Injectable delivery system for long-acting administration of drugs

Abstract

The present invention relates to an injectable delivery system for long-acting administration of drugs. The present invention includes compounds formed at least in part from peptidomimetic molecules. The compound is configured to link one or more drug molecules, and is further configured to release the one or more drug molecules under physiological conditions. A solution of the compound forms a hydrogel in response to an endogenous enzyme of a human or animal. A solution of the compound can be applied to the skin where it forms a hydrogel upon application, and any drug attached to the compound will then be gradually released.

Description

TECHNICAL FIELD

[0001] The present invention relates to a compound that can be used as an injectable delivery system for long acting administration of pharmaceuticals in solution. BACKGROUND

[0002] Injectable delivery systems for long acting administration of pharmaceuticals have a wide range of potential therapeutic or prophylactic uses. One particular potential use is as a contraceptive. Another use is in the prevention of HIV / AIDS. Currently, the only option available to simultaneously prevent unwanted pregnancy and HIV / AIDS is male and female condoms. However, patient acceptance and overall effectiveness of condoms has always been poor. Therefore, there is an urgent need for new practical HIV / AIDS co-contraceptive products. Currently, a number of concepts are in early clinical studies, the most promising of which is dapivirine + levonorgestrel vaginal ring.

[0003] Despite the popularity of long acting injectable contraceptives (e.g. ) and the clinical progress made with new long acting injectable antiretroviral formulations (e.g. GSK / Janssen’s injectable rilpivirine + cabotegravir: ), there have been no reports to date describing long acting injectable strategies for the co-administration of antiretroviral drugs and contraceptive drugs. This is very challenging because both HIV antiretroviral drugs and contraceptive drugs are water insoluble and tend to interact and aggregate when mixed in water based formulations such as suspensions.

[0004] Cabenuva® itself was recently approved by the FDA (USA) as well as the drug regulatory authorities in Europe, Australia and Zimbabwe. It is two separate injections of rilpivirine + cabotegravir, not a single administered combination product. Single injections can improve patient drug compliance, especially for those who dislike needles, and improve storage and distribution.

[0005] Existing long acting injectable technologies almost exclusively rely on pre-formed implants and suspensions, which have specific drawbacks that limit their use as single or combination HIV-contraceptive products. For example, pre-formed subcutaneous contraceptive implants containing non-biodegradable polymers (e.g. ) require expensive and painful surgery for insertion and removal. The procedure is also prone to infection.

[0006] Drug suspensions (e.g. rilpivirine + cabotegravir) are fundamentally unstable, requiring formulation strategies to ensure physical stability and drug particle size over the product shelf life, particularly in environments where daily temperature fluctuations are large and cold chain supply is lacking, such as the sub-Saharan Africa region where demand for the product is greatest. Instability of the formulation leads to problems in administering the product to patients. Unstable / insoluble particles can become trapped in the syringe, meaning not all product can be effectively administered.

[0007] Furthermore, these formulations typically produce relatively high initial drug concentrations (so-called burst effect) in the systemic area, after which the drug concentration steadily declines, making it difficult to optimise drug dosage and pharmacokinetics. This has significant implications for drug treatment / prevention strategies.

[0008] Polymeric subcutaneous implants already exist, with several products currently on the market, mainly in the field of contraception. These include and The active agents in these products are predominantly steroids. Other long-acting products include Implants containing the drug buprenorphine hydrochloride for opioid addiction.

[0009] Long-acting injectable treatments for the treatment of psychiatric disorders and drug dependency are also well known. They include intramuscular administration of: i) aqueous suspensions (e.g. paliperidone: ), ii) oil-based injections (e.g. haloperidol: trifluperidol: ), iii) microspheres (risperidone: risperdal naltrexone: ). Alternative long-acting systems tend to rely on pre-formed polymeric implants (buprenorphine: ), which have drawbacks limiting their wider use, such as containing non-biodegradable polymers, requiring painful and expensive surgery for insertion / removal. Similarly, these methods have significant limitations, including: poor adjustability; high burst release of drug making drug dosage difficult to control; persistent pain (oil-based injections); and poor physical stability (suspensions). There is also little scope to adjust their performance, for example to easily incorporate multiple drugs or future drug candidates.

[0010] Injectable drug delivery systems also have potential use in cancer therapy. Current long-acting delivery systems include OncoGel TM a paclitaxel controlled release depot formulation utilising the ReGel TM platform. It forms a gel at body temperature and is a low viscosity solution at room temperature. It is therefore an example of a thermosensitive controlled release delivery system.

[0011] The present invention avoids or mitigates the above-mentioned problems in the prior injectable products for long-acting administration of drugs. In particular, the present invention aims to provide a system that can be easily administered and can contain multiple drugs in a single product. The present invention further avoids or mitigates the problem of requiring individual drug doses to be administered at a high frequency to treat diseases, in particular to treat cancer and mental illness. The present invention aims to provide a new contraceptive and HIV prevention drug delivery platform. The present invention further avoids or mitigates the problem of known long-acting drug formulations producing a relatively high initial drug concentration in the systemic area. SUMMARY

[0012] According to a first aspect of the present invention, there is provided a compound formed at least in part from a peptidomimetic molecule, wherein the compound is configured to link one or more drug molecules, wherein the compound is further configured to release the one or more drug molecules under physiological conditions, and wherein a solution of the compound forms a hydrogel in response to an endogenous enzyme of a human or animal.

[0013] Ideally, the endogenous enzyme is an enzyme that is typically found in the skin and throughout the body.

[0014] The peptidomimetic molecule can be one or more of the group comprising a peptoid, a D-peptide or a beta-peptide (e.g. a beta-isopeptide), an N-methyl peptide, a cyclic peptide or a gamma peptide.

[0015] The compound is soluble and can be formulated as a solution for injectable administration. As the solution containing the compound forms a hydrogel in response to the endogenous enzyme, the solution will form a hydrogel upon administration to the skin of a human or animal recipient. The solution is capable of forming a tissue-like hydrogel that can be tailored to gradually release the drug over at least 28 days, 42 days or 49 days, or the required dosing interval. This will eliminate the need for patients to comply with complex drug dosing regimens on a daily basis and improve their adherence to the drug.

[0016] Preferably, the compound comprises a peptidomimetic backbone formed from one or more of the group comprising a peptoid, a D-peptide or a beta-isopeptide. Peptoids, D-peptides or beta-isopeptides are peptide-like molecules that, unlike peptides, are not rapidly broken down by proteases.

[0017] The endogenous enzyme of the human or animal can be a phosphatase, an esterase, a protease, a matrix metalloproteinase, a thrombin, a trypsin such as chymotrypsin, a beta-galactosidase, a lipase, a transglutaminase, a thermolysin, a glucose oxidase, a peroxidase or a tyrosinase. Preferably, the solution of the compound forms a hydrogel in response to a phosphatase. Advantageously, as phosphatases are present in the skin and tissues, the solution forms a hydrogel upon administration to the skin or tissues. Ideally, the compound comprises a phosphonate group that drives the formation of the hydrogel when it is cleaved.

[0018] Preferably, the compound comprises a site for covalent attachment of a drug. The site for covalent attachment can be provided by an amino acid having a primary amine (-NH2) as its functional group or an R group that allows attachment of a drug. These include the amino acid arginine and the unnatural amino acid variants 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, ornithine, epsilon lysine. This unnatural form differs from lysine in the length of the carbon / methylene chain (-CH2) between its primary amine group (-NH2) and alpha-carbon.

[0019] Similarly, the carbon / methylene chain (-CH2) length can vary for various cysteine derivatives. Cysteine has one methylene unit between its thiol group (-SH) and alpha-carbon, while homocysteine has two methylene units. Penicillamine (the d-isomer of dimethylcysteine) is an amino acid derivative that can potentially replace cysteine as it also contains a thiol group (-SH).

[0020] The drug covalent attachment site can be the epsilon-amino group of lysine, or L- or D-cysteine. This allows the drug to be readily attached to the compound for use as an injectable delivery system for long acting administration of the drug.

[0021] Preferably, the one or more drugs are releasable from the compound by hydrolysis. Advantageously, the drug will be released from the compound under physiological conditions. The one or more drugs can be attached to the compound by an ester linkage, a carbamate linkage, an amide linkage, an ether linkage, a disulfide linkage, or a hydrazone linkage.

[0022] The drug that can be attached or is attached to the compound can be an HIV / AIDS antiretroviral drug, a contraceptive, an antipsychotic, or a cancer treatment drug. The drug can be zidovudine, MIV-150, cabotegravir, lamivudine, etonogestrel, haloperidol, or doxorubicin.

[0023] The compound can comprise an L-peptide. Replacing a D-peptide in the compound with an L-peptide can increase the rate of degradation of the compound in vivo.

[0024] The compound of the above aspects of the invention, when attached to a drug, can be used as a medicament. The compound can be configured for use in the prevention or treatment of AIDS, a mental illness, cancer, or as a contraceptive.

[0025] The compound can have the following formula:

[0026]

[0027] Preferably, the concentration of the compound, with or without a drug attached, is retained at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after incubation with proteinase K for 28 days. Thus, the compound is biostable and is not susceptible to breakdown by proteases after administration.

[0028] According to a second aspect of the application, there is provided an injectable delivery system for long-term administration of a drug, the system comprising a solution comprising a compound of the first aspect of the application, wherein the solution can be injected under the skin, and wherein upon injection and exposure to enzymes present in or under the skin, the compound forms a hydrogel. The compound can also be attached to a drug.

[0029] The system is in the form of a soluble injectable to improve the convenience of administration under the skin (subcutaneously or intramuscularly) or to improve the convenience of administration to parts of the body that are difficult to deliver to (the eye, the spine, tumours). The system forms a hydrogel implant in response to enzymes (phosphatases) present in the skin and systemically, to release the drug over a long period of time, thereby eliminating the need for multiple daily dosing.

[0030] The injectable delivery system can be used as a medicament and can be configured for the prevention or treatment of AIDS, depression, cancer, or as a contraceptive.

[0031] wherein the drug can be detected in the recipient’s body after at least 28 days, 42 days, or 49 days.

[0032] According to a third aspect of the application, there is provided a compound having the following formula.

[0033] BRIEF DESCRIPTION OF DRAWINGS

[0034] A specific embodiment of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings in which:

[0035] Figure 1 The chemical structure of a) a peptoid-peptide (PP4G), (NPhe)4(Gly)4(L / DLys)-(L / DTyr[H2PO4])-OH, which is a compound according to the application, and b) model drugs tested with the system of the application: HIV / AIDS antiretroviral drugs (zidovudine, lamivudine, MIV-150, cabotegravir), contraceptive drugs (etonogestrel), antipsychotic drugs (haloperidol), and anticancer drugs (doxorubicin) is shown.

[0036] Figure 2A synthetic route showing model drug conjugation to compound PP4G according to the application. a i) tert-butyldimethylsilyl chloride (TBDMSCl), imidazole, in anhydrous DMF (16 hours). ai i) 4,4'-dimethoxytrityl chloride (DMTrCl), in anhydrous pyridine. ai i i) tert- butylammonium fluoride (TBAF), in tetrahydrofuran (THF) (6 hours). b) succinic anhydride, 4-dimethyl-aminopyridine (DMAP), anhydrous pyridine (12 hours). c) N-hydroxysuccinimide (NHS), N,N'-diisopropylcarbodiimide (DIC), in chloroform (6 hours). Upon completion, filtered to remove N,N'-diisopropylurea (DIU). di) sodium bicarbonate (NaHCO3) [to pH 7.6], water, acetone (2 hours). di i) re-dissolved in trifluoroacetic acid (TFA), methanol, acetonitrile (overnight).

[0037] Figure 3 Concept of enzyme-responsive peptoid-peptide hydrogels, such as compounds of the application, for sustained release of drugs (e.g., using the HIV NRTI antiretroviral lamivudine shown) is shown. i) Formulation administered as a soluble subcutaneous injection. ii) Phosphatase removal of phosphate groups leads to rapid formation of a hydrogel depot under the skin. iii) Under physiological conditions, ester bond hydrolysis leads to sustained release of unchemically modified drug from the hydrogel.

[0038] Figure 4 Rheological analysis of 5% w / v hydrogel containing a peptoid-peptide with 4 glycines (PP4G) and 5 glycines (PP5G) and no drug linked according to the application is shown.

[0039] Figure 5 Rheological analysis of 5% w / v hydrogel containing a peptoid-peptide with 4 glycines (PP4G: D peptide at KY amino acid position) covalently linked with the HIV / AIDs drug cabotegravir according to the application is shown. Storage modulus data is represented by solid circles and loss modulus by non-solid circles.

[0040] Figure 6 Rheological analysis of 5% w / v hydrogel containing a peptoid-peptide with 4 glycines (PP4G: L peptide at KY amino acid position) covalently linked with the HIV / AIDs drug zidovudine according to the application is shown. Storage modulus data is represented by solid circles and loss modulus by non-solid circles.

[0041] Figure 7Rheology analysis of 5% w / v hydrogel containing 4 glycine containing peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked with the HIV / AIDs drug MIV-150. Storage modulus data is represented by solid circles and loss modulus by non-solid circles.

[0042] Figure 8 Rheology analysis of 5% w / v hydrogel containing 4 glycine containing peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked with the contraceptive drug engest.

[0043] Figure 9 Rheology analysis of 5% w / v hydrogel containing 4 glycine containing peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked with the HIV / AIDs drug MIV-150 and the contraceptive drug engest also linked to separate PP4G molecules. These were mixed and formulated in a 9:1 ratio (PP4G-MIV-150:PP4G-ENG) as the potency of engest is very strong and therefore present in lower ratio in this formulation mixture.

[0044] Figure 10 Rheology analysis of 5% w / v hydrogel containing 4 glycine containing peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked with the antipsychotic drug haloperidol.

[0045] Figure 11 Biostability of peptide and peptoid-peptide hydrogel forming molecules according to the present application after 28 days incubation with the broad spectrum protease proteinase K. L-peptide NapFFKY(p)G-OH (small circles) and D-peptide NapffkY(p)G-OH (upright triangles) are peptide only controls which also form hydrogels in response to phosphatases.

[0046] Figure 12 Cumulative release of zidovudine (AZT) from physical encapsulation and chemical linkage to peptoid-peptide compounds according to the present application as well as L-peptide and D-peptide controls over 28 days in pH 7.4 phosphate buffer solution. Data relates to a) drug release over 28 days and b) the first 72 hours of drug release. It can be demonstrated that drug burst is reduced by 30-60% when conjugated chemically compared to physical mixing (see also Figures 13 to 16). Legend: (NPhe)4GGGGKY(p)-OH: peptoid-peptide containing 4 glycines (PP4G) and the L-enantiomer of the amino acids lysine (K) and tyrosine (Y); NapFFKY(p)G-OH: L-peptide hydrogel control; Napffky(p)G-OH: D-peptide hydrogel control.

[0047] Figure 13 Cumulative release of cabotegravir (CAB) from physical encapsulation and chemical linkage into peptoid-peptide compounds according to the application is shown over 28 days in pH 7.4 phosphate buffered solution. Data relate to a) drug release over 28 days, and b) the first 72 hours of drug release. Legend: (NPhe)4GGGGky(p)-OH: peptoid-peptide containing 4 glycines (PP4G) and the D-enantiomer of the amino acids lysine (k) and tyrosine (y).

[0048] Figure 14 Cumulative release of MIV-150 and etonogestrel (ENG) from physical encapsulation and chemical linkage into peptoid-peptide compounds according to the application is shown over 28 days in pH 7.4 phosphate buffered solution. Data relate to a) drug release over 28 days, and b) the first 72 hours of drug release. Legend: (NPhe)4GGGGky(p)-OH: peptoid-peptide containing 4 glycines (PP4G) and the D-enantiomer of the amino acids lysine (k) and tyrosine (y).

[0049] Figure 15 Cumulative release of haloperidol from physical encapsulation and chemical linkage into peptoid-peptide compounds according to the application is shown over 28 days in pH 7.4 phosphate buffered solution. Data relate to a) drug release over 28 days, and b) the first 72 hours of drug release.

[0050] Figure 16 a) In vivo zidovudine (AZT) drug plasma concentrations obtained over 35 days following subcutaneous administration of peptoid-peptide (PP4G), D-peptide containing variant in Sprague Dawley rats (n=6). Subcutaneous administration of PP4G (AZT) to Sprague Dawley rats showed that zidovudine (AZT) plasma concentrations were within the IC 50 range (30 to 130 ng / mL; indicated by horizontal bars) over 35 days. b) Body weight of Sprague Dawley rats (n=6) in control, intravenous and subcutaneous administration groups at the beginning (day 0) and end (day 35) of the experiment.

[0051] Figure 17 Sprague Dawley rats in vivo plasma concentrations of MIV-150 and etonogestrel (ENG) with peptoid-D-peptide drug administered alone are shown.

[0052] Figure 18 The plasma concentrations of MIV-150 and etogestrin (ENG) in Sprague-Dowley rats are shown, with the peptide-D-peptide drug administered as a combination product MIV-150:ENG (ratio of 8:2). Detailed Implementation

[0053] Examples of compounds according to the present invention have the following molecular formula

[0054]

[0055] This compound is a peptide-like substance containing four glycine residues, referred to herein as PP4G. When in solution and exposed to phosphatases, it can form a hydrogel.

[0056] refer to Figure 1 Structure a), i.e., the compound described above, provides a hydrogel-forming sequence 1 composed of aromatic functional groups, which can self-assemble into a hydrogel due to intermolecular interactions (e.g., π-π stacking of benzene rings, hydrogen bonding of amide groups). It serves as a peptide mimic backbone. In the embodiments provided above, the backbone is formed from peptide-like molecules and D-peptides, but alternative peptide mimic molecules can be used if desired.

[0057] The L or D peptide sequence can be selected at lysine and / or tyrosine 2 to modify the biostability / degradation of a specific dosing interval. When attached to the peptide mimic backbone, the phosphate group 3 imparts solubility. When this phosphate group is removed by phosphatases, for example, in the subcutaneous skin space, this acts as a physiological trigger, driving rapid hydrogel formation.

[0058] The compound also has sites for linking drug molecules. These linking sites can be the ε-amino group of lysine, or L- or D-cysteine. Lamivudine, MIV-150, and capecitabine can be covalently linked to embodiments of the invention via an ester-amide exchange reaction of succinic acid (drug-succinimide-NHS active ester) with the ε-amino group of lysine 4 (in...). Figure 2This ester-drug bond is readily hydrolyzed under physiological conditions (pH 7.4, H20, esterase) to release the unmodified drug from the peptoid-peptide hydrogel. Combining different types of HIV drugs such as these has clinical rationale because they will produce a synergistic effect through different antiviral modes of action. Etonogestrel (contraceptive) and haloperidol (antipsychotic) can also be covalently added to peptoid-peptides because it contains a single -OH group. Doxorubicin can be precisely conjugated to the thiol of L or D-cysteine through a Michael addition reaction involving a maleimide-glycine linker. In this case, the L or D-lysine of the peptoid-peptide is replaced with L or D-cysteine to enable covalent drug attachment.

[0059] Referring now to Figure 2 , Lamivudine (as shown) requires an additional synthetic step (a) to protect the active amine group (-NH2). MIV-150 (as shown) and Cabotegravir follow the same synthetic route and do not require this initial protection step. Then, the antiretroviral drugs follow similar synthetic steps (b-d) to activate the succinic anhydride to protect Lamivudine 5 and MIV-150 6. This creates a functional group that allows direct attachment (step d) to the terminal primary amide pendant group of the peptoid-peptide gelling agent to form an ester bond.

[0060] Referring now to Figure 4 , the figures show PP4G storage modulus 7, PP4G loss modulus 8, PP5G storage modulus 9, and PP5G loss modulus 10. The gel stiffness of PP4G and PP5G, defined by the frequency sweep (a), and the gel strength of PP4G and PP5G, defined by the strain sweep (b), are similar. However, PP4G gels faster in response to phosphatase. This is more advantageous for long-acting injectable administration. The rapid gel formation after injection acts as an additional diffusion barrier to prevent water from entering and leaving the gel. Water causes the breakage / hydrolysis of the drug-peptoid / peptide bond and transports the drug out of the hydrogel, resulting in a faster burst release of the drug.

[0061] Figure 5 Rheology data showing one embodiment of the present invention where PP4G is covalently bound to the HIV / AIDs drug Zidovudine. Figure 5 a) shows that drug attachment results in a slight decrease in gel stiffness compared to PP4G without drug attachment (see Figure 4 ). b) the gel strength of PP4G with attached Cabotegravir and PP4G without drug attachment is similar. c) PP4G covalently attached to Cabotegravir requires about 4 minutes to gel in the presence of phosphatase.

[0062] Figure 6 Rheology data showing one embodiment of the present invention where PP4G is covalently bound to the HIV / AIDs drug Zidovudine.Figure 6 The PP4G linked to the drug exhibits similar gel stiffness (a) and strength (b) compared to PP4G alone. c) Gel formation occurs about 45 minutes after exposure to phosphatase.

[0063] Figure 7 Rheology data showing one embodiment of the application where PP4G is covalently bound to the HIV / AIDs drug MIV-150. Figure 6 The PP4G linked to the drug exhibits similar gel stiffness (a) and strength (b) compared to PP4G alone. c) Gel formation occurs about 45 minutes after exposure to phosphatase.

[0064] Figure 8 Rheology analysis of a 5% w / v hydrogel containing a 4-glycine peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked to the contraceptive drug ethinyl estradiol is shown. The gel stiffness (a) is similar to PP4G alone; the storage modulus data is represented by solid circles and the loss modulus by non-solid circles. The gel strength (b) of the PP4G-EE hydrogel is slightly weaker compared to PP4G alone; the storage modulus 10 and loss modulus 11 are shown. c) Gel formation also occurs about 12 minutes after exposure to phosphatase; the storage modulus 10 and loss modulus 11 are shown.

[0065] Figure 9 Rheology analysis of a 5% w / v hydrogel containing a 4-glycine peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked to the HIV / AIDs drug MIV-150 and also to the contraceptive drug ethinyl estradiol on separate PP4G molecules is shown. These are mixed and formulated in a 9:1 ratio (PP4G-MIV-150:PP4G-EE) as the ethinyl estradiol is very potent and therefore is present in a lower ratio in this formulation mixture. The gel stiffness is shown to be slightly weaker (a) and the gel strength similar (b) compared to PP4G alone. c) Gel formation occurs about 30 minutes after exposure to phosphatase. The storage modulus 13 and loss modulus 14 are shown.

[0066] Figure 10 Rheology analysis of a 5% w / v hydrogel containing a 4-glycine peptoid-peptide (PP4G: D-peptide at ky amino acid position) according to the present application covalently linked to the anti-psychotic drug haloperidol is shown. The gel stiffness (a) and strength (b) are similar compared to PP4G alone. ci) Gel formation also occurs immediately upon exposure to phosphatase and a fully formed gel stiffness appears after about 270 minutes.

[0067] Reference is now made to Figure 11In the presence of proteinase-K, L-peptides rapidly degrade within hours. D-peptides exhibit significant stability after 28 days of exposure to proteinase-K. L-peptide variants of peptoid-peptides PP4G and PP4G-MIV-150, where the K (lysine) and Y (tyrosine) amino acids are L-enantiomers, disintegrate within days of proteinase K exposure. D-peptide variants of peptoid-peptide PP4G, where the k and y amino acids are non-natural D-enantiomers, remain significantly stable over 28 days of exposure, with about 90% of the compound concentration remaining after 28 days. Thus, biological stability can be tailored, for example, to disintegrate within a specific dosing interval, so as to allow administration of the next dose of PP4G+ drug.

[0068] Figure 12 It was shown that when zidovudine is chemically bound to the compounds of the present invention, the cumulative release of zidovudine is slower compared to physical mixtures of the peptide and zidovudine. Similar results were obtained for cabotegravir ( Figure 13 ), MIV-150 and etonogestrel ( Figure 14 ), and haloperidol ( Figure 15 ).

[0069] Natural peptides are components of proteins and tissues. They are composed of L-amino acids / L-peptides. Due to their high biocompatibility, they are promising for use as drug releasing hydrogel implants for subcutaneous administration, but are limited by their rapid degradation by enzymes in the human body within hours. Embodiments of the present invention overcome the stability problem by using peptide mimics, in particular a combination of peptoids and D-peptides, which retain the excellent properties of peptides (e.g. biocompatibility, ease of drug attachment) and have the ability to form stable hydrogels over the duration of treatment.

[0070] The compounds of the present invention can be tailored to degrade in vivo by converting D-peptides to L-peptides (and vice versa), over a period of months, degrading to non-toxic components that are excreted from the patient’s body, meaning that the implant does not need to be surgically removed.

[0071] The compounds of the present invention have a high degree of chemical versatility (i.e. a wide selection of chemical functional groups). Thus, a wide variety of drugs can be directly attached to the peptide mimic hydrogel that can be formed from a solution of the compound, so that a large amount of drug can be added to meet the in vivo treatment needs for at least 28 days or the desired dosing interval.

[0072] Upon hydrogel formation, the drug is released within seconds / minutes under physiological conditions, reducing the likelihood of a rapid burst release of the drug upon injection. The drug release shows the potential for sustained administration of the drug to minimize the pharmacokinetic peaks and troughs of drug concentration. According to the present invention, the peptoid-peptides described herein are deliberately manufactured small molecules that are inexpensive to manufacture, increasing their potential for clinical translation into a drug product and effective use within the healthcare budget, benefiting patients and society.

[0073] The concept of the present invention has been demonstrated with the following drugs:

[0074] - zidovudine, MIV-150, cabotegravir, lamivudine (HIV / AIDS antiretroviral drugs)

[0075] - etonogestrel (contraceptive), alone or in combination with MIV-150

[0076] - haloperidol (antipsychotic)

[0077] - doxorubicin (cancer).

[0078] Rheological analysis indicates phosphatase-directed self-assembly, with hydrogel formation within minutes. Peptoid-peptides containing D-amino acids at lysine (k) and tyrosine (y) positions are particularly promising for long-acting delivery and exhibit protease resistance. Release of the drug through hydrolysis of the drug-peptide linkage (e.g., ester bond) occurs under physiological conditions (37 °C, pH 7.4, H2O). Subcutaneous administration of peptoid-peptides covalently linked to zidovudine to Sprague-Dawley rats indicates that plasma concentrations of zidovudine are within the range of half-maximal inhibitory concentrations (IC 50 ) for 35 days (30 to 130 ng / mL).

[0079] The present invention overcomes the limitations of existing products by using a superior in situ forming, enzyme-responsive, peptidomimetic hydrogel drug delivery system. The use of this stimulus-responsive self-assembling peptidomimetic system as a long-acting in situ slow-release implant has not been previously investigated.

[0080] Figure 2 The synthesis of drug-linked peptoid-peptides is outlined. Overall, these motifs have multiple advantages over existing drug delivery systems. Specifically, the implants will be administered as low-viscosity and low-volume soluble injections, improving the convenience of user administration through the use of narrower bore needles. Since the present invention is a soluble injection, there are no physical stability issues observed with suspensions.

[0081] Upon administration (in Figure 3In response to the presence of phosphatases in the subcutaneous tissue, the hydrogel forms rapidly, with fast sol-gel kinetics (see Concept 2 for a complete overview). The gelation tendency was confirmed by the vial inversion test, where the "gel" remained suspended. The fibrous structure of the hydrogel was confirmed by scanning electron microscopy (SEM).

[0082] In addition to the chemical linkage of the drug to the peptoid-peptide, the hydrogel fibers provide a diffusion barrier for drug release, giving it sustained release properties and reducing the burst release of the drug. The formation of the gel can only be truly proven by rheological analysis. We obtained promising data, observing the formation of the hydrogel within minutes of exposure to phosphatases (rheological data for each peptoid-peptide + drug, Figures 4 to 10 ).

[0083] The drug can be covalently linked to the hydrogel-forming molecules of the present invention from the start. Peptidomimetics offer a wide selection of chemical functionalities that can directly and precisely link the drug to our hydrogel-forming molecules through labile ester bonds. Drug release will be controlled by the hydrolysis of this ester bond (see Concept Figure 3 iii), with a 30% to 60% reduction in the burst release of the drug ( Figure 12 ) when comparing the chemically conjugated drug to the physically mixed control drug. The peptidomimetic motif can be changed to allow for other bonds that are broken in the physiological environment (e.g., amide bonds), enabling the attachment of a variety of drugs and the control of their release rate.

[0084] As shown in Figure 16 , subcutaneous administration of PP4G (AZT) in the form of a D-peptide to Sprague Dawley rats showed that the plasma concentration of zidovudine (AZT) was at least in the IC 50 range of HIV (30 to 130 ng / mL) for at least 35 days. Preliminary results showed no toxicity, as the body weight of Sprague Dawley rats (n = 6) in the control group was similar to that of the intravenous and subcutaneous administration groups and the negative control group (without peptoid-peptide or drug) at the beginning (day 0) and end (day 35) of the experiment.

[0085] Unlike other stimuli-responsive in situ systems currently being studied, which detrimentally rely on organic solvent exchange, photo-initiation, thermoresponsive polymers, or pH-induced gelation, the system of the present invention utilizes endogenous enzymes as a safer, faster, and more convenient mechanism to trigger gelation.

[0086] There is also a need for in-situ forming systems that can deliver poorly water soluble drugs and enhance control over the release rate. One approach to increase solubility is to directly attach the drug to a water soluble polymer. In one embodiment, the hydrogel forming peptidomimetic compounds of the present invention have a single drug conjugable group that enables precise drug attachment and increased drug solubility, enabling stronger drug homogeneity and loading, and allows for the rate of drug release from the peptide-based hydrogel to be modulated (i.e., stimuli-responsive hydrogel formation and drug release / hydrolysis).

[0087] Peptide-based hydrogels are more amenable to manipulation at the molecular scale compared to synthetic polymers, with the ability to modulate features such as drug release, viscoelasticity, and mechanical properties. Furthermore, unlike traditional contraceptive implants, the peptide-based implants of the present invention biodegrade over time, eliminating the need for surgical removal. The compounds of the present invention can be formed as a solid powder formulation that dissolves in sterile water / buffer (e.g., water for injection) immediately prior to injection, i.e., at the medical center / clinic, which will reduce the impact of temperature fluctuations and lack of infrastructure in developing countries.

[0088] Figure 15 L-peptide variants of peptoid-peptide PP4G and PP4G-MIV-150 were demonstrated, where the K amino acid (lysine) and Y amino acid (tyrosine) are L-enantiomers, which break down within days of protease K exposure. D-peptide variants of peptoid-peptide PP4G, where the k and y amino acids are non-natural D-enantiomers, remained significantly stable over 28 days of exposure. Thus, biostability can be tailored, e.g., to break down within a specific dosing interval, in order to allow for administration of the next dose of PP4G+drug.

[0089] The drug attached to the peptidomimetic molecule and administered to the recipient is detectable at least 7, 14, 21, 28, 35, 42, or 49 days later. Figure 17 and Figure 18 It was shown that even 42 days ( Figure 18 ) or 49 days ( Figure 17 ) after administration, the drug attached to the peptidomimetic molecule of the present invention (MIV-150 or etonogestrel in this example) was still detectable. Figure 18 The data in FIG. 7 show that a single injectable product can systemically deliver multiple drugs. When a single injection was administered using our platform, clinically relevant concentrations of MIV-150 ( Figure 18 a, b) and the contraceptive drug ENG ( Figure 18 c) were systemically detectable over 42 days.

[0090] In addition to the above, the presence of phosphate groups on the compounds of the present application ensures that the product is in a soluble liquid form upon addition of water, facilitating easy administration to the patient's skin site by injection. The presence of phosphatases in the skin leads to removal of the phosphate groups, thereby reducing the overall solubility of the molecule and leading to the formation of a hydrogel Figure 3 ii).

[0091] The physiological environment under the skin (pH 7.4, 37°C, H20) leads to hydrolysis of the bond between the drug and the peptidomimetic, resulting in sustained release of the drug from the hydrogel network, i.e. reduced initial diffusion (burst) of the drug. Sustained drug release will minimize the peak and trough of the pharmacokinetics of the drug concentration. Other advantages associated with the peptidomimetic are as follows:

[0092] • Peptidomimetics have higher chemical versatility compared to conventional polymers, allowing precise drug conjugation and the ability to add specific enzyme-cleavable groups to control hydrogel formation.

[0093] • Peptidomimetics and their biodegradation products will act as structural mimics of peptides and will be biocompatible.

[0094] • The drug is directly conjugated to the hydrogel motif of the peptidomimetic, thereby overcoming the limitation of existing long-acting injectable formulations, i.e. low water solubility, which limits drug loading / therapeutic efficacy.

[0095] • Peptidomimetics will be more stable to protease degradation than the corresponding peptides and will maintain their hydrogel matrix and release properties for a longer period of time (increased half-life).

[0096] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs.

[0097] Where a range of values is provided, for example, a concentration range, a percentage range, or a ratio range, it is to be understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, and any other stated or intervening value or

[0098] It should be understood that the terms “a” and “one,” as used in the preceding and elsewhere in this text, mean “one or more” of the enumerated components. To those skilled in the art it will be clear that the use of the singular includes the plural unless specifically stated otherwise. Thus, the terms “a,” “one,” and “at least one” are used interchangeably herein.

[0099] Unless otherwise indicated, the use of numbers in the specification and claims to express quantities, properties, etc. (e.g., dimensions, weight, reaction conditions, etc.) are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated, the numerical parameters listed in the following specification and attached claims are approximations. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Moreover, all ranges disclosed herein are to be understood to be inclusive of the endpoints described.

[0100] Throughout this application, various embodiments are described using “comprising” language; however, it will be understood by those skilled in the art that, in certain situations, “comprising” can be replaced by “consisting essentially of’ or “consisting of.”

Claims

1. A compound at least partially formed of peptide mimic molecules, wherein: The compound is configured to link one or more drug molecules; The compound is also configured to release one or more drug molecules under physiological conditions; The solution of the compound responds to phosphatase to form a hydrogel; The compound comprises a peptide mimicry backbone formed from one or more of the group consisting of peptides, D-peptides, or β-isopeptides; Phosphate groups, which drive hydrogel formation when cleaved; and drug covalently linked sites.

2. The compound of claim 1, wherein the drug covalent linking site is provided by an amino acid having a primary amine (-NH2) as its drug-linking functional group.

3. The compound according to claim 2, wherein the drug covalently linked site is the ε-amino group of lysine, or L- or D-cysteine.

4. The compound according to any one of the preceding claims, wherein the one or more drugs are capable of being released from the compound by hydrolysis.

5. The compound according to any one of the preceding claims, wherein the one or more drugs are linked to the compound via an ester bond, a carbamate bond, an amide bond, an ether bond, a disulfide bond, or an hydrazone bond.

6. The compound according to any one of the preceding claims, wherein the drug capable of being linked to the compound is an HIV / AIDS retroviral drug, a contraceptive, an antipsychotic, or a cancer treatment drug.

7. The compound according to claim 6, wherein the drug is zidovudine, MIV-150, capecitabine, lamivudine, etogestene, haloperidol, or doxorubicin.

8. The compound according to any one of the preceding claims, wherein the compound comprises an L-peptide.

9. The compound according to any one of claims 1 to 8, wherein the compound has the following formula:

10. The compound of any one of the preceding claims, linked to a drug, for use as a pharmaceutical agent.

11. The compound according to claim 10, which is used for the prevention or treatment of AIDS, mental illness, cancer, or as a contraceptive.

12. The compound according to any one of the preceding claims, wherein the concentration of the compound, whether linked or not, is retained at least 10% after incubation with proteinase K for 28 days.

13. An injectable delivery system for long-acting administration of a drug, the system comprising a solution containing a compound of any one of the preceding claims linked to the drug, wherein the solution is injectable under the skin, and wherein, upon injection and exposure to an enzyme within or under the skin, the compound forms a hydrogel.

14. The injectable delivery system of claim 13, comprising a compound of any one of claims 1 to 12 linked to a first drug substance, and a compound of any one of claims 1 to 12 linked to a second drug substance, wherein the second drug substance is chemically different from the first drug substance.

15. The injectable delivery system of claim 13 or 14, used as a pharmaceutical agent.

16. The injectable delivery system of claim 15, for the prevention or treatment of AIDS, depression, cancer, or as a contraceptive.

17. The injectable delivery system according to any one of claims 13 to 16, wherein the drug can be detected in the recipient after at least 28 days.

18. The injectable delivery system of claim 17, wherein the drug can be detected in the recipient after at least 49 days.

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