Treatment of Neuropathy

Abstract

The present invention relates to the use of compositions and medicaments for treating or alleviating symptoms of neurological disorders such as Parkinson's disease and Alzheimer's disease. These objectives can be achieved with the formulation of a drug to inhibit or suppress the expression of TGF-β alone or in combination with apomorphine-based drug formulations.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that was created on August 30, 2022 and submitted electronically as an ASCII file with filename 018988-004WO1_SL.TXT and is 1864 bytes in size.

[0002] The present invention relates to therapeutic agents for treating or alleviating symptoms of neurological disorders, including Parkinson's disease. More specifically, the present invention discloses apomorphine-based compositions and drugs, and drugs for inhibiting or suppressing the expression of TGF-β, providing improved clinical outcomes for such diseases. The present invention provides stable formulations and methods of use of anti-TGF-β drugs, including apomorphine-based drugs and antisense oligonucleotide compositions, for neurological disorders, including Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, and excessive daytime sleepiness. [Background technology]

[0003] Parkinson's disease (PD) is the second most common neurological disorder. In recent years, non-motor symptoms of PD, such as excessive daytime sleepiness (EDS) and sexual dysfunction, have attracted attention. EDS is an inability to maintain wakefulness and alertness during the day, resulting in a state of uncontrollable sleepiness and sleep. EDS is the major health disorder in PD, affecting up to three-quarters of all PD patients. Thus, conventional methods and compositions for treating neurological disorders such as PD symptoms, including EDS and sexual dysfunction, have significant shortcomings in efficacy and side effects.

[0004] Apomorphine is a dopamine receptor agonist and has been used intranasally as an adjunct to Parkinson's disease. See T. van Laar et al., Arch. Neurol, 49: 482-484 (1992). Intranasal delivery of apomorphine for Parkinson's disease is disclosed in U.S. Patent No. 5,756,483. However, apomorphine has only been used for the "off-period" symptoms of Parkinson's disease. Thus, conventional methods and compositions for treating PD have significant drawbacks.

[0005] There is an urgent need for compositions and methods for treating PD symptoms, including EDS and sexual dysfunction.It would be beneficial to treat the early stage of PD with drugs such as apomorphine.In addition, since excessive TGF-β is expected to be built up in the later stage of PD, it is desirable to treat the later stage of PD with drugs such as apomorphine in combination with TGF-β inhibitors.

[0006] There has long been a need for the development of a safe, reliable intranasal formulation of apomorphine-based drugs for the treatment of neurological disorders that has few side effects and is fast acting.

[0007] There is an urgent need for methods and compositions for inhibiting and / or suppressing TGF-β that provide positive clinical outcomes in the treatment of neurological disorders and related conditions, such as Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, and excessive daytime sleepiness. Summary of the Invention

[0008] The present invention provides therapies, compositions, and methods for treating or alleviating the symptoms of neurological disorders.

[0009] In some embodiments, the present invention comprises drugs and compositions for inhibiting or suppressing TGF-β to provide improved clinical outcomes of neurological disorders.

[0010] In further embodiments, the present invention provides stable formulations of anti-TGF-β drugs for various treatments for neurological disorders. Examples of anti-TGF-β drugs include TGF-β inhibitors such as antisense oligonucleotides, artemisinin, its pharma- ceutically acceptable salt forms, esters, polymorphs or stereoisomers, and combinations thereof.

[0011] In general, the pathology of neuropathy is unpredictable, so new treatments will depend on clinical studies in different patient populations.

[0012] In a further aspect, the present disclosure provides a highly stable formulation of anti-TGF-β drug for the treatment of neurological disorders. The stable formulation of the present invention provides surprisingly improved clinical results. The stable formulation of drug for suppressing TGF-β can be used to alleviate the symptoms of neurological disorders and to alleviate the disease effects.

[0013] The methods and compositions of the present invention can be used to inhibit or suppress factors in the unpredictable pathology of neuropathy. In some embodiments, the present disclosure provides methods and compositions for inhibiting the activity of TGF-β and / or suppressing TGF-β-related pathology, which can improve the effectiveness of treating or alleviating the symptoms of neuropathy.

[0014] The compositions and formulations of the present disclosure can be used to inhibit and / or suppress TGF-β and can provide good clinical results for treating neurological disorders.

[0015] In some embodiments, enhanced treatments and formulations for treatment are discovered. For example, the improved compositions of the present disclosure can be used to treat or reduce symptoms of neurological disorders such as Parkinson's disease and Alzheimer's disease.

[0016] In some embodiments, the apomorphine-based composition of the present invention can be used to treat or reduce symptoms of neurological disorders, including Parkinson's disease and Alzheimer's disease, such as sexual dysfunction, erectile dysfunction and / or excessive daytime sleepiness.The improved apomorphine-based formulation of the present invention can control oxidation to improve purity and potency, and reduce side effects.The dosage of apomorphine-based drugs can be reduced in treating symptoms of neurological disorders, including Parkinson's disease and Alzheimer's disease.

[0017] In a further embodiment, the drug of the present invention for inhibiting the activity of TGF-β and / or suppressing TGF-β-related pathology can be used to treat or reduce symptoms of neurological disorders, including sexual dysfunction and excessive daytime sleepiness (EDS), in neurological disorders such as Parkinson's disease.The improved TGF-β suppression formulation of the present invention can counter the increase in TGF-β in Parkinson's disease pathology, reduce sexual dysfunction and EDS symptoms, and improve the effectiveness of treatment.

[0018] In a further embodiment, the present invention provides a therapy for treating a neurological disease or disorder by combining the use of a drug to inhibit or suppress the expression of TGF-β with the use of apomorphine, a prodrug of apomorphine, or a pharma- ceutically acceptable salt or ester thereof. This combination therapy can be used for symptoms of neurological diseases or disorders, including Parkinson's disease and Alzheimer's disease, such as male or female sexual dysfunction and / or excessive daytime sleepiness.

[0019] Embodiments of the present invention include the following.

[0020] A therapeutic composition for treating a neurological disease or disorder comprising a therapeutically effective amount of apomorphine, a prodrug of apomorphine, or a pharma- ceutically acceptable salt or ester thereof.

[0021] The therapeutic composition as described above, wherein the neurological disease or disorder is Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, or excessive daytime sleepiness.

[0022] The above therapeutic composition, wherein the neurological disease or disorder is early or late stage Parkinson's disease.

[0023] The above therapeutic composition, wherein the apomorphine is apomorphine hydrochloride.

[0024] The therapeutic composition as described above is suitable for intrathecal injection, infusion, or intranasal use.

[0025] The above therapeutic composition, which is a nasal powder formulation.

[0026] The therapeutic composition may be an aqueous or non-aqueous formulation comprising any one or more of a pH buffer, a thickening agent, a humectant, a preservative, and one or more pharmaceutical excipients.

[0027] The therapeutic composition is an aqueous gel solution, an aqueous suspension, an aqueous liposomal dispersion, an aqueous emulsion, an aqueous microemulsion, or a combination thereof.

[0028] The therapeutic composition described above is an aqueous solution having a drug concentration of 5 mg / mL or 10 mg / mL.

[0029] The therapeutic composition comprising a buffer selected from acetate, citrate, prolamine, carbonate, phosphate, and combinations thereof.

[0030] The therapeutic composition comprising a viscosity enhancing agent selected from methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

[0031] The therapeutic composition comprises a moisturizer selected from sorbitol, glycerol, mineral oil, vegetable oil, and combinations thereof.

[0032] The therapeutic composition described above, comprising a bioadhesive excipient.

[0033] The therapeutic composition comprises one or more of glycerin, glycol, propylene glycol, polyethylene glycol, polyethylene glycol 400, ascorbic acid, sodium ascorbate, disodium edetate, and sodium metabisulfite.

[0034] The above therapeutic composition, in which apomorphine is dispersed for improved solubility.

[0035] The therapeutic composition above which is active for between 15 and 60 minutes.

[0036] The therapeutic composition as described above, comprising a nasal dosage form of 0.5 mg or 1 mg in 0.1 mL per actuation.

[0037] The therapeutic composition as described above, comprising an intranasal formulation comprising one or more of an antioxidant, an antibacterial agent, a chelating agent, a preservative, and combinations thereof.

[0038] The therapeutic composition as described above, including an intranasal formulation dispensed with oxygen and nitrogen.

[0039] The therapeutic composition as described above, comprising a nasal formulation having a pH of 3.4.

[0040] The therapeutic composition as described above, comprising a nasal formulation that is stable after 3 months at 40° C. / 60% RH or after 24 months at 25° C. / 60% RH.

[0041] The therapeutic composition has reduced adverse or side effects and is medicamentally tolerable.

[0042] Use of the above therapeutic composition to treat or alleviate symptoms of a neurological disease or disorder in a human subject.

[0043] The above uses, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0044] Use of the above therapeutic composition in the manufacture of a medicament for treating or alleviating a symptom of a neurological disease or disorder in a human subject.

[0045] The above uses, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0046] Use of the above therapeutic composition to treat or alleviate symptoms of a neurological disease or disorder in a human subject, in combination with a standard therapeutic treatment for that disease or disorder.

[0047] The above uses, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0048] Use of said therapeutic composition for treating or alleviating the symptoms of a neurological disease in the human or animal body.

[0049] The above uses, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0050] A method for treating or alleviating a symptom of a neurological disease or disorder comprising administering the composition described above.

[0051] The above method, wherein the neurological disease or disorder is early or late stage Parkinson's disease.

[0052] The above method, wherein the administration is intranasal administration.

[0053] A therapeutic composition for treating a symptom of a neurological disease or disorder comprising a therapeutically effective amount of a drug for inhibiting or suppressing the expression of TGF-β.

[0054] The therapeutic composition as described above, wherein the neurological disease or disorder is Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction, or excessive daytime sleepiness.

[0055] The above therapeutic composition, wherein the neurological disease or disorder is early or late stage Parkinson's disease.

[0056] The above therapeutic composition further comprises one or more pharma- ceutically acceptable excipients selected from diluents, stabilizers, disintegrants and anti-caking agents.

[0057] The therapeutic composition described above, comprising one or more excipients selected from microcrystalline cellulose, polysorbate 80, crospovidone, croscarmellose sodium, and magnesium stearate.

[0058] The therapeutic composition as described above, which is suitable for use by intrathecal injection or infusion.

[0059] The therapeutic composition has reduced adverse or side effects and is medicamentally tolerable.

[0060] The above therapeutic composition, wherein the drug for inhibiting or suppressing the expression of TGF-β is an antisense oligonucleotide or inhibitor specific to TGF-β1, TGF-β2, or TGF-β3.

[0061] The drug for inhibiting or suppressing the expression of TGF-β is a TGF-β2 specific antisense oligonucleotide having any one of SEQ ID NOs: 1 to 9. SEQ ID NO:1, gtaggtaaaa acctaatat SEQ ID NO:2, gttcgtttag agaacagatc SEQ ID NO:3, taaagttcgt ttagagaaca g SEQ ID NO:4, agccctgtat acgac SEQ ID NO:5, gtaggtaaaa acctaatat SEQ ID NO:6, cgtttagaga acagatctac SEQ ID NO: 7, cattgtagat gtcaaaagcc SEQ ID NO:8, ctccctcatg gtggcagttg a SEQ ID NO: 9, cggcatgtct attttgta Chemically modified variants thereof, artemisinin extracts, and pharma- ceutically acceptable salts, salt polymorphs, esters, or isomers thereof, and any combination thereof. The above therapeutic composition is selected from the following:

[0062] The therapeutic composition as described above, wherein the drug for inhibiting or suppressing the expression of TGF-β comprises an artemisinin extract having a purity of 90-95%, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, and one or more pharma- ceutically acceptable excipients.

[0063] The therapeutic composition as described above, comprising a carrier comprising sterile water for injection, saline, isotonic saline, or a combination thereof.

[0064] The therapeutic composition as described above, which is substantially free of excipients.

[0065] The therapeutic composition above, wherein the composition is stable in the carrier at 37° C. for at least 14 days.

[0066] The above therapeutic compositions, wherein the composition is reconstituted from a lyophilized powder of the composition.

[0067] Use of the above therapeutic composition to treat or alleviate symptoms of a neurological disease or disorder in a human subject.

[0068] 49. The use of claim 48, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0069] Use of the above therapeutic composition to treat or alleviate symptoms of a neurological disease or disorder in a human subject, in combination with standard therapeutic treatment for the disease or disorder.

[0070] 51. The use of claim 50, wherein the standard of care comprises one or more additional medications including anti-inflammatory agents, anti-inflammatory steroids, piperiquine, pyronaridine, curcumin, frankincense, remdesivir, sonpraz D, Zifi CV / Zac D, CCM, Broclear, Budamate, Lapitas, Montec LC, low molecular weight heparin, prednisolone, paracetamol, B vitamin complex, vitamin C, pantoprozole, doxycycline, ivermectin, zinc, folacort rotacap inhalation, ceftriaxone injection, paracetamol tablets, fragmin injection, covifor tablets, azithromycin, dexamethasone injection, odourdansetron injection, multivitamin tablets, ascorbic acid tablets, calcium carbonate tablets, and zinc sulfate tablets.

[0071] 51. The use of claim 50, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0072] Use of said therapeutic composition for treating or alleviating the symptoms of a neurological disease in the human or animal body.

[0073] 54. The use of claim 53, wherein the neurological disease or disorder is early or late stage Parkinson's disease, Alzheimer's disease, or male or female sexual dysfunction.

[0074] A method for treating or alleviating a symptom of a neurological disease or disorder comprising administering the composition described above.

[0075] The above method, wherein the neurological disease or disorder is early or late stage Parkinson's disease.

[0076] The above method, wherein the administration is by intrathecal injection or infusion.

[0077] a therapeutically effective amount of a drug for inhibiting or suppressing the expression of TGF-β, and A therapeutically effective amount of apomorphine, a prodrug of apomorphine, or a pharma- ceutical acceptable salt or ester thereof. 23. A therapy for treating a symptom of a neurological disease or disorder in a patient in need of treatment comprising a combination of:

[0078] The above treatments, wherein the neurological disease or disorder is Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, or excessive daytime sleepiness.

[0079] The above treatment, wherein the neurological disease or disorder is early or late stage Parkinson's disease.

[0080] The above treatment, wherein the apomorphine is apomorphine hydrochloride.

[0081] The above treatment, wherein the drug for inhibiting or suppressing the expression of TGF-β comprises any one or more pharma- ceutically acceptable excipients selected from diluents, stabilizers, disintegrants and anti-caking agents.

[0082] The above treatment, wherein the drug for inhibiting or suppressing the expression of TGF-β comprises any one or more excipients selected from microcrystalline cellulose, polysorbate 80, crospovidone, croscarmellose sodium, and magnesium stearate.

[0083] The above treatment, wherein the drug for inhibiting or suppressing the expression of TGF-β is administered by intrathecal injection or infusion.

[0084] The above treatment, wherein the drug for inhibiting or suppressing the expression of TGF-β is an antisense oligonucleotide or inhibitor specific for TGF-β1, TGF-β2, or TGF-β3.

[0085] The drug for inhibiting or suppressing the expression of TGF-β is a TGF-β2 specific antisense oligonucleotide having any one of SEQ ID NOs: 1 to 9. SEQ ID NO:1, gtaggtaaaa acctaatat SEQ ID NO:2, gttcgtttag agaacagatc SEQ ID NO:3, taaagttcgt ttagagaaca g SEQ ID NO:4, agccctgtat acgac SEQ ID NO:5, gtaggtaaaa acctaatat SEQ ID NO:6, cgtttagaga acagatctac SEQ ID NO: 7, cattgtagat gtcaaaagcc SEQ ID NO:8, ctccctcatg gtggcagttg a SEQ ID NO: 9, cggcatgtct attttgta, Chemically modified variants thereof, artemisinin extracts, and pharma- ceutically acceptable salts, salt polymorphs, esters, or isomers thereof, and any combination thereof. The above treatments are selected from the following:

[0086] The above treatment, wherein the artemisinin comprises an artemisinin extract having a purity of 90-95%, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, and one or more pharma- ceutically acceptable excipients.

[0087] The above treatment, wherein the drug for inhibiting or suppressing expression of TGF-β comprises a carrier comprising sterile water for injection, saline, isotonic saline, or a combination thereof.

[0088] The above treatment, wherein the medicament for inhibiting or suppressing expression of TGF-β is substantially free of excipients.

[0089] The above treatment, wherein the drug for inhibiting or suppressing the expression of TGF-β is administered by intrathecal injection or infusion.

[0090] The above treatments, wherein the drugs for inhibiting or suppressing the expression of TGF-β have reduced adverse or side effects and are medicamentally tolerable.

[0091] The above treatment, wherein the drug for inhibiting or suppressing expression of TGF-β is stable in the carrier at 37° C. for at least 14 days.

[0092] The above treatment, wherein the drug for inhibiting or suppressing expression of TGF-β is reconstituted from a lyophilized powder of said composition.

[0093] The above treatments include using said agents in conjunction with standard therapeutic treatments for the disease or disorder.

[0094] The above treatments, where the standard of care includes one or more additional medications including anti-inflammatory agents, anti-inflammatory steroids, piperiquine, pyronaridine, curcumin, frankincense, remdesivir, Sonpraz D, Zifi CV / Zac D, CCM, Broclear, Budamate, Lapitas, Montec LC, low molecular weight heparin, prednisolone, paracetamol, B vitamin complex, vitamin C, pantoprozole, doxycycline, ivermectin, zinc, Folacort Rotacap Inhalation, Ceftriaxone Injection, Paracetamol Tablets, Fragmin Injection, Covifor Tablets, Azithromycin, Dexamethasone Injection, Odondansetron Injection, Multivitamin Tablets, Ascorbic Acid Tablets, Calcium Carbonate Tablets, and Zinc Sulfate Tablets.

[0095] The above treatments, wherein said drugs are administered together, simultaneously, sequentially or separately.

[0096] The above treatment comprises administering the apomorphine component alone during the early stages of the neurological disease or disorder, and administering both the apomorphine component and a drug that inhibits or suppresses the expression of TGF-β during the later stages of the neurological disease or disorder.

[0097] The above treatment, wherein the apomorphine component is administered alone in the early stages of a neurological disease or disorder in which the subject does not have elevated TGF-β, and wherein both the apomorphine component and a drug for inhibiting or suppressing expression of TGF-β are administered in the later stages of a neurological disease or disorder in which the subject has elevated TGF-β. [Brief description of the drawings]

[0098] [Figure 1] Figure 2 shows the uptake of free and Lipofectin®-conjugated FITC-labeled OT-101 in A172 human glioma cells.

[0099] [Diagram 2] FIG. 1 shows the effect of OT-101 / AP 12009 treatment on TGF-β2 secretion from the human GBM cell line A-172.

[0100] [Diagram 3] We present an analysis of novel compositions discovered to inhibit TGF-β using bioinformatics structure-based ligand design to identify and determine the primary and alternative binding sites for TGF-β1. Two active binding sites were determined: Site 1 contained residues Phe24-Lys37 and Site 2 contained residues Cys7-Gln19.

[0101] [Figure 4] 1 shows the clinical pharmacokinetic results of intranasal apomorphine administration in healthy subjects.

[0102] [Diagram 5] 1 shows the results of evaluation of apomorphine levels in cerebrospinal fluid (CSF) following intranasal and sublingual administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0103] The present invention provides compositions, therapies, and methods for treating or alleviating the symptoms of a neurological disease or disorder.

[0104] In one respect, the present invention encompasses novel formulations of apomorphine-based drugs that can be used to treat or alleviate symptoms of neuropathies, including sexual dysfunction and / or erectile dysfunction. The apomorphine-based formulations of the present invention can be improved to control, reduce and prevent oxidation of the formulation to maintain purity and potency and reduce side effects. With the improved apomorphine-based formulations of the present invention, the dose range of apomorphine-based drugs required to treat symptoms of neuropathies can be reduced with the simultaneous benefits of increased therapeutic efficacy and reduced side effects.

[0105] In some respects, the present invention provides improved drugs for inhibiting the activity of TGF-β and / or suppressing TGF-β-related pathologies, which can be used to treat or alleviate symptoms of neurological disorders. For example, sexual dysfunction and excessive daytime sleepiness (EDS), among others, can be symptoms of increased TGF-β activity in neurological disorders, including Parkinson's disease and Alzheimer's disease. The improved TGF-β suppression formulations of the present invention can counter such increases in TGF-β in neurological conditions, alleviating symptoms, including sexual dysfunction and EDS symptoms, and improving the efficacy of treatment.

[0106] In a further aspect, the present invention involves a combination therapy for treating neurological diseases or disorders by combining the use of drugs to inhibit or suppress the expression of TGF-β with the use of apomorphine-based drugs, which can be used to treat neurological diseases or disorders, including Parkinson's disease and Alzheimer's disease, for symptoms such as male or female sexual dysfunction, excessive daytime sleepiness, etc.

[0107] Use of anti-TGF-β drug preparations In some embodiments, the present invention includes drugs and compositions thereof for inhibiting or suppressing TGF-β to provide improved clinical outcomes of neurological diseases or disorders. Examples of anti-TGF-β drugs include TGF-β inhibitors such as antisense oligonucleotides, artemisinin, its pharma- ceutically acceptable salt forms, esters, polymorphs or stereoisomers, and combinations thereof.

[0108] In general, the pathology of neurological diseases or disorders is unpredictable, so new treatments require clinical studies on different patient populations.

[0109] In a further aspect, the present disclosure provides a highly stable formulation of anti-TGF-β drugs for the treatment of neurological disorders.The stable formulation of the present invention can provide surprisingly improved clinical results.The stable formulation of drugs for suppressing TGF-β can be used to alleviate the symptoms of sexual dysfunction and EDS and improve the efficacy of treatment.

[0110] The methods and compositions of the present invention can be used to inhibit or suppress factors in the unpredictable pathology of neuropathy. In some embodiments, the present disclosure provides methods and compositions for inhibiting the activity of TGF-β and / or suppressing TGF-β-related pathology, which can improve efficacy in treating or alleviating symptoms of neuropathy.

[0111] Use of apomorphine-based preparations In some embodiments, the present invention provides a nasal apomorphine formulation for treating or alleviating symptoms of neurological disorders. The nasal apomorphine formulation of the present invention may reduce the side effects of apomorphine administration. Such a nasal apomorphine formulation may reduce the effective dose required to achieve treatment or alleviation of symptoms.

[0112] In a further aspect, the present invention provides nasal apomorphine formulations that can be used to induce TGF-β expression in early stage neurological disorders and restore normal neuronal health.

[0113] In some embodiments, intranasal administration of dopamine receptor agonists can be used in amounts sufficient to treat or alleviate symptoms of neurological disorders, including Parkinson's disease and Alzheimer's disease, such as sexual dysfunction and / or erectile dysfunction.

[0114] In a further embodiment of the present invention, there is provided a treatment using an intranasal apomorphine formulation that can be used to treat or reduce symptoms in neurological disorders, such as Parkinson's disease (PD) and Alzheimer's disease, including male or female sexual dysfunction, anxiety, depression, and dementia, along with standard treatments for these conditions. Examples of standard treatments for these conditions include melatonin, vasodilators, sildenafil, estrogen, flibanserin, levodopa, carbidopa, safinamide, dopamine agonists, amantadine, anticholinergics, benztropine, MAO-B inhibitors, COMT inhibitors, cholinesterase inhibitors, donepezil, rivastigmine, galantamine, and memantine.

[0115] In a further embodiment of the present invention, there is provided a treatment using a nasal apomorphine formulation that can reduce the dose required for standard of care treatment for symptoms of neurological disorders such as Parkinson's Disease (PD) and Alzheimer's Disease, including male or female sexual dysfunction, anxiety, depression, and dementia, and can be used to treat or alleviate symptoms in neurological disorders.

[0116] In one embodiment, the active ingredient is apomorphine.

[0117] Examples of dopamine receptor agonists include apomorphine, chemically modified equivalents, and pharmaceutical salts thereof. Chemically modified equivalents of apomorphine may include prodrugs. Apomorphine-based drugs may be dispersed in aqueous or non-aqueous formulations.

[0118] The nasal delivery of the therapeutic composition may include a buffer to maintain the pH of the dopamine receptor agonist, a pharma- ceutically acceptable thickener, and a humectant. The therapeutic composition may further include one or more pharmaceutical excipients, or a preservative.

[0119] Buffers for intranasal administration can be acetate, citrate, prolamin, carbonate or phosphate buffers.

[0120] Examples of thickening agents include methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, and combinations thereof.

[0121] Examples of humectants include sorbitol, glycerol, mineral oil, vegetable oil, and combinations thereof.

[0122] In some embodiments, a formulation for nasal administration of the therapeutic composition of the present disclosure may comprise a therapeutically effective amount of a dopamine receptor agonist, a viscosity enhancing agent, and a humectant dispersed in a pH controlled buffer.

[0123] In a further aspect, formulations for nasal administration of the therapeutic compositions of the present disclosure may be tolerated without adverse side effects.

[0124] The present invention can also provide a nasal dosage unit for treating neurological disorders, including PD, such as male or female sexual dysfunction, that is tolerable without adverse side effects.The dosage unit can include an effective amount of a dopamine receptor agonist combined with a nasal carrier.An example of a nasal carrier includes a buffer.The pH of the buffer can be adjusted to enhance the nasal absorption of the dopamine receptor agonist.

[0125] The present invention can also provide a nasal dosage unit for treating male or female sexual dysfunction that is fast acting within about 60 minutes, or within about 45 minutes, or within about 30 minutes, or within about 15 minutes of administration.

[0126] The nasal carrier of the nasal dosage unit is preferably an aqueous solution, which may be selected from the group including aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions, and combinations thereof.

[0127] In some embodiments, carriers for nasal dosage units can be non-aqueous solutions. Examples of non-aqueous solutions include non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions and non-aqueous microemulsions, and combinations thereof.

[0128] In further embodiments, the nasal carrier of the nasal dosage unit can be a combination of aqueous and non-aqueous solutions.

[0129] In some embodiments, the carrier of the nasal dosage unit can be a powder formulation.Examples of powder formulations include powder mixtures, powder microspheres, coated powder microspheres, liposome dispersions, and combinations thereof.Powder microspheres can be formed from various polysaccharides and celluloses, such as starch, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol alginate, acacia, chitosan, and combinations thereof.

[0130] In a further embodiment, the nasal dosage unit may also include an excipient that has bioadhesive properties.

[0131] In certain embodiments, the buffer for the nasal dosage unit can have a pH of about 3 to about 10, or about 3.5 to 7.0.

[0132] In some embodiments, the nasal dosage unit can include a moisturizer. Examples of moisturizers include soothing agents, membrane conditioners, sweeteners, and combinations thereof.

[0133] In a further embodiment, the present invention provides a nasal composition for treating male or female sexual dysfunction, comprising a therapeutically effective amount of a dopamine receptor agonist dispersed to enhance solubility. The composition may include one or more of glycol derivatives, sugar alcohols, glycerin, propylene glycol, glycerin, polyethylene glycol 400, ascorbic acid, water, sodium ascorbate, and sodium pyrosulfite. The glycol derivative may be propylene glycol or polyethylene glycol. The sugar alcohol may be mannitol or xylitol.

[0134] The present invention is further directed to various formulations and methods for treating symptoms of neurological disorders, including PD, such as sexual dysfunction.The disclosed method can be used to treat or reduce symptoms of male or female sexual dysfunction by nasal administration of a therapeutically effective amount of dopamine receptor agonist before, during or after sexual activity.The formulation of the present invention can reduce side effects.

[0135] Examples of "dopamine receptor agonists" include apomorphine and pharmaceutical salts and chemically modified functional equivalents thereof, including, for example, prodrug forms of apomorphine. For example, apomorphine can exist in a free base form or as an acid addition salt.

[0136] In some embodiments, the dopamine receptor agonist can be apomorphine hydrochloride or other pharmacologically acceptable acid addition salts of apomorphine, such as hydrobromide, hydroiodide, bisulfate, phosphate, or acid phosphate.

[0137] Examples of adverse side effects include effects that are incompatible with the user's health or that are so unpleasant that they discourage continued use of the formulation. Examples of adverse side effects include low blood pressure, nausea, vomiting, blurred vision, sweating, and graying.

[0138] Apomorphine administered intranasally may become active in about 30 to about 45 minutes, or about 15 to about 20 minutes, or in less than 15 minutes.

[0139] The compositions of the present disclosure can be administered as a nasal spray, drops, suspension, gel, ointment, cream, or powder, or can be in the form of a nasal sponge.

[0140] In some embodiments, the compositions of the present disclosure can be made viscous by including natural gums, methylcellulose and derivatives, acrylic polymers such as Carbopol, and vinyl polymers such as polyvinylpyrrolidone.

[0141] In certain embodiments, compositions of the present disclosure may include excipients known in the art, such as preservatives, surfactants, cosolvents, adhesives, antioxidants, buffers, viscosity enhancing compounds, and compounds that adjust pH or osmolality.

[0142] In further embodiments, the compositions of the present disclosure may include an amount of a dopamine receptor agonist adjusted according to the age and weight of the patient.

[0143] In certain embodiments, the dose level of the dopamine receptor agonist may be adjusted to be effective in achieving an erection in the patient.

[0144] In further embodiments, the dose level of the dopamine receptor agonist can be adjusted to avoid or reduce adverse side effects to the patient. An acceptable level of adverse side effects can be determined by the tolerability of the formulation.

[0145] In some embodiments, for example, the level of adverse side effects of nausea and / or vomiting can be reduced or delayed by nasally delivering a dopamine receptor agonist at a controlled dissolution rate. The controlled dissolution rate can provide circulating serum and midbrain tissue levels of the dopamine receptor agonist sufficient to treat sexual dysfunction without inducing nausea and / or vomiting.

[0146] In a further embodiment, for doses of apomorphine greater than about 2 mg, adverse side effects can be reduced by co-administration with drugs such as nicotine or lobeline sulfate.

[0147] In further embodiments, the apomorphine formulations of the invention may be administered with an antiemetic compound such as metoclopramide, or a phenothiazine such as chlorpromazine, prochlorperazine, pipamazine, thiethylperazine or oxybenzyl hydrochloride, or a serotonin (5-hydroxytryptamine or 5-IIT) agonist such as domperidone or odansetron, or a histamine antagonist such as buclizine hydrochloride, cyclizine hydrochloride or dimenhydrinate, or a parasympathetic depressant such as scopolamine, metopimazine, trimethobenzamide, benzquinamine hydrochloride or diphenidol hydrochloride.

[0148] In certain embodiments, the apomorphine formulations of the present invention may be aqueous, non-aqueous, or a combination thereof. Aqueous solutions may include aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions, and combinations thereof. Non-aqueous solutions may include non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions, non-aqueous microemulsions, and combinations thereof.

[0149] In further embodiments, the apomorphine formulation of the present invention may include a buffer for maintaining pH, a pharma- ceutically acceptable thickener, and / or a moisturizer. The pH buffer may maintain the dopamine receptor agonist in a non-ionized form. The pH buffer may enhance the absorption of the dopamine receptor agonist across the nasal mucosa. Examples of buffers include acetate buffers, citrate buffers, prolamin buffers, carbonate buffers, and phosphate buffers.

[0150] Non-aqueous formulations may contain a buffer so that a favorable pH range can be achieved upon contact with the nasal mucosa.

[0151] In some embodiments, the dopamine receptor agonist formulations of the invention may have a pH of about 3.0 to about 10.0, or about 3.0 to about 7.0.

[0152] The dopamine receptor agonist formulation of the present invention may contain a pharma- ceutically acceptable thickening agent. Examples of thickening agents include methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof. Thickening agents may also be used in powder formulations.

[0153] The dopamine receptor agonist formulation of the present invention can include a moisturizing agent.The moisturizing agent can be used in an amount effective to reduce or prevent the drying or irritation of mucous membrane.Examples of moisturizing agents include sorbitol, mineral oil, vegetable oil, glycerol, soothing agents, membrane conditioners, sweeteners, and combinations thereof.

[0154] The dopamine receptor agonist formulations of the present invention may contain pharma- ceutically acceptable excipients and / or preservatives.

[0155] Examples of preservatives include benzyl alcohol, parabens, thimerosal, chlorobutanol, and benzalkonium chloride. Preservatives may be present in the composition at a concentration of up to about 2% by weight.

[0156] As used herein, "administered nasally" or "nasal administration" includes when a dopamine receptor agonist is combined with an appropriate delivery system for absorption across the nasal mucosa.

[0157] In some embodiments, the dopamine receptor agonist formulations of the present invention may comprise a therapeutically effective amount of a dopamine receptor agonist dispersed in a buffer to maintain the pH of the agonist, a pharma- ceutically acceptable viscosity enhancing agent, and a humectant.

[0158] In some embodiments, the dopamine receptor agonist formulations of the present invention may be effective in treating sexual dysfunction, such as male impotence and / or erectile dysfunction.

[0159] Apomorphine hydrochloride is a selective dopamine receptor agonist known to be involved in mediating erections. Apomorphine hydrochloride nasal sprays can be developed for the treatment of symptoms of neurological disorders including Parkinson's disease (PD) and Alzheimer's disease, such as male erectile dysfunction, female sexual dysfunction, and other neurological conditions. Formulations can be in aqueous solutions with drug concentrations of 5 mg and 10 mg per mL of solution. Formulations can be packaged in multi-dose glass containers and are available in dosage strengths of 0.5 mg and 1 mg per actuation (0.1 mL per actuation). Screw-on actuators are available for nasal administration.

[0160] Formulation of apomorphine hydrochloride into a liquid dosage form may be effective. Addition of antioxidants, chelating agents, preservatives, lowering the pH to 3.4, and replacement of oxygen by nitrogen flushing may be used in acceptable formulations. Packaging systems using containers with minimal head space may reduce interaction of atmospheric oxygen with the product. A sealing system using Trifoil® liners may provide sufficient protection against oxygen transmission. Stability testing of the formulation showed acceptable stability at 40°C / 60% RH for 3 months. The formulation may have acceptable stability at 25°C / 60% RH for 24 months actual time.

[0161] A. Drug Substance. Apomorphine hydrochloride is a USP monograph compound. It is a hemihydrate with the molecular formula C17H17NO2.1 / 2H2O and molecular weight 312.8. It is a white to off-white crystal. 1 g dissolves in 50 mL of water and approximately 20 mL of water at 80°C. The pH of a 1% w / v solution is 4.5-5.5. Apomorphine hydrochloride is water soluble.

[0162] In aqueous solution, apomorphine is oxidized to various derivatives of quinolinediones that lack emetogenic properties. The oxidized solution is emerald green in color, but color intensity is not a reliable indicator of the degree of oxidation. The rate of oxidation can be slowed by adding dilute hydrochloric acid to adjust the pH to between 3 and 4 and by adding sodium metabisulfite, making the solution essentially free of dissolved oxygen.

[0163] B. Excipients and Inactive Ingredients. The challenge in aqueous formulation of apomorphine hydrochloride is to control the oxidation of the drug substance. Functional excipients can be utilized in the formulation development. Antioxidants, antimicrobial preservatives, chelating agents, co-solvents can be added and the pH of the formulation can be lowered to 3.4. Additionally, deoxygenation by nitrogen purge can be performed.

[0164] Additional excipients may be used, as described below.

[0165] 1. Citric acid and sodium citrate: Buffer components. Citric acid has a pKa1 of 3.128, pKa2 of 4.761, and pKa3 of 6.396 at 25°C. Apomorphine hydrochloride is stable at low pH between 3.0 and 4.0, and formulations may target a pH of 3.5. Citric acid with sodium citrate as a buffer is effective at the desired pH of the formulation.

[0166] 2. Propylene glycol: Co-solvent. Propylene glycol can be used as a solvent in pharmaceutical preparations. It is generally considered a non-toxic substance and can be much less toxic than other glycols. It can also act as a preservative. It is sometimes used in spray solutions to stabilize droplet size. Propylene glycol can be used in concentrations of 10-30% in aerosol solutions and 5-80% in topical preparations. Propylene glycol has moisturizing and bactericidal properties. Apomorphine hydrochloride is easily oxidized in aqueous media. The stability of the formulation can be improved by replacing 7% of the water with a non-aqueous solvent.

[0167] 3. Glycerin: Co-solvent. Glycerin can be used as a solvent in pharmaceutical formulations. Glycerin has moisturizing properties. Replacing 5% of the water with a non-aqueous solvent can improve the stability of the formulation.

[0168] 4. Ascorbic Acid: Antioxidant. Apomorphine hydrochloride oxidizes in water. Aqueous formulations can use antioxidants to stabilize the drug. Ascorbic acid is a reducing agent and is more easily oxidized than the drug, so adding small amounts can protect the drug. Ascorbic acid is oxidized before apomorphine, so ascorbic acid can be used to slow the rate of oxidation of apomorphine.

[0169] 5. Sodium metabisulfite: Antioxidant. Sodium metabisulfite can be used as an antioxidant in oral, parenteral, and topical pharmaceutical preparations at concentrations of 0.1%, or 0.01% to 1%. In aqueous formulations, antioxidants can be used to stabilize the drug. The redox potential of sodium metabisulfite is slightly lower than that of apomorphine hydrochloride, so the addition of small amounts can protect the drug. Sodium metabisulfite can be used in acidic media.

[0170] 6. Disodium edetate: A chelating agent. Edetate can be used in pharmaceutical formulations as a chelating agent by sequestering trace metal ions and as an antioxidant synergist. Edetate can be used in combination with benzalkonium chloride, an antimicrobial preservative, to obtain a synergistic effect.

[0171] 7. Benzalkonium Chloride: Antibacterial preservative. Benzalkonium chloride is a quaternary ammonium compound that can be used as an antibacterial preservative. In nasal and otic preparations, it can be used at concentrations of 0.002-0.02%.

[0172] 8. Sodium hydroxide / hydrochloric acid. Can be used in small amounts to adjust the pH of the final preparation.

[0173] 9. Purified water: Solvent. Apomorphine hydrochloride can be dissolved in water with a combination of 12% non-aqueous solvents. The nasal formulation can be in aqueous liquid form.

[0174] Antioxidants can be used to enhance the stability of apomorphine formulations. Ascorbic acid or sodium pyrosulfite antioxidants can be used as reducing agents and have a lower redox potential than apomorphine hydrochloride. Formulations containing 0.1% and 0.01% ascorbic acid as well as 0.1% sodium pyrosulfite can be used. Apomorphine hydrochloride 0.5 mg / 0.1 mL formulations containing 0.01% ascorbic acid are unstable and may turn black after 7 weeks at 40°C. Apomorphine hydrochloride formulations with 0.1% sodium pyrosulfite are stable. Apomorphine hydrochloride formulations containing 0.1% sodium pyrosulfite can maintain a very light yellow color even after 16 weeks at 40°C. Sodium pyrosulfite can act as an antioxidant in the formulation. Antioxidants may be used in combination.

[0175] Use of anti-TGF-β antisense drug formulations The methods of the present invention include a process for treating or alleviating the symptoms of a neurological disorder in a patient in need of such treatment or alleviation. Such a process can be accomplished by preparing a pharmaceutical composition containing a drug for inhibiting or suppressing the expression of TGF-β and administering a therapeutically sufficient amount of the composition to the subject.

[0176] In some embodiments, the disclosure provides the use of a composition of drugs for inhibiting or suppressing expression of TGF-β to treat or alleviate symptoms of a neurological disorder in a human or animal.

[0177] In a further embodiment, the disclosure provides for the use of a composition of agents for inhibiting or suppressing expression of TGF-β in the preparation of a medicament for treating or alleviating a symptom of a neurological disorder.

[0178] In the process or use of the present invention, examples of neurological disorders include Parkinson's disease, Alzheimer's disease, fibrotic diseases, and cancer.

[0179] The present invention provides methods and formulations for a subject with a neurological disorder who may be hospitalized. The subject's hospitalization may be due to any one of the following: WHO COVID-19 Clinical Improvement Ordinal Scale Criteria3, subject is hospitalized without oxygen therapy; WHO COVID-19 clinical improvement sequence criteria 4, subject is hospitalized receiving oxygen treatment via mask or nasal cannula; WHO COVID-19 clinical improvement sequence criteria5, subject is hospitalized receiving non-invasive mechanical ventilation or high-flow oxygen; and WHO COVID-19 Clinical Improvement Order Criteria6, subject is intubated and mechanically ventilated and hospitalized.

[0180] A hospitalized subject of the present disclosure may be over 60 years of age, be hospitalized, and present with at least one medical risk factor selected from the following: Absolute lymphocyte count ≤ 1000 cells / mm 3 ; Age ≥ 60 years; High blood pressure; diabetes; Heart failure; and COPD.

[0181] In a further embodiment, the process or use of the present invention is directed to a method for treating a subject aged 35 years or older, hospitalized, and with a low PaO of less than 76 or 77 mmHg. 2 This can be applied when

[0182] In further embodiments, the disease may include fibrosis or multi-organ fibrosis symptoms resulting from any of pulmonary failure, cardiac failure, renal failure, and brain cognitive dysfunction, any of which may be based on neurological disorders that may result from Parkinson's disease, fibrotic diseases, or cancer.

[0183] In a further embodiment, the methods and / or uses of the present invention may be combined or applied with recognised standard of care treatments for either Parkinson's disease, fibrotic diseases, or cancer.

[0184] In a further embodiment, the process or use of the present invention can achieve surprisingly improved subject symptoms.Subjects receiving the composition of the present disclosure can have improved levels of inflammatory biomarkers.Examples of inflammatory markers include C-reactive protein, erythrocyte sedimentation rate, procalcitonin levels, plasma viscosity, and fibrinogen levels.

[0185] Examples of drugs for inhibiting or suppressing the expression of TGF-β of the present disclosure include antisense oligonucleotides specific for TGF-β1, TGF-β2, or TGF-β3.

[0186] Examples of drugs for inhibiting or suppressing the expression of TGF-β of the present disclosure include TGF-β2-specific antisense oligonucleotides shown in SEQ ID NOs: 1-9 herein.

[0187] SEQ ID NO:1, gtaggtaaaa acctaatat.

[0188] Sequence number 2, gttcgtttag agaacagatc.

[0189] Sequence number 3, taaagttcgt ttagagaaca g.

[0190] Sequence number 4, agccctgtat acgac.

[0191] Sequence number 5, gtaggtaaaa acctaatat.

[0192] Sequence number 6, cgtttagaga acagatctac.

[0193] Sequence number 7, cattgtagat gtcaaaagcc.

[0194] Sequence number 8, ctccctcatg gtggcagttg a.

[0195] Sequence number 9, cggcatgtct attttgta.

[0196] The antisense oligonucleotides shown in SEQ ID NOs: 1 to 9 herein may be chemically modified as known in the art.

[0197] Examples of drugs for inhibiting or suppressing the expression of TGF-β of the present disclosure include artemisinin extracts, its pharma- ceutically acceptable salts, salt polymorphs, esters, or isomers, and any combination thereof. In some embodiments, the present disclosure includes substantially pure artemisinin having a purity of at least 60%, or 70%, or 80%, or 90%, or 95%.

[0198] In certain embodiments, the drug for inhibiting or suppressing the expression of TGF-β of the present disclosure may be prepared from a lyophilized powder of the drug.

[0199] More specifically, the drug may be a TGF-β2 specific antisense oligonucleotide selected from SEQ ID NOs: 1-9, administered at 140 mg / m on days 1-7. 2 or 1000 mg / m on days 1 to 7. 2 or 180 mg / m on days 1 to 7 2 or 200 mg / m on days 1 to 7. 2 is administered or used by continuous intravenous infusion at a dose of

[0200] In some embodiments, the drug may be a TGF-β2 specific antisense oligonucleotide selected from SEQ ID NOs: 1-9, and chemically modified variants thereof, administered or used by continuous intravenous infusion with a Cmax value of 2-3 μg / mL.

[0201] In a further embodiment, the drug may be a TGF-β2 specific antisense oligonucleotide selected from SEQ ID NOs: 1-9 and chemically modified variants thereof, administered at 140 mg / m on days 1-7. 2 It is administered or used by continuous intravenous infusion at a dose of 500 mg per day on days 1-5, either alone or in combination with any form of artemisinin at a dose of 500 mg per day on days 1-5.

[0202] Examples of drugs for inhibiting TGF-β of the present disclosure include drugs for specifically inhibiting TGF-β1, TGF-β2, or TGF-β3.

[0203] Embodiments of the invention involving the administration or use of pharmaceutical compositions can reduce or suppress symptoms caused by TGF-β induced proteins.

[0204] Embodiments of the invention involving the administration or use of a pharmaceutical composition can alleviate or inhibit symptoms resulting from either Parkinson's disease, fibrotic diseases, or cancer.

[0205] The drug for inhibiting or suppressing the expression of TGF-β may be an artemisinin formulation comprising a 90-95% pure artemisinin extract, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, and one or more pharma- ceutically acceptable excipients. The excipients may comprise any one or more pharma- ceutically acceptable excipients selected from diluents, stabilizers, disintegrants, and anti-caking agents. In some embodiments, the excipients may comprise any one or more of microcrystalline cellulose, polysorbate 80, crospovidone, croscarmellose sodium, and magnesium stearate.

[0206] In a further embodiment, the drug for inhibiting or suppressing the expression of TGF-β may be an artemisinin compound or a derivative thereof, or a pharma- ceutically acceptable salt, salt polymorph, ester or isomer thereof.

[0207] As used herein, derivative encompasses chemical modifications that provide structural analogs of a compound. For example, substitutions or replacements of alkyl groups can provide structural analogs.

[0208] Embodiments of the invention include a process or use wherein the drug for inhibiting or suppressing expression of TGF-β is a compound that interacts with site I of TGF-β containing Trp30 and / or site II of TGF-β containing Arg15, Gln19, and Phe8, or a ligand comprising a small molecule or polypeptide, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof.

[0209] In some embodiments, the drug for inhibiting or suppressing expression of TGF-β may be a polypeptide or peptide mimetic of Site I of TGF-β comprising residues Phe24-Lys37 and / or Site II of TGF-β comprising residues Cys7-Gln19, or a pharma- ceutically acceptable salt, salt polymorph, ester or isomer thereof.

[0210] In a further embodiment, the drug for inhibiting or suppressing expression of TGF-β may be a humanized or non-humanized antibody or antibody fragment having affinity for site I of TGF-β comprising residues Phe24-Lys37 and / or site II of TGF-β comprising residues Cys7-Gln19.

[0211] In a further embodiment, the drug for inhibiting or suppressing the expression of TGF-β may be a compound comprising a sesquiterprene lactone or a derivative thereof, or a pharma- ceutically acceptable salt, salt polymorph, ester or isomer thereof.

[0212] In certain embodiments, the drug for inhibiting or suppressing the expression of TGF-β may be a compound containing three isoprenyl groups and a lactone ring, or a derivative thereof, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof.

[0213] In various embodiments, the processes or uses of the present invention can achieve surprisingly improved results: upon administration or use of the compositions of the present disclosure, a subject can experience reduced or inhibited symptoms due to either Parkinson's disease, fibrotic disease, or cancer.

[0214] In certain embodiments, the processes or uses of the present invention can achieve surprisingly improved results: subjects receiving administration or use of the compositions of the present disclosure may experience reduced intensive care unit time.

[0215] In a further embodiment, the process or use of the present invention may achieve surprisingly improved outcomes: subjects receiving administration or use of the disclosed compositions may experience reduced hospital stays.

[0216] The embodiments of the present invention further include pharmaceutical compositions for inhibiting or suppressing the expression of TGF-β, or for inhibiting or suppressing an inflammatory response, or for treating or alleviating any of the symptoms of Parkinson's disease, fibrotic diseases, or cancer in humans or animals. The pharmaceutical composition may include a TGF-β inhibitor, artemisinin, its pharma-ceutically acceptable salt forms, esters, polymorphs or stereoisomers, and any combination thereof, and a carrier. The TGF-β inhibitor may be selected from TGF-β2 specific antisense oligonucleotides SEQ ID NOs: 1-9 and chemically modified variants thereof. The carrier may be sterile water for injection, saline, isotonic saline, or a combination thereof.

[0217] Importantly, the composition of the present disclosure may be substantially excipient-free. The composition of the present invention that is substantially excipient-free has been found to be surprisingly stable in the carrier. In some embodiments, the composition can be stable in the carrier at 37° C. for at least 14 days, or at least 21 days, or at least 28 days. In further embodiments, the pharmaceutical composition for infusion can contain less than 1% by weight of excipients, or less than 0.5% by weight of excipients, or less than 0.1% by weight of excipients.

[0218] Embodiments of this invention further contemplate treatment modalities in which the compositions of this invention are administered or utilized in combination with standard of care therapies for the disease.

[0219] The present invention further provides a kit comprising a lyophilized powder of one or more TGF-β2-specific antisense oligonucleotides selected from SEQ ID NOs: 1 to 9, each of which is placed in a vial in an amount of 250 mg.

[0220] The present invention also provides a kit comprising a lyophilized powder of artemisinin or a derivative thereof, or a compound or ligand comprising a small molecule or polypeptide that interacts with site II of TGF-β comprising Arg15, Gln19, and Phe8, a sesquiterprene lactone or a derivative thereof, or a compound comprising three isoprenyl groups and a lactone ring and its derivatives, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, or any combination of the foregoing in an amount of 500 mg in a vial.

[0221] Antisense oligonucleotides The present invention describes compositions and methods for using TGF-β as an effective target for the treatment of either Parkinson's disease, fibrotic diseases or cancer.

[0222] Antisense oligonucleotides (ASOs) can be single-stranded deoxyribonucleotides complementary to mRNA targets. Antisense therapy can downregulate molecular targets, which can be achieved by inducing RNase H endonuclease activity, which cleaves the RNA-DNA heteroduplex with a significant reduction in the translation of the target gene. Other ASO mechanisms can include inhibition of 5' cap formation, alteration of the splicing process, such as splice switching, and steric hindrance of ribosomal activity.

[0223] Antisense therapeutic strategies can utilize single-stranded DNA oligonucleotides that inhibit protein production by mediating catalytic degradation of target mRNA or by binding to sites on mRNA required for translation. Antisense oligonucleotides can provide an approach to identify potential targets and therefore potential therapeutic agents.

[0224] Antisense oligonucleotides can be synthetic pieces of single-stranded DNA 15-30 nucleotides in length. ASOs bind specifically to complementary DNA / RNA sequences by Watson-Crick hybridization and, upon binding to the target RNA, can inhibit the translation process by inducing cleavage mechanisms or by inhibiting mRNA maturation. ASOs can selectively specifically inhibit gene expression. Chemical modifications of DNA or RNA can be used to increase stability.

[0225] For example, modifications can be introduced to the phosphodiester bond, sugar ring, and backbone. ASO antivirals can block the translation process by (i) ribonuclease H (RNAse H) or RNase P mediated cleavage of mRNA, or (ii) sterically (non-binding) blocking of enzymes involved in the translation of the target gene.

[0226] Without wishing to be bound by theory, sexual dysfunction may be related to significantly increased TGF-β in either Parkinson's disease, fibrotic disease, or cancer. Blockade of TGF-β may prevent or reduce fibrosis and its expanding complications. Knocking down TGF-β gene expression may improve immune responsiveness.

[0227] Use of apomorphine in combination with TGF-β inhibition In a further aspect, the present invention provides nasal apomorphine formulations that can be used to treat or reduce symptoms in late stage or severe neurological disorders.

[0228] In some embodiments, the present invention provides apomorphine formulations that can be administered using Ommaya reservoirs and catheters for the treatment of severe neurological disorders, including Parkinson's and Alzheimer's diseases.

[0229] Without wishing to be bound by theory, symptoms of neurological disorders including Parkinson's disease (PD) and Alzheimer's disease, such as sexual dysfunction, anxiety, depression, and dementia, are neurological disorders associated with dysregulation of TGF-β signaling. The TGF-β family of signaling pathways regulates psychiatric disorders. Parkinson's disease affects millions of patients. Clinical symptoms of PD include resting tremor, rigidity, bradykinesia, abnormal posture, and freezing. Some PD pathological findings include loss of nigrostriatal dopaminergic (DA) neurons and the associated loss of the neurotransmitter dopamine in the striatum, a brain region important for motor control. The TGF-β signaling pathway controls the development and survival of DA neurons. In PD, TGF-β affects adult brain function and homeostasis, as there is a reduction in DA neurons and loss of striatal dopamine. Activation of TGF-β increases the amount of TGF-β1 and TGF-β2 in the cerebrospinal fluid of PD patients, preventing the degeneration of DA neurons. Apomorphine may increase the expression of TGF-β, and its use in late-stage patients requires the combination of a TGF-β inhibitor such as OT-101.

[0230] Embodiments of the present invention provide nasal apomorphine formulations that can be used in combination with TGF-β inhibitors to treat or reduce symptoms in late stage or severe neurological disorders. This combination treatment may provide a balance of TGF-β related effects.

[0231] In certain embodiments, nasal apomorphine formulations can be used in combination with TGF-β inhibitors to treat symptoms of neurological disorders, including Parkinson's disease and Alzheimer's disease, such as male or female sexual dysfunction and other neurological disorders.

[0232] Examples of TGF-β inhibitors include antisense drugs against TGF-β, artemisinin and its derivatives.

[0233] Without wishing to be bound by theory, TGF-β has normal physiological levels necessary to maintain neuronal health, but increased TGF-β signaling can lead to damage in the brain, and TGF-β levels must be regulated and sometimes suppressed.

[0234] The present invention provides an intranasal apomorphine formulation that can be used to treat or reduce symptoms in early stages of neuropathy. Apomorphine can increase the expression of TGFβ, which is beneficial during the early stages of neuropathy. In the later stages of neuropathy, apomorphine must be used in combination with other drugs, at least drugs that suppress TGF-β. This apomorphine treatment can be combined with treatment using TGF-β inhibitors to regulate or suppress the level of TGF-β.

[0235] A further embodiment of this invention provides a TGF-β inhibitor formulation that can be used to treat or reduce symptoms in late stage or severe neurological disorders. Some TGF-β inhibitors can reduce TGFβ expression, sometimes by accumulating in sites such as the pineal gland. This TGF-β inhibitor treatment can be combined with treatment with a nasal apomorphine formulation to regulate or increase the level of TGF-β.

[0236] Additional embodiments of the present invention provide a TGF-β inhibitor formulation that can be used to treat or reduce symptoms in late stage or severe neurological disorders in combination with treatment using a nasal apomorphine formulation, and can be used with standard treatments for any neurological disorder, including Parkinson's disease (PD) and Alzheimer's disease, such as male or female sexual dysfunction, anxiety, depression, and dementia. Examples of standard treatments for these conditions include melatonin, vasodilators, sildenafil, estrogen, flibanserin, levodopa, carbidopa, safinamide, dopamine agonists, amantadine, anticholinergics, benztropine, MAO-B inhibitors, COMT inhibitors, cholinesterase inhibitors, donepezil, rivastigmine, galantamine, and memantine.

[0237] A further embodiment of this invention provides a TGF-β inhibitory formulation that can be used to treat or reduce symptoms in neurological disorders in combination with therapy using a nasal apomorphine formulation, which can reduce the dose required for standard of care treatment of any neurological disorder, including Parkinson's Disease (PD) and Alzheimer's Disease, such as male or female sexual dysfunction, anxiety, depression, and dementia.

[0238] Additional embodiments of the present invention provide a TGF-β inhibitory formulation that can be used to treat or alleviate symptoms in neurological disorders, neurological disorders, along with standard of care treatments for any of the following: Parkinson's Disease (PD), male or female sexual dysfunction, anxiety, depression, and dementia, in combination with treatment using a nasal apomorphine formulation.

[0239] In PD, non-motor symptoms may precede typical motor features by several years and play a major role in the deterioration of patients' quality of life. The embodiments of the present invention include the use of apomorphine alone in the early stages of the disease to maintain neuronal health, and in combination with TGF-β inhibitors in advanced severe neurological disorders. Bioassay of TGF-β2 in the spinal cord can be used to determine treatment regimens. Pathological levels of TGF-β can be modulated by the addition of TGF-β inhibitors.

[0240] A further embodiment of this invention provides treatment using nasal apomorphine formulations for neurological disorders, including Parkinson's and Alzheimer's disease, with symptoms such as male or female sexual dysfunction, anxiety, depression, and dementia.

[0241] Further embodiments of the present invention provide a treatment for neurological disorders including Parkinson's disease and Alzheimer's disease, which are accompanied by symptoms such as male or female sexual dysfunction, anxiety, depression, and dementia, by using a nasal apomorphine formulation in combination with a TGF-β inhibitor in sequence.For example, a TGF-β inhibitor can be administered.TGF-β inhibitors such as OT-101 (trabedersen) or artemisinin can inhibit the TGF-β surge that can cause brain damage.When neurological disorders progress and TGF-β exceeds physiological levels, apomorphine formulations can be used together with anti-TGF drugs.

[0242] All publications, including patents, patent application publications, and non-patent publications, as well as the sequence listing, referred to herein are each expressly incorporated by reference in their entirety for all purposes.

[0243] Although the foregoing disclosure has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be realized by this disclosure and made without undue experimentation within the scope of the appended claims, which are presented by way of example and not limitation. The invention includes all further embodiments, equivalents, modifications, etc. The invention includes any combination or mixture of the features, materials, elements, or limitations of the various exemplary components, examples, and claimed embodiments.

[0244] The terms "a," "an," "the," and similar terms in describing the invention and in the claims are intended to encompass both the singular and the plural. EXAMPLES

[0245] Example 1. Formulation of apomorphine hydrochloride. Dose reproducibility was determined by pump weight using a mechanical actuation station. Six different lots of apomorphine nasal spray and three lots of Pfeiffer nasal actuators (to deliver 0.1 g) were tested. Results showed consistency in delivered weight, with 11 good sprays after the first priming. Individual sprays were within 15% of the target weight, and the average weight was within 10% of the target weight.

[0246] Examples of formulations are shown in Table 1. [Table 1]

[0247] Example 2. Examples of excessive daytime sleepiness in neurological disorders such as Parkinson's and Alzheimer's diseases.

[0248] Parkinson's disease (PD) and Alzheimer's disease have non-motor symptoms, including excessive daytime sleepiness (EDS). EDS is defined as the inability to maintain wakefulness and alertness during major daytime waking episodes, resulting in periods of uncontrollable need for sleep, or involuntary lapses into sleepiness or sleep. EDS is the major health impairment in PD, occurring in 21–76% of PD patients. EDS in PD is not continuous, and its presence fluctuates over time. In general, the proportion of PD patients with EDS increases with longer follow-up periods. EDS is associated with and impacts other motor and non-motor symptoms of PD.

[0249] P001 was a completed Phase I / II dose-escalation study. The primary objective was to determine the MTD and DLTs of travedersen (OT-101) administered orally for 4 or 7 days every other week for 2 cycles as core treatment and up to 8 optional cycles, as described below. The study followed a classical cohort design with 3 evaluable patients per cohort. Patients treated with the first schedule received OT-101 for 7 consecutive days followed by a 7-day treatment-free interval in each treatment cycle (7 days on, 7 days off). After reaching the MTD with this schedule, a second schedule was started in which OT-101 was administered for 4 days followed by a 10-day treatment-free interval in each treatment cycle (4 days on, 10 days off). The MTD was not reached with this treatment schedule.

[0250] Insomnia was evaluated in P001. Consistent with the role of TGF-β in neuronal health, treatment with OT-101 was found to affect frequent insomnia in these patients. Thus, OT-101 may be beneficial for PD and Alzheimer's patients who suffer from excessive sleepiness in the later stages of the disease.

[0251] Of 61 patients treated with OT-101, psychiatric changes were observed in 23% of patients with sleep disorders (13%), insomnia (8%), anxiety (2%) and mood changes (2%).

[0252] Example 3. TGF-β2 specific phosphorothioate antisense oligodeoxynucleotides (OT-101; AP 12009; travedersen) are intended to reduce the levels of TGF-β2 protein in malignant gliomas. Human TGF-β2-specific phosphorothioate antisense oligodeoxynucleotide (OT-101; AP 12009; travedersen) (hereafter referred to as OT-101) is intended to reduce levels of TGF-β2 protein in malignant gliomas, thereby slowing disease progression.

[0253] Antisense oligodeoxynucleotides are short strings of DNA designed to downregulate gene expression by preventing the translation of a specific encoded protein at the mRNA level. OT-101 is a synthetic 18-mer phosphorothioate oligodeoxynucleotide (S-ODN) in which all 3'-5' linkages have been modified to phosphorothioate. The molecular formula is C 177 H 208 N 60 Na 17 O 94 P 17 S 17 and has a molecular weight of 6,143 g / mol. OT-101 was designed to be complementary to a specific sequence of human TGF-β2 mRNA after gene expression.

[0254] OT-101 is currently supplied as a lyophilized powder in three different quantities in 50 mL glass vials. Each vial is identified by the name of the investigational drug, trial number, dose group, mode of application, OT-101 content (mg), total volume after dissolution (mL), and resulting concentration (μM), sponsor name, manufacturer name, batch number, vial number, storage temperature, and expiration date. Oncotelic Inc. provides the study drug in sealed units packaged separately for each concentration. The package includes the appropriate vial and all components required for the application system (i.e., syringes, tubing, and filters). OT-101 lyophilized powder is dissolved in isotonic (0.9%) sodium chloride water before use. A leaflet with preparation instructions for administration at the desired concentration is included in the package.

[0255] Nonclinical in vitro studies of OT-101.

[0256] Functional in vitro assays showed that:

[0257] OT-101 exhibits efficient, time-dependent uptake into human tumor cells in the presence and absence of the liposomal carrier Lipofectin®.

[0258] OT-101 reduces TGF-β2 secretion by human tumor cells without the use of any carrier.

[0259] Of the OT-101 concentrations up to 80 μM used clinically over a 7-day period in A172 human high-grade glioma cells, 10 μM was the most effective concentration for inhibiting TGF-β2 production.

[0260] OT-101 reduces the proliferation of human tumor cells and at the same time stimulates the proliferation of PBMCs without affecting the viability of human PBMCs.

[0261] OT-101 restores immune function of human PBMCs from patients with high-grade glioma as demonstrated by immune cell-mediated cytotoxicity assays.

[0262] OT-101 inhibits the migration of human tumor cells.

[0263] Figure 1 shows the uptake of free and Lipofectin®-conjugated FITC-labeled OT-101 in A 172 human glioma cells. Representative fluorescence micrographs of A-172 human glioma cells after incubation with different formulations are shown: (A) start, 0 hours incubation; (B) "naked" FITC-OT-101 (5 μM) without carrier, 48 hours incubation; (C) FITC-Travedersen (200 nM) conjugated with Lipofectin® (3 μg / mL), 48 hours incubation. With reference to Figure 1, human A-172 glioblastoma cells incubated with FITC-OT-101 with or without Lipofectin® both showed an increase in the fluorescent signal up to 48 hours. The uptake of FITC-OT-101 was already observed after 3 hours of incubation time, with or without Lipofectin®. After 48 hours, the fluorescent signal was detectable in almost all cells and was of similar intensity in cell preparations incubated with or without Lipofectin®.

[0264] Figure 2 shows the effect of OT-101 / AP 12009 treatment on TGF-β2 secretion from human GBM cell line A-172. Cells were incubated with different concentrations of OT-101 / AP 12009 (1 μM to 80 μM) as indicated for 7 days. Secreted TGF-β2 was measured in cell supernatants by ELISA. Results represent the median, minimum, and maximum values ​​from three independent experiments.

[0265] Effect of OT-101 on TGF-β2 secretion from primary human high-grade glioma cells. The ability of OT-101 to reduce TGF-β2 secretion by primary human glioma cells was determined by measuring TGF-β2 concentrations in cell culture supernatants using an enzyme-linked immunosorbent assay (ELISA). Glioma cells from 10 high-grade glioma patients were cultured for 72 h (HTZ-209, -220, -243, -262, -349, -361, -378, -381) or 96 h (A-172) in the presence and absence of OT-101 (5 μM or 10 μM). In 8 of 10 glioma cell cultures, TGF-β2 secretion was reduced by up to 87%.

[0266] Inhibition of human high-grade glioma cell proliferation via OT-101. Two human HGG cell cultures (HTZ-243 and HTZ-349, representing WHO grades III and IV) were incubated with OT-101 (1 μM to 10 μM). The results in Table 2 showed a concentration- and time-dependent reduction in cell numbers within 6 days. [Table 2]

[0267] Example 4. Preparation of excipient-free stable drug solutions for inhibiting TGF-β. This example illustrates the preparation of a stable and compatible solution of an antisense drug for suppressing and inhibiting TGF-β, which is substantially excipient-free.

[0268] The experiments described below showed that 10 μM (61.43 μg / mL) OT-101 solutions in NaCl at 5° C. and 37° C. were surprisingly stable for at least 2 weeks. Furthermore, 7.35 mg / mL and 25 mg / mL OT-101 solutions in isotonic saline at 5° C. and 37° C. were surprisingly stable for at least 2 weeks.

[0269] The conditions of use and the results of the studies simulating clinical trials are shown in Tables 3 and 4. Table 3 shows the results when antisense oligonucleotides against TGF-β were administered to patients by intravenous infusion. [Table 3]

[0270] The experiments in Table 3 show that the antisense oligonucleotide OT-101 at 10 μM in NaCl at 5° C. and 37° C. was surprisingly stable for at least 2 weeks. The experiments in Table 3 show that the antisense oligonucleotide OT-101 in WFI at 5° C. was stable for at least 2 weeks.

[0271] Table 4 shows the results of administering antisense oligonucleotides against TGF-β to patients by intravenous infusion. [Table 4]

[0272] The experiments in Table 4 show that in NaCl at 5° C. and 37° C., 7.35 mg / mL and 25 mg / mL of the TGF-β antisense oligonucleotide travedersen were surprisingly stable for at least two weeks.

[0273] Further in-use stability studies of OT-101 at 10 μM (61.43 μg / mL) were performed. Analytical stock solutions at concentrations of 1.0 mg / mL and 10 μM (61.43 μg / mL) were used. The stability of OT-101 clinical concentration at 10 μM (61.43 μg / mL) in 0.9% NaCl was confirmed after storage at 5° C. and 37° C., and the stability of OT-101 analytical stock solution at 1 mg / mL in water for injection was confirmed after storage at 5° C. for 2 weeks. The materials used in the experiments are listed in Table 5. [Table 5]

[0274] The impurity profile of the samples was determined by RP-HPLC and the concentration was measured by UV spectrometry. The impurity profile of the samples by RP-HPLC is shown in Table 6. [Table 6]

[0275] The concentrations of the samples were compared to those of the reference samples (t = 0 days). The data are summarized in Table 7. Results were considered adequate if the concentrations were between 95 and 105% of the respective reference sample concentrations. [Table 7]

[0276] All UV spectra corresponded to the characteristic UV spectrum of OT-101, and the concentrations of all solutions were within ±0.8% of the baseline (t=0 day) concentration. This experiment showed that the concentration of a 10 μM (61.43 μg / mL) OT-101 solution in isotonic saline after storage for 2 weeks at 5°C and 37°C did not change substantially.

[0277] These experiments demonstrated that, based on the RP-HPLC impurity levels, UV spectra and concentration profiles described above, 10 μM OT-101 antisense oligonucleotide solutions in NaCl at 5° C. and 37° C. were surprisingly stable for at least 2 weeks.

[0278] Further in-use stability studies of OT-101 at 7.35 mg / mL and 25 mg / mL were performed. OT-101 solutions at concentrations of 7.35 mg / mL and 25 mg / mL in 0.9% NaCl were checked for stability after storage at 5° C. and 37° C. for 2 weeks. The materials used in the experiment are shown in Table 8. [Table 8]

[0279] The impurity profile of the samples was determined by RP-HPLC and the concentration was measured by UV spectrometry. The impurity profile of the samples by RP-HPLC is shown in Table 9. [Table 9]

[0280] The impurity profile was appropriate for the intended dosing.

[0281] The concentrations of the samples were compared to those of the reference samples (t=0 days). The data are summarized in Tables 10 and 11. Results were adequate when concentrations were 95-105% of the respective reference sample concentrations. [Table 10] [Table 11]

[0282] All UV spectra corresponded to the characteristic UV spectrum of OT-101, and the concentrations of all solutions were within ±3.58% of the baseline (t=0 day) concentration. This experiment demonstrated that the concentrations of 7.35 mg / mL and 25 mg / mL OT-101 solutions in isotonic saline after 2 weeks of storage at 5° C. and 37° C. were surprisingly stable and unchanged. Based on the above RP-HPLC impurity levels, UV spectra and concentration profiles, 7.35 mg / mL and 25 mg / mL OT-101 solutions in isotonic saline were surprisingly stable for at least 2 weeks at 5° C. and 37° C.

[0283] The above experiments further demonstrated that a 15 mg / mL OT-101 drug solution in isotonic saline at a flow rate of 1 mL / h was surprisingly stable for the intended drug delivery system for intravenous infusion over a period of 4 days.

[0284] The above experiments further demonstrated that a 10 μM (61.43 μg / mL) OT-101 drug solution in isotonic saline at a flow rate of 0.24 mL / h over a period of 7 days was surprisingly stable for the intended intravenous infusion drug delivery system.

[0285] Example 5. New medical compositions, preparations, and methods discovered for inhibiting TGF-β using primary and alternative binding sites. This example illustrates the identification and use of novel medical compositions, preparations, and methods discovered to inhibit TGF-β. Novel compositions, preparations, and methods were discovered using bioinformatics structure-based ligand design to identify and measure the primary and alternative binding sites of TGF-β1.

[0286] The protein crystal structure of TGFβ1 was obtained from the protein data bank (https: / / www.rcsb.org / ) with accession code 3KFD. The protein was prepared by adding hydrogen atoms and removing salts and ions. Missing side chains and loops were added. Finally, energy minimization was performed to relax the coordination. All other parameters were left as default. The PocketFinder bioinformatics platform was used to detect primary and alternative binding sites of the target protein. The results were analyzed to identify the structure of the binding site and the orientation of the residues adjacent to the bound ligand.

[0287] Ligand structures based on artemisinin were used for docking calculations with the structure of TGFβ1. Prior to docking, the test structures were optimized and relaxed in their coordination. Pocket residues were selected to generate grids before docking, and grids were generated for each identified site. Docking of the artemisinin ligand structures was performed within the grids generated for each target individually. Prior to docking, all parameters were left at default. Ten poses were generated for the docked ligand at each site, resulting in one final pose. Each docking output was scored and the conformation of the ligand was determined. The nature and type of binding interactions for the ligand were determined.

[0288] The three-dimensional structure of the protein consisted mainly of β-sheets and long flexible loops. The structure was not tightly packed, so targeting with small molecules required extensive computations. Small hydrophobic subpockets were formed, in which small molecules such as artemisinin could occupy with their polar sides exposed to the solvent. Solvent-exposed sites or pockets were detected when the solvent-accessible surface area of ​​the protein was very large.

[0289] As a result, two sites for binding activity were determined. As shown in Figure 3, site 1 contains residues Phe24-Lys37 and has a docking score of -1.230. Site 2 contains residues Cys7-Gln19 and has a docking score of -6.01. Sites 1 and 2 can be used to screen for molecules that bind to these pockets and inhibit TGF-β activity.

[0290] Site II showed improved ligand sampling inside the pocket for improved binding. The binding interactions of the ligand were within hydrogen-bonding distance, confirming the enzyme inhibitory activity. Furthermore, the polar groups of artemisinin occupied a deep pocket orientation, confirming the enzyme inhibitory activity. In particular, the results showed that the keto group of the ligand of artemisinin formed hydrogen bonds with the side chain of ARG15. Furthermore, the ether group of the ligand formed hydrogen bonds with the main chain NH of GLN19. Weak hydrophobic interactions were observed between the ligand and PHE8. The core of the pocket was exposed to the solvent. These structural features confirmed the enzyme inhibitory binding and activity.

[0291] New drug molecules or ligands have been identified that bind to Site 1 or Site 2. In some embodiments, artemisinin and its derivatives are drug molecules or ligands that bind to Site 1 or Site 2 and inhibit TGF-β targets, and may include pharma- ceutically acceptable salts, salt polymorphs, esters, or isomers thereof.

[0292] In a further embodiment, a compound or ligand comprising a small molecule or polypeptide that interacts with Site I of TGF-β containing Trp30 and / or Site II of TGF-β containing Arg15, Gln19, and Phe8, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, is a drug molecule or ligand that binds to Site 1 or Site 2 and inhibits a TGF-β target.

[0293] In a further embodiment, a polypeptide or peptidomimetic of Site I of TGF-β comprising residues Phe24-Lys37 and / or Site II of TGF-β comprising residues Cys7-Gln19, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, is a drug molecule or ligand that binds to Site 1 or Site 2 and inhibits a TGF-β target.

[0294] In one embodiment, an antibody or antibody fragment having affinity for Site I of TGF-β comprising residues Phe24-Lys37 and / or Site II of TGF-β comprising residues Cys7-Gln19 is a drug molecule or ligand that binds to Site 1 or Site 2 and inhibits a TGF-β target.

[0295] In an alternative embodiment, a compound comprising a sesquiterprene lactone or a derivative thereof, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, is a drug molecule or ligand that binds to Site 1 or Site 2 and inhibits a TGF-β target.

[0296] In a further embodiment, a compound comprising three isoprenyl groups and a lactone ring, or a derivative thereof, or a pharma- ceutically acceptable salt, salt polymorph, ester, or isomer thereof, is a drug molecule or ligand that binds to Site 1 or Site 2 and inhibits a TGF-β target.

[0297] Example 6. Bioavailability and tolerability studies of intranasal formulations of apomorphine hydrochloride. OBJECTIVES AND ENDPOINTS: To determine the tolerability, safety, and pharmacokinetics of apomorphine hydrochloride in healthy subjects. Safety and tolerability were assessed by adverse events and an intranasal tolerability questionnaire. Pharmacokinetic parameters: Cmax, tmax, AUC0-180, t1 / 2, and kel were derived.

[0298] METHODOLOGY: A single-center, single-dose, open-label study to evaluate the safety, tolerability, and pharmacokinetics of intranasal apomorphine hydrochloride at doses of 0.1 mg to 2.0 mg per 0.1 ml in healthy male subjects and at doses of 0.1 mg to 0.75 mg per 0.1 ml in healthy female subjects.

[0299] Each dose level study included one visit. Eligible subjects underwent a physical examination, nasal examination, and blood pressure, pulse rate, and respiratory rate were recorded before dosing. Blood samples were collected at 5, 10, 15, 20, 30, 45, 60, 90, 120, and 180 minutes after dosing, and subjects were evaluated for adverse events from dosing until discharge (approximately 3 hours after dosing). Blood pressure, pulse, and respiratory rate were recorded 30 minutes after dosing and at discharge. A nasal examination was also performed before discharge. Subjects were not permitted to eat during the study until the 120-minute blood draw was completed. Hot beverages were prohibited 90 minutes before dosing and 240 minutes after dosing. There was a minimum 3-day washout period between doses.

[0300] Diagnosis and Main Inclusion Criteria: Subjects recruited into the original protocol were healthy, non-smoking males aged 18-45 years. Protocol amendment 5 expanded the study to also allow participation of healthy, non-smoking female subjects aged 18-45 years. Subjects with nasal conditions likely to affect nasal absorption (e.g., chronic nosebleeds, allergic rhinitis, severe nasal septum deviation) were excluded from the study.

[0301] Drugs, Doses, and Regimen: At each treatment visit, male subjects received one dose of:

[0302] Apomorphine hydrochloride nasal spray, 0.1 mg per 0.1 ml; Lot #L / N 00015A Apomorphine hydrochloride nasal spray, 0.25 mg per 0.1 ml; Lot #L / N 00013A Apomorphine hydrochloride nasal spray, 0.50 mg per 0.1 ml; Lot #L / N 00014A Apomorphine hydrochloride nasal spray, 1.0 mg per 0.1 ml; Lot #L / N 99049A Apomorphine hydrochloride nasal spray, 2.0 mg per 0.1 ml; Lot #L / N 99049A At each treatment visit, female subjects received one dose of the following: Apomorphine hydrochloride nasal spray, 0.1 mg per 0.1 ml; Lot #L / N 00018A Apomorphine hydrochloride nasal spray, 0.25 mg per 0.1 ml; Lot #L / N 00019A Apomorphine hydrochloride nasal spray, 0.50 mg per 0.1 ml; Lot #L / N 00020A Apomorphine hydrochloride nasal spray, 0.75 mg per 0.1 ml; Lot #L / N 99023A.

[0303] Statistical Methods: Pharmacokinetic parameters were derived using PKAnalyst software. Data were fitted to a one-compartment, one-order input, one-order output model using a linear fitting procedure and a least-squares minimization algorithm.

[0304] RESULTS: A total of 32 healthy male volunteers received 75 doses of study treatment. Subjects were allowed to receive multiple dose levels: 16 subjects received only 1 dose level, 5 subjects received 2 dose levels, 2 subjects received 3 dose levels, 2 subjects received 4 dose levels, and 7 subjects received all 5 dose levels.

[0305] However, because of problems with the pharmacokinetic analysis of some samples at the 1 and 2 mg dose levels, only 47 doses were analyzed pharmacokinetically (12 at the 0.1 and 0.25 mg levels, 11 at the 0.50 mg level, and 6 each at the 1.0 and 2.0 mg levels).

[0306] In addition, 14 healthy female subjects received 48 doses of study treatment: 10 received all 4 dose levels, 2 received only 3 dose levels, and 2 received only 1 dose level, resulting in 12 subjects per dose level.

[0307] Pharmacokinetic Results: In men, plasma Cmax increased dose-dependently, with tmax achieved within approximately 20 minutes; a 50% decrease in plasma concentration was observed 40-60 minutes after dosing. Intersubject variability in Cmax (coefficient of variation [CV] 24-63%) and AUC (CV 26-60%) was relatively small. Table 12 summarizes the pharmacokinetic data in men. [Table 12]

[0308] In women, apomorphine was detectable in the blood within 5 minutes and reached a maximum value within 22 to 28 minutes after dosing in subjects. tmax was not dose-dependent. Cmax values ​​ranged from 0.031 to 0.479 ng / ml. Table 13 summarizes the pharmacokinetic data in women. [Table 13]

[0309] Pharmacokinetic studies with intranasal formulations of apomorphine have shown the following:

[0310] Maximum plasma concentrations of apomorphine were achieved more rapidly with the nasal formulation compared with published values ​​for the sublingual formulation (tmax values ​​of 15-20 and 45 minutes, respectively). Cmax was approximately four-fold higher with the nasal compared with the sublingual route (2.7 ng / ml and 0.7 ng / ml, respectively, for a 2 mg dose).

[0311] Exposure following nasal dosing of 2 mg in men was approximately twice that reported following the same dose given sublingually (AUC0-180 for the nasal formulation was 2.1 ng.h / ml compared to AUC0-∞ of 1.23 ng.h / ml for the sublingual formulation).

[0312] Nasally administered apomorphine was also cleared from the body much more rapidly than reported for the sublingual formulation: reported t values ​​ranged from 2 to 4 hours for the sublingual formulation versus 11 to 15 minutes for the nasal formulation.

[0313] Therefore, the nasal route of administration appears to be a more efficient drug delivery route for more rapid delivery of maximum plasma concentrations than the sublingual route. Apomorphine in SL apomorphine (Uprima) is rapidly absorbed from the sublingual cavity and is detectable in plasma within 10 minutes of placing the tablet under the tongue. Peak plasma concentrations are reached in approximately 40-60 minutes. Increasing the dosage strength of Uprima sublingual tablets results in a dose-proportional increase in Cmax and AUC. The bioavailability of apomorphine from sublingual tablets relative to subcutaneous administration was approximately 17-18%. Comparison with sublingual administration of apomorphine yielded the following findings:

[0314] AL-101(IN) was faster: The dissolution of the sublingual (SL) tablet itself may be limited. AL-101 (IN) was more efficient: higher Cmax of IN was associated with rapid uptake and better absorption; lower AUC of IN was associated with total absorption. AL-101 (IN) was less variable: Because of variability in Cmax, it can be difficult to predict safety (of the SL formulation) based on dose.

[0315] These data are presented graphically in FIG.

[0316] Example 7. Safety and efficacy of intranasal formulations of apomorphine hydrochloride. Title: A pilot, double-blind, double-dummy, controlled, crossover study to evaluate the tolerability, safety, and potential efficacy of an intranasal formulation of apomorphine hydrochloride versus placebo and Viagra in subjects with primarily psychogenic erectile dysfunction.

[0317] OBJECTIVES AND ENDPOINTS: To evaluate the tolerability, adverse drug reaction profile, and efficacy of intranasal apomorphine hydrochloride at doses of 0.25 mg to 1.0 mg per 0.1 ml compared with placebo and Viagra in male subjects with primarily psychogenic erectile dysfunction. The primary efficacy parameter was each subject's assessment of the quality of erection (on a 4-point scale). Secondary endpoints included frequency of erections, time from administration to erection, duration of erection, and efficacy index (EI) for subjects who achieved an erection. Safety was primarily assessed by adverse events, but cardiovascular effects were also investigated by monitoring blood pressure, heart rate, and oxygen saturation before and after administration. The integrity of the nasal mucosa in both nostrils was also evaluated before administration, at the onset of nasal symptoms, and at the end of each treatment visit.

[0318] METHODOLOGY: A single-center, single-dose, double-blind, double-dummy, controlled crossover study to evaluate the safety, tolerability, and efficacy of intranasal apomorphine hydrochloride at doses of 0.25 mg to 1.0 mg per 0.1 ml compared with placebo and Viagra in male subjects with primarily psychogenic erectile dysfunction. Subjects attended six site visits in total: an initial screening and eligibility visit, three treatment visits in Part 1, and two treatment visits in Part 2. Eligible subjects were randomized to the treatment sequence in Part 1 after the initial screening visit. Approximately two months later, subjects were randomized to the treatment sequence in Part 2.

[0319] At each treatment visit, a single dose of the study treatment was administered. Efficacy was measured by an ED questionnaire completed by each subject. After administration, all subjects viewed sexually explicit videotapes and magazines for approximately 60 minutes. At the end of this time, the questionnaire was completed and patients were asked to rate the quality of their erections on a 4-point scale. The primary efficacy variable was the subject's overall assessment of their erections, measured on a scale of 1 to 4: 1 = increased in size but not hard; 2 = hard but not hard enough for vaginal penetration; 3 = hard enough (but not completely hard) for vaginal penetration; 4 = completely hard.

[0320] Safety was measured by monitoring subjects' blood pressure, heart rate, and percent oxygen saturation (by pulse oximetry) before and after dosing (approximately 90 minutes after dosing began). In addition, subjects' nasal mucosal integrity was assessed before and at the end of dosing. Information on adverse events was collected throughout the study.

[0321] The duration of the entire study was 3-4 months per subject. The minimum time between the two treatments was 24 hours. The first part of the study was carried out over a period of one month, and the second part was carried out approximately two months later.

[0322] Diagnosis and main inclusion criteria: Subjects were heterosexual men aged 18-65 years with a self-reported history of erectile dysfunction of non-organic etiology for >6 months (confirmed by medical records or diagnosis by intracavernosal injection). Subjects were in overall good health, had no clinically significant laboratory profile, and had normal nasal mucosa in the nostril used for administration of the study product.

[0323] Subjects with nasal conditions likely to affect nasal absorption (e.g., chronic nosebleeds, allergic rhinitis, severe nasal septum deviations, etc.) were excluded from the study. Subjects with clinically significant cardiovascular or respiratory disease were also excluded, especially those receiving concomitant organic nitrates or nitric oxide donors.

[0324] Drugs, Doses, and Regimen: At each treatment visit, subjects received one dose of study treatment. Subjects received the following in randomized order:

[0325] Apomorphine hydrochloride nasal spray, 1.0 mg in 0.1 ml Viagra 50 mg tablets A placebo nasal spray formulation matching the apomorphine hydrochloride test formulation.

[0326] RESULTS: Of 24 subjects screened, 21 were enrolled and completed Phase 1 of the study. Of these 21 subjects, 18 completed Phase 2 of the study.

[0327] Efficacy Results: Using a global self-assessment score (grade 3 or 4), 39% efficacy was observed in the placebo group; 67% efficacy was observed in the Viagra group; efficacy in the nasal apomorphine groups ranged from 72-82%; the difference between apomorphine 0.5 mg and placebo was statistically significant. As a result, 60-70% of subjects treated with nasal apomorphine achieved a satisfactory erection (as reported by the subject) compared with approximately 30% in the placebo and Viagra groups; the difference between apomorphine 0.5 mg and placebo was statistically significant (p=0.03). The difference between apomorphine 0.5 mg and placebo was statistically significant (p=0.03).

[0328] Conclusions: This study found no statistically significant differences in the efficacy of apomorphine hydrochloride 0.25, 0.50, 1.0 mg, Viagra 50 mg, and placebo in initiating erections. The adverse event profile of each treatment was similar, and no serious adverse events were observed during the study. Small decreases in heart rate were detected after each dose of apomorphine and after placebo administration, but no clinically significant changes in cardiovascular parameters were detected.

[0329] Test 2

[0330] Title: A double-blind, fixed-dose, at-home proof-of-concept study to evaluate the safety and efficacy of apomorphine hydrochloride administered as a nasal spray formulation for the treatment of psychogenic or organic erectile dysfunction.

[0331] OBJECTIVES AND ENDPOINTS: To evaluate the safety and efficacy of apomorphine hydrochloride in a home setting in patients with psychogenic or organic erectile dysfunction. Primary efficacy was based on answers to SEP question 2 ("Were you able to achieve at least some erection?") and question 3 ("Were you able to insert your penis into your partner's vagina?"). Safety was assessed primarily by adverse events; nasal examinations were performed during clinic visits and vital signs were recorded.

[0332] METHODOLOGY: This was a randomized, multicenter, double-blind, fixed-dose study in men with ED of any etiology and severity.Baseline demographic analysis showed that 50% of study participants had psychogenic, 26% had mixed organic, and 24% had diabetic ED.

[0333] Following screening, patients were randomly assigned to one of four groups: placebo, 0.25 mg, 0.5 mg, or 1.0 mg apomorphine. Treatment consisted of up to 18 doses, with the test treatment administered 15–20 min before sexual intercourse, but no more than once per day. Patients completed a sexual encounter profile (SEP) in a diary at home each time they administered the test treatment and attempted sexual intercourse. Patients returned to the clinic after every six doses and completed a validated ED questionnaire (International Index of Erectile Function [IIEF] score) at the time of each clinic visit. In addition, they answered global efficacy questions at the end of the study.

[0334] Diagnosis and main inclusion criteria: Subjects were heterosexual men aged 18-75 years with erectile dysfunction of psychogenic or organic origin for more than 3 months.

[0335] Drugs, Dose, and Regimen: Subjects were randomized to one of the following treatments:

[0336] Placebo nasal spray Apomorphine hydrochloride nasal spray, 0.25 mg in 0.1 ml Apomorphine hydrochloride nasal spray, 0.50 mg in 0.1 ml Apomorphine hydrochloride nasal spray, 1.0 mg in 0.1 ml.

[0337] Statistical methods: Analysis of covariance (ANCOVA) and logistic regression with 95% confidence intervals, as appropriate, were used to compare treatment groups. Statistical tests were two-sided and performed at the 5% significance level.

[0338] Results: Of 246 patients screened, 184 were enrolled and 125 completed the study.

[0339] Efficacy Results: Compared to placebo, more patients receiving apomorphine hydrochloride were able to achieve some degree of erection and insert their penis into their partner's vagina. For example, the success rate of vaginal insertion was 73% and 82% for patients receiving 0.5 mg and 1.0 mg apomorphine hydrochloride compared to 36% for patients receiving placebo, as shown in Table 14. [Table 14]

[0340] Conclusions: The results indicate that intranasal apomorphine is a safe, well tolerated, and effective treatment for psychogenic or organic erectile dysfunction, particularly at the 0.5 mg and 1.0 mg dose levels.

[0341] A 6-month open-label extension study of approximately 30 patients was added to this study. Placebo subjects were titrated to 0.5 mg of active drug, 0.25 mg subjects were titrated to 1.0 mg of active drug, 0.5 mg subjects were titrated to 1.0 mg or remained on 0.5 mg apomorphine, and 1.0 mg subjects remained on that dose.

[0342] Test 3

[0343] Title: A pilot phase II randomized, double-blind, placebo-controlled, parallel-design study of the efficacy and safety of home-based, on-demand administration of intranasal apomorphine hydrochloride in premenopausal patients with acquired female sexual dysfunction.

[0344] OBJECTIVES AND ENDPOINTS: The objective of this study was to evaluate the safety and efficacy of home-administered intranasal apomorphine 0.5 mg compared with placebo in premenopausal women taking oral contraceptives and with female sexual arousal disorder.

[0345] METHODOLOGY: This study was designed as a pilot, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were enrolled in a 4-week pretreatment period followed by a 12-week home treatment period. Subjects completed pre- and post-treatment questionnaires regarding sexual function and a sexual event log after each home administration of study medication.

[0346] Diagnosis and main inclusion criteria: Premenopausal women taking oral contraceptives with a diagnosis of acquired female arousal disorder.

[0347] Drugs, Dosage, and Regimen: Apomorphine 0.5 mg nasal spray Placebo nasal spray.

[0348] Subjects will be randomly assigned to receive active or placebo in a 2:1 ratio. Subjects will be instructed to take the drug not more than once per 24-hour period. Eleven doses will be dispensed during the first 4-week treatment period, followed by 12 doses during the subsequent 4-week treatment periods.

[0349] RESULTS: Apomorphine was effective in treating female sexual arousal disorder.

[0350] A summary of efficacy and safety is shown in Table 15. Intranasal apomorphine has a low adverse event profile Over 200 patients (2,200 doses) participated in clinical trials of intranasal apomorphine (including patients up to 78 years old). The incidence of nausea is very low To date, no patients have experienced vomiting, fainting, or hypotension. The data is shown below Preferential delivery to the CNS reduces apomorphine-associated side effects Side effects of nasal apomorphine were superior to those of Viagra and Cialis. [Table 15]

[0351] Example 8. Evaluation of cerebrospinal fluid (CSF) apomorphine concentrations following intranasal and sublingual administration. OBJECTIVES AND ENDPOINTS: To compare CSF levels of apomorphine in healthy men after intranasal and sublingual administration, and to compare CSF apomorphine levels with plasma levels.

[0352] METHODOLOGY: This was an open crossover study in which two single doses of apomorphine were administered to each of six study arms, with at least a 3-day washout between doses.

[0353] After dosing, subjects underwent lumbar punctures. Lumbar punctures were performed 15, 20, and 30 minutes after dosing (one-third of the subjects in each group were scheduled to be sampled at each of these times). Blood samples were taken at 0, 5, 10, 20, 30, 60, and 120 minutes after dosing. Subjects were evaluated for adverse events from dosing until discharge (approximately 4 hours after dosing). Nasal examinations and vital signs were also recorded at intervals throughout the study. Subjects were followed up by telephone 24-48 hours after discharge.

[0354] Diagnostic and main inclusion criteria: Healthy men aged 18–40 years who were non-smokers.

[0355] Drugs, Doses, and Regimen: Subjects received apomorphine intranasally and sublingually as follows: JPEG2024531685000017.jpg31150

[0356] Results: (a) Subcutaneous formulations yielded levels in the CSF of 2.5-4.3% compared to plasma. (b) Nasal formulations yielded levels in the CSF of 26.7-44.1% compared to plasma. (c) Nasal formulations yielded CSF concentrations 4 standard deviations higher than subcutaneous formulations. (d) Direct administration to the CSF via nasal administration resulted in preferential accumulation in the CSF, suggesting little leakage from the CSF to the systemic circulation, whereas direct administration via lumbar puncture or Ommaya reservoir localized apomorphine to the CNS. (e) To avoid side effects associated with systemic apomorphine administration, nasal administration is preferred to deliver apomorphine to the CSF while minimizing systemic exposure. Further in this regard, intrathecal administration via lumbar puncture or Ommaya reservoir is preferred, especially for severe neurological disorders.

[0357] The results of this example are shown in FIG.

[0358] Example 9. Evaluation of the efficacy and safety of two doses of OT-101 in adult patients with recurrent high-grade glioma. The G004 study is a multinational, multicenter, open-label, positive-controlled, randomized, parallel-group, dose-finding study evaluating the efficacy and safety of two doses of OT-101 administered intratumorally as continuous high-flow microperfusion every 7 days every other week in adult patients with recurrent high-grade glioma (NCT00431561). In addition, the efficacy and safety of the two doses of OT-101 were compared with standard chemotherapy (TMZ or PCV). Ninety-eight patients (AA: 30; GBM: 68) were randomly assigned to one of two treatment arms (intent-to-treat population [ITT]) of OT-101 representing two different dose cohorts, namely 2.5 mg / cycle (N=48) and 19.8 mg / cycle (N=50), respectively.

[0359] In our phase 2 clinical trial (NCT00431561), OT-101 was continuously infused intracranially over 7 days by intracranial administration via an intratumoral catheter using a CED system in 89 adults with R / R high-grade gliomas (62 GBM and 27 AA). The planned minimum number of OT-101 cycles in a 7-day period was 4, and the maximum allowed number of OT-101 cycles in a 7-day period was 11.

[0360] Compared to the control group (TMZ), patients receiving OT-101 had three times the levels of psychiatric changes, with 32% of patients experiencing aggression (5%), agitation (5%), anxiety (5%), confusion (12%), insomnia (5%), and mood changes (2%).

Claims

1. 1. A therapeutic composition for treating a symptom of a neurological disease or disorder, comprising a therapeutically effective amount of a drug for inhibiting or suppressing expression of TGF-β, A therapeutic composition, wherein the drug for inhibiting or suppressing the expression of TGF-β is OT-101.

2. 2. The therapeutic composition of claim 1, wherein the neurological disease or disorder is Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, or excessive daytime sleepiness, and optionally the neurological disease or disorder is early or late stage Parkinson's disease.

3. 3. The therapeutic composition of claim 1, further comprising one or more pharmaceutically acceptable excipients selected from diluents, stabilizers, disintegrants, and anti-caking agents.

4. 3. The therapeutic composition of claim 1 or 2, suitable for use by intrathecal injection or infusion.

5. 3. The therapeutic composition of claim 1 or 2, a) containing a carrier comprising sterile water for injection, saline, isotonic saline, or a combination thereof; or b) substantially free of excipients; or c) stable in the carrier at 37°C for at least 14 days; or d) A therapeutic composition reconstituted from a lyophilized powder of said composition.

6. A therapeutic composition for treating a neurological disease or disorder, comprising:

10. A therapeutically effective amount of a drug for inhibiting or suppressing TGF-β expression according to claim 1, in combination with a therapeutically effective amount of apomorphine, a prodrug of apomorphine, or a pharmaceutically acceptable salt or ester thereof; or A therapeutic composition comprising a therapeutically effective amount of apomorphine, a prodrug of apomorphine, or a pharmaceutically acceptable salt or ester thereof, used in combination with a therapeutically effective amount of a drug for inhibiting or suppressing the expression of TGF-β as described in claim 1.

7. 7. The therapeutic composition of claim 6, wherein the neurological disease or disorder is Parkinson's disease, Alzheimer's disease, male or female sexual dysfunction, or excessive daytime sleepiness, and optionally the neurological disease or disorder is early or late stage Parkinson's disease.

8. 8. The therapeutic composition of claim 6 or 7, A drug for inhibiting or suppressing the expression of TGF-β is a) containing any one or more pharmaceutically acceptable excipients selected from diluents, stabilizers, disintegrants and anti-caking agents; or b) containing a carrier comprising sterile water for injection, saline, isotonic saline, or a combination thereof; or c) A therapeutic composition that is substantially excipient-free.

9. The therapeutic composition of claim 6 or 7, wherein the drug for inhibiting or suppressing the expression of TGF-β is administered by intrathecal injection, infusion, or direct intracranial administration.

10. The therapeutic composition of claim 6 or 7, wherein the drug for inhibiting or suppressing the expression of TGF-β and apomorphine, a prodrug of apomorphine, or a pharmaceutically acceptable salt or ester thereof are administered together, simultaneously, sequentially, or separately.

11. 1. A nasal apomorphine formulation for treating or alleviating symptoms of neurological disorders, comprising a therapeutically effective amount of apomorphine, a prodrug of apomorphine, or a pharmaceutically acceptable salt or ester thereof, Nasal apomorphine preparations, where the neurological disorder is male or female sexual dysfunction or excessive daytime sleepiness.

12. 12. The formulation of claim 11, the formulation comprising any one or more of a pH buffer, a thickening agent, a humectant, a preservative, and one or more pharmaceutical excipients; Optionally, the formulation comprises: a) a buffer selected from acetate, citrate, prolamin, carbonate, phosphate, and combinations thereof; or b) a thickening agent selected from methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof; or c) a humectant selected from sorbitol, glycerol, mineral oil, vegetable oil, and combinations thereof; or d) a bioadhesive excipient; or e) any one or more of glycerin, glycol, propylene glycol, polyethylene glycol, polyethylene glycol 400, ascorbic acid, sodium ascorbate, edetate disodium, and sodium metabisulfite; or f) A formulation comprising one or more of an antioxidant, an antimicrobial, a chelating agent, a preservative, and combinations thereof.

13. 13. The formulation according to claim 11 or 12, wherein the formulation comprises: a) Nasal powder formulation; b) an aqueous solution, preferably i) selected from aqueous gel solutions, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions, or combinations thereof; and / or ii) having a drug concentration of 5 mg / mL or 10 mg / mL in aqueous solution; or c) a non-aqueous solution, preferably selected from a non-gel aqueous solution, a non-aqueous suspension, a non-aqueous liposomal dispersion, a non-aqueous emulsion, a non-aqueous microemulsion, and combinations thereof; A formulation which is

14. 13. The formulation of claim 11 or 12, wherein the neurological disorder is a sexual dysfunction selected from male impotence and / or erectile dysfunction.

15. 13. The formulation of claim 11 or 12, a) 0.5 mg or 1 mg nasal dosage forms with 0.1 mL per actuation; b) Nasal preparations dispensed with oxygen and nitrogen; c) a nasal formulation at pH 3.4; or d) Stable nasal formulation after 3 months at 40°C / 60% RH or 24 months at 25°C / 60% RH 1. A formulation comprising:

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