Novel epithelial penetration enhancer

Abstract

The present invention relates to a composition comprising a cold water insoluble cross-linked dextrin and a compound selected from the group consisting of 1-decanoyl-racemic-glycerol and carboxymethyl cellulose. The invention also relates to a process for preparing such a composition. The invention also relates to the use of a cold water insoluble cross-linked dextrin in combination with a compound selected from the group consisting of 1-decanoyl-racemic-glycerol and carboxymethyl cellulose for increasing the epithelial penetration of an active ingredient or for the epithelial delivery of an active ingredient.

Description

Technical Field

[0001] This invention relates to epithelial delivery of poorly permeable drugs, particularly oral or rectal delivery of poorly permeable drugs such as biological drugs (e.g., therapeutic proteins). Background Technology

[0002] Improving the oral bioavailability of drugs with poor bioavailability is both a significant concern and a medical need. Maximizing oral bioavailability is therapeutically important because the degree of bioavailability directly affects plasma concentrations, therapeutic effects, and toxic effects following oral administration. Drugs with poor bioavailability are ineffective because most of the dose never reaches the plasma or exerts its pharmacological effect. Furthermore, meta-analyses of published results on structurally diverse drugs have shown a negative correlation between inter-subject variability in bioavailability and the degree of bioavailability. Therefore, low oral bioavailability leads to high variability and poor control in plasma concentrations and effects.

[0003] Incomplete oral bioavailability can be caused by a variety of factors. These factors include poor or low water solubility, drug degradation in gastric or intestinal fluids, poor intestinal membrane permeability, and metabolism in the foregut or liver.

[0004] Some physicochemical properties associated with poor membrane permeability include a low octanol / water partition coefficient, the presence of strongly charged functional groups, high molecular weight, a large number of hydrogen-bonded functional groups, and a high polar surface area. Compounds that benefit most from intestinal absorption-enhancing formulations typically possess one or more of these characteristics. Drugs involved in absorption-enhancing studies are often proteins, peptides, peptide analogs, or other high-molecular-weight polar drugs, such as heparin.

[0005] Among the strategies already developed for improving the intestinal permeability of those drugs, the use of the following permeability enhancers can be mentioned:

[0006] - Surfactants (e.g., polyoxyethylene (POE) ethers, POE esters, POE dehydrated sorbitol esters, dodecyl maltodextrin, nonylphenoxy polyoxyethylene surfactants, sucrose laurate)

[0007] - Fatty acids (e.g., sodium decanoate, caprylic acid, decanoic acid, oleic acid, linoleic acid, linolenic acid);

[0008] - Medium-chain glycerides (e.g., monoglycerides and diglycerides of caprylic and capric acids, glycerides of monohexanoate), are ultimately combined with emulsifiers or solubilizers;

[0009] - Steroidal detergents (e.g., bile salts (sodium taurocholate), chenodeoxycholate, ursodeoxycholate, saponins, glycyrrhizic acid esters, glycyrrhetinic acid, glycosylated bile acid analogs);

[0010] - Acylcarnitines and alkylcholines (e.g., medium-chain and long-chain fatty acid esters of carnitine and choline, such as palmitoyl-DL-carnitine chloride, lauroylcholine).

[0011] -N-acetylated α-amino acids and N-acetylated non-α-amino acids (e.g., N-cyclohexanoylleucine, N-(benzenesulfonyl)leucine, 4-[4-[(2-hydroxybenzoyl)amino]phenyl]butyric acid, N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC)).

[0012] - Chitosan and other mucosal adhesion polymers (e.g., anionic polyacrylic acid derivatives, polycarbofil and carbomer (i.e., Carbopol 934P), cationic chitosan, trimethyl chitosan).

[0013] - Secretion transport inhibitors (e.g., P-glycoprotein (Pgp) inhibitors, such as SDZ PSC 833, cyclosporine, polysorbate 80, POE 35, castor oil (Cremophor EL) ® Pluronic P85 ® );

[0014] -Cyclodextrin.

[0015] However, additional or more effective intestinal permeability enhancers are still needed.

[0016] Developing permeation enhancers for intestinal permeation will allow for improved bioavailability of poorly permeable drugs administered orally and rectally. It can also be applied to other epithelial routes of administration that require the active ingredient to cross the epithelium, such as skin, mucosal (e.g., vaginal, sublingual, buccal), transdermal, ophthalmic, nasal, intranasal, or bronchopulmonary routes.

[0017] Technical issues

[0018] The object of this invention is to provide an improved intestinal permeability enhancer, and more broadly, to provide an improved epithelial permeability enhancer for poorly permeable active ingredients, such as biopharmaceuticals.

[0019] The object of the present invention is to provide a material that improves the bioavailability of active ingredients such as biological drugs when taken orally or rectally, and more broadly, when taken via the epithelial route.

[0020] The object of this invention is to solve this technical problem by providing a solution that has other properties required for its intended purpose, such as in terms of purity and safety.

[0021] Introduction of the present invention

[0022] The inventors have solved the aforementioned problems by providing an epithelial (e.g., intestinal) permeability enhancer, which is a combination of the following substances:

[0023] -Cold water insoluble cross-linked dextrin; and,

[0024] -A compound selected from 1-decanoyl-racemic-glycerol and carboxymethyl cellulose (CMC).

[0025] As will be apparent from the Examples section below, these substances appear to work synergistically to allow for a high degree of enhancement intestinal permeability.

[0026] The results obtained in the Caco-2 cell model make it a promising permeation enhancer for intestinal routes (such as oral and rectal routes). This also makes it a promising permeation enhancer for other epithelial routes, such as skin routes, mucosal routes (e.g., vaginal, sublingual, buccal routes), transdermal routes, ophthalmic routes, nasal routes, transnasal routes, or bronchopulmonary routes. Summary of the Invention

[0027] This disclosure first relates to a composition comprising:

[0028] -Cold water insoluble cross-linked dextrin; and,

[0029] -A compound selected from 1-decanoyl-racemic-glycerol and carboxymethyl cellulose (CMC).

[0030] Preferably, the dextrin is selected from pyrodextrin, maltodextrin, cyclodextrin, or mixtures thereof. Preferably, the cold-water insoluble cross-linked dextrin can be obtained by reacting dextrin with a cross-linking agent selected from trimetaphosphate, dicarboxylic acid, dianhydride, carbonyl diimidazole, diphenyl carbonate, triphosgene, acyl dichloro, diisocyanate, diepoxide, or any mixture thereof. Preferably, the cold-water insoluble cross-linked dextrin can be obtained by reacting dextrin with a cross-linking agent, wherein the molar ratio of the cross-linking agent to the dehydrated glucose units of the dextrin is equal to or greater than 0.1:1. Preferably, the cold-water insoluble cross-linked dextrin is in particulate form.

[0031] This disclosure also relates to a composition comprising:

[0032] -Cold water insoluble cross-linked dextrin; and,

[0033] -A compound selected from 1-decanoyl-racemic-glycerol and carboxymethyl cellulose (CMC); and,

[0034] - Active ingredients.

[0035] Preferably, the active ingredient is selected from BCS Class III drugs, BCS Class IV drugs, biological products, or any mixture thereof. Preferably, the active ingredient is selected from proteins. Preferably, the active ingredient is loaded in the cold water-insoluble cross-linked dextrin.

[0036] This disclosure also relates to such compositions used as pharmaceutical agents, and the use of such compositions in food compositions (such as food supplements) or nutritional or cosmetic compositions.

[0037] Preferably, the compositions according to this disclosure are intended for administration via an epithelial route, preferably via a route selected from the following: intestinal route (including oral or rectal route), skin route, mucosal route (e.g., vaginal route, sublingual route, buccal route), transdermal route, ophthalmic route, nasal route, transnasal route, or bronchopulmonary route. Preferably, the compositions according to this disclosure are intended for administration via an intestinal route, preferably via an oral or rectal route, more preferably via an oral route. In other words, they are preferably oral or rectal compositions, more preferably oral compositions.

[0038] The term "epithelial route" traditionally refers to a route of administration that requires crossing the epithelium. This can be a systemic route or a localized route (e.g., the case of dermal application of an active ingredient that requires crossing the epidermis to reach the dermis). A systemic route is preferred.

[0039] This disclosure also relates to a method for preparing such compositions, comprising contacting the cold water-insoluble cross-linked dextrin with the compound selected from 1-decanoyl-racemic glycerol and carboxymethyl cellulose (CMC).

[0040] This disclosure also relates to the following combinations:

[0041] -Cold water insoluble cross-linked dextrin,

[0042] -A compound selected from 1-decanoyl-racemic-glycerol and carboxymethyl cellulose (CMC),

[0043] Used to increase the epithelial permeability of the active ingredient, preferably for increasing the intestinal permeability of the active ingredient.

[0044] This disclosure also relates to the following combinations:

[0045] -Cold water insoluble cross-linked dextrin,

[0046] -A compound selected from 1-decanoyl-racemic-glycerol and carboxymethyl cellulose (CMC),

[0047] Used for epithelial delivery of active ingredients, preferably for oral or rectal delivery of active ingredients, more preferably for oral delivery of active ingredients.

[0048] Preferably, the active ingredient is selected from BCS Class III drugs, BCS Class IV drugs, biological products, or any mixture thereof. Preferably, the active ingredient is selected from proteins. Attached Figure Description

[0049] Other features, details, and advantages will be shown in the following detailed description and accompanying drawings, wherein:

[0050] Figure 1

[0051] [ Figure 1 [This is a schematic diagram of a 24-well Caco-2 model (only the channel from the top to the outer side of the substrate is shown).]

[0052] Figure 2

[0053] [ Figure 2 [This is a bar chart showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nanosponge) and 1-decanoyl-racemic-glycerol.]

[0054] Figure 3

[0055] [ Figure 3 [This is a bar chart showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nano-sponge) and carboxymethyl cellulose (CMC).]

[0056] Figure 4

[0057] [ Figure 4 [This is a bar chart showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nanosponge) and sodium sapride.]

[0058] Figure 5

[0059] [ Figure 5 [This is a bar graph showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nanosponge) and lauryl-L-carnitine.]

[0060] Figure 6

[0061] [ Figure 6 [This is a bar graph showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nano-sponge) and mono-dodecyl nonethylene glycol ether.]

[0062] Figure 7

[0063] [ Figure 7[This is a bar graph showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nanosponge) and polyethylene glycol.]

[0064] Figure 8

[0065] [ Figure 8 [This is a bar graph showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nano sponge) and monodisperse 20µm silica.]

[0066] Figure 9

[0067] [ Figure 9 [This is a bar graph showing insulin penetration when using a combination of cold water-insoluble cross-linked dextrin (nano sponge) and monodisperse 150 nm silica.]

[0068] Figure 10

[0069] [ Figure 10 [This is a bar chart showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nano-sponge) and kaolinite.]

[0070] Figure 11

[0071] [ Figure 11 [This is a bar chart showing insulin permeation when using a combination of cold water-insoluble cross-linked dextrin (nano-sponge) and montmorillonite.] Detailed Implementation

[0072] The accompanying drawings and the following detailed description essentially contain some specific elements. They can be used to enhance the understanding of the invention and, if necessary, to define the invention.

[0073] Combinations comprising cold water-insoluble crostodextrin and compounds selected from 1-decanoyl-racemic-glycerol and CMC. thing

[0074] This invention first relates to a composition comprising:

[0075] -Cold water insoluble cross-linked dextrin; and,

[0076] -A compound selected from 1-decanoyl-racemic-glycerol and CMC.

[0077] The term "dextrin" conventionally refers to products obtained from starch hydrolysis, including maltodextrin, glucose syrup with a dextran equivalent (DE) of 20 to 30, caramelized dextrin, and cyclodextrin. Preferably, the dextrin selected according to this disclosure is selected from maltodextrin, caramelized dextrin, cyclodextrin, or any mixture thereof. More preferably, it is selected from maltodextrin, caramelized dextrin, or any mixture thereof. Even more preferably, it is selected from maltodextrin or any mixture thereof, i.e., preferably cold water-insoluble cross-linked maltodextrin.

[0078] The term "maltodextrin" traditionally refers to dextrin obtained by acidic and / or enzymatic hydrolysis of starch. Maltodextrin is typically characterized by a DE (degree of salinity) of less than 20. Preferably, the maltodextrin according to this disclosure has a DE equal to or greater than 1, preferably equal to or greater than 5, preferably equal to or greater than 10, preferably equal to or greater than 15. Preferably, it is equal to or less than 19. For example, it is equal to about 17.

[0079] The term "caramelized dextrin" traditionally refers to dextrin obtained by dry heating starch under acidic conditions, which typically leads to starch hydrolysis followed by relinking via α-1,6 bonds. Generally, these caramelized dextrins are classified as "white dextrin," "yellow dextrin," or "British gum" depending on the temperature, acidity, and humidity conditions used.

[0080] The term "cyclodextrin" refers to a natural or substituted cyclodextrin having 6 to 12 glucose units typically linked together via carbon C1 and C4. Cyclodextrins include α-, β-, and γ-cyclodextrins having 6, 7, and 8 glucose units, respectively. Preferably, the cyclodextrins according to this disclosure are selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or any mixture thereof, more preferably β-cyclodextrin. The cyclodextrins according to this disclosure may preferably be substituted with alkyl and / or hydroxyalkyl and / or sulfonylalkyl, particularly etherified. Preferably, the alkyl, hydroxyalkyl, and sulfonylalkyl groups according to the disclosure have 1 to 5 carbon atoms, preferably 1 to 4, more preferably 1, 3, or 4. Preferably, the substituted cyclodextrins according to this disclosure are selected from methyl-cyclodextrin, hydroxypropyl-cyclodextrin, sulfobutyl ether-cyclodextrin, or any mixture thereof. In contrast to chemicals with well-defined structures, substituted cyclodextrins are generally mixtures of substituted cyclodextrins with different substitution patterns, and therefore they are structurally distinct. More preferably, the cyclodextrin according to this disclosure is an unsubstituted cyclodextrin (i.e., natural cyclodextrin), and more preferably an unsubstituted β-cyclodextrin (i.e., natural β-cyclodextrin).

[0081] Dextrin is classically obtained from starch. The term "starch" conventionally refers to starch isolated from any suitable plant source using any technique well known to those skilled in the art. Isolated starch typically contains no more than 3% impurities; this percentage is expressed as the dry weight of the impurities relative to the total dry weight of the isolated starch. These impurities typically include proteins, colloidal substances, and fibrous residue. Suitable plant sources include, for example, legumes, cereals, and tubers.

[0082] Therefore, the dextrins according to this disclosure can be selected from legume dextrins (e.g., pea dextrin, broad bean dextrin), cereal dextrins (e.g., corn dextrin, rice dextrin, wheat dextrin, oat dextrin), and tuber dextrins (e.g., potato dextrin, cassava dextrin). Preferably, the dextrins according to this disclosure are selected from legume dextrins, cereal dextrins, or any mixture thereof.

[0083] Preferably, the legume paste is selected from pea dextrin, broad bean dextrin, or any mixture thereof, more preferably pea dextrin. The term "pea" classically includes all wild and mutant varieties of "smooth-skinned pea" and "wrinkled-skinned pea," regardless of the intended use of these varieties (human food, animal feed, and / or other uses). The term "pea" includes peas of the genus *Pisumgenius*, more specifically peas of the cultivated species *Sativum* and *Aestivum*. Mutant varieties can be those referred to as "r mutants," "rb mutants," "rug 3 mutants," "rug 4 mutants," "rug 5 mutants," and "lam mutants," as described in the article by C.L. Heydley et al. entitled "Developing novel pea starches," *Proceedings of the Symposium of the Industrial Biochemistry and Biotechnology Group of the Biochemical Society*, 1996, pp. 77-87. Preferably, the paste selected according to this disclosure is derived from smooth-skinned pea dextrin, more preferably from wild smooth-skinned pea dextrin.

[0084] Preferably, the cereal dextrin is corn dextrin.

[0085] Preferably, when the dextrin according to this disclosure is maltodextrin, it is legume maltodextrin, more preferably pea maltodextrin, more preferably smooth-skinned pea maltodextrin, and more preferably wild smooth-skinned pea maltodextrin.

[0086] Preferably, when the dextrin according to this disclosure is pyrodextrin, it is cereal pyrodextrin, preferably corn pyrodextrin.

[0087] In a preferred embodiment, the dextrin according to this disclosure is obtained from starch with an amylose content of 20% or higher, preferably 25% or higher, preferably 30% or higher, and preferably 35% or higher; this content is expressed as dry weight relative to the total dry weight of the starch. The amylose content is preferably 90% or lower, preferably 60% or lower, preferably 50% or lower, preferably 45% or lower, preferably 40% or lower, and preferably 38% or lower. Preferably, the starch is legume starch, preferably pea or broad bean starch, more preferably smooth pea starch, and even more preferably wild smooth pea starch. The amylose content can be determined by those skilled in the art through potentiometric analysis of iodine absorbed by the amylose to form a complex.

[0088] Preferably, the dextrin according to this disclosure, particularly the maltodextrin according to this disclosure, has a weight-average molecular weight (Mw) of 1000 Da or higher, preferably 5000 Da, preferably 8000 Da, or preferably 10000 Da, as determined by liquid chromatography combined with differential refractometer detection. This Mw is preferably equal to or lower than 200000 Da, preferably equal to or lower than 100000 Da, preferably equal to or lower than 50000 Da, preferably equal to or lower than 40000 Da, preferably equal to or lower than 30000 Da, preferably equal to or lower than 20000 Da, and preferably equal to or lower than 15000 Da. For example, it is equal to about 12000 Da.

[0089] The Mw is determined by liquid chromatography combined with differential refractometer detection, preferably using pullulan standards. Those skilled in the art can determine it according to the following protocol:

[0090] Use the following set of columns in the following order (e.g., Shodex OH pak SB-800 QH):

[0091] - Columns with a particle size of 8 μm, a pore size of 100 Å, an inner diameter of 8.0 mm, and a length of 300 mm (e.g., OH pak SB-802HQ - Waters réf. JWE 034256).

[0092] - Columns with a particle size of 6 μm, a pore size of 800 Å, an inner diameter of 8.0 mm, and a length of 300 mm (e.g., OH pak SB-803HQ - Waters réf. JWE 034257).

[0093] - Columns with a particle size of 13 μm, a pore size of 7000 Å, an inner diameter of 8.0 mm, and a length of 300 mm (e.g., OH pak SB-805 HQ - Waters réf. JWE 034259).

[0094] The Pulllan standards used (e.g., Kit Waters - Réf. JWE034207) have the following Mw values: P800, P400, P200, P100, P50, P20, P10, P5.

[0095] Conditions: Elution solvent: 0.1 M sodium nitrate aqueous solution containing 0.02% sodium azide filtered through a 0.02 μm filter; Mobile phase flow rate: 0.5 mL / min; Column temperature: 35 °C; Injection volume: 100 μL; Detector: RI attenuation: 16, internal temperature: 35 °C; Analysis time: 80 min.

[0096] Calibration was performed using glycerol (Mw=92), glucose (Mw=180), maltose (Mw=342), maltotriose (Mw=504), maltotetraose (Mw=667), maltopentose (Mw=829), maltohexaose (Mw=991), and maltoheptaose (Mw=1153).

[0097] Suitable examples of dextrins are commercially available. For example, the following product sold by ROQUETTE could be mentioned: KLEPTOSE. ® β-Cyclodextrin, Kleptose ® Linecaps (pea maltodextrin), GLUICIDEX ® 2 (Waxy corn dextrin), STABILYS ® A025 (Corn Caramelized Extract), STABILYS ® A053 (corn caramelized dextrin) and TACKIDEX ® series.

[0098] The cold-water-insoluble dextrin according to this disclosure is cross-linked, meaning it can be obtained by reacting dextrin with a cross-linking agent (or by reacting dextrin with a cross-linking agent). The cross-linking agent is typically multifunctional, i.e., it contains at least two reactive groups. Preferably, the cross-linking agent is bifunctional. Typically, in this disclosure, the reactive groups have atoms that have undergone nucleophilic attack, i.e., they carry a partially positive charge.

[0099] Preferably, the crosslinking agent according to this disclosure is selected from trimetaphosphate, dicarboxylic acid, dianhydride, carbonyl diimidazole, diphenyl carbonate, triphosgene, acyl dichloro, diisocyanate, diepoxide, or any mixture thereof. Preferably, the dicarboxylic acid is selected from polyacrylic acid, butanetetracarboxylic acid, succinic acid, tartaric acid, citric acid, or any mixture thereof. More preferably, it is selected from citric acid and / or tartaric acid. Preferably, the dianhydride is selected from diethylenetriaminepentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, benzophenone-3,3',4,4'-tetracarboxylic acid dianhydride, pyromellitic dianhydride, or any mixture thereof. More preferably, pyromellitic dianhydride. Preferably, the acyl chloride is selected from terephthaloyl chloride, sebacyl chloride, succinyl chloride, or any mixture thereof. More preferably, terephthaloyl chloride. Preferably, the diisocyanate is selected from toluene diisocyanate, isophorone diisocyanate, 1,4-phenylene diisocyanate, poly(hexamethylene diisocyanate), hexamethylene diisocyanate, or mixtures thereof. More preferably, it is hexamethylene diisocyanate.

[0100] Preferably, the crosslinking agent according to this disclosure is selected from trimetaphosphate, pyromellitic dianhydride, 1,1'-carbonyldiimidazole, hexamethylene diisocyanate, citric acid, tartaric acid, or mixtures thereof.

[0101] In a preferred embodiment, particularly when the paste is selected from maltodextrin and / or caramelized dextrin, the crosslinking agent is selected from trimetaphosphate. Sodium trimetaphosphate is more preferred.

[0102] In a preferred embodiment, particularly when the paste is selected from cyclodextrin, the crosslinking agent is pyromellitic dianhydride.

[0103] Preferably, the cold water-insoluble dextrin according to this disclosure can be obtained by reacting dextrin with a crosslinking agent (or by reacting dextrin with a crosslinking agent) without undergoing a previous ethylamine step (grafting with ethylamine groups).

[0104] Preferably, the molar ratio of the crosslinking agent to the dehydrated glucose units of dextrin is equal to or greater than 0.1:1, preferably equal to or greater than 0.2:1, and preferably equal to or greater than 0.20:1. Preferably, it is equal to or less than 10:1, preferably equal to or less than 5:1, preferably equal to or less than 4:1, preferably equal to or less than 3:1, preferably equal to or less than 2:1, preferably equal to or less than 1:1, preferably equal to or less than 1.0:1, preferably equal to or less than 0.9:1, preferably equal to or less than 0.8:1, preferably equal to or less than 0.7:1, preferably equal to or less than 0.6:1, preferably equal to or less than 0.5:1, preferably equal to or less than 0.4:1, and preferably equal to or less than 0.40:1. For example, it is equal to about 0.3:1.

[0105] In this disclosure, it refers to the amount or ratio of the components constituting the cold water-insoluble cross-linked dextrin. It should be understood that these amounts refer to the amounts of the starting materials (dextrin, cross-linking agent, and other final components) used to prepare the cold water-insoluble cross-linked dextrin. These amounts may differ slightly from the amounts actually present in the final matrix (i.e., in the cold water-insoluble cross-linked dextrin prepared therefrom), which, to the inventor's knowledge, are currently immeasurable.

[0106] The dextrin or cross-linked dextrin according to this disclosure can undergo a physical modification step, commonly referred to as a "cooking" or "gelatinization" step. This cooking step is well known to those skilled in the art and is typically carried out when the dextrin is at least partially in a particulate state. This cooking step allows the polymer molecules constituting the dextrin to be sufficiently and uniformly dispersed in a reaction solvent (e.g., water). This cooking step is particularly useful when the dextrin is a pyrodextrin. Preferably, cooking is performed prior to the cross-linking step.

[0107] The cross-linked dextrin according to this disclosure is insoluble in cold water. The term "cold water" conventionally refers to water placed at room temperature (typically 18°C ​​to 25°C). Preferably, the cross-linked dextrin according to this disclosure is insoluble in cold water with a pH of 7. Preferably, the cross-linked dextrin according to this disclosure is insoluble in cold water with a pH of 5. Preferably, the cross-linked dextrin according to this disclosure is insoluble in cold water with a pH of 9.

[0108] The cross-linked dextrin according to this disclosure is cold water insoluble. That is, the solubility of cross-linked dextrin in cold water is generally equal to or less than 20%, expressed as the dry weight of the soluble matter relative to the total dry weight of the cross-linked dextrin. This solubility is preferably equal to or less than 15%, preferably equal to or less than 10%, preferably equal to or less than 9%, preferably equal to or less than 8%, preferably equal to or less than 7%, preferably equal to or less than 6%, preferably equal to or less than 5%, preferably equal to or less than 4%, preferably equal to or less than 3%, preferably equal to or less than 2%, and preferably equal to or less than 1%. This solubility can be determined by those skilled in the art according to the following procedure: 2.5 g of the product to be tested (e.g., cross-linked dextrin particles obtained after grinding and sieving with a 315 μm sieve to remove coarse particles) is placed in 150 g of softened water and left to stand with stirring for 16 hours, then centrifuged at 4700 rpm for 15 minutes (e.g., using a VWR Mega Star 1.6 centrifuge). The supernatant is then placed in a pre-peeled crystallizer and placed in a vacuum oven at 55°C until there is no further weight loss (all water evaporates). Weigh the remaining (soluble fraction). This soluble fraction may contain soluble fractions of crostodextrin, but may also contain some residual impurities.

[0109] Preferably, the cold water-insoluble cross-linked dextrin of this disclosure is in particulate form. These particles may have an average diameter selected from 1 nm to 1000 μm, for example 10 nm to 500 μm, said diameter being measured on an aqueous suspension of the cold water-insoluble cross-linked dextrin. These particles may have an average diameter equal to or less than 1000 nm (also referred to as "nanosponges").

[0110] It can be used in the form of a nano-suspension (nano-sponge suspension) of the aforementioned cold water-insoluble cross-linked dextrin particles. The suspension can be prepared according to the following scheme:

[0111] 1. At room temperature, add the coarse powder to distilled water at a concentration of 10 mg / mL with stirring to begin preparing the suspension.

[0112] 2. Use a high-shear homogenizer (e.g., Ultraturrax) ® (IKA, Konigswinter, Germany) dispersed the suspension at 24,000 rpm for 10 minutes.

[0113] 3. (For example, using an EmulsiFlex C5 instrument (Avastin, USA)) High-pressure homogenization at a back pressure of 500 bar for 90 minutes to further reduce size.

[0114] 4. Purify the homogenized nanosuspension by dialysis, for example using a cellulose membrane (Spectrapor) with a rejection ratio of 12000 Da, to remove any possible synthetic residues.

[0115] 5. If necessary, the nano suspension should be stored at 4°C.

[0116] Preferably, the cold water-insoluble cross-linked dextrin particles according to this disclosure have an average diameter of 1 nm to 1000 nm. It is preferably equal to or greater than 10 nm, preferably equal to or greater than 50 nm, and preferably equal to or greater than 100 nm. This average diameter is a hydrodynamic diameter. It can be determined by those skilled in the art by laser scattering, for example using a 90Plus instrument (Brookhaven, NY, USA), preferably on a nanosponges suspension obtained, for example, according to the scheme given above, the suspension containing 10 mg / mL of nanosponges diluted with filtered (0.22 μm) distilled water using a dilution factor of 1 / 30 by volume.

[0117] Preferably, the polydispersity index relative to the average diameter is less than 1.00. This polydispersity index is typically greater than 0.01, or even equal to or greater than 0.05.

[0118] Preferably, the cold water-insoluble dextrin according to this disclosure has a zeta potential of less than 0 mV, preferably equal to or less than -10 mV, and preferably equal to or less than -20 mV. It is typically equal to or greater than -50 mV, and even equal to or greater than -40 mV. This zeta potential can be determined by those skilled in the art using electrophoretic mobility by dynamic light scattering of the cross-linked dextrin suspension at a scattering angle of 90° at a temperature of 25°C, for example using a 90 Plus instrument (Brookhaven, NY, USA). The sample is placed in an electrophoretic pool in which an electric field of 15 V / cm is applied. Preferably, the zeta potential is determined, for example, on a nanosponge suspension obtained according to the previously given protocol, the suspension containing 10 mg / mL of nanosponges diluted with filtered (0.22 μm) distilled water using a dilution factor of 1 / 30 by volume.

[0119] Preferably, the swelling index (SI%) of the cold water-insoluble cross-linked dextrin according to this disclosure is equal to or greater than 200%, preferably equal to or greater than 500%, preferably equal to or greater than 600%, preferably equal to or greater than 700%, preferably equal to or greater than 800%, preferably equal to or greater than 900%, preferably equal to or greater than 1000%, preferably equal to or greater than 1100%, preferably equal to or greater than 1200%, preferably equal to or greater than 1300%, preferably equal to or greater than 1400%, preferably equal to or greater than 1500%, preferably equal to or greater than 1600%. It is preferably equal to or less than 5000%, preferably equal to or less than 4000%, preferably equal to or less than 3000%, preferably equal to or less than 2000%.

[0120] The swelling index of the matrix (e.g., a cold water-insoluble dextrin according to this disclosure) is defined by the following formula:

[0121] [math]

[0122]

[0123] Where Wd is the weight of the matrix and Ws is the weight of the swollen matrix.

[0124] To determine the SI%, 1 g (dry weight) of matrix (after grinding and sieving through a 315 μm sieve to remove coarse particles) was dispersed in 100 mL of softened water in a graduated cylinder and left to swell for 24 hours. After 24 hours of contact, the matrix mixture dispersed in water was centrifuged to separate the supernatant (water) and the bottom layer (swollen matrix or gel). The swollen matrix was then weighed.

[0125] The dextrins according to this disclosure may undergo other chemical and / or physical modifications (i.e., crosslinking and final cooking) besides the preferred modifications described above, as long as they do not interfere with the desired properties, particularly in terms of safety and efficiency. However, and because they are not necessary to solve the technical problems disclosed herein, the dextrins according to this disclosure are preferably not further modified.

[0126] The cold-water insoluble cross-linked dextrin according to this disclosure may contain other components in its structure besides dextrin and a cross-linking pattern derived from a cross-linking agent, provided that they do not interfere with the desired properties of the cold-water insoluble cross-linked dextrin, particularly in terms of efficiency and safety. It should be understood that the term "other components" does not refer to minor impurities ultimately introduced by the dextrin and cross-linking agent. Examples of such other components are other polymers, such as proteins, which, if used, are typically also cross-linked.

[0127] However, and because it is not essential for solving the technical problems disclosed herein, the cold water-insoluble cross-linked dextrin according to this disclosure preferably has an amount of the other components equal to or less than 30%, preferably equal to or less than 20%, preferably equal to or less than 10%, preferably equal to or less than 5%, preferably equal to or less than 1%, preferably equal to or less than 0%; the percentages are expressed as dry weight relative to the total dry weight of the cold water-insoluble dextrin. More preferably, the cold water-insoluble cross-linked dextrin according to this disclosure does not contain the other components.

[0128] Therefore, in a preferred embodiment, the cold water-insoluble cross-linked dextrin according to this disclosure is composed of cross-linked dextrin. Preferably, the dextrin is selected from maltodextrin, caramelized dextrin, cyclodextrin, or any mixture thereof. More preferably, the cold water-insoluble dextrin is composed of cross-linked maltodextrin, or cross-linked caramelized dextrin, or cross-linked cyclodextrin.

[0129] Examples of suitable cold water-insoluble cross-linked dextrins and their preparation methods are described in patent applications WO 2016 / 004974 A1 (ROQUETTE) and WO 2021 / 254662 A1 (ROQUETTE).

[0130] The compositions according to this disclosure also comprise compounds selected from 1-decanoyl-racemic-glycerol and CMC.

[0131] CMC can be in salt form or protonated form. CMC salt is preferred. Sodium CMC is more preferred.

[0132] Preferably, the dry weight ratio of 1-decanoyl-racemic-glycerol to cold water-insoluble crostodextrin is 0.05:1 to 5:1. Preferably equal to or greater than 0.10:1. Preferably equal to or less than 4:1, preferably equal to or less than 3:1, preferably equal to or less than 2:1, preferably equal to or less than 1:1, preferably equal to or less than 1.0:1, preferably equal to or less than 0.9:1, preferably equal to or less than 0.8:1, preferably equal to or less than 0.7:1, preferably equal to or less than 0.6:1, preferably equal to or less than 0.5:1, preferably equal to or less than 0.4:1, preferably equal to or less than 0.3:1, preferably equal to or less than 0.2:1, preferably equal to or less than 0.20:1. For example, it is equal to about 0.15:1.

[0133] Preferably, the dry weight ratio of CMC to cold water-insoluble cross-linked dextrin is 0.05:1 to 5:1. Preferably, it is equal to or greater than 0.10:1, preferably equal to or greater than 0.2:1, preferably equal to or greater than 0.3:1, preferably equal to or greater than 0.4:1, preferably equal to or greater than 0.5:1, preferably equal to or greater than 0.6:1, preferably equal to or greater than 0.7:1, preferably equal to or greater than 0.8:1, preferably equal to or greater than 0.9:1, preferably equal to or greater than 1.0:1, preferably equal to or greater than 1.1:1, preferably equal to or greater than 1.2:1, preferably equal to or greater than 1.20:1. Preferably, it is equal to or less than 4:1, preferably equal to or less than 3:1, preferably equal to or less than 2:1, preferably equal to or less than 1.5:1, preferably equal to or less than 1.4:1, preferably equal to or less than 1.3:1, preferably equal to or less than 1.30:1. For example, it is equal to about 1.25:1.

[0134] The present invention also relates to the use of compositions according to this disclosure in pharmaceutical or food compositions (such as food supplements) or nutritional or cosmetic compositions.

[0135] The compositions according to this disclosure can be products intended for individual administration or compositions used to prepare compositions intended for individual administration. They can be powder compositions, tablets, or suspensions. The powder compositions can be administered as is, with water added later. They can also be encapsulated, for example, into hard capsules. The suspensions can be administered as is or encapsulated, for example, into soft capsules.

[0136] Contains cold water-insoluble crostodextrin, compounds selected from 1-decanoyl-racemic-glycerol and CMC, and active... Composition of ingredients

[0137] The combination of cold water-insoluble cross-linked dextrin and 1-decanoyl-racemic glycerol or CMC according to this disclosure allows for increased intestinal penetration (and more broadly, epithelial penetration) of the active ingredient.

[0138] Therefore, this disclosure also relates to a composition comprising:

[0139] -Cold water insoluble cross-linked dextrin; and,

[0140] - Compounds selected from 1-decanoyl-racemic-glycerol and CMC; and,

[0141] - Active ingredients.

[0142] Preferably, the composition is as previously described. Preferably, the cold water-insoluble cross-linked dextrin is as previously described.

[0143] The term "active ingredient" conventionally refers to any substance intended for pharmaceutical, veterinary, food, nutritional, or cosmetic purposes. Preferably, the active ingredient according to this disclosure is a pharmaceutical, nutritional, cosmetic, or veterinary active ingredient, more preferably a pharmaceutical active ingredient. The active ingredients according to this disclosure, particularly pharmaceutical active ingredients, can be selected from so-called small molecules or so-called large molecules (also referred to as "biologics"), such as proteins, nucleic acids, viruses, and cells. Biologics are generally not bioavailable when taken orally, for example because this route of administration leads to their degradation and / or because they cannot cross biological membranes (including epithelium). In other words, these are often active ingredients that require off-gut administration and seek systemic effects. Non-limiting examples of biologics are vaccines, blood components (e.g., clotting factors, blood fractionation products), antibodies (e.g., monoclonal antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, antibody fragments such as variable fragments of antibodies), allergens, hormones such as insulin, gene therapy agents, tissue, cell therapy agents, and recombinant therapeutic proteins. Preferably, the biologics according to this disclosure are selected from proteins. The term "protein" should be interpreted broadly. It specifically covers proteins, regardless of their manufacturing process or the number of their subunits. It also covers protein fragments, peptides, and oligopeptides. It can be selected from natural proteins, recombinant proteins, fusion proteins, or any mixture thereof. It should be understood that when a protein is derived from a natural product, such as a plant, it is preferably an isolated protein.

[0144] Preferably, the protein according to this disclosure has at least 5 amino acids, more preferably at least 10, more preferably at least 20, more preferably at least 30, more preferably at least 40, and more preferably at least 50. Preferably, the protein according to this disclosure has at most 5000 amino acids, more preferably at most 1000, more preferably at most 500, more preferably at most 400, more preferably at most 300, more preferably at most 200, more preferably at most 100, more preferably at most 90, more preferably at most 80, more preferably at most 70, and more preferably at most 60.

[0145] Preferably, the protein (e.g., a pharmaceutical protein) according to this disclosure is selected from enzymes, cytokines, hormones, growth factors, plasma factors, vaccines, and antibodies. Insulin is preferred. The term "insulin" encompasses insulin or any pharmaceutically active derivative thereof, with insulin being preferred.

[0146] Preferably, the active ingredient according to this disclosure is an active ingredient that needs to increase its epithelial (preferably intestinal) permeability. It is preferably selected from BCS Class III and / or Class IV drugs (according to the Biopharmaceutical Classification System of the U.S. Food and Drug Administration, effective November 1, 2022).

[0147] Non-limiting examples of active ingredients requiring increased epithelial (particularly intestinal) permeability include poorly absorbed antibiotics such as erythromycin, colistin, cefamandole, cefotaxime, hydroxycarboxyoxycycline, meropenem, penicillin G, ampicillin, cefoxitin, carrumonam, gentamicin, vancomycin; octreotide; calcitonin; cromoglycine; insulin; glucagon; recombinant human growth hormone; doxorubicin, paclitaxel, etoposide, azidothymidine, and arginine vasopressin. Preferably, the active ingredient according to this disclosure is a biological product, more preferably a protein, and even more preferably insulin.

[0148] Preferably, the active ingredient according to this disclosure is an active ingredient whose absorption can be enhanced by transport via tight junctions.

[0149] Preferably, the active ingredient according to this disclosure is intended to be administered via a route selected from the following: enteric route (including oral or rectal route), skin route, mucosal route (e.g., vaginal route, sublingual route, buccal route), transdermal route, ophthalmic route, nasal route, intranasal route, or bronchopulmonary route. Preferably, the active ingredient according to this disclosure is intended to be administered via the enteric route, more preferably via rectal or oral route. More preferably, it is intended for oral administration.

[0150] Preferably, the active ingredient is loaded in a cold water-insoluble cross-linked dextrin according to this disclosure. Where the nature of the association between the cross-linked dextrin and the active ingredient is unknown, the term "loaded" is intended to mean "associated with," whether within or on the surface of a matrix formed from the cross-linked dextrin.

[0151] Loading can be achieved by adding the active ingredient to, for example, a pre-formed nanosponge suspension prepared as described previously. The mixture is then stirred, for example, at room temperature for 30 minutes, to incorporate the active ingredient. The culture medium is then centrifuged, and the precipitate is collected. It can then be lyophilized for future use.

[0152] Preferably, the loading capacity of the cold water-insoluble cross-linked dextrin according to this disclosure is equal to or greater than 1%, the percentage being expressed as the dry weight of the active ingredient relative to the total dry weight of the loaded cold water-insoluble cross-linked dextrin. This loading capacity is preferably equal to or greater than 5%, preferably equal to or greater than 10%, and preferably equal to or greater than 15%. It is typically equal to or less than 50%, even equal to or less than 40%, even equal to or less than 30%, and even equal to or less than 20%. Those skilled in the art can determine this loading capacity according to the following scheme: the loading capacity is determined by a lyophilized loaded sample, preferably prepared as described above. Briefly, 2 mg to 3 mg of the weighed lyophilized delivery system loaded with the active ingredient is dispersed in 5 mL of distilled water. Sonication (15 min, 100 W) and centrifugation are performed to allow the active ingredient to be released from the cross-linked dextrin. The supernatant is then analyzed to quantify the active ingredient. The loading capacity of the delivery system is calculated as follows: [dry weight of active ingredient / dry weight of lyophilized loaded sample] × 100.

[0153] Compositions containing the active ingredients according to this disclosure can be dosage forms, i.e., products intended for individual administration or compositions that can be used to prepare dosage forms. They can be powder compositions, tablets, or suspensions. Powder compositions can be administered as is, with water added later. They can also be encapsulated, for example, into hard capsules. Suspensions can be administered as is or encapsulated, for example, into soft capsules.

[0154] In a preferred embodiment, the composition according to this disclosure is a suspension.

[0155] According to the use of the compositions disclosed herein

[0156] The present invention also relates to compositions comprising active ingredients according to the present disclosure for use as pharmaceutical agents, and to the use of compositions according to the present disclosure in food compositions such as food supplements or in nutritional or cosmetic compositions. In the context of the present invention, use as a pharmaceutical agent is intended for human or veterinary use, preferably human.

[0157] The present invention also relates to a method for treating or preventing diseases in an organism in need, comprising administering to the organism a composition comprising an active ingredient according to the present disclosure.

[0158] The present invention also relates to a method for feeding organisms in need, comprising administering to the organism a composition comprising an active ingredient according to the present disclosure.

[0159] Preferably, the pharmaceutical preparation and composition are as previously described. Specifically, the active ingredient is preferably loaded in a cold water-insoluble cross-linked dextrin.

[0160] The pharmaceutical agents and compositions are intended to be administered via a route selected from the following: enteric route (including oral or rectal route), skin route, mucosal route (e.g., vaginal route, sublingual route, buccal route), transdermal route, ophthalmic route, nasal route, transnasal route, or bronchopulmonary route. Preferably, the pharmaceutical agents and compositions are intended to be administered via the enteric route, preferably via the rectal or oral route. More preferably, they are intended to be administered orally.

[0161] Therefore, preferably, the pharmaceutical preparation and composition are oral or rectal compositions, specifically for oral or rectal administration of the active ingredient, respectively. More preferably, the pharmaceutical preparation and composition are oral compositions, specifically for oral administration of the active ingredient.

[0162] Preferably, the disease to be treated in this disclosure is diabetes, more preferably insulin-dependent diabetes, more preferably type 1 diabetes and / or gestational diabetes.

[0163] Preferably, the composition according to this disclosure is used in an organism suffering from diabetes, preferably insulin-dependent diabetes, more preferably type 1 diabetes and / or gestational diabetes. Preferably, the organism is a human or animal, preferably a mammal, more preferably a human.

[0164] Preferably, the compositions according to this disclosure are compositions intended for administration via the epithelial route. They are preferably oral or rectal compositions, more preferably oral compositions, i.e., compositions intended for oral administration. They can be compositions intended for administration as is, such as dosage forms containing the active ingredient, or compositions that can be used to prepare compositions intended for administration as is (e.g., dosage forms). They are preferably intended for administration to humans or animals, preferably mammals, more preferably humans. Preferably, the compositions containing the active ingredient according to this disclosure are pharmaceutical preparations, or food compositions, or nutritional compositions, or cosmetic compositions.

[0165] Other ingredients

[0166] The compositions according to this disclosure may contain other ingredients, provided that they do not interfere with the desired properties of the composition, particularly in terms of efficiency and safety. If the composition is a dosage form, these additional ingredients will generally depend on the final Galen formulation. Non-limiting examples of such other ingredients include: binders and fillers (e.g., lactose, microcrystalline cellulose, mannitol), (super)disintegrants (e.g., sodium glycolate starch, crospovidone, croscarmellose), minerals, granulating agents (e.g., polyvinylpyrrolidone, cellulose derivatives, gum arabic, dextrose, gelatin, maltodextrin, starch, starch derivatives, tragacanth gum), flavoring agents, coloring agents, flow aids (e.g., silica), anti-sticking agents (talc), lubricants (e.g., magnesium stearate), solvents (preferably water), buffers, and other penetration enhancers. However, and because they are not essential to achieving the desired effects of this disclosure, the compositions according to this disclosure preferably do not contain additional penetration enhancers.

[0167] Therefore, the present invention also relates to a composition comprising the following substances:

[0168] - Cold water-insoluble cross-linked dextrin, preferably cold water-insoluble cross-linked maltodextrin; and,

[0169] - Compounds selected from 1-decanoyl-racemic-glycerol and CMC; and,

[0170] -Optional active ingredients; and,

[0171] -Optional other ingredients.

[0172] Preferably, the cold water-insoluble cross-linked dextrin is as previously described. Preferably, the active ingredient is as previously described. It is typically loaded in the cold water-insoluble cross-linked dextrin. Preferably, the additional ingredients are as previously described. Preferably, the amounts of the ingredients are as previously described.

[0173] Method for preparing compositions according to the present disclosure

[0174] The present invention also relates to a method for preparing compositions according to the present disclosure, comprising contacting a cold water-insoluble cross-linked dextrin with a compound selected from 1-decanoyl-racemic-glycerol and CMC. The present invention also relates to compositions obtained or obtainable by said method.

[0175] Preferably, the composition is as previously described. Preferably, the cold water-insoluble cross-linked dextrin is as previously described.

[0176] When the composition is a composition containing an active ingredient, the method may advantageously include the step of loading (or “associating”) the active ingredient in the cold water-insoluble cross-linked dextrin. For loading, the cold water-insoluble cross-linked dextrin according to this disclosure can be used in a liquid, solid, or semi-solid state. For example, the cold water-insoluble cross-linked dextrin can be mixed with a small amount of water to obtain a gel. This gel is then mixed with the active ingredient to be loaded, either in powder form or dissolved in a suitable solvent, by kneading and / or mixing. Alternatively, the loaded cold water-insoluble cross-linked dextrin can be obtained by adding a selected amount of the cold water-insoluble cross-linked dextrin with an excess of the guest active ingredient dissolved in a suitable solvent, followed by stirring overnight at room temperature. The loaded cold water-insoluble cross-linked dextrin can be recovered by vacuum filtration.

[0177] The loaded cold water-insoluble cross-linked dextrin can then be blended with a compound selected from 1-decanoyl-racemic-glycerol and CMC.

[0178] Uses of cold water-insoluble crostodextrin in combination with compounds selected from 1-decanoyl-racemic-glycerol and CMC

[0179] This invention also relates to the following combinations:

[0180] -Cold water insoluble cross-linked dextrin,

[0181] Compounds selected from 1-decanoyl-racemic-glycerol and CMC

[0182] Used to increase epithelial permeability of the active ingredient, preferably for increasing intestinal permeability of the active ingredient, and / or for epithelial delivery of the active ingredient, preferably for oral or rectal delivery of the active ingredient, preferably for oral delivery of the active ingredient.

[0183] The present invention also relates to a method for increasing epithelial penetration of an active ingredient and / or a method for epithelial delivery of an active ingredient, the method comprising applying a combination of a cold water-insoluble cross-linked dextrin with a compound selected from 1-decanoyl-racemic glycerol and CMC.

[0184] Preferably, the cold water-insoluble cross-linked dextrin is as previously described. Preferably, the active ingredient is as previously described. Preferably, a biological product, more preferably a protein, more preferably insulin. Preferably, the amount and / or ratio of the cold water-insoluble cross-linked dextrin and / or a compound selected from 1-decanoyl-racemic-glycerol and CMC in the combination is as previously described for the compositions according to this disclosure.

[0185] The term "increased epithelial permeability" traditionally refers to the combination's ability to increase the amount of the active ingredient passing through from the top of the epithelium to the outer side of the epithelial base. In other words, this means that the combination can enhance the active ingredient's ability to cross the epithelium. The term "increased intestinal permeability" traditionally refers to the combination's ability to increase the amount of the active ingredient passing through the intestinal lumen into the blood compartment. This ability to enhance intestinal permeability can be evaluated by comparing the permeability of the active ingredient with that of the active ingredient in the presence of a so-called permeability enhancer. It can be determined, for example, by a Caco-2 cell permeability assay, in which the absorption of the active ingredient is measured. It can be determined according to the detailed protocol given below in the Examples section.

[0186] Preferably, the combination does not impair cell barrier integrity. Those skilled in the art can evaluate cell barrier integrity using a Caco-2 cell permeability assay, wherein fluorescein absorption is measured after exposure to the test combination. This can be evaluated according to the protocol (“fluorescein test”) given below in the Examples section. According to this test, the percentage of absorbed fluorescein is equal to or less than 2.0% dry weight, more preferably equal to or less than 1.5%, and even more preferably equal to or less than 0.7%. Those skilled in the art can also evaluate this membrane integrity using well-known TEER measurements, for example, according to the protocol (“TEER measurement”) given below in the Examples section.

[0187] The combination can be used by applying a cold-water insoluble cross-linked dextrin, a compound selected from 1-decanoyl-racemic-glycerol and CMC, and the active ingredient alone or as a composition. Preferably, the active ingredient is loaded in the cold-water insoluble cross-linked dextrin. Therefore, the method / use advantageously includes the step of loading (or “associating” the active ingredient in the cold-water insoluble cross-linked dextrin.

[0188] Preferably, the combination is used in the form of a composition according to this disclosure, preferably as previously described. It is preferably a composition containing an active ingredient as previously described.

[0189] Therefore, preferably, the present invention relates to the use of a composition comprising:

[0190] -Cold water insoluble cross-linked dextrin; and,

[0191] - Compounds selected from 1-decanoyl-racemic-glycerol and CMC; and,

[0192] -Active ingredients;

[0193] The cold water-insoluble cross-linked dextrin is loaded with the active ingredient and is used to increase the epithelial permeability of the active ingredient (preferably to increase the intestinal permeability of the active ingredient), and / or for the epithelial delivery of the active ingredient (preferably for oral or rectal delivery of the active ingredient, more preferably for oral delivery of the active ingredient).

[0194] Therefore, preferably, the present invention also relates to a method for increasing epithelial permeability of an active ingredient and / or a method for epithelial delivery of an active ingredient, comprising administering a composition to an organism in need, the composition comprising:

[0195] -Cold water insoluble cross-linked dextrin; and,

[0196] - Compounds selected from 1-decanoyl-racemic-glycerol and CMC; and,

[0197] -The active ingredient;

[0198] The cold water-insoluble cross-linked dextrin is loaded with the active ingredient.

[0199] In this disclosure, the amount of an ingredient is expressed as a weight percentage. Unless otherwise stated, these weights are the amount of the ingredient itself, or of the ingredient in powder or oil form. Powdered ingredients typically include small amounts of water (also referred to as moisture % or “loss on drying”) and / or small amounts of impurities. Conversely, in this disclosure, when dry weight is referred to, this refers to the weight without water.

[0200] Other features and advantages of the invention will become clear when reading the embodiments given below, which illustrate the invention but are not intended to limit it.

[0201] Example

[0202] 1. Evaluation of active ingredients using combinations of cold water-insoluble cross-linked dextrin (nano sponge) and various penetration enhancers. intestinal permeability .

[0203] The inventors screened various penetration enhancers that could be combined with cold water-insoluble cross-linked dextrin nanoparticles (hereinafter referred to as "nanosponges"). Insulin was selected as the active ingredient.

[0204] 1.1. Test Materials

[0205] Insulin permeability of different samples was measured, as shown in Table 1:

[0206] [Table 1]

[0207]

[0208] The nano-sponge is composed of cold-water insoluble pea maltodextrin (KLEPTOSE) cross-linked with sodium trimetaphosphate, having a DE of 17 and a Mw of 12000 Da. ® Linecaps (ROQUETTE) are composed of the following, obtained according to patent application WO 2021 / 254662 A1, Example 2 (page 13, line 8 to page 14, line 2), which is incorporated herein by reference.

[0209] The penetration enhancers tested were: 1-decanoyl-racemic glycerol, carboxymethyl cellulose (CMC), sodium sapoxetine (SNAC), lauroyl-L-carnitine, non-ethylene glycol monododecyl ether, polyethylene glycol 3000 50% (w / v) solution, 20 μm SiO2 silica, 150 nm SiO2 silica, kaolinite, and montmorillonite.

[0210] For all experiments, the insulin used was bovine insulin (Sigma / I5500).

[0211] The nano-sponge suspension was prepared as follows:

[0212] - At room temperature, with stirring, crude powder of cold water-insoluble cross-linked dextrin is added to distilled water at a concentration of 10 mg / mL to begin preparing a suspension.

[0213] -Use a high-shear homogenizer (Ultraturrax) ® (IKA, Konigswinter, Germany) dispersed the suspension at 24,000 rpm for 10 minutes.

[0214] - High-pressure homogenization was performed for 90 minutes at a back pressure of 500 bar using an EmulsiFlex C5 instrument (Avastin, USA) to further reduce the size.

[0215] - The homogenized nanosuspension was purified by dialysis (Spectrapore, cellulose membrane, 12000 Da cutoff) to remove any possible synthetic residues.

[0216] - The nano suspension is stored at 4°C.

[0217] The insulin-loaded nanosponges were prepared as follows: A 2 mg / mL solution of insulin powder was prepared in distilled water adjusted to pH 2.3 with phosphoric acid. The insulin solution was added to the nanosponge suspension prepared as described above, with a weight ratio of insulin solution to nanosponge suspension of 1:5. The mixture was stirred at room temperature for 30 minutes and then centrifuged. The supernatant was separated from the collected precipitate and lyophilized. The loading capacity of the nanosponges was 14 ± 1%, expressed as the dry weight of insulin relative to the total dry weight of the nanosponges.

[0218] 1.2. Intestinal osmotic assay (Caco-2 assay)

[0219] Insulin penetration was evaluated using a 24-well Readycell Caco-2 plate (CacoReady 24 Transwell (Costar) – KRECECCR01) via Caco-2 assay. In short ( Figure 1 Samples were prepared at the desired concentration in Caco-2 buffer A (Hanks balanced salt solution (HBSS) + 5 mM 2-(N-morpholino)ethanesulfonic acid (MES) pH 6.5), and 250 μL of each sample was placed in the top chamber of a Caco-2 plate. 750 μL of buffer BHBSS-HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (pH 7.4) was added to the basolateral chamber. The Caco-2 plate was incubated at 37 °C and 5% CO2, and insulin permeability was evaluated by measuring the amount of insulin reaching the basolateral chamber. All materials were tested at non-cytotoxic concentrations, and the insulin concentration for all samples was 7.5 UI / mL.

[0220] The detailed plan is as follows.

[0221] First, prepare the following stock solution:

[0222] - Free insulin stock solution: Dissolve insulin at a concentration of 2 mg dry weight / mL in H2O / HCl pH 2.

[0223] -Insulin-loaded nanosponges stock solution (prepared immediately): 15 mg of lyophilized insulin-loaded nanosponges (corresponding to 2.1 mg dry weight insulin) was added to 1 mL of autoclaved saline solution (water + 0.9% NaCl) and gently dispersed until the suspension was visually homogeneous. Therefore, the stock solution contains 2.1 mg dry weight / mL insulin, corresponding to 60 IU / mL insulin.

[0224] - Permeation enhancer stock solution: Prepare each permeation enhancer in HBSS buffer (10-fold concentrated compared to the highest concentration tested).

[0225] Then, samples were prepared from these stock solutions in buffer A to obtain the following concentrations (weights expressed as dry weight):

[0226] - "Free insulin": 7.5 UI / mL of insulin;

[0227] - "Insulin-loaded nanosponges": 7.5 UI / mL of insulin;

[0228] - "Insulin-loaded nanosponges + 1-decyl-racemic-glycerol": 7.5 UI / mL insulin + 1000 μM or 500 μM or 250 μM 1-decyl-racemic-glycerol (Sigma / M2140).

[0229] - "Insulin-loaded nanosponges + sodium carboxymethyl cellulose": 7.5 UI / mL insulin + 0.4% or 0.2% or 0.1% (w / v) CMC (Sigma / 419273).

[0230] - "Insulin-loaded nanosponges + saporixa sodium": 7.5 IU / mL insulin + 1 mg / mL or 0.5 mg / mL or 0.25 mg / mL saporixa sodium (SNAC) 203787-91-1;

[0231] - "Insulin-loaded nanosponges + lauroyl-L-carnitine": 7.5 UI / mL insulin + 0.25 mM or 0.125 mM or 0.625 mM lauroyl-L-carnitine (Sigma / 39953).

[0232] - "Insulin-loaded nanosponges + nonaethylene glycol monododecyl ether": 7.5 UI / mL insulin + 0.01 mM or 0.05 mM or 0.025 mM nonaethylene glycol monododecyl ether (Sigma / P9641).

[0233] - "Insulin-loaded nanosponges + polyethylene glycol": 7.5 UI / mL insulin + 0.2% or 0.1% or 0.05% (w / v) polyethylene glycol 3000 (Sigma / 81269).

[0234] - "Insulin-loaded nanosponges + 20μm SiO2 silica": 7.5 UI / mL insulin + 0.8% or 0.4% or 0.2% (w / v) 20μm SiO2 silica (Sigma / 904376).

[0235] - "Insulin-loaded nanosponges + 150nm SiO2 silica": 7.5 UI / mL insulin + 0.8% or 0.4% or 0.2% (w / v) 150nm SiO2 silica (Sigma / 904414).

[0236] - "Insulin-loaded nanosponges + kaolinite": 7.5 UI / mL insulin + 0.2% or 0.1% or 0.05% (w / v) kaolinite (Sigma / 03584).

[0237] - "Insulin-loaded nanosponges + montmorillonite": 7.5 UI / mL insulin + 0.4% or 0.2% or 0.1% (w / v) montmorillonite (Sigma / 69866).

[0238] For the "insulin-loaded nanosponges + permeability enhancer" sample, first dilute the permeability enhancer stock solution in buffer A, then add the insulin-loaded nanosponges stock solution at the target concentration and gently disperse.

[0239] Remove Caco-2 growth medium from 24-well Readycell Caco-2 plates. Then, add 250 μL of each sample prepared in buffer A [HBSS-MES (pH 6.5)] to the top chamber. Add 800 μL of buffer B [HBSS-HEPES (pH 7.4)] to the outer chamber. Collect 50 μL and transfer to a Greiner 651201 plate for analysis (blank = 0 min, incubation time = t0). All assays are performed in triplicate (n = 3).

[0240] Place the top chamber in the outer chamber of the basement and incubate for 120 minutes (37°C, 5% CO2).

[0241] At t0+15 min, t0+30 min, t0+60 min, and t0+120 min, 50 μL of culture medium was collected in the basal outer chamber and transferred to a Greiner 651201 plate for analysis. Insulin was detected using ultra-high performance liquid chromatography (UHPLC-QqQ) coupled with triple quadrupole mass spectrometry, with the detection limit optimized for testing all permeation enhancers. 50 μL of fresh buffer B was added to the basal outer chamber. The top chamber was then returned to the basal outer chamber.

[0242] The results are shown in Figures 2 to 11 middle.

[0243] 1.3. Results

[0244] By comparing two controls ("free insulin" and "insulin-loaded nanosponges"), it can be seen that the nanosponges increased insulin permeability. When the nanosponges were combined with 1-decanoyl-racemic-glycerol or CMC, a surprisingly high permeability enhancement was achieved. Figure 2 and Figure 3This enhancement is much greater than when the nanosponges are used alone. Although this increase was observed only at concentrations of 1-decanoyl-racemic-glycerol and CMC at 1000 μM and 0.2%, respectively, it should be noted that this does not imply poor performance at other concentrations. In fact, the insulin detection method used in this test may not have been sensitive enough to detect the increase at all tested concentrations. Regarding other permeation enhancers, no permeation enhancement was observed when they were used in combination with the nanosponges. Figures 4 to 11 The osmosis levels were similar to those obtained with free insulin, but lower than those obtained with nanosponges alone. In other words, these osmosis enhancers inhibited the osmosis effect of the nanosponges.

Claims

1. A composition comprising: - a cold water insoluble crosslinked dextrin; and, - a compound selected from 1-decanoyl-rac-glycerol and carboxymethylcellulose.

2. The composition according to claim 1, wherein the dextrin is selected from pyrodextrin, maltodextrin, cyclodextrin or mixtures thereof.

3. The composition according to claim 1 or 2, wherein the cold water insoluble crosslinked dextrin is obtainable by reacting a dextrin with a crosslinking agent selected from trimetaphosphate, dicarboxylic acid, dianhydride, carbonyldiimidazole, diphenyl carbonate, triphosgene, acyl dichloride, diisocyanate, diepoxide or any mixture thereof.

4. The composition according to any one of claims 1 to 3, wherein the cold water insoluble crosslinked dextrin is obtainable by reacting a dextrin with a crosslinking agent, wherein the molar ratio of the crosslinking agent to the anhydroglucose unit of the dextrin is equal to or higher than 0.1 :

1.

5. The composition according to any one of claims 1 to 4, wherein the cold water insoluble crosslinked dextrin is in particulate form.

6. The composition according to any one of claims 1 to 5, wherein the composition is intended to be administered by the epithelial route.

7. The composition according to any one of claims 1 to 6, wherein the composition is an oral composition.

8. The composition according to any one of claims 1 to 7, further comprising an active ingredient.

9. The composition according to claim 8, wherein the active ingredient is selected from a BCS class III drug, a BCS class IV drug, a biopharmaceutical or any mixture thereof.

10. The composition according to claim 8 or 9, wherein the active ingredient is selected from a protein.

11. The composition according to any one of claims 8 to 10, wherein the active ingredient is loaded in the cold water insoluble crosslinked dextrin.

12. The composition according to any one of claims 8 to 11, for use as a medicament.

13. The composition according to any one of claims 8 to 11, for non-pharmaceutical use in a food, nutraceutical or cosmetic composition.

14. A method for preparing a composition according to any one of claims 1 to 12, comprising contacting the cold water insoluble crosslinked dextrin with the compound selected from 1-decanoyl-rac-glycerol and carboxymethylcellulose.

15. The following combination: - a cold water insoluble crosslinked dextrin, - a compound selected from 1-decanoyl-rac-glycerol and carboxymethylcellulose, for use in increasing epithelial permeation of an active ingredient, preferably for use in increasing intestinal permeation of an active ingredient.

16. The following combination: - a cold water insoluble crosslinked dextrin, - a compound selected from 1-decanoyl-rac-glycerol and carboxymethylcellulose, for use in epithelial delivery of an active ingredient, preferably for use in oral or intrarectal delivery of an active ingredient, more preferably for use in oral delivery of an active ingredient.

17. The use according to claim 15 or 16, wherein the active ingredient is selected from a BCS class III drug, a BCS class IV drug, a biopharmaceutical or any mixture thereof.

18. The use according to any one of claims 15 to 17, wherein the active ingredient is selected from proteins.

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