Use of growth hormone inhibitor and pharmaceutical composition, formulation, and apparatus comprising growth hormone inhibitor

Abstract

Disclosed in the present invention is use of a growth hormone inhibitor and related active substances thereof in preparing a drug, a pharmaceutical composition, a formulation, or an apparatus for ameliorating, correcting, relieving, controlling, treating, or preventing ophthalmic diseases or symptoms. By means of applying an effective amount of the growth hormone inhibitor to a patient, the ophthalmic symptoms, especially myopia-related symptoms, of the patient can be significantly ameliorated, thereby achieving the effect of preventing and treating myopia. Moreover, the safety is good, thereby exhibiting clinical application prospects. Also provided in the present invention are a pharmaceutical composition, a formulation, and an apparatus comprising the described growth hormone inhibitor.

Description

Use of growth hormone inhibitors, and pharmaceutical compositions, preparations, and devices containing growth hormone inhibitors

[0001] The present invention claims priority from the prior Chinese application filed on December 11, 2023, entitled “Use of growth hormone inhibitors, and pharmaceutical compositions, preparations, and devices containing growth hormone inhibitors” and application number 202311693713.6. The contents of the prior Chinese application are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of biomedicine, and in particular to the field of treatment of myopia and related diseases. Technical Background

[0003] Myopia is a common eye disease. It refers to a refractive error in which, when the eye is at rest, parallel external light rays, after passing through the eye's refractive system, are not imaged on the retina but are instead imaged in front of the retina. Myopia can be divided into two types based on its refractive component: refractive myopia and axial myopia. The former refers to excessive curvature of the patient's cornea or lens, while the axial length is within the normal range; the latter refers to excessive growth of the patient's axial length, while the curvature of the cornea and lens is normal. Approximately 95% of myopia in children and adolescents in my country is caused by axial growth, i.e., axial myopia.

[0004] The pathogenesis of myopia is not yet fully understood. Early studies suggested that delayed accommodation of the lens causes parallel light rays to pass through the eye's refractive system and form an image on the retina, inducing axial length growth. However, it was later discovered that delayed accommodation is a consequence of myopia, not its cause.

[0005] In recent years, new studies have suggested that the pathogenesis of myopia may be related to scleral hypoxia, insufficient dopamine secretion in the eye, endoplasmic reticulum stress, and insufficient ipRGC function in the retina. However, these mechanistic studies still do not fully explain the cause and process of myopia, and there are few safe, non-toxic drugs that can be used clinically to truly treat myopia and related symptoms.

[0006] Therefore, providing a safe drug that can effectively treat or prevent myopia and related diseases is an urgent problem to be solved. Summary of the Invention

[0007] According to past clinical practice, the causes of the onset and progression of myopia in patients usually have the following two important clinical characteristics: first, the patients are in childhood and / or adolescence; second, the patients have a habit of working at close range for a long time, including studying, reading, watching electronic products, etc.

[0008] Based on extensive research, the inventors surprisingly discovered that the cause of myopia may be related to excessive secretion of growth hormone during near vision. Therefore, the present invention provides a method for improving, correcting, mitigating, controlling, treating, or preventing ophthalmic diseases, particularly myopia and its related symptoms, using growth hormone inhibitors and their derivatives.

[0009] In a first aspect, the present invention provides a use of a growth hormone inhibitor or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a related compound or extract thereof, or a crystalline compound thereof in the preparation of a drug, a pharmaceutical composition or preparation, or an ophthalmic device for improving, correcting, alleviating, controlling, treating or preventing ophthalmic diseases or symptoms.

[0010] Preferably, the growth hormone is human growth hormone.

[0011] The growth hormone inhibitor includes one or more of a compound that inhibits growth hormone secretion, a growth hormone receptor antagonist, a growth hormone-releasing hormone inhibitor, or a growth hormone antibody.

[0012] Preferably, the growth hormone inhibitor is a compound that inhibits the secretion of growth hormone.

[0013] Preferably, the growth hormone inhibitor is somatostatin and its analogs, and more preferably is a linear or cyclic peptide SSTR2 receptor agonist.

[0014] Preferably, the compound that inhibits growth hormone secretion is a linear polypeptide or a cyclic polypeptide, and the linear polypeptide or the cyclic polypeptide comprises an amino acid sequence of -Tyr-Trp-Lys-Val- or -Phe-Trp-Lys-Thr-.

[0015] Preferably, the linear polypeptide or cyclic polypeptide is an amino acid sequence comprising 4-30, or 6-28, or 8-14 amino acid residues.

[0016] Preferably, the linear polypeptide is selected from compounds comprising one or more of the following amino acid sequences:

[0017] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Gly-(SEQ ID NO:1),

[0018] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ala-(SEQ ID NO:2),

[0019] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ser-(SEQ ID NO:3),

[0020] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Abu-(SEQ ID NO:4),

[0021] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Thr-(SEQ ID NO:5),

[0022] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Phe-(SEQ ID NO:6),

[0023] -Phe-Cys-Phe-Trp-Lys-Thr-Cys-Tyr-(SEQ ID NO:7),

[0024] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Tyr-(SEQ ID NO:8),

[0025] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Trp-(SEQ ID NO:9),

[0026] -Phe-Cys-Phe-Trp-Lys-Thr-Cys-Pro-(SEQ ID NO:10),

[0027] -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Pro- (SEQ ID NO: 11).

[0028] Preferably, the cyclic polypeptide contains a ring comprising 6-12 amino acid residues, and is preferably selected from compounds comprising one or more of the following amino acid sequences.

[0029] -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Thr-(SEQ ID NO:12),

[0030] -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-(SEQ ID NO:13),

[0031] -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Trp-(SEQ ID NO:14),

[0032] -Nal-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-(SEQ ID NO:15),

[0033] -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Trp-(SEQ ID NO:16),

[0034] -cyclo[Ala-Tyr-Trp-Lys-Val-Phe]-(SEQ ID NO:17),

[0035] -cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-(SEQ ID NO: 18).

[0036] More preferably, the cyclic polypeptide is selected from one or more of somatostatin-28, somatostatin-14, octreotide, lanreotide, segliptide, pasireotide or vapreotide; more preferably, the cyclic polypeptide is selected from one or more of octreotide and lanreotide;

[0037] Preferably, the compound that inhibits growth hormone secretion is selected from one or more of octreotide, octreotide acetate, or octreotide microspheres with an average particle size of 0.5-500 μm.

[0038] Preferably, the growth hormone receptor antagonist is Pegvisomant.

[0039] Preferably, the ophthalmic disease or symptom includes myopia and myopia-related symptoms.

[0040] Preferably, the myopia includes one or more of axial myopia, congenital myopia, pseudomyopia, true myopia, pathological myopia, simple myopia, extreme myopia, severe myopia, high myopia, moderate myopia, low myopia, infantile myopia, childhood and / or adolescent myopia, accommodative tension myopia, primary myopia, secondary myopia, hereditary myopia, myopia combined with glaucoma, myopia with risk of glaucoma or myopia accompanied by high intraocular pressure.

[0041] Preferably, the myopia-related symptoms include: pathological axial length growth, increase in length and / or depth of the vitreous cavity, abnormal development of the eyeball related to visual impairment, refractive error, glaucoma, scleral staphyloma, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, anisometropia, vitreous liquefaction, vitreous opacity, retinal atrophy and degeneration or one or more of subretinal neovascularization.

[0042] Preferably, the myopic individual or the individual with a tendency to develop myopia is:

[0043] Children and / or adolescents, preferably those aged 3 to 26, or those aged 6 to 15;

[0044] or for minors, such as those whose eyes or eyeballs are still in the growth or development stage;

[0045] They may be school-age people, such as students from grades one to twelve; or people whose parents are highly myopic; or people in a pre-myopia state; or people with insufficient hyperopia reserves.

[0046] In one embodiment, the pharmaceutical composition or formulation of the present invention further comprises at least one other drug or other ophthalmic drug, and / or at least one physiologically / pharmaceutically acceptable excipient.

[0047] Preferably, the other ophthalmic drugs are drugs that have the effect of treating myopia.

[0048] Preferably, the growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound accounts for more than 0.05wt%, more than 0.1wt%, more than 1wt%, more than 10wt%, more than 20wt%, more than 30wt%, more than 40wt%, more than 50wt%, more than 60wt%, more than 70wt%, more than 80wt%, more than 90wt% or 100wt% of all active ingredients in the pharmaceutical composition or preparation.

[0049] In one embodiment, the pharmaceutical composition or formulation of the present invention is selected from: an injection, such as an aqueous solution, an oil suspension, an emulsion or a lyophilized powder injection; an oral preparation, such as a tablet, a capsule, a pill, a gum, a lozenge, an oral liquid or a dispersible powder or granules; an intranasal preparation, such as a nasal drop, a nasal wash or an aerosol nasal spray; a skin administration preparation, such as a solution, a suspension, a gel, a powder, a cream, an oil or a liposome.

[0050] Preferably, the pharmaceutical composition or preparation is a topical administration agent, preferably a topical administration agent for the eyes and periocular area or a preparation for topical administration to the mucus film of the nasal passage, preferably, the topical administration agent for the eyes and periocular area is selected from: one or more of: eye drops, eye ointments, eye creams, eye gels, eye sprays, on-the-spot powders, eye ointments, eye lotions, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, eye microspheres, eye sustained-release preparations, periocular injections or intraocular injections.

[0051] In a second aspect, the present invention provides an ophthalmic pharmaceutical composition or ophthalmic preparation, comprising the aforementioned growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, and at least one physiologically / pharmaceutically acceptable excipient.

[0052] Preferably, the ophthalmic preparation is selected from one or more of eye drops, eye ointments, eye creams, eye gels, eye sprays, eye powders, eye ointments, eye lotions, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections or intraocular injections.

[0053] Preferably, the concentration of the growth hormone inhibitor in the pharmaceutical composition or formulation is 0.001 μM to 100 mM, or 0.005 μM to 50 mM, or 0.01 μM to 1000 μM, or 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, or 0.1 μM to 15 μM; or the mass percentage of the growth hormone inhibitor in the pharmaceutical composition or formulation is less than 75%, or less than 50%, or less than 25%, or less than 10%, or less than 5%, or less than 1%, preferably less than 0.1% or less than 0.01%.

[0054] The ophthalmic pharmaceutical composition or ophthalmic preparation includes the following components:

[0055] Growth hormone inhibitor 0.001-25wt%, and matrix 10-99.999wt%.

[0056] Preferably, the matrix comprises: liposome 0-20 wt%, paraffin 0-20 wt%, lanolin 0-20 wt%, and vaseline 10-99 wt%.

[0057] The ophthalmic pharmaceutical composition or ophthalmic preparation includes the following components:

[0058] Growth hormone inhibitor 0.001-25wt%, moisturizer and / or viscosity increasing agent 0-40wt%, osmotic pressure regulator and / or pH regulator 0.0001-20wt%, preservative and / or antibacterial agent 0-10wt%, and gelling agent 0-20wt%; and optionally biocompatible polymer 1-50wt%; and optionally water 20-99.99wt%.

[0059] In a third aspect, the present invention provides an ophthalmic device.

[0060] The ophthalmic device comprises the aforementioned growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, and a component that can release drugs or has drug delivery function or potential drug delivery ability.

[0061] Preferably, the medical device is selected from instruments, equipment, consumables, systems, medical instruments, health care products or products that change the appearance of the eye; such as corneal contact lenses, glasses, corneal onlays, corneal inlays, intraocular lenses, liposomes, nanoparticles, nanosheets, hydrogels, sutures, OK lens cleaning or maintenance systems, eye patches, eye masks, cosmetic contact lenses, microneedles, eye sprays, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices or one or more myopia treatment devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1: (A) Age-related trends in axial length and height of emmetropes; (B) Age-related trends in axial length and height of myopes.

[0063] Figure 2: Schematic diagram of the axial length growth and growth hormone content in the sclera of form deprivation-induced myopic mice.

[0064] Figure 3: Schematic diagram of the axial length growth of mice in the blank group, control group, and experimental group injected with different concentrations of octreotide acetate intraperitoneally 4 weeks later.

[0065] Figure 4: Schematic diagram of the axial length growth (A) and refractive power change (B) of mice in the blank group, control group, and experimental group injected with octreotide acetate one week after injection.

[0066] Figure 5: Schematic diagram of axial length growth of mice in the control group and one week after intravitreal injection of octreotide acetate.

[0067] Figure 6: Schematic diagram of the axial length growth (A) and refractive power change (B) of mice in the control group and the experimental group treated with octreotide acetate or lanreotide acetate eye drops (1 μg / ul) after one week.

[0068] Figure 7: Schematic diagram of body weight (A), body length (B) and tail length (C) of mice before the first administration and after the last administration in Example 5 and Example 6. DETAILED DESCRIPTION

[0069] In the following description, numerous specific details are provided to provide a more thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the present invention may be practiced without one or more of these details. In other instances, certain technical features well known in the art are not described to avoid confusion with the present invention.

[0070] The following describes the implementation of the present invention in detail with reference to the definitions of terms:

[0071] IActive ingredients of pharmaceuticals

[0072] In one embodiment of the present invention, a growth hormone inhibitor is provided as a pharmaceutical active ingredient.

[0073] "Growth hormone (GH)" refers to the natural growth hormone produced by the growth hormone-secreting cells of the anterior pituitary gland of humans and animals, or a polypeptide having similar biological activity and chemical structure to the natural growth hormone produced. The growth hormone includes the natural growth hormone produced by the growth hormone-secreting cells of the pituitary gland, as well as the growth hormone expressed by genetically transformed microorganisms such as Escherichia coli, other bacteria or yeast. The growth hormone produced by the other method described may have the same amino acid sequence as the natural growth hormone, or may be an analog with one or more variations in the amino acid sequence, which may provide higher biological activity or certain other advantages. The growth hormone of the present invention especially includes human, bovine and porcine growth hormone, such as human, bovine and porcine growth hormone expressed by microorganisms. In particular, human growth hormone.

[0074] Growth hormone inhibitors refer to aspects of the biological activity and / or expression levels of genes and related gene products that inhibit or reduce GH and / or related hormones. For example, at the DNA level (for example, reducing DNA synthesis, increasing turnover, and / or reducing stability), or at the RNA level (for example, reducing transcription, increasing turnover, and / or reducing stability), or at the polypeptide level (for example, reducing translation, increasing turnover, and / or reducing stability), or at the post-translational modification level (for example, reducing activity and / or stability). Inhibitors can also reduce or inhibit the activity or expression level of downstream or upstream products in the hormone pathway. In certain aspects, inhibitors can be specifically combined or reacted with hormones described herein. Therefore, growth hormone inhibitors include compounds that inhibit growth hormone secretion, growth hormone receptor antagonists, inhibitors of somatotropin releasing hormone, or growth hormone antibodies, etc.

[0075] Common compounds that inhibit growth hormone secretion include natural somatostatin (SST, such as SST-14 or SST-28), as well as linear or cyclic polypeptides derived from natural somatostatin (somatostatin analogs, such as cyclic peptide SSTR2 receptor agonists). These compounds that inhibit growth hormone secretion typically have specific amino acid sequences, such as -Tyr-Trp-Lys-Val- or -Phe-Trp-Lys-Thr- fragments, or specifically -Tyr-D-Trp-Lys-Val- or -Phe-D-Trp-Lys-Thr- fragments.

[0076] The amino acids in the amino acid sequence of the present invention can be D-type or L-type. The amino acids of the present invention are represented by three-letter abbreviations and include common derivatization or protection situations of the corresponding amino acids at COOH, NH2 or side chain functional groups. For example, in the context of the present invention, Thr includes not only threonine itself, but also threonine alcohol (such as Thr(ol) in octreotide) or threonine amide (such as Thr-NH2 in lanreotide).

[0077] Preferably, the amino acid sequence of the linear or cyclic polypeptide as the compound inhibiting growth hormone secretion has 4-50, or 5-40, or 6-30, or 8-28, or 10-24, or 12-20, or 14-18 amino acid residues.

[0078] Preferably, the compound that inhibits growth hormone secretion is a linear polypeptide or a cyclic polypeptide.

[0079] The linear polypeptide is preferably a linear polypeptide with a length of 8, or 10, or 12, or 14, or 16, and preferably contains one or more of the following amino acid sequences: -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Gly-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ala-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ser-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Abu-, -Phe-Cys-Tyr-Trp-Lys-Val -Cys-Thr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Phe-, -Phe-Cys-Phe-Trp-Lys-Thr-Cys-Tyr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys- Tyr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Trp-, -Phe-Cys-Phe-Trp-Lys-Thr-Cys-Pro-, or -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Pro-.

[0080] The cyclic polypeptide contains a ring comprising 6-18, or 8-14, or 10-12 amino acid residues, and is preferably selected from compounds comprising one or more of the following amino acid sequences: -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Thr-, -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-, -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-, -Trp-, -Nal-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-, -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Trp-,- cyclo[Ala-Tyr-Trp-Lys-Val-Phe]-or-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-.

[0081] In the above formula, cyclo[] indicates that the amino acid residues in the brackets form a ring according to a method well known in the art, such as being connected to form a ring through chemical bonds, hydrogen bonds or other intermolecular interactions.

[0082] In particular, ring formation is achieved via disulfide bonds (-ss-).

[0083] Preferably, -Trp- in the above amino acid sequence is preferably -D-Trp- or -L-Trp-, more preferably -D-Trp-.

[0084] Preferably, -Phe- in the above amino acid sequence is preferably -D-Phe or -L-Phe, more preferably -D-Phe.

[0085] In some embodiments, the linear polypeptide is selected from one or more polypeptides having the following amino acid sequences:

[0086] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Gly (SEQ ID NO: 19),

[0087] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Ala (SEQ ID NO: 20),

[0088] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Ser (SEQ ID NO: 21),

[0089] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Abu (SEQ ID NO: 22),

[0090] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr (SEQ ID NO: 23),

[0091] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Phe (SEQ ID NO: 24),

[0092] D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Tyr (SEQ ID NO: 25),

[0093] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Tyr (SEQ ID NO: 26),

[0094] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp (SEQ ID NO: 27),

[0095] D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Pro (SEQ ID NO: 28) or

[0096] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Pro (SEQ ID NO: 29).

[0097] In some embodiments, the cyclic polypeptide is selected from one or more polypeptides having the following amino acid sequences:

[0098] D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr, cyclo[] is -ss-annulation (SEQ ID NO: 30), D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr, cyclo[] is -ss-annulation (SEQ ID NO: 31), D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp, cyclo[] is -ss-annulation (SEQ ID NO: 32), D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr, cyclo[] is -ss-annulation (SEQ ID NO: 33). NO:33), D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Trp, cyclo[] is -ss- ring (SEQ ID NO:34), cyclo[Ala-Tyr-D-Trp-Lys-Val-Phe] (SEQ ID NO:35), Ala-Gly-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys], cyclo[] is -ss- ring (SEQ ID NO:36). NO:36), or Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys], cyclo[] is -ss- to form a ring (SEQ ID NO:37).

[0099] In some embodiments, the cyclic polypeptide is selected from one or more polypeptides having the following amino acid sequences:

[0100] D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr(ol), cyclo[] is -ss- cyclization (octreotide) (SEQ ID NO: 38), D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2, cyclo[] is -ss- cyclization (lanreotide) (SEQ ID NO: 39),

[0101] D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2, cyclo[] is -ss- cyclization (vapreotide) (SEQ ID NO: 40), cyclo[Tyr(Bzl)-Phe-Hyp(Bom)-Phg-D-Trp-Lys] (pasireotide) (SEQ ID NO: 41), -cyclo(N-methyl-Ala-Tyr-D-Trp-Lys-Val-Phe) (segliptide) (SEQ ID NO:42), Ala-Gly-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys], cyclo[] is -ss- cyclized (somatostatin-14), or Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys], cyclo[] is -ss- cyclized (somatostatin-28).

[0102] Preferably, the cyclic polypeptide is selected from one or more of somatostatin-28, somatostatin-14, octreotide, lanreotide, segliptide, pasireotide or vapreotide.

[0103] Preferably, the cyclic polypeptide may be octreotide, or octreotide acetate, or octreotide microspheres with an average particle size of 0.5-500 μm.

[0104] Preferably, the cyclic polypeptide may be lanreotide or lanreotide acetate.

[0105] Preferably, the average particle size of the octreotide microspheres may be 1-400 μm, or 5-300 μm, or 10-200 μm, or 20-100 μm, or 50-80 μm.

[0106] In another embodiment of the present invention, the growth hormone inhibitor may be a growth hormone receptor antagonist, such as Pegvisomant.

[0107] Preferably, the compound used as the active ingredient of the drug also includes the optical isomers of the above-mentioned growth hormone inhibitor or its racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound.

[0108] Preferably, the above-mentioned active pharmaceutical ingredient "growth hormone inhibitor" can be the only active ingredient in the drug.

[0109] Preferably, the drug may also include other active ingredients, so that the above-mentioned active ingredients account for more than 0.05wt%, more than 0.1wt%, more than 1wt%, more than 10wt%, more than 20wt%, more than 30wt%, more than 40wt%, more than 50wt%, more than 60wt%, more than 70wt%, more than 80wt% or more than 90wt% of all active ingredients.

[0110] II. Pharmaceutical Compositions and Formulations

[0111] In one embodiment of the present invention, the concentration of the growth hormone inhibitor, its optical isomers or racemates, or solvates, or pharmaceutically acceptable salts, or prodrugs, or metabolites, or related compounds or extracts, or crystalline compounds thereof in the pharmaceutical composition of the present invention is not particularly limited, but is preferably a concentration that inhibits axial length elongation and / or refractive error when administered or topically applied to a patient. Specifically, upon administration, the lower limit of the concentration of the growth hormone inhibitor in the pharmaceutical composition is preferably 0.0001% (w / v), more preferably 0.001% (w / v), further preferably 0.01% (w / v), even more preferably 0.1% (w / v), and most preferably 0.5% (w / v). In consideration of drug safety and reducing side effects, the upper limit of its concentration is preferably 25% (w / v), more preferably 20% (w / v), further preferably 10% (w / v), even more preferably 5% (w / v), especially preferably 2% (w / v), even more preferably 1% (w / v), and even more preferably 0.5% (w / v).

[0112] Preferably, when topically applied to the patient's eyes, for eye drops, the applied concentration is preferably 0.0001-20% (w / v), more preferably 0.001-10% (w / v), further preferably 0.0-5% (w / v), even more preferably 0.1-0.5% (w / v), and particularly preferably 1% (w / v). For ophthalmic ointments, the applied concentration is preferably 0.01-5% (w / w), more preferably 0.1-3% (w / w).

[0113] In one embodiment of the present invention, the pharmaceutical composition further comprises at least one physiologically / pharmaceutically acceptable excipient. Different excipients may be added depending on the type of preparation.

[0114] Preferably, the preparation can be an injection, such as an aqueous solution, oil suspension, or emulsion or lyophilized powder injection; an oral preparation, such as a tablet, capsule, pill, oral gum, lozenge, oral liquid or dispersible powder or granules; an intranasal preparation, such as nasal drops, nasal wash or aerosol nasal spray; a skin administration preparation, such as a solution, suspension, gel, powder, cream, oil or liposome.

[0115] Preferably, the pharmaceutical composition or preparation is a topical administration agent, preferably a topical administration agent for the eyes and periocular area or a preparation for topical administration to the mucus membrane of the nasal passage, preferably, the topical administration agent for the eyes and periocular area is selected from the group consisting of: eye drops, eye ointments, eye creams, eye gels, eye sprays, on-the-spot powders, eye ointments, eye lotions, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, eye microspheres, eye sustained-release preparations, periocular injections or intraocular injections.

[0116] When used for topical administration, preferred excipients may also include surfactants, stabilizers, antibacterial agents, preservatives, gelling agents, solid or semisolid matrices, lubricants, osmotic pressure regulators, pH regulators, buffers, solubilizers, thickeners, humectants or solvents, etc.

[0117] When solid preparations are prepared, additives such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starch, agar, arginine ester, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerol, polyethylene glycol, sodium bicarbonate, magnesium stearate, or talc can be used. In addition, tablets can be prepared as required, usually with a coating, such as a sugar-coated tablet, an enteric-coated tablet, a film-coated tablet, a double-layer tablet, or a multi-layer tablet.

[0118] When making semi-solid preparations, animal and vegetable oils (olive oil, corn oil, castor oil, etc.), mineral oils (petroleum jelly, white petroleum jelly, paraffin, lanolin, etc.), waxes (jojoba oil, carnauba wax, beeswax, etc.) or partially synthetic or fully synthetic glycerol fatty acid esters (lauric acid, myristic acid, palmitic acid, etc.) can be used.

[0119] When liquid preparations are prepared, additives such as sterile aqueous solution (eg physiological saline), sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene glycol or ethanol may be used.

[0120] When preparing an injection, a sterile aqueous solution (e.g., physiological saline), an isotonic solution, or an oily solution (e.g., sesame oil, soybean oil) can be used. In addition, if necessary, an appropriate suspending agent, such as sodium carboxymethyl cellulose, a nonionic surfactant, or a dissolution aid (e.g., benzyl benzoate, benzyl alcohol), etc., can also be used simultaneously.

[0121] When preparing eye drops, aqueous liquids or aqueous solutions, particularly sterile aqueous solutions for injection, may be used. Various additives such as buffers, stabilizers, wetting agents, emulsifiers, suspending agents, surfactants, isotonic agents, preservatives, and viscosity-increasing agents may also be appropriately added to the eye drops.

[0122] Examples of buffers include phosphate buffers, borate buffers, citrate buffers, tartaric acid buffers, acetate buffers, or amino acids. Stabilizers include sodium edetate or citric acid. Wetting agents include glycerol. Emulsifiers include polyvinyl pyrrolidone. Suspending agents include hydroxypropyl methylcellulose or methylcellulose. Surfactants include Tween 80 or polyoxyethylene hydrogenated castor oil. Isotonicity agents include saccharides such as sorbitol, glucose, or mannitol, polyols such as glycerol or propylene glycol, or salts such as sodium chloride. Preservatives include quaternary ammonium salts such as benzalkonium chloride or benzylethonium chloride, parahydroxybenzoates such as methylparaben or ethylparaben, benzyl alcohol, phenylethyl alcohol, sorbic acid and its salts, thimerosal, or chlorobutanol. As the thickener, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof can be used.

[0123] When used as eye drops, the pH is usually adjusted to about 4-9, preferably about 6-8.5, and more preferably about 7.

[0124] An exemplary embodiment, such as a pharmaceutical composition or formulation, comprises:

[0125] Growth hormone inhibitor 0.001-25wt%, moisturizer and / or viscosity enhancer 0-40wt%, osmotic pressure regulator and / or pH regulator 0.0001-20wt%, preservative and / or antibacterial agent 0-10wt%, and water 20-99.99wt%.

[0126] Preferably, the growth hormone inhibitor is 0.01-20 wt%, or 0.05-10 wt%, or 0.1-5 wt%, or 0.5-2.5 wt%, or 1-1.5 wt%.

[0127] Preferably, the humectant and / or viscosity increasing agent is 0.1-20 wt%, or 1-10 wt%, or 2-5 wt%.

[0128] Preferably, the osmotic pressure regulator and / or pH regulator is 0.001-10 wt%, or 0.01-5 wt%, or 0.1-2 wt%, or 0.5-1 wt%.

[0129] Preferably, the preservative and / or bacteriostatic agent is 0.01-5 wt%, or 0.5-3 wt%, or 1-2 wt%.

[0130] Preferably, water is 50-99 wt%, or 60-98 wt%, or 70-95 wt%, or 80-90 wt%.

[0131] When the preparation is an ointment, an ointment base (petrolatum, lanolin) and a preservative (benzalkonium chloride, parabens, chlorobutanol, etc.) can be appropriately selected for preparation.

[0132] An exemplary embodiment, such as a pharmaceutical composition or formulation, comprises:

[0133] Growth hormone inhibitor 0.001-25 wt%, and base 10-99.999 wt%; and optionally, preservative 0-10 wt%.

[0134] Preferably, the growth hormone inhibitor is 0.01-20 wt%, or 0.05-10 wt%, or 0.1-5 wt%, or 0.5-2.5 wt%, or 1-1.5 wt%.

[0135] Preferably, the matrix comprises: 0-20 wt% liposomes, 0-20 wt% paraffin, 0-20 wt% lanolin and 10-99 wt% vaseline.

[0136] Preferably, the liposome content is 1-10 wt%, or 2-5 wt%.

[0137] Preferably, the paraffin is liquid paraffin, and the content is 0.1-18 wt%, or 1-15 wt%, or 2-12 wt%, or 5-10 wt%.

[0138] Preferably, the lanolin content is 0.1-18 wt%, or 1-15 wt%, or 2-12 wt%, or 5-10 wt%.

[0139] Preferably, the vaseline is yellow vaseline, and the content is 25-90 wt%, or 50-85 wt%, or 70-80 wt%.

[0140] When the preparation is an ophthalmic gel, it is preferably a temperature-sensitive ophthalmic gel or a controlled / slow-release ophthalmic gel.

[0141] An exemplary embodiment, such as a pharmaceutical composition or formulation, comprises:

[0142] Growth hormone inhibitor 0.001-25wt%, moisturizer and / or viscosity enhancer 0-40wt%, preservative and / or antibacterial agent 0-10wt%, and gelling agent 0.01-20wt%; and optionally biocompatible polymer 1-50wt%; and optionally water 20-99.99wt%.

[0143] Preferably, the content of the growth hormone inhibitor is 0.01-20 wt%, or 0.05-10 wt%, or 0.1-5 wt%, or 0.5-2.5 wt%, or 1-1.5 wt%.

[0144] Preferably, the moisturizing agent and / or viscosity increasing agent is propylene glycol, and the content is preferably 0.1-20 wt%, or 1-10 wt%, or 2-5 wt%.

[0145] Preferably, the content of the preservative and / or antibacterial agent is 0.01-5 wt%, or 0.5-3 wt%, or 1-2 wt%.

[0146] Preferably, the gelling agent is carbomer or polycarbophil, and the content is preferably 0.1-10 wt%, or 0.5-5 wt%, or 1-3 wt%.

[0147] Preferably, the biocompatible polymer is poloxamer, and the content is preferably 5-30 wt%, or 10-25 wt%, or 15-20 wt%.

[0148] Preferably, the water content is preferably 50-99 wt%, or 60-98 wt%, or 70-95 wt%, or 80-90 wt%.

[0149] III device

[0150] In one embodiment of the present invention, the present invention also provides a medical device, which comprises a growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, and at least one component that can release drugs or has drug delivery function or has potential drug delivery ability.

[0151] Preferably, the medical device is selected from instruments, equipment, consumables, systems, medical instruments, health care products or products that change the appearance of the eye; such as corneal contact lenses, glasses, corneal onlays, corneal inlays, intraocular lenses, liposomes, nanoparticles, nanosheets, hydrogels, sutures, OK lens cleaning or maintenance systems, eye patches, eye masks, cosmetic contact lenses, microneedles, eye sprays, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices or myopia treatment devices.

[0152] Preferably, the medical device is a contact lens. The contact lens can be a corneal reshaping lens, commonly known as an OK lens, a hard contact lens, or a soft contact lens. Preferably, the contact lens contains an effective therapeutic amount of the active pharmaceutical ingredient of the present invention. The active pharmaceutical ingredient can be delivered to the patient's eye while the patient wears the lens. For example, at least a portion of the surface or interior of the contact lens is a material that can controllably / slowly release the active pharmaceutical ingredient, such as a liposome or a polymer sustained-release material. The material that can controllably / slowly release the active pharmaceutical ingredient is combined with the active pharmaceutical ingredient.

[0153] In another example, the medical device may be an intraocular lens. The intraocular lens may be an aphakic intraocular lens or a phakic intraocular lens. The active pharmaceutical ingredient of the present invention is coated on and / or dispersed through the intraocular lens to obtain an implantable intraocular lens device.

[0154] IV Uses, Indications, and Treatment Methods

[0155] The drugs, pharmaceutical compositions, preparations or devices of the present invention can be used to treat ophthalmic diseases, wherein the active pharmaceutical ingredient, growth hormone inhibitor, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound can be used to prepare drugs for improving, correcting, slowing down, controlling, treating or preventing myopia and myopia-related symptoms.

[0156] The myopia includes axial myopia, congenital myopia, pseudomyopia, true myopia, pathological myopia, simple myopia, extreme myopia, severe myopia, high myopia, moderate myopia, low myopia, infantile myopia, childhood and / or adolescent myopia, accommodative tension myopia, primary myopia, secondary myopia, hereditary myopia, myopia combined with glaucoma, myopia with risk of glaucoma or myopia accompanied by high intraocular pressure.

[0157] In particular, the medicine, pharmaceutical composition, preparation or device of the present invention has a significant effect on the treatment of axial myopia. The axial myopia refers to the following state: due to the elongation of the axial length of the eye, the parallel light rays entering the eye are focused into an image on the front side of the retina, and therefore cannot see clearly. The eyes of animals, including humans, grow larger as they grow. When a concave lens is worn on a baby mouse, the axial length of the eye will stretch to the position where the image formed when the concave lens is worn can be clearly seen, that is, the axial length of the eye will stretch to a state where it can see clearly when the concave lens is worn. As a result, the axial length of the eye stretches, making it possible to produce an eye state similar to that of axial myopia.

[0158] In one embodiment of the present invention, suitable subjects for treatment are myopic individuals or individuals with a tendency to develop myopia. The myopic individuals or individuals with a tendency to develop myopia are children and / or adolescents, preferably those aged 3 to 26, more preferably those aged 6 to 15; or minors, preferably those whose eyes (eyeballs) are still in the growth or development stage; or school-age individuals, preferably those in grades 1 to 12; or those whose parents are highly myopic; or those in a pre-myopic state; or those with insufficient hyperopia reserve.

[0159] In one embodiment of the present invention, the treatment method of the present invention comprises administering to a patient (eg, the aforementioned subject) an effective amount of the drug, pharmaceutical composition, formulation or device of the present invention.

[0160] In one embodiment of the present invention, myopia refers to a patient having at least one eye with a spherical equivalent refraction SER ≤ -0.5 Diopter (D), or an eye within the range of SER < -0.49D, such as -1.0D, -2.0D. Alternatively, myopia refers to a condition in which a patient has an eye with SER ≤ -0.5D, or SER < -0.49D. Low myopia refers to a patient having at least one eye with a SER value within the range of -0.50D to -3.00D. It may also refer to a condition in which a patient has an eye with a SER value within the range of -0.50D to -3.00D. High myopia refers to a patient having at least one eye with a SER ≤ -6.0D, and may also refer to a condition in which a patient has an eye with SER ≤ -6.0D.

[0161] In one embodiment of the present invention, the premyopia state refers to "Premyopia", which refers to "eyes at risk of myopia". The premyopia state of the present invention refers to the condition of emmetropia or low hyperopia in people who have not reached the age of emmetropization (such as the condition of eyes with a SER between -0.5D and +0.75D in people under the age of 12, or a SER within the range of -0.5D to +0.75D), especially eyes with the following risk factors: genetic factors (for example, both parents are myopic) and / or environmental factors (for example, insufficient time spent outdoors) and / or behavioral factors (for example, a long time is spent completing close tasks).

[0162] In one embodiment of the present invention, pathological axial length growth refers to the annual growth of the axial length (AL) in people who have not developed myopia (SER > -0.5D) or have already developed myopia (SER ≤ -0.5D) exceeding the normal growth of their peers of the same age. For example, for children aged 6 - 11 years, the annual AL growth ≥ 0.20 mm, or the condition of eyes with an annual AL growth ≥ 0.20 mm within the range of children aged 6 - 11 years; for teenagers aged 13 - 15 years, the annual AL growth ≥ 0.15 mm, or the condition of eyes with an annual AL growth ≥ 0.15 mm within the range of teenagers aged 13 - 15 years; for teenagers or adults over 16 years old, the annual AL growth ≥ 0.1 mm, or the condition of eyes with an annual AL growth ≥ 0.1 mm within the range of teenagers or adults over 16 years old.

[0163] In the embodiment of the present invention, emmetropia of the present invention refers to people over 18 years old with SER of both eyes being -0.5 < SER ≤ 0.5, for example, 0D.

[0164] In one embodiment of the present invention, improving, correcting, slowing down, controlling, treating or preventing myopia and myopia - related symptoms means that after using the drugs, drug compositions, preparations or devices of the present invention, the progression of myopia in the treated patients is controlled, slowed down, reduced, delayed and / or alleviated within the following ranges relative to the untreated ones: between about 1 - 100%, between about 5 - 90%, between about 5 - 80%, between about 5 - 70%, between about 5 - 60%, between about 5 - 50%, between about 5 - 40%, between about 5 - 30%, between about 5 - 20%, between about 10 - 100%, between about 20 - 90%, between about 30 - 90%, between about 40 - 90%, between about 50 - 90% or between about 75 - 90%.

[0165] In one embodiment of the present invention, by using the drugs, drug compositions, preparations or devices of the present invention, the degree of inhibition of the progression of myopia in patients (the control amount of SER progression relative to the untreated population) is 1.0 - 7.0D, 1.0 - 6.0D, 1.0 - 5.0D, 1.0 - 4.0D, 1.0 - 3.0D, 1.0 - 2.0D, less than 7.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D or less than 1.0D.

[0166] In a specific embodiment of the present invention, the myopia - related symptoms include: pathological axial length growth, increase in the length and / or depth of the vitreous cavity of the eye, abnormal development of the eyeball related to visual impairment, refractive error, glaucoma, scleral staphyloma, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, anisometropia, vitreous liquefaction, vitreous opacity, retinal atrophy and degeneration or subretinal neovascularization.

[0167] Preferably, the medicament, pharmaceutical composition, preparation or decoration of the present invention can treat pathological axial length growth, increase in length and / or depth of vitreous cavity and scleral staphyloma.

[0168] After use of the medicaments, pharmaceutical compositions, formulations or devices of the present invention, the pathological axial length growth, increase in vitreous cavity length and / or depth, and development of scleral staphyloma in the treated patient is controlled, slowed, reduced, delayed and / or alleviated in the following ranges relative to untreated patients: about 1-100%, about 5-90%, about 5-80%, about 5-70%, about 5-60%, about 5-50%, about 5-40%, about 5-30%, about 5-20%, about 10-100%, about 20-90%, about 30-90%, about 40-90%, about 50-90% or about 75-90%.

[0169] The drug can be administered several times daily during treatment. When used as eye drops, it is preferably administered 1 to 6 times nightly, with 1 to 2 drops per dose being preferred, with 1 drop being approximately 0.001-0.02 ml, or 0.01 ml. When used as an intravitreal injection, a 0.001 to 3 w / w% formulation can be administered once every 4 to 8 weeks, or once a year, or once every 2 years.

[0170] The present invention is described in more detail below through specific examples.

[0171] Unless otherwise specified, data were expressed as mean ± SD (SD refers to Standard Deviation).

[0172] Example 1 Clinical Study: Relationship between Axial Growth and Height in Myopic and Emmetropic Populations

[0173] 1) Experimental samples

[0174] A total of 2,623 twins, including 7 triplets, were found living in Guangzhou, including 1,282 males and 1,341 females. They were aged 7-15 years when they first participated in the test.

[0175] 2) Detection method

[0176] During the period from 2006 to 2018, the experimental samples were measured for cycloplegic refraction, axial length, and height once a year. Among them, a computerized autorefractor (TOPCON KR8800, Japan) was used to measure cycloplegic refraction, a non-contact optical coherence biometer (IOLMaster, Carl Zeiss, Germany) was used to measure axial length, and a height measuring instrument (Wuxi Xiheng Weighing Equipment Factory Co., Ltd.) was used to measure height.

[0177] Samples with follow-up records in the year of 18 years old, and patients with limb disabilities affecting accurate height measurement and eye diseases affecting axial length and refraction measurement were excluded, and were determined as the research objects of the present invention, a total of 1621 people, including 723 males and 898 females.

[0178] According to the cycloplegic refraction measured at the age of 18 of the samples, the research objects of the present invention were divided into myopic population and emmetropic population. Among them, since the correlation between the left and right eyes was greater than 0.85, according to the general research method in the field, the following examples were all observed with the right eye. Samples with SER ≤ -0.5D in the right eye after cycloplegia were the myopic population, and samples with -0.5 < SER ≤ 0.5D in the right eye after cycloplegia were the emmetropic population. Finally, it was confirmed that among the research objects of the present invention: there were 200 people in the emmetropic population, including 94 males and 106 females; there were 1421 people in the myopic population, including 629 males and 792 females. The normal values of axial length and height development of the above populations are shown in Table 1.

[0179] 3) Test results

[0180] The statistical software STATA 16.0 (Stata Corp, USA) was used to calculate the average values and 95% confidence intervals (95% CI) of height and axial length of the research objects of the present invention at each age stage, as shown in Figure 1.

[0181] As can be seen from Table 1 and Figure 1A, in the emmetropic population, during the period of 7 - 14 years old, which is the peak period of growth and development and the period when growth hormone secretion is the most vigorous, height and axial length increased in parallel; on the other hand, as the growth of height slowed down (i.e., the level of growth hormone decreased), the growth of axial length also decreased in parallel. Even though the samples were in the third year of junior high school or high school at this time, and the burden of close-range learning was significantly higher than that in the primary school stage, the growth rate of their axial length also decreased significantly. Further, we used the threshold regression model to detect the turning points of the height and axial length development curves. The turning point of the height development curve was 11.59 years old, and the turning point of the axial length development curve was 11.60 years old, and the two almost completely coincided.

[0182] As can be seen in Table 1 and Figure 1B, the trends in the axial length and height growth curves for myopia are similar to those for emmetropia. Threshold regression results suggest that the turning point for the height curve is 11.98 years, and the turning point for the axial length curve is 11.86 years, which are also very close.

[0183] The above results suggest that in myopic and emmetropic people, height and axial length grow synchronously, and the secretion of growth hormone in the whole body changes synchronously with the growth of the axial length.

[0184] Table 1. Mean height and axial length of myopic and emmetropic people at different ages. *: Not listed here due to small sample size.

[0185] Example 2 Relationship between the content of growth hormone in eye tissue and eye axis growth

[0186] 1) Experimental samples

[0187] Three-week-old C57BL / 6 mice were selected and housed in the experimental animal room of the Zhongshan Eye Center of Sun Yat-sen University under a 12-h light (400-500 lux) / 12-h dark environment with free access to water and food (the same below).

[0188] Fifteen mice from the aforementioned sample were subjected to monocular form derivation (FD): a specially made opaque black eye mask was used to completely cover the right eye of the animal, while the other eye (left eye) received normal vision, thereby obtaining an experimental group of mice with induced myopia (the same below). In this example, the form derivation duration was three weeks.

[0189] In the following examples and figures, BC (blank control) is blank control mice, FD is form-deprived mice, OA is octreotide preparation (octreotide acetate aqueous solution), LA is lanreotide preparation (lanreotide acetate aqueous solution), NS is normal saline, IP is intraperitoneal injection, IVR is intravitreal injection, and "drops" is eye drops.

[0190] 2) Detection method

[0191] The mouse-specific spectral domain optical coherence tomography (SD-OCT, Envisu, Leica Microsystems) was used to measure the axial length of the right eye of the mice before and after the experiment and calculate the axial length growth (the same below). The cumulative axial length growth of the right eye = the axial length of the right eye at 6 weeks - the axial length of the right eye at 3 weeks.

[0192] After the 3-week experiment, protein in the mouse sclera was extracted using protein lysis buffer, and the growth hormone content in the sclera protein was detected using a mouse growth hormone ELISA kit.

[0193] 3) Test results

[0194] Pearson correlation analysis was used to analyze the relationship between the axial length growth of the right eye of mice and the growth hormone content in the sclera. The analysis results are shown in Figure 2. As can be seen, the two are significantly positively correlated (r=0.831, P<0.001), indicating that an increase in the growth hormone content in the sclera accelerates the growth rate of the axial length.

[0195] Example 3 Effects of Intraperitoneal Injection of Different Concentrations of Growth Hormone Inhibitors for Four Weeks on Axial Growth

[0196] 1) Experimental Materials

[0197] Growth hormone inhibitors include the following:

[0198] ① Octreotide acetate, purchased from MedChemExpress. Octreotide acetate powder was completely dissolved in normal saline to prepare a storage solution, stored at -20°C, and diluted to the experimental concentration before administration to individual mice. At room temperature, the overall appearance of the preparation was clear, transparent, and homogeneous, with no visible suspended matter. All experimental procedures were performed in a darkroom (the same applies below).

[0199] ② Lanreotide acetate was purchased from MedChemExpress. Lanreotide acetate powder was directly and completely dissolved in normal saline to prepare a storage solution, which was stored at -20°C and diluted to the experimental concentration before administration to individual mice. At room temperature, the overall appearance of the preparation was clear, transparent, and uniform, with no visible suspended matter. All experimental procedures were performed in a darkroom (the same applies below).

[0200] 2) Experimental methods and results

[0201] Three-week-old mice were divided into a blank group, a control group, and an experimental group. The blank group received no intervention, while the right eye was covered in both the experimental and control groups. Simultaneously, the experimental groups received intraperitoneal injections of 25, 50, or 100 μg / kg / d of octreotide acetate solution (at concentrations of 2.5 μg / mL, 5 μg / mL, and 10 μg / mL, respectively), while the control group received intraperitoneal injections of normal saline once daily for four weeks. Axial length was measured at 3 and 7 weeks of age. To eliminate the influence of individual mouse differences, axial length growth was calculated as follows: the difference in cumulative axial length growth between the two eyes = (right eye axial length at 7 weeks of age - left eye axial length) - (right eye axial length - left eye axial length at 3 weeks of age). The experimental conditions and results for each group are shown in Table 2 and Figure 3. A one-way ANOVA concluded that intraperitoneal octreotide significantly inhibited axial length growth (P < 0.05).

[0202] Table 2. Effects of intraperitoneal injection of different concentrations of growth hormone inhibitors for four weeks on axial length growth *The data are reported as mean ± standard error (SE).

[0203] Example 4 Effects of intraperitoneal injection of growth hormone inhibitors for one week on axial length growth and refractive power changes

[0204] Three-week-old mice were divided into a blank group, a control group, and an experimental group. The blank group received no intervention, while the right eye was covered in both the experimental and control groups. The experimental group received intraperitoneal injections of 50 μg / kg / d of octreotide acetate solution (5 μg / mL), while the control group received normal saline once daily for one week. Axial length and refractive power were measured at 3 and 4 weeks of age. To eliminate the influence of individual differences, the axial length growth between the two eyes was calculated as follows: the difference in cumulative axial length growth between the two eyes = (right eye axial length - left eye axial length) at 4 weeks of age - (right eye axial length - left eye axial length) at 3 weeks of age. The refractive power change was calculated as follows: the difference in refractive power change between the two eyes = (right eye refractive power - left eye refractive power) at 4 weeks of age - (right eye refractive power - left eye refractive power) at 3 weeks of age.

[0205] The experimental conditions and results for each group are shown in Table 3 and Figure 4. Using one-way ANOVA, it can be seen that the experimental group inhibited 68.8% of myopic axial length growth, inhibiting myopia caused by form deprivation, with a statistically significant difference (P < 0.05). The results of Examples 3 and 4 demonstrate that growth hormone inhibitors can significantly inhibit myopia at different administration times and dosages.

[0206] Table 3. Effects of intraperitoneal injection of growth hormone inhibitors for one week on axial length growth and refractive power changes *The data are reported as mean ± standard error (SE).

[0207] Example 5 Effect of intravitreal injection of growth hormone inhibitor on axial length growth

[0208] Form-deprived mice were obtained using the same method as in Example 4. The experimental group received a single intravitreal injection of 1 μg / ul octreotide acetate solution, while the control group received a single intravitreal injection of normal saline. The mice were observed for one week. The axial length of the mice was measured and the growth calculation formula was the same as in Example 4.

[0209] The experimental conditions and results of each group are shown in Table 4 and Figure 5. The group t-test analysis showed that the difference between the experimental group and the control group was statistically significant (P < 0.001), indicating that intravitreal injection of growth hormone inhibitors can significantly inhibit axial length growth.

[0210] Table 4. Effects of intravitreal injection of growth hormone inhibitors on axial length growth *The data are reported as mean ± standard error (SE).

[0211] Example 6 Effect of Growth Hormone Inhibitor Eye Drops on Axial Growth and Refractive Power

[0212] Form-deprived mice were obtained using the same method as in Example 4. Experimental Group 1 mice were administered 1 μg / ul of octreotide acetate eye drops, experimental Group 2 mice were administered 1 μg / ul of lanreotide acetate eye drops, and the control group was administered normal saline, one drop (approximately 10 μl) twice daily for one week. The axial length of the mice was measured at 3 and 4 weeks of age. The formula for measuring the axial length of the mice and calculating the growth amount was the same as in Example 4.

[0213] The experimental conditions and results for each group are shown in Table 5 and Figure 6. Using group t-test analysis, it was concluded that the differences between the experimental and control groups were statistically significant (P < 0.5). The results of Examples 4, 5, and 6 demonstrate that different administration routes and concentrations of growth hormone inhibitors can significantly inhibit axial length growth and myopia.

[0214] Table 5. Effects of growth hormone inhibitor eye drops on axial length growth *The data are reported as mean ± standard error (SE).

[0215] Example 7 Safety of Topically Applied Growth Hormone Inhibitors

[0216] The body weight, body length, and tail length of the mice in the experimental group (FD+OA) and the control group (FD) in Examples 5 and 6 were measured before the first administration and after the last administration. The body weight was measured using an electronic scale, and the body length and tail length were measured using a tape measure.

[0217] The results of group t-test analysis are shown in Figure 7. It can be seen that there was no statistical difference in weight (P = 0.079), body length (P = 0.144) and tail length (P = 0.686) between the experimental group and the control group, indicating that local administration of growth hormone inhibitors does not affect the growth and development of the administered individuals and is safe and reliable.

[0218] In the above embodiments, all technical solutions that fall within the scope of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, several improvements and modifications that do not depart from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. Use of a growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound in the preparation of a drug, pharmaceutical composition or preparation for improving, correcting, alleviating, controlling, treating or preventing ophthalmic diseases or symptoms; Preferably, the growth hormone is human growth hormone.

2. The use according to claim 1, wherein the growth hormone inhibitor comprises: One or more of a compound that inhibits growth hormone secretion, a growth hormone receptor antagonist, a somatotropin-releasing factor inhibitor, or a growth hormone antibody; Preferably, the growth hormone inhibitor is a compound that inhibits the secretion of growth hormone; Preferably, the growth hormone inhibitor is somatostatin and its analogs, and further preferably is a linear or cyclic peptide SSTR2 receptor agonist; Preferably, the compound that inhibits growth hormone secretion is a linear polypeptide or a cyclic polypeptide, and the linear polypeptide or the cyclic polypeptide comprises an amino acid sequence of -Tyr-D-Trp-Lys-Val- or -Phe-D-Trp-Lys-Thr-; Preferably, the linear polypeptide or cyclic polypeptide is an amino acid sequence comprising 4-30, or 6-28, or 8-14 amino acid residues; Preferably, the linear polypeptide is selected from compounds comprising one or more of the following amino acid sequences: -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Gly-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ala-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Ser-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Abu-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Thr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Phe-, -Phe-Cys-Phe-Trp- Lys-Thr-Cys-Tyr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Tyr-, -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Trp-, -Phe-Cys-Phe-Trp-Lys-Thr-Cys-Pro-, or -Phe-Cys-Tyr-Trp-Lys-Val-Cys-Pro-; Preferably, the cyclic polypeptide contains a ring comprising 6-12 amino acid residues, preferably selected from compounds comprising one or more of the following amino acid sequences: -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Thr-、 -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-、 -Phe-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Trp-、 -Nal-cyclo[Cys-Tyr-Trp-Lys-Val-Cys]-Thr-、 -Phe-cyclo[Cys-Phe-Trp-Lys-Thr-Cys]-Trp-、 -cyclo[Ala-Tyr-Trp-Lys-Val-Phe]- or -cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-; Preferably, the cyclic polypeptide is selected from one or more of somatostatin-28, somatostatin-14, octreotide, lanreotide, segliptide, pasireotide or vapreotide; more preferably, the cyclic polypeptide is selected from one or more of octreotide and lanreotide; Preferably, the compound that inhibits growth hormone secretion is selected from one or more of octreotide, octreotide acetate, or octreotide microspheres with an average particle size of 0.5-500 μm; Preferably, the growth hormone receptor antagonist is Pegvisomant.

3. The use according to any one of claims 1 or 2, wherein the ophthalmic disease or symptom comprises myopia and myopia-related symptoms; Preferably, the myopia includes one or more of axial myopia, congenital myopia, pseudomyopia, true myopia, pathological myopia, simple myopia, extreme myopia, severe myopia, high myopia, moderate myopia, low myopia, infantile myopia, childhood and / or adolescent myopia, accommodative tension myopia, primary myopia, secondary myopia, hereditary myopia, myopia combined with glaucoma, myopia with risk of glaucoma or myopia accompanied by high intraocular pressure; Preferably, the myopia-related symptoms include: One or more of pathological axial length growth, increase in vitreous cavity length and / or depth, abnormal eye development associated with visual impairment, refractive error, glaucoma, scleral staphyloma, amblyopia, macular hemorrhage, choroidal neovascularization, choroidal atrophy, macular degeneration or macular lesions, anisometropia, vitreous liquefaction, vitreous opacity, retinal atrophy and degeneration, or subretinal neovascularization. Preferably, the myopic individual or the individual with the myopia tendency is: a child and / or a teenager, preferably a person aged 3 to 26, or a person aged 6 to 15; or for minors, such as those whose eyes or eyeballs are still in the growth or development stage; They may be school-age people, such as students from grades one to twelve; or people whose parents are severely myopic; or people in a pre-myopia state; or people with insufficient hyperopia reserves.

4. The use according to any one of claims 1 to 3, wherein the pharmaceutical composition or preparation further comprises at least one other drug or other ophthalmic drug, and / or at least one physiologically / pharmaceutically acceptable excipient; Preferably, the other ophthalmic drugs are drugs having the effect of treating myopia; Preferably, the growth hormone inhibitor or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound accounts for more than 0.05wt%, more than 0.1wt%, more than 1wt%, more than 10wt%, more than 20wt%, more than 30wt%, more than 40wt%, more than 50wt%, more than 60wt%, more than 70wt%, more than 80wt%, more than 90wt% or 100wt% of all active ingredients in the pharmaceutical composition or preparation.

5. The use according to any one of claims 1 to 4, wherein the pharmaceutical composition or preparation is selected from: injections, such as aqueous solutions, oil suspensions, or emulsions, freeze-dried powder injections; oral preparations, such as tablets, capsules, pills, oral gels, lozenges, oral liquids, dispersible powders or granules; intranasal preparations, such as nasal drops, nasal washes or aerosol nasal sprays; skin administration preparations, such as one or more of solutions, suspensions, gels, powders, creams, oils or liposomes; Preferably, the pharmaceutical composition or preparation is a topical administration agent, preferably a topical administration agent for the eyes and periocular area or a preparation for topical administration to the mucus film of the nasal passage, and preferably the topical administration agent for the eyes and periocular area is selected from: one or more of eye drops, eye ointments, eye creams, eye gels, eye sprays, continual powders, eye ointments, eye lotions, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, eye microspheres, eye sustained-release preparations, periocular injections or intraocular injections.

6. An ophthalmic pharmaceutical composition or ophthalmic preparation, characterized in that: The ophthalmic pharmaceutical composition or ophthalmic preparation comprises the growth hormone inhibitor according to any one of claims 1 to 5, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, and at least one physiologically / pharmaceutically acceptable excipient; Preferably, the ophthalmic preparation is selected from one or more of eye drops, eye ointments, eye creams, eye gels, eye sprays, eye powders, eye ointments, eye lotions, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, eye microspheres, eye sustained-release preparations, periocular injections or intraocular injections; Preferably, the concentration of the growth hormone inhibitor in the pharmaceutical composition or preparation is 0.001 μM to 100 mM, or 0.005 μM to 50 mM, or 0.01 μM to 1000 μM, or 0.05 μM to 100 μM, more preferably 0.1 μM to 25 μM, or 0.1 μM to 15 μM; or the mass percentage of the growth hormone inhibitor in the pharmaceutical composition or preparation is less than 75%, or less than 50%, or less than 25%, or less than 5%, or less than 1%, preferably less than 0.1% or less than 0.01%.

7. The ophthalmic pharmaceutical composition or ophthalmic preparation according to claim 6, comprising any one of the following components (1) to (2): (1) 0.001-25wt% of growth hormone inhibitor, and 10-99.999wt% of matrix; Preferably, the matrix comprises: Liposome 0-20wt%, paraffin 0-20wt%, lanolin 0-20wt%, and vaseline 10-99wt%; (2) a growth hormone inhibitor 0.001-25 wt%, a moisturizer and / or a viscosity enhancer 0-40 wt%, an osmotic pressure regulator and / or a pH regulator 0.0001-20 wt%, a preservative and / or an antibacterial agent 0-10 wt%, and a gelling agent 0-20 wt%; and optionally a biocompatible polymer 1-50 wt%; and optionally water 20-99.99 wt%.

8. An ophthalmic device, characterized in that: The ophthalmic device comprises the growth hormone inhibitor according to any one of claims 6 to 7, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound, and a component that can release drugs or has drug delivery function or has potential drug delivery ability; Preferably, the medical device is selected from instruments, equipment, consumables, systems, medical instruments, health care products or products for changing the appearance of the eye; such as corneal contact lenses, glasses, corneal onlays, corneal inlays, artificial lenses, liposomes, nanoparticles, nanosheets, hydrogels, sutures, OK lens cleaning or maintenance systems, eye patches, eye masks, cosmetic contact lenses, microneedles, eye sprays, eye massagers, eye fumigators, ocular surface drug delivery devices, intraocular drug delivery devices, fundus drug delivery devices, implanted pumps, wearable devices, acupoint massagers, eye relaxation devices or myopia treatment devices. One or more.

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