Long-acting growth hormone dosage forms with superior efficacy compared to daily growth hormone

Abstract

This invention relates to a long-acting growth hormone or a pharmaceutical preparation containing such a long-acting growth hormone, and to a method for treating growth hormone deficiency with improved outcomes.

Description

[0001] This case is a divisional application of the application filed on March 3, 2020, entitled "A Long-Acting Growth Hormone Formulation with Superior Efficacy Compared to Daily Growth Hormone," with application number 2020800183773.

[0002] This invention relates to a long-acting growth hormone or a pharmaceutical preparation containing such a long-acting growth hormone, and to a method for treating growth hormone deficiency with improved outcomes.

[0003] Human growth hormone (hGH) is widely used to treat short stature caused by GH deficiency (GHD) or insufficiency, as well as other growth disorders. Growth hormone (GH) is currently only available in most areas as a formulation requiring daily injection.

[0004] Prescribing practices for daily growth hormone preparations indicate that dosing should be individualized based on each patient's weight and growth response. The typical dosage range for children with growth hormone deficiency is 0.17 mg / kg / week to 0.30 mg / kg / week.

[0005] Non-adherence to growth hormone therapy is common. It is prevalent because current hGH treatment requires daily injections for many years, which patients perceive as invasive. Non-adherence has been shown to negatively impact treatment outcomes. The ease of use of the injection device, its features, and the frequency of injections may play a significant role in adherence.

[0006] To improve compliance and treatment effectiveness, several companies have developed technologies for manufacturing long-acting growth hormone products.

[0007] Nutropin Depot® was the first approved long-acting growth hormone, based on encapsulating growth hormone in biodegradable microparticles. Nutropin Depot was available in the United States, but its approval was withdrawn in 2004.

[0008] Nutropin Depot is intended to be injected once or twice a month at a dose of 1.5 mg / kg / month or 0.75 mg / kg / twice a month. In clinical studies, Nutropin Depot increased the annual height growth rate in children with growth hormone deficiency, but the growth rate achieved with daily treatment was higher than that achieved with Nutropin Depot in historical studies.

[0009] Somatropin Biopartners was approved by the European Medicines Agency, but its use was subsequently discontinued in the European Union. Somatropin Biopartners is a long-acting growth hormone based on encapsulating growth hormone in biodegradable microparticles. It is intended for weekly administration. Clinical trials showed that pediatric patients with growth hormone deficiency, administered at a dose of 0.5 mg / kg / week, achieved a similar rate of height increase as those receiving a daily injection of 0.21 mg / kg / week (7 injections per day).

[0010] Of the approved long-acting growth hormones, none have shown superior efficacy compared to equimolar doses of daily growth hormone (somatropin). Besides the two long-acting growth hormone formulations that have received regulatory approval in Western countries, many other long-acting growth hormone formulations are under development.

[0011] For example, VRS-317 was studied in a phase 3 clinical trial in pediatric patients with GHD. Patients receiving somavaratan twice monthly had an annualized height-to-body ratio (AHV) of 9.44 cm, while those receiving genotropin daily had an AHV of 10.7 cm. These results indicate that the trial did not meet the primary endpoint of non-inferiority in annualized height-to-body ratio compared to daily growth hormone genotropin at a dose of 0.24 mg / kg / week.

[0012] Somatrogon (MOD-4023, hGH-CTP) was administered once weekly in a phase 2 dose-range study in pediatric patients with GHD. Specifically, patients were given doses of 0.25 mg / kg / week; 0.48 mg / kg / week; or 0.66 mg / kg / week. The 0.66 mg / kg / week dose is expected to provide similar efficacy to daily growth hormone and has been selected for further investigation in a phase 3 clinical trial to compare its efficacy with daily growth hormone (somatropin) administered at 0.24 mg / kg / week.

[0013] TV-1106 (albutropin) is being investigated in a Phase 2 dose-range study in pediatric patients with GHD, using a fixed weekly dosing regimen. Specifically, patients are administered a fixed dose of 0.554 mg / kg / week, 0.924 mg / kg / week, or 1.20 mg / kg / week. Neutralizing antibodies against TV-1106 have been detected, and development of TV-1106 has been discontinued.

[0014] Somapacitan (NNC0195-0092) has been studied in a dose range study of children with growth hormone deficiency. This trial compared three doses of somapacitan (0.04, 0.08, or 0.16 mg / kg / week) with daily growth hormone (somatropin) at a dose of 0.24 mg / kg / week. Compared to daily growth hormone, the 0.08 mg / kg / week and 0.16 mg / kg / week doses showed no significant difference in annualized height rate, while the lower doses were less effective. The mean annualized height rates at the three dose levels of somapacitan were 8.0 cm, 10.9 cm, and 12.9 cm, respectively, with the two highest doses equivalent to 11.4 cm of daily growth hormone.

[0015] Among long-acting growth hormones in clinical development, none have shown superior efficacy compared to equimolar doses of daily growth hormone (somatropin). Furthermore, several failed to demonstrate efficacy comparable to daily growth hormone in phase 3 clinical trials.

[0016] Furthermore, growth hormone therapy faces the challenge of a certain proportion of non-responders—those who do not respond to the significantly increased AHV compared to patients not receiving growth hormone therapy. This is unsatisfactory for patients. Therefore, it is necessary to reduce the number of non-responders.

[0017] In summary, despite numerous attempts, a long-acting growth hormone that demonstrates superior efficacy compared to daily growth hormone has yet to be developed. There is a need for a long-acting growth hormone that is more effective than daily growth hormone and increases the percentage of responders, which could help patients requiring growth hormone therapy achieve optimal therapeutic results.

[0018] Therefore, one object of the present invention is to overcome at least part of the above-mentioned disadvantages.

[0019] The objective is achieved by long-acting growth hormone or a pharmaceutical preparation containing said long-acting growth hormone, wherein administration of said long-acting growth hormone or pharmaceutical preparation to patients with growth hormone deficiency produces superior efficacy compared to administration of an equimolar amount of daily growth hormone (somatropin).

[0020] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical composition comprising said long-acting growth hormone, which is used in a method for treating growth hormone deficiency and has excellent efficacy.

[0021] In another aspect, the present invention relates to a method for treating a patient with growth hormone deficiency, the method comprising the step of administering to the patient an effective amount of long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone, wherein the treatment produces excellent efficacy.

[0022] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical preparation comprising said long-acting growth hormone, wherein said long-acting growth hormone or pharmaceutical preparation comprises a dose of 0.24 mg / kg / week of growth hormone or a growth hormone equivalent, and that administration of said long-acting growth hormone preparation to patients with growth hormone deficiency produces superior efficacy compared to administration of a daily dose of 0.24 mg / kg / week of somatotropin.

[0023] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical formulation comprising said long-acting growth hormone for a treatment method, wherein said long-acting growth hormone or pharmaceutical formulation is administered at a dose of 0.24 mg / kg / week of growth hormone or a growth hormone equivalent, and administration of the long-acting growth hormone pharmaceutical composition comprising said long-acting growth hormone produces superior efficacy compared to administration of a daily dose of 0.24 mg / kg / week of growth hormone.

[0024] In another aspect, the present invention relates to a method for treating a patient with growth hormone deficiency, the method comprising the step of administering a dose of 0.24 mg / kg / week of growth hormone or a growth hormone equivalent of long-acting growth hormone or a pharmaceutical preparation containing said long-acting growth hormone, wherein such treatment produces superior efficacy compared to administering a daily dose of 0.24 mg / kg / week of growth hormone.

[0025] It should be understood that the phrase "daily dose of growth hormone (somatropin) of 0.24 mg / kg / week" refers to the cumulative daily dose of growth hormone after 1 week of administration, which is 0.24 mg / kg. That is, the daily dose of growth hormone is (0.24 mg / kg / week) / (7 days / week) = 0.343 mg / day (rounded).

[0026] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical preparation containing the long-acting growth hormone for treating growth hormone deficiency, wherein the treatment increases the standard deviation fraction (SDS) of plasma IGF-1 levels by at least 0.2 higher than the equivalent daily dose of hGH.

[0027] In another aspect, the present invention relates to a method for treating growth hormone deficiency, the method comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone to a patient in need, wherein the treatment of the growth hormone deficiency increases plasma IGF-1 levels by at least 0.2 times the equivalent daily dose of hGH by an SDS.

[0028] It should be understood that SDS can be calculated at the level of a patient population, or it can be calculated for an individual patient by comparing the patient's data with data from a corresponding patient population available in the literature. In some embodiments, the increase is at least 0.25 SDS. In some embodiments, the increase is at least 0.3 SDS. In some embodiments, the increase is at least 0.35 SDS. In some embodiments, the increase is at least 0.4 SDS.

[0029] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical preparation containing the long-acting growth hormone, in a method for reducing the percentage of non-responsive individuals in a patient population suffering from growth hormone deficiency.

[0030] In another aspect, the present invention relates to a method for reducing the percentage of non-responders in a patient population suffering from growth hormone deficiency, the method comprising the step of administering an effective amount of the long-acting growth hormone of the present invention or a pharmaceutical preparation containing the long-acting growth hormone to patients in the patient population.

[0031] In some embodiments, the percentage of non-responders is reduced to less than 10%. In some embodiments, the percentage of non-responders is reduced to less than 9%. In some embodiments, the percentage of non-responders is reduced to less than 8%. In some embodiments, the percentage of non-responders is reduced to less than 7%. In some embodiments, the percentage of non-responders is reduced to less than 6%. In some embodiments, the percentage of non-responders is reduced to less than 5%. In some embodiments, the percentage of non-responders is reduced to less than 4%.

[0032] In another embodiment, the present invention relates to a long-acting growth hormone or a pharmaceutical composition comprising said long-acting growth hormone, used in a method of treating a non-responder to growth hormone therapy. In other words, the present invention relates to a long-acting growth hormone or a pharmaceutical composition comprising said long-acting growth hormone for treating a patient with growth hormone deficiency, wherein the patient is a non-responder. In some embodiments, the non-responder has previously been treated with daily growth hormone.

[0033] In another aspect, the present invention relates to a method for treating growth hormone deficiency in non-responders, the method comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition comprising the long-acting growth hormone to a patient in need. In some embodiments, the patient is a patient previously treated with daily growth hormone.

[0034] In another aspect, the present invention relates to a long-acting growth hormone or a pharmaceutical preparation containing the long-acting growth hormone, used in a method for increasing the percentage of responders in a patient population suffering from growth hormone deficiency.

[0035] In another aspect, the present invention relates to a method for increasing the percentage of responders in a patient population suffering from growth hormone deficiency, the method comprising the step of administering an effective amount of long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone to patients in the patient population.

[0036] In some embodiments, the percentage of respondents is increased to at least 90%. In some embodiments, the percentage of respondents is increased to at least 91%. In some embodiments, the percentage of respondents is increased to at least 92%. In some embodiments, the percentage of respondents is increased to at least 93%. In some embodiments, the percentage of non-responders is increased to at least 94%. In some embodiments, the percentage of non-responders is increased to at least 95%. In some embodiments, the percentage of non-responders is increased to at least 96%.

[0037] Surprisingly, it was found that equimolar administration of long-acting growth hormone provided a superior annual height rate (AHV) compared to daily growth hormone (somatropin).

[0038] Surprisingly, it was found that long-acting growth hormones that provide continuous PK exposure during dosing frequency are associated with superior AHV.

[0039] It is hypothesized that the PK properties of hGH released from TransCon hGH may lead to increased involvement of growth hormone receptors in target tissues, resulting in higher AHV and IGF-1 levels compared to the same dose of daily hGH.

[0040] Compared to intermittent exposure following daily hGH administration, the superior AHV delivery pattern of hGH to peripheral tissues following sustained release of hGH from long-acting growth hormone can explain this.

[0041] The pharmacokinetic effects of intermittent versus continuous hGH exposure in target tissues have been investigated in healthy adults, with hGH delivered via continuous infusion or pulsatile administration. Compared to pulsatile GH exposure, human growth hormone infusion was approximately twice as effective in increasing plasma IGF-I concentrations and IGF-I mRNA in muscle (Surya et al., J Clin Endocrinol Metab 94: 2828–2834, 2009). These data are supported by studies in adults with growth hormone deficiency, where continuous GH infusion was associated with significantly higher IGF-1 levels compared to equivalent daily bolus doses (Jorgensen et al., The Journal of Clinical Endocrinology & Metabolism, Volume 70, Issue 6, 1 June 1990, P1616–1623; Laursen et al., J Clin Endocrinol Metab, 86:1222–1228, 2001). However, no difference in clinical outcomes was observed in this study.

[0042] The administration of long-acting growth hormone with PK properties that provide sustained exposure over the course of dosing has surprisingly been associated with superior AHV. Previously, Nutropin Depot, a long-acting growth hormone based on PLGA encapsulation, failed to demonstrate superior therapeutic effects in children with GHD. In fact, daily growth hormone therapy achieved higher growth rates than Nutropin Depot compared to historical controls. Furthermore, when patients receiving daily growth hormone therapy switched to Nutropin Depot, their growth rates declined by a greater margin than could be explained by the normal decline experienced by patients continuing daily growth hormone therapy. The PK properties of Nutropin Depot may not have been optimized, as approximately 50–60% of GH exposure occurs in the first 2 days, while growth hormone levels return to baseline before the next injection (J Clin Endocrinol Metab, October 2001, 86(10):4700–4706; J Clin Endocrinol Metab, July 2004, 89(7):3234–3240).

[0043] Surprisingly, it was also found that equimolar administration of long-acting growth hormone provided a reduced rate of nonresponders compared to daily somatotropin.

[0044] In this invention, the terms used have the following meanings: As used herein, the term "human growth hormone (hGH)" refers to all hGH polypeptides, preferably derived from mammalian species, more preferably from humans and mammalian species, even more preferably from humans and rodent species, as well as their variants, analogs, orthologs, homologs and their derivatives and fragments, characterized by promoting growth during the growth phase and maintaining normal body composition, anabolism and lipid metabolism. Preferably, the term "hGH" refers to the hGH polypeptide of SEQ ID NO:1 and its variants, homologs and derivatives, which exhibit substantially the same biological activity, namely, promoting growth during the growth phase and maintaining normal body composition, anabolism and lipid metabolism. More preferably, the term "hGH" refers to the polypeptide of SEQ ID NO:1.

[0045] SEQ ID NO:1 has the following sequence: FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF As used herein, the term "somatropin" refers to a polypeptide having the sequence SEQ ID NO:1.

[0046] As used herein, the term "hGH peptide variant" refers to a peptide from the same species that is different from a reference hGH peptide. Preferably, the reference hGH peptide sequence is the sequence of SEQ ID NO:1. Generally, the differences are limited, and thus the amino acid sequences of the reference and variant are very similar overall and identical in many regions. Preferably, the hGH peptide variant is at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the reference hGH peptide (preferably the hGH peptide of SEQ ID NO:1). For a peptide having an amino acid sequence that is at least, for example, 95% "identical" to the query amino acid sequence, it means that the amino acid sequence of the subject peptide is identical to the query sequence, except that the subject peptide sequence may contain up to five amino acid changes per 100 amino acids of the query amino acid sequence. These changes to the reference sequence may occur at the amino-terminal (N-terminus) or carboxyl-terminal (C-terminus) position of the reference amino acid sequence, or at any position between these terminal positions; individually scattered between residues in the reference sequence, or scattered in one or more consecutive groups within the reference sequence. The query sequence can be the complete amino acid sequence of a reference sequence, or any fragment as specified herein. Preferably, the query sequence is the sequence of SEQ ID NO:1.

[0047] The hGH peptide variant can be a naturally occurring variant, such as a naturally occurring allelic variant encoding one of several alternative forms of hGH occupying a given locus on a chromosome or organism, or an isotype encoded by a naturally occurring splice variant derived from a single primary transcript. Alternatively, the hGH peptide variant can be an unknown naturally occurring variant that can be produced by mutagenesis techniques known in the art.

[0048] It is known in the art that one or more amino acids can be deleted from the N-terminus or C-terminus of a bioactive peptide or protein without significant loss of biological function.

[0049] Those skilled in the art will also recognize that some amino acid sequences of hGH peptides can be altered without significantly affecting the protein's structure or function. Such mutants include deletions, insertions, inversions, duplications, and substitutions that have little effect on activity, selected according to general rules known in the art. For example, Bowie et al., (1990), Science 247:1306-1310, provide guidance on how to perform phenotypic silencing amino acid substitutions, which is incorporated herein by reference in its entirety, in which the authors note two main approaches for investigating the tolerance of amino acid sequences to alterations.

[0050] The term hGH polypeptide also includes all hGH polypeptides encoded by hGH analogs, orthologs, and / or species homologs. As used herein, the term "hGH analog" refers to hGHs from different and unrelated organisms that perform the same function in each organism but are not derived from an ancestral structure shared by the organism's ancestors. Instead, similar hGHs arise separately and then evolve to perform the same or similar functions. In other words, similar hGH polypeptides are polypeptides with completely different amino acid sequences but the same biological activities, namely promoting growth during the growth phase and maintaining normal body composition, anabolism, and lipid metabolism.

[0051] As used in this article, the term "hGH orthologs" refers to hGHs in two different species whose sequences are related to each other through common homologous hGHs in their ancestral species, but have evolved to be different from each other.

[0052] As used herein, the term "hGH homolog" refers to hGH from different organisms that perform the same function in each organism and originate from an ancestral structure shared by the organism's ancestors. In other words, homologous hGH peptides are peptides with very similar amino acid sequences that possess the same biological activities, namely promoting growth during the growth phase and maintaining normal body composition, anabolism, and lipid metabolism. Preferably, an hGH peptide homolog can be defined as a peptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity with a reference hGH peptide (preferably the hGH peptide of SEQ ID NO: 1).

[0053] Therefore, the hGH polypeptide according to the invention can be, for example: (i) a polypeptide in which at least one amino acid residue is substituted by a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, and such substituted amino acid residue may or may not be a residue encoded by the genetic code; and / or (ii) a polypeptide in which at least one amino acid residue includes a substituent; and / or (iii) a polypeptide in which the hGH polypeptide is fused with another compound (such as a compound that increases the half-life of the polypeptide (e.g., polyethylene glycol)); and / or (iv) a polypeptide in which additional amino acids are fused with the hGH polypeptide, such as an IgG Fc fusion region peptide or a leader sequence or secretion sequence, or a sequence for purifying the polypeptide or precursor-protein sequence of the above forms.

[0054] The hGH polypeptide can be a monomer or a polymer. The polymer can be a dimer, trimer, tetramer, or multimer comprising at least five monomeric polypeptide units. The polymer can also be a homodimer or a heterodimer. The polymer of the present invention can be the result of hydrophobic, hydrophilic, ionic, and / or covalent bonding and / or can be indirectly linked through, for example, liposome formation. Preferably, the hGH polypeptide is a monomer.

[0055] As used herein, the term "hGH polypeptide fragment" refers to any peptide or polypeptide that contains a continuous span of an amino acid sequence of an hGH polypeptide (preferably the polypeptide of SEQ ID NO:1).

[0056] More specifically, the hGH polypeptide fragment comprises at least 6, preferably at least 8 or 10, and more preferably at least 12, 15, 20, 25, 30, 35, 40, 50, 60, 75, 100, 125, 150, 175, or 191 consecutive amino acids of the hGH polypeptide (more preferably the polypeptide of SEQ ID NO: 1). The hGH polypeptide fragment can also be described as a subgenus of the hGH polypeptide comprising at least 6 amino acids, wherein “at least 6” is defined as any integer between 6 and an integer representing the C-terminal amino acid of the hGH polypeptide (preferably the polypeptide of SEQ ID NO: 1). Further included are types of hGH polypeptide fragments with a length of at least 6 amino acids, as described above, further specified according to their N-terminal and C-terminal positions. The term “hGH polypeptide fragment” as a single type also includes all hGH polypeptide fragments with a length of at least 6 amino acids, as described above, which may be specifically specified by their N-terminal and C-terminal positions. That is, each combination of N-terminal and C-terminal positions that can be occupied by a fragment of at least 6 consecutive amino acid residues on any given amino acid sequence of the hGH polypeptide (preferably the hGH polypeptide of SEQ ID NO:1) is included in the present invention.

[0057] It should be noted that the above-mentioned types of polypeptide fragments can be alternatively described by formulas "a to b"; wherein "a" is equal to the N-terminal amino acid position in the polynucleotide, and "b" is equal to the C-terminal amino acid position in the polynucleotide; and further wherein "a" is equal to an integer between 1 and the number of amino acids in the hGH polypeptide sequence minus 6, and wherein "b" is equal to an integer between 7 and the number of amino acids in the hGH polypeptide sequence; wherein "a" is an integer at least 6 smaller than "b", preferably the hGH polypeptide sequence of SEQ ID NO:1.

[0058] As used herein, the term "long-acting growth hormone" or "long-acting growth hormone compound" refers to a compound comprising crystalline hGH or wherein hGH is embedded, fused, or conjugated to at least one other chemical compound or portion (e.g., a polymer or fatty acid-derived portion), and having an increased retention time in the body compared to unmodified hGH. Retention time is the time between two consecutive administrations in which the concentration of unmodified hGH (such as the hGH of SEQ ID NO:1 or SEQ ID NO:2) in plasma is at a therapeutically effective concentration. In some embodiments, this therapeutically effective level is a concentration of at least 2 ng hGH / ml plasma. For hGH, the retention time is approximately 12 hours. In some embodiments, the retention time of long-acting growth hormone is at least 24 hours. In some embodiments, the retention time of long-acting growth hormone is at least 36 hours. In some embodiments, the retention time of long-acting growth hormone is at least 48 hours. In some embodiments, the retention time of long-acting growth hormone is at least 72 hours.

[0059] It should be understood that the time between two consecutive administrations of long-acting growth hormone is also increased compared to standard hGH treatment administered once daily. In some embodiments, the time between two consecutive administrations is at least 2 days. In some embodiments, the time between two consecutive administrations is at least 3 days. In some embodiments, the time between two consecutive administrations is at least 4 days. In some embodiments, the time between two consecutive administrations is at least 5 days. In some embodiments, the time between two consecutive administrations is at least 6 days. In some embodiments, the time between two consecutive administrations is 1 week. In some embodiments, the time between two consecutive administrations is 2 weeks. In some embodiments, the time between two consecutive administrations is 4 weeks.

[0060] In some embodiments, the dosage is at least 0.16 mg / kg / week per administration. In some embodiments, the dosage range is from 0.16 mg / kg / week to 0.4 mg / kg / week, such as from 0.24 mg / kg / week to 0.3 mg / kg / week. In some embodiments, the dosage is 0.24 mg / kg / week. In some embodiments, the dosage is 0.3 mg / kg / week.

[0061] In some implementations, a therapeutically effective concentration is achieved within at least 50% of the dosing interval, i.e., within at least 50% of the time period between two consecutive administrations of long-acting growth hormone.

[0062] As used herein, the term "medicine" means a substance intended to treat, cure, prevent, or diagnose a disease or to otherwise enhance the physical or mental health of a patient. If a medicine is conjugated to another part, the portion of the resulting product derived from said medicine is referred to as the "medicine portion" or "bioactive portion".

[0063] As used herein, the term "prodrug" refers to a bioactive portion of a parent molecule that is reversibly and covalently linked to a specific protecting group via a reversible prodrug linker portion to alter or eliminate undesirable properties. This also includes enhancing desirable properties of the drug and inhibiting undesirable properties. The specific, non-toxic protecting group is referred to as a "carrier." The prodrug releases the reversibly and covalently bound bioactive portion in the form of its corresponding drug.

[0064] As used herein, the terms "growth hormone equivalent" and "hGH equivalent" refer to the total mass of hGH or the hGH moiety contained in a long-acting growth hormone compound. In other words, if the long-acting growth hormone compound is, for example, a prodrug (in which the hGH moiety is reversibly conjugated to a polymer), the term "growth hormone equivalent" refers to the total mass of the hGH moiety, not the total mass of the hGH prodrug. If the long-acting growth hormone compound is, for example, a fusion protein (in which the hGH moiety is fused to a natural or non-natural amino acid sequence), the term "growth hormone equivalent" refers to the total mass of the hGH moiety, not the total mass of the fusion protein.

[0065] As used in this article, the term "equimolar" refers to having the same number of moles.

[0066] The terms “formulation,” “pharmaceutical formulation,” “composition,” and “pharmaceutical composition” are used synonymously to refer to a combination of one or more long-acting hGH and one or more excipients, as well as any product that is directly or indirectly derived from any combination, complexation, or aggregation of any two or more components of the composition, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. In some embodiments, the terms “formulation,” “pharmaceutical formulation,” “composition,” and “pharmaceutical composition” refer to at least one long-acting hGH and at least one excipient.

[0067] As used herein, the term "liquid formulation" refers to a formulation comprising a long-acting hGH and at least one solvent. The preferred solvent is water.

[0068] As used herein, the term "dry formulation" refers to a long-acting growth hormone provided in dry form. Suitable drying methods include spray drying and lyophilization (also known as freeze-drying). The residual moisture content of such a dry formulation is at most 10%, preferably less than 5%, more preferably less than 2%, as determined by the Karl Fischer method. The preferred drying method is lyophilization. "Lyophilized formulation" refers to a formulation that is first lyophilized and then dehydrated by reduced pressure. This term does not exclude additional drying steps that may occur during the manufacturing process before the formulation is filled into its final container.

[0069] As used herein, the term "reconstituted formulation" refers to the result of adding a solvent, also known as a "reconstituted solution," to a dry formulation. Preferably, the amount of solvent is such that the dry formulation is completely dissolved in the resulting reconstituted formulation.

[0070] As used herein, the term "superior" refers to a statistically significantly better treatment outcome, such as for AHV. In some implementations, "statistically significantly better" is defined as a p-value less than 0.05, such as a p-value less than 0.01, using a suitable statistical model. In some implementations, this statistical model is an analysis of variance (ANOVA). In some implementations, this statistical model is an analysis of covariance (ANCOVA).

[0071] As used herein, the term “unit dose” refers to the amount of drug (especially long-acting growth hormone preparations) that constitutes a single dose, i.e., the amount of drug (especially long-acting growth hormone preparations) corresponding to a single administration.

[0072] As used herein, the term "unit dosage form" refers to the presentation of a unit dose, that is, any application device containing a unit dose of drug (particularly long-acting growth hormone preparations). Preferred application devices are selected from the following: needle injectors, injection pens, auto-injector pens, needle-free injectors, electro-injectors, and dual-chamber cartridges.

[0073] As used in this article, the term "efficacy" refers to efficacy in young children (na) (ve) The annualized rate of height increase and the percentage of responders among children who received growth hormone.

[0074] As used in this article, "pharmaceutical effective dose" refers to the amount of growth hormone or growth hormone equivalent sufficient to treat growth hormone deficiency.

[0075] As used in this article, the term “responder” refers to a growth hormone deficiency patient who receives growth hormone treatment and has an annualized height rate greater than 8.0 cm / year.

[0076] As used herein, the term "non-responder" refers to a growth hormone-deficient patient who receives growth hormone therapy and has an annualized height rate of less than 8.0 cm / year. It should be understood that the growth hormone therapy is a standard therapy with human growth hormone, such as daily administration of the human growth hormone of SEQ ID NO:1, in some embodiments, at a dose ranging from 0.17 mg / kg / week to 0.30 mg / kg / week. Exemplary doses are 0.24 mg / kg / week and 0.3 mg / kg / week of hGH of SEQ ID NO:1.

[0077] As used in this article, the term “annualized height rate” or “annual height rate” (“AHV”) is defined as the difference in height between the start of treatment and approximately 12 months after treatment.

[0078] As used herein, the term “about” in conjunction with a numerical value is used to indicate a range from and including a numerical value plus or minus no more than 10%, more preferably no more than 8%, even more preferably no more than 5%, and most preferably no more than 2%. For example, the phrase “about 20%” is used to indicate a range from and including 20% ​​+ / - 10%, preferably 20% + / - 8%, even more preferably 20% + / - 5%, and most preferably 20% + / - 2%.

[0079] As used herein, the term "excipient" refers to a diluent, adjuvant, or carrier that is administered together with a therapeutic agent.

[0080] As used herein, the term "hydrogel" refers to a network of hydrophilic or amphiphilic polymers composed of homopolymers or copolymers that is insoluble due to the presence of covalent chemical crosslinking. Crosslinking provides the network structure and physical integrity. Hydrogels exhibit thermodynamic compatibility with water, which allows them to swell in aqueous media.

[0081] As used herein, the term "functional group" refers to a group of atoms that can react with other functional groups. Functional groups include, but are not limited to, the following groups: carboxylic acid group (–(C=O)OH), primary or secondary amine group (–NH2, –NH–), maleimide group, mercapto group (–SH), sulfonic acid group (–(O=S=O)OH), carbonate group, carbamate group (–O(C=O)N<), hydroxyl group (–OH), aldehyde group (–(C=O)H), ketone group (–(C=O)–), hydrazine group (>NN<), isocyanate group, isothiocyanate group, phosphate group (–O(P=O)OHOH), phosphonate group (–O(P=O)OHH), haloacetyl group, haloalkyl group, acryloyl group, aryl fluorine group, hydroxylamine group, disulfide group, vinyl sulfone, vinyl ketone, diazonyl group, ethylene oxide group, and aziridinyl group.

[0082] As used herein, the term "part" refers to a portion of a molecule that lacks at least one atom compared to the corresponding reagent. For example, if a reagent of formula "HXH" reacts with another reagent and becomes part of the reaction product, the corresponding part of the reaction product has the structure "H–X–" or "–X–", where each "–" indicates a connection to another part. Thus, the bioactive part is released as a drug from the prodrug.

[0083] It should be understood that if a sequence or chemical structure of a radical is provided, wherein the radical is connected to two parts or interrupts one part, the sequence or chemical structure may be connected to the two parts in either direction, unless otherwise expressly stated. For example, the part "-C(O)N(R)-" may be connected to two parts or interrupt one part as "-C(O)N(R)-" or as "-N(R)C(O)-". Similarly, the part... It can connect two parts or it can discontinuate one part as Or as In cases where the long-acting growth hormone contains one or more acidic or basic groups, the present invention also contains their respective pharmaceutically or toxicologically acceptable salts, particularly pharmaceutically available salts. Therefore, long-acting growth hormones containing acidic groups according to the present invention can be used, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include: sodium salts, potassium salts, calcium salts, magnesium salts, or salts containing ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, or amino acids). Long-acting growth hormones containing one or more basic groups, i.e., protonable groups, can exist and can be used according to the present invention in the form of addition salts with inorganic or organic acids. Examples of suitable acids include: hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Other methods for converting basic groups into cations are known to those skilled in the art, such as alkylation of amines to produce positively charged ammonium groups and suitable counterions of the salt. If the long-acting growth hormone contains both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaine (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of long-acting growth hormone, which are not directly applicable to pharmaceuticals due to their low physiological compatibility, but can be used as intermediates, for example, in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0084] The term "pharmaceutical acceptable" means approved for use in animals, preferably in humans, by regulatory authorities such as the EMA (Europe) and / or FDA (USA) and / or any other national regulatory authority.

[0085] As used herein, the terms “reversible,” “reversibly,” “degradable,” or “degradable” relating to the connection between the first and second parts mean that the connection between the first and second parts is cleavable under physiological conditions, namely an aqueous buffer solution at pH 7.4 and 37°C, with a half-life ranging from one day to one month, such as from two days to three weeks, or from three days to two weeks. Therefore, the term “stable” relating to the connection between the first and second parts means that the connection between the first and second parts exhibits a half-life exceeding one month under physiological conditions.

[0086] As used herein, the term "water insoluble" means that less than 1 g of a compound can be dissolved in 1 liter of water at 20°C to form a homogeneous solution. Therefore, the term "water soluble" means that 1 g or more of a compound can be dissolved in 1 liter of water at 20°C to form a homogeneous solution.

[0087] As used herein, the term "polymer" refers to a molecule comprising repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked, or dendritic manner, or a combination thereof, and may be synthetic, biologically derived, or a combination of both. It should be understood that polymers may also contain one or more other chemical groups and / or one or more moieties, such as one or more functional groups. Preferably, soluble polymers have a molecular weight of at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, it preferably has a molecular weight of up to 1000 kDa, such as up to 750 kDa, up to 500 kDa, up to 300 kDa, up to 200 kDa, or up to 100 kDa. It should be understood that for insoluble polymers, such as cross-linked hydrogels, a meaningful molecular weight range cannot be provided.

[0088] As used herein, the term “polymeric” refers to a reagent or portion containing one or more polymers.

[0089] Those skilled in the art will understand that the polymer products obtained from polymerization reactions do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, the molecular weight range, molecular weight, range of monomer quantities in a polymer, and number of monomers in a polymer used herein refer to the number-average molecular weight and average number of monomers. As used herein, the term "number-average molecular weight" refers to the ordinary arithmetic mean of the molecular weights of individual polymers.

[0090] As used herein, the term "PEG group containing at least X% PEG" in relation to a portion or reagent means that the portion or reagent contains at least X% (w / w) ethylene glycol units (–CH2CH2O–), wherein the ethylene glycol units may be block-arranged, alternately arranged, or randomly distributed in the portion or reagent, preferably, all ethylene glycol units of the portion or reagent are present in one block; the remaining weight percentage of the PEG-based portion or reagent is preferably selected from the following portions and other portions of the linking group: C 1-50 Alkyl, C 2-50 alkenyl, C 2-50 alkynyl group, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indenyl, and tetrahydronaphthyl; and • The linking group is selected from the following: in Dashed lines indicate connections to the rest of the part or reagent, and R and R a They are selected independently from: H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0091] As used herein, the term “substituted” refers to the substitution of one or more -H atoms in a molecule or part by a different atom or group of atoms, which is called a “substituent”.

[0092] Preferably, one or more additional optional substituents are independently selected from the following: halogen, -CN, -COOR. x1 -OR x1 -C(O)R x1 -C(O)N(R) x1 R x1a -S(O)2N(R) x1 R x1a ), -S(O)N(R x1 R x1a -S(O)2R x1 -S(O)R x1 -N(R) x1 )S(O)2N(R x1a R x1b ), -SR x1 -N(R) x1 R x1a -NO2, -OC(O)R x1 -N(R) x1 )C(O)R x1a -N(R) x1 )S(O)2R x1a -N(R) x1 )S(O)R x1a -N(R) x1 )C(O)OR x1a -N(R) x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. x2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the following: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 (R) x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; R x1 R x1a R x1b Each can be selected independently from the following: -H, -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T 0 C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. x2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more groups selected from the following: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 (R) x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(Rx3 )-; Each T 0 Independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic and 8- to 11-membered heterobicyclic; wherein each T 0 Independently and arbitrarily selected by one or more identical or different R x2 replace; Each R x2 Independently selected from the following: halogen, -CN, oxo (=O), -COOR x4 -OR x4 -C(O)R x4 -C(O)N(R) x4 R x4a -S(O)2N(R) x4 R x4a ), -S(O)N(R x4 R x4a -S(O)2R x4 -S(O)R x4 -N(R) x4 )S(O)2N(R x4a R x4b ), -SR x4 -N(R) x4 R x4a -NO2, -OC(O)R x4 -N(R) x4 )C(O)R x4a -N(R) x4 )S(O)2R x4a -N(R) x4 )S(O)R x4a -N(R) x4 )C(O)OR x4a -N(R) x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R x3 R x3a R x4 R x4a R x4b Independently selected from the following: -H and C 1-6 Alkyl; wherein C 1-6The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0093] More preferably, one or more additional optional substituents are independently selected from the following: halogen, -CN, -COOR. x1 -OR x1 -C(O)R x1 -C(O)N(R) x1 R x1a -S(O)2N(R) x1 R x1a ), -S(O)N(R x1 R x1a -S(O)2R x1 -S(O)R x1 -N(R) x1 )S(O)2N(R x1a R x1b ), -SR x1 -N(R) x1 R x1a -NO2, -OC(O)R x1 -N(R) x1 )C(O)R x1a -N(R) x1 )S(O)2R x1a -N(R) x1 )S(O)R x1a -N(R) x1 )C(O)OR x1a -N(R) x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a -T 0 C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne group; wherein -T 0 C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally surrounded by one or more identical or different R groups. x2 Replace, and where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more groups selected from the following: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(Rx3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 (R) x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; Each R x1 R x1a R x1b R x3 R x3a Independently selected from the following: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; Each T 0 Independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic and 8- to 11-membered heterobicyclic; wherein each T 0 Independently and arbitrarily selected by one or more identical or different R x2 replace; Each R x2 Independently selected from the following: halogen, -CN, oxo (=O), -COOR x4 -OR x4 -C(O)R x4 -C(O)N(R) x4 R x4a -S(O)2N(R) x4 R x4a ), -S(O)N(R x4 R x4a -S(O)2R x4 -S(O)R x4 -N(R) x4 )S(O)2N(R x4a R x4b ), -SR x4 -N(R) x4 R x4a -NO2, -OC(O)R x4 -N(R) x4 )C(O)R x4a -N(R) x4 )S(O)2R x4a -N(R) x4 )S(O)R x4a-N(R) x4 )C(O)OR x4a -N(R) x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R x4 R x4a R x4b Independently selected from the following: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; Even more preferably, one or more additional optional substituents are independently selected from the following: halogen, -CN, -COOR. x1 -OR x1 -C(O)R x1 -C(O)N(R) x1 R x1a -S(O)2N(R) x1 R x1a ), -S(O)N(R x1 R x1a -S(O)2R x1 -S(O)R x1 -N(R) x1 )S(O)2N(R x1a R x1b ), -SR x1 -N(R) x1 R x1a -NO2, -OC(O)R x1 -N(R) x1 )C(O)R x1a -N(R) x1 )S(O)2R x1a -N(R) x1 )S(O)R x1a -N(R) x1 )C(O)OR x1a -N(R) x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a -T 0 C 1-6 Alkyl, C 2-6alkenyl and C 2-6 Alkyne group; wherein -T 0 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more identical or different R groups. x2 Replace, and where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally interrupted by one or more groups selected from the following: -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-、-S(O)2N(R x3 )-、-S(O)N(R x3 -, -S(O)2-, -S(O)-, -N(R) x3 )S(O)2N(R x3a )-、-S-、-N(R x3 )-、-OC(OR x3 (R) x3a )-、-N(R x3 )C(O)N(R x3a )-and-OC(O)N(R x3 )-; Each R x1 R x1a R x1b R x2 R x3 R x3a Independently selected from the following: -H, halogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; Each T 0 Independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic and 8- to 11-membered heterobicyclic; wherein each T 0 Independently and arbitrarily selected by one or more identical or different R x2 replace.

[0094] Preferably, up to 6 -H atoms of the optionally substituted molecule or part are independently substituted by a substituent, for example, 5 -H atoms are independently substituted by a substituent, 4 -H atoms are independently substituted by a substituent, 3 -H atoms are independently substituted by a substituent, 2 -H atoms are independently substituted by a substituent, or 1 -H atom is substituted by a substituent.

[0095] As used herein, the term "spacer base" preferably refers to a subset selected from the following: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z1 )-、-S(O)2N(R z1 )-、-S(O)N(R z1 -, -S(O)2-, -S(O)-, -N(R) z1 )S(O)2N(R z1a )-、-S-、-N(R z1 )-、-OC(OR z1 (R) z1a )-、-N(R z1 )C(O)N(R z1a )-、-OC(O)N(R z1 )-、C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O, -O-, -C(O)-, -C(O)N(R) z3 )-、-S(O)2N(R z3 )-、-S(O)N(R z3 -, -S(O)2-, -S(O)-, -N(R) z3 )S(O)2N(R z3a )-、-S-、-N(R z3 )-、-OC(OR z3 (R) z3a )-、-N(R z3 )C(O)N(R z3a )-and-OC(O)N(R z3 )-; R z1 and R z1a Each of the following can be selected independently: -H, -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-、-S(O)2N(R z4 )-、-S(O)N(R z4 -, -S(O)2-, -S(O)-, -N(R) z4 )S(O)2N(R z4a )-、-S-、-N(R z4 )-、-OC(OR z4 (R) z4a )-、-N(R z4 )C(O)N(R z4a )-and-OC(O)N(R z4 )-; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently optionally composed of one or more identical or different Rs. z2 replace; Each R z2 Independently selected from the following: halogen, -CN, oxo (=O), -COOR z5 -OR z5 -C(O)R z5 -C(O)N(R) z5 R z5a -S(O)2N(R) z5 R z5a ), -S(O)N(R z5 R z5a -S(O)2R z5 -S(O)R z5 -N(R) z5 )S(O)2N(R z5a R z5b ), -SR z5 -N(R) z5 R z5a -NO2, -OC(O)R z5 -N(R) z5 )C(O)R z5a -N(R) z5 )S(O)2R z5a -N(R) z5 )S(O)R z5a -N(R)z5 )C(O)OR z5a -N(R) z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R z3 R z3a R z4 R z4a R z5 R z5a and R z5b Each is independently selected from the following: -H and C 1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0096] More preferably, the term "spacer base" refers to a subset selected from the following: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z1 )-、-S(O)2N(R z1 )-、-S(O)N(R z1 -, -S(O)2-, -S(O)-, -N(R) z1 )S(O)2N(R z1a )-、-S-、-N(R z1 )-、-OC(OR z1 (R) z1a )-、-N(R z1 )C(O)N(R z1a )-、-OC(O)N(R z1 )-、C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-、-S(O)2N(R z3 )-、-S(O)N(R z3-, -S(O)2-, -S(O)-, -N(R) z3 )S(O)2N(R z3a )-、-S-、-N(R z3 )-、-OC(OR z3 (R) z3a )-、 -N(R z3 )C(O)N(R z3a )-and-OC(O)N(R z3 )-; R z1 and R z1a Each of the following can be selected independently: -H, -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-、-S(O)2N(R z4 )-、-S(O)N(R z4 -, -S(O)2-, -S(O)-, -N(R) z4 )S(O)2N(R z4a )-、-S-、-N(R z4 )-、-OC(OR z4 (R) z4a )-、-N(R z4 )C(O)N(R z4a )-and-OC(O)N(R z4 )-; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently optionally composed of one or more identical or different Rs. z2 replace; Each R z2 Independently selected from the following: halogen, -CN, oxo (=O), -COOR z5 -OR z5 -C(O)R z5-C(O)N(R) z5 R z5a -S(O)2N(R) z5 R z5a ), -S(O)N(R z5 R z5a -S(O)2R z5 -S(O)R z5 -N(R) z5 )S(O)2N(R z5a R z5b ), -SR z5 -N(R) z5 R z5a -NO2, -OC(O)R z5 -N(R) z5 )C(O)R z5a -N(R) z5 )S(O)2R z5a -N(R) z5 )S(O)R z5a -N(R) z5 )C(O)OR z5a -N(R) z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R z3 R z3a R z4 R z4a R z5 R z5a and R z5b Independently selected from the following: -H and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0097] Even more preferably, the term "spacer base" refers to a subset selected from the following: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z1 )-、-S(O)2N(R z1 )-、-S(O)N(R z1 -, -S(O)2-, -S(O)-, -N(R) z1 )S(O)2N(R z1a )-、-S-、-N(R z1)-、-OC(OR z1 (R) z1a )-、-N(R z1 )C(O)N(R z1a )-、-OC(O)N(R z1 )-、C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-20 Alkyl, C 2-20 alkenyl and C 2-20 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-、-S(O)2N(R z3 )-、-S(O)N(R z3 -, -S(O)2-, -S(O)-, -N(R) z3 )S(O)2N(R z3a )-、-S-、-N(R z3 )-、-OC(OR z3 (R) z3a )-、-N(R z3 )C(O)N(R z3a )-and-OC(O)N(R z3 )-; R z1 and R z1a Independently selected from the following: -H, -T, C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 alkynyl group; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; each R z2 Independently selected from the following: halogens and C 1-6 Alkyl; and Each R z3 R z3a R z4 R z4a R z5 R z5a and R z5b Selected independently from the following: -H and C1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0098] The term "discontinuous" refers to a group of atoms inserted into a portion between two carbon atoms, or, if the insertion is at one end of that portion, between a carbon and a hydrogen atom. It can be understood that if a portion is discontinuous by a group of atoms at one end, and if the discontinuous portion connects to a second portion, the discontinuous group of atoms can also be positioned such that it lies between the last atom of the portion and the first atom of the second portion.

[0099] As used herein, the term "C" used alone or in combination 1-4 "Alkyl" refers to a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of the molecule, the straight-chain or branched carbon atom... 1-4 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. When both parts of the molecule are composed of C... 1-4 When alkyl groups are connected, the C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4 Each hydrogen atom on the alkyl carbon may optionally be substituted with a substituent as defined above. Optionally, C 1-4 Alkyl groups can be discontinuous by one or more parts as defined below.

[0100] As used herein, the term "C" used alone or in combination 1-6 "Alkyl" refers to a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. If present at the molecule's end, both straight-chain and branched C atoms... 1-6 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. When both parts of the molecule are composed of C 1-6 When an alkyl group is attached, the C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-6 Each hydrogen atom of carbon can optionally be substituted with a substituent as defined above. Optionally, C 1-6 Alkyl groups can be discontinuous by one or more parts as defined below.

[0101] Therefore, "C"1-10 Alkyl", C 1-20 "alkyl" or "C" 1-50 "Alkyl" refers to an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively, wherein C 1-10 C 1-20 Or C 1-50 Each hydrogen atom of carbon can optionally be substituted with a substituent as defined above. Optionally, C 1-10 Alkyl or C 1-50 Alkyl groups can be discontinuous by one or more parts as defined below.

[0102] As used herein, the term "C" used alone or in combination 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 6 carbon atoms. Examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2 if present at the end of the molecule. 2-6 When an alkenyl group is attached, then the C 2-6 An example of an alkenyl group is -CH=CH-. C 2-6 Each hydrogen atom of the alkenyl moiety may optionally be substituted with a substituent as defined above. Optionally, C 2-6 The alkenyl group can be discontinuous by one or more parts as defined below.

[0103] Therefore, the term "C" used alone or in combination 2-10 "alkenyl", "C" 2-20 "Alkenyl" or "C" 2-50 "Alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon double bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms. 2-10 alkenyl, C 2-20 alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may optionally be substituted with a substituent as defined above. Optionally, C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 The alkenyl group can be discontinuous by one or more parts as defined below.

[0104] As used herein, the term "C" used alone or in combination 2-6 "Alynyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 6 carbon atoms. Examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3 if present at the end of the molecule. An example is -C≡C- when two moles of the molecule are linked by an alkynyl group. 2-6Each hydrogen atom of the alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may appear. Optionally, C 2-6 The alkynyl group can be discontinuous by one or more parts as defined below.

[0105] Therefore, as used herein, the term "C" used alone or in combination 2-10 "Alkyne", "C" 2-20 "Alkyne" and "C" 2-50 "Alkyne" refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 alkynyl group, C 2-20 alkynyl or C 2-50 Each hydrogen atom of the alkynyl group may optionally be substituted with a substituent as defined above. Optionally, one or more double bonds may appear. Optionally, C 2-10 alkynyl group, C 2-20 alkynyl or C 2-50 The alkynyl group can be discontinuous by one or more parts as defined below.

[0106] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 alkenyl, C 2-10 alkenyl, C 2-20 alkenyl, C 2-50 alkenyl, C 2-6 alkynyl group, C 2-10 alkynyl group, C 2-20 alkenyl or C 2-50 The alkynyl group may optionally be interrupted by one or more of the following: in Dashed lines indicate connections to the rest of the portion or reagent; and R and R a The following are selected independently from each other: H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0107] As used in this article, the term "C" 3-10 "Cycloalkyl" refers to a cyclic alkyl chain having 3 to 10 carbon atoms, which can be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon can be substituted with a substituent as defined above. The term "C" 3-10"Cycloalkyl" also includes bridged bicyclic compounds, such as norbornene or norbornene.

[0108] The term "8- to 30-membered carbon polycyclic group" or "8- to 30-membered carbon polycyclic group" refers to a cyclic portion having two or more rings with 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and may contain a maximum number of double bonds (fully, partially, or unsaturated aromatic or non-aromatic rings). Preferably, the 8- to 30-membered carbon polycyclic group refers to a bicyclic, tricyclic, tetracyclic, or pentacyclic group, more preferably a bicyclic, tricyclic, or tetracyclic group.

[0109] As used herein, the terms “3-to-10-membered heterocyclic group” or “3-to-10-membered heterocycle” refer to a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to a maximum number of double bonds (fully, partially, or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom to up to four ring atoms are substituted with heteroatoms selected from the following: sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), wherein the ring is connected to the remainder of the molecule by a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to: aziridine, ethylene oxide, thiapropylcyclohexane, acrylonitrile, ethylene oxide, thiapropylcyclohexane, aziridine, oxacyclohexane, oxacyclohexane, furan, thiophene, pyrrole, pyrrolidone, imidazole, imidazole, pyrazole, pyrazole, oxazolyl, isoxazolyl, isoxazolyl, thiazole, thiazoline, isothiazazole, isothiazolyl, thiazoline, thiazoline, thiadiazole, thiadizoline, tetrahydrofuran, tetrahydrothiophene, pyrrole, imidazole, pyrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoline, isothiazolyl, thiazoline, thiazoline, thiazoline, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazole, pyridine, pyrazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazolium, triazole, triazolyl, tetrazolyl, diaza, aza, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclic group may be substituted by a substituent as defined below.

[0110] As used herein, the term “8- to 11-membered heterobicyclic group” or “8- to 11-membered heterobicyclic” refers to a heterocyclic portion of two rings having 8 to 11 ring atoms, wherein at least one ring atom is shared by the two rings and may contain up to a maximum number of double bonds (fully, partially, or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom to up to six ring atoms are substituted with heteroatoms selected from the following: sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), wherein the rings are connected to the remainder of the molecule by a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicyclic rings are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoimidazolium, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzozaza, purine, and pteridine. The term 8- to 11-membered heterobicyclic also includes spirocyclic rings with two rings, such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocycles, such as 8-azabicyclic[3.2.1]octane. Each hydrogen atom of the 8- to 11-membered heterobicyclic group or the carbon atom of the 8- to 11-membered heterobicyclic ring can be substituted with a substituent as defined below.

[0111] Similarly, the terms "8- to 30-membered heteropolycyclic group" or "8- to 30-membered heteropolycyclic group" refer to a heterocyclic portion having more than two rings, preferably three, four or five rings, having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds (fully, partially or unsaturated aromatic or non-aromatic rings), wherein at least one ring atom and up to 10 ring atoms are substituted with heteroatoms selected from the following: sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-), wherein the rings are connected to the rest of the molecule by carbon or nitrogen atoms.

[0112] As used in this article, "halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine or chlorine is usually preferred as the halogen.

[0113] Generally speaking, the terms "comprise" or "comprising" also cover "consist of" or "consisting of".

[0114] According to the present invention, a long-acting growth hormone formulation is provided, wherein administration of the long-acting growth hormone formulation to a patient with growth hormone deficiency produces superior efficacy compared to administration of an equimolar dose of daily growth hormone.

[0115] In one embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using a syringe with a needle.

[0116] In another embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using an injection pen.

[0117] In another embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using an auto-injector pen.

[0118] In another embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using a needle-free injector.

[0119] In another embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using an electronic injector.

[0120] In another embodiment, the long-acting growth hormone or a pharmaceutical composition containing the long-acting growth hormone is administered using a dual-chamber cartridge, preferably a dual-chamber cartridge loaded into a pen-type device or an electro-injector.

[0121] In one embodiment, the long-acting growth hormone formulation or pharmaceutical composition comprising the long-acting growth hormone contains growth hormone embedded or encapsulated in a polymer or lipid-containing matrix or carrier. Preferred polymer matrices include polymers selected from: 2-methacryloyl-ethoxyphosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(acid anhydride), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethyl acrylate), poly(hydroxypropyl methacrylamide), poly(methyl methacrylate). Hydroxypropyl ester), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-glycolic acid copolymer), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitosan, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnose galacturonic acid, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and its copolymers.

[0122] Preferred polymers are selected from the following: PEG, polylactic-co-glycolic acid (PLGA), and hyaluronic acid. Most preferably, the polymer is PEG.

[0123] In one embodiment, the polymer matrix is ​​a hydrogel comprising polymers selected from: 2-methacryloyl-ethoxyphosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkoxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(acid anhydride), poly(asparagine), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethyl acrylate), poly(hydroxypropyl methacrylamide), poly(ethyl ...methyl methacrylamide), poly(hydroxyethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl methacrylamide), poly(hydroxymethyl Hydroxypropyl methacrylate, poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-glycolic acid copolymer), poly(methacrylamide), poly(methacrylate), poly(methyl oxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitosan, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnose galacturonic acid, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan and its copolymers.

[0124] Preferred hydrogels comprise polymers selected from PEG, polylactic-co-glycolic acid (PLGA), and hyaluronic acid. Most preferably, the hydrogel is a PEG-based hydrogel.

[0125] In another embodiment, the long-acting growth hormone formulation comprises crystalline growth hormone.

[0126] In another embodiment, the long-acting growth hormone comprises a growth hormone moiety fused with a natural or non-natural amino acid sequence. Preferred amino acid sequences are selected from the following: the C-terminal peptide of human chorionic gonadotropin as described in US2012 / 0035101 (which is incorporated herein by reference); albumin; the XTEN sequence described in WO2011123813A2 (which is incorporated herein by reference); the proline / alanine random coil sequence described in WO2011 / 144756A1 (which is incorporated herein by reference); the proline / alanine / serine random coil sequence described in WO2011 / 144756A1 (which is incorporated herein by reference); and Fc fusion proteins. This fusion can be stable or reversible.

[0127] In another embodiment, the long-acting growth hormone comprises a chemically modified growth hormone or an analogue thereof, including polyethylene glycol-modified hGH and hGH modified with a fatty acid derivative. Preferred fatty acid derivatives are those disclosed in WO2005 / 027978A2 and WO2014 / 060512A1, which are incorporated herein by reference. This chemical modification, in the form of a PEG or fatty acid derivative moiety, can be stably or reversibly linked to the hGH moiety. In some embodiments, the chemical modification is a PEG moiety stably linked to the hGH moiety. In some embodiments, the chemical modification is a PEG moiety reversibly linked to the hGH moiety. In some embodiments, the chemical modification is a fatty acid derivative moiety stably linked to the hGH moiety. In some embodiments, the chemical modification is a fatty acid derivative moiety reversibly linked to the hGH moiety.

[0128] In another embodiment, the long-acting growth hormone is an hGH prodrug, wherein the hGH moiety is reversibly conjugated to the polymerized moiety or the fatty acid-derived moiety. In some embodiments, the hGH moiety is released from the hGH prodrug in an unmodified form.

[0129] Preferably, the long-acting growth hormone is a polymeric hGH prodrug disclosed in WO05099768A2 and WO2009 / 133137A2, which are incorporated herein by reference. Therefore, the long-acting growth hormone is preferably a polymeric hGH prodrug of formula (Ia) or (Ib): (Ia), (Ib), in -D is the hGH part that is connected to the rest of the molecule through the amine functional group; n is 0, 1, 2, 3 or 4; -X- is a chemical bond or spacer group; =Y1 and =Y5 are independently selected from the following: =O and =S; -Y2- and -Y3- are selected from the following: -O- and -S-; -Y4- is selected from the following: -O-, -NR 5 -and-C(R) 6 R 6a )-; -R 1 It is a carrier, preferably containing at least 40% water-soluble PEG-based moiety; -R 2 -R 3 -R 5 -R 6 -R 6a The following are selected independently from each other: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -R 4 Selected from the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; -W- Selected from C 1-20 Alkyl groups, optionally interrupted by one or more groups selected from the following: C 3-10 Cycloalkyl, 8- to 30-membered carbon polycyclic, 3- to 10-membered heterocyclic, -C(O)-, -C(O)N(R) 7 -, -O-, -S- and -N(R) 7 )-; -Nu is selected from the following nucleophiles: -N(R 7 R 7a ), -N(R 7 OH), -N(R) 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH, -Ar is selected from the following: in The dashed line indicates the connection to the rest of the prodrug. -Z 1 -Selected from the following: -O-, -S-, and -N(R) 7 )-,and -Z 2 -is-N(R) 7 )-;as well as -R 7 -R 7a -R 7b Selected independently from: -H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; The prodrugs in formulas (Ia) and (Ib) are optionally further substituted.

[0130] In some embodiments, the long-acting hGH has formula (Ia). In some embodiments, the long-acting hGH has formula (Ib).

[0131] In a preferred embodiment, the =Y of equations (Ia) and (Ib) 1 Yes = O.

[0132] In a preferred embodiment, the -Y of formulas (Ia) and (Ib) 2 -Yes-O-.

[0133] In a preferred embodiment, the -Y of formulas (Ia) and (Ib) 3 -Yes-O-.

[0134] In a preferred embodiment, the -Y of formulas (Ia) and (Ib) 4 -Yes-NR 5 -

[0135] In a preferred embodiment, the =Y of equations (Ia) and (Ib) 5 Yes = O.

[0136] In a preferred embodiment, n in equations (Ia) and (Ib) is 0 or 1. Most preferably, n in equations (Ia) and (Ib) is 0.

[0137] Preferably, R in formulas (Ia) and (Ib) 1 It has a molecular weight of 10 to 250 kDa, or even more preferably 15 to 150 kDa.

[0138] In a particularly preferred embodiment, R of formulas (Ia) and (Ib) 1It has a molecular weight of 30 to 50 kDa, or even more preferably 35 to 45 kDa, or even more preferably 38 to 42 kDa, with the most preferred molecular weight being about 40 kDa.

[0139] In another equally preferred embodiment, R of formulas (Ia) and (Ib) 1 It has a molecular weight of 60 to 100 kDa, or even more preferably 70 to 90 kDa, or even more preferably 75 to 85 kDa, and most preferably has a molecular weight of about 80 kDa.

[0140] Preferably, R in formulas (Ia) and (Ib) 1 It is branched and contains at least three aggregate parts.

[0141] More preferably, R of equations (Ia) and (Ib) 1 It contains at least one branching point, preferably at least two branching points, and at least three polymer chains, said polymer chains preferably being PEG-based, wherein each branching point is preferably selected from the following: -N<, -CR 8 < and >C<, where R 8 Selected from: -H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group; wherein C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more identical or different R groups. 9 Replace, and where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally punctured by the following groups: -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-、-S(O)2N(R 10 )-、-S(O)N(R 10 -, -S(O)2-, -S(O)-, -N(R) 10 )S(O)2N(R 10a )-、-S-、-N(R 10 )-、-OC(OR 10 (R) 10a )-、 -N(R 10 )C(O)N(R 10a )-and-OC(O)N(R 10 )-; where R 9 R 10 and R 10a Selected from: -H, C 1-6 Alkyl, C 2-6 alkenyl and C2-6 Alkyne group.

[0142] In a preferred embodiment, R of formulas (Ia) and (Ib) 1 Includes at least two parts C extending from it. 1 and C 2 The first branching point BP 1 At least one of these components includes at least a second branching point BP. 2 At least two parts P 1 and P 2 From the second branching point BP 2 Extended. More preferably, R 1 It includes two parts C that extend from it. 1 and C 2 The first branching point BP 1 Part C 1 Includes at least two parts P extending from it. 1 and P 2 BP branching point 2 And this part C 2 Includes at least two parts P extending from it. 3 and P 4 The third branch point BP 3 .

[0143] In another preferred embodiment, R 1 Includes part C 1 It contains the first branch point BP 1 The second branch point BP 2 and the third branch point BP 3 At least one part P 1 From BP 1 Extension, at least one part P 2 From BP 2 Extension, and at least one part P 3 From BP 3 Extended. More preferably, R 1 Includes part C 1 It contains the first branch point BP 1 The second branch point BP 2 The third branch point BP 3 and the fourth branch point BP 4 At least some of P 1 From BP 1 Extend, at least part of P 2 From BP 2 Extend, at least part of P 3 From BP 3 Extension, and at least part of P 4 From BP4 extend.

[0144] Preferably, BP 1 BP 2 BP 3 and BP 4 Selected independently from: -CR 8 <, >C< and -N<, where R 8 Selected from: -H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group; wherein C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more identical or different R groups. 9 Replace, and where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally punctured by the following groups: -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-、-S(O)2N(R 10 )-、-S(O)N(R 10 -, -S(O)2-, -S(O)-, -N(R) 10 )S(O)2N(R 10a )-、-S-、-N(R 10 )-、-OC(OR 10 (R) 10a )-、 -N(R 10 )C(O)N(R 10a )-and-OC(O)N(R 10 )-; where R 9 R 10 and R 10a Selected from: -H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0145] Preferably, C 1 and C 2 Selected independently from: C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. 11 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-、-S(O)2N(R 12 )-、-S(O)N(R 12 -, -S(O)2-, -S(O)-, -N(R) 12 )S(O)2N(R 12a )-、-S-、-N(R 12 )-、-OC(OR 12 (R) 12a )-、 -N(R 12 )C(O)N(R 12a )-and-OC(O)N(R 12 )-; Wherein -T- is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic, wherein each -T- is independently optionally surrounded by one or more identical or different R- groups. 11 replace; Each R 11 Independently selected from the following: halogen, -CN, oxo (=O), -COOR 12 -OR 12 -C(O)R 12 -C(O)N(R) 12 R 12a -S(O)2N(R) 12 R 12a ), -S(O)N(R 12 R 12a -S(O)2R 12 -S(O)R 12 -N(R) 12 )S(O)2N(R 12a R 12b ), -SR 12 , -N(R 12 R 12a -NO2, -OC(O)R 12 -N(R) 12 )C(O)R 12a -N(R) 12 )S(O)2R 12a -N(R) 12 )S(O)R12a -N(R) 12 )C(O)OR 12a -N(R) 12 )C(O)N(R 12a R 12b ), -OC(O)N(R 12 R 12a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; And each of R 12 R 12a and R 12b Each of the following is selected independently: -H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be replaced by one or more identical or different halogens.

[0146] Preferably, P 1 P 2 P 3 P 4 The polymer portion is independent of each other, and more preferably contains PEG base chains containing at least 40% PEG, even more preferably at least 50% PEG, even more preferably at least 60% PEG, even more preferably at least 70% PEG, even more preferably at least 80% PEG, even more preferably at least 90% PEG, and most preferably at least 95% PEG.

[0147] In a preferred embodiment, P 1 P 2 P 3 and P 4 They have molecular weights of 5 kDa to 20 kDa, more preferably 7 to 15 kDa, and even more preferably 8 to 12 kDa, with the most preferred molecular weight being about 10 kDa.

[0148] In another preferred embodiment, P 1 P 2 P 3 and P 4 They each have a molecular weight of 10 to 30 kDa, more preferably 15 to 25 kDa, or even more preferably 17 to 23 kDa, and most preferably about 20 kDa.

[0149] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 1The part containing formula (II): (II), in -BP 1 <、-BP 2 <、-BP 3 <Selected independently from the following: -N< and -C(R 8 )<; R 8 Selected from the following: H, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group; -P 1 -P 2 -P 3 -P 4 They are independent PEG-based chains that contain at least 40% PEG and have a molecular weight of 5 to 30 kDa; -C 1 -、-C 2 - Selected independently from the following: C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. 9 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-、-S(O)2N(R 10 )-、-S(O)N(R 10 -, -S(O)2-, -S(O)-, -N(R) 10 )S(O)2N(R 10a )-、-S-、-N(R 10 )-、-OC(OR 10 (R) 10a )-、 -N(R 10 )C(O)N(R 10a )-and-OC(O)N(R 10 )-; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently optionally composed of one or more identical or different Rs. 9 replace; Each R 9 Independently selected from: halogen, -CN, oxo (=O), -COOR 11 -OR 11 -C(O)R 11 , -C(O)N(R 11 R 11a -S(O)2N(R) 11 R 11a ), -S(O)N(R 11 R 11a -S(O)2R 11 -S(O)R 11 , -N(R 11 )S(O)2N(R 11a R 11b ), -SR 11 -N(R) 11 R 11a -NO2, -OC(O)R 11 -N(R) 11 )C(O)R 11a -N(R) 11 )S(O)2R 11a -N(R) 11 )S(O)R 11a -N(R) 11 )C(O)OR 11a -N(R) 11 )C(O)N(R 11a R 11b ), -OC(O)N(R 11 R 11a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups are optionally substituted with one or more identical or different halogens; and Each R 10 R 10a R 11 R 11a and R 11b Independently selected from: -H and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0150] In a preferred embodiment, BP of formula (II) 1 It is –N<.

[0151] In a preferred embodiment, BP of formula (II) 2 and BP 2 Both are –CH<.

[0152] If the first branching point BP 1 It is advantageous for the connection sites of X to be separated by no more than a certain number of atoms.

[0153] Preferably, the critical distance in the prodrugs of formulas (Ia) and (Ib) is less than 60 atoms, more preferably less than 50 atoms, even more preferably less than 40 atoms, even more preferably less than 30 atoms, even more preferably less than 20 atoms, and most preferably less than 10 atoms.

[0154] If the prodrug has formula (Ia), the term "critical distance" refers to R. 1 The first branching point BP included 1 The shortest distance measured by the number of atoms between the atoms marked with an asterisk in equation (a), or, if the prodrug has equation (Ib), the term "critical distance" refers to R. 1 The first branching point BP included 1 The number of atoms between the atoms marked with an asterisk in equation (b): (a) (b); The dashed lines represent the connection with the remaining part of the prodrug of formula (Ia) in case (a), and the connection with the remaining part of the prodrug of formula (Ib) in case (b).

[0155] In a preferred embodiment, -P of formula (II) 1 -P 2 -P 3 -P 4 They have molecular weights of 5 kDa to 20 kDa, more preferably 7 to 15 kDa, and even more preferably 8 to 12 kDa, with the most preferred molecular weight being about 10 kDa.

[0156] In another preferred embodiment, -P of formula (II) 1 -P 2 -P 3 -P 4 They each have a molecular weight of 10 to 30 kDa, more preferably 15 to 25 kDa, or even more preferably 17 to 23 kDa, and most preferably about 20 kDa.

[0157] In a preferred embodiment, C of formula (II) 1 and C 2 It is a C-shaped group interrupted by one or more of the following groups. 1-50 Alkyl groups: -O-, -C(O)N(R) 10 )- and 3- to 10-membered heterocyclic groups; wherein the 3- to 10-membered heterocyclic groups are substituted by at least one oxo (=O).

[0158] Most preferably, C of formula (II) 1 and C 2 It has formula (IIa) (IIa), in The dashed line marked with an asterisk indicates the relationship between BP and BP. 1 The connection; The unmarked dashed lines represent BP and BP respectively. 2 or BP 3 The connection; q1 is 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q1 is 4, 5, 6, 7 or 8; more preferably, q1 is 5, 6 or 7; most preferably, q1 is 6; q2 is 1, 2, 3, 4 or 5; preferably, q2 is 1, 2 or 3; most preferably, q2 is 2; q3 is 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q3 is 2, 3, 4 or 5; more preferably, q3 is 2, 3 or 4; most preferably, q3 is 3; q4 is 1, 2 or 3; preferably, q4 is 1.

[0159] In a preferred embodiment, P of formula (II) 1 P 2 P 3 and P 4 They each possess equation (IIb) independently. (IIb), in The dashed line indicates a connection to R. 1 The rest, i.e., connected to BP respectively. 2 or BP 3 , m is 0 or 1. p is an integer from 57 to 1420, more preferably from 85 to 850; and q is selected from the following: 1, 2, 3, 4, 5 and 6.

[0160] In a preferred embodiment, p in formula (IIb) is in the range of 170 to 284, even more preferably in the range of 198 to 255, and most preferably in the range of 215 to 238.

[0161] In an equally preferred embodiment, p of formula (IIb) is in the range of 340 to 568, even more preferably in the range of 398 to 510, and most preferably in the range of 426 to 482.

[0162] More preferably, -R 1 The part containing (IIc): (IIc) in p1, p2, p3, and p4 are independently integers from 57 to 1420, or even more preferably from 85 to 850.

[0163] In a preferred embodiment, p1, p2, p3 and p4 of formula (IIc) are independently selected from integers of 170 to 284, even more preferably 198 to 255, and most preferably 215 to 238.

[0164] In an equally preferred embodiment, p1, p2, p3 and p4 of formula (IIc) are independently selected from integers of 340 to 568, even more preferably 398 to 510, and most preferably 426 to 482.

[0165] In a preferred embodiment, -R of formula (Ib) 2 Selected from the following: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R of formula (Ib) 2 Selected from the following: -H, methyl, ethyl, n-propyl, and isopropyl. Even more preferably, -R of formula (Ib) 2 Selected from -H, methyl, and ethyl. Most preferably, -R of formula (Ib) 2 Yes, it's -H.

[0166] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 3 Selected from the following: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 3 Selected from the following: -H, methyl, ethyl, n-propyl, and isopropyl. Even more preferably, -R of formulas (Ia) and (Ib) 3 Selected from -H, methyl, and ethyl. Most preferably, -R of formulas (Ia) and (Ib) 3 Yes, it's -H.

[0167] In a preferred embodiment, each -R of formulas (Ia) and (Ib) 4 Independently selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 4 Selected from the following: methyl, ethyl, n-propyl, and isopropyl. Even more preferably, -R of formulas (Ia) and (Ib) 4 Selected from methyl and ethyl.

[0168] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 5 Selected from the following: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 5 Selected from the following: -H, methyl, ethyl, n-propyl, and isopropyl. Even more preferably, -R of formulas (Ia) and (Ib) 5 Selected from methyl and ethyl. Most preferably, -R of formulas (Ia) and (Ib) 5 It is a methyl group.

[0169] In a preferred embodiment, the -R of formulas (Ia) and (Ib) 6 and -R 6a Independently selected from the following: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 6 and -R 6a Independently selected from the following: -H, methyl, ethyl, n-propyl, and isopropyl. Even more preferably, -R of formulas (Ia) and (Ib) 6 and -R 6a Independently selected from -H, methyl, and ethyl. Most preferably, -R of formulas (Ia) and (Ib) 6 and -R 6a Both are -H.

[0170] In a preferred embodiment, X in formulas (Ia) and (Ib) is preferably selected from the following: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z1 )-、-S(O)2N(R z1 )-、-S(O)N(R z1 -, -S(O)2-, -S(O)-, -N(R) z1 )S(O)2N(R z1a )-、-S-、-N(R z1 )-、-OC(OR z1 (R) z1a )-、 -N(R z1 )C(O)N(R z1a )-、-OC(O)N(R z1 )-、C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T-, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-、-S(O)2N(R z3 )-、-S(O)N(R z3 -, -S(O)2-, -S(O)-, -N(R) z3 )S(O)2N(R z3a )-、-S-、-N(R z3 )-、-OC(OR z3 (R) z3a )-、 -N(R z3 )C(O)N(R z3a )-and-OC(O)N(R z3 )-; R z1 and R z1a Each of the following can be selected independently: -H, -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 Alkyne group; wherein -T, C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-50 Alkyl, C 2-50 alkenyl and C 2-50 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z4 )-、-S(O)2N(R z4 )-、-S(O)N(R z4 -, -S(O)2-, -S(O)-, -N(R) z4 )S(O)2N(R z4a)-、-S-、-N(R z4 )-、-OC(OR z4 (R) z4a )-、-N(R z4 )C(O)N(R z4a )-and-OC(O)N(R z4 )-; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently optionally composed of one or more identical or different Rs. z2 replace; Each R z2 Independently selected from the following: halogen, -CN, oxo (=O), -COOR z5 -OR z5 -C(O)R z5 -C(O)N(R) z5 R z5a -S(O)2N(R) z5 R z5a ), -S(O)N(R z5 R z5a -S(O)2R z5 -S(O)R z5 -N(R) z5 )S(O)2N(R z5a R z5b ), -SR z5 -N(R) z5 R z5a -NO2, -OC(O)R z5 -N(R) z5 )C(O)R z5a -N(R) z5 )S(O)2R z5a -N(R) z5 )S(O)R z5a -N(R) z5 )C(O)OR z5a -N(R) z5 )C(O)N(R z5a R z5b ), -OC(O)N(R z5 R z5a ) and C 1-6 Alkyl; wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R z3 Rz3a R z4 R z4a R z5 R z5a and R z5b Independently selected from the following: -H and C 1-6 Alkyl; wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0171] More preferably, X in formulas (Ia) and (Ib) is selected from the following: C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 Alkyne group; wherein C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally surrounded by one or more identical or different R groups. z2 Replace, and where C 1-10 Alkyl, C 2-10 alkenyl and C 2-10 The alkynyl group is optionally interrupted by one or more of the following groups: -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-、-S(O)2N(R z3 )-、 -S(O)N(R z3 -, -S(O)2-, -S(O)-, -N(R) z3 )S(O)2N(R z3a )-、-S-、-N(R z3 )-、 -OC(OR z3 (R) z3a )-、-N(R z3 )C(O)N(R z3a )-and-OC(O)N(R z3 )-; Each T is independently selected from the following: phenyl, naphthyl, indenyl, indenyl, tetrahydronaphthyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 8- to 11-membered heterobicyclic, 8- to 30-membered carbon polycyclic and 8- to 30-membered heteropolycyclic; wherein each T is independently optionally composed of one or more identical or different Rs. z2 replace; Each R z2 Selected independently from C 1-6 Alkyl, wherein C 1-6 Alkyl groups may optionally be substituted with one or more of the same or different halogens; Each R z3 R z3aIndependently selected from the following: -H and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more of the same or different halogens.

[0172] Even more preferably, X in equations (Ia) and (Ib) is C. 1-10 Alkyl groups, optionally interrupted by one or more of the following groups: -C(O)O-, -O-, -C(O)-, -C(O)N(R) z3 )-、-S-、-N(R z3 )-、-OC(OR z3 (R) z3a )-and-OC(O)N(R z3 )-; where R z3 and R z3a Independently selected from -H and C 1-6 alkyl.

[0173] Most preferably, X in equations (Ia) and (Ib) has the characteristics of equation (III). (III), in The dashed line marked with an asterisk indicates the intersection with R. 1 The connection; Unmarked dashed lines indicate connections to the remaining portion of the prodrug; q5 is 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q5 is 1, 2, 3, 4 or 5; more preferably, q5 is 2, 3 or 4; most preferably, q5 is 3; Preferably, Ar in formulas (Ia) and (Ib) is phenyl. Most preferably, Ar in formulas (Ia) and (Ib) is... , The dashed lines indicate connections to the rest of the prodrug in formula (Ia) or formula (Ib).

[0174] Preferably, W in formulas (Ia) and (Ib) is C. 1-20 Alkyl group, optionally C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 -, -O-, -S- and -N(R) 7 - Discontinuous. Even more preferably, W in equations (Ia) and (Ib) is C. 1-10 Alkyl group, optionally C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 -, -O-, -S- and -N(R) 7 - Discontinuous. Even more preferably, W in equations (Ia) and (Ib) is C.1-6 Alkyl group, optionally C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 -, -O-, -S- and -N(R) 7 - Discontinuous. Most preferably, W in equations (Ia) and (Ib) is... , in The dashed line indicates the connection to the rest of the molecule.

[0175] Preferably, -Nu in formulas (Ia) and (Ib) is -N(R) 7 R 7a ).

[0176] Preferably, -R in formulas (Ia) and (Ib) 7 and -R 7a The radicals are independently selected from the following: -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferably, -R in formulas (Ia) and (Ib) 7 and -R 7a The radicals are independently selected from -H, methyl, ethyl, n-propyl, and isopropyl. Even more preferably, the -R radicals of formulas (Ia) and (Ib) are... 7 and -R 7a The components are independently selected from methyl or ethyl. Most preferably, the -R of formulas (Ia) and (Ib) 7 and -R 7a All are methyl groups.

[0177] Most preferably, the long-acting growth hormone is a polymeric hGH prodrug of formula (IV). in D is the hGH moiety that is attached to the rest of the molecule via an amine functional group; and p1, p2, p3, and p4 are independently integers from 57 to 1420, or even more preferably from 85 to 850.

[0178] In a preferred embodiment, p1, p2, p3 and p4 of formula (IV) are independently selected from 170 to 284, even more preferably from 198 to 255, and most preferably from 215 to 238 integers.

[0179] In a similarly preferred embodiment, p1, p2, p3 and p4 of formula (IV) are independently selected from 340 to 568, even more preferably from 398 to 510, and most preferably from 426 to 482 integers.

[0180] Preferably, the long-acting growth hormone formulation comprises at least one long-acting growth hormone selected from the following: ACP-001, ACP-011, VRS-317, MOD-4023, Somatrogon, hGH-CTP, Albutropin, ARX201, ALTU-238, PHA-794428, hGH-OctoDex, NNC126-0083, Somapacitan, Somavaratan, Nutropin Depot, LB03002, Somatropin Biopartners, LAPS-hGH, NNC0195-0092, Hytropin, GX-H9, Jintrolong, and TV-1106.

[0181] In some embodiments, the long-acting growth hormone is ACP-001. ACP-001 has the structure of formula (IV), wherein p1, p2, p3, and p4 range from 398 to 510, meaning that the molecular weight of the four PEG moieties is approximately 80 kDa.

[0182] In some embodiments, the long-acting growth hormone is ACP-011. ACP-011 has the structure of formula (IV), wherein p1, p2, p3, and p4 range from 198 to 255, meaning that the molecular weight of the four PEG moieties is approximately 40 kDa.

[0183] In some embodiments, the long-acting growth hormone is Somapacitan. Somapacitan has the following structure: , The dashed line represents the sulfur linkage to cysteine ​​at position 101 of SEQ ID NO:2, which is: FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSCVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF SEQ ID NO:2 corresponds to SEQ ID NO:1, wherein the leucine at position 101 is replaced by cysteine.

[0184] In one embodiment, the pharmaceutical composition comprising the long-acting growth hormone is a liquid formulation.

[0185] In another embodiment, the pharmaceutical composition containing the long-acting growth hormone is a dry preparation.

[0186] In a preferred embodiment, the pharmaceutical composition containing the long-acting growth hormone is stable at refrigeration temperature (i.e., 2 to 8°C) for at least 3 months.

[0187] In another preferred embodiment, the pharmaceutical composition comprising the long-acting growth hormone is stable at room temperature (i.e., at 18 to 30°C) for at least 3 months.

[0188] In another preferred embodiment, the long-acting growth hormone is administered in combination with a C-type natriuretic peptide agonist.

[0189] In another preferred embodiment, the long-acting growth hormone is administered in combination with soluble FGFR3.

[0190] This liquid or dry pharmaceutical composition containing the long-acting growth hormone comprises one or more excipients. Excipients used in parenteral formulations can be classified as, for example, buffers, isotonic modifiers, preservatives, stabilizers, anti-adsorption agents, oxidative protectants, thickeners / thickeners, or other adjuvants. However, in some cases, an excipient may have dual or triple functions. Pharmaceutical compositions containing the long-acting growth hormone preferably contain one or more excipients selected from the following: (i) Buffers: Physiologically tolerable buffers are used to maintain the pH within the desired range, such as sodium phosphate, bicarbonate, succinate, histidine, citrate and acetate, sulfate, nitrate, chloride, and pyruvate. Antiacids such as Mg(OH)2 or ZnCO3 may also be used.

[0191] (ii) Isotonic adjusters: to minimize pain caused by cell damage due to osmotic pressure differences at the injection site. Examples include glycerol and sodium chloride. The effective concentration can be determined by osmoregulation using an estimated serum osmolality of 285-315 mOsmol / kg.

[0192] (iii) Preservatives and / or antimicrobial agents: Multi-dose parenteral preparations require the addition of sufficient concentrations of preservatives to minimize the risk of infection to patients at the time of injection, and corresponding regulatory requirements have been established. Typical preservatives include: m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride.

[0193] (iv) Stabilizers: Stabilization is achieved by enhancing protein stability, disrupting denaturation, or through direct binding of excipients to proteins. Stabilizers can be: amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, and proline; sugars such as glucose, sucrose, and trehalose; polyols such as glycerol, mannitol, and sorbitol; salts such as potassium phosphate and sodium sulfate; chelating agents such as EDTA and hexaphosphate; ligands such as divalent metal ions (zinc, calcium, etc.); and other salts or organic molecules such as phenolic derivatives. In addition, oligomers or polymers such as cyclodextrin, dextran, dendritic polymers, PEG, PVP, protamine, or HSA can be used.

[0194] (v) Anti-adsorption agents: These are primarily ionic or nonionic surfactants, or other proteins or soluble polymers, used to coat or competitively adsorb onto the inner surface of the formulation container. Examples include poloxamer (Pluronic F-68), PEG-dodecyl ether (Brij 35), polysorbate 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA and HSA, and gelatin. The concentration and type of excipient chosen depend on the effects to be avoided, but typically form a monolayer of surfactant at the interface, just above the CMC value.

[0195] (vi) Oxidizing agents: Antioxidants such as ascorbic acid, tetrahydropyrimidine, methionine, glutathione, thioglycerol, morin, polyethyleneimine (PEI), propyl gallate, and vitamin E. Chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid may also be used.

[0196] (vii) Thickeners or viscosity enhancers: These delay the settling of particles in vials and syringes, promote mixing and resuspension of particles, and make the suspension easier to inject (i.e., less force on the syringe plunger). Suitable thickeners or viscosity enhancers include: carbomer thickeners such as Carbopol 940 and Carbopol Ultrez 10; cellulose derivatives such as hydroxypropyl methylcellulose (EIPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C); colloidal magnesium silicate (Veegum) or sodium silicate; hydroxyapatite gel; tricalcium phosphate gel; xanthan gum; carrageenan such as Satia gum; and UTC. 30. Aliphatic poly(hydroxy acids) such as poly(D,L-lactic acid or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) and their copolymers (PLGA), terpolymers of D,L-lactide, glycolide and caprolactone, poloxamer, hydrophilic and hydrophobic poly(oxyethylene) blocks (e.g., Pluronic®) constituting poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblocks, polyether ester copolymers such as polyethylene terephthalate / polybutylene terephthalate copolymers, sucrose isobutyrate acetate (SAIB), dextran or its derivatives, and combinations of dextran and PEG. Polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and its derivatives, polyalkylimides, poly(acrylamide-diallyl dimethylammonium copolymer (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs) such as dermatin sulfate, chondroitin sulfate, keratin sulfate, heparin, heparan sulfate, hyaluronic acid, ABA triblock copolymers or AB block copolymers composed of hydrophobic A-blocks (such as polylactide (PLA) or poly(lactide-glycolic acid copolymer (PLGA)) and hydrophilic B-blocks (such as polyethylene glycol (PEG) or polyvinylpyrrolidone). These block copolymers, as well as the aforementioned poloxamer, can exhibit antithermal gel behavior (a fluid state at room temperature to facilitate application, and a gel state at body temperature after injection above the sol-gel transition temperature).

[0197] (viii) Spreading or dispersing agents: These alter the permeability of connective tissue by hydrolyzing components of the extracellular matrix in the intercellular spaces, such as, but not limited to, hyaluronic acid and polysaccharides present in the intercellular spaces of connective tissue. Spreading agents include, but are not limited to, hyaluronidase, which temporarily reduces the viscosity of the extracellular matrix and promotes the diffusion of injected drugs.

[0198] (ix) Other additives: such as wetting agents, viscosity modifiers, antibiotics, hyaluronidase, etc. Acids and bases (such as hydrochloric acid and sodium hydroxide) are necessary additives for pH adjustment during the manufacturing process.

[0199] Another aspect of the present invention is a method for treating patients suffering from growth disorders, wherein the method includes the step of administering an effective amount of the long-acting growth hormone preparation of the present invention to the patient. The administration of the long-acting growth hormone produces superior efficacy compared to equimolar daily administration of growth hormone.

[0200] In some implementations, the superior efficacy is measured in terms of annualized height rate.

[0201] Another aspect of the invention is a method for treating growth hormone deficiency, wherein the method includes the step of administering a long-acting growth hormone preparation to a patient suffering from growth hormone deficiency, and wherein the administration of long-acting growth hormone results in a reduction in non-responders compared to the administration of an equimolar dose of daily growth hormone.

[0202] Preferably, the long-acting growth hormone preparation is administered to the patient over a period of at least two days between administrations. More preferably, the period between administrations is at least three days, even more preferably at least four days, even more preferably at least five days, even more preferably at least six days, and most preferably seven days. In another embodiment, the period between administrations is 14 days or one month.

[0203] Preferably, the treatment for the growth hormone deficiency lasts for at least 6 months, such as at least 8 months, such as at least 10 months, such as at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 20 months, such as at least 24 months, such as at least 30 months, or such as at least 36 months.

[0204] Another aspect of the invention is a method for administering the long-acting growth hormone preparation to patients with growth hormone deficiency, wherein the administration of the long-acting growth hormone produces superior efficacy compared to the administration of an equimolar dose of daily growth hormone. As used herein, the term "growth hormone deficiency" refers to any condition that benefits from growth hormone administration. Preferably, growth hormone deficiency is selected from the following: childhood growth hormone deficiency (GHD), idiopathic short stature (ISS), short stature homeobox (SHOX) gene mutation, Turner syndrome (TS), Noonan syndrome (NS), Prader-Willi syndrome (PWS), small for gestational age infants (SGA), chronic renal insufficiency (CRI), adult growth hormone deficiency (GHD), wasting due to HIV or AIDS or other malignancies, short bowel syndrome (SBS), sarcopenia, and weakness.

[0205] In another embodiment, the growth hormone deficiency is adult GHD. In another embodiment, the growth hormone deficiency is ISS. In another embodiment, the growth hormone deficiency is a SHOX gene mutation. In another embodiment, the growth hormone deficiency is TS. In another embodiment, the growth hormone deficiency is NS. In another embodiment, the growth hormone deficiency is PWS. In another embodiment, the growth hormone deficiency is SGA. In another embodiment, the growth hormone deficiency is CRI. In another embodiment, the growth hormone deficiency is wasting due to HIV or AIDS or other malignancies. In another embodiment, the growth hormone deficiency is SBS. In another embodiment, the growth hormone deficiency is sarcopenia. In another embodiment, the growth hormone deficiency is asthenia. In a preferred embodiment, the growth hormone deficiency is childhood GHD.

[0206] Example method Cation exchange chromatography The conjugates were purified by cation exchange chromatography using an AKTA Pure system (GE Healthcare) equipped with a 279 mL Macrocap SP column. The respective reaction mixtures were loaded onto a column pre-equilibrated in 20 mM sodium acetate, 10 mM L-methionine buffer, pH 4.0 (buffer A). After loading, the column was washed with three column volumes of buffer A to remove any unreacted PEG reagent. The monoconjugates were eluted using a gradient of more than 15 column volumes of 0–30% buffer B (20 mM sodium acetate, 1 M sodium chloride, pH 4.5). Unreacted growth hormone was eluted using a gradient of more than three column volumes of 30–80% B. The column was washed with three column volumes of 100% buffer B. The loading flow rate was 20 mL / min, and the flow rate during elution was 25 mL / min. Elution was monitored by detection at 280 nm.

[0207] Height measurement and height rate measurement Height was measured using a calibrated wall-mounted (e.g., Harpenden or similar) rangefinder. The result was the arithmetic mean of three independent measurements taken at each follow-up visit. The measurement time, the name of the developmental researcher, and the results were recorded. Calculations of height rates were performed centrally.

[0208] Example 1: Transient synthesis of 4x10 kDa mPEG-connector-hGH monoconjugate 1 Following similar steps described in WO2009 / 133137A2, a 4 x 10 kDa mPEG-linker-hGH monoconjugate 1 was synthesized; in detail, the manufacturing process was carried out as follows: Replace the hGH buffer with 100 mM sodium borate (pH 9) and adjust the hGH concentration to 10 mg / mL. Dissolve an excess of the 40 kDa 4-arm branched mPEG-pentafluorophenyl carbonate derivative relative to hGH in water to prepare a 6% (w / w) reagent solution. Add this reagent solution to the hGH solution at a 1:1 ratio (based on weight) and mix. Incubate the reaction mixture at 12–16 °C for 105 min with stirring, then quench the reaction mixture by adding 4 volumes of a solution containing 27 mM acetic acid and 12.5 mM L-methionine to 1 volume of the reaction mixture to lower the pH to 4–4.5. After sterile filtration, incubate the reaction mixture at room temperature for 16 ± 4 h. Purify the 4 x 10 kDa mPEG-linker-hGH monoconjugate 1 by cation exchange chromatography.

[0209] Buffer exchange was performed using a tangential flow filtration system, and the 4 x 10 kDa mPEG-connector-hGH monoconjugate 1 was adjusted to the desired concentration. Therefore, the eluent from cation exchange chromatography was ultrafiltered and percolated into a formulation buffer (10 mM succinic acid, 85 g / L trehalose dihydrate, adjusted to pH 5.0 with 1 M Tris solution). The trehalose concentration was reduced to 65 g / L using the same system, and the concentration of this stock solution was adjusted to 105 ± 3 mg / mL of 4 x 10 kDa mPEG-connector-hGH monoconjugate 1 (corresponding to 35 ± 1 mg hGH eq. / mL). Based on this stock solution of compound 1, the formulations shown in Table 2 were prepared by diluting the stock solution with a high concentration of formulation buffer (10 mM succinic acid, 89 g / L trehalose dihydrate, adjusted to pH 5.0 with 1 M Tris base).

[0210] Table 1: Formulation of 4x10kDa mPEG-linker-hGH monoconjugate

[0211] Example 2: Preparation of formulations containing 4 x 10 kDa mPEG-linker-hGH monoconjugate 1 for clinical research. For use as an investigational drug in clinical studies, 4 x 10 kDa mPEG-connector-hGH monoconjugate 1 was converted into a lyophilized drug product in glass vials and packaged as a lyophilized powder in disposable glass vials for reconstitution with sWFI to provide a concentration (<0.60 mL) suitable for providing a clinically relevant dose volume for pediatric patients. It is available in two vial configurations: 12.1 mg hGH / vial and 24.2 mg hGH / vial.

[0212] Table 2: Formulation of 4x10 kDa mPEG-linker-hGH monoconjugate

[0213] After reconstitution with water for injection (WFI), the 4x10 kDa mPEG-connector-hGH monoconjugate 1 was used as a single-use sterile solution for subcutaneous (sc) injection.

[0214] Example 3: Phase 3 Pediatric Study In a phase 3 pediatric growth hormone deficiency trial, the formulation of Example 3, comprising 4 x 10 kDa mPEG-connector-hGH monoconjugate 1, was investigated. Pediatric patients meeting internationally recognized criteria for GHD were recruited in North America, Europe, and Oceania, including short stature as measured by height and height rate, two hGH stimulation tests, bone age assessment, and IGF-I levels below -1 standard deviation (or SDS). This phase 3 trial was a multicenter, open-label study that enrolled approximately 161 treatment-naïve children with GHD, who were randomized 2:1 to receive either weekly 4 x 10 kDa mPEG-connector-hGH monoconjugate 1 (0.24 mg / kg / week subcutaneously) or daily Genotropin® (34 μg / kg / day or 0.24 mg / kg / week subcutaneously) for 52 weeks. The primary endpoint was annualized HV at week 52. Secondary endpoints included safety and tolerability; annualized HV over 52 weeks; change in standard deviation of height (SDS) over 52 weeks; serum IGF-1 and IGFBP-3 levels and corresponding changes in SDS over 52 weeks; and the incidence of anti-human growth hormone antibodies, including neutralizing antibodies. Additionally, non-responders in both groups were analyzed.

[0215] In summary, the randomized, open-label, active-controlled trials demonstrated that the 4x10 kDa mPEG-connector-hGH monoconjugate 1 (n=105) met its primary objective of non-inferiority and, moreover, was superior to daily Genotropin (n=56) at the primary endpoint of annualized height rate (AHV) at week 52. In a preliminary analysis of the intention-to-treat population using ANCOVA, the 4x10 kDa mPEG-connector-hGH monoconjugate 1 showed an AHV of 11.2 cm / year, compared to 10.3 cm / year for daily hGH. The treatment difference was 0.86 cm / year, with a 95% confidence interval of +0.22 to +1.50 cm / year, demonstrating its superiority (p=0.0088).

[0216] At each follow-up, the AHV of the 4x10 kDa mPEG-connector-hGH monoconjugate 1 was greater than that of the daily hGH, and the treatment difference reached statistical significance from week 26 onwards and persisted throughout the trial. The incidence of adverse responses (AHV < 8.0 cm / year) in the 4x10 kDa mPEG-connector-hGH monoconjugate 1 group and the daily hGH group was 4% and 11%, respectively.

[0217] The 4x10 kDa mPEG-connector-hGH monoconjugate 1 was safe and well-tolerated, with typical adverse events associated with daily hGH treatment, and was comparable between the two groups. Furthermore, compared to an approximate mean IGF-1 SDS of 0.04x10 kDa mPEG-connector-hGH monoconjugate 1 at week 52, the peak and trough insulin-like growth factor 1 (IGF-1) SDS observed with 0.04x10 kDa mPEG-connector-hGH monoconjugate 1 were approximately +1.3 and -0.5, respectively, at week 52. Additionally, observed IGF-1 SDS > 2.0 were uncommon (<10% of subjects), while IGF-1 SDS > 3.0 were rare (<3% of subjects). Two subjects in each treatment group experienced injection site reactions that were considered adverse events.

[0218] Example 4: Phase 2 pediatric study Somapacitan (NCT02616562, Novo Nordisk; https: / / clinicaltrials.gov / ct2 / show / NCT02616562) Somapacitan has the structure shown elsewhere in this article.

[0219] Design: This study was a multicenter, randomized, controlled, double-blind (Somapacitan dose) phase 2 trial conducted at 29 sites in 11 countries, with a 26-week primary phase and a 26-week extension phase. Fifty-nine pre-pubescent children with GHD who had not received GH treatment were randomized; 58 completed the trial.

[0220] Intervention: Subcutaneous administration of three doses of Somapacitan (0.04 [n=16], 0.08 [n=15] or 0.16 mg / kg / week [n=14]) and daily GH (0.034 mg / kg / day [n=14]).

[0221] Primary outcome measurement: The primary endpoint was HV at week 26. Secondary efficacy endpoints included HV SDS and IGF-I SDS.

[0222] Results: At week 26, the mean (SD) annualized HV in the Somapacitan group were 8.0 (2.0) cm / year, 10.9 (1.9) cm / year, and 12.9 (3.5) cm / year, respectively, compared to 11.4 (3.3) cm / year for daily GH; estimated treatment difference (Somapacitan 0.16 mg / kg / week - daily GH): 1.7 [95% CI -0.2; 3.6] cm / year. HV persisted at week 52, with significantly higher levels in Somapacitan at 0.16 mg / kg / week compared to daily GH. The mean (SD) change in HV SDS from baseline at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) in the Somapacitan group, compared to 7.41 (4.08) for daily GH. The model-derived mean (SD) IGF-I SDS for the Somapacitan group were -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, while that observed for daily GH was -0.40 (1.50). Safety and tolerability were consistent with those observed for daily GH.

[0223] Abbreviations AHV Annualized Height Rate API active pharmaceutical ingredients cGMP (Current Good Manufacturing Practice) GH (Growth Hormone) GHD (Growth Hormone Deficiency) Hgh (Human Growth Hormone) mPEG (methoxylated poly(ethylene glycol)) PEG (Polyethylene Glycol) European Pharmacopoeia USP (United States Pharmacopeia) Tris(tris(hydroxymethyl)aminomethane)

Claims

1. A long-acting growth hormone or a pharmaceutical preparation containing the long-acting growth hormone for the treatment of growth hormone deficiency, wherein the treatment increases plasma IGF-1 levels by at least 0.2 standard deviation fractions compared to an equivalent daily dose of hGH.

2. The long-acting growth hormone or pharmaceutical preparation according to claim 1, wherein the increase is at least 0.3 SDS.

3. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the growth hormone deficiency is childhood growth hormone deficiency.

4. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the long-acting growth hormone is applied no more than once a week.

5. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the dose of long-acting growth hormone administered each time is at least 0.16 mg / kg / week.

6. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the dosage is from 0.24 mg / kg / week to 0.3 mg / kg / week.

7. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the time between two consecutive administrations is 1 week.

8. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the growth hormone deficiency has been treated for at least 6 months.

9. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the pharmaceutical preparation is a dry preparation.

10. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the pharmaceutical preparation is a liquid preparation.

11. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the long-acting growth hormone is a polymeric hGH prodrug of formula (IV). in D is the hGH portion that is attached to the rest of the molecule via an amine functional group; p1, p2, p3, and p4 are independent integers from 170 to 284.

12. The long-acting growth hormone or pharmaceutical preparation according to claim 11, wherein p1, p2, p3, and p4 are independently integers from 198 to 255.

13. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the hGH portion is a polypeptide of SEQ ID NO:

1.

14. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the long-acting growth hormone is ACP-011.

15. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the long-acting growth hormone is Somapacitan.

16. The long-acting growth hormone or pharmaceutical preparation according to claim 1 or 2, wherein the long-acting growth hormone is administered using an auto-injector pen.

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