matrix agents, which, in contact with the mucous membranes, offer a reinforced bio-adhesive capacity.
These substances can be used alone and create a viscous film or a more or less solid structure, in which the active ingredient(s) are dissolved or dispersed.
These same substances can be used in combination with other excipients with the aim of reinforcing the structure of the aforesaid matrix film and their bio-adhesive property.
In combination with other excipients, these matrix agents play the role of “binder”.
By “binder” we mean substances acting as cements between the particles of a network with the aim of reinforcing a more or less solid structure.
Thus, these matrix substances avoid the dispersion of the other excipients within the secretions of the organism by their imprisonment in the viscous gangue or the spongy structure formed at the surface of the mucous membrane.
As a result, depending on the solidity of the obtained matrix film, the action of the aforesaid film or the release of an active ingredient included in such a system can vary between 1 to 48 hours according to the action site of the aforementioned preparation.
Preferably according to the invention, the release time of the active ingredient is between 2 and 12 hours for the oral, nasal, and ocular administration and the release time of the active ingredient is greater than 12 hours for vaginal administration.
Matrix agents allowing attainment the aforementioned films and playing the role of “binder” belong to the class of the natural polymers, polysaccharides:
The polysaccharides retained within the framework of this invention are the carrageenans.
The carrageenans have been known for more than 600 years in the medical field and in the nutritional field in particular for their original property, which consists of gelifying milk by simply heating it.
They are polysaccharides, polymers of galactose more or less sulfated.
The carrageenans are extracted from different algae: Chondrus crispus, Gigartina stellata, Gigartina acicularis, Gigartina skottsbergii, Gigartina pistillata, Gigartina chamissoi, Iridea, Eucheuma cottoni, Eucheuma spinosum.
The extraction process used lead to different types of carrageenans the basic skeleton of which is a chain of D-galactose residues alternatively bonded at α-(I-3) and β-(I-4).
The different qualities are due to the quantity and the position of the sulphate groups and to the presence or not of 3,6 anhydro bridge on galactose bonded at 1 and 4.
The proportion of the different sulphates groups and the anhydrogalactose bridge at 3,6 allowed isolation of different types of carrageenans. They are the iota-, kappa-, lambda-, beta-, nu-, and mu-carrageenans.
The lambda-forms exhibit many sulfurated groups compared to the kappa-forms. The iota-forms are intermediate.
The mu- and nu-forms are in lesser quantities and are considered as impurities decreasing the gelifying effect of the iota- and kappa-forms.
The types of carrageenans retained for the present invention are the lambda- and the iota-carrageenans.
Compared to the kappa-carrageenans, the lambda- and the iota-carrageenans offer no syneresis phenomenon.
Lambda-carrageenans offer no gelifying properties, but thickening.
In the case of the iota-carrageenans, the gelifying property develops only if the preparation is subjected to heat.
Whether it be the iota- or the lambda-carrageenans, they are hygroscopic hydrocolloid substances.
Resulting from the contact with the mucous membranes, these substances will have the possibility of developing bio-adhesive properties like the conventional excipients bio-adhesive such as Carbopol® or carboxymethylcellulose defined as polymers suitable for forming more or less solid three-dimensional networks also.
The conventional bio-adhesive mechanism of the excipients known as bio-adhesives is defined as being an interaction of the aforesaid excipient with mucus covering the mucous membranes of the organism. This mucus is generally highly hydrated and offers a certain viscosity due to the presence of a glycoproteine, mucin.
According to their chemical nature, high molecular weight polymers, these excipients known as bio-adhesives are hygroscopic. Thus, in contact with the mucous membranes, these polymers expand quickly with the formation of hydrogen bonds between the hydrophilic groups of the polymer and those of the mucus and inter alia those of the mucin. Consequently there is formation of a three-dimensional network from a polymer/mucin interaction.
However, the hydrogen bonds are bonds of weak energy. Consequently a dilution of the medium or the constant “washing” of a support will lead to a rapid breaking of these bonds thus decreasing the bio-adhesive character of these excipients.
On the other hand, in the case of iota- and lambda-carrageenans, the bio-adhesive character is known as “reinforced” because besides the creation of the hydrogen bonds observed with the conventional excipients, other bonds are formed with the support.
In fact, it has been noted that the iota- and lambda-carrageenans possess sulphate groups on the skeleton of the molecule. These chemical groups are very reactive and create complexing reactions with certain molecules having free protons on some of their atoms such as nitrogen and sulphur. Because of the presence of these free protons, N²⁺ or S⁴⁺, anionic groups, such as the sulphate groups of the carrageenans, SO₄ ²⁻, react very strongly with these molecules.
Thus, the iota- and lambda-carrageenans in contact with mucin and of the mucous membrane, having in both cases nitrogen atoms, will create a three-dimensional network constituted:

- by hydrogen bonds formed between the OH groups of polysaccharide and those of mucin and the water present in mucus
- by complexation bonds between the sulphate groups of polysaccharide and the nitrogen atoms of mucin and the mucous membrane.

The “reinforced” bio-adhesive character has been revealed by a comparative study between Carbopol®934P NF and the lambda-carrageenans (Benvisco® LPB 2301).
The study is based on the realization of 2 solutions having a defined viscosity of 3000 mPa.
The viscosity of the solution was not chosen arbitrarily but according to the final mechanical properties of the solution: easily diffusible solution (sprayable).
Thus, for a viscosity of 3000 cPs, the concentrations in agents bio-adhesives are:

- 2.0% for the lambda-carrageenans.
- 0.6% for Carbopol®

Beyond these values, the products obtained no longer display the appearance of viscous solutions, but of gels.
Contrary to all the studies carried out on the bio-adhesivity using a stainless steel support, the studies of the bio-adhesivity of these solutions has been carried out on biological cellulose membrane (osmotic membrane) impregnated with a solution of mucin to 5% in a pH 6.8 phosphate buffer.
The impregnation of the membrane is effectuated in the 30 seconds before the deposit of the solutions.
The impregnation of the membrane is such that a liquid film is formed at the surface of the latter thus simulating what occurs in the area of the different mucous: wetness of the mucous membranes.
0.5 ml of solution to be tested is deposited at the surface of this impregnated membrane, at 6 cm from the inferior edge.
The “reinforced” character of the bio-adhesivity is tested by “washing” the deposit with a pH 6.8 buffered medium simulating the different secretions of the organism.
The “washing” of these deposits is carried out by using the tablet disintegration apparatus described in Pharmacopee Europeenne, 4^thedition.
This apparatus sketches out a back and forth movement from top to bottom at the ratio of 30 per minute and with an amplitude of 12 cm.
The impregnated membrane is attached to a rigid support (glass plate), itself vertically attached to the lever drawing out the back and forth movement.
The disintegration apparatus as well as a chronometer are activated when the deposit surplus begins to drain to the inferior part of the membrane.
Besides the comparative study conducted between Carbopol® and the lambda-carrageenans impregnated on membrane, a parallel study has been carried out on a simply moistened membrane.
By “simply moistened” we mean the absence of an aqueous film at the surface of the membrane.
Contrary to all expectations, lambda-carrageenans in contact with liquid film at the surface of the biological membrane offer a contact time definitely more substantial than Carbopol® placed under the same conditions.
A significant difference of 2 minutes 36 seconds (2′36″) is observed in the case of Carbopol®, between contact times on simply moist membrane and impregnated membrane against a nonsignificant difference of 1 minute 45 seconds (1′45″) for the lambda-carrageenans.


	Wet membrane	Impregnated Membrane

Lambda-carrageenans	9′43″ ^±0′47″	8′52″ ^±0′16″
Carbopol ®	9′29″ ± 0′43″	6′52″ ^±0′9″

This difference of behavior is all the more significant because the carrageenans have a rheology totally different from that of Carbopol®.
In fact, the liquid-based carrageenan preparations are characterized as Newtonian products that is to say that they flow freely under the effect of only their mass, which is not the case of Carbopol
Furthermore, these same products are also characterized as thixotropic solutions, that is to say that these aforementioned solutions, having the appearance of a solid at rest, liquefy rapidly, under the effect of an agitation. This property is not observed with Carbopol.
Thus, after deposit of the carrageenans solution at the surface of the wet membrane, this flow has been clearly observed from the moment of placement in vertical position of the support and continues from the moment of activation of the apparatus. On the other hand, in the case of Carbopol®, this flow was clearly less pronounced after activation of the apparatus.
However, contrary to all expectations, on impregnated membrane, the mobile liquid film at the surface of the membrane, free of all flow in vertical position, saw its flow impeded by the presence of the carrageenans at its surface. Contrary to the results observed on the wet membrane, the flow of the deposit is practically nonexistent when the apparatus is activated.
In the case of Carbopol®, an opposite result is observed. The liquid film at the surface of the membrane is not impeded in its flow thus driving the effectuated deposit with it.
This bio-adhesive property has also been demonstrated by the recording of the flow times of a carrageenan-based solution on a 45°-inclined plane covered with the same biological membrane impregnated or not impregnated with mucin. Significant time differences have been noted between the flow on non-impregnated membrane and impregnated membrane.


			Aptitude to	Bio-adhesivity
Concentration			the adhesion	factor
in	Without	With	F_aa	F_ba

carrageenans	mucin	mucin	Data	Mean	Data	Means

2%	38″	54″	16″	12″	1.42	1.31
	43″	52″	9″	±3″	1.21	±0.11
	41″	53′′′	12″	28.47%	1.29	8.11%
3%	5′52	7′58	126″	122″	1.36	1.34
	5′59	8′01	122″	±3″	1.34	±0.02
	6′03	8′02	119″	2.87″	1.33	1.13%
5%	17′58	22′05	247″	251″	1.23	1.23
	17′59	22′14	255″	±4″	1.24	±0.005
	18′08	22′19	251″	1.59%	1.23	0.47%

Despite the carrageenans being the object of a certain number of patents in more diverse fields other than pharmaceuticals, cosmetics, and dietetics, they are, however, seldom used in the realization of forms having prolonged release and even less for the realization of bio-adhesive systems having prolonged release.
In fact, in the field of forms having prolonged release we can cite inter alia, international application WO 03101424 mentioning carrageenans for the realization of matrices having prolonged release in solid form.
In the case of U.S. Pat. No. 6,355,272, the carrageenans are complexed with the active ingredient, which is gradually released over time in the digestive tract.
Similarly international application WO 0100177 shields the amoxicycline/carrageenans combination for a prolonged release of the antibiotic.
Hercules in his U.S. Pat. No. 6,358,525 shields different hydroxypropylcellulose and hydrocolloid based compositions such as the carrageenans, in order to slow down the availability of the active substances to the organism.
The patent application US2004019010 uses the carrageenan gels as substitute for the vitreous humour of the eye during ocular surgeries, such as cataract. The vitreous humour is replaced by these gels which, gradually over time, see their viscosity diminished to avoid an excessively strong intra-ocular pressure. These gels can be combined with active substances such as anti-inflammatory drugs, antibiotics, etc, which thus avoid any post-operative complications.
U.S. Pat. No. 5,403,841 shields carrageenans for the ophthalmic application of certain active ingredients. In the present case, a bio-adhesion of the carrageenans is not claimed but, instead, a quasi-instantaneous increase of the viscosity carrageenan-based solution instilled in the eye.
Likewise patent EP424043 clearly refers to the use of the carrageenans to increase the release time of the ingredients in the eye. This result would be due to an increase in the viscosity of the lachrymal liquid by interaction of the carrageenans with the proteins of the tears, the lysozymes among others. In no case is the interaction process described. In fact no mention is made:

- of creation of hydrogen bonds
- of complexing reaction
- of precipitation reaction, which can also be an augmentation mechanism of the bioavailability by formation of in situ microcrystals.

Furthermore there is absolutely no mention made of a bio-adhesive activity of these preparations in the cornea, the exterior layer of which is covered with a mixture of lipids and mucin.
Regarding the oral area, it is made mention in U.S. Pat. No. 5,672,356 of the use of the carrageenans as gelling agent delaying the release of the active ingredient, the bio-adhesion being supplied by the copolymer of methylvinyl ether and maleic anhydride.
Regarding the esophagus, U.S. Pat. No. 6,610,667 shields a composition of which the principal agent of bio-adhesion is alginate and has a lesser degree of other hydrocolloids such as the xanthan gum, galactomananes, glucomananes and carrageenans. The application is mainly centered around the combination alginate/gum xanthane or alginate/galactomananes or glucomananes. Furthermore, the esophagus is far from being a cavity of easy access from the exterior.
The international application WO2004/075920 uses the carrageenans as vector of active ingredients in the pulmonary area with the aim of delaying their release. Here also, the lungs are far from being considered as a cavity in the same fashion as the oral, vaginal, or rectal, cavity therefore far from being easily accessible from the exterior. Furthermore, the pulmonary secretions are definitely less substantial than those observed to exit from the salivary or lachrymal glands.
Other patents such as patent EP1452168 concern cutaneous applications of the carrageenans. The patent application US2002071861 makes use of the carrageenans but the bio-adhesive aspect of these preparations is supplied by carboxymethylcellulose, hydroxypropylmethylcellulose and Carbopol®.
Finally, the patents U.S. Pat. No. 6,159,491, U.S. Pat. No. 5,069,906 and U.S. Pat. No. 4,983,393 refer to the use of the carrageenans in prolonged release systems intended for vaginal administration.
U.S. Pat. No. 6,159,491 makes use of a combination of Carbopol® (Polycarbophil®) with carrageenans and agarose of high purity with the aim of having a release twice. In the present case the carrageenans are used as gellants, delaying the release of the active substances and Carbopol® as bio-adhesive.
U.S. Pat. No. 5,069,906 and U.S. Pat. No. 4,983,393 shield the carrageenans only as a matrix agent delaying the release of the actives. The bio-adhesive character is not mentioned.
In the present invention, according to the zone treated, the concentration in matrix agent, especially carrageenans, in the medium varies from 0.5% to 30% in relation to the final mass of the preparation.
The hydrating solvent of the matrix agent, especially carrageenans, can be aqueous or hydro-alcoholic. The proportion of the alcoholic phase can vary from 10% to 90% in mass in relation to the total volume of the hydrating phase.
The alcoholic phase can be embodied by ethylic alcohol and isopropyl alcohol.
The addition of certain ions can enable a better hydration of the carrageenans and at the same time enable augmentation of their concentration in the medium.
The agents supporting this hydration belong to the class of alkalines and the alkaline-earths. They are inter alia:

- sodium and potassium salts of hydrochloric, sulphuric, nitric, phosphoric, citric acids and derivatives,
- and potassium and sodium hydroxides.

The proportion of alkaline and alkaline-earth ions introducible into the medium varies between 0% to 50% in mass in relation to the total mass of the preparation.
The aqueous phase used can be buffered to support the stability of the active substances but also the stability of the matrix agent.
In fact, the carrageenans in the presence of dextrose, in neutral medium, undergo progressive hydrolysis in time, increased by the action of heat.
It is thus that in neutral medium and on a 24 hour period one observes a reduction in the viscosity of the product by a progressive hydrolysis of the carrageenans releasing acid radicals in the medium.
Within the acid framework of buffer solutions, the compositions can be as follows:

- sodium hydrochloric/chloride acid or potassium hydrochloric/phtalate acid or hydrochloric/glycocolle acid buffer.
- citric acid/citrate or citric acid/sodium hydroxide buffer
- lactic acid/lactate buffer.

The proportion of the different components make it possible to maintain an acid pH ranging between 2 and 5.
In the case of the carrageenans a better stability is observed in neutral or basic medium.
The buffer solutions that can be thus used respond to the following compositions:

- phosphates buffer: sodium or potassium phosphate
- carbonates buffer: bicarbonate/carbonate
- phthalate buffer: potassium/hydrochloric acid diphthalate
- borates buffer: boric acid/sodium borate

The value of the pH of the buffered medium can vary from 5 to 12.
The present invention is intended for the administration of a certain number of active substances.
The active substances that can be in such a form belong to certain pharmacological categories, namely analgesics, anti-inflammatories antispasmodics, cytotoxics, antibiotics, antifungals, disinfectants, pesticides, hormones, antivirals, antimigraine agents, anti-allergics, analeptics, respiratory agents, spermicides, anti-hemmorrhoidal agents, vasoconstrictors, vasodilators, antipruritics, uterorelaxants, antiglaucoma agents, mydriatics, antiasthmatics.
These substances can be incorporated in the dissolved state in the aqueous or hydro-alcoholic phase of the preparation subject to the present invention or in the solid state dispersed in the matrix film.
Despite that a certain number of these substances can be solubilized in the hydration medium of the carrageenans, others require a solubilization in an organic phase.
Among organic solvents usable without danger to the human organism are retained:

- vegetable oils, hydrogenated vegetable oils, ethoxylated vegetable oils: olive oil, hazel nut oil, coconut oil, castor oil, soy oil, sesame oil, etc.
- mineral oils: paraffin, isoparaffin, cycloparaffin, silicone oils, isohexadecane, isododecane, and derivatives, etc
- natural oils, squalane, hexamethyltetracosane, the mono-, di- and triglycerides, etc.
- synthetic oils: polyisobutene, hydrogenated polyisobutene, etc.
- and other solvents: ethanol, propanol-1, propanol-2, polypropylene, propylene carbonate, dimethyl isosorbide ether, polyoxyethylene glycols (Macrogols), glycerol, fatty acid esters of polyethylene, fatty acid esters of propylene glycol, dicaprylate/dicaprate esters of propylene glycol, caprylate/caprate esters of glycerol, fatty acid esters of polyoxyethylene/polyoxypropylene glycol, triacetin, isopropyl myristate, glycofurol, liquid fatty acid esters, ethyl acetate, butanol, propylene glycol acetate, butyl acetate, ethylene glycol monobutyl ether, ethyl lactate, butyl acetate, diethylene glycol-monoethyl ether, glycerin monooleate, glycerin linoleate, fatty acid glycerol esters, fatty acid esters of glycerol and PEG etc.

The proportion of these different solvents, used in these preparations, depends on the solubility of the active ingredients and can vary from 1% to 50% in volume in relation to the total volume of the hydrating phase.
In certain cases, these solvents require the use of surface-active agents to avoid any phase separation between the hydrating phase and the organic solution of actives.
The surface-active agents usable in the present invention are:

- nonionic surface-active agents:
- sorbitan esters: polysorbates, Spans, Tweens, etc. . . .
- polyethoxylated fatty acids: stearate of PEG-8 stearate through stearate of PEG-100;
- polyethoxylated fatty alcohols: mixtures of monolaurate ethers of PEG having from 4 to 23 oxyethylene groups in the polyoxyethylene chain, etc. . . .
- glycol esters: methylglycol stearate;
- glycerol esters: glycerol monostearate, PEG-75 stearate, glycol and PEG 6-32 stearate, etc. . . .
- PEG esters;
- saccharose esters;
- fatty alcohol and PEG ethers: Brij;
- ethers of alkylphenols and PEG;
- surface-active agents having an amid function:
- monoethanol amides of coprah fatty acids, monoethanol amide of lauric acid, etc. . . .
- diethanolamide of myristic acid, of lauric acid, etc. . . .
- monoisopropanolamide of lauric acid.
- phospholipids, such as phosphatidylcholine, phosphatidylserine,
- the ionic surface-active agents:
- sulphate derivatives: sodium laurylsulfate and its derivatives;
- sulphonated derivatives: sodium dodecylsulfosuccinate and its derivatives;
- quaternary ammonium compounds: cetyltrimethylammonium chloride; lauryl pyridium chloride, distearyldimethylammonium chloride, etc. . . .
- amphoterics: coprah alkyldimethylammonium betaines, fatty acid amides with betaines, lauryl-α-iminodiproprionic acid and its derivatives, lauryl-myristyl-α-aminoproprionic acid and its derivatives, etc. . . .

Furthermore the surface-active agents can be used to reinforce the bio-adhesive properties of the carrageenans, among them the phospholipides such as the phosphatidylcholine.
Based on the same tests as previously the phosphatidylcholine increases the bio-adhesive capacity of the carrageenans in a significant manner. For a same viscosity and a lesser concentration the difference of flow time on impregnated membrane and on non-impregnated membrane is on the order of 414 seconds. In the absence of phospholipides this difference is only 122 seconds

Viscosity	carrageenans	mucin	mucin	Data	Mean	Data	Means

2533 cPs	2% + phospholipides	9′38	17′11	453″	414″	1.78	1.72
		9′54	15′31	337″	±67″	1.56	±0.14
		9′12	16′46	454″	16.22%	1.82	8.13%
2625 cPs	3%	5′52	7′58	126″	122″	1.36	1.34
		5′59	8′01	122″	±3″	1.34	±0.02
		6′03	8′02	119″	2.87%	1.33	1.13%

The quantity of these substances used to promote the solubilization or the dispersion of the active ingredients as well as increase the bio-adhesive capacity of the carrageenans can vary from 0 to 50% in weight in relation to the total mass of the excipients.
Besides the fact that the active ingredients can be solubilized in the hydrating phase or in another solvent, these can also be incorporated in the solid state creating a bio-adhesive suspension.
As a result the active ingredients must satisfy a particle size criterion.
Thus the granulometric distribution of the powders can spread from 1 μm to 1000 μm, preferably ranging between 1 μm and 250 μm.
As was demonstrated during a certain number of trials, the carrageenans created a viscous film, of gelatinous appearance and of soft to firm consistency according to the concentration.
A reinforcement of this structure can be effectuated by introduction into the medium substances that, with contact with the secretions, are going to increase the solidity of this network.
Many substances can play this role. But only the starches have been retained, in particular their derivatives, because they are products that are more or less soluble in the hydration medium that reinforce the matrix structure of the carrageenans with the aid of their aptitude to form viscous networks in contact with the water.
Thus the native starches are retained as structuring agents in the aforementioned invention as well as their derivative products resulting from:

- physical modifications: pre-gelatinization
- chemical modifications:
- chemical or enzymatic dextrinisation reaction
- acid hydrolysis
- oxidation reaction
- substitution reaction by:
- phosphoric acid
- adipic acid
- acetic acid
- hydroxypropyl or hydroxyethyl groups.

These different structuring agents can be obtained from starches of wheat, rice, corn, manioc and potato.
The quantities used in order to obtain an action and/or a release of the active ingredient between 2 and 48 hours can vary from 0 to 50% in mass in relation to the total mass of the preparation
An important factor to rapidly obtain a compact structure, is the size of the particles of these aforesaid substances. Because the finer the particles, the more substantial the expansion capacity and the greater the density of the network formed (fewer inter-particle interstices).
Thus the particle size of the starches and modified starches making such results attainable must range between 1 μm and 1000 μm with a preference for a size ranging between 1 μm and 100 μm.
Preservation additives and dyes can be introduced into the composition.
The proportion of preservative can vary from 0% to 10% in mass in relation to the total mass of the preparation.
The dyes can be water-soluble or fixed on alumina lacquer or another support.
The optimum percentage of required dye ranges between 0.01% and 5% in mass in relation to the total mass of the preparation.
In the case of preparations intended for the oral cavity, moistening products can be added to the bio-adhesive medium.
By “moistening” we mean substances that bring a certain moisture to the medium in which they are present by way of their intrinsic hygroscopic properties, namely fixation of the moisture of the surrounding atmosphere moisture.
These products have the characteristic of facilitating the hydration of the carrageenans, which is realized by an increase in the bio-adhesivity of the latter.
Thus based on the same tests as previously, it appears that the glycerin, for an identical concentration in carrageenans, leads to a flow time on the membrane impregnated with mucin, clearly greater than a simple aqueous preparation of carrageenans.
In fact, at a flow distance of 10 cm, the preparation does not reach this distance after 60 minutes of deposit because of a strong reaction with the support


		Aptitude to	Bio-adhesivity
Concentration		the adhesion	factor
in	Without	F_aa	F_ba

carrageenans	mucin	With mucin	Data	Mean	Data	Mean

3% + glycerine	36′42	8.4 cm in 60′	/
15400 cPs	36′35	8.7 cm in 60′	/	/	/	/
	36′33	8.2 cm in 60′	/
3%	5′52	7′58	126″	122″	1.36	1.34
	5′59	8′01	122″	±3″	1.34	±0.02
	6′03	8′02	119″	2.87%	1.33	1.13%

Along a distance of 7.5 cm, it appears clearly that the difference in flow between the two preparations is definitely significant. The factor of bio-adhesiveness, which is nothing other than the relationship between the flow time of the preparation with mucin over the flow time without mucin, is definitely higher than the one with carrageenans alone regarding a same concentration in carrageenans that this is for an identical concentration in carrageenans or an identical viscosity of the medium.

carrageenans	mucin	mucin	Data	Mean	Data	Mean

3% + glycerine	23′05	49′02	1557″	1548″	2.12	2.11
15400 cPs	23′10	48′56	1546″	±7″	2.11	±0.01
	23′15	48′58	1543	0.47%	2.10	0.47%
3%	1′43	2′32	49″	44″	1.47	1.45
2625 cPs	1′38	2′24	46″	±5″	1.47	±0.04
	1′45	2′13	38″	12.82%	1.40	2.79%
	10′01	13′49	228″	219″	1.38	1.38
5%	10′13	13′39	206″	±11″	1.37	±0.005
15933 cPs	9′44	13′28	224″	5.34%	1.38	0.42%

Among these substances are the polyols, such as glycerin, sorbitol, maltitol, xylitol, mannitol, etc.
These products can be used with a concentration ranging between 1 and 30% in mass in relation to the total mass of the liquid phase.
These preparations being intended, among other things, to be applied to the oral mucous membrane, flavors as well as sweetening substances can be added in the bio-adhesive medium.
The flavors can be of natural or synthetic origin same as the sweetening substances.
Besides saccharose conventionally used as a sweetening substance, aspartame, acesulfam, sodium saccharin and sodium cyclamate can be retained as sweetening agents.
Depending on the sweetening substance used, the concentration in the medium can vary from 0.1% to 30% in mass in relation to the total mass of the preparation.
The solutions or suspensions thus realized, creating in situ matrix systems with prolonged release, have viscosities going from 100 mPa and 500,000 mPa.
These solutions or suspensions can be packaged:

- in multidosage vials: bottles or tubes
- in single dose: unidose, Bottle-Pack®, nozzle tubes having single use
- in spray: liquid spray or foam formation

Such systems, after application, lead to an action and/or the progressive release of the active ingredient over a period that can go from 1 hour to 48 hours, this kinetic release being little or not dependent on surrounding biological factors. This dissolution kinetic can be of the order of zero or 1 depending on the type of excipients used to obtain such a release.
Besides the use of these systems within the framework of a prolonged release of an active within a cavity, these same systems, in the absence of any therapeutic molecule, are of interest from a mechanical standpoint and, inter alia, regarding the lubrication of the mucous membranes when these are subject to dryness, such as oral dryness in the oligoptyalism, vaginal dryness, nasal dryness and corneal dryness in the case of Sjôgren disease.
In fact, these systems, by consequence of the intrinsic lubricating character of the carrageenans being amplifiable by the incorporation of mineral or vegetable oils, or surface-active agents, allow maintenance of a lubricating action over an 8-hour period.
The examples of preparations appearing hereafter are possible composition formulas according to the present invention and they do not limit it in any way.

EXAMPLE 1

Hydrating Bio-Adhesive Gel for Oligoptyalism


	Lambda-carrageenans	5.00%
	Mint flavor	0.02%
	Vanilla flavor	0.50%
	Aspartame	0.01%
	Demineralized water	94.47%

EXAMPLE 2

Lubricating Bio-Adhesive Gel for Oligoptyalism


	Lambda-carrageenans	5.00%
	Polysorbate 80	2.50%
	Vegetable oil	2.50%
	Mint flavor	0.02%
	Vanilla flavor	0.50%
	Aspartame	0.01%
	Demineralized water	89.47%

EXAMPLE NUMBER 3

Hydrating Bio-Adhesive Vaginal Gel


	Lambda-carrageenans	5.00%
	Hyaluronic acid	2.50%
	Paraffin oil	1.00%
	Auto-emulsionable glycerol monostearate	8.00%
	Sodium methyl parahydroxybenzoate	0.08%
	Sodium propyl parahydroxybenzoate	0.02%
	Sodium hydroxide	QS pH 3.5 to 4.5
	Demineralized water	73.40%

EXAMPLE NUMBER 4

Bio-Adhesive Gel for Oral Mycoses


	Lambda-carrageenans	2.50%
	Miconazole	2.00%
	Pre-gelatinized starch	2.50%
	Polysorbate 20	2.00%
	Sodium methyl parahydroxybenzoate	0.08%
	Sodium propyl parahydroxybenzoate	0.02%
	Ethanol with 96% V/V	1.50%
	Demineralized water	89.40%

BIBLIOGRAPHY

(1) WANG E. S. N and Coll., Corneal absorption reinforcement of certain mydriatics, J. Pharm. Sci., 1970, 59, 11, p: 1559-1563
(2) HASS J. S., and Coll., The effect of methylcellulose on response to solutions of pilocarpine, S. Afr. Med. J., 1975, 49, p: 1259-1265
(3) GOLDBERG I. and Coll., efficacity and patient acceptance of pilocarpine gel, Am. J. Ophtalmol. 1979, 15, 3, p: 843-846
(4) MANDELL A. I., and Coll., Multiclinic evaluation of pilocarpine gel, Invet. Ophtalmol. Vis. Sci., (Suppl.), avril 1979, p: 165
(5) MARCH W. F. and Coll., Duration of effect of pilocarpine gel, Arch. Ophtalmol., 1982, 100, 12, p: 1270-1271
(6) SCHOENWALD R. D. and Coll., Effect of particle size on ophtalmic bioavailability of dexamethasone suspension in rabbits, J. Pharm. Sci., 1980, 69, 4, p: 391-395
(7) HUI H. W., and Coll. Ocular Delivery of progesterone using a bioadhesive polymer, Intl. J. Pharma., 26 (1), 203-213, 1985
(8) NAGAI T., and Coll. Powder Dosage Form of insulin for nasal administration, J. Contr. Rel., 1(1), 15-22, 1984
(9) CHU J. S and Coll., viscometric study of polyacrylic acid Systems and mucoadhesive sustained release gels, Pharmaceutical research, 9 (11), 1408-12, 1991
(10) HOSNY E. A, and Coll. Bioavailibility of sustained release indomethacin suppositories containing Polycarbophil®, Intl. J. Pharma., 113 (January 16), 209-213, 1995.

Claims

1. A viscous liquid composition having reinforced bio-adhesive capacity, for a local application in pasty form with prolonged release of an active ingredient, characterized in that it includes:

(i) a matrix agent allowing the in situ formation of a matrix film with reinforced bio-adhesive capacity obtained by a reaction of complexation of the matrix agent with one of the components of local secretions or of the mucous membrane,

(ii) a hydration medium for the matrix agent and

(iii) an active ingredient.

2. A viscous liquid composition according to claim 1, characterized in that the matrix agent belongs to the family of polysaccharides.

3. A viscous liquid composition according to claim 2, characterized in that polysaccharide belongs to the family of the carrageenans.

4. A viscous liquid composition according to claim 3, characterized in that the carrageenan is selected among the lambda- and the iota-carrageenans

5. A viscous liquid composition according to claim 3, characterized in that the carrageenan is has a concentration ranging between 0.5% and 30% in mass in relation to the total mass of the composition.

6. A viscous liquid composition according to claim 1, characterized in that the hydration medium of the matrix agent is an aqueous solution or hydro-alcoholic.

7. A viscous liquid composition according to claim 6, characterized in that the hydro-alcoholic phase includes ethanol or isopropyl alcohol.

8. A viscous liquid composition according to claim 6, characterized in that the proportion in alcoholic phase lies between 10% and 90% in mass in relation to the volume total of the hydrating phase.

9. A viscous liquid composition according to claim 1, characterized in that it furthermore includes alkaline or alkaline-earth ions.

10. A viscous liquid composition according to claim 9, characterized in that the proportion of alkaline or alkaline-earth ions varies from 0 to 50% in mass in relation to the total mass of the composition.

11. A viscous liquid composition according to claim 9, characterized in that the alkaline or alkaline-earth ions are introduced in the form of hydroxide or a salt of hydrochloric, sulphuric, nitric, phosphoric, citric acid and/or a derivative.

12. A viscous liquid composition according to claim 12, characterized in that the aqueous phase of the hydration medium is a buffer solution.

13. A viscous liquid composition according to claim 12, characterized in that the value of the pH of the buffer solution varies from 2 to 12.

14. A viscous liquid composition according to claim 12, characterized in that the buffer solution is constituted by the couples hydrochloric acid/sodium chloride, hydrochloric acid/potassium phthalate, hydrochloric acid/glycol, citric acid/citrates, citric acid/sodium hydroxide, lactic acid/lactate, monosodium phosphate/disodium phosphate, monopotassium phosphate/dipotassium phosphate, bicarbonate/carbonate, acid/potassium diphthalate, or boric acid/sodium borate.

15. A viscous liquid composition according to claim 1, characterized in that the active ingredient is solubilized in the hydrating phase or in an organic solvent.

16. A viscous liquid composition according to claim 15, characterized in that the organic solvent is selected among vegetable oils, mineral oils, natural oils, synthetic oils, conventional lipophilic solvents, hydrophilics and non-toxic hydro-lipophilics.

17. A viscous liquid composition according to claim 1, characterized in that it furthermore includes a surface-active agent

18. A viscous liquid composition according to claim 17, characterized in that the surface-active agent belongs to the class of ionic, nonionic and amphoteric surface-active agents.

19. A viscous liquid composition according to claim 17, characterized in that the concentration of surface-active agent lies between 0 and 50% in mass in relation to the total mass of the excipients.

20. A viscous liquid composition according to claim 1, characterized in that the active ingredient in the solid state is dispersed in the form of powder of a granulometry ranging between 1 μm and 1000 μm.

21. A viscous liquid composition according to claim 20, characterized in that the granulometry of the active ingredient lies between 1 μm and 250 μm.

22. A viscous liquid composition according to claim 1, characterized in that it furthermore includes starch of rice, of potato, of corn, of manioc, and their derivatives.

23. A viscous liquid composition according to claim 22, characterized in that modified starch or the starch concentration lies between 0 and 50% in mass in relation to the total mass of the composition.

24. A viscous liquid composition according to claim 1, characterized in that it includes a conservation moistening, coloring, flavoring and/or sweetening agent.

25. A viscous liquid composition according to claim 24 characterized in that the concentration in preservatives lies between 0 and 10%.

26. A viscous liquid composition according to claim 24 characterized in that the concentration in moistening agents lies between 1 and 30%.

27. A viscous liquid composition according to claim 24, characterized in that the concentration in dyes lies between 0 and 5%.

28. A viscous liquid composition according to claim 24, characterized in that the concentration in sweetening substances lies between 0 and 30%.

29. A viscous liquid composition according to claim 24, characterized in that the sweetening substances are natural or synthetic chosen among saccharose, aspartame, acesulfam, sodium cyclamate or sodium saccharinate.

30. A viscous liquid composition according to claim 1 characterized in that it presents a viscosity ranging between 100 mPa and 500,000 mPa.

31. A viscous liquid composition according to claim 1 characterized in that the release time of the active ingredient lies between 2 and 12 hours for the oral, nasal, and ocular routes.

32. A viscous liquid composition according to claim 1 characterized in that the release time of the active ingredient is greater than 12 hours for the vaginal route.

33. A viscous liquid composition according to claim 1, characterized in that the active ingredient belongs to a therapeutic class selected among: analgesics, anti-inflammatories, antispasmodics, cytotoxics, antibiotics, antifungals, disinfectants, anti-parasitics, hormones, antivirals, anti-migraine agents, antiallergics, respiratory agents, analeptics, spermicides, anti-hemorrhoidal agents, vasoconstrictors, vasodilators, antipruritics, uterorelaxants, antiglaucoma agents, mydriatics and antiasthmatics.

34. A viscous liquid composition according to claim 1 furthermore including alkaline or alkaline-earth ions of sodium or potassium.