MX2007009984A - Solid ophthalmic drug for external use. - Google Patents

Abstract

A solid ophthalmic drug for external use by which a pharmacologically active ingredient can be continuously and conveniently administered locally to eye. By applying this solid ophthalmic drug for external use, which is a solid drug containing the pharmacologically active ingredient in a base optionally containing an oily solid base, to the skin surface involving the eyelid surface, the pharmacologically active ingredient penetrates through the eyelid skin and is delivered locally to an eye tissue in the backside of the eyelid.

Description

SOLID LUMIC OFT DRUG FOR EXTERNAL USE TECHNICAL FIELD The present invention relates to a novel form of an ophthalmic pharmaceutical preparation for external use, more specifically to an ophthalmic solid pharmaceutical preparation for external use, and in particular to an ophthalmic solid pharmaceutical preparation for external use, solid pharmaceutical preparation. which is designed so that a portion of it is applied to the surface of the skin including the front surface of the eyelids by rubbing these directly on the surface of the skin to allow the pharmacologically active ingredient to be transferred, through the area of the skin. the skin, towards the eye tissues such as the conjunctiva, cornea and the like.

BACKGROUND TECHNIQUE Among the forms of ophthalmic pharmaceutical preparation for external use, that is, for topical application to the eye, the most popular have been the drops, with the ophthalmic ointment following them. These forms of pharmaceutical preparations are designed to put the pharmaceutical preparations in direct contact with the cornea or conjunctiva of the eye to allow their active ingredients are transferred to those regions. Although eye drops are easy to apply and excellent in their rapidity of action, they are easily washed by the tear fluid. Therefore, when the local concentration of a pharmacologically active ingredient must be maintained for a prolonged period of time, frequent instillation into the eye is sometimes required. Although most eye drops contain one or more condoms to prevent the growth of microorganisms, condoms are probably a cause of irritation to the conjunctiva and cornea. In addition, eye drops containing a condom are subject to limitation since they can not be applied immediately before going to sleep, because the exchange of the tear fluid causes them to be lost when one is sleeping, the applied eye drops of This way they are not washed by the tear fluid. On the other hand, although ophthalmic ointment is as excellent as eye drops in its rapidity of action, with, in general, a somewhat longer duration of effect compared to eye drops, it has disadvantages due to the difficulty encountered. by a patient when he tries to apply this by himself, causes blurred vision during some time interval after the application when covering the tear film, and makes them adhere to the edges of the eyelids, and the like. One of the novel methods proposed with respect to ophthalmic pharmaceutical preparation forms for external use is a transdermal treatment system consisting of a support layer and a pressure sensitive adhesive reservoir layer made of a polymeric material containing pilocarpine. (Patent Document 1). This is a system by which "it is intended to allow pilocarpine to be transmitted to the eye by means of the blood flow that has received the pilocarpine absorbed through the skin on the surface of which the system was fixed. drug to posterior ocular tissues, such as lenses, vitreous body, choroid, and retina, to which a pharmacologically active ingredient in general is difficult to access either by topical instillation or subconjunctival injection, as well as to better guarantee patient compliance , an ophthalmic transdermal patch containing a drug-containing layer which homogeneously contains a drug and a transdermal absorption enhancer in a base matrix has also been proposed (Patent Document 2). A method for the treatment of the syndrome has also been proposed. of the dry eye on the basis of a patch or transdermal pad (Patent Document 3). In addition, a preparation of the transdermal absorption type for the treatment of ophthalmic diseases has been proposed., which, by having a layer of a plaster containing a drug on a support layer, is applied to the surface of the skin, including the front surface of the eyelids (Patent Document 4), and can transdermally release a drug, to treat ophthalmic diseases to the outer segments of the eye including the conjunctival, lacrimal and corneal tissues in a relatively short time and allows it to continuously exhibit its pharmacological effects. This preparation allows one to administer a drug to the local tissues of the eye through the skin and substantially not via blood circulation, fixing it to the surface of the skin, including the front surface of the eyelids, which are adjacent to the outer segments of the eye. However, any of the above preparation forms, which are used being fixed to the skin, include, as an essential component, a sheet of fabric or some other support member that supports the drug-containing layer, and therefore , the preparation must be maintained on the skin together with the support member through all the time during the which is the administration of the drug. To allow the drug to be transmitted to the eye tissues of interest as selectively as possible, it is necessary to fix the preparation to the surface of the skin including the surface of the eyelids. However, this not only captures the eye and makes it look luminous but also produces problems for the user such as a sense of discomfort, or impaired movements of the eyelids (opening and closing of the eyelids, blindness), depending on the position in the eye. which is applied, as well as its size. [Patent Document 1] Publication of Japanese Patent Application H8-509716 [Patent Document 2] WO 01/26648 [Patent Document 3] USP 6277855 [Patent Document 4] WO 2004/064817 DESCRIPTION OF THE INVENTION THE PROBLEM TO BE RESOLVED BY THE INVENTION Against the foregoing background, the purpose of the present invention is to provide a novel type of method for delivering a pharmacologically active ingredient to local ocular tissues, and also a novel form of an ophthalmic pharmaceutical preparation for use. external, which is free of the problem previous in appearance during application, does not produce a sense of discomfort on the eyelids in the user, or does not prevent the movement of the eyelids, and allows a continuous administration of a pharmacological ingredient with greater ease. [Means to solve the Problem] The inventors herein, as a result of research for the above purpose, found that a solid pharmaceutical formulation which is prepared to contain a pharmacologically active ingredient, using material which is capable of forming a solid which is gentle enough to be applied by rubbing this on the skin, could be held in the hand and applied by rubbing on the surface of the skin, including the front surface of the eyelids, thus allowing the continuous administration of this to the anterior segment of the eye through the skin of the eyelids. Thus, the present invention provides the following. (1) An ophthalmic solid pharmaceutical preparation for external use comprising a base containing a pharmacologically active ingredient, wherein the solid pharmaceutical preparation is designed to be applied by rubbing onto the surface of the skin, including the surface of either eyelid to release through the skin of the eyelids, the ingredient pharmacologically active to local ocular tissues located on the posterior side of the eyelids. (2) The ophthalmic solid pharmaceutical preparation for external use according to (1) above, wherein the base comprises an oily solid base. (3) The ophthalmic solid pharmaceutical preparation for external use according to (2) above, wherein the oily solid base is a wax or petrolatum. (4) Ophthalmic solid pharmaceutical preparation for external use according to (3) above, where the wax is animal wax or vegetable wax. (5) The ophthalmic solid pharmaceutical preparation for external use according to one of (1) to (4) above, wherein the preparation contains a skin permeation enhancer. (6) The ophthalmic solid pharmaceutical preparation for external use according to (5) above, wherein the skin permeation enhancer is selected from the group consisting of an ester consisting of a fatty acid and a lower aliphatic alcohol, and a surfactant. (7) The ophthalmic solid pharmaceutical preparation for external use according to (6) above, wherein the ester content is 30-60% by weight. (8) Ophthalmic solid pharmaceutical preparation for external use according to (6) or (7) above, where the ester is isopropyl myristate or isopropyl palmitate, and where the surfactant is a non-ionic surfactant. (9) The ophthalmic solid pharmaceutical preparation for external use according to one of (1) to (8) above, wherein the base comprises an oily solid base, wherein the content of the oily solid base in the pharmaceutical preparation is 15-60% by weight. (10) The ophthalmic solid pharmaceutical preparation for external use according to one of (1) to (9) above, wherein the pharmacologically active ingredient is selected from the group consisting of non-steroidal anti-inflammatory agents, antiallergic agents, antiglaucoma agents, anti-catalase agents , antimicrobial agents, antiviral agents, antifungal agents, antibiotics, sulfa agents, steroid antiinflammatory agents, mitotic agents, mydriatic agents, local astringents, vasoconstrictors, anticholinesterases, superficial anesthetics and vitamins. (11) The ophthalmic solid pharmaceutical preparation for external use according to one of (1) to (10) above, wherein the form of the pharmaceutical preparation is a short bar. (12) An ophthalmic bar-like preparation comprising a generally cylindrical container body defining an opening end, and a member movable bottom which fits inside the body of the container and can be translated in the direction towards the open end and drive means for causing the moving lower means to move in the direction towards the open end, where the preparation Ophthalmic solid pharmaceutical for external use according to one of (1) to (11) above is contained, in the container body, between the end that can be opened and the mobile lower limb, where the ophthalmic solid pharmaceutical preparation for external use it can be projected from the body of the container as a result of the forward translation of the movable lower member actuated by the driving means. (13) A method for releasing a pharmacologically active ingredient to ocular local tissues located on the posterior side of the eyelids, the method comprising rubbing an ophthalmic solid pharmaceutical preparation for external use comprising a base containing a pharmacologically active ingredient, on the surface of the skin, including the surface of either eyelid to apply the preparation. (14) The method according to (13) above, wherein the base comprises an oily solid base. (15) The method according to (14) above, where the oily solid base is wax or petrolatum. (16) The method according to one of (13) to (15) above, wherein the ophthalmic solid pharmaceutical preparation for external use contains a skin permeation enhancer. (17) The use of an oily solid base for the manufacture of an ophthalmic solid pharmaceutical preparation for external use containing a pharmacologically active ingredient to release the pharmacologically active ingredient to the tissues located on the posterior side of the eyelids. (18) The use of an oily solid base and a skin permeation enhancer for the preparation of an ophthalmic solid pharmaceutical preparation for external use containing a pharmacologically active ingredient to release the pharmacologically active ingredient to the tissues located on the side posterior of the eyelids. (19) Use according to (17) or (18) above, where the oily solid base is wax or petrolatum.

THE EFFECT OF THE INVENTION By holding in the hand and rubbing it on the surface of the skin, including the front surface of the eyelids, the ophthalmic solid pharmaceutical preparation for external use of the present invention can be used to apply a pharmacologically active ingredient, together with its base, to the surface of the skin. The pharmacologically active ingredient contained in the applied pharmaceutical preparation thus infiltrates through the skin and efficiently reaches local ocular tissues located on the side where the application was made, such as the conjunctiva, cornea and the like, not through the systemic distribution by the circulation of the blood or via the metabolism of the pharmacologically active ingredient. In this way, the present invention achieves the release of the pharmacologically active ingredient to local ocular tissues, and allows a highly continuous release of this and prolonged, sustained pharmacological activity, while avoiding the risks of side effects that would be encountered with the systemic administration of a pharmacologically active ingredient. In addition, the present invention does not require a support member such as is needed in the case of a patch-type preparation, its application being effected across the surface of the skin, including the front surface of the eyelids, nests a lumpy appearance or a sense of discomfort to its user, nor does it impede the movement of the eyelids. In this way, it can be applied anywhere in daily life, thus serving to improve compliance of the patient and to allow the effect of the pharmaceutical preparation to be fully expressed. further, it allows to control the period of time during which its pharmacological effect lasts, adjusting the number of times that the pharmaceutical preparation is rubbed on the skin, for example, 1-10 times. Also, according to the present invention, the contact of a high concentration of a pharmacologically active agent with the cornea and conjunctiva, as is common in the case of eye drops or ophthalmic ointment, is avoided, and allows an agent pharmacologically active substance gradually infiltrates through the skin of the eyelids. Therefore, even a pharmacologically active agent that is irradiated at higher concentrations could be used.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a side view of a vertical diffusion cell. Figure 2 illustrates a graph showing the result of an in vitro skin permeation test 1. Figure 3 illustrates a graph showing the result of an in vitro skin permeation test 2. Figure 4 illustrates a graph showing the result of an in vitro skin permeation test 3.

Figure 5 illustrates a graph showing the result of an in vitro skin permeation test 4. Figure 6 illustrates a graph showing the concentration profile of the drug in the tear fluid after rubbing of the pharmaceutical preparation. Figure 7 illustrates a graph showing the concentration profile of the drug in the conjunctiva after rubbing the pharmaceutical preparation. Figure 8 illustrates a graph showing the concentration profile of the drug in the plasma after rubbing of the pharmaceutical preparation. The Fiqura 9 illustrates a graph that compares the concentration profiles of the drug in the conjunctiva, between the application by rub of the pharmaceutically solid preparation and the topical instillation of drops for eyes.

EXPLANATION OF THE SIGNS 1 Vertical diffusion cell 2 Donor cell 3 Donor cell compartment 4 Receiving cell 5 Receiving cell compartment 6 Magnetic stirrer tip 7 Clamp BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, "the surface of the skin including the surface of the eyelids" means the surface of the skin that defines the surface (front surface) of the upper and lower eyelids plus the surface of the skin adjacent to it. Although the preferred area to which the pharmaceutical preparation of the present invention is applied is the surface of the skin defining the upper and lower eyelid surface, the application of the preparation of the invention to the surface of the surrounding area of the skin it is also allowed and preferable to further increase the amount of pharmacologically active agent that infiltrates through the skin. In the present invention, "the local tissues of the eye located on the posterior side of the eyelids" means the tissues that occur in the orbit, including the cornea, bulbar conjunctiva, sclera, aqueous humor, iris, lens, ciliary bodies, choroid, retina and body or vitreous humor, as well as the palpebral conjunctiva and the lacrimal fluid. In the present invention, when it is said that the pharmaceutical preparation is "solid" it means that the pharmaceutical preparation lacks substantial fluidity, retains its shape (of the composition), and is of such hardness which allows a user to apply this by rubbing it on its exposed portion on the skin. According to the present invention, the components forming the base of the pharmaceutical preparation of the invention are not in direct contact with the anterior tissues of the eye (conjunctiva, cornea, etc.). Therefore, even when that component can be used, which can not be included in eye drops because it would cause eye irritation, it does not affect the surface of the skin. Examples of those components include, for example, a variety of compounds that improve the transdermal absorption of pharmacologically active ingredients. By formulating a pharmaceutical preparation using those compounds when desired, it is possible to improve the transdermal absorption of a pharmacologically active ingredient and thereby release a therapeutically necessary amount of the ingredient relatively quickly and continuously to the external tissues of the eye. When the pharmaceutical preparation of the present invention is applied to the surface of the skin (where a number of various bacteria and fungi are commonly present), it is not necessary that the pharmaceutical preparation of the present invention be provided as a sterile preparation. In addition, the preparation can be either condom-free, while that composition selected can not allow the growth of bacteria or fungi. In the formulation of the pharmaceutical preparation of the present invention, a variety of oily or aqueous bases can be used which form a solid which contains a pharmacologically active ingredient and which has such a softness that allows a user to apply the preparation by rubbing it on the surface of the skin. In addition, there is a variety of transdermal absorption enhancers well known to those skilled in the art, from which a transdermal absorption enhancer can be chosen when desired and added to the base at the desired concentration according to the permeability of the skin so that a given pharmacologically active agent is released to local ocular tissues and the concentration at which it exhibits its pharmacological activity in local ocular tissues. In the present invention, examples of bases include, but are not limited to, waxes, ie natural waxes such as vegetable waxes (eg, carnauba wax, Japan wax, candelilla wax), animal wax (eg, wax) of bees, whalewax, wool wax), petroleum wax (e.g., paraffin wax, microcrystalline wax), mineral wax (e.g., mountain wax, ozokerite), synthetic waxes (e.g. carbowax), and the like, petrolatum, lanolin, hydrogenated rosin resin / glyceryl diisostearate, hydrogenated polyisobutene, polyethylene, fatty acid cholesteryl, higher fatty acid esters (eg, isopropyl myristate, isopropyl palmitate, oleic acid, propylene glycol) , hexyl laurate, decyl oleate, glyceryl monostearate), higher aliphatic alcohols (eg, cetyl alcohol, isostearyl alcohol, lauryl alcohol, oleyl alcohol), squalene, squalane, polyethylene glycol, higher fatty acids (eg, isostearic acid) , lauric acid, oleic acid, linoleic acid, linolenic acid), animal oils (e.g. lard), vegetable oils (e.g., castor oil) and the like, but any of the bases that can form solid pharmaceutical preparations, as well as a combination of them, can be used. Among those bases, a particularly preferred example is a combination of an oily solid base such as waxes, petrolatum or squalane with a higher fatty acid ester such as isopropyl myristate or isopropyl palmitate. Among them, higher fatty acid esters such as isopropyl myristate and isopropyl palmitate are preferable, since they not only serve as bases to form a solid pharmaceutical preparation but also to function simultaneously with an enhancer for the permeation of the skin to pharmacologically active ingredients. Various other ingredients may also be employed in the base to control the nature of the solid preparation. Examples of these ingredients include plastibase, carboxyvinyl polymer, polyacrylic acid, sodium polyacrylate, cellulose derivatives (methylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and the like), polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, alginic acid, sodium alginate, gelatin, polysaccharide thickener (eg, gum arabic, tragacanth gum, guar gum, xanthan gum), glycerol, sorbitol, ethylene glycol, propylene glycol and the like. The content of oily solid bases in the pharmaceutical preparation of the present invention is preferably 15-60% by weight, more preferably 20-60% by weight, and even more preferably 35-55% by weight . For example, where a combination of waxes (animal waxes such as beeswax and vegetable waxes such as candelilla wax) and higher fatty acid esters such as isopropyl myristate, isopropyl palmitate, and the like are used, the content of the waxes in The pharmaceutical preparation is preferably 15-60% by weight, more preferably 20-60% by weight, and even more preferably 35-55% by weight. In addition, the content of higher fatty acid esters is preferably 30-60% by weight, more preferably 35-55% by weight. The pharmaceutical preparation of the present invention may also contain a permeation enhancer. skin. Examples of skin permeation enhancers include, but are not limited to, aliphatic alcohols, fatty acids and their salts, fatty acid esters, polyolalkyl ethers, glycerides, medium-chain fatty acid polyethers, alkyl lactates, esters of alkyl of dibasic acid, acylated amino acids, pyrrolidones, hydroxycarboxylic acids, or dicarboxylic acids, monoterpenes and a variety of surfactants, and the like. Any of. These skin permeation enhancers, or two or more of them, can be used alone or in combination. Some of them are also those components that can be used to adjust the physical properties (for example, hardness, viscosity, plasticity) of the base. Examples of the aliphatic alcohols mentioned above include ethanol, polyols such as glycerol, diethylene glycol, propylene glycol and polyethylene glycol, and higher aliphatic alcohols. Among the higher preferred aliphatic alcohols they are the higher aliphatic alcohols having 12-22 carbon atoms, which may be saturated or unsaturated, such as oleyl alcohol, lauryl alcohol, and the like. Examples of fatty acids mentioned above and their salts include, but are not limited to, salts of capric acid, myristic acid, palmitic acid, lauric acid, stearic acid, isostearic acid, palmitoleic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, (for example, sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt). Examples of the fatty acid esters mentioned above include, but are not limited to, esters of fatty acids having 10 or more carbon atoms such as capric acid, lauric acid, palmitic acid, stearic acid and the like with lower aliphatic alcohols which they have less than 12 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, hexanol, pentanol, heptanol, and the like. Specific examples thereof include isopropyl myristate, diisopropyl adipate, isopropyl palmitate and the like. Examples of polyols mentioned above include, but are not limited to ethers formed from polyols such as glycerol, ethylene glycol, propylene glycol, 1,3-bicyclic glycol, diglycerol, polyglycerol, diethylene glycol, polyethylene glycol, dipropylene glycol, propylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharides, reduced oligosaccharides, and the like and alkyl alcohols, (e.g. polyoxyethylene alkyl ether). The alkyl alcohol portion thereof preferably has 6-20 carbon atoms. Preferred polyoxyethylene alkyl ethers are those consisting of an alkyl portion having 6-20 carbon atoms and a plooxyethylene chain having 1-9 repeating units (-0-CH2CH2-). Specific examples of those polyoxyethylene alkyl ethers include polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and the like. With respect to the glycerides, any of the monoglycerides, diglycerides and triglycerides can be employed, alone or in combination. The fatty acids as components of the glycerides are preferably those having 6-18 carbon atoms. Examples of those fatty acids include octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, stearic acid and oleic acid. In addition, lactic acid, tartaric acid, 1,2,6-hexantriol, benzyl alcohol, lanolin, hydroxide potassium and tris (hydroxymethyl) aminomethane can also be used as skin permeation enhancers. Examples of the monoterpenes mentioned above include a-limonene, l-menthol and the like. As the surfactants mentioned above, anionic surfactants, cationic surfactants, non-ionic surfactants and ampholytic surfactants can be employed. Examples of anionic surfactants include fatty acid salts, alkyl sulfate salts, polyoxyethylene alkyl sulfate salts, alkylsulfocarbonic acid salts, alkyl ether carbonic acid salts, N-lauroyl sarcosine and the like. Examples of cationic surfactants include amine salts, quaternary ammonium salts and the like. Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and the like. Examples of ampholytic surfactants include alkylbetaine, dimethyl alkylglycine, lecithin and the like. In addition, additional examples of skin permeation enhancers include 1-dodecylazabicycloheptan-2-one, pyrrothiodecane, 2-pyrrolidone, 1-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, decylmethylsulfoxide, fumaric acid, maleic acid, myristyl lactate, cetyl lactate, lauric acid diethanolamide and the like. Among the aforementioned skin permeation enhancers, particularly preferred are higher aliphatic alcohols such as lauryl alcohol and the like, fatty acids such as isostearic acid and the like, higher aliphatic esters such as isopropyl myristate, isopropyl palmitate and the like, polyoxyethylene alkyl ethers, such as polyoxyethylene oleyl ether, potassium hydroxide, tris (hydroxymethyl) aminomethane and the like, and it is particularly preferred to use a mixture of two or more of them. Skin permeation enhancers can be included in a solid pharmaceutical preparation in any desired weight ratio, so long as it does not adversely affect the physical properties of the solid pharmaceutical preparation. They are included in general, at 1-60% by weight, preferably 10-60% by weight, more preferably at 30-60% by weight of the total solid pharmaceutical preparation. When higher fatty acid esters such as isopropyl myristate, isopropyl palmitate and the like are used as skin permeation enhancers, those esters are preferably contained at 30-60% by weight, and more preferably preferable to 35-55% by weight of the total solid pharmaceutical preparation. For example, the polyoxyethylene oleyl ethers which can be used in the present invention are those in which the average number of ethylene oxides added to the oleyl portion is preferably 4.5-5.5, particularly preferably about 5. They can be produced by reaction, with oleyl alcohol, ethylene oxide with a hydroxy index of 4.4-5.5, as determined by the method stipulated in the thirteenth edition of the Japanese Pharmacopoeia in the section "Hydroxy index" included in the Test method of fixed oils and fats. As the polyoexethylene oleyl ether, the Nonion E-205S produced by NOF Corporation, for example, can be preferably used. As for pharmacologically active ingredients, drugs that have also typically been used for ophthalmic diseases and drugs known to be useful for the same purpose can also be used in the present invention. These drugs include non-steroidal antiinflammatory agents, antiallergic agents (Hl blockers), antiglaucoma agents (α-blockers, β-l blockers, carbonic anhydrase inhibitors), anti-catalase agents, antimicrobial agents, antiviral agents, antifungal agents, antibiotics, sulfa agents, steroidal antiinflammatory agents, miotic agents, mydriatic agents, local astringents, vasoconstrictors, anticholinesterase agents, surface anesthetics, and vitamins (eg, vitamin B 2, vitamin B2 coenzyme type) and the like. Specifically, they are exemplified by the following compounds: acyclovir, azulene, anthranilic acid, ascorbic acid, amlexanox, isopropyl unoprostone, idoxuridine, ibudilast, indomethacin, epinephrine, erythromycin, lysozyme hydrochloride, apraclonidine hydrochloride, oxybuprocaine hydrochloride, carteolol hydrochloride, cyclopenter hydrochloride, dipivefrin hydrochloride, cefmenoxim hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, phenylephrine hydrochloride, bunazosin hydrochloride, betaxolol hydrochloride, befunolol hydrochloride, levocabastine hydrochloride, levobunolol hydrochloride, hydrochloride of lomefloxacin, ofloxacin, carbacol, dipotassium glycyrrhizinate, glutathione, sodium cromoglycate, chloramphenicol, hydrocortisone acetate, prednisolone acetate, cyanocobalamin, diclofenac sodium, distigmine bromide, homatropine bromohydrate, naphazoline nitrate, calcium diiodo stearate, sulfisoxazole, sulbenicillin sodium, tazanolast, dexamethasone, tobramycin, tranilast, tropicamide, nipradilol, norfloxacin, pimaricin, pirenoxin, cetotifen fumarate, pranoprofen, flavin adenine dinucleotide, fluorometholone, prednisolone, sodium bromfenac, pemirolast potassium, heleniena, timolol maleate, myopine, dexametasone sodium metasulfobenzoate, iodide ecotiopate, latanoprost, lidocaine, atropine sulfate, gentamicin sulfate, sisomycin sulfate, dibecacin sulfate, micronomycin sulfate, dexamethasone sodium phosphate, betamethasone sodium phosphate, levofloxacin, olopatadine hydrochloride, epinastine hydrochloride and the like. Among those therapeutic agents for ophthalmic diseases, those preferred from the standpoint of transdermal absorption and skin permeability are those compounds having a molecular weight no greater than 1000, more preferably those having a molecular weight no greater than 800, more preferably those having a molecular weight of not more than 600, and particularly preferred are those having a molecular weight of not more than 500. Among those agents, antimicrobial agents, anti-allergic agents, anti-inflammatory agents (steroidées, etc.) are preferred. Non-steroidal agents, antiglaucoma agents and anticatarata agents, with antiallergic agents and anti-inflammatory agents are not steroids being particularly preferred. Examples thereof include ketotifen fumarate (anti-allergic, antihistaminic agent, molecular weight; 425.51), and diclofenac sodium (non-steroidal anti-inflammatory agent; molecular weight of 318.13). The form of the pharmaceutical preparation of the present invention can be as desired, for example, as a short bar, as a solid, rectangular, as a disc, and so on. This is preferably prepared as a bar-type preparation contained in a container, so that the pharmaceutical preparation can be applied without touching it directly. In a particularly preferred embodiment, the pharmaceutical preparation is contained in a container which is generally cylindrical and can be opened at its front end, and whose sheath is formed by a movable lower member which can be slid by the operation from outside, longitudinally in direction towards the front end, and the solid pharmaceutical preparation is contained in the enclosed space with the cylindrical internal side surface of the container body and the movable lower member. That movable lower member can be made in any desired shape, and it can be of the same configuration as that of well-known conventional bar-type lipsticks or glues. By example, the movable lower member is installed in the body of the cylindrical container, being coupled by a screw with a nut therethrough extending along the central axis of the container, and engages within the internal shape of the side walls of the container group so as not to rotate relative to the body of the container. And the screw, which is secured at its proximal end to the center of a rotating finger-shaped clamping member which is attached to the proximal end of the container body and can be rotated to the outside around the body axis of the container, provides , together with the clamping member in the form of a rotating finger, means for moving the moving lower member. In this case, the rotation of the screw by the rotation of the clamping member in the form of a rotating finger causes the moving lower member, which is threadably engaged with the screw and whose rotation is blocked by the coupling by the container body. to move longitudinally inside the container body through the threaded mechanism formed by the screw.

EXAMPLES The present invention is described in more detail below with reference to the examples. However, it is not intended that the present invention be limited to the examples.

[Provision of a solid pharmaceutical preparation] According to the following formula, ketotifen fumarate (Sigma Chemical) was chosen as an example of a pharmacologically active ingredient, and beeswax (Wako Pure Chemical Industries, Ltd.) and the isopropyl myristate (Wako Pure Chemical Industries, Ltd.), which also acts as a skin permeation enhancer, as a base. As skin permeation enhancers candidates to be added to those ingredients, were chosen lauric acid, oleic acid, L-menthol, limonene, polyoxyethylene lauryl ether, sodium laurel sulfate (all produced by Wako Pure Chemical Industries, Ltd.) , polyoxyethylene oleyl ether (NOFABLE EAO-9905; Nof Corporation), and glycerol monooleate (NOF Corporation) to prepare each of the solid pharmaceutical preparations as shown in Table 1. Briefly, according to each formula, they added isopropyl myristate and an additional skin permeation enhancer to the heavy ketotifen fumarate in a beaker be shaken well. To this was added beeswax and mixed well at about 75 ° C, and the mixture was quickly poured into compartment 3 of the donor side (donor cell 2) of the vertical diffusion cell (Modified Franz cell) 1 illustrated in Figure 1, and allowed to solidify in the cells, using this as a template.

[Table 1] 100% weight values; IPM = Isopropyl myristate, POEL = Polyoxyethylene lauryl ether, SDS = Sodium lauryl sulfate, POEO = Polyoxyethylene oleyl ether, GO = glycerol mono-oleate.

[Skin permeation test 1 in vi tro] For each of the solid pharmaceutical preparations shown in Table 1.

Referring to Figure 1, compartment 5 on the receptor side (recipient cell 4) of each vertical diffusion cell 1 was filled with approximately 10 mL of drug-free phosphate buffer (pH.7.4). A piece of intact abdominal skin of a hairless mouse was cut and fixed to cover the opening of each recipient cell 4, with its external surface facing upwards (effective diffusion area: 1.72 cm 2). In this position, the lower surface of the skin was constantly left in contact with the phosphate buffer in the recipient cell 4. The donor cell 2 was mounted on the fixed skin over the opening of the recipient cell 4, with one of the solid pharmaceutical preparations of the formulas mentioned above Al a AlO (of these, Al is the control), which had been formed using the compartment 3 of the donor side as a mold, projecting down approximately 1 mm from the opening of the donor cell 2, and was secured with a clip 7. Then, the skin permeability experiments were initiated. By constantly stirring the buffer, a magnetic stirrer tip 6, a sampling of 200 μl was made to predetermined intervals of the recipient cell 4, immediately supplemented with the same amount of drug-free phosphate buffer to maintain the volume of the receptor solution constant. During the experiment, the temperature was maintained at 37 ° C. The determination of ketotifen fumarate in the samples was carried out by CLAP under the following conditions. The results are shown in Figure 2 and Table 2. < Conditions of CLAP > Detector: UV spectrophotometer (detection wavelength of 300 nm) Column: Capcell pak C18 MG S5 μm, 4.5 x 250 mm (manufactured by Shiseido) Protection Column: TSK-GEL ODS-80Ts (manufactured by Tosoh Corporation) Column temperature: constant temperature at approximately 40 ° C Mobile phase: Tris (hydroxymethyl) aminomethane buffer) 0.1 M (manufactured by Wako Pure Chemical Industries) (pH 9) / acetonitrile = 30: 70 Speed Flow Rate: 1.0 mL / min Injection Volume: 30μL [Table 2] dQ / dt [μg / cm2 / hr] = skin permeation rate of a drug per unit of time, td [hr] = time delay In Figure 2 (time curve Q-t), the axis of the ordinates represents the cumulative quantity that infiltrated per unit area (Q), and the abscissa axis represents time (t). In Table 2, the time delay (td [hr]) is the ordinate at the origin with the extension of the linear portion of the time curve Qt in Figure 2. dQ / dt represents the amount of pharmacologically active ingredients (μg) ) that permeates per unit area (1 cm2) per unit time (1 hr). As is evident from Table 2 and Figure 2, although the continuous permeation of the ketotifen fumarate towards the recipient side cell was observed with any of the solid pharmaceutical preparations, a marked increase in the permeation of the skin with the solid preparation containing sodium lauryl sulfate, glycerol monooleate or polyoxyethylene oleyl ether in addition to isopropyl myristate, compared to the solid preparation of formula Al (control), which contained only a permeation enhancer of the skin, isopropyl myristate, which also acts as a base. Among others, it was found that polyoxyethylene oleyl ether was very effective.

[Skin permeation test 2 in vi tro] To closely examine the effect of polyoxyethylene oleyl ether at different concentrations on skin permeation of pharmacologically active ingredients, solid pharmaceutical preparations containing polyoxyethylene oleyl ether at different concentrations (0, 1, 5 and 8% by weight) were prepared according to the formulas set forth in Table 3, and the skin permeation rates were measured in the previous tests. The results are shown in Figure 3 and Table 4. The formula Bl is the control in this test. In the following test examples, Nonion E-205S (Yuca Sangyo Co., Ltd.) was used as polyoxyethylene oleyl ether (POEO).

[Table 3] [Table 4] n = 3, Values that represent the mean + standard deviation As is evident from Figures 3 and 4, the increase induced by the polyoxyethylene oleyl ether in the permeation rate of the skin the pharmacologically active ingredient was dose dependent, with a remarkable acceleration of the velocity d.e. skin of the pharmacologically active ingredient using polyoxyethylene oleyl ether at a concentration of between 1% by weight and 5% by weight.

[Skin permeation test 3 in vi tro] To examine the influence of the concentration of a pharmacologically active ingredient on the skin permeation of the pharmacologically active ingredient, the solid pharmaceutical preparations of the forms shown in Table 5 were prepared with variable concentrations of ketotifen fumarate, and its skin permeation was tested in the same way as in the previous tests. The results are shown in Figure 4 and Table 6.

[Table 5] [Table 6] n = 3, values that represent the mean ± standard deviation. As can be seen in Figure 4 and Table 6, when the concentration of ketotifen fumarate in the solid pharmaceutical preparation was increased, from 1% to 2, 4 and 8% by weight, its skin permeation rate increased approximately parallel to the concentration of ketotifen fumarate, is say 1.76 times to 2% by weight, 3.24 times to 4% by weight and 6.22 times to 8% by weight compared to the 1% by weight formula.

[In vitro skin permeation test 4] The permeation in the skin of a pharmacologically active ingredient of a solid pharmaceutical preparation containing the same, when applied by rubbing the preparation on the skin, was compared to the achieved skin permeation. when the solid pharmaceutical preparation was mounted on the skin. Agree to the formula C4 in Table 5, isopropyl myristate and polyoxyethylene oleyl ether were added to the heavy ketotifen fumarate in a beaker, and stirred well. To this was added beeswax and mixed well at about 75 ° C. The mixture was then poured into portions in a labial tube (volume 5 mL, H68.0 mm x fl6.0 mm) which had been adjusted to have a gap of approximately 15 mm depth from the top of the container (approximately 2 ml in volume) by turning its screw, and allowed to solidify at room temperature environment to give a solid cylindrical ophthalmic pharmaceutical preparation for external use. The permeation of the skin of the ketotifen fumarate was examined under two conditions, in one of which the solid pharmaceutical preparation was applied in a sufficient quantity of the labial tube rubbing this 10 times in a split skin of a mouse (applied to the area of approximately 4 cm2) and the skin was placed on the recipient cell, and on the other of which the solid pharmaceutical preparation was placed on the skin in the same manner as in the tests mentioned above. The results are shown in Figure 5. Figure 5 shows that the skin permeation rate of the ketotifen fumarate where the solid pharmaceutical preparation was rubbed on the surface of the Skin was not less than where the solid pharmaceutical preparation was placed on the surface of the skin.

[Skin permeation test 5 in vi tro] The permeation rates of the skin were compared between two solid pharmaceutical preparations whose bases were defined among themselves. Briefly, according to the formulas in Table 7, the solid pharmaceutical preparations were prepared in tubes for labials (volume 5 mL, H68.0 mm x fl6.0 mm) and rubbed on sheets of excised mouse skin; which were then fixed on the recipient cells to measure the skin permeation rates of the ketotifen fumarate. The results are shown in Table 8.

[Table 7] [Table 8] As seen in Table 8, both solid pharmaceutical preparations exhibited continuous high skin permeation. In addition, no difference was found between the two formulas, indicating that various oil bases can be employed which are capable of forming solid pharmaceutical preparations having appropriate hardness to facilitate rubbing.

[In vivo drug transfer test] A test was conducted as follows to examine whether a pharmacologically active ingredient could be transferred to ocular tissues after application by rubbing a solid pharmaceutical preparation containing a pharmacologically active ingredient on the surface of the skin, including the frontal surface of the eyelids of rabbits. < Provision of a solid pharmaceutical preparation > Using ketotifen fumarate as the pharmacologically active ingredient, a solid pharmaceutical formulation of the cylindrical rod type was prepared in a tube for lipstick according to the following formula. (Formula C4) ketotifen fumarate 8g beeswax 42 g isopropyl myristate 45 g polyoxyethylene oleyl ether 5 g total amount 100 g Heavy ketotifen fumarate in a beaker was added isopropyl myristate and polyoxyethylene oleyl ether and mixed well . Beeswax was added to these and mixed well at approximately 75 ° C. It was then poured into portions in a labial tube (volume: 5 mL, H68.0 mm x fl6.0 mm) and allowed to solidify at room temperature to give a solid pharmaceutical preparation of the bar type. < Administering the solid pharmaceutical preparation > The day before the test, the rabbits were subjected to hair removal around their upper and lower eyelids in both eyes. The rabbits were kept in containers and their skin area of 3.5-4 cm2 was marked below one of the eyes including the lower eyelid, and the previous solid pharmaceutical preparation was then applied by rubbing it 10 times on that area. The net amount of ketotifen fumarate applied was about 14.4 mg as a calculated base on the reduced amount of the solid pharmaceutical preparation and the proportion of each component of the preparation. < Sampling of tissues > At 4, 8 and 24 hours after the application of the solid pharmaceutical preparation, the remaining pharmaceutical preparation was gently cleaned on the surface of the skin. To avoid contamination with the pharmaceutical preparation still remaining on the skin, the area to which the application was made was covered with a tape, and then the tear fluid was collected using a capillary. After the blood sampling, the rabbits were euthanized with an excess amount of sodium pentobarbital solution. The collected blood was centrifuged for approximately 5 minutes, and the plasma was transferred to Eppendorf tubes. The anterior segments of the eye were washed with saline, and the pharmaceutical preparation was cleansed from the skin of the lower eyelid, and the ocular globule was removed with the conjunctiva attached. The conjunctiva was taken from the excised eye on a sheet of filter paper. The conjunctiva thus removed was frozen and stored at -80 ° C. < Measurement of ketotifen fumarate in tissues > (1) Measurement of fluid concentration lacrimal: The wet weight of the tear fluid collected in an Eppendorf tube was measured. With the addition of the mobile phase to them, the samples in the three tubes were combined in one and the total amount of approximately 160 μl was centrifuged at 14,000 rpm for 5 minutes. 150 μl of the supernatant was transferred to a bottle, and 50 μl of this was injected into a CLAP for quantitative measurement. (2) Measurement of concentration in the conjunctiva: The wet weight of the conjunctiva taken in spitz tubes was measured. To this was added 1 ml of 10 mM disodium hydrogen phosphate buffer (pH 7.0) and the conjunctiva was crushed. In addition, 4 ml of acetonitrile was added, and the mixture was stirred at 300 rpm, for 10 minutes. After centrifugation at 3000 rpm for 10 minutes, 4 ml of each supernatant was removed in separate test tubes for concentration and allowed to dry under reduced pressure for approximately 18 hours in a centrifugal evaporator (the samples in the 3 tubes were finally combined in one during the concentration). Then, this was dissolved again by the addition of 300 μl of the mobile phase, and the total volume was transferred in an Eppendorf tube. After ultracentrifugation for 5 minutes at 14000 rpm, the supernatant was filtered through a membrane filter (0.22 μm). The filtrate was transferred to a flask, and 50 μl was injected of this in a CLAP for its quantitative measurement. (3) Measurement of the concentration in the plasma: From the plasma taken in the Eppendorf tube, 1 ml was transferred to a test tube, and 1 ml of 10 mM sodium diacid phosphate buffer (pH 7.0) was added, and the mixture was stirred. In addition, 4 ml of acetonitrile was added, and the mixture was stirred at 300 rpm, for 10 minutes. After centrifugation at 3000 rpm for 10 minutes, 4 ml of each supernatant was removed in separate test tubes for concentration and allowed to dry under reduced pressure for approximately 18 hours in a centrifugal evaporator (the samples in the three tubes were finally combined in one during the concentration). Then, this was dissolved again by the addition of 500 μl of the mobile phase, and the total volume was transferred into an Eppendorf tube. After ultracentrifugation for 5 minutes at 14000 rpm, the supernatant was filtered through a membrane filter (0.22 μm). The filtrate was transferred to a flask, and 50 μl of it was injected into a CLAP for quantitative measurement. The concentration of ketotifen fumarate in the lacrimal fluid, conjunctiva and plasma 4, 8 and 24 hours after the application by rubbing of the solid pharmaceutical preparation is shown in Figures 6, 7 and 8 and Tables 9, 10 and 11 respectively .

[Table 9] [Table 10] [Table 11] Tables 9-11, after the application of the solid pharmaceutical preparation by rubbing, the concentration of the drug in the lacrimal fluid on the side to which the preparation was applied reached 0.440 μg / g in 4 hours, and this, although it was reduced subsequently, it remained at a value of 0.216 μg / g even 24 hours after the application. On the opposite side, to which no solid pharmaceutical preparation was applied, the concentration of the drug in the lacrimal fluid reached approximately 60% of that on the side to which the preparation was applied at four hours after the application, and was gradually reduced. then, and reached, 24 hours after the application, a level comparable to that on the side to which the preparation was applied. The concentration of the drug in the conjunctiva (lower palpebral conjunctiva) was 0.353 μg / ga 24 hours after application by rubbing in the eye to which the solid preparation was applied, which was somewhat lower than the concentration of the drug in the tear fluid, which reached a high value of 0.598 μg / g at 8 hours after application, and still remained at a value of 0.447 μg / g even at 24 hours after application. In contrast, the concentration of the drug in the conjunctiva of the opposite eye was consistently of the order of 0.1 μg / g without showing any significant fluctuation.

The concentration of the drug in the plasma was 0.046 μg / ml at 4 hours after the application, and it was reduced to 0.030 μg / ml at 8 hours and then at 0.017 mg / ml at 24 hours after application. The above data were fed into a SKIN-CAD program (Biocom Systems, Inc., Fukuoka, Japan) for analysis of the skin permeation of the drugs, together with the permeation parameters in hairless mouse skin and the parameters for the kinetics of rabbit tear fluid, to simulate a contraction profile of ketotifen fumarate in the conjunctiva of rabbits. The parameters used are shown in Table 12.

[Table 12] From the simulation, it was found that the expected values were transferred, when it was assumed that 3% of ketotifen fumarate was administered to the lacrimal fluid, agrees well with the values obtained in the experiment. According to the references, the absorption rate of drugs absorbed by subvascular tissues in normal capillary vessels is approximately 3-5% (K. Tojo, Mathematical models of transdermal and topical drug delivery, 2nd edition, Biocom Systems, Fkuoka , Japan 2005), and the previous transfer rate of 3% (ie, the rate of absorption in the tear fluid) almost agrees with it. On the basis of this absorption rate (3%), the concentration of the drug in the conjunctiva was simulated again, this time with the assumption that the solid pharmaceutical preparation was rubbed on the skin only once, not ten times, replacing the parameter of the thickness of the drug in SKIN-CAD with 1/10 of the value in the previous test, that is to say with 0.005 cm. In addition, Table 13 shows the data showing the concentration of ketotifen fumarate in the conjunctiva after topical instillation of eye drops of cetotifen fumarate (0.967% W / V) to rabbit eyes (source: Distribution of 14C-ketotifen fumarate in Rabbit Eye Tissue After Administration Ophthalmic, Shinichi Ota, Journal of Clinical Therapeutics and Medicines, 4 (11), 1988).

[Table 13] As is evident from Tables 10 and 13, the concentration of the drug in the conjunctiva is high at 0.25 hours after topical instillation, but it is dramatically reduced subsequently, ie, up to about 1/5 in 0.5 hours after instillation. topical, and 1/10 to one hour after topical instillation. In contrast, the conjunctival concentration of the drug after rub application of the solid pharmaceutical preparation, as shown in Table 10 and Figure 7, reached its high value at 8 hours after application and remained high for a period of time. of noticeably prolonged time, instead of lacking the dramatic increase immediately after application. As for the concentration of the drug in the conjunctiva, the results of the previous test where the solid pharmaceutical preparation was applied (Table 10, application of 10 times), a graph was produced by means of the SKIN-CAD that agrees with the results, the data after the above topical instillation (Table 13) and the results of the simulation by the SKIN-CAD where the solid pharmaceutical preparation was rubbed only once (1 time application) are shown together in Figure 9. Figure 9 shows that, in contrast to topical instillation, after applying the solid pharmaceutical preparation (10 times), the concentration of the drug in the conjunctiva was maintained for a very long time exceeding 24 hours. In Figure 9, the simulation graph of a one-time application of the solid pharmaceutical preparation indicates that even with a single application of the solid pharmaceutical preparation it can be achieve a remarkably durable and sustained conjunctival drug concentration compared to topical instillation. Taken together, these results show that the application by rub of a solid pharmaceutical preparation allows a much longer maintenance of the concentration of the drug in local ocular tissues, compared to topical instillation.

[Preparation Example 1] Cetotifen Fumarate 8 g Beeswax 42 g Isopropyl myristate 45 g Polyoxyethylene oleyl ether 5 g Total amount 100 g To the heavy ketotifen fumarate in a beaker were added isopropyl myristate and polyoxyethylene oleyl ether, and stirred well. Beeswax was added to this and mixed well at approximately 75 ° C. The mixture was then poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

[Preparation Example 2] Cetotifen Fumarate 8 g Beeswax 14 g Candelilla wax 5 g Squalene 23 g Isopropyl myristate 45 g Polyoxyethylene oleyl ether 5 g Total amount 100 g Heavy ketotifen fumarate in a beaker was added squalane, isopropyl myristate and polyoxyethylene oleyl ether, and stirred well. Beeswax and candelilla wax were added to this and mixed well at approximately 75 ° C. The mixture was then poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

[Preparation Example 3] Ketotifen fumarate 10 g Vaseline 40 g Lauryl alcohol 5 g Isopropyl palmitate 45 g Polyoxyethylene oleyl ether 5 g Total amount 100 g Heavy ketotifen fumarate in a beaker wasopropyl myristate and polyoxyethylene oleyl ether, and mixed well. Lauryl alcohol was also added and mixed well. To this was added petrolatum at approximately 60 ° C and mixed well. So the mixture was poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

[Preparation Example 4] Diclofenac sodium 10 g Vaseline 40 g isopropyl palmitate 45 g Sodium lauryl sulfate 5 g Total amount 100 g To heavy sodium diclofenac in a beaker wasopropyl palmitate and sodium lauryl sulfate and I mix well. To this was added petrolatum and mixed at approximately 60 ° C. The mixture was then poured into portions in a predetermined mold to give a solid pharmaceutical preparation.

[Preparation Example 5] Pilocarpine Hydrochloride 5 g Candelilla wax 35 g Isopropyl myristate 55 g Glycerol monooleate 5 g Total amount 100 g [Preparation Example 5] A heavy pilocarpine hydrochloride in a glass of precipitate was added isopropyl myristate and glycerol monooleate and mixed well. To this was added candelilla wax and mixed well at about 75 ° C. The mixture was then poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

[Preparation Example 6] Iolopatadine hydrochloride 5 g Beeswax 55 g Isopropyl myristate 35 g Polyoxyethylene oleyl ether 5 g Total amount 100 g Heavy olopatadine hydrochloride in a beaker was added isopropyl myristate and polyoxyethylene oleyl ether, and mixed well. Beeswax was added to this and mixed well at approximately 75 ° C. The mixture was then poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

[Preparation Example 7] Epinastine hydrochloride 10 g Beeswax 40 g Isopropyl myristate 45 g Polyoxyethylene oleyl ether 5 g Total amount 100 g To the heavy epinastine hydrochloride in a beaker was added isopropyl myristate and polyoxyethylene oleyl ether, and stirred well. Beeswax was added to this and mixed well at approximately 75 ° C. The mixture was then poured into portions in a predetermined mold and allowed to solidify to give a solid pharmaceutical preparation.

INDUSTRIAL APPLICABILITY The present invention can be used to provide a novel form of ophthalmic pharmaceutical preparation for external use having an excellent property that allows the continuous delivery of the pharmacologically active agent to ocular tissues over an extended period of time.

Claims (19)

1. CLAIMS 1. Ophthalmic solid pharmaceutical preparation for external use comprising a base containing a pharmacologically active ingredient, wherein the solid pharmaceutical preparation is designed to be applied by rubbing on the surface of the skin, including the surface of either eyelid to release, through the skin of the eyelids, the pharmacologically active ingredient to local ocular tissues located on the back side of the eyelids.
2. 2. Ophthalmic solid pharmaceutical preparation for external use according to claim 1, wherein the base comprises an oily solid base.
3. 3. Ophthalmic solid pharmaceutical preparation for external use according to claim 2, wherein the oily solid base is wax or petrolatum.
4. 4. Ophthalmic solid pharmaceutical preparation for external use according to claim 3, wherein the wax is an animal wax or vegetable wax.
5. Ophthalmic solid pharmaceutical preparation for external use according to one of claims 1 to 4, wherein the preparation contains an enhancer in the permeation of the skin.
6. 6. Ophthalmic solid pharmaceutical preparation for external use according to claim 5, wherein the skin permeation enhancer is selected from the group that consists of an ester consisting of a fatty acid and a lower aliphatic alcohol, and a surfactant.
7. 7. Ophthalmic solid pharmaceutical preparation for external use according to claim 6, wherein the content of the ester is 30-60% by weight.
8. 8. Ophthalmic solid pharmaceutical preparation for external use according to claim 6 or 7, wherein the ester is isopropyl myristate or isopropyl palmitate, and wherein the surfactant is a non-ionic surfactant.
9. 9. Ophthalmic solid pharmaceutical preparation for external use according to one of claims 1 to 8, wherein the base comprises an oily solid base, wherein the content of the oily solid base in the pharmaceutical preparation is 15-60% by weight.
10. Ophthalmic solid pharmaceutical preparation for external use according to one of claims 1 to 9, wherein the pharmacologically active ingredient is selected from the group consisting of non-steroidal anti-inflammatory agents, antiallergic agents, antiglaucoma agents, anticatarata agents, antimicrobial agents, antiviral agents, antifungal agents, antibiotics, sulfa agents, steroidal anti-inflammatory agents, miotic agents, mydriatic agents, local astringents, vasoconstrictors, anticholinesterases, superficial anesthetics and vitamins.
11. 11. Ophthalmic solid pharmaceutical preparation for external use according to one of claims 1 to 10, wherein the form of the pharmaceutical preparation is short bar.
12. 12. Bar-type ophthalmic preparation comprising a generally cylindrical container body defining an end that can be opened, a movable lower member which is placed inside the body of the container and can be moved in the direction towards the end can be open, and drive means for causing the movable lower member to move in the direction toward the open end, where the ophthalmic solid pharmaceutical preparation for external use according to any of claims (1) to (11) above is contained, in the body of the container, between the end that can be opened and the mobile lower member, where the ophthalmic solid pharmaceutical preparation for external use can be projected from the body of the container as a result of the forward translation of the movable lower member actuated by the members of drive.
13. 13. Method for releasing a pharmacologically active ingredient to local ocular tissues located on the posterior side of the eyelids, the method comprising rubbing an ophthalmic solid pharmaceutical preparation for external use comprising a base that contains a pharmacologically active ingredient, on the surface of the skin, including the surface of either eyelid to apply the preparation.
14. 14. Method according to claim 13, wherein the base comprises an oily solid base.
15. 15. Method according to claim 14, wherein the oily solid base is wax or petrolatum.
16. 16. Method according to any of claims 13 to 15, wherein the ophthalmic solid pharmaceutical preparation for external use contains a skin permeation enhancer.
17. 17. Use of an oily solid base for the preparation of an ophthalmic solid pharmaceutical preparation for external use containing a pharmacologically active ingredient to release the pharmacologically active ingredient to the tissues located on the posterior side of the eyelids.
18. 18. Use of an oily solid base and a skin permeation enhancer for the preparation of an ophthalmic solid pharmaceutical preparation for external use containing a pharmacologically active ingredient to release the pharmacologically active ingredient to the tissues located on the back side of the skin. the eyelids.
19. 19. Use according to claim 17 or 18, wherein the oily solid base is wax or petrolatum.