HK1103657A - Methods of using and compositions comprising thalidomide for the treatment and management of pulmonary hypertension - Google Patents

Abstract

Methods of treating, preventing and managing pulmonary hypertension are disclosed. Specific methods encompass the administration of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent, surgery and/or lung transplantation. Specific second active agents are capable of reducing pulmonary artery pressure. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

Compositions comprising thalidomide for the treatment and management of pulmonary hypertension and methods of use thereof

1. Field of the invention

The present invention relates to methods of treating, preventing and managing pulmonary hypertension comprising the administration of thalidomide, either alone or in combination with known therapies. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of thalidomide in combination with surgery, transplantation therapy and/or other standard therapies for the treatment of pulmonary hypertension.

2. Background of the invention

Pathology of PH

Pulmonary hypertension ("PH") refers to a condition characterized by a sustained rise in pulmonary arterial pressure. L.J. Rubin, The New England Journal of Medicine, 336 (2): 111, 1997. PH originates from various etiologies and therefore it is useful to classify the disease. Rich, Advances in pulmonary hypertension, 1 (1): 3,2002. The World Health Organization (WHO) groups pulmonary hypertension into groups according to known etiologies and defines primary pulmonary hypertension as a separate entity of unknown etiology (supra). In addition, after the New York Heart Association (NYHA) functionally classified the disease, the WHO studied the functional classification of heart disease so that patients could be compared according to their clinical severity (supra). The functional classifications are listed in table 1 below.

TABLE 1 WHO functional Classification of Pulmonary Hypertension (PH)

Class I	Patients had PH but had no physical activity restrictions.
		Class II	The patient suffers from PH, slightly limiting physical activity.
Class III	The patient suffers fromWith PH, physical activity is significantly restricted.

Class IV

The patient suffered from PH, was unable to perform any physical activity, and was asymptomatic.

Pulmonary Hypertension (PH) is divided into primary and secondary forms. Rich, Advances in pulmony Hypertension, 1 (1): 3,2002. Primary Pulmonary Hypertension (PPH) is a disease of unknown etiology, while Secondary Pulmonary Hypertension (SPH) is caused by either an intrinsic solid disease of the lung or an extrinsic disease of the lung (supra). PPH is divided histopathologically into three, the arteriogenic plexus disease, recurrent thromboembolism and the venous occlusive disease (supra). Patients with PPH are further divided into sporadic and familial (supra, page 4). About 12% of PPH patients are reported to have familial PPH (supra). However, this may underestimate the true prevalence of familial PPH, as it may cross generations (ibid). Recently, it has been reported that the PPH-1 gene appears in about half of patients with familial PPH. Deng, Am J Respir Crit Care med, 161: 1055-1059, 2000. It was reported that 25% of patients with sporadic PPH tested positive for the PPH-1 gene (see above).

In SPH, the mechanism is often multifactorial depending on the underlying cause. Rich, Advances in pulmony Hypertension, 1 (1): 4,2002. Heart disease, lung disorders, and combinations thereof are the most common causes of SPH (supra). Patients with pulmonary hypertension associated with collagen vascular disease have clinical features of both entities (supra). Most commonly, collagen vascular disease has been present for many years before the onset of PH, but sometimes the opposite (supra).

Innate systemic intrapulmonary bypass may cause PH, which may be associated with increased blood flow and blood pressure delivery to the pulmonary circulation (supra). The association between liver disease and PH may be associated with portal hypertension (supra). It is not completely clear why portal hypertension produces PH (see above).

The presence of the HIV virus may cause PH, possibly by activating cytokine or growth factor channels (ibid). Several drugs and toxins have also been associated with the development of PH, although the causal relationship is uncertain (supra). The strongest relationship between drug uptake and PH evolution has been studied with fenfluramine (supra). Although the syndrome cannot be distinguished from PPH, studies have shown that this patient is more susceptible and has a poorer prognosis (supra) than a similar PPH patient. This may be the cause of pulmonary vascular disease due to the unique molecular pathway triggered by fenfluramine (supra).

Persistent pulmonary hypertension in newborns is different from congenital abnormalities of the heart and pulmonary vasculature, but is similar to PPH and is generally more responsive to acute and chronic vasodilatory therapy. Rich, Advances in pulmony Hypertension, 1 (1): 5,2002.

In other patients, PH is caused by pulmonary venous hypertension (ibid), the pathophysiology and clinical course of which is markedly different from pulmonary arterial hypertension. End-of-seat breathing and nocturnal paroxysmal dyspnea are characteristic features that may cause dyspnea (supra). These patients often have a history of chronic congestive heart failure and/or recurrent pulmonary edema that becomes illegible when right ventricular failure occurs (supra).

PH is also associated with respiratory disorders and/or hypoxemia, including chronic obstructive pulmonary disease, interstitial lung disease, sleep disordered breathing, alveolar hypoventilation, chronic altitude disease, neonatal lung disease, and alveolar-capillary dysplasia (supra). Although hypoxemia may be present in all forms of PH, it is characteristic of these conditions (ibid). These patients often have difficulty breathing at rest and with minimal activity, and have only a weak clinical PH profile (supra).

The PH may result from chronic thrombotic or thrombotic diseases such as sickle cell disease, other coagulative diseases, chronic thromboembolism, connective tissue disease, lupus, and schistosomiasis. Rich, advanced plasma Hypertension, 1 (1): 5-6, 2002. These patients often show clinical signs and symptoms that are indistinguishable from pulmonary hypertension (ibid).

Inflammatory diseases such as schistosomiasis, sarcoidosis and pulmonary capillary hemangiomas directly affect the pulmonary vasculature and can also contribute to PH. Rich, Advances in pulmony Hypertension, 1 (1): 6,2002. Schistosomiasis is probably the most common cause of PH worldwide, despite the fact that it has never been seen in europe and america (ibid). Sarcoidosis can greatly destroy the pulmonary parenchyma and the pulmonary vascular bed and cause PH only by lung destruction and consequent hypoxemia (ibid). Patients may also develop PH due to the pulmonary circulation associated with the fleshy process (supra). Pulmonary capillary hemangiomas are a very rare disease involving the pulmonary capillary bed that occurs at different stages (supra), often associated with frequent hemoptysis, severe PH and a progressive fatal process within a short period of time (supra).

Common PH symptoms reported in national vision surveys include dyspnea, fatigue, weakness, chest pain, recurrent fainting, seizures, mild headaches, neurological deficit, leg edema, and palpitations. Rich, Annals of Internal Medicine, 107; 217, 1987; the Merck Manual, 595 (17 th edition, 1999). In the pulmonary arterioles, patients with PH experience vascular intimal hyperplasia and consequent narrowing of the blood vessels (see above). In further cases, medial (smooth muscle) hypertrophy and areas of hyperplasia, irreversible mesh damage and necrotic arteries (supra) occur.

The pathophysiology of PH is poorly understood. Irritation of the endothelium, such as hormonal or mechanical effects, is thought to result in vascular scarring, endothelial dysfunction, and proliferation of the inner and middle layers. The Merck Manual 1703 (17 th edition, 1999).

Loss of pulmonary vasodilatory nerves and excess vasoconstrictive nerves may both play a role in PH (supra). Increased expression of potent vasoconstricting neuroendothelin-1 (ET-1) was found in the muscular pulmonary artery and reticular lesions of patients with PH. Chantick, Advances in pulmony Hypertension, 1 (1): 14, 2002. In addition, Prostacyclin (PGI) in pulmonary arteries in the lungs of patients with PH has been reported₂) Expression of synthase and endothelial nitric oxide synthase (eNOS) is reduced. Rubin, Clinics in Chest Medicine, 22 (3): 2001. this reduced expression is thought to trigger key changes in the pulmonary endothelium at severe PH (supra). PGI₂And reduced Nitric Oxide (NO) levels are also causally related to increased pulmonary vasoconstriction, as well as progressive structural changes in the pulmonary arteries, growth of vascular smooth muscle cells, and increased endothelial apoptosis due to loss of NO-protection of endothelial cells (ibid). These effects are important in the pathogenesis and progression of PH (supra).

Recent PH studies have shown that abnormal endothelial cells play a major role in the initiation and development of PH. Rubin, Clinics in Chest Medicine, 22(3), 2001. It was demonstrated that endothelial cells overgrowing at severe PH annihilate blood vessels and disrupt lung circulation, suggesting that somatic mutations in angiogenesis-or apoptosis-related genes such as transforming growth factor beta (TGF- β) receptor 2 may underlie endothelial cell proliferation in PPH patients (ibid). The loss of these important cellular growth mechanisms allows for clonal expansion of endothelial cells from a single cell with selective growth benefits (supra). On the other hand, proliferating endothelial cells in SPH patients are considered polygonal (supra). From this finding, it is known that non-mutated local vascular factors, such as increased shear stress, play an important role in initiating endothelial cell proliferation (ibid). In PPH and SPH, it is presumed that the pulmonary vascular bed contains progenitor-like cells with an abnormal growth regulating ability (supra). The major difference in pathogenesis between primary and secondary lung endothelial cell proliferation is likely to be the primary mechanism associated with endothelial progenitor recruitment (supra). In PPH, endothelial cells proliferate from a mutated single cell, whereas in SPH several progenitor-like cells are activated (supra).

PH treatment

Existing PH treatments depend on the stage and mechanism of the disease. Commonly used PH treatments include anticoagulation, oxygenating, conventional vasodilator therapy, transplantation, and surgery.

Several studies have shown that survival is increased when patients are treated with anticoagulants, regardless of the histopathological subtype. Rubin et al, The New England Journal of Medicine, 336 (2); 115, 1997. Warfarin was used to maintain the international normalized ratio at 1.5 to 2 times the control value, as long as there were no contraindications against the coagulation. Tapson, Advances in pulmony Hypertension, 1 (1): 16, 2002.

Digoxin is used to prevent and treat SPH-related upper ventricular arrhythmias and patients with left ventricular failure. However, no randomized controlled clinical trials were performed to confirm the effectiveness of this strategy in PPH patients. Tapson, Advances in pulmony Hypertension, 1 (1): 16, 2002. Diuretics are reported to be useful in reducing excessive preload in right ventricular failure patients. Rubin et al, The New England Journal of Medicine, 336 (2); 115, 1997. Oxygenating may be used in patients with blood oxygenation induced by rest or exercise (supra) and v.f. tapson, Advances in pulmony Hypertension, 1 (1): 16, 2002.

For patients who do not respond to drug treatment, an atrial septal ostomy or a lung transplantation is performed. The merck Manual 1704 (17 th edition, 1999), l.j.rubin, Advances in pulmony hypertension, 1 (1): 16 and 19, 2002. Atrioventricular arteriostomies tend to act as a graft bridge (supra). However, there has been little extensive research on interatrial septostomy (ibid). The availability of lung organ transplantation is also limited (supra, page 19). In addition, long-term complications after transplantation, such as chronic rejection and opportunistic infections, also prevent its long-term effectiveness in many patients (ibid).

Current drugs used to treat PH include calcium channel blockers and pulmonary vasodilators. The merck Manual 1704 (17 th edition, 1999), v.f. tapson, Advances in pulmony hypertension, 1 (1): 16, 2002. Calcium channel blockers are the most widely used drugs for treating PH. Studies have shown that this drug improves PPH patients by 20-30%. The New England journal of Medicine, 336 (2); 114, 1997.

The currently available vasodilators are epoprostenol (EPO, Floran)^®) Treprostinil (Remodulin)^®) And bosentan (Tracleer)^®). Tapson, Advances in pulmony hypertension, 1 (1): 16, 2002; chantick, Advances in pulmony hypertension, 1 (1): 14-15, 2002. More recently bosentan has been approved for initial PH treatment in patients with NYHA class III and IV symptoms. The inner layer cell active agent is reported to improve the motor ability and has application prospect in interrupting or reversing the stimulation of pulmonary vessels. However, the use of vasodilators is controversial in patients with undiminished pulmonary artery pressure and increased cardiac output leading to a dramatic decrease in vascular resistance. Rubin et al, The New England Journal of medicine, 336 (2); 114, 1997. Thus, there remains a need for a safe and effective method of treating and controlling PH.

2.3. Thalidomide

Thalidomide is under the trade name Thalomid^®Racemic compounds are sold under the chemical name α - (N-phthalimide) glutarimide or 2- (2, 6-dioxo-3-piperidyl) -1H-isoindole-1, 3(2H) -dione. The compounds have structure I:

thalidomide was originally developed in the 50's of the 20 th century for the treatment of vomiting of pregnancy, but was no longer used due to its teratogenic effects. Thalidomide has been approved in the united states for the acute treatment of cutaneous symptoms of leprosy, leprosy erythema nodosum, Physicians' Desk Reference, 1153-1157 (57 th edition, 2003). The sale of thalidomide is strictly controlled (ibid.) because its administration to pregnant women can lead to birth defects. The role of thalidomide in the treatment of other diseases, such as chronic graft versus host disease, rheumatoid arthritis, sarcoidosis, some inflammatory diseases of the skin, and inflammatory bowel disease, has been studied. See generally Koch, h.p., prog.med.chem.22: 165-242(1985). See also Moller, d.r. et al, j.immunol.159: 5157-5161 (1997); vasiliauskas, e.a., et al, Gastroenterology 117: 1278-1287 (1999); ehrenpris, e.d. et al, Gastroenterology 117: 1271-1277(1999). Further, it is believed that thalidomide may be combined with other drugs to treat ischemia/reflexes (recursion) associated with coronary and cerebral obstructions. See U.S. patent No. 5,643,915, which is incorporated herein by reference.

Thalidomide has been reported to have been used in clinical studies for the treatment of specific cancer types, such as refractory multiple myeloma, brain tumor, melanoma, breast cancer, colon cancer, mesothelioma, and renal cell carcinoma. See, for example, Singhal, S. et al, New England J.Med.341(21), 1565-1571 (1999); and Marx, g.m. et al, proc.am.soc.clin.oncology 18: 454a (1999). Further reports suggest that thalidomide can be used to prevent the development of chronic cardiomyopathy in rat species caused by doxorubicin. Costa, p.t. et al, Blood 92 (10: suppl.1): 235b (1998). Other reports on the use of thalidomide to treat specific cancers include the treatment of malignant glioma multiformes in combination with carboplatin. McCann, J., Drug Topics 41-42 (21/6/1999). Thalidomide has also been reported as an antiemetic agent during treatment of astrocytomas. Zwart, D., Arzneim. -Forsch.16(12)1688-1689 (1966).

Even with the common mechanism by which thalidomide contributes to the treatment of some cancers, its nature is unclear. See, e.g., Moreira, a.l. et al, j.expr.med.177: 1675-1680 (1993); McHugh, s.m. et al, clin.expert.immunol.99: 160-167 (1995); and Moller, d.r. et al, j.immunol.159: 5157-5161(1997). However, thalidomide is reported to be an anti-angiogenic agent that inhibits the production of tumor necrosis factor (TNF- α) and interleukin 12 (IL-12). See, e.g., Moller, d.r. et al, j.immunol.159: 5157-5161 (1997); moreira, a.l. et al, j.exp.med.177: 1675-1680 (1993); U.S. Pat. Nos. 5,593,990, 5,629,327 to D' Amato, and 5,712,291 and U.S. Pat. No. 5,385,901 to Kaplan. In vitro studies have shown that thalidomide can affect the production of various other proteins. See, e.g., McHugh, s.m. et al, clin.exp.immunol.99: 160-167(1995). Thalidomide may also affect mechanisms associated with epithelial or endothelial function or growth. D' Amato m. et al, proc.natl.acad.sci.91: 4082-4085(1994).

3. Summary of the invention

The invention encompasses methods of treating or preventing pulmonary hypertension ("PH") comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of controlling PH (e.g., prolonging their time to a state of remission), which comprise administering to a patient in need of such control a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof.

One embodiment of the invention includes the administration of thalidomide, such as, but not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogs, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, surgery and lung transplantation, alone or in combination with therapies conventionally used to treat, prevent or control PH.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits comprising thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and optionally a second agent that are useful in the treatment, prevention, and/or control of PH.

4. Detailed description of the invention

A first embodiment of the invention encompasses methods of treating, managing or preventing PH comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof.

The terms "pulmonary hypertension", "PH" and "PH and related disorders" as used herein, unless otherwise indicated, include, but are not limited to: primary Pulmonary Hypertension (PPH), Secondary Pulmonary Hypertension (SPH), familial PPH, sporadic PPH, anterior capillary pulmonary hypertension, Pulmonary Arterial Hypertension (PAH), pulmonary arterial hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arterial disease (TPA), plexogenic pulmonary arterial disease, functional class I-IV pulmonary hypertension, and pulmonary hypertension related to, associated with, or subject to: left ventricular abnormalities, mitral valve disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary venous malformation drainage, pulmonary vein occlusive disease, collagen vascular disease, congenital heart disease, HIV viral infection, drugs and toxins such as fenfluramine, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep disordered breathing, alveolar hypoventilation, chronic altitude disease, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other diseases of coagulation, chronic thromboembolism, connective tissue disease, lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangioma.

Another embodiment of the invention encompasses methods of treating, preventing and/or managing PH, which comprise administering to a patient in need of such treatment, prevention and/or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogs, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, and other agents described, for example, in Physician's Desk Reference 2003. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule). Specific examples of the second active agent include, but are not limited to, amlodipine, diltiazem, nifedipine, adenosine, epoprostenol (Floran)^®) Treprostinil (Remodulin)^®) Bosentan (Tracleer)^®) Rodenticide, digoxin, nitric oxide, L-arginine, iloprost, betaprost, and sildenafil (Viagra)^®)。

Another embodiment of the invention encompasses a method of reversing, reducing or avoiding adverse effects associated with administration of a treatment for the treatment of PH, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and optionally a second active agent.

Procedures such as lung transplantation may be necessary to treat patients with PH who do not respond to drug treatment. It is believed that the combined use of thalidomide and lung transplantation is particularly beneficial in patients with PH. It is believed that thalidomide may act in combination with transplantation therapy to reduce complications such as chronic rejection and opportunistic infections associated with transplantation. Accordingly, the invention encompasses methods of treating or controlling PH comprising administering thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) prior to, during, or after transplant therapy.

Another embodiment of the present invention encompasses pharmaceutical compositions that may be used in the methods of the present invention. Particular compositions include thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and optionally a second active agent.

The invention also encompasses single unit dosage forms comprising thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof.

The invention also includes kits comprising thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and a second active agent. For example, a kit may contain a compound of the invention and a calcium channel blocker, vasodilator, prostacyclin analog, endothelin antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, lipid lowering agent, thromboxane inhibitor or other agent useful in treating a patient with PH.

4.1. Compounds of the invention

Compounds useful in the invention include racemic thalidomide, stereoisomerically enriched or stereoisomerically pure thalidomide, and pharmaceutically acceptable salts, solvates (e.g., hydrates), stereoisomers, clathrates, and prodrugs thereof.

As used herein, unless otherwise indicated, the term "stereomerically pure" refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. Typical stereomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound; more preferably, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound; more preferably, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound; and most preferably comprises greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

As used herein, unless otherwise indicated, the term "stereomerically enriched" refers to compositions containing greater than about 60% by weight of one stereoisomer of a compound, and preferably includes greater than about 70% by weight, more preferably greater than about 80% by weight, of one stereoisomer of a compound.

The term "enantiomerically pure" as used herein, unless otherwise indicated, refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

Thalidomide is commercially available (from Celgene corp., New Jersey) or can be prepared according to known methods. See, e.g., i.d. franta et al, toxicol.appl.pharmacol.7, 268(1965), incorporated herein by reference. Enantiomerically pure thalidomide can be resolved using known resolving agents or chiral columns as well as other standard organic chemical synthesis techniques. See, e.g., Blaschke, Arzneimitelforschung 29: 1640-1642 (1979); shealy et al, chem.indes.1030 (1965); and Casini et al, Farmaco Ed. Sci.19: 563(1964).

As used herein, unless otherwise specifically indicated, the term "pharmaceutically acceptable salt" includes, but is not limited to, salts of the acidic or basic moieties of the compounds to which the term refers. The basic moiety is capable of forming various salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of these basic compounds are those which form non-toxic acid addition salts, i.e., acids which form salts containing pharmaceutically acceptable anions. Suitable organic acids include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, oleic acid, tannic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucuronic acid, saccharic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, or pamoic acid (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoic acid)). Suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid. In addition to the acids described above, the compounds containing an amino moiety may form pharmaceutically acceptable salts with various amino acids.

Naturally occurring acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, that is, salts containing a pharmaceutically acceptable cation, such as, but not limited to, alkali or alkaline earth metal salts, especially calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

As used herein, the term "derivative" as used to describe a compound or chemical moiety refers to a compound or chemical moiety in which the saturation of at least one bond is changed (e.g., a single bond is changed to a double or triple bond) or in which at least one hydrogen atom is replaced with a different atom or chemical moiety. Examples of different atoms and different chemical moieties include, but are not limited to, halogen, oxygen, nitrogen, sulfur, hydroxyl, methoxy, alkyl, amine, amide, ketone, and aldehyde.

Unless otherwise indicated, the term "prodrug" as used herein refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, thalidomide derivatives containing biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO₂-ONO or-ONO₂Part of a thalidomide derivative.

As used herein, unless otherwise indicated, the terms "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to a carbamate, carbonate, ureide, or phosphate, respectively, of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

The term "biohydrolyzable ester" as used herein, unless otherwise indicated, refers to an ester of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters, and choline esters.

As used herein, unless otherwise indicated, the term "biohydrolyzable amide" refers to an amide of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

4.2. A second active agent

Thalidomide can be used in combination with other pharmaceutically active compounds ("second active agents") in the methods and compositions of the present invention. In preferred embodiments, the second active agent is capable of reducing pulmonary artery pressure or vascular resistance, inhibiting thrombosis or thromboembolism, or ensuring patient compliance. Examples of such second active agents include, but are not limited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogs, endothelin antagonists, phosphodiesterase inhibitors (e.g., PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, and other known therapeutic agents that lower pulmonary artery pressure.

A particular second active agent is an anticoagulant agent that may be used to treat patients with PH at increased risk of developing thrombosis and thromboembolism. A particular anticoagulant is warfarin (Coumadin)^®)。

Other second active agents include diuretics, cardiac glycosides, and oxygen. Digoxin treatment is used to enhance right ventricular function in right ventricular failure patients. Diuretics are used to control peripheral edema. Oxygen supplementation may be used in patients with resting or exercise-induced hypoxemia.

Calcium channel blockers such as diltiazem and nifedipine may also be used as secondary active agents, particularly in vasoreactive patients catheterized in the right ventricle. These drugs are thought to act on vascular smooth muscle, thereby increasing pulmonary vascular resistance and decreasing pulmonary artery pressure. Tapson, Advances in pulmony Hyperension, 1 (1): 16-17, 2002.

Other second active agents include vasodilators, especially for patients with NYHA type III and IV who have right ventricular failure who are unresponsive or intolerant to calcium channel blockers. Examples of vasodilators include, but are not limited to, prostacyclins (e.g., prostaglandin I)₂(PGI₂) Epoprostenol (EPO, Floran)^®) Treprostinil (Remodulin)^®) And Nitric Oxide (NO).

The other second active agent is an endothelin antagonist. An example is bosentan (Tracleer)^®) It competitively binds to endothelin-1 (ET-1) receptors, lowering pulmonary artery pressure.

Specific second Activity for use in the present inventionAgents include, but are not limited to, amlodipine, nifedipine, diltiazem, epoprostenol (Floran)^®) Treprostinil (Remodulin)^®) Bosentan (Tracleer)^®) Prostacyclin, warfarin (Coumadin)^®) Tadalafil (Cialis)^®) Simvastatin (Zocor)^®) Oomatrala (Vanlev)^®) Irbesartan (Avapro)^®) Pravastatin (pravastatin)^®) Digoxin, nitric oxide, L-arginine, iloprost, betaprost, and sildenafil (Viagra)^®)。

4.3. Treatment and control method

The methods of the invention include methods for preventing, treating and/or controlling various types of PH. As used herein, unless otherwise indicated, the term "preventing" includes, but is not limited to, inhibiting or avoiding one or more symptoms associated with PH. Symptoms associated with PH include, but are not limited to, dyspnea, fatigue, weakness, chest pain, recurrent fainting, seizures, mild headaches, neurological deficit, leg edema, and palpitations. As used herein, unless otherwise indicated, the term "treatment" refers to administration of the composition after the onset of PH symptoms, whereas "prevention" refers to administration prior to the onset of symptoms, particularly to patients at risk of developing PH. As used herein, unless otherwise indicated, the term "controlling" includes preventing PH recurrence in a patient who has had PH, and/or prolonging the time a patient who has had PH is in remission.

The invention includes methods of treating or controlling patients who have previously received PH therapy as well as patients who have not previously received PH therapy. Because patients with PH have different clinical manifestations and various clinical outcomes, it is preferable to treat patients according to the severity and stage of the disease. The methods and compositions of the present invention may be used in patients with various stages or types of PH, including but not limited to primary PH, secondary PH, and NYHA or WHO functional class I-IV.

The invention encompasses methods comprising administering thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) suffering from, or at risk of, PH. A particular patient population includes young women, since pH affects most young women of reproductive age, but is typically present in women between 50 and 60 years of age. Patients with familial PH history are also preferred candidates for preventive regimens.

In one embodiment of the invention, thalidomide is administered in a single or divided daily dose of about 50 to about 2,000 mg/day, about 100 to about 1,500 mg/day, about 120 to about 1,200 mg/day, about 150 to about 1,000 mg/day, or about 200 to about 800 mg/day.

4.3.1. Combination therapy with a second active agent

Particular methods of the invention comprise administering 1) thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and 2) a second active agent. Examples of second active agents are disclosed herein (see, e.g., section 4.2).

The administration of thalidomide and the second active agent to a patient may be performed simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the bloodstream) and the disease being treated. A preferred route of administration of thalidomide is oral. Another preferred route of administration of thalidomide is parenteral, particularly for patients in the pre-transplant phase or patients in the late PH phase. Preferred routes of administration for the second active agents of the invention are known to those of ordinary skill in the art. See, for example, Physicians' Desk Reference, 594-597 (57 th edition, 2003).

The specific amount of the second active agent will depend upon the specific active agent used, the type of pH being treated or controlled, the severity and stage of the pH, and the amount of thalidomide and optional additional active agents concurrently administered to the patient. In a particular embodiment of the invention, the second active agent is amlodipine, diltiazem, nifedipine, prostacyclin, epoprostenol (Floran)^®) Treprostinil (Remodu)lin^®) Bosentan (Tracleer)^®) Rodenticide (Coumadin)^®) Tadalafil (Cialis)^®) Simvastatin (Zocor)^®) Oomatrala (Vanlev)^®) Irbesartan (Avapro)^®) Pravastatin (pravastatin)^®) Digoxin, nitric oxide, L-arginine, iloprost, betaprost, or sildenafil (Viagra)^®)。

In one embodiment of the invention, thalidomide is administered with a second active agent commonly used to treat PH to reduce the treatment time. In a specific embodiment, beginning at week 1, about 200 to about 800 mg/day of thalidomide is administered with an amount of the second active agent that can be determined by one of skill in the art based on professional judgment. Beginning at weeks 5,9, 13, and 17, administration of the second active agent is decreased in increments of 25% of the starting dose of the second active agent. Starting at week 17, if the patient's symptoms have not worsened, then the dose of the second active agent is 0 mg/day. If the patient's symptoms worsen, the amount of the second active agent may be increased to stabilize the patient.

In one embodiment of the invention, the second active agent is administered parenterally, orally or by inhalation. For example, epoprostenol (Floran) is administered by continuous IV infusion through a permanently indwelling central venous catheter^®). The initial dose was about 2-4ng/kg/min, depending on the initial response under close observation with the ICU in place with a right ventricular float catheter. Subsequently, the dose was determined from outpatient analysis, and some patients could exceed 40ng/kg/min after one year of treatment. Iloprost is preferably administered by inhalation. Betaprost is preferably administered orally.

In another embodiment of the invention, treprostinil (Remodulin) is administered by continuous subcutaneous infusion^®) The initial dose was about 1.25 ng/kg/min. Subsequent doses may be increased by about 1.25ng/kg/min for four weeks per week, followed by 2.5ng/kg/min per week. Preferably, the dose does not exceed about 40 ng/kg/min.

In another aspect of the inventionIn one embodiment, bosentan (Tracleer) is administered orally^®) The starting dose was about 62.5mg twice a day for four weeks, then about 125mg twice a day.

4.3.2 use with surgery or transplantation

The invention encompasses methods of treating or controlling PH comprising administering thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, in conjunction with surgery or transplantation therapy. As described elsewhere, treatment of PH varies depending on the stage and mechanism of the disease. An atrial septostomy or lung transplant may be necessary for patients with PH who do not respond to drug treatment. The combined use of thalidomide and an atrial septal ostomy or a lung transplant is considered to have unexpected benefits. In addition, thalidomide has been shown to provide additive or synergistic immunomodulatory activity when administered before, during, or after surgery or transplantation therapy in patients with PH. For example, thalidomide may reduce complications associated with conventional therapies.

4.4. Pharmaceutical compositions and single unit dosage forms

The pharmaceutical compositions may be formulated for use in a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more additional active agents. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise an active agent (e.g., thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof, and a second active agent) disclosed herein. Examples of optional additional active agents are disclosed herein (see, e.g., section 4.2).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), transdermal or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets, such as fast dissolving tablets; a caplet; capsules, such as soft elastic gelatin capsules; a cachet; keeping in mouth; a lozenge; a band agent such as a quick-dissolving band in an oral liquid; a dispersant; suppositories; powder preparation; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; a liquid dosage form suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of the dosage form of the present invention will typically vary depending on its use. For example, a dosage form for the acute treatment of a disease may contain an amount of one or more active agents that is greater than the amount contained in a dosage form for the chronic treatment of the same disease. Similarly, a parenteral dosage form will contain less of the one or more active agents than an oral dosage form used to treat the same disease. The manner in which these particular dosage forms of the invention are contained, as well as other manners, will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided in the present specification. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the route by which the dosage form is administered to a patient. For example, oral dosage forms (e.g., tablets) may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may depend on the particular active agent in the dosage form. For example, some excipients (e.g., lactose), or when exposed to water, may accelerate the decomposition of some active agents. Active agents containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono-or disaccharides. As used herein, the term "lactose-free" means that the amount of lactose, if any, is insufficient to substantially accelerate the rate of degradation of the active agent.

The lactose-free compositions of the invention may contain excipients well known in the art, listed, for example, in U.S. pharmacopeia (USP)25-NF20 (2002). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active agent, binder/filler and lubricant. Preferably, the lactose-free dosage form contains the active agent, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active agent, as water promotes the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine properties of the formulation over time, such as shelf life or stability. See, e.g., Jens t. carstensen, Drug Stability: principles & Practice, second edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, water and heat will accelerate the decomposition of some compounds. Thus, the effect of water on the formulation is very significant, as moisture and/or humidity is often encountered during manufacture, handling, packaging, storage, shipment, and use of the formulation.

The anhydrous pharmaceutical compositions and dosage forms of the invention can be manufactured with anhydrous or low moisture content ingredients and under low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active agent comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity is expected during manufacture, packaging, and/or storage.

Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged with materials known to prevent exposure to water, so that they can be packaged in a suitable kit. Examples of suitable packaging include, but are not limited to, sealed films, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of an active agent. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

As with the amount and type of excipient, the type and amount of a particular active agent in a dosage form may vary depending on a variety of factors, including, but not limited to, the route of administration to the patient. However, a typical dosage form of the invention comprises about 50-2,000 mg of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof. A typical dosage form comprises about 50mg, 100mg, 200mg, 300mg, or 400mg of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof. Certain dosage forms also contain, for example, from about 1mg to about 1000mg, from about 5mg to about 500mg, from about 10mg to about 350mg, from about 50mg to about 200mg of the second active agent. The specific amount of the second active agent will, of course, depend upon the specific active agent used, the type of PH being treated or controlled, and the amounts of thalidomide and any optional additional active agents concurrently administered to the patient.

4.4.1 oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be formulated in discrete dosage forms such as, but not limited to, tablets (e.g., chewable and fast dissolving tablets), caplets, capsules (e.g., soft elastic gelatin capsules), liquids (e.g., flavored syrups), and strips (e.g., fast dissolving strips). These dosage forms contain a predetermined amount of active agent and may be prepared by pharmaceutical methods well known to those of ordinary skill in the art. See Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms are prepared by intimately mixing the active agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients may take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form. Pharmaceutical compositions and dosage forms are generally prepared by: the active agent is intimately mixed with a liquid carrier, a well-dispersed solid carrier, or both, and the dosage form is then coated, if necessary, by standard aqueous or non-hydrated techniques.

For example, tablets may be made by compression or compression molding. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form, for example, as a powder or granules, optionally mixed with excipients. Compression molded tablets may be prepared by compression molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that may be used in the oral dosage forms of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable form packs of microcrystalline celluloseIncluding but not limited to materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICELRC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103^TMAnd Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, cellulose powder, dextrates (dextrates), kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention is present in an amount of about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that does not significantly alter the release of the active agent, either too much or too little, should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used varies with the type of formulation and is readily determined by one skilled in the art. Typical pharmaceutical compositions contain from about 0.5% to about 15% by weight of disintegrant, preferably from about 1% to about 5% by weight of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or sweet starch, other starches, pregelatinized starch, other starches, clays, other alginates, other celluloses, gums, and mixtures thereof.

Lubricants useful in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), solidified aerosol of synthetic silica (sold by Degussa Co. of Plano, TX), CAB-O-SIL (a sintered silica product sold by Cabot Co. of Boston, MA), and mixtures thereof. Lubricants, if used at all, are generally used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

Preferred solid oral dosage forms of the invention comprise thalidomide, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide and gelatin. See, for example, U.S. patent application Ser. No. 10/608,077 filed on 30/6/2003, the entire contents of which are incorporated herein by reference.

4.4.2 fast-Release dosage forms

The single unit dosage forms of the present invention may be fast-release dosage forms such as, but not limited to, fast-dissolving tablets, tapes, transdermal agents, suspensions, and liquid dosage forms. The dosage form may provide immediate or rapid release of one or more active agents. For example, a fast dissolving tablet or tape may simply be inserted into a patient's mouth and readily dissolved in the oral fluid to achieve the desired therapeutic effect. The fast-release dosage forms of the present invention can rapidly disintegrate in the mouth to form a suspension of particles and release their contents so as not to interfere with the normal biological activity of the active agent.

The immediate release dosage forms may be prepared by pharmaceutical methods well known to those skilled in the art. Examples include, but are not limited to, those described in Remington's Pharmaceutical Sciences, 18 th edition, MackPublishing, Easton PA (1990); pharmacopoeia No.23, chapter 1216 (1995); and those described in U.S. Pat. Nos. 3,962,417, 4,613,497, 4,940,588, 5,055,306, 5,178,878, 5,225,197, 5,464,632, and 6,024,981, which are incorporated herein by reference. For example, coatings that dissolve rapidly may be used to provide faster release of the active agent. The amount of the coating agent and the coating thickness may vary depending on the type of the preparation, but can be easily determined by those skilled in the art. The type and thickness of the coating can be readily determined by those skilled in the art based on such characteristics as the desired blood level of active agent, the rate of release, the solubility of active agent, the desired properties of the dosage form, etc., if faster release of active agent is desired.

4.4.3 sustained Release dosage forms

The active agents of the present invention may be administered by controlled release devices or delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in the following patents: U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms may be used to provide sustained or controlled release of one or more active agents by using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to produce desired release profiles in varying proportions. Suitable controlled release formulations include those described herein, which are well known to those skilled in the art and are readily selected for use with the active agents of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for controlled release and for oral administration, including but not limited to tablets, capsules, gelcaps, and caplets.

All controlled release drug products share the following common objectives: the curative effect of the medicine is improved to exceed the curative effect of the non-released product. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by: the disease is cured or controlled in the shortest time with the least amount of medicine. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency and improved patient compliance. In addition, controlled release formulations may be used to affect the time at which the effect begins or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (e.g., adverse side effects).

Most controlled release formulations are designed to initially release an amount of drug (active agent) that immediately produces the desired therapeutic effect, and gradually and continuously release amounts of other drugs to maintain that level of therapeutic or prophylactic effect over an extended period of time. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that will compensate for the amount of drug that is metabolized and excreted from the body. Controlled release of the active agent can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.4.4 parenteral dosage forms

Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial routes. Since their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products that can be dissolved or suspended in a pharmaceutically acceptable carrier for injection, injectable suspensions, and emulsions.

Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: USP water for injection; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active agents disclosed herein may also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and their derivatives can be used to increase the solubility of thalidomide. See, for example, U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.4.5 topical and transmucosal dosage forms

Topical and transmucosal administration forms of the present invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th editions, Mack Publishing, Easton PA (1980& 1990); and Introduction to Pharmaceutical DosageForms, 4 th edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that may be used in the preparation of the topical and transmucosal dosage forms of the present invention are well known to those skilled in the art of pharmacy and depend on the particular tissue to which a given pharmaceutical composition or dosage form is to be administered. In fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form a non-toxic and pharmaceutically acceptable solution, emulsion, or gel. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of such other ingredients are well known in the art. See, for example, Remington's pharmaceutical Sciences, 16 th and 18 th edition, Mack Publishing, Easton PA (1980& 1990).

The pH of the pharmaceutical composition or dosage form may also be adjusted to enhance delivery of one or more active agents. Similarly, the polarity of the solvent vehicle, its ionic strength, or tonicity can be adjusted to enhance delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active agents to enhance delivery. In this regard, stearates can serve as lipid carriers, emulsifiers or surfactants, as well as delivery or penetration enhancers for the formulation. Different salts, hydrates or solvates of the active agent may also be used to adjust the properties of the resulting composition.

4.4.6 kits

It is generally preferred that the active agents of the invention are not administered at the same time or by the same route of administration. Thus, the present invention includes kits that, when used by medical personnel, can simplify the administration of an appropriate amount of an active agent to a patient.

A typical kit of the invention comprises a dosage form of thalidomide, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), stereoisomer, clathrate, or prodrug thereof. The kit of the invention may also contain additional active agents such as amlodipine, diltiazem, nifedipine, adenosine, epoprostenol (Floran)^®) Treprostinil (Remodulin)^®) Bosentan (Tracleer)^®) Rodenticide (Coumadin)^®) Tadalafil (Cialis)^®) Simvastatin (Zocor)^®) Oomatrala (Vanlev)^®) Irbesartan (Avapro)^®) Pravastatin (pravastatin)^®) Digoxin, nitric oxide, L-arginine, iloprost, betaprost, and sildenafil (Viagra)^®) Or a combination thereof. Examples of additional active agents include, but are not limited to, those described (see, e.g., section 4.2).

The kit of the invention may also comprise a device for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

The kits of the invention may also comprise a pharmaceutically acceptable carrier that can be used to administer one or more active agents. For example, if the active agent is in solid form and must be formulated for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP water for injection; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Examples of the embodiments

The following studies are intended to illustrate the present invention, but not to limit the scope of the present invention.

5.1. Pharmacological testing

One biological effect of thalidomide is the reduction of TNF- α synthesis. Thalidomide promotes the degradation of TNF- α mRNA. The inhibitory effect of thalidomide on TNF-. alpha.production by human PBMC after LPS-stimulation was determined in vitro. IC inhibition of TNF-alpha production by thalidomide on LPS-stimulated PBMC₅₀194 μ M (50.1 μ g/ml).

Clinical trials in patients with PH

Clinical trial 1

Thalidomide is administered to a PH patient in an amount of about 200 to about 800 mg/day for three months. The trials were randomized, double-blind and placebo-controlled. In total 20 patients were involved, 10 receiving the compound of the invention and 10 receiving placebo. The patient appeared stable to continuous administration of prostacyclin and pulmonary systolic blood pressure was greater than 70mm Hg. The patient was given 200mg at the start of the trial and then increased to 400mg at weeks 2 and 3 with a maximum dose of 800mg over a period from week 4 to three months. Right ventricular intubation was performed at baseline and 3 months. Patients were routinely monitored monthly. Neurological examinations were performed at baseline, 1,2 and 3 months. Patients were monitored for sedation and peripheral neuropathy at baseline, 1,2, and 3 months. ANC was monitored at 1,2 and 3 months.

Clinical trial 2

In one embodiment of the invention, thalidomide is administered in a single or divided dose, with a daily dose of about 200 to about 800 mg/day. Compounds were administered to PH patients for 12 weeks and then analyzed for decreased walking distance, dyspnea grade, functional classification, pulmonary hemodynamic response. The first trial involved 32 PH patients. At the start of the trial, the patients all belong to the newly revised new york heart association functional classification III. Patients are maximally treated with conventional therapies and are in a stable state, including calcium channel antagonists and diuretics. Two thirds of patients received 400mg of thalidomide for 4 weeks, then 800mg of the compound for 8 weeks. One third of the patients received placebo. The primary effect endpoint event was a 6 minute walk distance. Patients receiving the compounds of the invention walk on average 70 meters after 12 weeks, while placebo patients walk less distance. Furthermore, treated patients were improved in dyspnea grade and functional classification compared to placebo patients. Pulmonary hemodynamic measurements demonstrated a decrease in pulmonary arterial pressure and pulmonary vascular resistance and an increase in cardiac output 12 weeks after treatment, compared to the worsening of pulmonary hemodynamics in placebo patients. All these changes were highly significant in the treated patients compared to placebo.

Extension test

Based on the results of trial 2 above, an extended clinical trial was performed with 213 PH patients for at least 16 weeks. PH patients of WHO functional class III or IV were tested. 213 patients received 200mg or 400mg thalidomide or placebo randomly, with a 1: 1 ratio. The primary effect endpoint event, i.e., 6 minute walk distance, was analyzed at week 16. The treated patient walked 36.4 more meters at week 16 compared to 44.2 meters for the treatment effect, while the distance walked was reduced by 7.8 meters for the placebo group. Death, premature discontinuation of drug at the time of the trial, hospitalization for PH exacerbation, or use of epoprostenol were defined as clinical exacerbations, with 37% of placebo-treated patients experiencing clinical exacerbations, and only 11% of patients treated with the compounds of the invention. The functional classification of the treated patients was significantly improved over placebo patients.

The embodiments of the invention described herein are intended to be merely illustrative of the scope of the invention. The full scope of the invention is better understood with reference to the appended claims.

Claims (8)

1. A method of treating, preventing or managing pulmonary hypertension, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The method of claim 1, further comprising administering to the patient a therapeutically or prophylactically effective amount of a second active agent.

3. The method of claim 2, wherein the second active agent is capable of reducing pulmonary arterial pressure or reducing symptoms of pulmonary hypertension.

4. The method of claim 2, wherein the second active agent is an anticoagulant, diuretic, cardiac glycoside, calcium channel blocker, vasodilator, prostacyclin analog, endothelin antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, lipid lowering agent, or thromboxane inhibitor.

5. The method of claim 2, wherein the second active agent is amlodipine, diltiazem, nifedipine, epoprostenol, treprostinil, bosentan, warfarin, tadalafil, simvastatin, omatra, irbesartan, pravastatin, digoxin, nitric oxide, L-arginine, iloprost, betaprost, or sildenafil.

6. The method of claim 1, wherein the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension.

7. The method of claim 1, wherein the pulmonary hypertension is functional classification I, II, III, or IV pulmonary hypertension.

8. A method of treating or managing pulmonary hypertension, which comprises administering to a patient in need of such treatment or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during, or after surgery.