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

Abstract

The invention discloses a growth hormone inhibitor and application of related active substances of the growth hormone inhibitor in preparation of drugs, pharmaceutical compositions, preparations or devices for improving, correcting, slowing down, controlling, treating or preventing ophthalmic diseases or symptoms, and by applying an effective amount of the growth hormone inhibitor to a patient, the ophthalmology, especially myopia-related symptoms of the patient can be obviously improved. And the traditional Chinese medicine composition is good in safety and has a clinical application prospect. The invention also provides a pharmaceutical composition, a preparation and a device containing the growth hormone inhibitor.

Description

[0001] This invention claims the priority of a Chinese prior application titled "Use of Growth Hormone Inhibitor, Pharmaceutical Composition, Preparation, and Device Containing Growth Hormone Inhibitor" with an application number of 202311693713.6 and filed on December 11, 2023. The content of the above prior application is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedicine, particularly to the field of the treatment of myopia and its related diseases. Technical Background

[0003] Myopia is a common ophthalmic disease, which refers to a refractive error in which, under the condition of static accommodation of the eyeball, parallel light rays from the outside world, after passing through the refractive system of the eyeball, cannot form an image on the retina but form an image in front of the retina. Myopia can be divided into refractive myopia and axial myopia according to its refractive components. The former refers to the situation where the curvature of the patient's cornea or lens is too large, while the axial length of the eye is within the normal range; the latter refers to the situation where the axial length of the patient's eye grows excessively, while the curvatures of the cornea and lens are normal. Approximately 95% of myopia in Chinese children and adolescents is axial myopia caused by the growth of the eye axis.

[0004] The pathogenesis of myopia has not been fully understood yet. Early studies believed that the lag of lens accommodation, which causes parallel light rays from the outside world to form an image behind the retina after passing through the refractive system of the eyeball, and then induces the growth of the eye axis, is the cause of myopia in patients. However, it was later found that the lag of lens accommodation is the result of myopia onset, rather than the cause.

[0005] In recent years, some new studies have proposed that the pathogenesis of myopia may be related to scleral hypoxia mechanism, insufficient secretion of intraocular dopamine, endoplasmic reticulum stress, and insufficient function of ipRGC in the retina, etc. However, the above mechanistic studies still have not fully explained the causes and processes of myopia, and there are few safe and non-toxic drugs that can be used clinically and truly achieve the treatment of myopia and related symptoms.

[0006] Therefore, providing a safe drug that can effectively treat or prevent myopia and its 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 patients usually have the following two important clinical characteristics: First, the patient is in childhood and / or adolescence; Second, the patient has the living habits of long-term close work, including studying, reading, using electronic products, etc.

[0008] Based on a large number of studies, the inventors surprisingly found that the cause of myopia may be related to the excessive secretion of growth hormone in patients in the near-vision state. Therefore, the present invention provides a solution for using growth hormone inhibitors and their derivatives to improve, correct, slow down, control, treat or prevent ophthalmic diseases, especially myopia and its related symptoms.

[0009] In a first aspect, the present invention provides the use of a growth hormone inhibitor or its optical isomer 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 in the preparation of a drug, a pharmaceutical composition or a preparation, or an ophthalmic device for improving, correcting, slowing down, controlling, treating or preventing an ophthalmic disease or symptom.

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

[0011] The growth hormone inhibitor includes: one or more of a compound that inhibits the secretion of growth hormone, a growth hormone receptor antagonist, an inhibitor of growth hormone-releasing hormone, 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 a linear or cyclic peptide SSTR2 receptor agonist.

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

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

[0016] Preferably, the linear polypeptide is selected from compounds containing 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, 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, seglitide, pasireotide or vapreotide; more preferably, the cyclic polypeptide is selected from one or more of octreotide and lanreotide;

[0037] Preferably, the compound for inhibiting growth hormone secretion is selected from one or more of octreotide, or acetate of octreotide, 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, ultra-high myopia, severe myopia, high myopia, moderate myopia, low myopia, infantile myopia, childhood and / or adolescent myopia, accommodation spasm myopia, primary myopia, secondary myopia, hereditary myopia, myopia complicated with glaucoma, myopia at risk of glaucoma onset or myopia with high intraocular pressure.

[0041] Preferably, the myopia-related symptoms include one or more of pathological eye axis growth, increase in vitreous cavity length and / or depth 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.

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

[0043] Children and / or adolescents, preferably the population aged 3 to 26 years old, or the population aged 6 to 15 years old;

[0044] or for the underage population, such as those with eyes or eyeballs still in the growth or development stage;

[0045] or for the school-age population, such as students in grades one to twelve; or for those with highly myopic parents; or for those in the pre-myopia state; or for those with insufficient hyperopia reserve.

[0046] In one embodiment, the pharmaceutical composition or preparation 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 drug is a drug having a therapeutic effect on myopia.

[0048] Preferably, the growth hormone inhibitor or its optical isomer 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 accounts for more than 0.05 wt%, more than 0.1 wt%, more than 1 wt%, more than 10 wt%, more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, more than 80 wt%, more than 90 wt% or 100 wt% of all active ingredients in the pharmaceutical composition or preparation.

[0049] In one embodiment, the pharmaceutical composition or preparation of the present invention is selected from: injections, such as aqueous solutions, oil suspensions, emulsions or lyophilized powder injections; oral preparations, such as tablets, capsules, pills, chewing gums, lozenges, oral liquids or dispersible powders or granules; intranasal medications, such as nasal drops, nasal washes or aerosol nasal sprays; topical medications, such as solutions, suspensions, gels, powders, creams, oils or liposomes.

[0050] Preferably, the pharmaceutical composition or preparation is a topical medication, preferably a topical medication for the eye and the periocular region or a preparation for topically administering to the mucus membrane of the nasal passage. Preferably, the topical medications for the eye and the periocular region are selected from: eye drops, eye ointments, eye creams, ophthalmic gels, eye sprays, eye powders, eye oil ointments, eye washes, eye foams, eye implants, eye patches, eye masks, impregnated contact lenses, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections or intravitreal injections.

[0051] In a second aspect, the present invention provides an ophthalmic pharmaceutical composition or ophthalmic preparation, which comprises the aforementioned growth hormone inhibitor or its optical isomer 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, 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, ophthalmic gels, eye sprays, ophthalmic powders, eye oil ointments, eye lotions, eye foams, ophthalmic implants, eye patches, eye masks, impregnated contact lenses, ophthalmic microspheres, ophthalmic sustained-release preparations, periocular injections or intravitreal injections.

[0053] 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 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 comprises the following components:

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

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

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

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

[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 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, and a component capable of releasing a drug or having a drug delivery function or having a potential drug delivery ability.

[0061] Preferably, the medical device is selected from instruments, equipment, consumables, systems, medical devices, health care products, or products for changing the appearance of the eyes; such as contact lenses, glasses, corneal covers, corneal inlays, intraocular lenses, liposomes, nanoparticles, nanosheets, hydrogels, sutures, OK lens cleaning or maintenance systems, eye patches, eye masks, colored contact lenses, microneedles, eye sprays, eye massagers, eye fumigators, ocular surface drug delivery devices, intravitreal drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices, or myopia treatment devices, etc. Description of the Drawings

[0062] Figure 1 : (A): Graph showing the changing trends of axial length and height with age in emmetropic people; (B): Graph showing the changing trends of axial length and height with age in myopic people.

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

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

[0065] Figure 4 : Schematic diagram showing the axial length increase (A) and refractive error change (B) of mice in the blank group, control group, and experimental group injected with octreotide acetate intraperitoneally after 1 week.

[0066] Figure 5 : Schematic diagram showing the axial length increase of mice in the control group and the experimental group injected with octreotide acetate intravitreally after 1 week.

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

[0068] Figure 7 : Schematic diagram showing the 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 of the Embodiments

[0069] In the following description, numerous specific details are given to provide a more thorough understanding of the present invention. However, it is obvious to those skilled in the art that the present invention can be implemented without one or more of these details. In other instances, in order to avoid confusion with the present invention, some well-known technical features are not described.

[0070] The following describes the embodiments of the present invention in detail in combination with the definition of terms:

[0071] I Pharmaceutical active ingredient

[0072] In a specific embodiment of the present invention, somatostatin 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 of humans and animals, or a polypeptide having a biological activity and chemical structure similar to that of 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 may have the same amino acid sequence as the natural growth hormone, or may be an analogue with one or more variations in the amino acid sequence, and such variations may provide higher biological activity or certain other advantages. The growth hormone of the present invention particularly includes human, bovine and porcine growth hormones, such as human, bovine and porcine growth hormones expressed by microorganisms. In particular, human growth hormone.

[0074] Somatostatin inhibitors refer to aspects that inhibit or reduce the biological activity and / or expression level of genes and related gene products of GH and / or related hormones. For example, at the DNA level (e.g., reducing DNA synthesis, increasing turnover, and / or reducing stability), or at the RNA level (e.g., reducing transcription, increasing turnover, and / or reducing stability), or at the polypeptide level (e.g., reducing translation, increasing turnover, and / or reducing stability), or at the post-translational modification level (e.g., reducing activity and / or stability). The inhibitor can also reduce or inhibit the activity or expression level of downstream or upstream products in the hormone pathway. In a specific aspect, the inhibitor can specifically bind or react with the hormone described herein. Therefore, somatostatin inhibitors include compounds that inhibit growth hormone secretion, growth hormone receptor antagonists, inhibitors of growth hormone releasing hormone, or growth hormone antibodies, etc.

[0075] Common compounds that inhibit growth hormone secretion such as natural somatostatin (Somatostatin, SST, such as SST-14 or SST-28), and linear or cyclic polypeptides derived from natural somatostatin (somatostatin analogues, such as cyclic peptide SSTR2 receptor agonists). These compounds that inhibit growth hormone secretion usually have a specific amino acid sequence, such as the -Tyr-Trp-Lys-Val- or -Phe-Trp-Lys-Thr- fragment, or specifically the -Tyr-D-Trp-Lys-Val- or -Phe-D-Trp-Lys-Thr- fragment.

[0076] The amino acids in the amino acid sequence of the present invention can all be of the D-type or L-type. The amino acids of the present invention are represented by three-letter abbreviations and include common derivatization or protection cases of the corresponding amino acids at COOH, NH 2 or side chain functional groups. For example, in the context of the present invention, Thr includes not only threonine itself but also threoninol (such as Thr(ol) in octreotide) or threonine amide (such as Thr-NH 2 ).

[0077] Preferably, the amino acid sequence of the linear polypeptide or cyclic polypeptide as the compound for 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 for inhibiting growth hormone secretion is a linear polypeptide or a cyclic polypeptide.

[0079] The linear polypeptide preferably has 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 having 6 - 18, or 8 - 14, or 10 - 12 amino acid residues, and is preferably selected from compounds containing one or more of the following amino acid sequences:

[0081] -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]-.

[0082] In the above formula, cyclo[] indicates that the amino acid residues within the brackets form a ring in a manner well-known in the art, such as forming a ring through chemical bonds, hydrogen bonds, or other intermolecular interactions.

[0083] In particular, the ring formation is achieved through a disulfide bond (-S-S-).

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

[0085] Preferably, -Phe- in the above amino acid sequence is preferably -D-Phe or -L-Phe, more preferably -D-Phe.

[0086] In some specific embodiments, the linear polypeptide is selected from one or more of the polypeptides having the following amino acid sequences:

[0087] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Gly (SEQ ID NO:19),

[0088] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Ala (SEQ ID NO:20),

[0089] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Ser (SEQ ID NO:21),

[0090] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Abu (SEQ ID NO:22),

[0091] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr (SEQ ID NO:23),

[0092] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Phe (SEQ ID NO:24),

[0093] D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Tyr (SEQ ID NO:25),

[0094] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Tyr (SEQ ID NO:26),

[0095] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp (SEQ ID NO:27),

[0096] D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Pro (SEQ ID NO:28) or

[0097] D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Pro (SEQ ID NO:29).

[0098] In some specific embodiments, the cyclic polypeptide is selected from one or more of the polypeptides having the following amino acid sequences:

[0099] D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr, where cyclo[] is -S-S- cyclized (SEQ ID NO: 30), D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr, where cyclo[] is -S-S- cyclized (SEQ ID NO: 31), D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp, where cyclo[] is -S-S- cyclized (SEQ ID NO: 32), D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr, where cyclo[] is -S-S- cyclized (SEQ ID NO: 33), D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Trp, where cyclo[] is -S-S- cyclized (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], where cyclo[] is -S-S- cyclized (SEQ ID 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], where cyclo[] is -S-S- cyclized (SEQ ID NO: 37).

[0100] In some specific embodiments, the cyclic polypeptide is selected from one or more of the polypeptides having the following amino acid sequences:

[0101] D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr(ol), where cyclo[] is -S-S- cyclized (octreotide) (SEQ ID NO: 38), D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH 2 , where cyclo[] is -S-S- cyclized (lanreotide) (SEQ ID NO: 39),

[0102] D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH 2, cyclo[-S-S-]cyclized (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) (segltide) (SEQ ID NO:42), Ala-Gly-cyclo[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys], cyclo[-S-S-]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[-S-S-]cyclized (somatostatin-28).

[0103] Preferably, the cyclic polypeptide is selected from one or more of somatostatin-28, somatostatin-14, octreotide, lanreotide, segltide, pasireotide or vapreotide.

[0104] Preferably, the cyclic polypeptide can be octreotide, or acetate salt of octreotide, or octreotide microspheres with an average particle size of 0.5 - 500 μm.

[0105] Preferably, the cyclic polypeptide can be lanreotide, or acetate salt of lanreotide.

[0106] Preferably, the average particle size of octreotide microspheres can be 1 - 400 μm, or 5 - 300 μm, or 10 - 200 μm, or 20 - 100 μm, or 50 - 80 μm.

[0107] In another embodiment of the present invention, the above growth hormone inhibitor can be a growth hormone receptor antagonist, such as pegvisomant.

[0108] Preferably, the compound as the pharmaceutically active ingredient further includes the optical isomer or racemate of the above growth hormone inhibitor, or its solvate, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or its related compound or extract, or its crystalline compound.

[0109] Preferably, the above pharmaceutically active ingredient "growth hormone inhibitor" can be the only active ingredient in the drug.

[0110] Preferably, the drug may further include other active ingredients, such that the above-mentioned drug active ingredients account for more than 0.05 wt%, more than 0.1 wt%, more than 1 wt%, more than 10 wt%, more than 20 wt%, more than 30 wt%, more than 40 wt%, more than 50 wt%, more than 60 wt%, more than 70 wt%, more than 80 wt% or more than 90 wt% of all active ingredients.

[0111] II Pharmaceutical Compositions and Preparations

[0112] In one embodiment of the present invention, the concentration of the somatostatin inhibitor and its optical isomers 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 in the pharmaceutical composition of the present invention is not particularly limited, but preferably when administered or topically applied to a patient, the concentration that inhibits the elongation of the axial length of the eye and / or refractive error. Specifically, when administered, the lower limit of the concentration of the somatostatin 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). Considering 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), particularly preferably 2% (w / v), particularly more preferably 1% (w / v), and particularly further preferably 0.5% (w / v).

[0113] Preferably, when topically applied to the patient's eye, for eye drops, the application 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 eye ointments, the application concentration is preferably 0.01 - 5% (w / w), more preferably 0.1 - 3% (w / w).

[0114] In one embodiment of the present invention, the pharmaceutical composition further includes at least one physiologically / pharmaceutically acceptable excipient. Different excipients can be added according to different preparation types.

[0115] Preferably, the preparation can be an injection, such as an aqueous solution, an oil suspension, or an emulsion or a freeze-dried powder injection; an oral preparation, such as a tablet, a capsule, a pill, a chewing gum, a lozenge, an oral liquid or a dispersible powder or granule; a nasal preparation, such as a nasal drop, a nasal wash or an aerosol nasal spray; a skin preparation, such as a solution, a suspension, a gel, a powder, a cream, an oil or a liposome.

[0116] Preferably, the pharmaceutical composition or preparation is a topically administered agent, preferably an agent for topical administration to the eye and the periorbital region or a preparation for topical administration to the mucus membrane of the nasal passage. Preferably, the agents for topical administration to the eye and the periorbital region are selected from: eye drops, eye ointments, eye creams, ophthalmic gels, eye sprays, eye powders, eye oil ointments, eye lotions, eye foams, ophthalmic implants, eye patches, eye masks, impregnated contact lenses, ophthalmic microspheres, ophthalmic sustained-release preparations, periorbital injections or intraocular injections.

[0117] When used for topical administration, the excipients preferably may further include surfactants, stabilizers, bacteriostatic agents, preservatives, gelling agents, solid or semi-solid matrices, lubricants, osmotic pressure regulators, pH regulators, buffers, solubilizing agents, thickening agents, humectants or solvents, etc.

[0118] When preparing solid preparations, additives such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starch, agar, arginine esters, chitin, chitosan, pectin, tragacanth, gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, glycerol, polyethylene glycol, sodium bicarbonate, magnesium stearate or talc, etc. may be used. Moreover, tablets may be made into commonly coated tablets when necessary, such as sugar-coated tablets, enteric-coated tablets, film-coated tablets, bilayer tablets or multi-layer tablets.

[0119] When preparing semi-solid preparations, animal and vegetable oils (such as olive oil, corn oil, castor oil, etc.), mineral oils (such as petrolatum, white petrolatum, paraffin, lanolin, etc.), waxes (such as jojoba oil, carnauba wax, beeswax, etc.) or partially synthetic or fully synthetic glycerol fatty acid esters (such as lauric acid, myristic acid, palmitic acid, etc.) may be used.

[0120] When preparing liquid preparations, additives such as sterile aqueous solutions (such as physiological saline), sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene glycol or ethanol, etc.

[0121] When preparing injections, sterile aqueous solutions (such as physiological saline), isotonic solutions or oily liquids (such as sesame oil, soybean oil) may be used. Additionally, appropriate suspending agents, such as sodium carboxymethyl cellulose, non-ionic surfactants or solubilizing aids (such as benzyl benzoate, benzyl alcohol), etc. may also be used when necessary.

[0122] When preparing eye drops, aqueous liquids or aqueous solutions, especially sterile aqueous injection solutions, may be used. Various additives such as buffers, stabilizers, wetting agents, emulsifiers, suspending agents, surfactants, isotonic agents, preservatives and thickening agents, etc. may also be appropriately added to the eye drops.

[0123] Buffers can be, for example, phosphate buffers, boric acid buffers, citrate buffers, tartaric acid buffers, acetate buffers or amino acids. Stabilizers can be, for example, sodium edetate or citric acid. Humectants can be, for example, glycerol. Emulsifiers can be, for example, polyvinylpyrrolidone. Suspending agents can be, for example, hydroxypropylmethylcellulose or methylcellulose. Surfactants can be, for example, Tween 80 or polyoxyethylene hydrogenated castor oil. Isotonic agents can be, for example, sugars such as sorbitol, glucose or mannitol, or polyols such as glycerol or propylene glycol, or salts such as sodium chloride. Preservatives can be, for example, quaternary ammonium salts such as benzalkonium chloride or benzethonium chloride, or parabens such as methyl paraben or ethyl paraben, or benzyl alcohol, phenethyl alcohol, sorbic acid and its salts, thimerosal or chlorobutanol. Viscosity-increasing agents can be, for example, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose and its salts.

[0124] When used as an eye drop, the pH is usually adjusted to about 4 - 9, preferably adjusted to about 6 - 8.5, more preferably adjusted to about 7.

[0125] An exemplary formulation, such as a pharmaceutical composition or preparation, contains:

[0126] Somatostatin 0.001 - 25 wt%, humectant and / or viscosity-increasing agent 0 - 40 wt%, osmotic pressure regulator and / or pH regulator 0.0001 - 20 wt%, preservative and / or bacteriostatic agent 0 - 10 wt%, and water 20 - 99.99 wt%.

[0127] Preferably, the somatostatin 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%.

[0128] Preferably, the humectant and / or viscosity-increasing agent is 0.1 - 20 wt%, or 1 - 10 wt%, or 2 - 5 wt%.

[0129] 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%.

[0130] Preferably, the preservative and / or bacteriostatic agent is 0.01 - 5 wt%, or 0.5 - 3 wt%, or 1 - 2 wt%.

[0131] Preferably, the water is 50 - 99 wt%, or 60 - 98 wt%, or 70 - 95 wt%, or 80 - 90 wt%.

[0132] When the preparation is an ointment, the ointment base (petroleum jelly, lanolin) and preservatives (benzalkonium chloride, parabens, chlorobutanol, etc.) can be appropriately selected for preparation.

[0133] An exemplary formulation, such as a pharmaceutical composition or preparation, contains:

[0134] Growth hormone inhibitor 0.001 - 25 wt%, and matrix 10 - 99.999 wt%; and optionally, preservative 0 - 10 wt%.

[0135] 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%.

[0136] Preferably, the matrix includes: liposome 0 - 20 wt%, paraffin 0 - 20 wt%, lanolin 0 - 20 wt%, and petrolatum 10 - 99 wt%.

[0137] Preferably, the liposome content is 1 - 10 wt%, or 2 - 5 wt%.

[0138] 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%.

[0139] Preferably, the lanolin content is 0.1 - 18 wt%, or 1 - 15 wt%, or 2 - 12 wt%, or 5 - 10 wt%.

[0140] Preferably, the petrolatum is yellow petrolatum, and the content is 25 - 90 wt%, or 50 - 85 wt%, or 70 - 80 wt%.

[0141] When the preparation is an ophthalmic gel, it is preferably a temperature - sensitive ophthalmic gel or a controlled / sustained - release ophthalmic gel.

[0142] An exemplary formulation, such as a pharmaceutical composition or preparation, contains:

[0143] Growth hormone inhibitor 0.001 - 25 wt%, humectant and / or thickening agent 0 - 40 wt%, preservative and / or bacteriostatic agent 0 - 10 wt%, and gelling agent 0.01 - 20 wt%; and optionally, biocompatible polymer 1 - 50 wt%; and optionally, water 20 - 99.99 wt%.

[0144] Preferably, the growth hormone inhibitor content 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%.

[0145] Preferably, the humectant and / or tackifier is preferably propylene glycol, and the content is preferably 0.1-20 wt%, or 1-10 wt%, or 2-5 wt%.

[0146] Preferably, the content of the preservative and / or bacteriostatic agent is preferably 0.01-5 wt%, or 0.5-3 wt%, or 1-2 wt%.

[0147] Preferably, the gelling agent is preferably carbomer or polycarbophil, and the content is preferably 0.1-10 wt%, or 0.5-5 wt%, or 1-3 wt%.

[0148] Preferably, the biocompatible polymer is preferably poloxamer, and the content is preferably 5-30 wt%, or 10-25 wt%, or 15-20 wt%.

[0149] Preferably, the water content is preferably 50-99 wt%, or 60-98 wt%, or 70-95 wt%, or 80-90 wt%.

[0150] III Device

[0151] In one embodiment of the present invention, the present invention further provides a medical device, which includes a somatostatin or its optical isomer 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, and at least one component that can release a drug or has a drug delivery function or has the potential for drug delivery.

[0152] Preferably, the medical device is selected from instruments, equipment, consumables, systems, medical devices, health care products or products for changing the appearance of the eyes; such as contact lenses, glasses, corneal covers, corneal inlays, intraocular lenses, liposomes, nanoparticles, nanosheets, hydrogels, sutures, OK lens cleaning or maintenance systems, eye patches, eye masks, colored contact lenses, microneedles, eye sprays, eye massagers, eye fumigators, ocular surface drug delivery devices, intravitreal drug delivery devices, fundus drug delivery devices, implantable pumps, wearable devices, acupoint massagers, eye relaxation devices or myopia treatment devices.

[0153] Preferably, the medical device is a contact lens. The contact lens can be an orthokeratology lens, commonly known as an OK lens, a rigid contact lens, or a soft contact lens. Preferably, the contact lens contains an effective therapeutic amount of the drug active ingredient of the present invention. The drug active ingredient can be delivered to the patient's eye during the process of the patient wearing the lens. For example, at least a part of the surface or inside of the contact lens is a material that can control / slowly release the drug active ingredient, such as a liposome or a polymer sustained-release material. The material that can control / slowly release the drug active ingredient is combined with the drug active ingredient.

[0154] For 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 pharmaceutically active ingredient of the present invention is coated on the intraocular lens and / or dispersed through the intraocular lens to obtain an implantable intraocular lens device.

[0155] IV Uses, Indications and Treatment Methods

[0156] The drug, pharmaceutical composition, preparation or device of the present invention can be used for treating ophthalmic diseases, wherein the pharmaceutically active ingredient somatostatin or its optical isomer 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 can be used for preparing a drug for improving, correcting, slowing down, controlling, treating or preventing myopia and myopia-related symptoms.

[0157] The myopia includes axial myopia, congenital myopia, pseudomyopia, true myopia, pathological myopia, simple myopia, ultra-high myopia, severe myopia, high myopia, moderate myopia, low myopia, infantile myopia, child and / or adolescent myopia, accommodation spasm myopia, primary myopia, secondary myopia, hereditary myopia, myopia complicated with glaucoma, myopia at risk of glaucoma onset or myopia accompanied by high intraocular pressure.

[0158] In particular, the drug, pharmaceutical composition, preparation or device of the present invention has a significant effect on treating axial myopia. The axial myopia refers to the following state: due to the elongation of the eye axis, the parallel light rays entering the eye are focused into an image in front of the retina, so that the image cannot be seen clearly. In animals including humans, the eyes grow larger as they grow. When a concave lens is worn on young rats, the eye axis will elongate to a position where the image can be clearly seen when wearing the concave lens, that is, the eye axis will elongate to a state where the image can be seen clearly when wearing the concave lens. As a result, the eye axis elongates, and thus a state of the eye similar to axial myopia can be produced.

[0159] In one embodiment of the present invention, suitable treatment subjects of the present invention are myopic individuals or individuals with a tendency to develop myopia. Among them, myopic individuals or individuals with a tendency to develop myopia are children and / or adolescents, preferably those aged 3 to 26 years old, more preferably those aged 6 to 15 years old; or are underage individuals, preferably those whose eyes (eyeballs) are still in the growth or development stage; or are school-age individuals, preferably students in grades one to twelve; or are individuals whose parents are highly myopic; individuals in a pre-myopia state; or are individuals with insufficient hyperopia reserve.

[0160] In one embodiment of the present invention, the treatment method of the present invention includes administering an effective amount of the drug, pharmaceutical composition, preparation or device of the present invention to a patient (such as the aforementioned treatment subject).

[0161] In one embodiment of the present invention, myopia refers to a patient having at least one eye with a spherical equivalent refraction (SER) of SER ≤ -0.5 Diopter (D), or an eye within the range of SER < -0.49 D, such as -1.0 D, -2.0 D. Or myopia refers to the condition of an eye of a patient with SER ≤ -0.5 D, or within the range of SER < -0.49 D. Low myopia refers to a patient having at least one eye with an SER value within the range of -0.50 D to -3.00 D. It can also refer to the condition of an eye with an SER value within the range of -0.50 D to -3.00 D. High myopia refers to a patient having at least one eye with SER ≤ -6.0 D, and it can also refer to the condition of an eye with SER ≤ -6.0 D.

[0162] In one embodiment of the present invention, the premyopia state refers to "Premyopia", which means "an eye at risk of myopia". The premyopia state of the present invention refers to the appearance of emmetropia or low hyperopia in a population who has not reached the age of emmetropization (for example, the SER of people under 12 years old is between -0.5 D and +0.75 D, or the condition of an eye with an SER within the range of -0.5 D to +0.75 D), especially eyes combined 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, spending a long time on close-range tasks).

[0163] In one embodiment of the present invention, pathological axial elongation refers to the annual increase in axial length (AL) of a population who has not yet developed myopia (SER > -0.5 D) or has already developed myopia (SER ≤ -0.5 D) exceeding the normal increase of people of the same age. For example: the annual AL increase of children aged 6 - 11 years old is ≥ 0.20 mm, or the condition of an eye with an annual AL increase of children aged 6 - 11 years old within the range of ≥ 0.20 mm; the annual AL increase of teenagers aged 13 - 15 years old is ≥ 0.15 mm, or the condition of an eye with an annual AL increase of teenagers aged 13 - 15 years old within the range of ≥ 0.15 mm; the annual AL increase of teenagers or adults after 16 years old is ≥ 0.1 mm, or the condition of an eye with an annual AL increase of teenagers or adults after 16 years old within the range of ≥ 0.1 mm.

[0164] In the embodiment of the present invention, emmetropia of the present invention refers to a population at the age of 18 with SER of both eyes being -0.5 < SER ≤ 0.5, such as 0 D.

[0165] 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 drug, pharmaceutical composition, preparation or device of the present invention, the myopia progression of the treated patient is controlled, slowed down, reduced, delayed and / or alleviated within the following ranges relative to the untreated: 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%.

[0166] In one embodiment of the present invention, by using the drug, pharmaceutical composition, preparation or device of the present invention, the degree of inhibition of the patient's myopia progression (the amount of SER progression control 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.

[0167] In a specific embodiment of the present invention, the myopia-related symptoms include: pathological axial elongation, 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 degeneration or subretinal neovascularization.

[0168] Preferably, the drug, pharmaceutical composition, preparation or decoration of the present invention can treat pathological axial elongation, increase in the length and / or depth of the vitreous cavity of the eye, and scleral staphyloma.

[0169] After using the drug, pharmaceutical composition, preparation or device of the present invention, the development of pathological axial elongation, increase in the length and / or depth of the vitreous cavity of the eye, and scleral staphyloma in the treated patient is controlled, slowed down, reduced, delayed and / or alleviated within the following ranges relative to the untreated: 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%.

[0170] For a drug that can be administered several times a day during the treatment process, when used as an eye drop, it is preferably administered 1 to 6 times a day, once every night, and preferably 1 to 2 drops each time. One drop is about 0.001 - 0.02 ml, or 0.01 ml. When used as an intravitreal injection, a preparation of 0.001 - 3 w / w% can be administered once every 4 to 8 weeks, once a year, or once every two years.

[0171] The present invention will be described in more detail below through specific examples.

[0172] Unless otherwise specified, the data are expressed as mean ± standard deviation (mean ± SD, SD refers to Standard Deviation).

[0173] Example 1 Clinical Study: Relationship between Axial Length Growth and Height in Myopic and Emmetropic Populations

[0174] 1) Experimental samples

[0175] 1308 pairs of twins living in Guangzhou, including 7 triplets, a total of 2623 people, of which 1282 are male and 1341 are female. Their ages at the first detection were 7 - 15 years old.

[0176] 2) Detection methods

[0177] 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 Instrument Factory Co., Ltd.) was used to measure height.

[0178] 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 1621 people were determined as the research objects of the present invention, including 723 males and 898 females.

[0179] According to the cycloplegic refraction measured at the age of 18 in the samples, the research subjects 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 methods in the art, the right eye was used as the observation object in the following examples. 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 subjects of the present invention: there were 200 emmetropic people, including 94 males and 106 females; 1421 myopic people, including 629 males and 792 females. The normal development values of the eye axis and height of the above populations are shown in Table 1.

[0180] 3) Test results

[0181] The statistical software STATA 16.0 (Stata Corp, USA) was used to calculate the average values and 95% confidence intervals (95% CI) of the height and eye axis length of the research subjects of the present invention at each age stage, as Figure 1 shown.

[0182] As can be seen from Table 1 and Figure 1 A, in the emmetropic population, during the peak growth and development period from 7 to 14 years old, that is, the period when the growth hormone secretion is the most vigorous, the height and eye axis length increased in parallel; on the other hand, as the growth of height slowed down (that is, the growth hormone level decreased), the growth of the eye axis also decreased in parallel. Even though the samples were in the ninth grade 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 eye axis also decreased significantly. Further, we used the Threshold regression model to detect the turning points of the height and eye axis length development curves. The turning point of the height development curve was 11.59 years old, and the turning point of the eye axis length development curve was 11.60 years old, and the two almost completely coincided.

[0183] As can be seen from Table 1 and Figure 1 B, in the myopic population, the trends of the eye axis length and height growth curves were similar to those in the emmetropic population. The results of the threshold regression indicated that the turning point of the height curve was 11.98 years old, and the turning point of the eye axis length development curve was 11.86 years old, and the two were also very close.

[0184] The above results suggest that: in the myopic and emmetropic populations, the height and eye axis length showed synchronous growth, and the secretion amount of the whole body growth hormone was synchronously changed with the growth of the eye axis.

[0185] Table 1. Average values of height and eye axis of myopic and emmetropic populations at different ages.

[0186]

[0187] *: Not listed here due to the small sample size.

[0188] Example 2 Relationship between the Content of Growth Hormone in Eye Tissues and Axial Length Growth

[0189] 1) Experimental samples

[0190] Three-week-old C57BL / 6 mice were selected and housed in the experimental animal room of Zhongshan Eye Center of Sun Yat-sen University in a 12-h light (400-500 lux) / 12-h dark environment with free access to water and food (the same below).

[0191] The 15 mice in the above sample were subjected to monocular form derivation (FD): a special opaque black eye mask was used to completely cover the right eye of the animal, and the other eye (left eye) obtained normal vision, so as to obtain the experimental group mouse samples induced with myopia (the same below). In this example, the form derivation period was 3 weeks.

[0192] In the following examples and drawings of the specification, BC (blank control) is blank control mice, FD is form deprivation 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.

[0193] 2) Detection method

[0194] The mouse-specific spectral domain optical coherence tomography (SD-OCT, Envisu, Leica Microsystems) was used to detect 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.

[0195] 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.

[0196] 3) Test results

[0197] Pearson correlation analysis was used to analyze the relationship between the axial length growth of the right eye of mice and the content of growth hormone in the sclera. The analysis results are as follows: Figure 2 As shown in Figure 2, the two are significantly positively correlated (r=0.831, P<0.001), indicating that the higher the content of growth hormone in the sclera, the faster the growth rate of the eye axis will be.

[0198] Example 3 Effect of Intraperitoneal Injection of Different Concentrations of Growth Hormone Inhibitor for Four Weeks on Axial Length Growth

[0199] 1) Experimental Materials

[0200] Growth hormone inhibitors are selected from the following substances:

[0201] ① Octreotide acetate was purchased from MedChemExpress. The octreotide acetate powder was directly and completely dissolved in physiological saline to prepare a stock solution, which was stored at -20 °C. After dilution to the experimental concentration, it was administered to individual test mice. At room temperature, the overall appearance of this preparation was clear, transparent, homogeneous, and without visible suspended substances to the naked eye. All experimental operations were carried out in a dark room (the same below).

[0202] ② Lanreotide acetate was purchased from MedChemExpress. The lanreotide acetate powder was directly and completely dissolved in physiological saline to prepare a stock solution, which was stored at -20 °C. After dilution to the experimental concentration, it was administered to individual test mice. At room temperature, the overall appearance of this preparation was clear, transparent, homogeneous, and without visible suspended substances to the naked eye. All experimental operations were carried out in a dark room (the same below).

[0203] 2) Experimental methods and results

[0204] Three-week-old mice were selected and divided into a blank group, a control group, and an experimental group. Among them, the blank group was not given any intervention. In the experimental group and the control group, the right eyes were covered. At the same time, the mice in the experimental group were intraperitoneally injected with 25, 50, 100 μg / kg·d octreotide acetate solution (concentrations were 2.5 μg / mL, 5 μg / mL, and 10 μg / mL respectively), and the mice in the control group were intraperitoneally injected with physiological saline, once a day for 4 weeks. The axial lengths of the eyes were measured at 3 weeks and 7 weeks of age respectively. Among them, in order to eliminate the influence of individual differences in mice, the calculation formula for the increase in the axial length of the mouse eye was: the difference in the cumulative increase in the axial length between the two eyes = (right eye axial length - left eye axial length) at 7 weeks of age - (right eye axial length - left eye axial length) at 3 weeks of age. The experimental conditions and results of each group are shown in Table 2 and Figure 3 As shown, by using one-way ANOVA, it can be concluded that intraperitoneal injection of octreotide can significantly inhibit the increase in axial length (P < 0.05).

[0205] Table 2. Effects of intraperitoneal injection of different concentrations of somatostatin on axial length increase for four weeks

[0206]

[0207] * Recorded using mean ± standard error (mean±SE, SE refers to Standard Error).

[0208] Example 4 Effect of Intraperitoneal Injection of Growth Hormone Inhibitor for One Week on Axial Length Growth and Diopter Change

[0209] Three-week-old mice were divided into a blank group, a control group, and an experimental group. Among them, the blank group received no intervention, and the right eyes of the experimental group and the control group were covered. Mice in the experimental group were intraperitoneally injected with 50 μg / kg·d octreotide acetate solution (concentration: 5 μg / mL), and mice in the control group were injected with normal saline, once a day for 1 week. The axial length and refractive power of the mice were measured at 3 weeks and 4 weeks of age respectively. Among them, in order to eliminate the influence of individual differences in mice, the calculation formula for the increase in axial length of mice is: the difference in the cumulative increase in axial length 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 calculation formula for the change in refractive power of mice is: the difference in the change in refractive power 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.

[0210] The experimental conditions and results of each group are shown in Table 3 and Figure 4 As shown, by using one-way ANOVA, it can be seen that the experimental group inhibited 68.8% of the myopic axial length growth and inhibited the myopia caused by form deprivation, and the difference was statistically significant (P < 0.05). The results of Example 3 and Example 4 show that growth hormone inhibitors can significantly inhibit myopia at different dosing times and doses.

[0211] Table 3. Effect of Intraperitoneal Injection of Growth Hormone Inhibitor for One Week on Axial Length Growth and Diopter Change

[0212]

[0213] * Recorded using mean ± standard error (mean ± SE, SE refers to Standard Error).

[0214] Example 5 Effect of Intravitreal Injection of Growth Hormone Inhibitor on Axial Length Growth

[0215] Mice after form deprivation were obtained by the same method as in Example 4. Mice in the experimental group were injected once with 1 μg / μL octreotide acetate solution into the vitreous cavity, and mice in the control group were injected with normal saline into the vitreous cavity once, and observed for 1 week. The measurement and calculation formula for the increase in axial length of mice were the same as in Example 4.

[0216] The experimental conditions and results of each group are shown in Table 4 and Figure 5 As shown, by using the unpaired t-test analysis, it can be concluded that the difference between the results of the experimental group and the control group was statistically significant (P < 0.001), indicating that intravitreal injection of growth hormone inhibitor can significantly inhibit axial length growth.

[0217] Table 4. Effect of intravitreal injection of growth hormone inhibitor on axial length growth

[0218]

[0219] Recorded as mean ± standard error (mean±SE, SE refers to Standard Error).

[0220] Example 6 Effect of Growth Hormone Inhibitor Eye Drops on Axial Length Growth and Diopter

[0221] Mice after form deprivation were obtained by the same method as in Example 4. In experimental group 1, mice were instilled with 1 μg / μl octreotide acetate eye drops, in experimental group 2, mice were instilled with 1 μg / μl lanreotide acetate eye drops, and the control group was instilled with normal saline, twice a day, one drop each time (about 10 μl), and the administration was for 1 week. The axial lengths of the mice were measured at 3 weeks and 4 weeks of age respectively. The calculation formulas for the axial length measurement and growth increment of the mice were the same as those in Example 4.

[0222] The experimental conditions and results of each group are shown in Table 5 and Figure 6 As shown, it can be concluded by using the unpaired t-test analysis that there is a statistically significant difference in the results between the experimental group and the control group (P < 0.5). The results of Example 4, Example 5 and Example 6 show that growth hormone inhibitors with different administration methods and different administration concentrations can significantly inhibit axial length growth and myopia.

[0223] Table 5. Effect of growth hormone inhibitor eye drops on axial length growth

[0224]

[0225]

[0226] Recorded as mean ± standard error (mean±SE, SE refers to Standard Error).

[0227] Example 7 Safety of Local Application of Growth Hormone Inhibitor

[0228] The body weights, body lengths and tail lengths of the mice in the experimental groups (FD+OA) and the control group (FD) in Example 5 and Example 6 were measured before the first administration and after the last administration. Among them, the body weight was measured using an electronic scale, and the body length and tail length were measured using a tape measure.

[0229] The results of the unpaired t-test analysis are as Figure 7 shown. It can be seen that there are no statistically significant differences in the data such as body weight (P = 0.079), body length (P = 0.144) and tail length (P = 0.686) between the experimental group and the control group of mice, indicating that local administration of growth hormone inhibitors does not affect the growth and development of the administered individuals, and is safe and reliable.

[0230] In the above embodiments, all technical solutions falling within the concept of the present invention are within the protection scope of the present invention. It should be noted that for those of ordinary skill in the art, several improvements and modifications made without departing from the principle of the present invention should also be regarded as within the protection scope 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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