TWI484952B - Compositions and methods of administering rapamycin analogs with paclitaxel using medical devices - Google Patents

Description

Composition and method for administering rapamycin analogue and paclitaxel using medical device

The present invention relates to novel compounds having immunomodulatory activity and/or anti-restenosis activity and synthetic intermediates for the preparation of such novel compounds, and in particular to macrolide immunomodulators. More specifically, the present invention relates to semi-synthetic analogs of rapamycin, methods of preparing the same, pharmaceutical compositions comprising the same, and methods of treatment using the same.

Introduce

Since the introduction of organ transplantation and immunomodulation, the broad use of the compound cyclosporine (cyclosporin A) has been found and has led to a significant increase in the success rate of the transplantation procedure. Recently, some species of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara et al. disclose a large number of macrocyclic compounds isolated from the genus Streptomyces , including the immunosuppressive agent FK-506 (which is a 23-member macrolide) isolated from the S. tsukubaensis strain. (Okuhara et al., 1986).

Other related natural products (including FR-900520 and FR-900523, which differ from FK-506 in that their alkyl substituents on C-21) have been isolated from S. hygroscopicus yakushimnaensis . Another analog, FR-900525 (produced by Streptomyces faecalis), differs from FK-506 in that it replaces the hexahydronicotinic acid moiety with a proline group. Unsatisfactory negative effects associated with cyclosporine and FK-506, such as nephrotoxicity, have led to the continual search for immunosuppressive compounds with improved efficiency and safety, including locally effective but systemically ineffective immunosuppressants (Luly , 1995).

Rapamycin

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus and found to have antifungal activity in vitro and in vivo, especially against Candida albicans (C. Vezina et al. J. Antibiot .1975, 28, 721; SNSehgal et al., J. Antibiot 1975, 28, 727; . HABaker et al. J. Antibiot .1978, 31, 539; U.S. Pat. No. 3,929,992; and U.S. Patent No. 3,993,749 number).

It has been shown that rapamycin alone (Surendra, 1989) or in combination with picibanil (Eng, 1983) has anticancer activity. In 1977, rapamycin was also shown to be effective as an immunosuppressant in the experimental allergic encephalomyelitis model (model for multiple sclerosis) and the adjuvant arthritis model (model for rheumatoid arthritis). And showed its effective inhibition of the formation of IgE-like antibodies (Martel et al., 1977).

The immunosuppressive effect of rapamycin has also been disclosed in FASEB, 1989, 3, 3411 because it prolongs the survival of organ transplants in tissue incompatible rodents (Morris and Meiser, 1989). The ability of rapamycin to inhibit T cell activation is revealed by M. Strauch ( FASEB, 1989, 3, 3411). These and other biological effects of rapamycin have been previously reviewed (Morris, 1992).

Rapamycin has been shown to reduce neovascular intimal hyperplasia in animal models and reduce the rate of restenosis in humans. It has been publicly shown that rapamycin also exhibits evidence of an anti-inflammatory effect, which supports its selection as a drug of choice for the treatment of rheumatoid arthritis. Since cytomycin and its analogs have been proposed to prevent restenosis because cell proliferation and inflammatory balloon angioplasty and stent placement are thought to form an inducing factor for restenosis.

Monoester and diester derivatives of rapamycin (esterification at positions 31 and 42) have been shown to be useful as antifungal agents (Rakhit, 1982, U.S. Patent No. 4,316,885) and water solubility of rapamycin. Prodrug (Stella, 1987, US Patent No. 4, 650, 803).

The fermentation and purification of rapamycin and 30-desmethoxyrapamycin have been described in the literature (C. Vezina et al . J. Antibiot. (Tokyo), 1975, 28 (10), 721; SNSehgal et al. , J. Antibiot. (Tokyo), 1975, 28(10), 727; 1983, 36(4), 351; NL Paiva et al. J. Natural Products, 1991, 54 (1), 167-177).

A number of chemical modifications have been attempted for rapamycin. These include the preparation of monoester and diester derivatives of rapamycin (Caufield, 1992), 27-oxime of rapamycin (Failli, 1992a), and the 42-side oxy analogue of rapamycin (Caufield). , 1991), bicyclo rapamycin (Kao, 1992a), rapamycin dimer (Kao, 1992b), decyl ether of rapamycin (Failli, 1992b) and aryl sulfonates and amine groups Sulfonate (Failli, 1993). Recently, rapamycin has been synthesized in its naturally occurring enantiomeric form (Hayward et al, 1993; Nicolauou et al, 1993; Romo et al, 1993).

Rapamycin such as FK-506 is known to bind FKBP-12 (Siekierka, JJ; Hung, SHY; Poe, M.; Lin, CS; Sigal, NH Nature, 1989, 341, 755-757; Harding, MW; Galat, A.; Uehling, DE; Schreiber, SL Nature 1989, 341, 758-760; Dumont, FJ; Melino, MR; Staruch, MJ; Koprak, SL; Fischer, PA; Sigal, NHJ Immunol. 1990, 144, 1418-1424; Bierer, BE; Schreiber, SL; Burakoff, SJ Eur. J. Immunol. 1991, 21, 439-445; Fretz, H.; Albers, MW; Galat, A.; Standaert, RF; Lane, WS Burakoff, SJ; Bierer, BE; Schreiber, SL J. Am. Chem. Soc. 1991, 113, 1409-1411). It has also been shown that the rapamycin/FKBP-12 complex binds to another protein, m-TOR, which is different from calcineurin (FK-506/FKBP-12 complex inhibited protein) (Brown, EJ; Albers, MW; Shin, TB; Ichikawa, K; Keith, CT; Lane, WS; Schreiber, SL Nature 1994, 369, 756-758; Sabatini, DM; Erdjument-Bromage, H.; Lui, M.; P.; Snyder, SH Cell, 1994 , 78 , 35-43).

Other drugs have been used to combat unwanted cell proliferation. An illustrative example of such drugs is paclitaxel. Paclitaxel, which is a miscellaneous alkaloid extracted from Pacific Yew and Taxus brevifolia , is a key cytoskeletal component (tubulin, a basic component of microtubules) that is critical in cell division. Thus, cell proliferation is prevented (Miller and Ojima, 2001).

support

In the 1970s, Andreas Gruentzig developed percutaneous transluminal coronary angioplasty (PTCA). The first canine coronary artery dilatation was implemented on September 24, 1975; the following year, the study showing the use of PTCA was presented at the annual meeting of the American Heart Association. Shortly thereafter, the first human patient was studied in Zurich (Switzerland), followed by the first American human patient in San Francisco and New York. Regarding the treatment of patients with obstructive coronary artery disease, although this procedure changes the implementation of interventional cardiology, this procedure does not provide a long-term solution. The patient receives only temporary relief of chest pain associated with vascular occlusion; routine procedures are often required. Determining the presence of restenosis lesions severely limits the use of this novel procedure. In the late 1980s, stents were introduced to keep blood vessels open after angioplasty. Stenting involves 90% of the angioplasty performed today. The rate of restenosis was 30-50% change in patients treated with balloon angioplasty prior to introduction of the stent. The introduction of stenting resulted in a further improvement in the outcome, with a restenosis rate of 15-30%. After stenting, restenosis damage is mainly caused by neointimal hyperplasia. Neovascular intimal hyperplasia and atherosclerotic disease are significantly different in time course and histopathological appearance. Restenosis is the healing process of a damaged coronary artery wall in which neovascular intimal tissue significantly impinges on the lumen of the blood vessel. Vascular radiotherapy appears to be effective in preventing under-stent restenosis. However, radiation has practical and cost-limiting limitations, and there are questions about safety and durability.

Stent and combination therapeutic agent

By reducing restenosis by at least 50%, the primary efforts made by the interventional device population to manufacture and evaluate drug elution stents have reached initial goals. However, there remains a need for improved topical drug delivery devices, such as drug-impregnated polymer coated stents, which provide a safe and effective tool for the prevention and treatment of restenosis. For example, two commercially available single drug-dissolving stents reduce restenosis and improve patient outcome, but they do not eliminate restenosis or avoid adverse safety issues. Patients and particularly at risk patients (including diabetic patients, patients with small blood vessels and patients with acute coronary syndrome) may benefit from topical drug delivery devices (such as stents with improved capabilities).

Drug delivery devices comprising a combination of drugs are known. However, this technique does not appear to teach a particularly effective combination of drugs for topical administration (e.g., from stent dissociation). For example and as discussed further below, Falotico teaches an EVA-PBMA polymer coated stent comprising a combination of rapamycin/dexamethasone that reduces neovascular area, percentage of stenosis, and inflammation. The score is far from being effective in delivering a single rapamycin or dexamethasone alone.

In one aspect, embodiments of the invention are directed to a drug delivery system having a support structure capable of carrying at least one pharmaceutically acceptable carrier or excipient and having a taxane or a derivative thereof, a prodrug Or a therapeutic composition of a salt and a second drug or a derivative thereof, a prodrug or a salt thereof, wherein the formation of neointimal hyperplasia is reduced when the system is implanted into the lumen of the blood vessel of the subject as compared with the control system. The subject can be, for example, a human or a pig. Pacific paclitaxel: the second drug weight ratio r is 10:0.01 r 0.01:10, and in some cases, r = 1:10. The drug delivery system can include a stent and can include a third or more drug or other therapeutic substance (including biological agents). Other therapeutic substances include, but are not limited to, anti-proliferative agents, anti-platelet agents, steroid and non-steroidal anti-inflammatory drugs, anti-lipemic agents, antithrombotic agents, thrombolytic agents. The subject can be a mammal, including but not limited to humans and pigs.

Another object of embodiments of the present invention is directed to a system for providing controlled release delivery of a drug for treating or inhibiting neovascular intimal hyperplasia in a blood vessel. The system comprises paclitaxel or a salt, prodrug or derivative thereof and a second medicament or a salt, prodrug or derivative thereof, wherein paclitaxel supplements the activity of the second medicament, and wherein the second medicament supplements the activity of paclitaxel. Pacific paclitaxel: the second drug weight ratio r is 10:0.01 r 0.01:10, and in some cases, r = 1:10. The drug delivery system can include a stent and can include a third or more drug or other therapeutic substance (including biological agents). Other therapeutic substances include, but are not limited to, anti-proliferative agents, anti-platelet agents, steroid and non-steroidal anti-inflammatory drugs, anti-lipemic agents, antithrombotic agents, thrombolytic agents. The subject can be a mammal, including but not limited to humans and pigs.

Another object of embodiments of the present invention is directed to a pharmaceutical composition comprising paclitaxel or a salt, prodrug or derivative thereof and a second medicament or a salt or derivative thereof, wherein the composition is administered on a medical device In the blood vessels of the subject, wherein the paclitaxel: the second drug has a weight ratio r of 10:0.01 r 0.01:10, and wherein the formation of neovascular intimal hyperplasia is reduced when the system is implanted into the lumen of the blood vessel of the subject compared to the control system. The ratio can be r = 1: 10 and the formulation is further associated with a medical device, including a stent or a coated stent. The subject can be a mammal, including but not limited to humans and pigs. In another aspect, the invention is directed to the administration or administration of any of the described systems or compositions (including paclitaxel or a salt, prodrug or derivative thereof and a second medicament or a salt, prodrug thereof or a derivative wherein the paclitaxel: second drug has a weight ratio r of 10:0.01 r 0.01:10) A method of treating a subject.

In another aspect, the invention is directed to any system or composition comprising (including paclitaxel or a salt, prodrug or derivative thereof, and a second medicament or a salt, prodrug or derivative thereof, wherein paclitaxel : the weight ratio r of the second drug is 10:0.01 r 0.01:10) of the set.

In another aspect, the invention is directed to a drug delivery system comprising a stent comprising a coating on a surface, the coating having a treatment comprising paclitaxel and a second drug or derivative thereof, prodrug or salt thereof a composition wherein neointimal hyperplasia is reduced when compared to a control drug delivery system 10%, and wherein the paclitaxel: second drug weight ratio r is 10:0.01 r 0.01:10. The ratio r can be r = 1:10.

In all aspects of the invention, the second agent can be a salt, prodrug or derivative of rapamycin, a rapamycin analogue, and rapamycin.

definition

The term "prodrug" as used herein refers to a compound that is rapidly converted, in vivo, for example, by hydrolysis in blood to the parent compound of the above formula. A thorough discussion is provided by Higuchi and Stella (Higuchi and Stella, 1987; Roche, 1987) and Roche (Roche, 1987), both of which are incorporated herein by reference.

The term "related to" as used herein refers to a compound that can be in a variety of forms including, but not limited to, mixed, unmixed, microspheres, mixed with a coating, and mixed with a support structure. Those skilled in the art are aware of changes in the interaction between drugs, coatings/drugs, and drug/coating/support structures.

The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of the embodiments of the present invention which is suitable for contact with humans and lower mammals in the context of sound medical judgment. Proper toxicity, irritation, and allergic reactions are proportional to the reasonable benefit/hazard ratio and are effective for their intended use. Other examples include pharmaceutically acceptable prodrugs derived from C-31 hydroxyl groups.

The term "prodrug ester" as used herein refers to any of a number of ester-forming groups that are hydrolyzed under physiological conditions. Examples of the prodrug ester group include etidinyl, propyl sulfonyl, trimethylethenyl, pentyloxymethyl, ethoxymethyl, decyl, methoxymethyl, dihydroindenyl and Similar groups, as well as ester groups derived from the coupling of a natural or non-naturally occurring amino acid with a C-31 hydroxyl group of a compound of the invention.

R = R ¹ C(O)R ² R ³ ; R ¹ C(S)R ² R ³ wherein R ¹ =O, SR ² = none, O, N, S, various alkyl, alkenyl, alkynyl groups, Heterocyclyl, aryl R ³ = none, various alkyl, alkenyl, alkynyl, heterocyclyl, arylalkyl, alkenyl, alkynyl, heterocyclyl, aryl groups may be substituted or unsubstituted.

The term "support structure" means a framework that can include or support a pharmaceutically acceptable carrier or excipient, which can include one or more therapeutic agents or substances, such as one or more drugs and/or Or other compound. The support structure is typically formed from a metal or polymeric material. Suitable support structures that can be formed from a polymeric material, including a biodegradable polymer, can include a therapeutic agent or substance, including, but not limited to, U.S. Patent Nos. 6,413,272 and 5,527,337, each incorporated herein by reference (Igaki, 2002) ;Stack et al., 1996).

The term "supplementary" as used herein refers to the behavior exhibited by at least two drugs in combination, wherein their respective pharmaceutically active activities benefit from the combination, for example with additional activity; for example, having separate but beneficial activities which aid in breastfeeding All required pharmacological effects in animals; and wherein the combination drugs are not effective in reducing each other's biological activity.

"Subject" means a vertebrate, including but not limited to mammals, including monkeys, dogs, cats, rabbits, cows, pigs, goats, sheep, horses, rats, mice, guinea pigs, and humans.

"Therapeutic substance" means any substance that exerts a beneficial effect on a subject when appropriately administered to a subject at an appropriate dose.

Rapamycin, a rapamycin analogue or a derivative or salt thereof refers to all analogs and derivatives of rapamycin and salts thereof. Examples include tacrolimus, 1,2,3,4-tetrahydro-rapamycin, and others, including those described by Skotnicki et al. (Skotnicki et al., 1994) (incorporated herein by reference).

treatment method

Compounds of the invention including, but not limited to, the compounds illustrated in the Examples have immunomodulatory activity in mammals, including humans. As immunosuppressive agents, the compounds of the embodiments of the present invention are useful for the treatment and prevention of immunomodulatory diseases, including diseases or tissues (including heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine (intestinum). Transplantation resistance of tenue), limbs, muscles, nerves, duodenum, small-bowel, islet cells and their analogues; graft-versus-host disease caused by bone marrow transplantation; including rheumatoid arthritis, whole body Autoimmune diseases of lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, spheroid nephritis and the like. Other uses include the treatment and prevention of skin manifestations of inflammatory and hyperproliferative skin diseases and immune-regulating diseases, including psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheic dermatitis, lichenitis, Pemphigus, bullous pemphigoid, bullous epidermis, rubella, angioedema, vasculitis, erythema, subcutaneous eosinophilia, lupus erythematosus, acne and alopecia areata; including dry keratoconjunctivitis, spring conjunctivitis , uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia and ocular pemphigus associated with Behcet's disease (autologous regulation and others). In addition, including asthma (such as bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, and dusty asthma), especially chronic or refractory asthma (such as delayed asthma and tracheal overreaction), bronchitis, allergies Reversible obstructive tracheal diseases of rhinitis and the like are targets of the compounds of the invention. Inflammation of the mucosa and blood vessels includes vascular damage caused by gastric ulcers, ischemic diseases, and thrombosis. Furthermore, hyperproliferative vascular diseases including intimal smooth muscle cell proliferation, restenosis, and angiogenesis (especially following biologically or mechanically mediated vascular injury) can be treated or prevented by the compounds of the present invention.

The compounds or drugs described herein can be applied to a stent coated with a polymeric compound. The polymer coating of the compound or drug into the stent can be carried out by immersing the polymer coated stent in a solution comprising the compound or drug for a sufficient time (such as five minutes); and then (such as) The coated stent is dried by means of air drying for a sufficient time (such as 30 minutes). Other methods of applying the therapeutic substance, including spraying, can be used. The polymer coated stent comprising the compound or drug can then be delivered to the coronary vessel by deployment from a balloon catheter or via a self-expanding stent. Other devices that can be used to introduce the medicament of the present invention to the vascular structure other than the stent include, but are not limited to, grafts, catheters, and balloons. In addition, other compounds or drugs that can be used in place of the agents of the invention include, but are not limited to, A-94507 and SDZ RAD (aka Everolimus).

The compounds described herein for polymer coated stents can be used in combination with other agents. Such agents which are most effective in preventing restenosis in combination with the compounds of the present invention can be classified into anti-proliferative, anti-platelet, anti-inflammatory, antithrombotic, and thrombolytic agents. These categories can be subdivided. For example, the anti-proliferative agent can be anti-mitotic. Anti-mitotic agents inhibit or affect cell division, thereby preventing the process typically involved in cell division from occurring. One subclass of anti-mitotic agents includes vinca alkaloids. Representative examples of vinca alkaloids include, but are not limited to, vincristine, paclitaxel, etoposide, nocodazole, indirubin, and anthracycline derivatives (such as Daunol) Daunorubicin, daunomycin, and plicamycin. Other subclasses of anti-mitotic agents include anti-mitotic alkylating agents such as tauromustine, bofumustine and fotemustine, and anti-mitotic metabolites such as Amethotrexate, fluorouracil, 5-bromodeoxyuridine, 6-azacytidine nucleoside and cytarabine. Anti-mitotic alkylating agents affect cell division by covalently modifying DNA, RNA or protein thereby inhibiting DNA replication, RNA transcription, RNA translation, protein synthesis or a combination of the foregoing.

Examples of anti-mitotic agents include, but are not limited to, paclitaxel. As used herein, paclitaxel includes the alkaloid itself and its naturally occurring forms and derivatives, as well as its synthetic and semi-synthetic forms.

An antiplatelet agent is a therapeutic entity by (1) inhibiting platelet adhesion to the surface, usually the surface of prothrombin, (2) inhibiting platelet aggregation, (3) inhibiting activation of platelets, or (4) combining the foregoing effect. Activation of platelets is thereby the process of transforming platelets from a quiescent state to a state in which platelets undergo a large number of morphological changes induced by contact with the prothrombin surface. These changes include changes in platelet shape, with the formation of pseudopods (binding membrane receptors) and secretion of small molecules and proteins such as ADP and platelet factor 4. Antiplatelet agents that act as platelet adhesion inhibitors include, but are not limited to, eptifibatide, tirofiban, RGD (Arg-Gly-Asp)-based peptides that inhibit gpIIbIIIa or αvβ3 binding, Blocking antibodies that bind gpIIaIIIb or αvβ3, antibodies against P-selectin, antibodies against E-selectin, compounds that block P-selectin or E-selectin binding to their respective ligands, whey acid, and anti-Werber's (von) Willebrand) factor antibody. Agents that inhibit ADP-regulated platelet aggregation include, but are not limited to, disagregin and cilostazol.

Anti-inflammatory drugs can also be used. Examples of such anti-inflammatory agents include, but are not limited to, prednisone, dexamethasone, hydrocortisone, estradiol, triamcinolone, mometasone, Fluticasone, clobetasol and non-steroidal anti-inflammatory drugs such as acetaminophen, ibuprofen, naproxen, adalimumab and sulindac ( Sulindac). An arachidonic acid ester metabolite prostacyclin or prostacyclin analog is an example of a vasoactive anti-proliferative agent. Other examples of such agents include those that block cytokine activity or inhibit cytokines or chemokines from binding to similar receptors to inhibit pre-inflammatory signals that are converted by cytokines or chemokines. Representative examples of such agents include, but are not limited to, anti-IL1, anti-IL2, anti-IL3, anti-IL4, anti-IL8, anti-IL15, anti-IL18, anti-MCP1, anti-CCR2, anti-GM-GSF, and anti-TNF antibodies.

Antithrombotic agents include chemical and biological entities that can be intervened at any stage in the aggregation pathway. Examples of specific entities include, but are not limited to, small molecules that inhibit Factor Xa activity. In addition, heparin-type agents such as heparin, heparin sulfate, and low molecular weight heparin (such as having the trademark Clivarin) can be directly or indirectly inhibited. Compounds) and synthetic oligosaccharides (such as the trademark Arixtra) Compound). Also included are direct thrombin inhibitors such as melagatran, ximelagatran, argatroban, inogatran, and phenyl Phe-Pro-Arg blood of thrombin. A peptidomimetic of the binding site of the fibrinogen matrix. Another deliverable antithrombotic agent is a Factor VII/VIIa inhibitor, such as an anti-Factor VII/VIIa antibody, rNAPc2, and a tissue factor pathway inhibitor (TFPI).

A thrombolytic agent can be defined as an agent that aids in the degradation of a blood clot (clot), which can also be used as an adjuvant because the action of dissolving the clot helps to disperse the platelets that are trapped in the blood fiber matrix of the thrombus. Representative examples of thrombolytic agents include, but are not limited to, urokinase or recombinant urokinase, pro-urokinase or pre-recombinant urokinase, tissue plasminogen activator or recombinant forms thereof, and streptokinase.

Other drugs which can be used in combination with the compounds of the invention are cytotoxic drugs, such as apoptosis inducing agents (such as TGF) and topoisomerase inhibitors, including 10-hydroxycamptothecin, irinotecan and arbutin. Doxorubicin. Other types of drugs which can be used in combination with the compounds of the present invention are drugs which inhibit cell dedifferentiation and drugs which inhibit cell growth.

Other agents which may be used in combination with the compounds of the invention include antilipemic agents (such as fenofibrate), matrix metalloproteinase inhibitors (such as batimidate), antagonists of the endothelin A receptor (such as dassentan) And αvβ3 integrin receptor antagonists.

Embodiments of the invention further include a third therapeutic drug or substance. When the second drug and/or the third therapeutic drug are utilized, including but not limited to an anti-proliferative agent, an anti-platelet agent, an anti-inflammatory drug, an anti-lipid agent, an antithrombotic agent, a thrombolytic agent, a salt thereof, and a prodrug And derivatives or any combination thereof. When the second drug and/or the third therapeutic drug is a glucocorticol, it includes, but is not limited to, methylprednisolone, prednisolone, prednisone, triamcinolone , dexamethasone, mometasone, beclomethasone, ciclesonide, bedesonide, triamcinolone, clobeta Clobetasol, flunisolide, loteprednol, budesonide, fluticasone, salts, prodrugs and derivatives thereof, or any combination thereof. When the second drug and/or the third therapeutic agent is a steroid hormone, it includes, but is not limited to, estradiol and salts, prodrugs and derivatives thereof, or any combination thereof. In an embodiment, the second drug and/or the third therapeutic agent may be small molecules and biological agents that reduce the activity of inflammatory cytokines. When the second drug and/or the third therapeutic agent utilizes an anti-cytokine therapeutic agent, it is selected from the group consisting of, but not limited to, an anti-TNFα therapeutic agent, adalimumab, an anti-MCP-1 therapeutic agent, a CCR2 receptor antagonist, A group consisting of an anti-IL-18 therapeutic, an anti-IL-1 therapeutic, and a salt, prodrug and derivative thereof, or any combination thereof. When the second drug and/or the third therapeutic agent utilizes an anti-proliferative agent, it includes, but is not limited to, an alkylating agent, including cyclophosphamide, chlorambucil, busulfan Carnitustine and lomustine; antimetabolites, including methotrexate, fluorouracil, cytarabine, thioglycol and pentastatin; vinca alkaloids, including vinblastine and vinca Neobase; antibiotics, including doxorubicin, bleomycin, and mitomycin; anti-proliferative agents, including cisplatin, procarbazine, etoposide, and fentanyl Bolt; its salts, prodrugs and derivatives or any combination thereof. When the second drug and/or the third therapeutic agent utilizes an anti-platelet agent, including but not limited to glycoprotein IIB/IIIA inhibitors, including abciximab, eptifibatide, and tirofiban; gland Glycoside reuptake inhibitors, including dipyridamole; ADP inhibitors, including clopidogrel and ticlopidine; cyclooxygenase inhibitors, including acetyl sulphate, phosphoric acid Diesterase inhibitors, including cilostazol; salts, prodrugs and derivatives thereof, or any combination thereof. When the second drug and/or the third therapeutic drug utilizes an anti-inflammatory drug, it includes, but is not limited to, steroids, including dexamethasone, hydrocortisone, fluticasone, clobetasol, mometasone, and estradiol. And non-steroidal anti-inflammatory drugs, including acetaminophen phenol, ibuprofen, naproxen, sulindac, piroxicam, mefenamic acid; inhibiting cytokines or chemokine-binding receptors Anti-inflammatory drugs that inhibit pre-inflammatory signals, including antibodies to IL-1, IL-2, IL-8, IL-15, IL-18, and TNF; salts, prodrugs, and derivatives thereof, or any combination thereof. When the second drug and/or the third therapeutic agent utilizes an antithrombotic agent, it includes, but is not limited to, heparin, including unseparated heparin and low molecular weight heparin, including clivarin, dalteparin ), enoxaparin, nadroparin, and tinzaparin; direct thrombin inhibitors, including argatroban, hirudin, hirulog, herugen Salts, prodrugs and derivatives thereof or any combination thereof. When the second drug and/or the third therapeutic agent utilizes an antilipemic agent, it is selected from the group consisting of nicotinic acid, probucol, HMG CoA reductase inhibitor (including mevastatin) , lovastatin, simvastatin, pravastatin, fluvastatin, fibric acid derivatives (including fenofibrate, clofibrate, gemfibrozil), lipid lowering agents (including Salts, prodrugs and derivatives) or any combination thereof. When the second drug and/or the third therapeutic drug utilizes a thrombolytic agent, it includes, but is not limited to, a hammer stimulation, urokinase, prourokinase, tissue plasminogen activator (including alteplase) , reteplase, tenectaplase, salts, prodrugs and derivatives thereof, or any combination thereof.

polymer

When used in the present invention, the coating can comprise any polymeric material in which the therapeutic agent (i.e., drug) is substantially soluble or effective. The purpose of the coating is to act as a controlled release vehicle for the therapeutic agent or as a reservoir for the therapeutic agent delivered at the site of injury. The coating can be polymeric and can be further hydrophilic, hydrophobic, biodegradable or biodegradable. The material used for the polymeric coating may be selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamines, polyvinyl alcohol, Polyethylene oxide, glycosaminoglycan, polysaccharide, polyester, polyurethane, polyoxo, polyorthoester, polyanhydride, polycarbonate, polypropylene, polylactic acid, polyglycolic acid, polyhexyl A mixture and copolymer of a lactone, a polyhydroxybutyrate valerate, a polypropylene decylamine, a polyether, and the foregoing polymers. Coatings prepared from polymeric dispersions, including polyurethane dispersions (BAYHYDROL, etc.) and acrylic latex dispersions, may also be used with the therapeutic agents of the present invention.

Biodegradable polymers useful in the present invention include polymers including poly(L-lactic acid), poly(DL-lactic acid), polycaprolactone, poly(hydroxybutyrate), polyacetate. Ester, polyxanone, poly(hydroxyvalerate), polyorthoester, copolymer (including poly(lactide-co-glycolide), polyhydroxyl (butyrate- Co-valerate, polyglycolide-co-trimethylene carbonate), polyanhydride, polyphosphate, polyphosphate-urethane, polyamino acid, polycyanoacrylate, organism Molecules (including blood fiber, fibrinogen, cellulose, starch, collagen, and hyaluronic acid) and mixtures of the foregoing polymers. Biostable materials suitable for use in the present invention include polymers comprising the following polymers: polyurethane, polyoxo, polyester, polyolefin, polyamine, polycaprolactam, polyimine, poly Vinyl chloride, polyvinyl methyl ether, polyvinyl alcohol, acrylic polymer and copolymer, polyacrylonitrile, polystyrene copolymer of olefinic monomer and olefin (including styrene acrylonitrile copolymer, methacrylic acid Methyl ester copolymer, ethyl vinyl acetate), polyether, human cotton, cellulose (including cellulose acetate, nitrocellulose, cellulose propionate, etc.), parylene and its derivatives and Mixtures and copolymers of the foregoing polymers.

In some embodiments, the polymer includes, but is not limited to, poly(acrylate) (such as poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(isopropyl methacrylate), Poly(isobutyl methacrylate), poly(second butyl methacrylate), poly(n-butyl methacrylate), poly(2-ethylhexyl methacrylate), poly(methacrylic acid) Ester), poly(cyclohexyl methacrylate), poly(n-hexyl methacrylate), poly(isobornyl methacrylate) and poly(trimethylcyclohexyl methacrylate), poly(acrylic acid) Methyl ester), poly(ethyl acrylate), poly(n-propyl acrylate), poly(isopropyl acrylate), poly(n-butyl acrylate), poly(isobutyl acrylate), poly(butyl butyl acrylate) Ester), poly(pentyl acrylate), poly(n-hexyl acrylate), poly(cyclohexyl acrylate), and any derivatives, analogs, homologs, homologs, salts, copolymers, and combinations thereof.

In some embodiments, the polymer includes, but is not limited to, poly(ester urethane), poly(ether urethane), poly(ureidourethane), poly(amino carboxylic acid) Triester copolymer of styrene and isobutylene, copolymers of polyoxymethylene, fluoropolyoxygen, poly(ester), poly(ethylene), poly(propylene), poly(olefin), poly(isobutylene) , a triblock copolymer of styrene and ethylene/butylene, a triblock copolymer of styrene and butadiene, a copolymer of ethylene-alpha olefin, a halogenated ethylene polymer and a copolymer (such as poly(ethylene chloride) And poly(ethylene fluoride)), poly(halogenated vinylene) (such as poly(vinylidene) and poly(fluoroethylene)), poly(vinylidene fluoride-co-hexafluoropropylene), poly(tetrafluoroethylene) , poly(tetrafluoroethylene-co-chlorotrifluoroethylene), poly(vinyl ether) (such as poly(vinyl methyl ether)), poly(acrylonitrile), poly(vinyl ketone), poly (vinyl aromatic) a compound (such as poly(styrene)), a poly(vinyl ester) (such as poly(vinyl acetate)), a copolymer of an olefinic monomer and an olefin (such as a copolymer of methacrylic acid, a copolymer of acrylic acid) , a copolymer of N-vinylpyrrolidone, Poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol) (EVAL), poly(cyanoacrylate), copolymer of poly(maleic anhydride) and maleic anhydride, acrylonitrile- Copolymer of styrene, copolymer of ABS resin and ethylene-vinyl acetate) and any derivatives, analogs, homologs, homologs, salts, copolymers and combinations thereof.

In some embodiments, the polymer includes, but is not limited to, poly(decylamine) (such as Nylon 66 and poly(caprolactam)), alkyd, poly(carbonate), poly(碸) ), poly(formaldehyde), poly(indenine), poly(esteramine), poly(ether) (including poly(alkylene glycol) such as poly(ethylene glycol) and poly(propylene glycol), epoxy Resin, human cotton, human cotton-triacetate, biomolecules (such as blood fiber, fibrinogen, starch, poly(amino acid), peptide, protein, gelatin, chondroitin sulfate, dermatan sulfate (D- Glucuronic acid or a copolymer of L-iduronic acid with N-ethinyl-D-galactosamine), collagen, hyaluronic acid and glycosaminoglycan), other glycans (such as poly(N) -Ethyl glucosamine), chitin, polyglucosamine, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, nitrocellulose, cellulose propionate , cellulose ethers and carboxymethyl cellulose) and any derivatives, analogs, homologs, homologs, salts, copolymers and combinations thereof.

Another polymer useful in the present invention is poly(MPC _w : LAM _x : HPMA _y : TSMA _z ), where w, x, y, and z represent the molar ratio of the monomers used in the feedstock used to prepare the polymer. And MPC represents the unit 2-methylpropenyloxyethylphosphonium choline, LMA represents the unit of lauryl methacrylate, HPMA represents the unit 2-hydroxypropyl methacrylate, and TSMA represents the unit methacrylic acid 3-trimethoxydecylpropyl propyl ester. Drug-impregnated stents can be used to maintain the opening of coronary arteries previously occluded by thrombus and/or atherosclerotic plaques. Delivery of anti-proliferative agents reduces the rate of restenosis under the stent. Polymers useful in the present invention include zwitterionic polymers including phosphonium choline units.

Other treatable conditions include, but are not limited to, ischemic enteropathy, inflammatory bowel disease, necrotizing enterocolitis, enteritis/allergy (including celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis), neuropathy (including polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple nerves) Inflammation, mononeuritis and radiculopathy), endocrine diseases (including hyperthyroidism and Basedow disease), blood diseases (including pure red blood cell aplastic anemia, aplastic anemia, low-forming anemia, Idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granulocytopenia, pernicious anemia, macroglobulin anemia, and red blood cell insufficiency), bone disease (including osteoporosis), respiratory disease (including sarcoidosis) , fibrous lung and idiopathic interstitial pneumonia), skin diseases (including dermatomyositis, leukoplakia, common ichthyosis, photoallergic sensitivity and cutaneous T-cell lymphoma), circulatory diseases (including arteries) Syndrome, atherosclerosis, aortic inflammatory syndrome, nodular polyarteritis and non-inflammatory cardiomyopathy), collagen disease (including scleroderma, Wegener granulomatosis and Sjogren syndrome) ), obesity, eosinophilic fasciitis, periodontal disease (including gum, root canal, alveolar bone and cementum damage), renal syndrome (including spheroid nephritis), male alopecia or alopecia premature aging ( By preventing hair loss or providing hair growth and/or promoting hair growth and hair growth), muscular dystrophy, pyoderma and Sezary syndrome, Addison disease, ROS-regulating diseases (eg organs Injury, including organ (including heart, liver, kidney and digestive tract) ischemia-reperfusion injury (which occurs during protection, transplantation) or ischemic diseases (such as thrombosis and myocardial infarction), intestinal diseases (including Toxin-shock, pseudomembranous colitis and colitis caused by drugs or radiation), kidney disease (including ischemic acute renal insufficiency and chronic renal insufficiency), lung disease (including lung-oxygen or drugs (Pacocote ( Toxin disease caused by paracort) and bleomycin Carcinoma and emphysema), eye diseases (including cataract, calculus, retinitis pigmentosa, age-related macular degeneration, vitreous crust and corneal alkali burn), dermatitis (including polymorphous erythema, linear IgA sclerotia and Cement dermatitis) and others, including gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (such as air pollution), old age, carcinogenesis, cancer metastasis, and hypobaric disease, Disease caused by histamine or leukotriene-C ₄ release, Behcet's disease (including intestinal, vascular or neurobehide disease and white affecting the mouth, skin, eyes, vulva, joints, epididymis, lungs, kidneys, etc.) Say's disease). In addition, the compounds of the present invention are useful for the treatment and prevention of liver diseases, including immunogenic diseases (such as chronic autoimmune liver disease, including autoimmune hepatitis, primary biliary cirrhosis, and sclerosing cholangitis), partial hepatectomy. Acute hepatic necrosis (eg necrosis caused by toxins, viral hepatitis, shock or anoxia), B-viral hepatitis, non-A/non-B hepatitis, sclerosis (including alcoholic cirrhosis) and liver failure ( These include fulminant hepatic failure, delayed onset liver failure, and "chronic acute" liver failure (acute liver failure on chronic liver disease), and in addition to the major chemical effects, antiviral effects of these compounds on the drugs that patients may use, The anti-inflammatory effect and the expansion of the cardiotonic effect have potentially useful activities and are therefore suitable for a variety of diseases.

The ability of the compounds of the invention to treat proliferative diseases can be as previously described in Bunchman ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi et al, Biochem. Biophys. Res. Comm. 191 840-846 (1993); This is demonstrated by the method described in Shichiri et al., J. Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle hyperplasia, systemic sclerosis, cirrhosis, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathy, psoriasis, scleroderma, benign prostatic hyperplasia, cardiac hyperplasia, Restenosis after arterial injury or other pathological stenosis of blood vessels. In addition, these compounds antagonize cellular responses to some growth factors and thus possess anti-angiogenic properties, which makes them useful agents for controlling or reversing certain tumor growth and fibrotic diseases of the lung, liver and kidney.

The aqueous liquid compositions of the embodiments of the present invention are particularly useful for the treatment and prevention of various ocular diseases, including autoimmune diseases including, for example, keratoconus, keratitis, corneal epithelial dystrophy, corneal leukoplakia, Mooren ulcers. , scleritis and Graves' eye lesions) and corneal transplant rejection.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the embodiments of the invention may be used neat or in the form of a pharmaceutically acceptable salt, ester or prodrug if present. . Alternatively, the compound can be administered as a pharmaceutical composition comprising a combination of the relevant compound and one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of a compound of the invention means a compound that is sufficient to treat a condition in a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions of the present invention is determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose for any particular patient will depend on a number of factors, including the severity of the condition and condition being treated, the activity of the particular compound employed, the particular composition employed, the patient's age, weight, and overall Health, sex and diet, time of administration, route of administration and rate of excretion of the particular compound used, duration of treatment, combination or consistency with the particular compound employed, and similar factors well known in the medical arts. For example, it is entirely within the skill to start the dosage of the compound in an amount lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

The total daily dose of a compound of the present invention administered to a human or lower animal can vary from about 0.01 to about 10 mg/kg per day. For the purpose of oral administration, the dosage may range from about 0.001 to about 3 mg/kg per day. For the purpose of local delivery from the stent, the daily dose received by the patient depends on the length of the stent. For example, a 15 mm coronary stent can include a drug that varies from about 1 to about 600 mg, and can deliver the drug over a period of time ranging from several hours to several weeks. If desired, the effective daily dose can be divided into multiple doses for the purpose of administration, and thus, a single dose of the composition can include such amounts or submultiples thereof to form a daily dose. For topical administration, the present invention can be used by those skilled in the art and the dosage will depend on the site of application.

Within the scope of the present invention, a suitable polymer layer for loading a drug is provided with great flexibility. For example, within the therapeutic range parameters associated with the compound of interest (typically between therapeutic efficacy and toxicity), the ratio of the compounds used in combination can vary relative to each other. For example, an embodiment has a total drug:polymer ratio of 90:10, wherein the ratio of drugs in the combination can be 1:1. Thus, the stent of the present invention for delivering a quetiamus/dexamethasone combination can comprise 10 mcg/mm zetamus and 10 mcg/mm in a PC polymer layer having a 5 mcg/mm PC overcoat. Dexamethasone. However, the total drug:polymer ratio can be lower, such as 40:60 or less. The upper limit of the total amount of the drug depends on a number of factors, including the miscibility of the selected drug in the selected polymer, the stability of the drug/polymer mixture (eg, bactericidal compatibility), and the physical properties of the mixture. (eg fluidity/handleability, elasticity, brittleness, viscosity (no mesh or bridge formed between the stent rods), coating thickness (substantially increasing the stent profile or causing delamination or cracking or difficulty curling). Embodiments of the invention include stent rods spaced about 60-80 microns apart, which indicates that the drug/polymer/polymer overcoat has an upper thickness limit of about 30 microns; however, for drug delivery as described elsewhere, Use any bracket size, rod size and spacing and/or bracket structure. In an embodiment, the therapeutic amount of the Moss drug comprises quetiamus or everolimus, and is at least 1 μg per millimeter of stent. In other embodiments, the second drug is a glucocorticol. When the second drug is utilized in the embodiment, the second drug is dexamethasone and the therapeutic amount is at least 0.5 μg per millimeter of stent.

It is expected that the thickness of the outer coating (if an outer coating is used) should not unduly impede the release kinetics of the drug. The overcoat layer may also be loaded with one or more drugs which may be the same or different from the drug in the polymer layer supporting the base drug.

In general, combining the drugs used in the present invention does not adversely affect the desired activity of other drugs in the combination. The proposed drug for use in the combination may have a complementary activity or mechanism of action. Thus, one of the proposed combinations should not inhibit the desired activity, such as the anti-proliferative activity of another drug. No drug should cause or enhance the degradation of another drug. However, due to, for example, degradation during sterilization, a seemingly unsuitable drug may actually be useful due to the interaction of another drug. Therefore, dexamethasone which was degraded during EtO sterilization when used alone was observed to be successfully used in combination with quetiamus because of the hydrophobicity of quetiamus. In addition, it has been observed that quetiamus reduces the rate of dissolution of dexamethasone, as described in U.S. Patent Application Serial No. 10/796,423, the entire disclosure of which is incorporated herein by reference.

The pharmaceutical composition of the embodiments of the present invention comprises a compound and a pharmaceutically acceptable carrier or excipient which can be orally, rectally, parenterally, cerebrally, intravaginally, intraperitoneally, locally (e.g. Administration or delivery to the pericardial space by powder, ointment, drip or dermal patch, buccal (eg oral or nasal spray) or topical (eg in a stent placed in a vascular structure such as in a balloon catheter) Transfer to or within the myocardium. The phrase "pharmaceutically acceptable carrier" means a non-toxic solid, semi-solid or liquid filler, diluent, sealing material or formulation aid of any type. The term "parenteral" as used herein refers to all modes of administration other than oral administration including, but not limited to, intravenous, intraarterial, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection, drip, Percutaneously and placed (such as within a vascular structure).

The pharmaceutical composition of the present invention for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension, nanoparticle suspension or emulsion and for reconstitution of sterile prior to use. A sterile powder of the injection solution or dispersion. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (including glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose, and suitable mixtures thereof, Vegetable oils (including olive oil) and injectable organic esters (including ethyl oleate). Suitable fluidity can be maintained, for example, by the use of a coating material comprising lecithin, by the maintenance of the desired particle size under the conditions of the dispersion, and by the use of a surfactant.

Such compositions may also include adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial agents and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It is also desirable to include isotonic agents, including sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents including extended absorption, including aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. Subsequently, the rate of absorption of the drug depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable reservoir forms are made by forming a microcapsule matrix of the drug in a biodegradable polymer, including polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by trapping the drug with liposomes or microemulsions that are compatible with body tissues.

Injectable, for example, by filtration through a filter that retains bacteria or by incorporating the bactericide into a sterile solid composition that is soluble or dispersible in sterile water or other sterile injectable medium just prior to use. Formulation sterilization.

Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the active compound is combined with at least one inert, pharmaceutically acceptable excipient or carrier (including sodium citrate or dicalcium phosphate) and/or a) filler or excipient (including starch, Lactose, sucrose, glucose, mannitol and citric acid), (b) binders (such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic), c) humectants (including Glycerin), d) disintegrants (including agar, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate), e) solution retarders (including paraffin), f) absorption enhancers (including a quaternary amine compound), g) a wetting agent (such as cetyl alcohol and glyceryl monostearate), h) an adsorbent (including kaolin and bentonite), and i) a lubricant (including talc, calcium stearate, hard) Magnesium citrate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof are mixed. In the case of capsules, lozenges and pills, the dosage form may also contain a buffer.

Solid compositions of a similar type may also be employed as fillers in soft, semi-solid and hard-filled gelatin capsules or in liquid-filled capsules (using excipients such as lactose and high molecular weight polyethylene glycols and the like) Agent.

Solid dosage forms (not limited to lozenges, dragees, capsules, pills, and granules) having a coating and shell comprising other coatings well known in the casing and pharmaceutical formulation techniques can be prepared for oral administration. It may optionally contain a creaming agent and may also be a composition that only (or preferentially) releases the active ingredient in a prolonged manner in a particular portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric materials and waxes. The embedding compositions comprising the drug can be placed on a medical device comprising a stent, a graft, a catheter and a balloon.

The active composition may also be in the form of microcapsules, if appropriate, having one or more of the excipients described above.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and spirits. Liquid dosage forms can include, in addition to the active compound, inert diluents commonly employed in the art, such as water or other solvents, solubilizers and emulsifiers, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin , fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants including humectants, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.

In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, Agar and tragacanth and their mixtures.

Topical administration includes administration to the skin (including the surface of the eye). Compositions for topical application to the skin also include ointments, creams, lotions and gels. For the treatment of immunomodulatory conditions of the eye (including autoimmune diseases, allergic or inflammatory conditions and corneal transplantation), another form of topical administration is administration to the eye. The compounds of the invention can be delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound remains in contact with the surface of the eye for a time sufficient for the compound to penetrate the cornea and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous , aqueous, vitreous, cornea, iris / ciliary body, lens, choroid / retina and sclera. Pharmaceutically acceptable ophthalmic vehicles can, for example, be ointments, vegetable oils or encapsulated materials.

Compositions for mucosal administration, especially for inhalation, can be prepared as dry powders which may or may not be pressurized. In a non-pressurized powder composition, the active ingredient in the form of a fine powder may be mixed with a larger pharmaceutically acceptable inert carrier (including particles having a size of, for example, up to 100 microns in diameter) use. Suitable inert carriers include sugars, including lactose. Desirably, at least 95% by weight of the active ingredient microparticles have an effective particle size in the range of 0.01 to 10 microns. In transrectal or vaginal transmucosal administration, the formulation includes a suppository or retention enemas by using a compound of the invention with a suitable non-irritating excipient or carrier comprising cocoa butter, polyethylene glycol or suppository wax It is prepared by mixing (which is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and releases the active compound).

Alternatively, the composition can be pressurized and include a compressed gas (including nitrogen) or a liquefied gas propellant. The liquefied propellant medium and indeed the total composition is such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also include a surfactant. The surfactant can be a liquid or solid nonionic surfactant or can be a solid anionic surfactant. In other embodiments, the use of a solid anionic surfactant is in the form of a sodium salt.

The compounds of the examples of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are typically obtained from phospholipids or other lipid materials. Liposomes are formed by hydrating liquid crystals of single or multiple flakes dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, examples of compositions in liposome form may include stabilizers, preservatives, excipients, and the like. The lipids in the examples are natural and synthetic phospholipids and phospholipids choline (lecithin). Methods of forming liposomes are known in the art. See, for example, the book Prescott, Methods in Cell Biology . Volume XIV, Academic Press, New York, NY (1976), page 33 and the following.

The compounds of the embodiments of the invention may also be administered in combination with one or more systemic immunosuppressive agents. Immunosuppressive agents within the scope of the invention include, but are not limited to, IMURAN Azathioprine sodium, brequinar sodium, SPANIDIN Gusperimus trihydrochloride (also known as deoxyspergualin), imidazole (mizoribine) (also known as bredinin), CELLCEPT Mycophenolate, NEORAL Cyclosporin A (also in the trademark SANDIMMUNE Different formulations of cyclosporin A purchased under), PROGRAF Tacrolimus (also known as FK-506), sirolimus and RAPAMUNE Everolimus, leflunomide (also known as HWA-486), glucocorticoids (including splashed nylon and its derivatives), antibody therapeutics (including orthoclone (OKT3)), and Zenapax , leukemia therapeutic agents and anti-thymocyte globulin (including rabbit thymoglobulin).

Example

In one embodiment of the invention, the compound is of the formula:

In another embodiment of the invention, the compound is of the formula:

Preparation of the compounds of the invention

The compounds and methods of the examples of the present invention are better understood in conjunction with the following synthetic schemes for the preparation of the compounds of the present invention.

The compounds of the invention can be prepared by a variety of synthetic routes. A representative method is shown in Scheme 1.

As shown in Scheme 1, the C-42 hydroxyl group of rapamycin is converted to a triflate or fluorosulfonate leaving group to give A. Substituting the leaving group with a tetrazole in the presence of a non-nucleophilic hindered base (including 2,6-lutidine, diisopropylethylamine) to give isomers B and C, isomer B and C It was separated and purified by flash column chromatography.

The synthetic methods are better understood by reference to the following examples, which illustrate the preparation of the compounds of the invention and are not intended to limit the scope of the invention as defined in the appended claims.

Example 1 42 (2-tetrazolyl)-rapamycin (the less polar isomer) Example 1A

The solution of rapamycin (100 mg, 0.11 mmol) in dichloromethane (0.6 mL) was taken sequentially with 2,6-dimethylpyridine (53 μL, 0.46 mmol, 4.3) at -78 °C under nitrogen atmosphere. Ethyl) and trifluoromethanesulfonic anhydride (37 [mu]L, 0.22 mmol) were taken and stirred for 15 min then warmed to room temperature and eluted with a pad of diethyl ether (6 mL). The fractions including the triflate are concentrated and concentrated to yield the designated compound as an amber foam.

Example 1B 42 (2-tetrazolyl)-rapamycin (the less polar isomer)

A solution of Example 1A in isopropyl acetate (0.3 mL) was purified eluting elute eluting eluting This mixture was partitioned between water (10 mL) and ether (10 mL). The organics were washed with brine (10 mL) and dry (Na ₂ SO ₄₎ and washed. Concentrated organics gave a viscous yellow solid by using hexanes (10 mL), hexanes: ether (4:1 (10 mL), 3:1 (10 mL), 2:1 (10 mL), 1: It was purified by chromatography on 1 (10 mL)), ether (30 mL), hexane: acetone (1:1 (30 mL)). One of the isomers is collected in the ether fraction.

MS (ESI) m / e 966 (M) ^-

Example 2 42 (1-tetrazolyl)-rapamycin (more polar isomer)

The slower moving band of the column was collected from the hexane:acetone (1:1) mobile phase from Example 1B to yield the indicated compound.

MS (ESI) m / e 966 (M) ^-

Mixed lymphocyte reaction assay for rapamycin analogues Pharmacokinetics of rapamycin analogues

Comparison of immunosuppressive activity of the compounds of the examples of the invention with rapamycin and two rapamycin analogues: 40-epi-N-[2'-pyridone]-rapamycin and 40-table-N -[4'-pyridone]-rapamycin, both of which are disclosed in (Or et al., 1996). The activity was determined using a human mixed lymphocyte reaction (MLR) assay as described by Kino et al., 1987. As shown in Table 1, the assay results demonstrate that the compounds of the invention are effective immunomodulators at the concentration of the nanomolar.

The pharmacokinetic behavior of Example 1 and Example 2 was characterized according to a single 2.5 mg/kg intravenous dose in the stone crab macaque (n=3 per group). Each compound was prepared as 20% ethanol: 30% propylene glycol: 2% cetyl polyoxyethylene ether EL: 48% dextrose 5% solution in water vehicle 2.5 mg/mL. A 1 mL/kg intravenous dose was injected slowly (about 1-2 minutes) into the saphenous vein of the monkey. Blood samples were obtained from the femoral artery or vein of each animal prior to dosing and at 0.1 (intravenous), 0.25, 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, and 30 hours after dosing. The EDTA protected samples were thoroughly mixed and extracted for subsequent analysis.

An aliquot of blood (1.0 mL) was hemolyzed with 20% methanol (0.5 mL) in water containing the internal standard. The dissolved sample was extracted with a mixture of ethyl acetate and hexane (1:1 (v/v), 6.0 mL). The organic layer was evaporated to dryness with a stream of nitrogen at room temperature. The sample was rehydrated in methanol: water (1:1, 150 μL). The title compound (50 μL injection) was separated from the contaminant by reverse phase HPLC with UV detection. The sample was kept at low temperature (4 ° C) throughout the process. All samples from each study were analyzed as a single batch on HPLC.

The area under the curve (AUC) measurements for Example 1 , Example 2, and the internal standard were determined using the Sciex MacQuan ^{T M} software. A calibration curve was obtained from the peak area ratio (parent drug/internal standard) of the cone blood standard using the least squares linear regression of the relationship between the ratio and the theoretical concentration. Within the range of the standard curve (these methods are linear for both compounds with a correlation greater than 0.99), the estimated quantitative limit is 0.1 ng/mL. The maximum blood concentration (C _{m a x} ) and the time to maximum blood concentration (T _{m a x} ) were read directly from the observed blood concentration-time data. Blood concentration data was submitted to a multi-exponential curve device using CSTRIP to obtain an assessment of pharmacokinetic parameters. The parameters evaluated are further defined using NONLIN84. The area under the blood concentration-time curve (AUC _{0 - t} ) from 0 to t hours (the last time point at which blood concentration can be measured) after administration was calculated using a linear trapezoidal rule for the blood-time curve. The remaining area extrapolated to infinity is determined as the final measured blood concentration (C _t ) divided by the terminal elimination rate constant (β), and AUC _{0 - t is added} to produce the total area under the curve (AUC _{0 - t} ).

Shorter terminal as shown in FIG. 1 and Table 2, when compared to rapamycin, Example 1 and Example 2 have substantially the surprising elimination half-life (t _1/2). Thus, only the compounds of the invention provided sufficient efficiency ( Table 1 ) and shorter elimination half-lives ( Table 2 ).

Co-administered paclitaxel and second drug using a stent

When co-administered paclitaxel and a second drug (including rapamycin, analog or derivative) using a stent implanted in a blood vessel, the paclitaxel:second drug weight ratio r is such that the activity of one drug does not impair the other The activity of the drug (i.e., interference) and the total effect of co-administration is an additional and sometimes synergistic ratio. Pacific paclitaxel: The useful ratio of the second drug is greater than about 7:10, or about 7:10 r 0.01:10, or about 7:10 r 0.1:10, and or about r=1:10.

When applied to an implantable medical device, including a stent for implantation of a blood vessel, a typical dose of the therapeutic substance is from 0.01 μg/mm to 100 μg/mm. Generally, the maximum value of paclitaxel is indicated by the methods of polymers, drugs, and manufacturing devices. While other doses are effective and useful, when paclitaxel and the second drug are applied to the stent, typical doses are from 0.01 μg/mm to 20 μg/mm or from 0.1 μg/mm to 15 μg/mm and/or from 1 μg/mm to 10 Gg/mm. However, as long as the paclitaxel: second drug ratio remains at about 7:10 r 0.01:10 or about 7:10 r Any dosing regimen can be used at 0.1:10 and/or r = 1:10 without significantly compromising biosafety.

Polymer layer and therapeutic substance on medical device

Within the scope of the present invention, a polymer layer suitable for loading a drug is provided with great flexibility. For example, within the therapeutic range parameters associated with the drug of interest (typically between therapeutic efficacy and toxicity), the ratio of drugs used in combination varies relative to each other. For example, an embodiment has a total drug:polymer ratio of 90:10, wherein the ratio of drugs in the combination can be 1:1. Thus, a stent that delivers a paclitaxel/second pharmaceutical combination can include 10 μg/mm paclitaxel and 10 μg/mm second drug in a PC polymer layer with a 5 μg/mm PC overcoat. However, the total drug:polymer ratio can be lower, for example 40:60 or less. The upper limit of the total amount of the drug depends on several factors including the miscibility of the selected drug in the selected polymer, the stability of the drug/polymer mixture (eg, bactericidal compatibility), and the physical properties of the mixture ( For example, flow/handleability, elasticity, brittleness, viscosity (no mesh or bridge formed between the stent rods), coating thickness (substantially increasing the stent profile or causing delamination or cracking or difficulty in curling). Embodiments of the invention include stent rods spaced about 60-80 microns apart, which indicates that the drug/polymer/polymer overcoat has an upper thickness limit of about 30 microns; however, for the drug delivery described herein, any of the drugs can be utilized Bracket size, rod size and spacing and/or bracket structure. It is expected that the thickness of the outer coating (if an outer coating is used) should not unduly impede the release kinetics of the drug. The overcoat layer may also be loaded with one or more drugs which may be the same or different from the drug in the polymer layer carrying the base drug.

In general, the combination of the drugs used in the present invention does not adversely affect the desired activity of other drugs in the combination. Thus, one of the proposed combinations should not inhibit the desired activity, such as the anti-proliferative activity of another drug. No drug should cause or enhance the degradation of another drug. However, drugs that appear to be unsuitable due to, for example, degradation during sterilization may otherwise be otherwise useful due to the interaction of another drug. Therefore, it was observed that dexamethasone, which was degraded separately during EtO sterilization, was successfully used in combination with quetiamus because of the hydrophobicity of quetiamus. In addition, it has been observed that quetiamus reduces the rate of dissolution of dexamethasone, as described in U.S. Patent Application Serial No. 10/796,423, the entire disclosure of which is incorporated herein by reference.

Test of neovascular intimal hyperplasia and endothelialization after stent implantation

This test was used to determine the effect of dual drugs on neovascular intimal hyperplasia and endothelialization. The test uses a technically recognized porcine coronary over-extension model (Schwartz, RS, Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol . February 1992; 19(2): 267 -274) and usually for about 2-8 weeks. Typically the experimental construct comprises at least one scaffold control that is completely similar to the experimental scaffold except that it changes a single variable, including the therapeutic substance or polymer.

In one example, two primary coronary arteries were implanted in each pig with a test stent and a third primary coronary artery was implanted with a control stent. The additional control group was pigs implanted with three control scaffolds, one implanted in each of the primary coronary arteries. The brackets should be the same size or as close as possible.

The stent is implanted using standard techniques. At the end of the study, animals were euthanized and the heart removed, washed and fixed using standard tissue antiseptic techniques (including formalin, formaldehyde, etc.). The stretched blood vessels are excised and then infiltrated and inserted into a suitable medium (including methyl methacrylate (MMA), paraffin or cryogenic medium) for sectioning. Divide all segments containing the stretched blood vessels to obtain information: (for example) a portion of the three stents and two control portions. Continuous thin sections (about 5 μm) are typically used to each extent and stained to visualize cells and tissues (eg, hematoxylin and eosin (HE) and Masson's Verhoeff Elastin (MVE)). Slices are assessed and evaluated using image analysis systems or other technically accepted methods of morphological data collection and quantification. Data were evaluated for neovascular intimal area, neovascular intima thickness, and percentage of stenotic area.

Example 3

The purpose of this example was to determine the effect of rapamycin analogues on neovascular intimal formation in stented pig coronary arteries. This example demonstrates that when the rapamycin analogue quetiamus is mixed and delivered from a biocompatible BiodiviYsio PC coronary stent, it beneficially affects neovascular intimal hyperplasia and lumen size in the porcine coronary arteries. This finding suggests that if properly applied to humans, the delivery of quetiamus from a medical device is substantially clinically beneficial by limiting neovascular intimal hyperplasia.

The agent quetiamus is a rapamycin analogue. The study presented in this example was designed to assess the ability of the rapamycin analogue, quetiamus, to reduce neovascular intimal hyperplasia in a porcine coronary stent model. The efficiency of quetiamus in this model indicates that quetiamus limits the clinical potential of coronary and vascular restenosis in the stent after percutaneous revascularization. The use of domestic pigs is due to the fact that this model appears to be comparable to other studies that seek to limit neovascular intimal hyperplasia in human subjects.

The examples were tested for the dissolution of the coronary stent from the juvenile farm pigs and compared to the control stents. The control scaffold is a drug-free coated polymer. Importantly, the polymer itself does not substantially stimulate neovascular intimal hyperplasia. Since the dissolving drug disappears, the inflammatory response to the polymer can imaginably lead to a late "catch up phenomenon" in which the restenosis process is not stopped, but is subdued. This phenomenon leads to restenosis in the data of human subjects.

The stent was implanted into two of the blood vessels of each pig. Pigs used in this model are typically 2-4 months old and weigh 30-40 Kg. Therefore, two coronary stents were implanted into each pig by visually evaluating the usual stent: arterial ratio at 1.1-1.2. Beginning on the day of the start of the procedure, pigs were given aspirin (325 mg daily) and continued for the remainder of the procedure. General anesthesia was achieved by intramuscular injection followed by intravenous ketamine (30 mg/kg) and xylazine (3 mg/kg). At the time of induction, intramuscular administration included additional drugs such as atropine (1 mg) and flosilillin (1 g). During the stenting procedure, a rapid injection of 10,000 units of heparin was administered.

The artery is accessed by reducing the right external carotid artery and placing an 8F sheath. After the procedure, the animals are raised on a normal diet without cholesterol or other special supplements.

A BiodivYsio stent with a target size of 3.0 mm was used. See Figure 2 . The two coronary arteries of each pig were randomly assigned to deploy the stent. The stent is a drug-dissolving stent (polymer plus drug stent) or a polymer-coated stent (polymer-only stent). The stent is delivered by means of a standard catheter and wire. The stent balloon is inflated to a suitable size for less than 30 seconds.

Each pig has a polymer-only scaffold and a polymer plus drug scaffold placed in the isolated coronary artery such that each pig has a drug scaffold and a control scaffold.

Sample sizes of 20 total pigs were selected to detect salient differences in neovascular intimal thickness at a power of 0.95 and 0.12 mm at β 0.02 with a standard deviation of 0.15 mm.

Animals were euthanized for 28 days for histopathological examination and quantification. After the heart is removed from the perfusion pump system, the left atrial appendage is removed to access the proximal coronary artery. Dissect the coronary artery segment with injury so that there is no epicardium. The segment containing the lesion is separated whereby sufficient tissue is contained at each end to contain uncontained blood vessels. The aforementioned sections each having a length of 2.5 cm were embedded and treated by means of standard plastic embedding techniques. Tissues were then processed and stained with hematoxylin-eosin and elastic-van Gieson techniques.

The length measurements were performed on the plane of the micrograph using low and high power optical microscopy using a digital microscopy system with calibration calibration lines and a computer connected to the computer using the calibrated analysis software.

The severity of vascular injury and neovascular intimal response were measured by calibrated digital microscopy. Those skilled in the art are familiar with the importance of the integrity of the inner elastic layer. The histopathological damage score in the vessel with the stent has been confirmed due to its close correlation with neovascular intima thickness. This score is related to the depth of damage and is as follows:

Quantitative measurements of lesions were evaluated for all stent rods of each stent section. Neovascular intima thickness was also measured at each stent rod point using a calibrated digital image. The area of the inner cavity, the area under the inner elastic thin layer and the area within the outer elastic thin layer are also measured.

The middle bracket section is used for measurement, analysis and comparison. Information about the proximal and distal segments is also recorded (and is included in the information section of this report).

Paired t-tests were performed to compare variables across the polymer-only scaffold (control) and the polymer plus drug scaffold (treatment group). In this study, no animal died before the scheduled time.

Table 3 shows the pigs and arteries used. In Table 3 , LCX means the circumflex artery of the left coronary artery, LAD means the left anterior descending coronary artery, and RCA means the right coronary artery.

Table 4 shows an overview of all data on the mean loss and neovascular intima thickness of each stent (including the proximal, middle, and distal segments). Table 4 also shows lumen dimensions, percent stenosis, and arterial size as measured by the inner elastic thin layer (IEL) and the outer elastic thin layer (EEL).

There were no statistically significant differences in neovascular intimal area or thickness between the test group (polymer plus drug stent) or the control group (polymer-only stent) in the proximal, middle or distal segments. This observation is very consistent with previous studies, thus allowing a statistical comparison of the test device (polymer plus drug scaffold) to the control device (polymer only scaffold) using only the middle segment. Table 5 shows a statistical t-test comparison across the test and control groups. There were statistically significant differences in neovascular intimal thickness, neovascular vascular area, luminal size, and percentage of luminal stenosis. Drug-dissociated stents were significantly beneficial. In contrast, there was no statistically significant difference between the test group (polymer plus drug stent) and the control group (polymer only stent) with respect to the mean damage fraction, the outer elastic thin layer or the inner elastic thin layer area. The difference.

The reference arteries on the proximal and distal sides of the stretched segment are observed and quantified. These vessels appeared normal in all conditions and were not damaged in the control group (polymer stent only) and the test group (polymer plus drug stent). See Figures 3A and 3B. The following data shows that there is no statistically significant difference in size between the stent in the control group and the stent in the test group.

The data proves that there is a statistically significant difference in the morphometric measurement of efficiency, preferring the stent of the solute. The stent of the present invention results in a lower neovascular intimal area, a lower neovascular intima thickness, and a larger lumen area. There were no significant differences in inflammatory or insult parameters between the test group (polymer plus drug stent) and the control group (polymer only stent). There was no significant difference in arterial size (including stents) compared to the test group. These recent findings indicate that there are no significant differences in the arterial remodeling characteristics of drug-containing polymer coatings.

At least mild inflammation was found on the polymer plus drug stent and the polymer only stent. This finding indicates that the polymer shows good biocompatibility even without drug loading. Other studies have shown that when the drug is completely removed from the polymer, the polymer itself produces sufficient inflammation to cause neovascular intima. This observation may be responsible for the late catch-up phenomenon in the late stage of clinical restenosis. Because the polymer in this example did not cause inflammation in the coronary arteries, late-stage problems associated with polymers after drug depletion were unlikely.

In summary, the scaffold from the polymer-dissolved compound, quetiamus, showed a decrease in neovascular intimal hyperplasia when placed in the coronary artery in the porcine model.

Example 4

The purpose of this example was to determine the rate of release of the quetiamus drug from a biocompatible polymer coated 316L electropolished stainless steel coupon containing pendant phosphatidylcholine.

The rubber septum from the lid of the HPLC vial was removed from the vial and placed in a glass vial such that the "Teflon" side was facing up. These spacers are used as carriers for the test sample. The test sample was a 316L stainless steel test piece previously coated with a biocompatible polymer (PC polymer) containing pendant phosphatidylcholine. Coronary stents are typically made of 316L stainless steel and can be coated with PC polymer to provide a reservoir for the loaded drug. The coated test piece for the simulated stent was placed on the septum. A solution of quetiamus and ethanol (10 μL) was applied to the surface of each test piece by using a glass Hamilton syringe. The solution contained quetiamus (30.6 mg) dissolved in 100% ethanol (3.0 mL). The syringe was washed with ethanol between each application. Place the cap of the glass bottle loosely on the bottle to ensure proper ventilation. The test piece was allowed to dry for a minimum of 1.5 hours. Twelve coupons were loaded in this manner - six were used to determine the average amount of drug loaded onto the device, and six were used to measure the time required to release the drug from the device.

To determine the total amount of quetiamus loaded onto the test piece, the test piece was removed from the bottle and placed in a 50/50 acetonitrile/0.01 M phosphate buffer (pH 6.0, 5.0 mL). The test piece was placed in a 5210 Branson sonicator for one hour. The test piece was then removed from the solution and the solution was assayed by HPLC.

Fresh aliquots (10.0 mL) of 0.01 M phosphate buffer at pH 6.0 were immersed in and removed from each of the following time intervals - 5, 15, 30, and 60 minutes. Time release studies were performed. For the remaining time points of 120, 180, 240, 300, 360 minutes, a 5.0 mL volume of buffer was used. To facilitate mixing during drug release, the sample was placed on a low speed Eberbach shaker device. After the final sample test was completed, all solution aliquots were assayed by HPLC.

HPLC analysis was performed using a Hewlett Packard Series 1100 tool with the following configuration: injection volume = 100 μl acquisition time = 40 minutes flow rate = 1.0 ml / min column temperature = 40 ° C wavelength = 278 nm mobile phase = 65% acetonitrile / 35% H ₂ O column = YMC ODS-A S5 μm, 4.6 x 250 mm Part No. A12052546WT

The results of the above experiments show the following release data (Table 6):

Example 5

The purpose of this example was to determine the loading and release of quetiamus from a 15 mm BiodivYsio drug delivery scaffold.

To load the stent with the drug, a solution of quetiamus in ethanol at a concentration of 50 mg/mL was prepared and dispersed in twelve bottles. The polymer coated twelve individual stents were placed on a fixture designed to hold the stent in a vertical position and the stent was vertically immersed in the drug solution for five minutes. The stent and fixture are removed from the vial and the excess drug solution is aspirated by contacting the stent with the adsorbent material. The stent was then dried in air for 30 minutes in a reverse vertical position.

The scaffolds were removed from the fixture and each scaffold was placed in 50/50 acetonitrile/phosphate buffer (pH 5.1, 2.0 mL) and sonicated for one hour. The stent is removed from the solution and the drug concentration of the solution is assayed, which allows calculation of the initial amount of drug on the stent. This method is shown independently to remove at least 95% of the drug from the stent coating. The stent included an average of 120 ± 9 micrograms of drug.

The drug loaded scaffold was placed on the fixture in individual vials and placed in 0.01 M phosphate buffer (pH = 6.0, 1.9 mL). These samples were placed on a low speed Eberbach shaker device to provide back and forth agitation. To avoid approaching the saturation of the drug in the buffer, the scaffold was periodically transferred to fresh buffer bottles at 15, 30, 45, 60, 120, 135, 150, 165, 180, 240, 390 minutes. At the end of the drug release period studied, the drug concentration of the lysis buffer bottle was determined by HPLC. The data represents the cumulative release of the drug as a function of time, which is shown in tabular form in Table 7 below:

Example 6

The tetrazolium analog temazos of rapamycin has been shown to have damage in porcine coronary stents and (Robinson, KA, Dube, HMEfficacy Evaluation of zotarolimus Loaded Coronary Stents in Yucatan Miniswine-Preclinical Laboratory Study, 09/20 /2001 and Schwartz, RSEfficacy Evaluation of a Rapamycin Analog (A-179578). Delivered from the Biocompatibles Bio divYsio PC Coronary Stents in Porcine Coronary Arteries, Technical Report, Mayo Clinic and Foundation, Rochester, MN.) Anti-restenosis activity in the model (Gregory, C. Summary of Study Evaluating Effects of zotarolimus in a Rat Model of Vascular Injury). The purpose of this example was to evaluate the safety and pharmacokinetics (PK) of a single intravenous (IV) dose of gradual increase of quetiamus in healthy men.

Currently, the first study in humans, the safety and pharmacokinetics of quetiamus, was studied after intravenous administration of quetiamus at a dose ranging from 100 to 900 μg. Intravenous single-dose administration mimics the fastest accidental release of sultasis from drug-coated stents in vivo.

This was a single escalating, double-blind, randomized, placebo-controlled, phase 1 single-center study. Sixty healthy adult males were divided into 5, IV, 100, 300, 500, 700, and 900 μg dose groups. The population information of the subjects is summarized in Table 8 .

Subjects were randomly assigned to receive a single intravenous dose of quetiamus or matched intravenous placebo in the fasted condition, as shown in the dosing diagrams shown in Table 9.

Higher doses were administered after assessing safety data from the aforementioned lower dose group. The treatment group was separated for at least 7 days. For safety reasons, each treatment component was divided into two groups of six subjects, and the doses of the two groups were separated by at least one day.

The dose was administered in a rapid IV over 3 minutes under 8 subjects. In each dose group, 4 subjects received quetiamus and 4 subjects received a placebo. The blood concentration of quetiamus was sampled over 168 hours and measured using LC-MS/MS with a LOQ of 0.20 ng/mL.

0.083 (5 min), 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72, 96, 120 before administration (0 hours) and after the first day of study At 144 and 168 hours, 7 mL of blood samples were collected by venipuncture into a vacuum collection tube containing edetic acid (EDTA).

The blood concentration of quetiamus was determined using a confirmed liquid/liquid extraction HPLC tandem mass spectrometry method (LC-MS/MS). (Ji et al., 2004). The lower limit of quantification of quetiamus using a 0.3 mL blood sample was 0.20 ng/mL. All calibration curves have a measurement coefficient (r ² ) greater than or equal to 0.9923.

Safety is assessed based on adverse events, physical examinations, vital signs, ECG, injection points, and laboratory test assessments.

Non-interval methods were used to assess the pharmacokinetic parameter values of quetiamus. These parameters include: quetiamus concentration (C ₅ ) at 5 minutes after administration, dose-normalized C ₅ , elimination rate constant (β), half-life (t _{1 / 2} ), from time 0 to final dose area of the blood concentration and the time curve in time concentrations measured (AUC _{0 - Finally),} dose-normalized of AUC _{0 - Finally,} extrapolated to the area under the curve of blood concentration versus time of infinite moment of (AUC _{0 - no limit)} , the dose normalized AUC _{0 - no limit,} total clearance (CL) and volume of distribution (Vd _β).

The mean blood concentration-time curves after intravenous administration of quetiamus are shown in Figures 4 and 5 , respectively, in a linear ratio and a logarithmic linear ratio.

The mean ± SD pharmacokinetic parameters of quetiamus are shown in Table 10 after administration of each of the two therapies.

To investigate the issue of dose proportionality and linear pharmacokinetics, an analysis of convariance (ANCOVA) was performed. Subjects were categorized by dose level and weighted as a covariate. Analysis of the variables comprising _β, Vd β, the dose-normalized C ₅ and standardization of dose AUC _{0 -} standardization of _{the last} dose and AUC _{0 - no limit} on the number. The primary test of the premise of dose constancy is a test of the dose level effect with respect to the monotonic function of the dose. In addition, the highest and lowest dose levels were compared within the framework of ANCOVA.

6 depicts the universe Mok Division C _{m a x,} AUC _{0 - no limit} to the proportion of the dose into _{- the last} and AUC _0. Seen in this figure, as the dose normalized C _{m a x} and AUC _{0 - most} monotonic trend was not observed _after the statistically significant, the inference-based dose-proportional increase in these parameters. AUC ₀ for standardized dose universe Secretary of Ta Mok _{- no limit,} the monotonous trend observed significant dose of the concomitant significant (p = 0.0152). However, dose-normalized AUC ₀ for all groups _{- no limit} of the pairwise comparison shows only the 100 μg dose normalized AUC _{0 -} significantly different from the 900 μg and 300 μg of the dose-normalized AUC _{0 unlimited} statistically _{- infinite} (respectively p = 0.0032 and p = 0.0316). A statistically significant monotonic trend with beta was also observed. This bias may be due to a slight overestimation of β in the 100 μg dose group. Zhou average Ta Mok Division C ₅ (a concentration at 5 minutes) and AUC _{0 - No limit} will increase as the proportion to the dose, as shown in Table 11.

The mean half-life at the doses studied varied between 26.0 and 40.2 h and was not significantly different over the 300-900 μg dose range. Cytametol was well tolerated at all doses and no clinically significant physical examination results, vital signs or laboratory measurements were observed.

safety

The most common treatment-emergency adverse event associated with quetiamus (reported by two or more subjects in any treatment group) is the injection point response and pain.

Most adverse events are mild and naturally resolved to a severe extent.

There were no serious adverse events reported in this study.

There were no significant clinical changes in physical examination results, vital signs, clinical laboratory or ECG parameters during the study.

in conclusion

On the 100-900 μg dose range of about C ₅ and AUC _{0 - unlimited} universe of IV Pharmacokinetic Mok Division dose proportional. In general, the 100-900 μg dose range in the universe Mok Division of substantially linear pharmacokinetics, such as by C _5, AUC _{0 - the last} and AUC _{0 - infinitely} increased proportional to the dose shown. A single dose of IV up to 900 μg was administered without consideration of safety.

The average elimination half-life of quetiamus varied from 26.0 to 40.2 hours over the range of doses studied. The average clearance and volume of the distribution varied from 2.90 to 3.55 L/h and 113 to 202 L, respectively. Regarding β and to a significant extent regarding Vd _β , the observed deviation from the linear kinetics was attributed to an overestimation of β for the 100 μg dose group.

Subjects are generally well tolerated with a single dose of quetiamus of 100 to 900 μg.

Example 7

This study was designed to assess the pharmacokinetics of quetiamus after multiple doses and to assess the safety of healthy subjects when their systemic exposure is maximized. The primary goal is to achieve a total exposure of quetiamus that is significantly higher than the expected level of drug eluted from the coated stent. The study investigated the pharmacokinetics and safety of quetiastat in a phase 1 and multiple dose escalation study (after multiple intravenous injections of 200, 400, and 800 μg per day for 14 consecutive days in healthy subjects). Sex.

method

A phase 1, multiple escalating dose, double-blind, placebo-controlled randomized study. The 60-minute QD IV injection of quetiamus was divided into three daily once-a-day (QD) therapies (200, 400 or 800 μg QD, 16 of each active and 8 placebos) for 14 consecutive days. 72 subjects. Blood samples were collected 24 hours prior to dosing on the 10th, 11th, 12th, and 13th days after the first administration, and 168 hours after the 14th day. On days 1, 14, 16, 18 and 20, urine samples were collected over 24 hours. The concentration of quetiamus in blood and urine was determined using the confirmed LC/MS/MS method. The pharmacokinetic parameters were determined by interval analysis. All day AUC _{0 - ∞} (including all 14 doses from time 0 to infinite blood concentration-time curve area). Estimate dose and time - linear and stable state. The fraction of the drug eliminated in the urine is determined.

In this study, 72 generally healthy male and female subjects were enrolled. Population information is summarized in Table 12 .

As shown in Table 13 , subjects were randomly divided into three groups (Groups I, II, and III) at two different points. Within each group, subjects were equally divided between the two study sites, with 12 subjects enrolled at each site (8 subjects: quetamos, 4 subjects: placebo). The administration schedules in each dose group are shown below: + Subject 2112 stopped the study prematurely; on the 19th day of the study, the subject withdrew from the accreditation.

On Days 1 to 14 of the study, for Groups I, II, and III, subjects received a single 60-minute daily (QD) 200, 400, or 800 μg zeamolmus vein for fasting. Intravenous or placebo matched intravenous injection. The drug was administered via a syringe pump connected to a y-point device which was also injected with 125-150 mL of a 5% aqueous solution of dextrose (D5W) over 60 minutes. The group is then administered with the last dose of the previous group separated from the first dose of the next group for at least 7 days, during which time the safety data from the previous group is analyzed. The dose increase is dependent on the safety analysis of the lower dose group.

A 5-mL blood sample was collected in a tube containing potassium EDTA to evaluate 0.25, 0.5, 1.0, 1 hour, 5 minutes, 1.25, 1.5 after administration (0 hours) and on the first and 14th days of the study. , 2, 3, 4, 8, 12, 18 and 24 hours of quetiamus concentration. Additional samples were collected at the 36, 48, 72, 96, 120, 144 and 168 hours prior to the start of the study on day 14 of the study and on days 10, 11, 12 and 13. Urine was collected in preservative-free containers at the following intervals after the start of the study on days 1, 14, 16, 18 and 20: 0 to 6, 6 to 12, 12 to 18 and 18 to 24 hours.

The blood and urine concentrations of quetiamus were determined using a confirmed liquid/liquid extraction HPLC tandem mass spectrometry (LC-MS/MS). Using a 0.3 mL blood sample, the lower limit of quantitation of quetiamus was 0.20 ng/mL, and using a 0.3 mL urine sample, the lower limit of quantitation of quetiamus was 0.50 ng/mL.

Safety is assessed based on adverse events, physical examinations, vital signs, ECG, injection points, and laboratory test assessments.

result

The plasma concentration-time data of all subjects were described by a three-interval open model with first-order elimination. For the therapies studied, the mean interval pharmacokinetic parameters ranged from CL 4.0-4.6 L/h; V ₁ 11.3-13.1 L; V _{s s} 92.5-118.0 L and terminal elimination t _{1 / 2} 24.7-31.0 h . On the first and fourth days of the study, the pharmacokinetics of quetiamus was linearly consistent with the dose. The pharmacokinetic model met both day 1 and day 14 data, indicating time-linear pharmacokinetics. AUC _0-day study of the therapy _{- ∞} from 677-2395 ng. Hr/mL changes. An average of 0.1% of the dose of quetiamus was recovered in the urine within 24 hours after administration.

Pharmacokinetics and statistical analysis

The pharmacokinetic parameter values of quetiamus were evaluated for individual subjects using interval analysis. Simultaneously simulating the first dose from the first day of the study, the last dose on the 14th day of the study, and the lowest concentration on the 10th, 11th, 12th, and 13th days of the study for each individual subject. data. The measured parameters are: volume of intermediate interval (V ₁ ), terminal elimination rate constant (γ), clearance rate (CL), volume of distribution under steady state (V _{s s} ), half-life (t _{1 / 2} ), The maximum concentration (C _{m a x} ), the time of maximum concentration (T _{m a x} ), the area under the curve of blood concentration and time on day 14 (AUC _τ ), and the corresponding dose normalized C _{m a x} and AUC _τ . The best model of each individual subject was used to predict the concentration-time curve of individual subjects over a 14-day period to assess chronic exposure during the duration of the study, ie C _{m a x} and all-day AUC _{0 - ∞} (considering All 14 doses in the study, from 0 to infinity, predicted area under the blood concentration-time curve).

To assess the dose proportionality of the study day 14 dose, covariance analysis (ANCOVA) was performed on dose normalized C _{m a x} , dose normalized AUC, and terminal elimination rate constants. The center and dose are factors and the body weight is a public variable. In order to solve the problem of whether or not the steady state is reached, the center and the dose level are used as factors to perform repeated measurement analysis on the dose pre-dose concentration normalized to the dose on days 10-14.

Pharmacokinetics

The plasma concentration-time data of all subjects were described by a three-interval open model with first-order elimination. The mean blood concentrations of quetiamus on Day 1, Day 14, and Days 1 to 14 are shown in Figure 7 . The mean ± SD of the pharmacokinetic parameters of quetiamus is shown in Table 14 .

Because the deviation between the observed diagnostic curve and the predicted diagnostic curve was not observed on the therapy being studied, the range of interval pharmacokinetic parameters at the dose therapy studied was very narrow and not on the dose therapy studied. A meaningful trend on the second parameter was observed; the dose linearity of quetiamus was inferred on the dose therapy studied.

The following figure depicts the 14th day of quetiamus C_{m a x} And AUC_{0 - 2 4 h} It is proportional to the dose.Figures 8a, 8b and 8c Mean quetiamus blood concentration-time curves for the 200, 400, and 800 μg QD dose groups on Days 1, 14 and 1-14 were shown. For each dose group, the model fully describes the data on Days 1 and 14 and the days between them, such asFigure 9 Illustrated (examples of mean and predicted blood concentration versus time curves for 800 μg QD dose group data). The excellent quetiamus concentration-time data observed by day 3 to day 14 by assuming a linear dynamics 3 interval model is consistent with the quetiamus display time constant clearance rate.

As shown in FIG. 9, 10-14 days on study dose-normalized pre-dose concentrations not observed statistically significant.

The median values of C _{m a x} for the 200, 400, and 800 μg QD dose groups were 11.4, 22.1, and 38.9 ng/mL, respectively. Corresponding to the full-day AUC _{0 - ∞} median values are 677, 1438 and 2395 ng. h/mL.

The fraction of the temasis dose eliminated in the urine was calculated for the 800 μg QD dose group. On average, about 0.1% of the quetiamus was recovered in the urine within 24 hours on the first day and the 14th day.

safety

The most common treatments associated with quetiamus - emergency adverse events are pain, headache, injection point reaction, dry skin disease, abdominal pain, diarrhea and rash. Most adverse events are mild and naturally resolved to a severe extent. There were no serious adverse events reported in this study. In particular, none of the subjects showed any clinical or biochemical evidence of immunosuppression, delayed QTc, or clinically significant adverse events.

in conclusion

In the dose therapy studied, the pharmacokinetics of quetiamus was proportional to the dose and constant over time when administered intravenously for 14 consecutive days.

The steady state of QD administration of quetiamus was reached on day 10, on which the first lowest sample was measured.

Because about 0.1% of the daily dose is excreted in the urine as an unaltered drug, renal excretion is not the primary route of elimination of quetiamus.

Zetamos are generally well tolerated when administered in multiple doses of 200, 400 and 800 μg for 14 consecutive days.

Example 8 Antiproliferative activity of quetiamus and paclitaxel

Experiments were conducted to investigate the interaction between quetiamus (ABT-578) and paclitaxel when administered in combination. The in vitro proliferation assay was used to determine the effect of paclitaxel and quetiamus on anti-proliferative activity in human coronary artery smooth muscle (hCaSMC) and endothelial cells (hCaEC). Proliferation of vascular smooth muscle cells and migration to the vascular neovascular intima are characteristic pathological responses seen in restenosis lesions (Lafont and Libby, 1998). As a result, an in vitro assay specifically measuring the anti-proliferative activity of candidate anti-restenosis compounds against human coronary artery smooth muscle and endothelial cells predicts potential anti-stenosis activity in vivo.

A compound or combination of compounds that attenuate growth factor-regulated human coronary artery smooth muscle cells (hCaSMC) proliferation is a candidate anti-restenosis agent as measured by an in vitro sputum incorporation assay. The 氚 incorporation assay is an accurate and sensitive method for determining cell number and proliferation. This assay was used to determine whether an agent exhibiting anti-proliferative activity in a single case also showed similar activity in the combination. In addition, agents that exhibit inefficient antiproliferative activity block the activity of more potent anti-proliferative agents when administered in combination. A clear example of the effect of tacrolimus on the weakening of the antiproliferative activity of quetiamus ( Fig. 10A ). To determine the potential anti-restenotic activity of the combination of quetiamus and paclitaxel, the proliferation of hCaSMC was measured in the presence of each compound and combination.

Pacific paclitaxel interferes with microtubule depolymerization and blocks cellular processes in S phase (Schiff and Horwitz, 1980). Similar to rapamycin, quetiamus blocks cyclin-dependent kinase via mTOR inhibition and inhibits cell cycle progression in the G1-S phase (Marx et al, 1995; Sehgal, 1998; Sehgal, 2003).

To determine whether paclitaxel impairs or increases the activity of quetiamus, the effect of combination of paclitaxel alone and quetiamus and paclitaxel with quetiamus on growth factor-induced proliferation was determined. For the additive, the data is analyzed using the isobologram method and the combined index analysis. The isobologram is the Cartesian curve of the dose pair, which produces a certain degree of effect in combination. The results of the illustrated drug combinations and similar studies are conventional methods because the paired values at the experimental points below or above the line connecting the pivot points respectively indicate the promoting and non-promoting interactions.

Hyperplasia test ³ H thymidine uptake

Cell proliferation was monitored by incorporation of ³ H-thymidine into newly synthesized cellular DNA (stimulated by serum and growth factors). The exponentially growing hCaSMCs were seeded in 96-well flat-bottom tissue culture dishes at 5000 cells per well (10,000 cells per well for hCaEC). The cells were attached overnight. The next day, the growth medium was removed and the cells were washed twice with unsupplemented (basal) medium to remove traces of serum and growth factors. A basal medium (200 μL) was added to each well and the cells were incubated in a medium lacking growth factors and serum to starve and synchronize them to the G0 state. After starvation in the medium lacking serum and growth factors (48 hours for hCaSMC and 39 hours for hCaEC), cells were supplemented with 200 μL of supplemented medium in the absence or presence of the drug. In all wells, dimethyl hydrazine (DMSO) was maintained at a final concentration of 0.1%. After a 72 hour incubation period, 25 μL (1 μCi per well) of ³ H-thymidine (Amersham Biosciences; Piscataway, NJ) was added to each cell. The cells were incubated at 37 °C for 16-18 hours and the cells were harvested onto a 96-well plate containing a bonded glass fiber filter using a cell harvester (Harvester 9600, TOMTEC; Hamden, CT). Filter disks were air dried overnight and MicroScint-20 (25 μL; PerkinElmer; Wellesley; MA) was added to each filter well and the plates were counted using a TopCount micro-quantitative disk scintillation counter (PerkinElmer). The control group included only medium, starved cells, and cells in intact medium. The drug activity was established by measuring the inhibition of the incorporation of ³ H-thymidine into the newly synthesized DNA relative to cells grown in intact medium.

Data are presented as percent inhibition of ³ H-thymidine incorporation relative to vehicle-treated controls and are mean ± SEM of 3-4 experiments. Generating a semi-logarithmic curve from the average value of inhibition of the experimental drug concentration, and 50% with respect to the degree of inhibition of pushing the outer incubated in complete medium lacking the drugs in each experiment to determine the cell IC _{5 0} (by median inhibitory concentration (concentration that reduces cell proliferation by 50%)). Final IC _{5 0} of the experiment the average of 3-4.

In these experiments, the x-axis represents the varying drug concentration. Each plot contains a separate quetiamus and Pacific paclitaxel curve. The setting of the curves in each figure was generated by adding paclitaxel to a given concentration of cetamol at a fixed concentration. Each curve represents a dose response of quetiamus (concentration is given on the x-axis) in the presence of a specified fixed concentration of paclitaxel.

Two methods were used to analyze the effect of combination of quetiamus and paclitaxel on proliferation. An equivalent line graph is generated at several effective levels (Tallarida et al., 1989). A concentration response curve conforming to the nonlinear regression (Prism, GraphPad Software; San Diego , CA) to obtain EC _{5 0} and the gradient value. The 4-parameter equation is used to determine the concentration that causes specific anti-proliferative effects (Equation 1): Y = bottom + (top-bottom) / (1 + 10^((LogEC _{5 0} -X) * slope)) X is the concentration logarithm. Y is the reaction or: Where X = the logarithm of the drug concentration that produces the Y reaction, and the top and bottom values are limited to 100 and 0, respectively. In addition to the isobologram, the Chou and Talalay methods were used to collate the data with the following exceptions (Chou and Talalay, 1984). The regression model generated for each curve was replaced by a median impact data (log-logit curve), which is a more accurate simulation of the concentration-response curve because of the nonlinear 4-parameter equation. The median impact curve is severely affected by fractional occupancy values below 0.2 and above 0.8. The combination index (CI) of several drug combinations of 25%, 50%, 60%, and 75% was calculated according to Equation 2.

(D) ₁ /(D _x ) ₁ +(D) ₂ /(D _x ) ₂ +((D) ₁ (D) ₂ )/(D _x ) ₁ (D _x ) ₂ =CI (Equation 2)

Wherein (D) ₁ and (D) ₂ are the concentrations of the drug 1 and the drug 2 in the combination, and (D _x ) ₁ and (D _x ) ₂ are the concentrations of the drug 1 alone and the drug 2 alone. Assuming that each drug acts according to its potency, the CI value reflects the sum of the effects of the combination. Equation 2 describes the predictive effect of a combination of two non-specific compounds with each other. CI is equal to 1 if each drug promotes a combined effect based on its own dose-dependent fractional occupancy. A CI value of less than 1 is considered to be synergistic, and a value significantly greater than 1 is considered to be a weak addition. Since the relationship between CI and synergy, addition or reduction can depend on the degree of action, CI is determined at several levels of action using multiple drug combinations. The CI value is plotted as a function of the degree of action (or f _a ) (the CI value is calculated below). Similar to the isobologram analysis method, the CI value depends on the degree of action and varies with the degree of action. Therefore, it is important to consider the degree of action when comparing CI values. The accuracy of the CI value is then determined by the accuracy of the concentration values used in its calculations. In this study, a precise method (in accordance with the asymptotic curve of the GraphPad software) was used to calculate the drug concentration from each cumulative dose response curve for several degrees of action. The dose response curve can be in accordance with the data, which demonstrates activity that is almost dose independent. This is especially evident when analyzing the dose response curve produced in the presence of one of the high concentration test agents. In such cases, an error in the concentration of the drug determined from the dose response curve can result in _a high CI value at _a low degree of action (f _a ). Thus, a well-defined dose response curve generated near or above the half-value-maximum effect (i.e., f _a about 0.5) produces a CI value that is the most accurate predictor of drug combination activity. In these cases, it is considered that the CI value below 1 is strongly added, and the value significantly exceeding 1 is weakly added. It is considered that the value close to 1 is attached.

result

This study demonstrates the activity of agents on two cell types involving restenosis, human coronary artery smooth muscle (hCaSMC) and endothelial cells (hCaEC). The results are given in Figure 10 and Table 15 . Figure 10 shows the anti-proliferative activity of tacrolimus blocking quetiamus in vitro smooth muscle cells ( Fig. 10A ). The anti-proliferative activity of quetiamus, paclitaxel (P), and combination in vitro smooth muscle cells ( Fig. 10B ) and endothelial cells ( Fig. 10C ) was also shown. Figures 10D-G show isobologram analysis of combined anti-proliferative activity in smooth muscle cells. The concentration at which a particular degree of anti-proliferative activity is produced is determined by a dose response curve generated by a non-linear curve consistent with the mean of the data. Figure 10H-K shows an isobologram analysis of anti-proliferative activity of quetiamus and paclitaxel in endothelial cells. The concentration of the compound which produces a certain degree of activity is determined from the average data. Figure 10L-M shows a combination index (CI) analysis of anti-proliferative activity of a combination of ABT-578 and paclitaxel in hCaSMC and hCaEC. The degree of CI was determined from the mean data using the method of Chou and Talalay (Chou and Talalay, 1984).

Information from individual individual agents shows that quetiamus and paclitaxel inhibit proliferation in a dose-dependent manner in each cell type. Figure 10B/C shows that inhibition of hyperplasia by quetiamus is not blocked by paclitaxel. Increasing the concentration of paclitaxel and quetiamus almost completely inhibited the proliferation of hCaEC and hCaSMC. Such information is displayed at a low level of effectiveness (ie 50% proliferative inhibition) The effects of the combination of paclitaxel and quetiamus are predicted by the sum of their individual activities. Except for a high degree of inhibition, this relationship is maintained to a large extent. Under high inhibition, the anti-proliferative activity slightly exceeds the anti-proliferative activity predicted by the activity of each individual drug. The isobologram and CI analysis of hCaSMC data showed that the combination of paclitaxel (2.5 nM) and quetiamus demonstrated potentially potent antiproliferative activity at high levels of action (60 and 75%).

ND ^* 5 nM paclitaxel alone or in concentrations above 5 nM to more than 50% proliferation inhibition, calculated in this hinder these experiments ABT-578 IC _{5 0.}

These data show that paclitaxel does not block the antiproliferative activity of quetiamus. In addition, high concentrations of quetiamus and paclitaxel exhibited synergistic anti-proliferative activity.

Example 10 Dissolution test of beneficial agents Coating the stent with PC1036

The coated stent was prepared prior to any experiment. These brackets are 3.0 mm x 15 mm 316L electropolished stainless steel brackets. Each scaffold was sprayed with a filtered 20 mg/mL solution of phosphonium choline polymer PC-1036 (Biocompatibles Ltd., Farnham, Surrey, UK) in ethanol (EtOH). The stent was initially air dried and then cured at 70 ° C for 16 hours. It is then subjected to gamma irradiation at less than 25 KGy.

Treatment substance loading stent

In these experiments, the agent was loaded onto the stent and the dissolution profile was examined. In general, the process is as follows. A plurality of PC coated stents were loaded with each drug combination solution. The drug solution is typically in the range of 2-20 mg/mL of quetiamus and 1.0-7.0 mg/mL of paclitaxel in 100% ethanol, with about 10% PC1036 added to the solution to enhance film formation. The loading of the dual drug and single drug stent is achieved by spraying a suitable drug spray onto the stent in a one-way spray system in a separator unit. All DES lysed stents were fabricated from Abbott Laboratories TriMaxx N5 construction 15 mm x 3.0 mm stents, and all catheters were Medtronic (Minneapolis, MN) OTW, 15 mm x 3.0 mm. The quantities produced for each combination include units for accelerated dissolution, drug loading levels, impurity profiles, and animal efficiency tests. The scaffold is weighed and then loaded with the drug solution. All stents were spray-loaded to their target drug content from a solution containing the appropriate drug and PC1036 in ethanol (in a ratio of 91:9). For the paclitaxel: quetiamus combination, 7 μg/mm paclitaxel and 10 μg/mm quetiamus, 3.5 μg/mm paclitaxel and 5 μg/mm quetiamus, 1 μg/mm Pacific Scaffolds were prepared with paclitaxel and 10 μg/mm quetiamus, 7 μg/mm secluded paclitaxel, and 10 μg/mm sterolimus alone. Once loaded, all of the stents were dried in an open bottle at 40 ° C for 30 minutes in an open bottle and weighed to determine the drug load. The drug-loaded scaffold was then overcoated with 5 μg/mm PC1036 by spraying with a 10 mg/mL polymer in ethanol.

After the overcoating, the stent was cured in an oven at 70 ° C for 2 hours, and then weighed to determine the weight of the overcoat layer. After the drug is loaded, the stent is assembled onto the catheter and crimped onto the balloon. The coating and physical defects of the stent are then visually inspected. Insert the stent/catheter into a packing ring and place the stent/catheter in a Tyvek bag. The bag was sealed with a Vertrod (San Rafael, CA) instant heat sealer. Place the bracket identification mark in the bottom corner on the front side of the bag, outside the sealed area containing the product. The product is then placed in a white box that is in detail labeled with the product and shipped for EtO sterilization. After sterilization, the product is packaged in a foil pouch containing an oxygen scavenger and a desiccant capsule. Mark the bag with the bracket identification number and product details. The bag was packaged while flushing with nitrogen.

Self-supporting drug

For each drug, three scaffolds were used to assess the total amount of drug loaded. The stent was immersed in 6 mL of 50% acetonitrile, 50% aqueous solution and sonicated for 20 minutes. The concentration of each drug in the extraction solution was analyzed by high pressure liquid chromatography (HPLC).

At the end of the dissolution experiments discussed below, the scaffolds were removed from the dissolving medium and immersed in 6 mL of 50% acetonitrile, 50% aqueous solution and sonicated for 20 minutes. The concentration of each drug in these bottles indicates the amount of drug remaining on the stent at the end of the dissolution test.

Dissolution process

For evaluation of in vitro drug detachment, scaffolds (n=3 for each group) were deployed and then placed in 10 mM acetate buffer (pH=4.0) with 1% Solutol HS 15 (BASF; Florham Park, NY). The solution (heated to 37 ° C in a USP Type II dissolution apparatus). Solubilizers are needed because of the extremely low water solubility of the drugs. The buffered medium is used to minimize degradation of the "Moss" drug (which occurs at pH values above 6). Treatment with buffer at pH 4 solves this problem. Because these drugs have minimal dissociation in these pH ranges, pH has little effect on the dissolution rate. Samples were taken from the dissociation tank at selected time intervals using an injection sampler equipped with only Teflon, stainless steel or glass surfaces. Aliquots were collected after 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h. Samples were analyzed for the concentration of quetiamus and paclitaxel via HPLC. Data are expressed as the average percentage of dissolved drug and dissolved in micrograms.

In the HPLC method, column switching is required to minimize the Solutol contamination of the analytical column and allow for pre-washing of the catheter column, or the system is coated with Solutol and the chromatographic retention is significantly altered. The sample is first injected into the front catheter column. Once the analyte peak is eluted from the anterior catheter column and passed through the analytical column, the anterior catheter column is converted out of the analytical path. The pre-catheter column is then washed to remove Solutol prior to the next injection.

result

Figure 11-13 shows accelerated dissolution rates of the following quetiamus and paclitaxel-loaded stents: 7 μg/mm paclitaxel and 10 μg/mm quetiamus, 3.5 μg/mm paclitaxel, and 5 μg/mm Cytosine, 1 μg/mm paclitaxel and 10 μg/mm quetiamus, 7 μg/mm cisplatin alone and 10 μg/mm sterolimus alone (each drug loaded to 5 μg/mm as above) The support of the polymer PC1036 outer coating).

In Figure 11 , the 24 hour dissolution profile is shown as the case where the benefit agent is paclitaxel and the second benefit agent is external temasimus. The dissolution was carried out as described above. The paclitaxel single drug stent exhibited a combination of two release profiles, with the initial large burst (about 60%) followed by a slower, zero order release rate, while the dual drug stent containing paclitaxel and quetiamus did not have a burst release.

FIG 12 show the same information as the FIG. 11, it has been normalized by the total drug measured on the stent after the final extraction stent. As can be seen, 100% of the two drugs are recovered from the stent coating and the total drug recovered is very consistent with the drug load predicted by the stent weight uptake during the drug loading process. These data are accompanied by the drug efficacy of the same batch and the relevant substance test on the stent. The drug is stable in the polymer coating when manufactured as described above. The small standard deviation shows that a dual drug-dissolved scaffold can be fabricated under reproducible dissolution kinetics.

In Figure 13 , the four curves are the dissolution curves of the individual quetiamus and the quetiamus in the presence of paclitaxel under the same conditions (the drug released in micrograms versus time). As can be seen, the three curves belonging to the scaffold with 10 μg/mm alone or in combination with paclitaxel are very similar. This indicates that Pacific paclitaxel has almost no effect on the dissolution curve of quetiamus. The fourth curve (PTX 3.5 and quetiamus 5) gives the expected behavior to dissolve half of the drug (in fact, other scaffolds).

Example 11 Intravascular neointimal formation after stent implantation

A model study of porcine coronary over-extension (Schwartz, 1992) was performed to examine neovascular intima formation 28 days after stent implantation. The study evaluated a large randomized drug-eluting stent versus a temasis-loaded control (10 μg/mm; ZoMaxx ^{T M} ) scaffold. Unexpectedly, the combination of quetiamus and paclitaxel delivered on the scaffold is highly efficient, improving the reduction of neovascular intimal hyperplasia in the widely used porcine coronary over-extension model.

A model study of porcine coronary over-extension (Schwartz, 1992) was performed to examine neovascular intima formation 28 days after stent implantation. The study evaluated a large number of randomized drug-dissolved stents and control ZoMaxx ^{T M} stents.

Experimental structure and method

In each pig, two primary coronary arteries were implanted with one test stent, and a ZoMaxx ^{T M} stent coated with quetiamus (10 μg/mm or 1.69 μg/mm ² ) was implanted into the third major coronary artery. artery. In addition, three drug-free TriMaxx ^{T M} stents (Abbott Laboratories; Abbott Park, IL) were implanted into each of three pigs (9 stents in total) for comparison. The compared scaffolds included the ZoMaxx ^{T M} scaffold (3.0 x 15 mm), commercially available sirolimus (8.5 μg/mm or 1.40 μg/mm ² ) - polymer coated Cypher Stent (3.0 x 13 mm; Cordis Corp.; Miami, FL) and Pacific paclitaxel (6.8 μg/mm or 1.0 μg/mm ² )-polymer coated Taxus Bracket for the stent (3.0 x 16 mm; Boston Scientific; Natick, MA). The remaining set of brackets is 3.0 x 15 mm. The paclitaxel stent (PTX-7) loaded with PC-1036 was included in the study with the same drug load (eg Taxus, 7 μg/mm) but as a delivery tool. Further, as shown in Table 16, three sets of combined scaffolds were coated with varying amounts of quetiamus and paclitaxel loaded.

Finally, a drug-free solution of the TriMaxx scaffold was included to identify the baseline of neovascular intima formation.

The stent is implanted with a 1.30 balloon/artery ratio as determined by quantitative coronary angiography. There were no heart or stent-related mortality in the study. After 28 days, the animals were euthanized and the hearts were removed and perfused with a lactating Ringer solution at approximately 100 mm Hg until blood clearance, followed by fixation with 10% neutral buffered formalin. The stretched blood vessels are removed, followed by penetration and insertion of methyl methacrylate (MMA). All sections containing the expanded vessels were sectioned using three sections of the stent plus two control sections. Two consecutive thin sections (about 5 microns) were used to varying degrees and stained with hematoxylin and eosin (HE) and Masson's Verhoeff Elastin (MVE). The sections were evaluated and evaluated using the BIOQUANT ^{T M} TCW98 image analysis system. The mean values of neovascular intimal area, neovascular intima thickness, and stenotic area % of all stents in the eight groups are shown in Figures 14-16 .

Compared to the TriMaxx ^{T M} stent, as depicted by conventional morphometric measurements, ZoMaxx ^{T M} , Cypher And Taxus The stent statistically reduces the formation of neovascular intima. A combination stent containing 1 μg/mm paclitaxel and 10 μg/mm quetiamus (PTX/Zot 1/10) showed a significant reduction in neovascular intimal hyperplasia compared to TriMaxx ^{T M} . In addition, with ZoMaxx ^{T M} and Cypher And Taxus Compared to the stent, the PTX/Zot 1/10 combination stent also showed further improvement in neovascular intimal reduction. Table 17 summarizes the improvements achieved by the ZoMaxx ^{T M} and PTX/Zot 1/10 combination drug stents compared to the TriMaxx ^{T M.}

Compared with the TriMaxx ^{T M} control group, the current technology single drug stent ZoMaxx ^{T M} , Cypher And Taxus Each of them showed a significant reduction in neovascular intimal formation. For example, the average reduction in the neovascular intima of the ZoMaxx ^{T M} stent was 34.5% compared to the control group. The PTX/Zot 1/10 combination stent yielded further improvements in reducing neovascular intima formation as compared to the impressive results seen in the best single drug stents available in commercial and clinical trials. The PTX/Zot 1/10 combination drug-eluting stent reduced the neovascular intima formation by an average of 46.8% when compared to the TriMaxx ^{T M} drug-free stent. With ZoMaxx ^{T M} and Cypher And Taxus In contrast, the additional significant reductions in neovascular intimal formation were 18.8, 21.7, and 21.5%, respectively ( Table 18 ).

Based on previously published information (Falotico, 2003; Suzuki et al, 2001), it is concluded that the combination of the Moss drug and the second drug will not provide a benefit. Unexpectedly, the combination of paclitaxel and quetiamus is highly effective when delivered in a suitable combination, which improves the reduction of neovascular intimal hyperplasia in a widely used porcine coronary artery overextension model. Figures 17 and 18 demonstrate the significance of the results between quetiamus and paclitaxel (PTX/Zot 1/10) and the previously disclosed sirolimus and dexamethasone results (Falotico, 2003; Suzuki et al., 2001). difference. Previous experiments have shown no benefit between a combination stent and a single drug eluting stent. Even for the control TriMaxx ^{T M} and BX Velocity Compared to the significant improvement, the combined products were substantially better than the control group in the pig model with the same overextension ratio, and were substantially and statistically significantly better than the single drug lysing scaffold ZoMaxx ^{T M} .

Stents coated with 7 μg/mm paclitaxel and 10 μg/mm quetiamus (PTX/Zot 7/10) were statistically equivalent to the neovascular intima formation with the ZoMaxx scaffold (Figures 14-16). Therefore, the ideal weight ratio of the paclitaxel derivative to the Moss drug is between 7:10 and 0.1:10, with an optimum ratio equal to 1/10. Reduction of total drug dose to 3.5 μg/mm paclitaxel and 5 μg/mm quetiamus (PTX/Zot 3.5:5) resulted in non-optimal efficacy, equivalent to drug-free dissolving TriMaxx scaffolds ( Figures 14-16 ). Therefore, when the ratio of paclitaxel derivative to mojito is close to 7:10, the optimal total dose of paclitaxel derivative and mojito on the 15 mm stent should not be below about 150 μg.

Example 12 (Prophecy) Clinical Application

The introduction of stents that deliver a single anti-proliferative agent and subsequent widespread use have reduced the rate of restenosis in the general clinical population by at least 10%. However, there is a clear rationale for the delivery of appropriate drug combinations from the scaffold to treat patients in the general clinical population and to deliver from a large subset of cardiovascular diseases to further reduce restenosis rates and adverse clinical events. For example, it is widely accepted that in patients with diabetes mellitus with stents, the rate of restenosis is significantly increased compared with those without the disease, and the inflammatory response to stenting is present in diabetic and non-diabetic patients (Aggarwal et al. People, 2003). In addition, inflammation is associated with acute coronary syndrome (ACS, a term that defines a range of acute myocardial ischemic conditions, including unstable colic, non-ST-segment elevation myocardial infarction, and associated with persistent ST-segment elevation Characteristics of patients with infarction). These patients are often the primary candidates for stent deployment and have significantly higher rates of cyclic ischemia, reinfarction, and subsequent need for repeated PCI procedures relative to the general patient population undergoing percutaneous intervention (PCI). Ultimately, obesity is often associated with pre-inflammatory conditions and endothelial dysfunction. Two conditions are known to be independent predictors of early restenosis after coronary stent placement. In fact, there has been a link between obesity (adipocyte-derived interleukin-6 (IL-6)) and coronary artery disease, indicating an increase in this inflammatory cytokine and CAD development in the patient's subset. Contact (Yudkin et al., 2000).

Diabetic patients are known to exhibit higher levels of inflammatory marker c-reactive protein (CRP) than non-diabetic patients (Aggarwal et al, 2003; Dandona and Aljada, 2002). This protein has been clearly identified as an important inflammatory mediator in patients with coronary artery disease and is a predictor of adverse events in patients with severe unstable colic (Biondi-Zoccai et al, 2003). CRP is known to stimulate human endothelial cells to produce monocyte chemotactic protein (MCP-1). The release of this mediator is achieved by the injection of monocytes, resulting in a marked inflammatory state, as these cells are intensified and migrate into the endothelial space where they form oxidized low density lipoprotein (LDL). ) foam cells. Plasma IL-6 and tumor necrosis factor-α (TNF-α) are inflammatory cytokines, which are also elevated in obese patients and type 2 diabetic patients. In fact, elevated levels of highly sensitive CRP, IL-6 or serum vascular cell adhesion molecule-1 (VCAM-1) have been associated with increased mortality in patients with coronary artery disease (Roffi and Topol, 2004). Since neovascular intimal formation (characterized by the restenosis process) has been shown to be exacerbated by inflammation, it is desirable to use a combination of an anti-inflammatory drug and an anti-proliferative active agent (such as paclitaxel and quetiamus) to the local vascular environment. Clearly useful in people with diabetes.

The rupture of atherosclerotic plaque is important for the onset of acute coronary syndrome (Grech and Ramsdale, 2003). Plaque rupture can be induced by increasing the concentration of matrix metalloproteinases secreted by the foam cells, which results in plaque instability and ultimate rupture of the thin fiber cap covering the developmental lesion. In addition, tissue factor activation on the surface of foam cells results in thrombin-forming factor VII. The production of this protein leads to platelet activation and agglutination, as well as the clear formation of fibrinogen into blood fibers and thrombus. The initial concern about the deployment of stents with this configuration does not seem to be found. This is because stent deployment and technical improvements have shown that patients with stents have less ischemic, reinfarction and recurrent angioplasty. Need (Grech and Ramsdale, 2003). The intimate relationship between inflammation and the development of coronary artery injury makes the use of a combination of agents that deliver anti-inflammatory and anti-proliferative activities, such as paclitaxel and quetiamus, to the local vascular environment an attractive treatment for such patients. method.

Deploying the subgroups in patients with ischemic heart disease diagnosed with stenotic lesions in the coronary arteries and in a subset of clinical populations at higher risk of circulating coronary artery disease and other adverse clinical events support. Other targets for intervention include peripheral vascular disease such as stenosis in the superficial femoral artery, renal artery, ileum, and sub-knee blood vessels. The percutaneous vascular access is used via the femoral or iliac artery to reach the target vessel of the interventional procedure and the introducer cannula is inserted into the vessel. The guidewire is then passed over the target lesion and the balloon catheter is inserted either online or using a rapid exchange system. The surgeon determines the appropriate size of the stent to be implanted by on-line coronary angiography (QCA) or by visual estimation. The stent is deployed using appropriate pressure as indicated by the compliance of the stent, and a post-procedural vascular photograph is then available. When the procedure is completed, the patient is regularly monitored for the presence of a colic condition and any adverse events. The need for repeat procedures is also assessed.

It is to be understood that the foregoing detailed description and the accompanying claims Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention, including, but not limited to, chemical structures, substituents, derivatives, intermediates, synthetic methods, formulations, and/or methods of using the invention. They have changed and corrected.

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Figure 1 shows the blood concentration ± SEM (n = 3) of a tetrazolium-containing rapamycin analogue taken in monkeys.

2 is a side elevational view showing a stent suitable for use in the present invention.

Figure 3A is a cross-sectional view of a vascular slice in which a polymer coated stent is placed.

Figure 3B is a cross-sectional view of a blood vessel segment in which a polymeric drug coated stent is placed.

Figure 4 shows a linear blood concentration-time curve for a single elevated intravenous dose of quetiamus in humans.

Figure 5 shows the mean blood concentration-time curve in logarithmic linear scale as the intravenous dose of quetiamus is monotonically elevated in the human body.

Figure 6 shows that the quetiamus C _{m a x} and AUC parameters are proportional to the dose as the intravenous dose in the human body increases monotonically.

Figure 7 shows the mean blood concentration-time curve of quetiamus along with multiple intravenous doses in the human body.

Figure 8 shows the average quetiamus blood in the 200, 400 and 800 μg QD (daily) dose groups on Day 1 ( Figure 8a ), Day 14 ( Figure 8b ), and Days 1-14 ( Figure 8c ). Concentration-time curve.

Figure 9 shows quetiamus concentration-time data observed on days 1 to 14 for the 800 μg QD dose group.

Figure 10 shows the anti-proliferative activity of tacrolimus blocking quetiamus in vitro smooth muscle cells (Fig. 10A). The anti-proliferative activity of quetiamus, paclitaxel (P) and combinations in vitro smooth muscle cells (Fig. 10B) and endothelial cells (Fig. 10C) was also shown. Proliferation was determined by measuring the mean ± SEM of 3 experiments, unless otherwise mentioned. Figures 10D-G show equivalent dose analysis combining anti-proliferative activity in smooth muscle cells. The concentration at which a particular degree of anti-proliferative activity is produced is determined by a dose response curve generated by a non-linear curve consistent with the mean of the data. Figure 10H-K shows an equivalent dose analysis of anti-proliferative activity in endothelial cells in combination with quetiamus and paclitaxel. The average data is used to determine the concentration of the compound that produces a particular degree of activity. Figure 10L-M shows the combination index (CI) analysis of the anti-proliferative activity of ABT-578 in combination with paclitaxel in hCaSMC and hCaEC. The degree of CI was determined from the average data using Chou and Talalay (Chou and Talalay, 1984) methods.

Figure 11 shows that paclitaxel alone (7 μg/mm), paclitaxel (7 μg/mm) and quetiamus (10 μg/mm), paclitaxel (3.5 μg/mm) and quetiamus (5 Release of paclitaxel in μg/mm) or paclitaxel (1 μg/mm) and quetiamus (10 μg/mm) loaded scaffold.

Figure 12 shows self-use of paclitaxel alone (7 μg/mm), paclitaxel (7 μg/mm) and quetiamus (10 μg/mm), paclitaxel (3.5 μg/mm) and quetiamus (5 μg) /mm) or paclitaxel release percentage of paclitaxel (1 μg/mm) and quetiamus (10 μg/mm)-loaded stents.

Figure 13 shows the use of celeptolimus alone (10 μg/mm), paclitaxel (7 μg/mm) and quetiamus (10 μg/mm), paclitaxel (3.5 μg/mm) and quetiamus ( Cytosolic release of 5 μg/mm) or paclitaxel (1 μg/mm) and quetiamus (10 μg/mm) loaded scaffolds.

Figure 14 shows neovascular intimal area (30% overextension) after implantation of drug-dissolved (single and multiple) stents and drug-free stents in porcine vessels for 28 days; the number in the box shows the number of stents per group.

Figure 15 shows neovascular intimal area (30% overextension) after implantation of drug-dissolved (single and multiple) stents and drug-free stents in porcine blood vessels for 28 days; the number in the box shows the number of stents per group.

Figure 16 shows the percentage of stenotic area (30% overextension) after implantation of drug-dissolved (single and multiple) stents and drug-free stents in porcine blood vessels for 28 days; the number in the box shows the number of stents per group.

Claims (72)

A drug delivery system comprising a support structure comprising a pharmaceutically acceptable carrier or excipient; a plurality of therapeutic agents associated with the support structure comprising a taxane or a salt thereof and a second treatment a drug or a salt thereof; and wherein when compared to a control system, neovascular intimal hyperplasia is reduced when the system is implanted into the lumen of the subject, wherein the second therapeutic agent is rapamycin ( rapamycin) or Mok universe Division (of zotarolimus); wherein the taxane: medicament ratio r of the second weight ratio of 7:10 r 0.01:10. The system of claim 1, wherein the subject is a pig. The system of claim 1, wherein the subject is a human. The system of claim 1, wherein the taxane is paclitaxel, and the paclitaxel and the second drug are present in a ratio r of a paclitaxel:second drug that exerts an additional effect. The system of claim 4, wherein the paclitaxel: second drug ratio r is 7:10 by weight ratio r 0.1:10. The system of claim 5, wherein r = 1:10. The system of claim 1, wherein the taxane and the second drug are present in a ratio r of a taxane:second drug that exerts an additional effect. The system of claim 1, wherein r = 1:10. The system of claim 1 further comprising a third therapeutic agent. The system of claim 9, wherein the third drug is a rapamycin analogue or a prodrug or salt thereof; the restriction is that the rapamycin analogue is not zotarolimus. The system of claim 1, wherein the drug delivery system comprises a medical device. The system of claim 1, wherein the drug delivery system comprises a stent. The system of claim 9, wherein the third therapeutic agent is selected from the group consisting of an anti-proliferative agent, an anti-platelet agent, an anti-inflammatory agent, an anti-lipemic agent, an antithrombotic agent, a thrombolytic agent, and the like. Salts, prodrugs and derivatives or any combination thereof. The system of claim 9, wherein the third therapeutic agent is a saccharide steroid comprising a group consisting of: methylprednisolone, prednisolone, prednisone, triamcinolone (triamcinolone), dexamethasone, mometasone, beclomethasone, ciclesonide, bedesonide, triamcinolone, Clobetasol, flunisolide, loteprednol, budesonide, fluticasone, salts, prodrugs and derivatives thereof or any combination. The system of claim 9, wherein the third therapeutic agent is a steroid hormone comprising estradiol and salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 9, wherein the third therapeutic drug is one of a small molecule and a biological composition group capable of reducing inflammatory cytokine activity member. The system of claim 9, wherein the third drug comprises an anti-cytokine therapeutic agent selected from the group consisting of anti-TNFα therapeutic agents, adalimumab, anti-MCP-1 therapeutic agents, and CCR2 receptors. a body antagonist, an anti-IL-18 therapeutic, an anti-IL-1 therapeutic, a salt, a prodrug and a derivative thereof, or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises an anti-proliferative agent selected from the group consisting of alkylating agents, including cyclophosphamide, chlorambucil, and busulfan (busulfan), carmustine and lomustine; antimetabolites including methotrexate, fluorouracil, cytarabine, thioglycol and pentostatin; Alkaloids, including vinblastine and vincristine; antibiotics, including doxorubicin, bleomycin, and mitomycin; anti-proliferative agents, including cisplatin, procarbazine ), etoposide and teniposide; salts, prodrugs and derivatives or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises an antiplatelet agent selected from the group consisting of glycoprotein IIB/IIIA inhibitors, including abciximab, eptifibatide (abciximab) Eptifibatide) and tirofiban; adenosine reuptake inhibitors, including dipyridamole; ADP inhibitors, including clopidogrel and ticlopidine; Enzyme inhibitors, including acetyl sulphate; and phosphodiesterase inhibitors, including Cilotazol; such salts, prodrugs and derivatives or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises an anti-inflammatory drug selected from the group consisting of steroids, including dexamethasone, hydrocortisone, fluticasone, clobetasol, moMole Hesone and estradiol; and non-steroidal anti-inflammatory drugs, including acetaminophen, ibuprofen, naproxen, sulindac, piroxicam, mefenamic acid (mefenamic acid); an anti-inflammatory drug that inhibits cytokine or chemokine-binding receptors to inhibit pre-inflammatory signals, including antibodies to IL-1, IL-2, IL-8, IL-15, IL-18, and TNF; Salts, prodrugs and derivatives or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises an anti-thrombotic agent selected from the group consisting of heparin, including unsegmented heparin and low molecular weight heparin, including clivarin, Dalteparin, enoxaparin, nadroparin, and tinzaparin; direct thrombin inhibitors, including argatroban, hirudin, and blackrule , herugen; such salts, prodrugs and derivatives or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises an anti-lipemic agent selected from the group consisting of nicotinic acid, probucol, HMG CoA reductase inhibitors (including mevastatin, Lovastatin, simvastatin, pravastatin, fluvastatin, including fenofibrate (fenofibrate), clofibrate, a fibric acid derivative of gemfibrozil, salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 9, wherein the third therapeutic agent comprises a thrombolytic agent selected from the group consisting of: streptokinase, urokinase, prourokinase, including alteplase, reteplase (Reteplase), tissue plasminogen activator of tenectalpase, salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 9, wherein the third therapeutic substance comprises an antibody. A system for providing controlled release delivery of a medicament for treating or inhibiting neovascular intimal hyperplasia in a vascular lumen, comprising: a plurality of therapeutic agents comprising a taxane or a salt thereof and a second drug or a salt thereof; And wherein the taxane can supplement the activity of the second drug, and the second drug can supplement the activity of the taxane, wherein the second drug is rapamycin or quetiamus; wherein the taxane: r = the ratio of the drug weight ratio is 7:10 r 0.01:10. The system of claim 25, further comprising a third drug, wherein the taxane or the second drug complements the activity of the third drug; and the third drug can supplement the taxane or the second drug Activity. The system of claim 25, further comprising a third drug, wherein the taxane comprises paclitaxel, and paclitaxel or the second drug complements the activity of the third drug; and the third drug is replenishable The activity of paclitaxel or the second drug. The system of claim 25, wherein the therapeutic agent is associated with a medical device. The system of claim 28, wherein the medical device comprises a stent. The system of claim 29, wherein the stent further comprises a coating on the surface. The system of claim 30, wherein the coating comprises a polymer. The system of claim 31, wherein the polymer comprises a phosphonium choline polymer. The system of claim 31, wherein the polymer is selected from the group consisting of fluoropolymers, poly(acrylates), polyoxyxides, resins, nylons, and poly(decylamines). The system of claim 25, wherein the therapeutic agent is associated with the coating. The system of claim 25, wherein the taxane is paclitaxel and the paclitaxel and the second drug are present in a ratio r that provides an additional effect. The system of claim 35, wherein the paclitaxel: second drug ratio r is 7:10 by weight r 0.1:10. The system of claim 36, wherein r = 1:10. The system of claim 25, wherein the drug delivery system comprises a medical device. The system of claim 25, wherein the drug delivery system comprises a stent. The system of claim 25, further comprising a third therapeutic agent. The system of claim 40, wherein the third drug is a rapamycin analogue Or a prodrug or salt thereof; the restriction is that the rapamycin analogue is not quetiamus. The system of claim 40, wherein the third therapeutic substance is selected from the group consisting of an anti-proliferative agent, an anti-platelet agent, an anti-inflammatory agent, an anti-lipemic agent, an antithrombotic agent, a thrombolytic agent, and the like. Salts, prodrugs and derivatives or any combination thereof. The system of claim 42, wherein the anti-inflammatory agent is one selected from the group consisting of: dexamethasone, hydrocortisone, estradiol, acetaminophen, ibuprofen, naproxen, Fluticasone, clobetasol, adalimumab, sulindac, salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 40, wherein the third drug is a saccharide steroid comprising a group consisting of methylprednisolone, prednisolone, prednisone, triamcinolone, dexamethasone, and mometasone. Beclomethasone, ciclesonide, bettydine, triamcinolone, clobetasol, flunisolide, loteprednol, budesonide, fluticasone, salts, prodrugs and derivatives Or any combination thereof. The system of claim 40, wherein the third drug is a steroid hormone comprising estradiol and the salts, prodrugs and derivatives or any combination thereof. The system of claim 40, wherein the third agent is a member of a group of small molecules and biological agents that reduce inflammatory cytokine activity. The system of claim 40, wherein the third drug comprises an anti-cytokine therapeutic agent selected from the group consisting of anti-TNFα therapeutic agents, adalimumab, anti-MCP-1 therapeutic agents, CCR2 receptor antagonists , anti-IL-18 A therapeutic agent, an anti-IL-1 therapeutic, a salt, a prodrug and a derivative thereof, or any combination thereof. The system of claim 40, wherein the third therapeutic substance comprises an antibody. A pharmaceutical composition comprising a taxane or a salt thereof and a second drug or a salt thereof, wherein the ratio r of the taxane: second drug is 7:10 by weight r 0.01:10; wherein the second drug is rapamycin or quetiamus; wherein if the composition is administered to a subject in a blood vessel on a medical device, when compared to a control system The neovascular intimal hyperplasia is reduced when the system is implanted into the lumen of the subject; and wherein the composition is formulated for local delivery to the subject. The composition of claim 49, wherein r = 1:10. The composition of claim 49, wherein the taxane is paclitaxel. The composition of claim 49, wherein the composition is associated with the medical device. The composition of claim 52, wherein the medical device comprises a stent. The composition of claim 52, wherein the stent comprises a coating on the surface, and wherein the composition is associated with the coating. The composition of claim 49, wherein the subject is a human. A pharmaceutical composition comprising a taxane or a salt thereof and a second drug or a salt thereof, wherein the ratio r of the taxane: second drug is 7:10 by weight r 0.01:10; wherein the second drug is rapamycin or quetiamus; wherein the composition is administered to the subject in a blood vessel on a medical device, wherein when compared to a control system, The neovascular intimal hyperplasia is reduced when the system is implanted into the lumen of the subject's blood vessels; and wherein the composition is administered intra-arterially. The composition of claim 56, wherein the taxane is paclitaxel, wherein when administered topically, the effect of the paclitaxel supplements the activity of the second drug, and the second drug supplements the activity of paclitaxel. The composition of claim 56, wherein r = 1:10. The system of claim 56, further comprising a third therapeutic drug or substance. The system of claim 59, wherein the third therapeutic agent is selected from the group consisting of an anti-proliferative agent, an anti-platelet agent, an anti-inflammatory agent, an anti-lipemic agent, an antithrombotic agent, a thrombolytic agent, and the like. Salts, prodrugs and derivatives or any combination thereof. The system of claim 59, wherein the third therapeutic agent is a saccharide steroid comprising a group consisting of methylprednisolone, prednisolone, prednisone, triamcinolone, dexamethasone, and mometasone , beclomethasone, ciclesonide, bettydine, triamcinolone, clobetasol, flunisolide, loteprednol, budesonide, fluticasone, salts, prodrugs and derivatives Or any combination thereof. The system of claim 59, wherein the third therapeutic agent is a steroid hormone comprising estradiol and salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 59, wherein the third therapeutic agent is capable of reducing inflammation A member of the group consisting of small molecules of cytokine activity and biological agents. The system of claim 59, wherein the third drug comprises an anti-cytokine therapeutic agent selected from the group consisting of anti-TNFα therapeutic agents, adalimumab, anti-MCP-1 therapeutic agents, CCR2 receptor antagonists An anti-IL-18 therapeutic, an anti-IL-1 therapeutic, a salt, a prodrug and a derivative thereof, or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises an anti-proliferative agent selected from the group consisting of alkylating agents, including cyclophosphamide, chlorambucil, busulfan, and cardio Mustard and lomustine; antimetabolites, including methotrexate, fluorouracil, cytarabine, thioglycol and pentastatin; vinca alkaloids, including vinblastine and vincristine; antibiotics, including doxorubicin, Bleomycin and mitomycin; anti-proliferative agents, including cisplatin, procarbazine, etoposide, and teniposide; such salts, prodrugs, and derivatives, or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises an antiplatelet agent selected from the group consisting of glycoprotein IIB/IIIA inhibitors, including abciximab, eptifibatide, and tirofi Class; adenosine reuptake inhibitors, including dipyridamole; ADP inhibitors, including clopidogrel and ticlopidine; cyclooxygenase inhibitors, including acetyl sulphate; and phosphodiesterase inhibitors , including cilostazol; such salts, prodrugs and derivatives, or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises an anti-inflammatory agent selected from the group consisting of steroids, including dexamethasone, hydrocortisone, fluticasone, clobetasol, and mometasone. Estradiol And non-steroidal anti-inflammatory drugs, including acetaminophen, ibuprofen, naproxen, sulindac, piroxicam, mefenamic acid; inhibiting cytokines or chemokine-binding receptors to inhibit pre-inflammatory signals Anti-inflammatory drugs, including antibodies to IL-1, IL-2, IL-8, IL-15, IL-18, and TNF; such salts, prodrugs, and derivatives, or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises an anti-thrombotic agent selected from the group consisting of heparin, including unsegmented heparin and low molecular weight heparin, including clefparin, dalteparin, Enoxaparin, nadroparin and tinzaparin; direct thrombin inhibitors, including argatroban, hirudin, black lulu, black root; salts, prodrugs and derivatives or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises an anti-lipemic agent selected from the group consisting of niacin, probucol, including mevastatin, lovastatin, simvastatin, pravud Statins, HMG CoA reductase inhibitors of fluvastatin, fibric acid derivatives including fenofibine, clofibrate, gemfibrozil, salts, prodrugs and derivatives thereof, or any combination thereof. The system of claim 59, wherein the third therapeutic agent comprises a thrombolytic agent selected from the group consisting of: streptokinase, urokinase, prourokinase, including alteplase, reteplase, and nepna Tissue plasminogen activator, salts, prodrugs and derivatives thereof, or any combination thereof. A kit comprising a system as claimed in claim 1 or 25. A kit comprising a composition as claimed in claim 49 or 56.