Concentration regulator for in-vivo substance or drug in in-vivo semi-closed system

Abstract

The purpose of the present invention is to adjust the concentration of an in-vivo substance or a drug in an in-vivo semi-closed system, for example, to improve or suppress the intraocular concentration of an intravitreal formulation, for example, a vitreous body injection formulation such as an anti-VEGF drug. The present invention provides a concentration regulator for an in-vivo substance or a drug in an in-vivo semi-closed system, the concentration regulator containing, as an active ingredient, a drug that promotes or suppresses the production or discharge of a body fluid in the in-vivo semi-closed system.

Description

Concentration regulators for biological substances or drugs in semi-closed biological systems

[0001] The present invention relates to regulating the concentration of a substance or drug in a semi-closed system in vivo, such as increasing or suppressing the intraocular concentration of an intravitreal preparation such as an anti-VEGF drug or other intravitreal injection preparation.

[0002] Exudative age-related macular degeneration (nAMD) is the leading cause of acquired blindness in developed countries. It is a disease characterized by age-related degeneration of macular tissue. Increased levels of vascular endothelial growth factor (VEGF) in the aqueous humor are known to contribute to the progression of nAMD. Treatment for nAMD involves intravitreal injection of anti-VEGF drugs, but the efficacy is believed to last for one to three months. The only method currently available to sustain this effect is repeated injections. The short duration of anti-VEGF drug efficacy is thought to be due to systemic drug delivery via the aqueous humor circulation via an outflow pathway (see Non-Patent Documents 1, 5, and 6).

[0003] However, intravitreal injections pose significant problems in terms of complications and costs. First, the risk of ocular complications such as endophthalmitis is known to be 0.019-1.6%, and the risk of systemic complications such as myocardial infarction and cerebral infarction associated with arterial thromboembolism is known to be 0.4-0.5%, respectively (Non-Patent Document 2). Furthermore, intravitreal injections are extremely expensive, with a single dose costing over 100,000 yen. This also poses a problem of extremely high medical costs. Therefore, it is desirable to administer as few injections as possible.

[0004] Drugs that control the dynamics of aqueous humor production and outflow are widely used as eye drops for glaucoma. Aqueous humor is produced in the ciliary body and excreted through two outflow pathways (the trabecular pathway and the uveoscleral pathway). Glaucoma eye drops are classified by their mechanism of action as parasympathomimetics, sympathomimetics, sympatholytics, prostaglandins, and carbonic anhydrase inhibitors. They act to suppress aqueous humor production and promote outflow, thereby lowering intraocular pressure (Non-Patent Document 1). Glaucoma eye drops cost less than 3,000 yen for one month of use, which is less than 1 / 30 the price of anti-VEGF drugs. Although not used as eye drops for glaucoma, sympathomimetics promote aqueous humor regeneration.

[0005] Although many studies have attempted to improve the treatment of nAMD by increasing the molecular weight of anti-VEGF drugs or adding mechanisms of action other than VEGF, no studies have investigated how to maintain the efficacy of intravitreal injections.

[0006] On the other hand, posterior vitreous detachment (PVD), an age-related change, is known to suppress the onset of nAMD. PVD increases the fluidity of the vitreous, allowing inflammatory cytokines to escape from the eye, reducing chronic inflammation within the eye and making nAMD less likely to occur. In fact, epidemiological studies have shown that PVD is less prevalent in nAMD patients, and that PVD eyes also exhibit reduced levels of inflammatory cytokines overall (Non-Patent Document 4). Vitrectomy, which involves replacing the vitreous gel with aqueous humor, is often performed to artificially induce this, but due to its invasive nature, it is only expected to be a secondary effect of other surgeries. However, eye drops are minimally invasive.

[0007] Therefore, if substances that promote the onset and progression of disease, including drugs, are dominant, the production and outflow of aqueous humor will be promoted, and conversely, if inhibitory substances are dominant, the production of aqueous humor will be suppressed, thereby regulating the concentration of intraocular substances and ultimately improving health.In addition, the human body also has semi-closed systems such as the spinal cavity and joint cavities, similar to the eyeball.

[0008] Folia Pharmacol. Jpn. 128, 250-254 (2006) Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013; 27(7): 787-794. doi:10.1038 / eye.2013.107 Journal of the Japanese Geriatrics Society, Vol. 52, No. 3 (2015: 7) 200-205 Hidenori Takahashi et al. Effects of posterior vitreous detachment on aqueous humor levels of VEGF and inflammatory cytokines. BRITISH JOURNAL OF OPHTHALMOLOGY. 99(8) 1065-1069 2015 August Tim U Krohne et al. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol. 2008 Oct; 146(4): 508-12Tim U Krohne et al. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012 Oct; 154(4): 682-686.e2

[0009] Therefore, an object of the present invention is to regulate the concentration of a biological substance or drug in a semi-closed system in the body, such as by increasing or suppressing the anterior chamber concentration of an intravitreal preparation such as an intravitreal injection preparation of an anti-VEGF drug or the like.

[0010] The present inventors have wondered whether it might be possible to maintain the concentration of intravitreal preparations, such as intravitreal injection drugs, for a long period of time by controlling the dynamics of aqueous humor production and outflow. That is, for example, they have wondered whether intraocular drug concentrations might be maintained for a longer period of time by combining intravitreal injection of an anti-VEGF drug with glaucoma eye drops that suppress aqueous humor production. As a result of extensive research, they have found that aqueous humor production inhibitors or aqueous humor outflow promoters, such as glaucoma drugs, increase or decrease the anterior chamber concentration of intravitreal preparations, such as intravitreal injection preparations of anti-VEGF drugs. Drugs that promote or inhibit the production or outflow of body fluids in a semi-closed system in vivo regulate the concentration of biological substances or drugs in a semi-closed system in vivo. The anterior chamber and the vitreous communicate with each other within the same eye, and the concentration of intravitreal preparations in the anterior chamber is approximately 1 / 40 of the concentration in the vitreous.

[0011] That is, the present invention provides the following. [Aspect 1] A concentration regulator for an in vivo substance or drug in a semi-closed in vivo system, the concentration regulator comprising as an active ingredient a drug that promotes or inhibits the production or excretion of body fluid in the semi-closed in vivo system. [Aspect 2] A concentration regulator according to Aspect 1, wherein the body fluid in the semi-closed in vivo system is aqueous humor, and the semi-closed in vivo system is the anterior chamber. [Aspect 3] A concentration regulator according to Aspect 1, wherein the drug that promotes or inhibits the production or excretion of body fluid in the semi-closed in vivo system is an aqueous humor production inhibitor or an aqueous humor outflow promoter, and the concentration regulator for an in vivo substance or drug in a semi-closed in vivo system is an agent that increases or suppresses the concentration of the in vivo substance or drug in the anterior chamber. [Aspect 4] A concentration regulator according to Aspect 3, wherein the aqueous humor production inhibitor or aqueous humor outflow promoter is a therapeutic agent for glaucoma. [Aspect 5] The concentration regulator according to Aspect 4, wherein the antiglaucoma agent is an α2 agonist, a sympathetic beta-blocker, a carbonic anhydrase inhibitor, or a prostanoid receptor-associated drug. [Aspect 6] The concentration regulator according to Aspect 1, wherein the drug is an intravitreal formulation. [Aspect 7] The concentration regulator according to Aspect 6, wherein the intravitreal formulation is an anti-VEGF drug. [Aspect 8] The concentration regulator according to Aspect 7, wherein the anti-VEGF drug is an anti-VEGF-A drug, an anti-VEGF-B drug, or an anti-PlGF drug. [Aspect 9] The concentration regulator according to Aspect 8, wherein the anti-VEGF drug is aflibercept. [Aspect 10] The concentration regulator according to Aspect 1, wherein the in vivo substance is a physiologically active substance. [Aspect 11] The concentration regulator according to Aspect 10, wherein the physiologically active substance is a cytokine. [Aspect 12] The concentration regulator according to Aspect 11, wherein the cytokine is CXCL1 or TNF-α.

[0012] According to the present invention, the concentration of a substance or drug in a semi-closed system in the body can be adjusted by promoting or inhibiting the production or excretion of body fluids in the semi-closed system in the body, such as by controlling the dynamics of aqueous humor production or outflow, thereby controlling the drug concentration in the anterior chamber. According to a more specific embodiment of the present invention, the number of intravitreal injections can be reduced, thereby reducing the incidence of complications due to intravitreal injections, thereby improving the prognosis of nAMD, leading to reduced medical costs for nAMD, and reducing the number of hospital visits, thereby easing the burden on patients. The use of glaucoma eye drops to control the drug concentration of anti-VEGF drugs, as in a more specific embodiment of the present invention, leads to drug repositioning and has the advantages of reliability due to confirmed safety and pharmacokinetics at the clinical level, and low cost due to the use of a large amount of existing data (see Non-Patent Document 3, above).

[0013] Figure 1 is a graph showing the results of univariate analysis of the instillation score and Eylea concentration. Figure 2 is a graph showing the results of multivariate analysis of age, sex, axial length, and instillation score, with Eylea concentration as the dependent variable.

[0014] The present invention provides an agent for regulating the concentration of a substance or drug in a biological semi-closed system in the body, which comprises as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the biological semi-closed system.

[0015] Examples of semi-closed systems in the body include the eyeball, the anterior chamber, the abdominal cavity, the skull, the spinal cavity, the joint cavity, etc. Examples of body fluids in semi-closed systems in the body include aqueous humor, cerebrospinal fluid, and intra-articular fluid.

[0016] The present invention provides an agent for regulating the concentration of an in vivo substance or drug in a semi-closed in vivo system, which agent contains as an active ingredient a drug that promotes or suppresses the production or excretion of body fluids in the semi-closed in vivo system. The drug that promotes or suppresses the production or excretion of body fluids in the semi-closed in vivo system is, for example, an aqueous humor production inhibitor or an aqueous humor outflow promoter, and the agent for regulating the concentration of an in vivo substance or drug in a semi-closed in vivo system is, for example, an agent that increases or suppresses the concentration of the in vivo substance or drug in the anterior chamber.

[0017] Aqueous humor production inhibitors are agents that inhibit the production of aqueous humor or are expected to inhibit the production of aqueous humor, while aqueous humor outflow promoters are agents that promote the outflow of aqueous humor or are expected to promote the outflow of aqueous humor. Examples of aqueous humor production inhibitors or aqueous humor outflow promoters include glaucoma treatments such as glaucoma eye drops, carbonic anhydrase inhibitors (e.g., powder or tablet) such as acetazolamide, and intracranial pressure-reducing or osmotic diuretics such as mannitol infusion. Similar effects can be expected from oral medications, injections, inhalants, etc. that are compatible with the mechanism of action, without being limited to the drug form of eye drops. Although these drugs act systemically and therefore have unreasonable side effects, for example, oral administration of Diamox (acetazolamide) significantly suppresses aqueous humor production.

[0018] Examples of aqueous humor production inhibitors or aqueous humor outflow promoters include aqueous humor production inhibitors, aqueous humor main outflow promoters, aqueous humor accessory outflow promoters, and aqueous humor production inhibitors and accessory outflow promoters. Examples of aqueous humor production inhibitors include sympathetic beta-blockers, carbonic anhydrase inhibitors, αβ-blockers, etc. Examples of aqueous humor main outflow promoters include Rho kinase inhibitors, parasympathomimetics, etc. Examples of accessory aqueous humor outflow promoters include prostanoid receptor-related drugs such as prostaglandins, etc. Examples of aqueous humor production inhibitors and accessory outflow promoters include adrenergic α2 receptor agonists, etc. Examples of the antiglaucoma agent include prostaglandins (PGs), prostanoid receptor-associated drugs such as latanoprost, travoprost, tafluprost, and bimatoprost; sympathetic beta-blockers (beta-blockers) such as timolol maleate, carteolol hydrochloride, and betaxolol hydrochloride; carbonic anhydrase inhibitors (CAIs) such as dorzolamide hydrochloride, brinzolamide, and Diamox (acetazolamide); alpha-2 agonists such as brimonidine and brimonidine tartrate; sympathetic alpha-2 stimulants; ROCK inhibitors (Rho-kinase inhibitors) such as ripasudil hydrochloride hydrate; sympathetic alpha-1 blockers such as bunazosin hydrochloride; sympathetic alpha-1 beta-blockers such as nipradilol; isopropyl Examples of suitable eye drops include ion channel openers such as unoprostone, parasympathomimetics such as pilocarpine hydrochloride, parasympathomimetics, sympathomimetics such as dipivefrine hydrochloride, osmotic diuretics such as mannitol, selective EP2 receptor agonists such as omidenepag isopropyl, and their respective combination eye drops.Preferably, α2 agonists such as brimonidine, sympathetic β-blockers, carbonic anhydrase inhibitors, prostanoid receptor-associated drugs such as prostaglandins, etc.In addition, sympathetic β-blockers (β-blockers) such as timolol maleate, carteolol hydrochloride, and betaxolol hydrochloride, carbonic anhydrase inhibitors (CAIs) such as dorzolamide hydrochloride, brinzolamide, and diamox (acetazolamide), and α2 agonists such as brimonidine and brimonidine tartrate have been shown to reduce aqueous humor flow.In addition, it has been reported that intravenous administration of epinephrine increases aqueous humor flow, and in the future, the development of eye drops containing sympathomimetics such as epinephrine may be expected to increase aqueous humor flow as an aqueous humor production promoter.

[0019] The present inventors have discovered that the concentration of a substance or drug in a semi-closed system in vivo can be adjusted by administering a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system. Specifically, the intravitreal concentration of an intravitreal preparation can be increased or decreased by administering, for example, an aqueous humor production inhibitor or an aqueous humor outflow promoter, such as a glaucoma treatment agent. Furthermore, the intravitreal preparation can be applied to promote the outflow of specific adverse ophthalmic substances, such as intraocular inflammatory cytokines, or conversely, to retain physiologically active substances with neuroprotective properties in the eye. The intravitreal preparation is a preparation that is localized within the vitreous body, and may be administered by eye drops, intravitreal injection, intraarterial injection, intravenous injection, subcutaneous injection, subconjunctival injection, or by other methods, such as intranasal, transbronchial, intramuscular, transdermal, or oral routes, but is preferably administered by intravitreal injection. Specifically, the intravitreal preparation is preferably an intravitreal injection preparation. Intravitreal preparations include, for example, anti-VEGF drugs, anti-cancer drugs, and antibodies against various uveitis. Many of these drugs are already on the market. However, according to the findings of the present inventors, intravitreal preparations are not limited to these already on the market, and new drugs developed in the future will also be considered. Examples of anti-VEGF drugs include anti-VEGF-A drugs, anti-VEGF-B drugs, and anti-PlGF drugs. Examples of anti-VEGF drugs include Eylea (aflibercept), pegaptanib, bevacizumab, ranibizumab, brolucizumab, and faricimab. Eylea (aflibercept) is an anti-VEGF-A drug, an anti-VEGF-B drug, and an anti-PlGF drug. The anterior chamber concentration of an intravitreal preparation can be measured, for example, by anterior chamber paracentesis.

[0020] The biological substance is, for example, a physiologically active substance, and examples of the physiologically active substance include cytokines, etc. Preferred examples of cytokines include CXCL1 and TNF-α, and examples of cytokines include interleukins (IL), hematopoietic factors (CSF, EPO, TPO), interferons (IFN), tumor necrosis factors (TNF), growth factors, growth factors (EGF, FGF, PDGF), and chemokines (IL-8).

[0021] When administering to a subject a drug that promotes or inhibits the production or excretion of body fluids in a semi-closed in vivo system, which is an active ingredient of the agent for regulating the concentration of an in vivo substance or drug in a semi-closed in vivo system of the present invention, the subject is preferably a person who has received a drug in an intravitreal preparation, etc. Here, the dose of the drug in an intravitreal preparation, etc., is, for example, 0.5 mg to 6.0 mg of the active ingredient per dose for a typical adult (body weight 60 kg).

[0022] When administering to a subject a drug that promotes or inhibits the production or excretion of body fluids in a semi-closed system in the body, which is an active ingredient of the agent for regulating the concentration of an in vivo substance or drug in a semi-closed system in the body of the present invention, the subject may, for example, be a subject suffering from exudative age-related macular degeneration (nAMD) or a subject suffering from other diseases that can be treated with anti-VEGF drugs. Examples of other diseases that can be treated with anti-VEGF drugs include diabetic retinopathy, retinal vein occlusion, myopic choroidal neovascularization, neovascular glaucoma, retinopathy of prematurity, and intraocular neovascular diseases in general, including other rare diseases. The subject is not particularly limited and can be selected appropriately depending on the purpose. Examples include mammals such as humans, mice, rats, cows, pigs, monkeys, dogs, and cats, with humans being preferred.

[0023] The concentration regulator of a biological substance or drug in a semi-closed biological system of the present invention may consist of a drug that promotes or suppresses the production or excretion of body fluids in the semi-closed biological system, or may be formulated as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier.

[0024] The pharmaceutical composition may be formulated into a dosage form for oral use such as tablets, capsules, elixirs, microcapsules, etc., or into a dosage form for parenteral use such as eye drops, injections, ointments, patches, etc.

[0025] Examples of pharmaceutically acceptable carriers include solvents such as sterilized water and physiological saline; binders such as gelatin, corn starch, tragacanth gum, and gum arabic; excipients such as crystalline cellulose; and leavening agents such as corn starch, gelatin, and alginic acid.

[0026] Pharmaceutically acceptable carriers include additives such as lubricants such as magnesium stearate, sweeteners such as sucrose, lactose, and saccharin, flavorings such as peppermint and rhododendron oil, stabilizers such as benzyl alcohol and phenol, buffers such as phosphates and sodium acetate, solubilizers such as benzyl benzoate and benzyl alcohol, antioxidants, preservatives, surfactants, and emulsifiers.

[0027] Pharmaceutical compositions can be formulated by combining the above-mentioned carriers appropriately and mixing them in unit dosage forms required for generally accepted pharmaceutical practice.

[0028] When the pharmaceutical composition is an injection, examples of the solvent for the injection include isotonic solutions containing adjuvants such as physiological saline, glucose, D-sorbitol, D-mannose, D-mannitol, sodium chloride, etc. The solvent for the injection may contain alcohol such as ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactants such as Polysorbate 80 (trademark), HCO-50, etc.

[0029] The administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is not particularly limited and can be appropriately selected depending on the target organ in which the symptom is manifested. For example, the administration can be carried out by methods known to those skilled in the art, such as eye drops, intra-arterial injection, intravenous injection, subcutaneous injection, subconjunctival injection, etc., as well as intranasal, transbronchial, intramuscular, transdermal, or oral administration.

[0030] The dosage of the concentration regulator of the present invention for a biological substance or drug in a semi-closed biological system varies depending on the symptoms, but in the case of oral administration, it is generally 250 mg to 1,000 mg of the active ingredient per day for an adult (body weight 60 kg) (especially when Diamox (acetazolamide) is taken orally according to the package insert).

[0031] When administered parenterally, the single dose of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention will vary depending on the subject, target organ, symptoms, and administration method. For example, in the form of eye drops, for an adult (body weight 60 kg), it can be administered by instilling one drop at a time, once or twice a day. In the form of injection, for an adult (body weight 60 kg), it can be administered by intravenous or local injection of, for example, about 60 mg to 180 mg of the active ingredient per day (particularly when 20% mannitol is administered by infusion as instructed in the package insert).

[0032] The administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is carried out, for example, before, simultaneously with, or after the administration of the drug to the subject. When the administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is carried out before the administration of the drug to the subject, the administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is carried out, for example, 1 to 6 hours before the administration of the drug to the subject. When the administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is carried out after the administration of the drug to the subject, the administration of the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention to a subject is carried out, for example, 1 to 6 hours after the administration of the drug to the subject.

[0033] The present invention provides a method for regulating the concentration of a substance or drug in a semi-closed in vivo system, comprising administering to a subject a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed in vivo system.The present invention also provides a pharmaceutical composition for use in regulating the concentration of a substance or drug in a semi-closed in vivo system, comprising as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed in vivo system.Furthermore, the present invention provides the use of a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed in vivo system in the manufacture of a pharmaceutical composition for use in regulating the concentration of a substance or drug in a semi-closed in vivo system.

[0034] Example 1: Subjects and Selection Criteria: The present inventors have been collecting aqueous humor samples during intravitreal injections for nAMD for over 10 years, and have frozen and stored tens of thousands of samples. Therefore, subjects were selected from 13 individuals who used glaucoma eye drops and whose aqueous humor concentration was measured 28 days after intravitreal injection of Eylea. Age- and gender-matched subjects (21 individuals) whose aqueous humor concentration was measured 28 days after intravitreal injection of Eylea served as controls. The glaucoma eye drops used included Xalatan (latanoprost), Lumigan (bimatoprost), Cosopt (dorzolamide hydrochloride / timolol maleate solution), Aiphagan (brimonidine tartrate), Tapros (tafluprost), and Duotrava (travoprost / timolol maleate solution). Age, gender, axial length, and eye drop scores were assessed for these subjects and controls. Eylea is an anti-VEGF drug. Glaucoma eye drops, which act by inhibiting aqueous humor production, are thought to increase the concentration of intravitreal injections, so the eye drop score was assigned a +1. On the other hand, glaucoma eye drops, which act by promoting aqueous humor outflow, are thought to decrease the concentration of intravitreal injections, so the eye drop score was assigned a -1.

[0035] Test details: Based on the above assumptions, a univariate analysis was performed on the instillation score and Eylea concentration. In addition, a multivariate analysis was performed on age, sex, axial length, and instillation score, with Eylea concentration as the dependent variable.

[0036] Results: Figure 1 shows the results of univariate analysis of the eye drop score and Eylea concentration. As shown in Figure 1, a higher eye drop score was associated with a higher Eylea concentration (P = 0.0092). Figure 2 shows the results of multivariate analysis of age, sex, axial length, and eye drop score, with Eylea concentration as the dependent variable. As shown in Figure 2, the factor most strongly associated with Eylea concentration was the eye drop score (P = 0.145). These results suggest that the use of glaucoma eye drops that inhibit aqueous humor production may increase the intraocular concentration of intravitreal injectable preparations such as anti-VEGF drugs, while the use of glaucoma eye drops that promote aqueous humor outflow may decrease the intraocular concentration of intravitreal injectable preparations such as anti-VEGF drugs.

[0037] Example 2: Regulation of biological substance or drug concentrations by drugs that promote or inhibit fluid production or excretion in a semi-closed biological system: An increase in aflibercept concentration in the anterior chamber was observed with topical brimonidine. The mean aflibercept concentration was 18 (standard deviation (SD) 6.4) and 6.5 (6.6) pg / mL, respectively, in 6 eyes vs. 74 eyes, p < 0.0001. Because topical brimonidine primarily reduces intraocular pressure by inhibiting aqueous humor production, it is believed that the suppression of aqueous humor production reduced aflibercept outflow from the main outflow pathway via the trabecular meshwork-Schlemm's canal and the accessory outflow pathway via the uveosclera, thereby suppressing the concentration decrease. An increase in aflibercept concentration in the anterior chamber was observed with topical β-blockers and carbonic anhydrase inhibitors (CAIs), which purely inhibit aqueous humor production. Beta-blockers: Aflibercept concentrations were 15 (9.3) and 6.2 (6,2) pg / mL in 10 eyes vs. 70 eyes, respectively, p < 0.0001. CAI: Aflibercept concentrations were 16 (7.9) and 6.6 (6,6) pg / mL in 7 eyes vs. 73 eyes, respectively, p = 0.0007. Because beta-blockers and carbonic anhydrase inhibitors suppress aqueous humor production and lower intraocular pressure, it is likely that the suppression of aqueous humor production reduced the outflow of aflibercept and prevented the concentration decrease. Therefore, it is likely that similar changes in concentrations may occur not only with drugs but also with physiologically active substances naturally present in the eye. Therefore, we selected CXCL1, a cytokine involved in inflammation but with little interaction, and measured its concentration using a bead assay. In 5 eyes and 239 eyes receiving topical prostaglandins (to promote accessory outflow), the mean CXCL1 concentrations were 20 (SD 26) and 64 (3.2) pg / mL, respectively, with a p = 0.044 indicating a significantly lower CXCL1 concentration in the prostaglandin group. Conversely, in 3 eyes receiving topical beta-blockers or carbonic anhydrase inhibitors, TNF-α concentrations were measured, as these are not related to inflammation. The mean TNF-α concentrations were 1.5 (SD 0.36) and 0.69 (0.028) pg / mL, respectively, with a p = 0.035 indicating a significantly higher TNF-α concentration in the beta-blocker or carbonic anhydrase inhibitor groups.This indicates that the concentration of not only drugs but also intraocular substances in general can be increased or decreased by adjusting the intraocular circulation, such as by suppressing aqueous humor production or promoting its outflow, through eye drops. This also suggests that the same is true for all semi-closed systems in the body where the production and outflow of internal fluids can be manipulated, such as cerebrospinal fluid and the peritoneal cavity. It has long been known that removing the vitreous, a gel-like substance, during vitrectomy and replacing it with low-viscosity aqueous humor accelerates the clearance of anti-VEGF drugs and reduces intraocular cytokines. However, no ophthalmologist had ever imagined that the concentration could also be manipulated through eye drops, making the present inventors' findings quite surprising.

[0038] Example 3: As shown in Table 1 below, it was found that the present invention reduces drug prices by several tens of thousands of yen per year. As shown in Table 1 above, the vitreous concentration (pg / mL) on Day 0 is calculated by administering 2 mg of aflibercept to a vitreous volume of 4.5 mL. Because measurements are performed in the anterior chamber, where measurements are easily performed, the anterior chamber concentration is 1 / 40th of that in the vitreous, so it is set at 1 / 40. The concentration (pg / mL) on Day 28 is the concentration actually collected from patients with and without brimonidine eye drops, which both inhibits production and promotes outflow, reducing flow by 37%. From this, the concentration (pg / mL) on Day 84, when the effect is calculated to be no longer effective, can be calculated. Since brimonidine is still effective, the value on Day 84, 2.22446E-12, is copied into the column for brimonidine eye drops, yielding 90.42 days. This indicates that the annual number of Eylea administrations will be reduced from 4.345 to 4.037, resulting in a reduction of ¥42,862 in annual drug price. The generic price of brimonidine is low at 129 yen / mL, so if the eye dropper bottle is discarded after one month as recommended by the pharmaceutical company, the annual cost would be 7,740 yen. Therefore, the present invention is expected to reduce drug prices by 42,862 yen per year and reduce the risks, invasiveness, and discomfort associated with eye puncture, such as endophthalmitis.

Claims

1. A concentration regulator for substances or drugs in the body in a semi-closed system, the active ingredient of which is a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system.

2. The concentration regulator according to claim 1, wherein the body fluid in the semi-closed system in the body is aqueous humor, and the semi-closed system in the body is the anterior chamber.

3. The concentration regulator according to claim 1, wherein the drug that promotes or suppresses the production or discharge of body fluids in a semi-closed system in the body is an aqueous humor production inhibitor or an aqueous humor outflow promoter, and the concentration regulator of an endogenous substance or drug in the endogenous semi-closed system in the body is an agent that enhances or suppresses the concentration of an endogenous substance or drug in the anterior chamber.

4. The concentration regulator according to claim 3, wherein the aqueous humor production inhibitor or aqueous humor outflow promoter is a glaucoma treatment agent.

5. The concentration regulator according to claim 4, wherein the antiglaucoma drug is an alpha 2 agonist, a sympathetic beta blocker, a carbonic anhydrase inhibitor or a prostanoid receptor-associated drug.

6. The concentration regulator according to claim 1, wherein the drug is an intravitreal formulation.

7. The concentration regulator according to claim 6, wherein the intravitreal preparation is an anti-VEGF drug.

8. The concentration regulator according to claim 7, wherein the anti-VEGF drug is an anti-VEGF-A drug, an anti-VEGF-B drug, or an anti-PlGF drug.

9. The concentration regulator according to claim 8, wherein the anti-VEGF drug is aflibercept.

10. The concentration regulator according to claim 1, wherein the biological substance is a physiologically active substance.

11. The concentration regulator according to claim 10, wherein the physiologically active substance is a cytokine.

12. The concentration regulator according to claim 11, wherein the cytokine is CXCL1 or TNF-α.