TW201637648A - Drug delivery system targeting lacrimal gland - Google Patents

Abstract

Provided is a non-invasive drug delivery system for efficiently delivering a drug to the lacrimal gland, said system being characterized in that the drug is administered to the eyelid skin once a day.

Description

Lacrimal gland drug delivery system

The present invention relates to a non-invasive drug delivery system for delivering a drug to the lacrimal gland, characterized in that the drug is administered to the eyelid skin once a day.

Dry eye syndrome begins with the symptoms of dry eyes, the so-called discomfort of foreign bodies, and if it worsens, it will cause a major obstacle to daily life. Although the rickets of dry eye syndrome are not fully understood, it is considered that the decrease in the amount of tears on the corneal conjunctiva due to the decrease in tear secretion and the increase in tear evaporation is the main cause.

Since the tear system is secreted by the lacrimal gland, if the abnormality of the lacrimal gland is caused, the quality and/or the abnormality of the tear fluid may occur, and as a result, dry eye syndrome may occur. Therefore, in the treatment of dry eye, the migration of drugs to the lacrimal gland is an important means to improve the therapeutic effect.

As described in Patent Document 1, cyclosporine is widely known as a compound having a therapeutic effect on dry eye syndrome, and in the United States and the like, cyclosporin-containing eye drops (Restasis (registered trademark) 0.05%) are used as dry. Eye treatment agent.

On the other hand, it is not easy to continuously move the drug to the lacrimal gland by eye-catching. In fact, in Non-Patent Document 1, since a sufficient amount of cyclosporine does not migrate to the lacrimal gland by eyedropping Therefore, a novel upper scleral implant that makes this possible is proposed.

However, there is currently no known method for continuously delivering drugs to the lacrimal gland in a non-invasive manner.

Prior technical literature Patent literature

Patent Document 1 Japanese Patent No. 4711516

Non-patent literature

Non-Patent Document 1 Investigative Ophthalmology and Visual Science, 46(2), 655-662 (2005)

Summary of invention

The problem to be solved by the present invention is to provide a non-invasive drug delivery system capable of delivering a drug to the lacrimal gland by administering the drug to the orbital skin once a day.

The present inventors conducted intensive studies to explore a non-invasive lacrimal gland drug delivery system, and found that bivalent choline (bethanechol) and metoprolone acetate (methenolone) were administered to the eyelids of normal rabbits. Acetate), GTx-024 (Ostarine: MK-2866), nandrolone decanoate, levofloxacin or voriconazole, the drug will be spotted than the drug The invention has been completed by moving more efficiently and continuously to the lacrimal gland.

That is, the present invention relates to the following.

(1) A non-invasive drug delivery system for delivering a drug to the lacrimal gland, characterized in that the drug is administered to the eyelid skin once a day.

(2) The drug delivery system according to (1), wherein the percutaneous absorption preparation containing the drug is administered to the eyelid skin once a day.

(3) The drug delivery system of (1), which delivers the drug to the lacrimal gland through the local tissue of the eye.

(4) The drug delivery system according to (1), which delivers the drug to the lacrimal gland at least 24 hours after administration of the eyelid skin.

(5) The drug delivery system according to (1), wherein the drug is delivered to the lacrimal gland in a manner of C1>C2 for at least 24 hours after administration of the eyelid skin, where C1 represents a percutaneous drug containing the drug. The concentration of the lacrimal gland of the drug after X hours of administration of the eyelid skin of the absorbent preparation; and C2 means the X-ray of the eye for topical administration of the drug containing the amount of the drug contained in the above-mentioned percutaneous absorption type preparation The concentration of the lacrimal gland of the drug; and the X system indicates any natural number from 1 to 24.

(6) The drug delivery system according to (1), wherein the drug is a drug having a pharmacological action on the lacrimal gland.

(7) The drug delivery system according to (1), wherein the drug is a drug having a preventive and/or therapeutic effect on dry eye.

(8) The drug delivery system according to (7), wherein the drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist.

(9) The drug delivery system according to (8), wherein the muscarinic receptor antagonist is choline urate or Carpronium.

(10) The drug delivery system according to (2), wherein the percutaneous absorption type preparation is an ointment or an emulsion preparation.

(11) A percutaneous absorption type preparation for delivering a drug non-invasively to a lacrimal gland, which is characterized in that it is administered to the eyelid skin once a day.

(12) A percutaneous absorption type preparation for delivering a drug to a lacrimal gland through a local tissue of the eye.

(13) A percutaneous absorption type preparation for delivering a drug to the lacrimal gland at least 24 hours after administration of the eyelid skin.

(14) A percutaneous absorption type preparation for delivering a drug to a lacrimal gland in a manner of becoming C1 > C2 for at least 24 hours after administration of the eyelid skin, wherein C1 is a transdermal absorption type containing the drug The concentration of the lacrimal gland of the drug after X hours of administration of the eyelid skin of the preparation; C2 is the drug after the eye for X hours of the topical administration preparation of the eye containing the drug contained in the above-mentioned percutaneous absorption type preparation The concentration in the lacrimal gland; and the X system indicates any natural number from 1 to 24.

(15) The percutaneous absorption type preparation according to (11), wherein the percutaneous absorption type preparation contains a drug having a pharmacological action on the lacrimal gland.

(16) The percutaneous absorption type preparation according to the above aspect, wherein the percutaneous absorption type preparation contains a drug having a preventive and/or therapeutic effect of dry eye.

(17) The percutaneous absorption type preparation according to the above aspect, wherein the drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist.

(18) The percutaneous absorption type preparation according to (17), wherein the muscarinic receptor antagonist is choline urate or caprolin.

(19) The percutaneous absorption type preparation according to any one of (11) to (18), wherein the preparation is an ointment or an cream.

(20) A tear secretion promoting agent comprising a muscarinic receptor antagonist, which is characterized in that it is administered to the eyelid skin once a day.

(21) A therapeutic agent for dry eye, which comprises a muscarinic receptor antagonist, which is characterized in that it is administered to the eyelid skin once a day.

Further, the present invention also relates to the following.

(22) A method for delivering a drug to a lacrimal gland of a test object in a non-invasive manner, which comprises administering a drug to the eyelid skin of the test object once a day.

(23) The method according to (22), which comprises administering a drug-containing percutaneous absorption type preparation to the eyelid skin of the test object once a day.

(24) The method according to (22), which delivers the drug to the lacrimal gland through the local tissue of the eye.

(25) The method according to (22), wherein the drug is delivered to the lacrimal gland at least 24 hours after administration of the eyelid skin.

(26) The method according to (22), wherein the drug is delivered to the lacrimal gland at a time of C1 > C2 for at least 24 hours after administration of the eyelid skin, C1 is a concentration in the lacrimal gland of the drug after X hours of administration of the orbital skin-containing preparation containing the drug; and C2 is a topical administration of the eye containing the drug contained in the above-mentioned percutaneous absorption-type preparation. The concentration of the lacrimal gland of the drug after X hours of the preparation was used; and X is an arbitrary natural number from 1 to 24.

(27) The method according to (22), wherein the drug is a drug having a preventive and/or therapeutic effect on dry eye.

(28) The method according to the above aspect, wherein the drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist.

(29) The method according to (28), wherein the muscarinic receptor antagonist is choline urate or caprolin.

(30) The method according to (23), wherein the percutaneous absorption type preparation is an ointment or an emulsifiable concentrate.

(31) A method for increasing the prophylactic and/or therapeutic effect of a drug having pharmacological action on a lacrimal gland, which comprises administering the eyelid skin having the necessary test substance once a day.

(32) A method for promoting secretion of tears, characterized in that a muscarinic receptor antagonist is administered to the orbital skin once a day.

(33) A method for treating dry eye, characterized in that a muscarinic receptor antagonist is administered to the eyelid skin once a day.

(34) Use of a medicament for producing a percutaneous absorption preparation for delivering a drug non-invasively to a lacrimal gland, characterized in that the percutaneous absorption preparation is administered to an eyelid once a day skin.

(35) The use according to (34), wherein the percutaneous absorption type preparation contains a drug having a pharmacological action on the lacrimal gland.

(36) The use according to claim 34, wherein the percutaneous absorption type preparation contains a drug having a preventive and/or therapeutic effect on dry eye.

(37) The use according to (36), wherein the drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist.

(38) The use according to (37), wherein the muscarinic receptor antagonist is choline urate or caprolin.

(39) The use according to any one of (34) to (38), wherein the dosage form is an ointment or an emulsifiable concentrate.

(40) Use of a muscarinic receptor antagonist for producing a tear secretion promoting agent, characterized in that the tear secretion promoting agent is administered to the eyelid skin once a day.

(41) Use of a muscarinic receptor antagonist for the manufacture of a therapeutic agent for dry eye, characterized in that the therapeutic agent for dry eye is administered to the eyelid skin once a day.

According to the present invention, the drug is administered to the eyelid skin once a day, and the drug can be more and continuously delivered to the lacrimal gland compared with the case where the drug is spotted, and the pharmacological effect can be exerted on the lacrimal gland for a long period of time. Reduce the side effects of the drug.

Fig. 1 is a graph showing the change in concentration in the lacrimal gland and the aqueous humour after administration of uric acid choline and eyelid skin.

Fig. 2 is a graph showing the transition of the concentration in the lacrimal gland after administration of the eyelid skin of the metoprolol acetate.

Fig. 3 is a diagram showing the transition of the concentration of the larynx and the eyelid skin after administration of GTx-024.

Fig. 4 is a diagram showing the transition of the concentration of the lacrimal gland after the administration of the eye and the eyelid skin of the nodolin.

Fig. 5 is a graph showing the change in concentration in the lacrimal gland after administration of levofloxacin and voriconazole to the eyelid skin.

Form for implementing the invention <Drug delivery system>

The present invention relates to a non-invasive drug delivery system for delivering a drug to the lacrimal gland, characterized in that the drug is administered to the eyelid skin once a day. In the present invention, the drug is delivered to the lacrimal gland by the eyelid skin through the local tissue of the eye.

<eyelid skin>

In the present invention, the eyelid skin means the upper eyelid, the lower eyelid, or the skin in the vicinity thereof, and preferably means the skin of the upper eyelid.

<eye local tissue>

In the present invention, the ocular local tissue means ocular tissue located on the inner side of the eyelid skin, such as conjunctival tissue and scleral tissue.

<drug>

In the present invention, the drug is not particularly limited as long as it is a drug acceptable as a medicine. For example, a drug used for prevention and/or treatment of an eye disease can be cited.

In the present invention, the drug is also a salt of a drug, and is not particularly limited as a salt which can be tolerated as a medicine, and examples thereof include inorganic substances such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Acid salt, with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, gluconic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, lactanoic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid a salt of an organic acid such as p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid or sulfonic acid; a quaternary ammonium salt with methyl bromide or methyl iodide; and bromide, chloride, iodide, etc. a salt of a halide ion; a salt with an alkali metal such as lithium, sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; a metal salt with iron or zinc; a salt with ammonia; Amine, 2-amine ethanol, 2,2-iminobisethanol, 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2 -( Methyl) -1,3-propanediol, because Puluo Ka (procaine), N, N- bis (phenylmethyl) -1,2-ethanediamine, etc. The organic amine salts.

<Molecular weight of drug>

In the present invention, the molecular weight, fat solubility, and melting point of the drug or its salt affect the skin permeability, and the molecular weight is, for example, 130 to 820, more preferably 160 to 480.

<Pharmacological action of drugs>

In the present invention, the drug is not particularly limited as long as it has a pharmacological action on the lacrimal gland, but is preferably a drug having a tear secretion promoting action, a mucin secretion promoting action, an immunosuppressive action, an antibacterial action, and an antifungal action. The drug used for the prevention and/or treatment of an eye disease is particularly preferably a drug having dry eye, lacrimal gland inflammation, microbial infection in lacrimal gland, prevention and/or therapeutic effect of lacrimal adenocarcinoma.

Examples of the drug having the preventive and/or therapeutic effect of dry eye include muscarinic receptor antagonism such as choline urate, caprolin, pilocarpine, ceviomeline, muscarinic, and the like. Agents (choline esters), cyclosporine, rapamycin (sirolimus), tacrolimus and other immunosuppressants (macrolide), di Diquafosol or a salt thereof (nucleotide derivative), rebamipide or a salt thereof (quinolinone derivative), GTx-024 (selective androgen receptor modulator), etc. Preferably, however, it is a muscarinic receptor antagonist, more preferably choline urate or caprolin.

For drugs having the preventive and/or therapeutic effects of dry eye, such as melanonate acetate, norronate, choline urate, caplin, pilocarpine, cevimeline, muscarinic Cyclosporine, rapamycin (sirolimus), tacrolimus, diquamoff or a salt thereof, rebamipide or a salt thereof, GTx-024, preferably norronate.

For drugs having a prophylactic and/or therapeutic effect of lacrimal gland inflammation, for example, diclofenac, bromfenac.

For drugs having the preventive and/or therapeutic effects of microbial infections in the lacrimal gland, for example, levofloxacin, sitafloxacin, tosufloxacin, gatifloxacin, mo Moxifloxacin, antifungal voriconazole, fluconazole, itraconazole, fosfluconazole, as avirulence acyclovir, serovar Valaciclovir, vidarabine, preferably voriconazole.

<compound>

In the present invention, the medicament also includes muscarinic receptor antagonists (choline esters) such as choline urate, caprolin, pilocarpine, cevimeline, muscarinic, etc., cyclosporine, rapa Immunosuppressant (megaring lactone), diquafene or its salt (nucleotide derivative), rebamipide or its salt (quinine) a steroid drug, fluoxetine (nordeoxacin), norfloxacin, norfloxacin, norfloxacin (norfloxacin), norfloxacin (norfloxacin) New quinolone (New Quinolones) synthetic antibacterial, fluconazole, itraconazole, fluconazole, ofloxacin, levofloxacin, sitafloxacin, toloxacin, gatifloxacin, moxifloxacin An anti-viral drug such as an azole antifungal drug such as azole or voriconazole, a non-steroidal anti-inflammatory drug (NSAID) such as diclofenac or bromfenac, acyclovir, valaciclovir, and adenosine, but preferably It is a muscarinic receptor antagonist, a selective androgen receptor modulator, a steroid drug, a new quinolone synthetic antibacterial, an azole antifungal, and a urea. Choline, GTx-024, methenolone acetate nandrolone decanoate, levofloxacin, voriconazole.

Choline urate is a compound represented by the following formula.

Kaplin is a compound represented by the following formula.

Metinolone acetate (17β-acetamidooxy-1-methyl-5α-androst-1-en-3-one) is a compound represented by the following formula.

GTx-024((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropionate The amine is a compound represented by the following formula.

Levofloxacin ((3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperidine) Base-7-sideoxy-2,3-dihydro-7H-[1,4] And [2,3,4-ij]quinoline-6-carboxylic acid) is a compound represented by the following formula.

Voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1- The base-2-butanol) is a compound represented by the following formula.

Nandrolate (17β-hydroxy-19-normanrosin-4-en-3-one-17-phthalate) is a compound represented by the following formula.

<Method of administration of drugs, number of administrations>

In the present invention, the drug is preferably administered to the eyelid skin once a day, but may be once every 2 days, once every 3 days, once every 4 days, depending on the age, weight, judgment of the doctor, and the like. 1st on the 5th, 1st on the 6th, or 1st on the 7th The frequency of the second is administered to the eyelid skin. In the present invention, "administering" includes, for example, applying a drug-containing ointment or creaming agent to a site to be administered, spraying a drug-containing spray to a site of administration, and adhering a drug-containing patch to a tablet. Inject the site. Therefore, for example, when a patch is selected as a dosage form, "the frequency is applied to the eyelid skin once a day" means "adhesive to the eyelid skin at a frequency of once a day".

<Drug dosage>

In the present invention, the amount of the drug administered to the eyelid skin is 0.000001 to 1000 mg, preferably 0.000005 to 500 mg, more preferably 0.00001 to 100 mg, even more preferably 0.00005 to 50 mg, most preferably 0.0001 to 10 mg.

<Transdermal absorption preparation>

In the present invention, the drug can be administered as a transdermal absorption preparation.

<Composition of transdermal absorption preparation>

In the present invention, the percutaneous absorption type preparation contains an additive such as a drug, a base, and optionally an absorption enhancer.

<Amount of drug in transdermal absorption preparation>

In the present invention, the concentration of the drug contained in the percutaneous absorption type preparation varies depending on the administration form and the administration form, but in the case where a dosage form suitable for eyelid skin administration such as an emulsion preparation, an ointment, or the like is selected, 0.000001~50%(w/w), preferably 0.000005~40%(w/w), more preferably 0.00001 ~30% (w/w), preferably 0.00005~20% (w/w), preferably 0.0001~10% (w/w).

<Base in a transdermal absorption preparation>

In the present invention, the base to be used in the percutaneous absorption preparation is not particularly limited as long as it is a base for the external preparation, and examples thereof include hydrocarbons (white petrolatum) and liquid paraffin. , fatty acid esters (isopropyl myristate, etc.), waxes (beeswax, lanolin, etc.), higher fatty acids (stearic acid, etc.), higher alcohols (stearyl alcohol, cetyl alcohol, etc.), vegetable oils (菎Sesame oil, etc.), vitamin E, water, polyol (glycerol, propylene glycol, 1,3-butanediol, etc.), lower alcohol (ethanol, isopropanol, etc.), and mixtures thereof.

<Additives in transdermal absorption preparations>

In the present invention, the additive used in the percutaneous absorption type preparation is not particularly limited as long as it is an additive for an external preparation, and examples thereof include a surfactant (emulsifier), an absorption enhancer, and a preservative (preservative). ), antioxidants, pH adjusters, tonicity modifiers, and the like.

In the present invention, the surfactant (emulsifier) used in the percutaneous absorption preparation is not particularly limited as long as it is a surfactant for the external preparation, and examples thereof include a W/O type emulsifier and O/. Specific examples of the W-type emulsifier include glycerin monostearate, sorbitan monostearate, polyoxyethylene hardened castor oil 60, and polysorbate 60.

In the present invention, the absorption enhancer used in the percutaneous absorption preparation is not particularly limited if it is an absorption enhancer for an external preparation. Examples thereof include a solvent such as water or an alcohol, a surfactant, a fatty acid ester such as isopropyl myristate, another alkyl ester, an anthracene such as ε-amine hexanoic acid or menthol, and pyrrole. Pyridone, urea, phospholipids, etc.

In the present invention, the preservative (preservative) used in the percutaneous absorption preparation is not particularly limited as long as it is a surfactant for the external preparation, and examples thereof include methyl p-hydroxybenzoate and p-hydroxybenzene. Propyl formate, phenoxyethanol, thymol, and the like.

In the present invention, the antioxidant used in the percutaneous absorption type preparation is not particularly limited as long as it is an antioxidant for the external preparation, but examples thereof include sodium hydrogen sulfite, ascorbic acid, tocopherol, and dibutylhydroxytoluene. , sodium edetate hydrate, benzotriazole and the like.

In the present invention, the pH adjuster used in the percutaneous absorption type preparation is not particularly limited as long as it is a pH adjuster for an external preparation, and examples thereof include citric acid hydrate, sodium citrate hydrate, and lactic acid. , diisopropanolamine, acetic acid, sodium acetate hydrate, and the like.

In the present invention, the tonicity adjusting agent used in the percutaneous absorption type preparation is not particularly limited as long as it is a tonicity adjusting agent for an external preparation, and examples thereof include sodium chloride, potassium chloride, glucose, and fructose. Mannitol, sorbitol, lactose, sucrose, glycerin, urea, and the like.

<Formulation of transdermal absorption preparation>

In the present invention, the percutaneous absorption type preparation is a preparation containing a drug and the drug is delivered through the skin, and is not particularly limited, but examples thereof include external preparations, especially external solid preparations, external powders, external liquid preparations, and liniments. , lotion, spray, topical aerosol, pump spray, ointment, Examples of the cream, the gel, the patch, the tape, the lozenge, the lotion, and the like include an emulsifiable concentrate, an ointment, a patch, a topical solution, an emulsion, and the like.

Ointments can be formulated with mineral white petrolatum, liquid paraffin or animal and vegetable oils. Further, when a polyethylene glycol or the like is used as a base, a water-soluble ointment can be prepared.

The emulsion system can use animal, plant, petroleum, synthetic hydrocarbons, oils, wax esters, higher alcohols as oils; polyol fatty acid esters, ethylene oxide addition nonionic surfactants, anionic interfacial activity Agent, cationic surfactant, amphoteric surfactant, lecithin derivative as a surfactant; and thickened polymer such as polycarbophil or carboxyvinyl polymer as a thickener, used as necessary Preservatives and/or absorption enhancers are used to prepare.

For the tablet, an adhesive (which may also contain a tackifying resin, a crosslinking agent, a plasticizer, a surfactant, an antioxidant, etc.) and a support may be used, and a preservative and/or an absorption enhancer may be used as needed. modulation. Further, in the case of application to the eyelid skin, the peeling force is low as a function of the adhesive tape.

Examples of the adhesive used for the tablet include an acrylic, a lanthanide, and a rubber. Examples of the tackifier resin to be added to the adhesive include rosin-based, lanthanide, and petroleum resin-based. In the case of a crosslinking agent, a polyisocyanate system is mainly used. Examples of the support include non-woven fabrics, films, sheets, and the like. Examples of the preservative include p-hydroxybenzoic acid esters, chlorobutanol, and sorbic acid. Examples of the absorption enhancer include alcohols, fatty acids and salts thereof, alcohol amines, alkyl ethers, and glycerides. interface An active agent and a water-soluble solvent such as dimethyl hydrazine, dimethylformamide or pyrrolidone.

As the liquid preparation or the emulsion, a commonly used base such as water (refined water, distilled water, etc.), a lower alcohol such as ethanol, a polyol such as glycerin, or a surfactant such as polyoxyethylene (60) hardened castor oil can be used. And modulation.

<Method of administration of percutaneous absorption type preparation, number of administrations>

In the present invention, the percutaneous absorption type preparation is preferably administered to the eyelid skin once a day, but may be once every 2 days, once every 3 days, or 4 days depending on the age, body weight, judgment of the doctor, and the like. The frequency is applied to the eyelid skin at a frequency of once, once every 5 days, once every 6 days, or once every 7 days. Further, in the present invention, the "administration" means that the patch is adhered to the administration site. Therefore, for example, when a patch is selected as a dosage form, "administering to the eyelid skin at a frequency of once a day" means "adhesive to the eyelid skin at a frequency of once a day".

<Comparison of the percutaneous absorption preparation of the present invention and the preparation for topical administration to the eye>

Further, the drug delivery system of the present invention delivers the drug to the lacrimal gland in a manner of becoming C1 > C2 for at least 24 hours after administration of the eyelid skin.

C1 is a concentration in the lacrimal gland of the drug after X hours of administration of the orbital skin-containing preparation containing the drug; and C2 is a topical administration of the eye containing the drug contained in the above-mentioned percutaneous absorption-type preparation. The concentration of the lacrimal gland of the drug after X hours of the eye of the preparation; The X system indicates any natural number from 1 to 24.

<Eye preparation for topical administration>

In the present invention, the topical administration of the eye refers to a preparation suitable for the ocular tissue of the conjunctival sac or the like, and is not particularly limited as long as it is capable of puncturing (including spotting), but is preferably an eye drop or Eye ointment.

The drug delivery system of the present invention allows for efficient and sustained migration of the drug to the lacrimal gland. Specifically, in comparison with the case where the eye containing the drug contained in the above-mentioned percutaneous absorption type preparation is topically administered, the percutaneous absorption type preparation containing the drug is subjected to eyelid skin. The concentration of the lacrimal gland in the case of administration indicates a high value during the 24 hours after the administration.

<delivery method>

The present invention relates to a method for delivering a drug to the lacrimal gland, which is characterized by administering the drug once a day to the skin of the eyelid. The above detailed description of the drug delivery system and the transdermal absorption preparation of the present invention is also applicable to the delivery method of the present invention.

The results of the pharmacological test and the formulation examples are shown below, but the examples are intended to provide a better understanding of the present invention and not to limit the scope of the present invention.

Example [Pharmacological test 1]

The concentration of the lacrimal urinary urinary urinary tract and the concentration in the aqueous sample after the choline chloride of uric acid was administered to the normal rabbits or the eyes were measured and compared.

(drug modulation method) ‧Ointment containing 20% choline chloride urate

0.9 g of white petrolatum and 0.7 g of isopropyl myristate were thoroughly mixed, and 0.4 g of choline urate chloride was added to the mixed ointment base, and kneaded sufficiently to prepare (total amount 2 g). In addition, as for the urate choline chloride, the product purchased from Abcam (model number: ab141045) (the same applies to the following examples).

‧ Eye drops containing 2% choline chloride

After dissolving 0.2 g of choline urate chloride, 0.001 g of sodium dihydrogen phosphate, and 0.009 g of sodium chloride in purified water, an appropriate amount of sodium hydroxide was added to prepare a pH of 6 (total amount 10 mL).

(experiment method)

Rabbits (Japanese white, male, purchased from KITAYAMA LABES CO., LTD.) were used in the test. In order to apply the ointment, a hairdressing scissors and an electric razor are used to remove the skin around the eyelids in a manner that does not cause skin damage, and further tape stripping treatment is performed. About 50 μL of the ointment containing 20% choline chloride was applied to the eyelid skin of the rabbit eye, and the drug concentration in the lacrimal gland of both eyes and the drug concentration in the water sample were measured after 1, 3 and 6 hours.

Further, regarding the eye drop containing 2% choline chloride of urinary acid, after 50 μL of the eyes of both eyes, the drug concentration in the lacrimal gland of both eyes and the drug concentration in the aqueous solution were measured by LC/MS for 1 and 3 hours. .

(result)

The test results are shown in Fig. 1, Table 1, and Table 2.

(examine)

As shown in Table 1, the drug concentration (administered in the eye) in the lacrimal gland after administration of 20% choline chloride choline chloride was 10.6 and 14.4 μg/g after 1 and 3 hours. Therefore, it is presumed that the drug concentration of the lacrimal gland after 1 and 3 hours of administration of the ointment containing 2% choline chloride is 1.06 and 1.44 μg/g left. right. On the other hand, the drug concentration (administered eye) in the lacrimal gland after administration of 2% choline chloride choline chloride was 0.145 and 0.128 μg/g after 1 and 3 hours. That is, the case where the percutaneous absorption type preparation containing the choline chloride of urate is administered to the eyelid skin is more preferable than the case where the eye drop containing the same amount of choline urate chloride is spotted. About 10 times the amount of choline urate is delivered to the lacrimal gland.

Moreover, the ratio of the drug concentration in the lacrimal gland/the concentration of the aqueous solution (both administered to the eye) after 20 and 20 hours of administration of the choline chloride ointment containing urate was made to contain 2% choline chloride of urinary acid. The ratio of the eye drops of the compound is 19.0 times and 48.3 times, and more drugs can be delivered to the lacrimal glands by eyelid skin administration than eye drops.

[Pharmacological test 2]

The time-dependent changes in the concentration of metoprolol in the lacrimal gland after administration of the skin of the skin of minotinol acetate were investigated.

(drug modulation method)

An ointment containing 2% (w/v) metinolone acetate was prepared by dissolving 0.4 g of fentanol acetate in a measuring flask to a volume of 20 mL using castor oil.

(Test method and drug administration method)

Rabbits (Japanese white, male, purchased from KITAYAMA LABES CO., LTD.) were used in the test. On the day before the drug was administered, the upper right eyelid was shaved with a hairdressing scissors under general anesthesia, and dressed before the administration. Elizabethan collar. A 2% (w/v) minotinol acetate ointment (50 μL) was applied to the upper right eyelid skin in a single application.

(evaluation method)

Rabbits were euthanized 2, 4, 8 and 24 hours after the administration, and the right upper lacrimal gland tissue (3 at each time point) was removed. The lacrimal gland tissue was homogenized with methanol, and the concentration of metinolone (the activity of metoprolol acetate itself) in the centrifuge supernatant was determined by LC-MS/MS. The concentration of metinolol in the lacrimal gland tissue was calculated from the tissue wet weight measured before homogenization and the metinolol concentration of the assay sample.

(result)

As shown in Fig. 2, it was confirmed that the metoprolol concentration in the lacrimal gland after administration of the skin of the skin of the metoprolone was hardly changed from 4 hours to 24 hours after the administration, and was maintained for a long time.

(examine)

As described above, when the metoprolol acetate is administered to the eyelid skin, the concentration of the metoprolol in the lacrimal gland tissue lasts at least 24 hours, suggesting that the metoprolol acetate can be used once a day. It is administered to the eyelid skin and is continuously delivered to the lacrimal gland.

[Pharmacological test 3]

GTx-024, which is a compound of completely different structure from choline urate and metoprolone acetate, was administered to the orbital skin of eyeballs or to the concentration of lacrimal gland of GTx-024 after normal eyes, and was compared and reviewed separately. .

(drug modulation method) ‧ Ointment containing 25% GTx-024

The preparation was carried out by dissolving 0.5 g of GTx-024 in 1.5 g of castor oil (total amount 2 g).

(experiment method)

Rabbits (Japanese white, male, purchased from KITAYAMA LABES CO., LTD.) were used in the test. In order to apply the ointment, a hairdressing scissors and an electric razor are used to remove the hair around the eyelids in a manner that does not cause skin damage. About 50 μL of the ointment containing 25% GTx-024 was applied to the eyelid skin of the rabbit single eye, and the drug concentration in the lacrimal glands of both eyes after 2, 4, 8 and 24 hours was measured.

Further, after 50 μL of a 25% GTx-024 ointment was applied to a single eye, the drug concentration in the lacrimal glands of both eyes after 1 hr, 2 hr, and 4 hr was measured by LC/MS.

(result)

As shown in Fig. 3 and Table 3, it was shown that the ointment containing 25% GTx-024 was administered to the eyelid skin, and the high concentration of the lacrimal gland was maintained for 24 hours after the administration. On the other hand, it was confirmed that the ointment containing 25% of GTx-024 was spotted, and the concentration in the lacrimal gland was significantly lowered 4 hours after the administration.

(examine)

From the above results, not only a muscarinic receptor antagonist, but a drug having a chemical structure and a pharmacological action different from this, compared with an eyedrop containing an equivalent amount of the drug. When the percutaneous absorption preparation containing the drug is administered to the orbital skin, more drugs can be delivered to the lacrimal gland. Further, since the concentration of the drug in the lacrimal gland is maintained, the pharmacological effect can be continued for 24 hours after the administration of the eyelid skin.

Therefore, in comparison with the case where the topical administration preparation containing the drug is spotted, the drug-containing percutaneous absorption preparation is administered to the eyelid skin once a day, at least after administration. During the 24-hour period, more drugs can be transferred to the lacrimal gland.

[Pharmacological test 4]

The time-dependent changes in the concentration of Nandrolone in the lacrimal gland after the administration of nodolinate in the eyelid skin were studied.

(drug modulation method)

0.06 g of noon phthalate was weighed, castor oil was added, and the volume was adjusted to 3 mL in a measuring flask to prepare an ointment containing 2% (w/v) norronate.

(Test method and drug administration method)

Rabbits (Japanese white, male, purchased from KITAYAMA LABES CO., LTD.) were used in the test. The day before the drug was administered, the upper right eyelid was shaved with a hairdressing scissors under general anesthesia, and the I-shaped collar was worn before the administration. A 2% (w/v) noryl phthalate ointment (50 μL) was applied to the upper right eyelid skin in a single application. Further, in other animals, the preparation was spotted on the right eye.

(evaluation method)

Rabbits were euthanized 2, 4, 8 and 24 hours after the administration, and the right upper lacrimal gland tissue (3 at each time point) was removed. The lacrimal gland tissue was homogenized with methanol, and the concentration of Nandrolone (nanoic acid ester itself) in the centrifuge supernatant was determined by LC-MS/MS. The concentration of Noron in the lacrimal gland tissue was calculated from the tissue wet weight measured before homogenization and the concentration of the Nylon of the assay sample.

(result)

As shown in Fig. 4 and Table 4, it was confirmed that the concentration of Nandrolone in the lacrimal gland after administration of the nodolinate eyelid skin was maintained at a high concentration from 4 hours to 24 hours after the administration. On the other hand, it is understood that the concentration of Nandrolone in the lacrimal gland after norophthalate is from 2 hours after administration to 24 hours, which is much lower than that of the case where the eyelid skin is administered.

(examine)

From the above results, it was confirmed that even a drug having a chemical structural formula or a pharmacological action different from a muscarinic receptor antagonist, metinolone acetate, and GTx-024 would contain an equivalent amount of the drug. When the eye drop of the drug is applied to the eye, the case where the percutaneous absorption type preparation containing the drug is administered to the eyelid skin is to deliver more medicine to the lacrimal gland. Further, since the concentration of the drug in the lacrimal gland is maintained, the pharmacological effect can be continued for 24 hours after the administration of the eyelid skin.

Therefore, it was confirmed again that the drug-containing percutaneous absorption preparation was administered to the orbital skin once a day, and the concentration of the lacrimal gland of the drug was maintained at least for a period of 24 hours after the administration.

[Pharmacological test 5]

The time-dependent changes in the concentration of the compound in the lacrimal gland after administration of levofloxacin and voriconazole to the eyelid skin were investigated.

(drug modulation method)

0.03 g of levofloxacin was weighed and adjusted to a volume of 2 mL with a vitamin E to prepare an ointment containing 1.5% (w/v) levofloxacin. Further, 0.1 g of voriconazole was weighed, and an ointment containing 5% (w/v) of voriconazole was prepared by using a vitamin E to a volume of 2 mL in a measuring flask.

(Test method and drug administration method)

Rabbits (Japanese white, male, purchased from KITAYAMA LABES CO., LTD.) were used in the test. The day before the drug was administered, the upper right eyelid was shaved with a hairdressing scissors under general anesthesia, and the I-shaped collar was worn before the administration. A 1.5% (w/v) levofloxacin ointment (50 μL) was applied to the upper right eyelid skin for a single application, and a 5% (w/v) voriconazole ointment (50 μL) was applied to the left upper eyelid skin.

(evaluation method)

The rabbits were euthanized at 3, 6, and 24 hours after the administration, and the lacrimal gland tissues above and below were removed (4 at each time point). The lacrimal gland tissue was homogenized in 50% acetonitrile, and the concentration of levofloxacin and voriconazole in the centrifuge supernatant was determined by LC-MS/MS. The concentration of the compound in the lacrimal gland tissue was calculated from the tissue wet weight measured before homogenization and the drug concentration of the assay sample.

(result)

As shown in Fig. 5, it was confirmed that the concentration of lacrimal gland after administration of levofloxacin and voriconazole to the orbital skin was maintained at a high concentration from 3 hours to 24 hours after administration of the drug.

(examine)

From the above results, it was confirmed that even with a muscarinic receptor antagonist, metinolone acetate, GTx-024, norronate, The chemical structure and pharmacological action of the drug, since the transdermal absorption preparation containing the drug is administered to the orbital skin, the drug concentration in the lacrimal gland is maintained, so that the pharmacological treatment can be continued for 24 hours after the administration of the eyelid skin. effect.

Therefore, it was confirmed again that the drug-containing percutaneous absorption preparation was administered to the orbital skin once a day, and the concentration of the lacrimal gland of the drug was maintained constant at least for 24 hours after the administration.

Prescription Example 1: Emulsion (2% (w/w))

100g

To the mixture of the medium chain fatty acid and the polyoxyethylene castor oil, 1% polycarbophil which is sufficiently dissolved with choline chloride of urinary acid is added, thereby preparing an emulsifiable concentrate. An emulsifiable concentrate having a concentration of choline chloride of urinary acid of 1% (w/w) to 20% (w/w) can be prepared by changing the amount of choline chloride of urate.

Prescription Example 2; Ointment (2% (w/w))

100g

To the uniformly-melted white petrolatum and liquid paraffin, urate choline chloride was added, and these were sufficiently mixed, and then gradually cooled to prepare an ointment. An ointment having a concentration of choline chloride of urinary acid of 0.01% (w/w) to 10% (w/w) can be prepared by changing the amount of choline chloride to be added.

Prescription Example 3: Emulsion (2% (w/w))

100g

In a mixture of medium chain fatty acid and polyoxyethylene castor oil, nouryl phthalate was added and dissolved, and then 1% polycarbophil was added to prepare an emulsifiable concentrate. An emulsion of 0.01% (w/w) to 10% (w/w) of nortonate can be prepared by changing the amount of the addition of norronate.

Prescription Example 4; Ointment (2% (w/w))

100g

To the uniformly blended white petrolatum and liquid paraffin, noon phthalate was added, and these were sufficiently mixed, and then slowly cooled to prepare an ointment. An ointment having a concentration of norbornene ester of 0.01% (w/w) to 10% (w/w) can be prepared by changing the amount of the addition of norronate.

Industrial availability

The present invention can provide a non-invasive drug delivery system characterized in that a drug is administered to the orbital skin once a day for delivering the drug to the lacrimal gland efficiently.

Claims (21)

A non-invasive drug delivery system for delivering a drug to the lacrimal gland, characterized in that the drug is administered to the eyelid skin once a day. The non-invasive drug delivery system of claim 1, wherein the drug-containing percutaneous absorption preparation is administered to the orbital skin once a day. The non-invasive drug delivery system of claim 1, which delivers the drug to the lacrimal gland through the local tissue of the eye. The non-invasive drug delivery system of claim 1 wherein the drug is delivered to the lacrimal gland during at least 24 hours after administration of the eyelid skin. The non-invasive drug delivery system of claim 1, which delivers the drug to the lacrimal gland in a manner of becoming C1 > C2 for at least 24 hours after administration of the eyelid skin, wherein C1 is a transdermal absorption type containing the drug. The concentration of the lacrimal gland of the drug after X hours of administration of the eyelid skin of the preparation; C2 is the drug after the eye for X hours of the topical administration preparation of the eye containing the drug contained in the above-mentioned percutaneous absorption type preparation The concentration in the lacrimal gland; and the X system indicates any natural number from 1 to 24. The non-invasive drug delivery system of claim 1, wherein the drug is a drug having pharmacological effects on the lacrimal gland. The non-invasive drug delivery system of claim 1, wherein the drug is a drug having a preventive and/or therapeutic effect on dry eye. The non-invasive drug delivery system according to claim 7, wherein the aforementioned drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist. The non-invasive drug delivery system of claim 8, wherein the aforementioned muscarinic receptor antagonist is choline urate or Carpronium. The non-invasive drug delivery system of claim 2, wherein the aforementioned percutaneous absorption type preparation is an ointment or an emulsion. A percutaneous absorption type preparation for delivering a drug to a lacrimal gland non-invasively, which is characterized in that it is administered to the eyelid skin once a day. A percutaneous absorption preparation according to claim 11, which is for delivering a drug to the lacrimal gland through the local tissue of the eye. A percutaneous absorption preparation according to claim 11, which is for delivering the drug to the lacrimal gland during at least 24 hours after administration of the eyelid skin. The percutaneous absorption type preparation according to claim 11, which is for delivering the drug to the lacrimal gland in a manner of becoming C1>C2 for at least 24 hours after administration of the eyelid skin, wherein the C1 line indicates a transdermal absorption type containing the drug. The concentration of the lacrimal gland of the drug after X hours of administration of the eyelid skin of the preparation; C2 is the drug after the eye for X hours of the topical administration preparation of the eye containing the drug contained in the above-mentioned percutaneous absorption type preparation The concentration in the lacrimal gland; and the X system indicates any natural number from 1 to 24. The percutaneous absorption type preparation according to claim 11, wherein the percutaneous absorption type preparation contains a drug having a pharmacological action on the lacrimal gland. The percutaneous absorption type preparation according to claim 11, wherein the percutaneous absorption type preparation contains a drug having a preventive and/or therapeutic effect on dry eye. The percutaneous absorption type preparation according to claim 16, wherein the drug having the preventive and/or therapeutic effect of dry eye is a muscarinic receptor antagonist. The percutaneous absorption preparation of claim 17, wherein the aforementioned muscarinic receptor antagonist is choline urate or caprolin. The transdermally absorbable preparation according to any one of claims 11 to 18, which is in the form of an ointment or an emulsifiable concentrate. A tear secretion promoting agent comprising a muscarinic receptor antagonist, which is characterized in that it is administered to the eyelid skin once a day. A dry eye treatment agent comprising a muscarinic receptor antagonist, which is characterized in that it is administered to the eyelid skin once a day.