JP2024096881A - Jelly preparation for sublingual administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a jelly preparation for sublingual administration that retains the advantages of sublingual administration, such as rapid drug absorption and systemic transfer, and avoidance of degradation by drug-degrading enzymes and the first-pass effect in the digestive tract or liver, while causing little discomfort and being able to retain the shape for a relatively long time without being disintegrated by saliva, allowing the same to be retained under the tongue for a relatively long time.

SOLUTION: The present invention includes, for example, a semi-solid jelly preparation for sublingual administration having a jelly-like form, which is mainly composed of a drug or an allergen for desensitization therapy, a gel base, and water, and has a jelly strength in the range of 10,000 Pa to 300,000 Pa (excluding those containing trivalent metal ions).

SELECTED DRAWING: Figure 6

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention belongs to the technical field of jellies (jelly-like preparations) containing medicinal ingredients. The present invention relates to a jelly that is administered sublingually from which the medicinal ingredients are applied to the whole body.

For example, some elderly people and children have difficulty taking tablets. For those people who have difficulty taking tablets, jelly preparations in which medicines are made into a gelatinous form are known. These are also listed as oral jelly preparations in the Japanese Pharmacopoeia.

On the other hand, the sublingual area is covered with oral mucosa, and there are veins (lingual vein and sublingual vein) that connect to the vena cava via the internal jugular vein through a thin mucosa. Therefore, the absorption and systemic transfer of drugs from the sublingual area is extremely fast, and the therapeutic effect can be observed immediately after drug administration. In addition, there are almost no drug-degrading enzymes in the oral cavity, and the absorbed drugs are not subject to the first-pass effect in the digestive tract or liver. From this perspective, sublingual tablets, which are oral tablets that dissolve medicinal ingredients quickly under the tongue and are absorbed through the oral mucosa, are listed in the Japanese Pharmacopoeia. In this way, the absorption of medicinal ingredients (drugs) from the sublingual area has been done for a long time, but until now, drugs that are expected to have a fast effect, such as nitroglycerin and opioid painkillers, have been applied to sublingual administration, especially for the purpose of controlling pain during heart attacks and emergency situations. The mainstream formulations are quickly disintegrating tablets and sublingual sprays.

Patent Literature 1 discloses a sublingual formulation of apomorphine, which is required to be immediately effective. Patent Literature 1 lists lozenges, pills, tablets, films, and strips as specific formulations for sublingual administration of apomorphine. Patent Literature 1 also lists a hydrogel formulation that is dispensed and administered under the tongue.

JP 2016-147882 A

As described above, sublingual administration of medicinal ingredients (drugs) has many advantages, such as the fact that drugs are generally absorbed and transferred to the whole body very quickly from the sublingual route, the therapeutic effect can be exerted quickly after drug administration, and the decomposition by drug-degrading enzymes and the first-pass effect in the digestive tract or liver can be avoided.
However, compared with oral administration agents, the number of sublingual agents in clinical use is extremely limited. The reasons for this include, for example, the following:

(1) Drugs administered sublingually are washed away by saliva secreted in the oral cavity, making it difficult to keep them under the tongue for a long period of time.
(2) Therefore, it is difficult to apply this method to drugs other than those with high membrane permeability that are rapidly absorbed through the sublingual mucosa after dissolution.
(3) It is difficult to hold a solid preparation under the tongue for a long period of time due to discomfort or irritation.
(4) Because it is absorbed extremely quickly sublingually, the blood concentration becomes extremely high immediately after administration, which may cause temporary side effects.

An object of the present invention is to provide a new preparation for sublingual administration that can solve the above-mentioned problems associated with sublingual administration.

As a result of extensive research, the inventors focused on jelly formulations, which are widely known as a form of oral administration preparation, and discovered that the above problems could be solved by using such jelly formulations, thus completing the present invention.

The present invention can include, for example, the following.
[1] A semi-solid jelly preparation for sublingual administration, characterized in that it is mainly composed of a drug or an allergen for hyposensitization therapy, a gel base, and water.
[2] The jelly for sublingual administration described in [1] above, further comprising one or more additives selected from the group consisting of thickeners, pH adjusters, buffers, suspending/dispersing agents, sweeteners, flavorings, fragrances, excipients, colorants, stabilizers, solubilizers, surfactants, and preservatives.
[3] The jelly for sublingual administration described in [1] or [2] above, wherein the drug is a drug that is easily metabolized or decomposed in the body, or a drug that is not sufficiently absorbed in the body by oral administration.
[4] The jelly for sublingual administration according to any one of the above-mentioned [1] to [3], wherein the drug is an immunosuppressant, a Ca antagonist, a PP inhibitor, a peptide drug, a nucleic acid, a low membrane permeable drug, or a low solubility drug.
[5] The jelly for sublingual administration described in [4] above, wherein the peptide drug is insulin, a GLP-1 analogue, calcitonin, or vasopressin.
[6] The jelly for sublingual administration described in [1] or [2] above, wherein the allergen is pollen, dust mites, house dust, or particulate matter suspended in the air.
[7] The gel base is selected from the group consisting of (1) pectin, agar, carrageenan, gellan gum, xanthan gum, locust bean gum, guar gum, tara gum, tamarind seed gum, psyllium seed gum, starch, curdlan, chitosan, pullulan, furcellaran, celluloses, hyaluronic acid, alginic acid or a salt thereof, mannans, gelatin, collagen, and whey; or (2) polyacrylic acid or a salt thereof, polylactic acid, poly The jelly for sublingual administration according to any one of the above [1] to [6], which is one or more synthetic polymers selected from the group consisting of glycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, poly(N-substituted acrylamide), poly(N-substituted methacrylamide), poly(N-vinyl acetamide), polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, and polyvinyl alcohol, or both of (1) and (2).
[8] The jelly for sublingual administration described in any one of [1] to [7] above, which has a flat plate shape.
[9] The jelly for sublingual administration described in [8] above, which has a semicircular arc-shaped portion or an approximately circular arc-shaped portion in its planar shape.
[10] A jelly for sublingual administration described in [8] or [9] above, having a slit to avoid the lingual frenulum or sublingual caruncle.
[11] The jelly for sublingual administration according to any one of the above [8] to [10], having a thickness within the range of 0.1 mm to 10 mm.
[12] The jelly for sublingual administration according to any one of the above [1] to [11], having a jelly strength in the range of 1,000 Pa to 1,000,000 Pa.
[13] A system for administering drugs or allergens, comprising a jelly for sublingual administration according to any one of [1] to [12] above, and a means for inserting the jelly for sublingual administration under the tongue of a recipient.

According to the present invention, while maintaining the advantages of sublingual administration, such as rapid absorption and systemic transfer of drugs, and avoidance of decomposition by drug-degrading enzymes and first-pass effects in the digestive tract or liver, there is little discomfort, and the drug can be kept in a relatively long form under the tongue without being broken down by saliva, so that the drug can be kept for a relatively long time. Therefore, even medicinal ingredients that are not expected to have a very immediate effect can be administered sublingually for systemic application. In addition, immune tolerance can be efficiently induced by exposing the whole body to an allergen for hyposensitization therapy.

FIG. 1 is a schematic diagram showing one embodiment of a jelly according to the present invention. FIG. 2 is a schematic diagram showing another embodiment of the jelly according to the present invention. 1 shows the drug absorbability in rats from the jelly of the present invention containing antipyrine (ANT). The upper figure shows the time course of ANT concentration in plasma, with the vertical axis showing plasma concentration (ng/mL) and the horizontal axis showing time (min). The lower figure shows the time course of ANT bioavailability (BA) up to 120 minutes after administration, with the vertical axis showing BA (%) and the horizontal axis showing time (min). 1 shows the drug absorbability in rats from the jelly of the present invention containing propranolol (PPR). The upper figure shows the time course of PPR concentration in plasma, with the vertical axis showing plasma concentration (ng/mL) and the horizontal axis showing time (min). The lower figure shows the time course of PPR bioavailability (BA) up to 120 minutes after administration, with the vertical axis showing BA (%) and the horizontal axis showing time (min). 1 shows the drug absorbability in rats from the jelly of the present invention containing atenolol (ATE). The upper figure shows the time course of ATE concentration in plasma, with the vertical axis showing plasma concentration (ng/mL) and the horizontal axis showing time (min). The lower figure shows the time course of ATE bioavailability (BA) up to 120 minutes after administration, with the vertical axis showing BA (%) and the horizontal axis showing time (min). 1 is a diagram showing the shape and dimensions of a jelly according to the present invention, the left diagram being a plan view with dimensions added, and the right diagram being a photograph of the actual product. 1 is a photograph showing the state in which the jelly according to the present invention is applied sublingually to a human.

The present invention will be described in detail below.
1. Jelly preparation for sublingual administration according to the present invention The jelly preparation for sublingual administration according to the present invention (hereinafter referred to as "jelly preparation of the present invention") is a semi-solid jelly preparation, characterized in that it is mainly composed of a drug or an allergen for hyposensitization therapy, a gel base, and water. The jelly preparation of the present invention may further contain additives. The jelly preparation of the present invention may have a disk-like or flat plate-like shape. The jelly preparation of the present invention may have a jelly strength that causes little discomfort when inserted into the sublingual cavity or a jelly strength suitable for maintaining its shape.

Here, the term "semi-solid jelly agent" refers to a composition in a viscoelastic state in which a sol (e.g., polymer solution, micelle solution, suspension, emulsion) has lost fluidity and maintains a certain shape. There are no particular limitations on the structure as long as it has a structure in which a fluid such as water is trapped in a three-dimensional network formed by polymers or colloidal particles, and the crosslinking points of the three-dimensional network may be physical bonds (e.g., hydrogen bonds, entanglement of molecules, etc.) or chemical bonds (e.g., covalent bonds).
The term "mainly composed of" means that other components are permitted to be contained within a range that does not impair the effects of the present invention, and does not limit the content of other components, but the content of such other components is usually less than 50% by weight based on the total amount, preferably 30% by weight or less, more preferably 20% by weight or less to 10% by weight or less, and may be 0% by weight.

"Jelly strength" refers to the value shown as the stress at the top of the upward convex shape (considered to be the breaking stress) when a stress-strain curve is plotted with the stress of the sample on the vertical axis and the compressive strain rate of the sample on the horizontal axis. A breaking stress measuring device, such as Yamaden's RHEONER RE2-3305C, can be used for the measurement.

1.1 Drug or allergen for hyposensitization therapy The jelly of the present invention contains a drug or an allergen for hyposensitization therapy (hereinafter also referred to as "drug, etc."). The drug is not particularly limited as long as it has medical activity. Among them, for example, drugs that are easily metabolized or decomposed in the body or drugs that cannot be sufficiently absorbed in the body by oral administration are preferable.
The above-mentioned hyposensitization therapy includes desensitization therapy, and also includes not only conventional allergen-specific immunotherapy (or antigen-specific immunotherapy), but also, for example, peptide immunotherapy and CpG-DNA immunotherapy as allergy therapies.

Examples of drugs that are easily metabolized or decomposed in the body include drugs that are easily metabolized in the digestive tract or liver, and drugs that are easily decomposed in the digestive tract.

Drugs that are susceptible to first-pass metabolism in the digestive tract or liver include, for example, immunosuppressants, calcium antagonists, and benzodiazepines. Examples of immunosuppressants include tacrolimus and cyclosporine. Examples of calcium antagonists include nifedipine, nicardipine, and diltiazem. Examples of benzodiazepines include midazolam and triazolam. Other examples of drugs that are susceptible to first-pass metabolism in the digestive tract or liver include allopurinol, propranolol, isoproterelol, levodopa, estradiol, testosterone, pentazocine, and lidocaine.

Examples of drugs that are easily decomposed in the digestive tract include proton pump inhibitors (PP inhibitors) and macrolide antibiotics.

Examples of PP inhibitors include omeprazole, lansoprazole, esomeprazole, etc. Examples of macrolide antibiotics include erythromycin, etc.

Drugs to which the present invention is preferably applied include, for example, peptide drugs such as insulin, GLP-1 analogues (e.g., semaglutide, liraglutide, exenatide), calcitonin, and vasopressin; nucleic acid drugs; low membrane permeability drugs; and low solubility drugs.

A low-membrane-permeable drug is a drug that is not sufficiently absorbed after oral administration because membrane permeation becomes the rate-limiting factor, and specific examples include alendronate, pranlukast, and atenolol. A low-solubility drug is a drug that is not sufficiently absorbed after oral administration because the dissolution process in the digestive tract becomes the rate-limiting factor, and examples include albendazole and telmisartan.

Allergens for hyposensitization therapy are not particularly limited as long as they can be used for that purpose. An allergen is a natural or artificial causative substance (antigen) that causes allergic symptoms, and "allergens for hyposensitization therapy" refer to allergens for treating allergic diseases that are used for the purpose of the therapy. Specifically, examples of such allergens include pollen, house dust, fungi, animal antigens, insect antigens, other particulate matter (PM) suspended in the air, endotoxins, peptide drugs, and allergens bound to bacterial CpG-DNA. The allergens may be obtained from nature, or may be genetically modified allergens or genome-edited allergens.

Examples of pollen include cedar pollen, cypress pollen, ryegrass pollen, timothy grass pollen, orchard grass pollen, white birch pollen, ragweed pollen, giant ragweed pollen, mugwort pollen, Japanese knotweed pollen, solidago altissima pollen, red pine pollen, and alder pollen.

House dust can include mites such as dust mites, animal body dirt, feces, urine, fibers, etc. Specific examples of dust mites include house dust mites, house dust mites, and Dermatophagoides pteronyssinus.

Fungi include, for example, Aspergillus, Alternaria, Penicillium, Candida, Cladosporium, Aspergillus, and Malassezia.

Examples of animal antigens include dog hair, cat hair, feathers, rabbit hair, and sheep hair.

Insect antigens include, for example, bee venom, mosquitoes, cockroaches, midges, butterflies, and moths.

Examples of PM include soil particles such as yellow sand, exhaust particles such as diesel exhaust particles (DEP or DPM), tire wear dust, soot, volcanic ash, PM10, suspended particulate matter (SPM), PM2.5, and PM0.1.

In addition, examples of peptide drugs that can be used as allergens for the above-mentioned hyposensitization therapy include peptides derived from allergens, peptides containing T cell epitopes derived from allergens, and multi-epitope peptides that link multiple T cell epitopes (multi-T cell epitope peptides).

The amount of drug or other substance contained in the jelly of the present invention varies depending on the type of drug or other substance contained therein and the type of gel base used, but can be appropriately selected as desired within the range of, for example, 0.1 to 20% by weight.

1.2 Gel Base The jelly of the present invention contains a gel base. Examples of the gel base used in the jelly of the present invention include natural polymers and synthetic polymers that form a gel by the action of water. The natural polymers and synthetic polymers may be used in combination, or may be a complex of these.
The gel base is used in oral medicinal jellies and food jellies, and similar substances can be used. In addition, for example, when a synthetic polymer is used, a jelly that is to be taken out of the mouth after a certain time has elapsed since administration can be used.

Examples of such natural polymers include polysaccharides and proteins (including glycoproteins). The polysaccharides and proteins may be used in combination, or may form complexes of these (e.g., proteoglycans, etc.).

Examples of the polysaccharides include agar, pectin, pectic acid, pectinic acid, carrageenan (κ-carrageenan, ι-carrageenan, etc.), gellan gum (native gellan gum, deacylated gellan gum, etc.), xanthan gum, locust bean gum, guar gum, tara gum, tamarind seed gum, psyllium seed gum, starch, curdlan, chitin, chitosan, pullulan, furcellaran, celluloses (nitrocellulose, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, microfibrous cellulose, fermented cellulose, etc.), hyaluronic acid, alginic acid or salts thereof, mannans (konjac mannan, galactomannan, etc.), gum arabic, karaya gum, tragacanth gum, arabinogalactan, ghatti gum, glucosamine, soybean polysaccharides, etc. Among these, agar, pectin, and alginates are preferred.
These polysaccharides may be used alone or in combination of two or more kinds.

Examples of the protein include gelatin, collagen, whey, actin, tubulin, hemoglobin S, insulin, fibrin, albumin (egg white albumin, serum albumin, etc.), myosin, egg white protein, soybean protein, casein, etc. Among these, gelatin is preferred.
These proteins may be used alone or in combination of two or more.

The synthetic polymer is not particularly limited as long as it does not irritate the mucous membrane in the oral cavity, and examples thereof include polyacrylic acid or a salt thereof, polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, N-substituted acrylamide, N-substituted methacrylamide, N-vinyl acetamide, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, etc. Among these, polyethylene oxide, polyethylene glycol, and polyvinyl alcohol are preferred.
These synthetic polymers may be used alone or in combination of two or more.
The synthetic polymer may be used in combination with a crosslinking agent, if necessary. Examples of the crosslinking agent used in this case include N,N'-methylenebisacrylamide, glutaraldehyde, formaldehyde, ethylene oxide, polyisocyanate, and dimethylol urea. The crosslinking agent may be used alone or in combination of two or more.

These gel bases may be used alone or in combination of two or more. When using a combination of gel bases, it is preferable to use a combination of carrageenan and locust bean gum, a combination of agar, xanthan gum, and locust bean gum, or a combination of carrageenan, xanthan gum, locust bean gum, and sodium polyacrylate.

The content of the gel base in the jelly of the present invention varies depending on the type of gel base and the desired jelly strength, and may be appropriately selected depending on the effective amount of the drug, etc., and is not particularly limited, but as a guideline, for example, a range of 0.01 to 10% by weight is appropriate. From the viewpoint of maintaining the shape of the jelly of the present invention under the tongue, it is preferable to make it 0.1% by weight or more, and more preferably 0.3% by weight or more. Also, from the viewpoint of discomfort under the tongue, it is preferable to make it 5% by weight or less, and more preferably 3% by weight or less.

1.3 Water The jelly preparation of the present invention contains water. Such water is not particularly limited, and examples thereof include purified water, distilled water, mineral water, and tap water. Water containing minerals may be used, and the water quality may be hard water or soft water. Among them, purified water is preferred in consideration of reactivity with drugs and gel bases.

The amount of water contained in the jelly of the present invention varies depending on the desired jelly strength, etc., and can be appropriately selected depending on the effective amount of drugs, etc., the amount of gel base, etc.

1.4 Additives The jelly of the present invention may contain any additive in an appropriate amount depending on necessity and purpose. Examples of the additives include thickeners, pH adjusters, buffers, suspending/dispersing agents, sweeteners, flavorings, fragrances, excipients, colorants, stabilizers, solubilizers, surfactants, and preservatives.
For example, by blending these additives in accordance with the preferences of the recipient of the jelly of the present invention, the jelly can be made to have a flavor, texture, etc. that is easy for the recipient to take. Also, for example, by diversifying the blending variations, the jelly can be made to have a flavor, texture, etc. that the recipient will not tire of, for those who need to take drugs continuously for a long period of time, such as throughout their life, or for several years in desensitization therapy.

Examples of thickeners include xanthan gum, locust bean gum, guar gum, tara gum, tamarind seed gum, starches, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, carmellose or a salt thereof, glucomannan, agar, and succinoglycan.
Examples of pH adjusters include glucono-delta lactone, anhydrous citric acid, citric acid or a salt thereof, malic acid, ascorbic acid, maleic acid, malonic acid, glutamic acid or a salt thereof, acetic acid or a salt thereof, propionic acid, aspartic acid, adipic acid, fumaric acid, phthalic acid, succinic acid or a salt thereof, tartaric acid or a salt thereof, lactic acid or a salt thereof, sodium hydroxide, potassium hydroxide, monoethanolamine, diethanolamine, phosphoric acid or a polymer thereof, and a salt thereof.

Examples of buffering agents include phosphoric acid or its salts, carbonates, citric acid or its salts, tartaric acid or its salts, and acetic acid or its salts.

Examples of suspending and dispersing agents include starches, lactose, polyoxyethylene polyoxypropylene glycol, ethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose, crystalline cellulose-carmellose sodium, gum arabic, sucrose fatty acid esters, glycerin fatty acid esters, propylene glycol, polyoxyethylene hydrogenated castor oil, macrogol, polysorbate, and sodium lauryl sulfate.

Examples of sweeteners include sucrose, powdered reduced maltose syrup, aspartame, acesulfame potassium, thaumatin, sucralose, saccharin, sodium saccharin, erythritol, xylitol, maltitol, mannitol, advantame, dipotassium glycyrrhizinate, stevia, dextrin, lactulose, neotame, isomalt, fructose, brown sugar, and honey.

Flavoring agents that can be used include, for example, citric acid or its salts, ascorbic acid or its salts, glutamic acid or its salts, fruit juice, menthol, cinnamon powder, cacao powder, brown sugar, honey, and green tea powder.

Flavors include, for example, menthol, apple flavor, acerola flavor, orange flavor, lemon flavor, grape flavor, strawberry flavor, sweet potato flavor, beef flavor, peach flavor, maple flavor, tomato flavor, plum wine flavor, lemon tea flavor, chocolate flavor, cherry flavor, green tea flavor, and vanilla flavor.

Examples of excipients include sugar alcohols, starches, celluloses, and dextrin.
As the sugar alcohol, for example, maltitol, lactitol, mannitol, erythritol, xylitol, trehalose, sorbitol, and isomalt can be used.
As the starch, for example, potato starch, rice starch, and wheat starch can be used.
Examples of the cellulose that can be used include ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose, and crystalline cellulose-carmellose sodium.

Examples of coloring agents include edible tar-based dyes, carotenoid-based dyes, chlorophyll-based dyes, curcumin, betanin, carthamin, riboflavin, carminic acid, and caramel.

Examples of stabilizers include tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, erythorbic acid, sodium erythorbate, ascorbic acid, and sodium ascorbate.

Examples of solubilizers include propylene glycol, glycerol, polyethylene glycol, macrogol, polysorbate, sodium lauryl sulfate, sucrose fatty acid esters, glycerin fatty acid esters, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid esters, lecithin, and cyclodextrins (α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β-cyclodextrin, and maltosyl β-cyclodextrin).

Examples of surfactants include polysorbates, sodium lauryl sulfate, sucrose fatty acid esters, glycerin fatty acid esters, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, propylene glycol fatty acid esters, and lecithin.

Preservatives include, for example, sorbic acid or its salts, benzoic acid or its salts, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), milt protein extracts (milt protein, milt hydrolysate, protamine, nuclear protein), and polylysine (ε-polylysine).

The above various additives may be used alone or in combination of two or more.

1.5 Shape The shape of the jelly of the present invention may be appropriately selected as desired, but is preferably a flat plate that can be stored in the sublingual cavity. When the jelly of the present invention has a flat plate shape, the thickness thereof is, for example, appropriately within the range of 0.1 mm to 10 mm, and preferably within the range of 0.5 mm to 5 mm.

Generally, teeth grow in the lower jaw of a human being in an approximately arc-like arrangement, and therefore the jelly of the present invention preferably has a semicircular or approximately arc-like portion in its planar shape, as shown in Fig. 1. The approximately arc includes not only circular arcs, but also quadratic curves such as elliptical arcs and conic sections, and similar free curves.
The jelly of the present invention may also have a shape having a plurality of semicircular or approximately circular arc portions, such as a crescent shape.

In addition, since the lingual frenulum and sublingual caruncle are present under the human tongue, it is preferable that the jelly of the present invention has a slit to avoid them. The shape of the slit is not particularly limited as long as it avoids the lingual frenulum and sublingual caruncle, and it can be, for example, a linear slit or a cutout in a wedge, rectangle, semicircle, oval, or other shape. Figure 2 shows an example of the shape of the jelly of the present invention having a roughly semicircular cutout.

From the viewpoint of discomfort when applied sublingually, it is preferable that the width of the slit is wider as long as it does not exceed the width of the jelly of the present invention itself. When the width of the slit is made the same as the width of the jelly of the present invention, it can have a shape as shown in the right figure of Figure 2, for example. The width of the slit is suitably within the range of 10 mm to 50 mm, for example, and preferably within the range of 30 mm to 45 mm.

The shape of the jelly of the present invention can be a general shape that fits the sublingual cavity of an unspecified or specified number of people, or it can be an individual shape that fits the sublingual cavity of each individual recipient.

1.6 Jelly Strength The jelly strength of the jelly preparation of the present invention may be appropriately selected as desired, but is suitably within the range of 1,000 Pa to 1,000,000 Pa, and preferably within the range of 10,000 Pa to 300,000 Pa.
The jelly of the present invention can have a jelly strength that makes it difficult for the jelly to disintegrate in the sublingual cavity throughout the sustained release period of a drug, etc. From the viewpoint of maintaining such a shape, the jelly strength is preferably 10,000 Pa or more, and more preferably 30,000 Pa or more.
In addition, the jelly of the present invention can have a jelly strength that causes little discomfort when stored in the sublingual cavity. From the viewpoint of causing little discomfort, the jelly strength is preferably 300,000 Pa or less, and more preferably 200,000 Pa or less.

2. Method for Producing the Jelly of the Present Invention The jelly of the present invention can be basically produced by the same method as that for producing oral jellies as medicines and jellies as foods.
Specifically, for example, a gel base is first added to an appropriate amount of water as a dispersion medium, and dispersed, suspended or dissolved. The form of the gel base to be added is not particularly limited, and it may be used as it is, or may be powdered by a conventional method, or may be in the form of flakes, etc.
This liquid is heated with stirring until the gel base is completely dissolved, after which other various additives are added as necessary.

Thereafter, the solution (sol) is cooled to a temperature about 5° C. to 20° C. higher than the gelation temperature, and a drug or the like that has been separately prepared is added to and mixed with the solution (sol).
Finally, a specified amount of the sol is filled into a predetermined mold, cooled, and gelled to form a jelly. The mold can be shaped to be suitable for the sublingual cavity of a person to whom the jelly of the present invention is to be applied. The jelly can be molded not only by the mold as described above, but also by three-dimensional modeling using a 3D printer or the like, or by cutting out a desired shape from a large jelly base material.
The strength of the jelly can be adjusted by changing the contents of water, gel base, thickener, etc. in the jelly agent.

3. Drug administration system using jelly of the present invention The drug administration system of the present invention (hereinafter referred to as the "system of the present invention") is characterized by comprising the jelly of the present invention and a means for inserting the jelly of the present invention under the tongue of a recipient.
By implementing the system of the present invention, a sufficient amount of drug or the like for treatment can be retained under the tongue of the recipient for a certain period of time. In addition, the discomfort felt under the tongue can be reduced compared to solid preparations such as tablets. By appropriately combining good sublingual absorption of drugs or the like, drugs with low membrane permeability, drugs that cannot be sufficiently absorbed in the body by oral administration due to degradation in the digestive tract or first-pass metabolism in the digestive tract and liver, and even medium-molecule drugs such as peptides can be efficiently delivered to the body.

The system of the present invention may also include the following means.
A means for obtaining specific information about a recipient A means for producing the jelly of the present invention

The "means by which the jelly of the present invention can be inserted under the tongue of a recipient" typically includes the fingers of a person's own or a different person's hand, but may also be a device or instrument suitable for sublingual insertion.
Sublingual insertion of the jelly of the present invention can be performed, for example, by an inserter inserting the jelly of the present invention into an appropriate position under the tongue of a recipient. Such inserters include the recipient himself/herself, family members, caregivers, assistants, medical personnel, etc. The inserter can indirectly insert the jelly of the present invention under the tongue of a recipient using a dedicated device or instrument.
The "applicant" is not particularly limited as long as it is a person who needs it, and specific examples include patients.

(1) In the case where the system of the present invention includes a means for acquiring unique information about the recipient, the unique information may include, for example, medical information about the recipient, information about the five senses preferences of the recipient, and information about the shape of the sublingual cavity of the recipient.

Examples of medical information on beneficiaries include drug prescriptions (drug names, dosages, administration periods, etc.), medical condition, medical history, severity, prognosis, test names, test results, and test findings. Methods for obtaining such information include, for example, medical records, questionnaires, and interviews.

Examples of preference information for the five senses of the recipient include preferences for color, shape, smell and aroma, taste, and tactile preferences such as texture on the tongue and teeth. Methods for obtaining this information include, for example, questionnaires and interviews.

Means by which information regarding the shape of the sublingual cavity of the recipient can be obtained include, for example, taking a mold, computed tomography (CT), magnetic resonance imaging (MRI), and 3D scanning. Measurements using these means can provide various data on the shape of the sublingual cavity.

When using a mold-taking method, the impression material can be, for example, an alginate impression material, agar impression material, or a silicone impression material. In this case, information about the shape of the sublingual cavity is embodied in the impression material after the mold is taken.

When using means such as CT, MRI, or 3D scanning, for example, a three-dimensional measuring X-ray CT device, a magnetic resonance imaging device, or a 3D laser scanner can be used. In this case, information on the shape of the sublingual cavity can be obtained in the form of electronic data, etc., from each device or a computer connected to them.

(2) In the Case Where the System of the Invention Includes a Means for Producing the Jelly Preparation of the Invention When the system of the invention includes a means for producing the jelly preparation of the invention, the production method is as described above.
In addition, based on the above-mentioned specific information on the recipient, a custom-made jelly of the present invention suitable for the recipient can be provided. In this case, the type and amount of the drug, etc. can be determined, for example, based on the acquired medical information on the recipient. The type and amount of the additive can also be determined, for example, based on the acquired medical information on the recipient and the five senses preference information on the recipient.

In addition, in the manufacturing process of the jelly of the present invention, the sol solution before gelation is usually poured into a mold, and then cooled by a cooling means to form a semi-solid jelly. At this time, the mold can be selected or created based on, for example, information on the shape of the sublingual cavity of the recipient or information on the five senses preferences of the recipient.

The jelly may be formed by three-dimensional modeling instead of using a mold as described above. In this case, for example, the jelly of the present invention can be formed using a 3D printer or the like based on the sublingual cavity shape information of the recipient and the five senses preference information of the recipient. As another method that does not rely on a mold, for example, a method of cutting out a shape based on the sublingual cavity shape information of the recipient from a large jelly base material can be considered.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

The raw materials used are as follows:
・AGAR: Kanten "PS-96" (manufactured by Ina Food Industry Co., Ltd.)
ANT: Antipyrine PRP: Propranolol ATE: Atenolol

Example 1: Production of a jelly for rats First, 50 mg of AGAR was added to 10 mL of water, and dispersed and suspended.
Next, the suspension was heated with stirring to completely dissolve the AGAR.
Then, each drug shown in Table 1, which had been prepared separately, was added to the solution cooled to about 80° C. and mixed so that the dose per rat was the amount shown in Table 1. The dose of each drug was determined with reference to a single clinical dose for humans.
Finally, the solution was poured into a mold, cooled and gelled to obtain a plate-shaped jelly having a length of 5 mm, a width of 3 mm and a thickness of 2 mm (jelly of the present invention, Example 1).

<Drug absorption evaluation test>
As an in vivo test method in rats to investigate the drug absorption from the jelly of the present invention, the jelly of the present invention obtained above was applied sublingually to rats under anesthesia, and blood was then collected from the carotid artery to measure the blood concentration.
The time course of the drug concentration in plasma after administration of the jelly preparation of the present invention containing each drug is shown in the upper part of Figures 1 to 3, and the time course of the absorption rate into the blood (bioavailability) up to 120 minutes calculated by the deconvolution method using the plasma concentration after intravenous administration is shown in the lower part of Figures 1 to 3. The bioavailability (BA) 120 minutes after administration of the jelly preparation of the present invention is shown in Table 1.

The jelly of the present invention could be easily applied sublingually to anesthetized rats and remained stable under the tongue for up to 2 hours.

As shown in Figures 1 to 3, in rats, absorption from the jelly of the present invention applied sublingually was sustained for all drugs, and the extremely high blood concentrations immediately after administration, as seen with immediate-release sublingual tablets, were not observed. This means that the drug was released gradually from the jelly of the present invention, and it is believed that blood concentrations can be controlled by adjusting the release rate depending on the type and concentration of the jelly base.

As shown in Table 1, a high bioavailability of 50% or more was obtained for ANT and PRP, which have high membrane permeability. In particular, it is known that when PPR is orally administered, the BA is low at around 20-40% due to first-pass metabolism in the liver, but it has been revealed that the jelly formulation of the present invention can provide an extremely high BA for such drugs.

As described above, it is clear that the jelly of the present invention is a sustained-release preparation that allows control of the drug absorption rate, and is highly applicable to drugs that are easily metabolized in the digestive tract or liver because it is delivered directly into the systemic blood circulation.

Example 2: Production of a jelly for humans First, 250 mg of AGAR was added to 50 mL of water, and dispersed and suspended.
Next, the suspension was heated with stirring to completely dissolve the AGAR.
Then, food coloring was added as a simulant drug to the solution cooled to about 80° C. and mixed.
Finally, the solution was poured into a mold, cooled and gelled to obtain a jelly having a shape as shown in FIG. 6 and a thickness of 3 mm (jelly of the present invention, Example 2).

<Wearing evaluation test>
As shown in FIG. 7, when the jelly of the present invention was applied under the tongue of a human, no discomfort was felt and the shape was maintained for more than 20 minutes.

The jelly of the present invention is useful as a pharmaceutical for sublingual administration because it retains the advantages of sublingual administration, such as rapid absorption and systemic transfer of drugs and the avoidance of decomposition in the digestive organs and the first-pass effect in the digestive tract or liver, while causing little discomfort and being able to retain its shape for a relatively long time without being broken down by saliva. In addition, the system of the present invention can administer drugs (the jelly of the present invention) based on the unique information of the recipient, which makes it possible to realize tailor-made medicine (individualized medicine).

Claims (11)

A semi-solid jelly preparation for sublingual administration having a jelly-like form (excluding those containing trivalent metal ions), which is characterized by being composed mainly of a drug or an allergen for hyposensitization therapy, a gel base, and water, and having a jelly strength within the range of 10,000 Pa to 300,000 Pa . The jelly preparation for sublingual administration according to claim 1, further comprising one or more additives selected from the group consisting of thickeners, pH adjusters, buffers, suspending/dispersing agents, sweeteners, flavoring agents, fragrances, excipients, colorants, stabilizers, solubilizers, surfactants, and preservatives. 3. The jelly for sublingual administration according to claim 1, wherein the drug is a drug that is easily metabolized or decomposed in the body, or a drug that is not sufficiently absorbed in the body by oral administration. The jelly for sublingual administration according to any one of claims 1 to 3 , wherein the drug is an immunosuppressant, a Ca antagonist, a PP inhibitor, a peptide drug, a nucleic acid, a low membrane permeable drug, or a low solubility drug. The jelly for sublingual administration according to claim 4 , wherein the peptide drug is insulin, a GLP-1 analogue, calcitonin, or vasopressin. 3. The jelly for sublingual administration according to claim 1 , wherein the allergen is pollen, dust mites, house dust, or particulate matter suspended in the air. The jelly preparation for sublingual administration according to any one of claims 1 to 6, wherein the gel base is (1) one or more natural polymers selected from the group consisting of pectin, agar, carrageenan, gellan gum, xanthan gum, locust bean gum, guar gum, tara gum, tamarind seed gum, psyllium seed gum, starch, curdlan, chitosan, pullulan, furcellaran, celluloses, hyaluronic acid, alginic acid or a salt thereof, mannans, gelatin, collagen, and whey; or (2) one or more synthetic polymers selected from the group consisting of polyacrylic acid or a salt thereof, polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, poly(N-substituted acrylamide), poly(N-substituted methacrylamide), poly(N-vinyl acetamide), polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, and polyvinyl alcohol, or both of (1) and ( 2 ). The jelly for sublingual administration according to any one of claims 1 to 7 , which has a flat plate shape. The jelly for sublingual administration according to claim 8 , which has a semicircular arc-shaped portion or a substantially circular arc-shaped portion in a planar shape. 10. A jelly for sublingual administration according to claim 8 or 9 , having a slit for avoiding the lingual frenulum or sublingual caruncle. The jelly for sublingual administration according to any one of claims 8 to 10 , which has a thickness within the range of 0.1 mm to 10 mm.

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