JP2007056012A - Noninvasive drug delivery system to posterior part tissue of eye by using ointment-like composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a noninvasive administration drug delivery system having excellent drug migration properties to the posterior part tissue of the eye through the local part tissue of the eye. <P>SOLUTION: The drug delivery system having excellent drug migration properties to the posterior part tissue of the eye through the local part tissue of the eye is constructed by administering an ointment-like composition containing 0.01-10% (W/V) medicine and having (2/1)-(10/1) ratio of formulated vaseline/liquid paraffin to the surface of the eye. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a non-invasive drug delivery system for posterior eye tissues such as the retina, choroid, sclera, optic nerve, optic nerve surrounding tissue, and vitreous body.

  Diseases in the posterior segment of the eye such as the retina, choroid, sclera, optic nerve, tissue around the optic nerve, and vitreous are often intractable diseases, and many exhibit severe symptoms that can cause blindness. Typical diseases include age-related macular degeneration, diabetic retinopathy, diabetic macular edema, uveitis, retinitis pigmentosa, proliferative vitreoretinopathy, central retinal vein occlusion, branch retinal vein occlusion, central retina Arterial occlusion, retinal artery branch occlusion, retinal detachment, cytomegalovirus retinitis, optic nerve disorder associated with glaucoma and the like. These are all diseases that can cause a decrease in visual acuity and blindness, and development of an effective pharmacotherapy for such posterior eye tissue diseases is desired.

  Effective drugs for posterior eye diseases include steroids such as betamethasone and dexamethasone, anti-inflammatory agents such as bromophenac, quinolone compounds, antibacterial agents such as erythromycin, antiviral agents such as ganciclovir and acyclovir, and methotrexate. Anti-cancer agents such as MMP inhibitors, angiogenesis inhibitors such as endostatin and VEGF inhibitors, neuroprotective agents such as MK-801 and timolol, antioxidants such as catechin and vitamin E, bone resorption inhibitors such as bisphosphonates, Many drugs such as drugs related to visual function maintenance such as retinoic acid and its derivatives can be mentioned. However, although many useful drugs are recognized, the posterior ocular tissue that is the disease site is located in the back of the ocular tissue, and it is very difficult to transfer the drug to the site. It has been a challenge in developing a pharmacotherapy for this disease.

  Here, in the pharmacological treatment of eye diseases, treatment by eye drops is the most common, and convenience is excellent. However, there is a problem in that it is difficult for the drug to transfer to the posterior ocular tissue in the eye drop administration.

  Therefore, systemic administration such as intravenous injection or oral administration has been attempted as a method for administering drugs for posterior ocular diseases. However, in these administration methods, since the amount of drug transferred to the posterior ocular tissue, which is a disease site, is very small, frequent and high-dose administration is necessary to deliver a sufficient amount of drug to the posterior ocular tissue. From the viewpoint of drug treatment of posterior segment tissue, there is a problem in efficiency.

On the other hand, administration methods such as injection into the vitreous, subtenon capsule, subconjunctiva, and implants have also been tried as drug treatment methods for posterior ocular diseases. For example, Non-Patent Document 1 describes a drug delivery system for posterior ocular tissue by intravitreal injection, and Patent Documents 1 and 2 administer sustained-release microparticles containing a drug under the conjunctiva. Drug delivery systems to the posterior ocular tissue and drug delivery systems to the posterior ocular tissue by administering fine particles containing a drug under the Tenon capsule are described. Patent Document 3 describes a biocompatible implant for transferring a drug to the posterior segment tissue. These administration methods have the merit that a sufficient amount of the drug can be transferred to the disease site because the drug is directly administered and implanted in the disease site or in the nearby tissue. However, since these are administration methods and delivery techniques that involve the invasion of ocular tissue, patients may suffer stress and pain during administration. In addition, these administration methods cannot be performed by the patient's own hands and need to be performed exclusively by the doctor's hands, so there are also problems in terms of convenience.
JP 2003-313119 A Japanese Patent Laying-Open No. 2005-097275 Special Table 2004-535886 Journal of ocular pharmacology and therapeutics, (2001) 17/4 393-401

  Accordingly, it has been desired to develop a drug delivery system that does not have tissue invasiveness at the time of administration associated with an administration method such as injection or implant, and that can efficiently transfer a drug to a diseased site.

  That is, it is an important issue to develop a drug delivery system by non-invasive administration that has excellent drug transfer to the posterior ocular tissue via the local ocular tissue.

  As a result of intensive studies, the present inventors have surprisingly found an ointment-like composition containing 0.01 to 10% by weight of a drug and having a petrolatum / liquid paraffin weight ratio of 2/1 to 10/1. It has been found that the means for administering to the ocular surface is very useful as a non-invasive drug delivery system with excellent drug transfer to the posterior ocular tissue.

  Since the drug delivery system of the present invention is a non-invasive drug delivery system, unlike the administration methods such as injection and implant that are widely used in the medical field, there is no tissue invasiveness due to administration. In addition, patients do not suffer from the stress and pain associated with administration such as injections and implants.

  Since the ointment-like composition used in the drug delivery system of the present invention is administered to the ocular surface and can be administered by the patient himself, it is conventionally compared with injections and implants widely used in the medical field. It is excellent in terms of convenience.

That is, the present invention
(1) By administering an ointment-like composition containing 0.01 to 10% by weight of a drug and having a petrolatum / liquid paraffin weight ratio of 2/1 to 10/1 to the ocular surface, Non-invasive drug delivery system with improved drug migration,
(2) The noninvasive drug delivery system according to (1) above, containing 0.1 to 5% by weight of a drug and having a petrolatum / liquid paraffin weight ratio of 3/1 to 9/1,
(3) The noninvasive drug delivery system according to (2), wherein the drug is transferred to the posterior ocular tissue through a local eye tissue,
(4) The non-invasive drug territory system according to (3), wherein the posterior eye tissue is the retina, choroid, sclera, optic nerve, optic nerve surrounding tissue, or vitreous body,
(5) The noninvasive drug territory system according to the above (3), wherein the drug is a drug for treatment or prevention of retina, choroid, sclera, optic nerve, perioptic nerve tissue or vitreous disease,
(6) The above-mentioned (3), wherein the drug is an anti-inflammatory agent, immunosuppressive agent, antiviral agent, anticancer agent, antithrombotic agent, angiogenesis inhibitor, optic neuroprotective agent, antibacterial agent, antifungal agent or antioxidant agent. Non-invasive drug delivery system,
About.

  The drug delivery system of the present invention is excellent in the drug transfer property directly to the posterior segment tissue. The direct drug transfer to the posterior ocular tissue refers to the transfer of the drug to the posterior ocular tissue via the local ocular tissue regardless of the whole body route. . That is, the drug delivery system of the present invention is excellent in drug migration to the posterior ocular tissue via the ocular local tissue. In particular, the drug delivery system of the present invention is excellent in drug migration to the posterior ocular tissue via the conjunctival and scleral tissues.

  The amount of the drug contained in the ointment-like composition of the present invention is 0.0001 to 95% by weight, preferably 0.001 to 30% by weight, more preferably 0.01 to 10% by weight, still more preferably 0.00. 1 to 5% by weight. The weight ratio of petrolatum / liquid paraffin of the ointment-like composition of the present invention is 1/100 to 100/1, preferably 1/10 to 10/1, more preferably 2/1 to 10/1, Preferably it is 3/1 to 9/1.

  The drug delivery system of the present invention is used for the treatment or prevention of diseases of the retina, choroid, sclera, optic nerve, perioptic nerve tissue, or vitreous. Specific examples of the disease include inflammation caused by various causes, viral and bacterial infections, diseases caused by retinal choroidal neovascularization, diseases caused by retinal ischemia, and optic neuropathy caused by glaucoma. More specifically, uveitis, cytomegalovirus retinitis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative vitreoretinopathy, retinal detachment, retinitis pigmentosa, central retinal vein occlusion Retinal vein branch occlusion, central retinal artery occlusion, retinal artery branch occlusion, and the like.

  There is no restriction | limiting in particular about the drug contained in the ointment-like composition of this invention, The drug suitable for an object disease can be selected. Specifically, steroid drugs such as betamethasone, dexamethasone, triamcinolone, prednisolone, fluorometholone, hydrocortisone, fluocinolone acetonide or derivatives thereof; hormone drugs such as progesterone or testosterone or derivatives thereof; bromofenac, diclofenac, etc. Anti-inflammatory agents; cytokine suppressors such as TNF-α inhibitors, anti-TNF-α antibodies, PDE-IV inhibitors, ICE inhibitors; immunosuppressive agents such as cyclosporine, tacrolimus; anti-cancer agents such as ganciclovir, acyclovir, interferon β Antiviral agents such as quinolone compounds, clarithromycin and erythromycin; ACE inhibitors such as captopril; HMG-CoA reductase inhibitors such as pravastatin and simvastatin; fluorouracil; Anti-cancer agents such as totrexate and MMP inhibitor; endostatin, VEGF inhibitor, anti-VEGF antibody, antisense oligonucleotide, PKC inhibitor, adhesion factor inhibitor, angiogenesis inhibitor such as vasostatic steroid; MK-801, timolol , Neuroprotective agents such as creatine, taurine and BDNF, neurotrophic factors, carbonic anhydrase inhibitors such as acetazolamide, thrombolytic agents such as urokinase, circulation improving agents, antifungal agents, catechins, antioxidants such as vitamin E, Examples include bone resorption inhibitors such as bisphosphonates, drugs related to visual function maintenance such as retinoic acid and derivatives thereof, and the like.

  The ointment-like composition of the present invention can be produced and prepared by kneading or melting a drug as an active ingredient into a base. The base of the ointment-like composition is selected from those known or commonly used. For example, hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), higher fatty acids or higher fatty acid esters, waxes, surfactants, higher alcohols, silicone oils, glycols, vegetable oils, animal oils, water , One or two or more selected from absorption promoters and anti-rash agents are used. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, an antiseptic, a flavoring agent and the like may be included. Further, as a specific production example of an ointment-like composition, an ointment-like composition containing 0.8% by weight of fluorescein or sodium fluorescein as a fluorescent dye instead of a drug, and having a petrolatum / liquid paraffin weight ratio of 4 An ointment-like composition that is 1 is shown in the examples below. Here, the reason why the fluorescent dye is used in place of the drug is to evaluate the transferability to the posterior eye tissue easily and with high sensitivity.

  The ointment-like composition used in the drug delivery system of the present invention may be administered to the ocular surface, and at the time of administration, it does not require any special technique and can be administered to the ocular surface by the patient himself.

  The number of administrations of the ointment-like composition of the present invention can be appropriately selected according to symptoms, age, base, etc., but an appropriate amount may be administered 1 to several times a day (for example, 1 to 6 times).

  As will be described in detail in the test section described later, by administering an ointment-like composition containing 0.8% by weight of a fluorescent dye and having a petrolatum / liquid paraffin weight ratio of 4/1 to the ocular surface, There is a clear difference in the concentration of the fluorescent dye present in the retina choroid of the non-administered eye. That is, by administering the ointment-like composition of the present invention to the ocular surface, it is possible to improve the transfer of the drug directly to the posterior ocular tissue via the ocular local tissue.

  The preparation of the ointment-like composition of the present invention, the fluorescent dye concentration measurement test in the posterior ocular tissue, and formulation examples are shown below, but these examples are for better understanding of the present invention. It does not limit the range.

1. Test 1
1. Using ointment-like composition and ophthalmic solution containing fluorescent dye, migration to posterior ocular tissue via local ocular tissue was examined. 1-1. Formulation preparation

  White petrolatum (39.6 g) and liquid paraffin (10.0 g) were melted and stirred until uniform. Fluorescein (LogP = 3) (0.4 g) is gradually added to the melt, and the mixture is stirred until it is uniform, then cooled gradually, and a 0.8% (W / W) fluorescein-containing preparation (ointment) Like composition). Hereinafter, this preparation is referred to as Test preparation 1.

Comparative Example 1

  Fluorescein (16 mg) is weighed in a mortar, and 2 ml of phosphate buffered saline containing 0.1% (W / W) polysorbate 80 is gradually added dropwise and suspended, and 0.8% (W / W) fluorescein-containing suspension is added. A cloudy ophthalmic solution was obtained. Hereinafter, this preparation is referred to as Comparative preparation 1.

1-2. Test Method Test preparation 1 prepared in Example 1 was applied to the conjunctival sac of one eye (right eye) of a rat (dosage of fluorescein: 40 μg per eye), and sacrificed 30 minutes later. Both eyes of the eye were removed and the retina choroid was collected. The collected retina choroid is taken as a sample for 2 eyes, a methanol / water (1/1) mixture (250 μl) is added to this, homogenized, and centrifuged (13,000 rpm, 10 minutes) to remove insoluble matter. The fluorescence intensity was measured (Em: 485 nm, Ex: 530 nm), and the concentration of fluorescein in the retina choroid was calculated. The calculation of the fluorescein concentration was performed using a calibration curve. The calibration curve was prepared by using a methanol / water (1/1) mixed solution in which fluorescein was dissolved as a standard solution and adding it to the choroid of the normal eye, followed by the same recovery operation as described above.

  On the other hand, blood is collected before the rat is sacrificed by the above-described operation, and the obtained sample is centrifuged (13000 rpm, 10 minutes), insoluble matter is removed, and the fluorescence intensity is measured (Em: 485 nm, Ex: 530 nm), and the concentration of fluorescein in plasma was calculated. The calibration curve was prepared by using a methanol / water (1/1) mixed solution in which fluorescein was dissolved as a standard solution, adding this to plasma, and then performing the same recovery operation as described above.

  In addition, the comparative preparation 1 was instilled into one eye (right eye) of a rat (dosage of fluorescein: 40 μg per eye), and thereafter the same operation as described above was performed, and in the retina choroid 30 minutes after administration. And the fluorescein concentration in plasma was calculated.

1-3. Test Results and Discussion FIG. 1 shows the concentration of fluorescein in the retina choroid in the administered eye and the non-administered eye 30 minutes after administration of the test preparation 1 and the comparative preparation 1 (6 eyes, 3 cases). FIG. 2 shows the plasma fluorescein concentration 30 minutes after administration of the test preparation 1 and the comparative preparation 1 (6 eyes, 3 cases).

  As is clear from FIG. 1, in the fluorescein concentration in the retina choroid, the eye administered with the test preparation 1 showed a clearly higher value compared to the non-administered eye, whereas the eye administered with the comparative preparation 1 was non-administered eye. A slightly higher value was shown. Further, as apparent from FIG. 2, the test preparation 1 showed a clearly lower value than the comparative preparation 1 in the fluorescein concentration in plasma. Therefore, it was found that by using the ointment-like composition of the present invention, it is possible to promote the transfer of the fluorescent dye to the retina choroid tissue via the local eye tissue. That is, it was suggested that administration of the ointment-like composition of the present invention to the ocular surface can promote the transfer of the drug to the posterior ocular tissue via the local ocular tissue.

2. Test 2
Use of ointment-like composition containing fluorescein, a fat-soluble fluorescent dye, and ointment-like composition containing sodium fluorescein, a water-soluble fluorescent dye, to transfer to the posterior ocular tissue via local ocular tissue 2-1. Formulation preparation

  White petrolatum (39.6 g) and liquid paraffin (10.0 g) were melted and stirred until uniform. Fluorescein sodium (LogP = −0.5) (0.4 g) is gradually added as a water-soluble fluorescent dye in the melt, and the mixture is stirred until it is uniform and then gradually cooled to 0.8%. (W / W) A fluorescein sodium-containing preparation (ointment-like composition) was obtained. Hereinafter, this preparation is referred to as test preparation 2.

2-2. Test method Test preparations 1 and 2 were subjected to the same operation as “1-2. Test method” (dosage of fluorescein or fluorescein sodium: 40 μg per eye), and 0.5 to 1.5 hours after administration The concentration of fluorescein in the choroid was calculated.

2-3. Test Results FIG. 3 shows the concentration of fluorescein in the retina choroid in the administered eye and the non-administered eye after the lapse of a fixed time (0.5, 1.5 hours) of the preparations 1 and 2 (6 eyes, 3 eyes) Example).

2-4. Discussion As is apparent from FIG. 3, the test preparation 1 which is an ointment-like composition containing a fat-soluble fluorescent dye and the test preparation 2 which is an ointment-like composition containing a water-soluble fluorescent dye are contained in the choroid. In the fluorescein concentration, a difference was observed between the administration eye and the non-administration eye even after 0.5 hours and 1.5 hours after administration. Therefore, although there is a difference in the degree of promotion of migration to the posterior ocular tissue, the ointment-like composition of the present invention can migrate to the posterior ocular tissue regardless of the fat solubility of the drug contained in the composition. It was suggested that it could be promoted.

3. Formulation example Formulation example 1 Ointment-like composition (in 100 g)
Triamcinolone 0.8g
White petrolatum 79.2g
Liquid paraffin 20g

FIG. 1 is a graph showing the fluorescein concentration in the retina choroid in the administration eye and non-administration eye 30 minutes after administration of the test preparation 1 and the comparative preparation 1. FIG. 2 is a graph showing plasma fluorescein concentrations 30 minutes after administration of test preparation 1 and comparative preparation 1. FIG. 3 is a graph showing the concentration of fluorescein in the retina choroid in the administration eye and the non-administration eye after the lapse of a certain time after administration of test preparations 1 and 2.

Claims (6)

Transfer of the drug to the posterior ocular tissue by administering an ointment-like composition containing 0.01 to 10% by weight of the drug and having a petrolatum / liquid paraffin weight ratio of 2/1 to 10/1 to the ocular surface Non-invasive drug delivery system with improved performance. The non-invasive drug delivery system according to claim 1, comprising 0.1 to 5% by weight of a drug and having a petrolatum / liquid paraffin weight ratio of 3/1 to 9/1. The non-invasive drug delivery system according to claim 2, wherein the drug is transferred to the posterior eye tissue through a local eye tissue. The non-invasive drug territory system according to claim 3, wherein the posterior eye tissue is the retina, choroid, sclera, optic nerve, optic nerve surrounding tissue, or vitreous. 4. The noninvasive drug territory system according to claim 3, wherein the drug is a drug for treating or preventing a retina, choroid, sclera, optic nerve, perioptic nerve tissue, or vitreous disease. The non-invasive drug according to claim 3, wherein the drug is an anti-inflammatory agent, an immunosuppressive agent, an antiviral agent, an anticancer agent, an antithrombotic agent, an angiogenesis inhibitor, an optic neuroprotective agent, an antibacterial agent, an antifungal agent or an antioxidant. Delivery system.

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