Software Technology for “Medical devices that contain rapamycin analogs.”

Medical Device – Karl W. Mollison, Angela M. LeCaptain, Sandra E. Burke, Keith R. Cromack, Peter J. Tarcha, Yen-Chih J. Chen, John L. Toner, Abbott Laboratories

Abstract for “Medical devices that contain rapamycin analogs.”

A medical device is a support structure that can contain or support a pharmaceutically acceptable carrier/excipient. The carrier may include a coating and the therapeutic substance containing the coating, such as drugs. The medical devices supporting this invention are, among others, coronary stents and peripheral stents. They also include catheters, arteriovenous grafts and by-pass grafts. Drug delivery balloons are used in the vasculature. This invention allows for the use of drugs that include Formula (I). Formula (I) drugs can be combined with other drugs including anti-proliferative, antiplatelet, antiinflammatory, antithrombotic, cytotoxic, agents that inhibit cytokine binding, cell dedifferentiation inhibitors and anti-lipaemic agents, matrix metaloproteinase inhibitors or cytostatic drugs.

Background for “Medical devices that contain rapamycin analogs.”

“The widely-used compound cyclosporine (cyclosporinA) has seen a lot of use in the fields organ transplantation and immunomodulation. It has also led to a significant improvement in the success rate of transplantation procedures. Recently, several macrocyclic compounds with potent immunomodulatory properties were discovered. Okuhara et al., in European Patent Application No. Published Jun. 11 June 1986. A number of macrocyclic compounds were isolated from Streptomyces genus. These include the immunosuppressant FK-506, an immunosuppressant macrocyclic lactone with 23 members, and which was isolated from a S. tsukubaensis.”

“Other natural products, such FR900523 and FR900523, differ from FK-506 by their alkyl substituent C-21, were isolated from S. hygroscopicus yakushimnaensis. S. tsukubaensis also produced FR-900525, which differs from FK-506 by replacing a pipecolic acid moiety of the compound with a proline group. Side-effects such as nephrotoxicity and cyclosporine have been a source of concern. There is a continuing search for immunosuppressants that are more effective and safer, including an immunosupressant which is both topically and systemically ineffective (U.S. Pat. No. 5,457,111).”

“Rapamycin, a macrocyclic triene-antifungal antibiotic, is produced by Streptomyces Hygroscopicus. It was found to be particularly effective against Candida albicans in vitro as well as in vivo (C. Vezina and others, J. Antibiot. 1975, 28, 721; S. N. Sehgal et al., J. Antibiot. 1975, 28, 727; H. A. Baker et al., J. Antibiot. 1978, 31, 539; U.S. Pat. No. No. No. 3,993,749).”

“”

“Rapamycin (U.S. Patent. No. No. No. No. 4,401,653 has been proven to have antitumor activities. Rapamycin, which was discovered to have antitumor activity in 1977 in two models of experimental allergic encephalomyelitis, multiple sclerosis, and adjuvant arthritis, was also effective in suppressing the production IgE-like antibody formation (R. Martel, Can. J. Physiol. Pharmacol., 1977, 55, 48).”

“The immunosuppressive effect of rapamycin has also been revealed in FASEB 1989, 3, 3411 and its ability to prolong the survival time organ grafts of histoincompatible rodents (R. Morris Med. Sci. Res., 1989, 17, 877). M. Strauch, FASEB 1989, 3, 3411, revealed the ability of rapamycin inhibit T-cell activation. These and other biological effects are discussed in Transplantation Reviews 1992, 6, 39-87.

Rapamycin has been shown in animal models to decrease neointimal proliferation and in humans to lower the rate of restenosis. There is evidence that rapamycin has an anti-inflammatory effect. This characteristic supports its use as an agent to treat rheumatoidarthritis. Rapamycin and its analogs have been suggested to prevent restenosis, as both inflammation and cell proliferation are believed to be the main causes of the formation restenotic lesions following balloon angioplasty or stent placement.

“Mono-ester, di-ester derivatives and rapamycin (esterification at position 31 and 42) have been proven to be effective as antifungal agents (U.S. Patent. No. No. No. 4,650,803).”

“Fermentation, purification and 30-demethoxyrapamycin were described in the literature” (C. Vezina and al. J. Antibiot. (Tokyo), 1975, 28 (10), 721; S. N. Sehgal et al., J. Antibiot. (Tokyo), 1975, 28(10), 727; 1983, 36(4), 351; N. L. Pavia et al., J. Natural Products, 1991. 54(1), 167-177).

Numerous chemical modifications have been made to rapamycin. These include the preparation mono- and di-ester derivatives (WO 92/05179), 27 oximes (EPO 467606), 42-oxo analogs (U.S. Patent. No. 5,023,262); bicyclic Rapamycins (U.S. Patent. No. 5,120,725); rapamycin dimers (U.S. Pat. No. No. No. No. No. 5,177,203). Rapamycin was synthesized recently in its naturally occurring enantiomeric form (K. C. Nicolaou et. al., J. Am. Chem. Soc., 1993, 115, 4419-4420; S. L. Schreiber, J. Am. Chem. Soc., 1993, 115, 7906-7907; S. J. Danishefsky, J. Am. Chem. Soc., 1993, 115, 9345-9346.”

It is known that FKBP-12 can be bound to rapamycin (Siekierka J. J. Immunol., 1990, 144, 1418-1424; Bierer, B. E.; Schreiber, S. L.; Burakoff, S. J., Eur. J. Immunol., 1991, 21, 439-445; Fretz, H.; Albers, M. W.; Galat, A.; Standaert, R. F.; Lane, W. S.; Burakoff, S. J.; Bierer, B. E.; Schreiber, S. L., J. Am. Chem. Soc., 1991, 113, 1409-1411). Recent research has shown that the FKBP-12/rapamycin complex binds to another protein. This protein is different from calcineurin (Brown E. J.; Albers M. W. and Shin, T. B., Ichikawa K.; Keith C. T., Lane W. S. S.; Schreiber S. L. Nature 1994, 369/756; Sabatini D. M., Erdjument-Bromage H.; Lui P.

Andreas Gruntzig developed “Percutaneous transluminal Coronay Angioplasty (PTCA).” This procedure was first performed in 1970. Sep. 24, 1975 was the first time a canine had their coronary dilated. The American Heart Association presented studies demonstrating the effectiveness of PTCA at its annual meetings the next year. The first human patient was soon studied in Zurich in Switzerland. This was followed by the first American patients in San Francisco, and New York. Although this procedure was a significant change in interventional cardiology for patients suffering from obstructive or severe coronary artery disease, it did not offer long-term relief. The procedure provided temporary relief from the chest pain that is associated with vascular obstruction. Repeat procedures were frequently necessary. The new procedure was not able to be used because of the presence of restenotic lesion. Stents were developed in the 1980’s to preserve vessel integrity after angioplasty. Stenting is used in over 90% of all angioplasty procedures today. Prior to the advent of stents the incidence of restenosis was between 30% and 50% in patients who had balloon angioplasty. In-stent restenosis can result in a 70% recurrence rate for some patients. However, the angiographic restenosis rate is only 20% in de novo stents. The restenosis rate was reduced to 15% to 20% by the placement of the stent. This is the highest percentage possible with mechanical stenting. Restenosis is caused by neointimal Hyperplasia. This is distinct from atherosclerotic diseases in both time-course and histopathological appearance. Restenosis refers to the healing of damaged coronary arteries walls. Neointimal tissue can impinge significantly on the vessel lumen. Vascular brachytherapy seems to be effective against in-stent restenosis lesions. Radiation has its limitations in practicality and cost, as well as lingering concerns about safety and longevity.

Accordingly, it is hoped to decrease the rate of restenosis by at minimum 50% from its current level. The interventional device community is making a lot of effort to develop and evaluate drug-eluting devices. If they are successful, such devices would have many benefits, primarily because they would not require any auxiliary therapies (e.g., chronic oral pharmacotherapy or peri-procedural techniques) to function.

“In one aspect the present invention are disclosed compound represented by the structural formula:

“”

“Or a pharmaceutically acceptable prodrug or salt thereof.”

“Another object is the invention to provide synthetic methods for the preparation such compounds from starting material obtained by fermentation, and chemical intermediates that are useful in such synthetic processes.”

“Another object of the invention” is to provide pharmaceutical compositions that contain at least one of these compounds as active ingredients.

“Yet another object is the invention to provide a method for treating a variety disease states, including restenosis, post-transplant tissue reject, immune and autonomic dysfunction, fungal growth and cancer.”

“Another aspect of the invention is a medical device that includes a support structure with a coating on its surface, the coating comprising a therapeutic substance such as a drug. The medical devices supporting this invention are, among others, coronary stents and peripheral stents. They also include catheters, arteriovenous grafts and by-pass grafts. Drug delivery balloons are used in the vasculature. This invention is suitable for the use of drugs such as, but not limited to:

“”

“Or a pharmaceutically acceptable prodrug or salt thereof”

“”

“Or a pharmaceutically acceptable prodrug or salt thereof (hereinafter referred to as A-179578 or ABT-578).

“”

“Or a pharmaceutically acceptable prodrug or salt thereof;”

“”

“or a pharmaceutically acceptable salt or prodrug thereof (hereinafter alternatively referred to as SDZ RAD or 40-O-(2-hydroxyethyl)-rapamycin);”

“”

“Or a pharmaceutically acceptable prodrug or salt thereof (hereinafter referred to as A-94507).”

The polymeric coatings are suitable for this invention, and can include, but not limit to, any polymeric material that has the therapeutic agent, i.e. the drug, substantially soluble. The coating can be non-biodegradable, hydrophilic, biodegradable or hydrophobic. This medical device decreases restenosis in the vasculature. Direct coronary delivery of A-179578, a drug that reduces restenosis, is expected to lower the rate to around 0% to 25%.

“Definition and Definition of Terms”

“Prodrug” is a generic term for compounds that are rapidly transformed in vivo to the parent compound of the above formula. “Prodrug” is a term that refers to compounds that are quickly transformed in vivo to their parent compound, such as by hydrolysis in blood. T. Higuchi, V. Stella and others provide a detailed discussion in?Prodrugs As Novel Delivery Systems,? Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche (ed. ),?Bioreversible Carriers in Drug Design. American Pharmaceutical Association, Pergamon Press 1987. Both of these are incorporated by reference in this document.

“Pharmaceutically acceptable prodrugs” is a term that refers to prodrugs of the compound of the present invention that are suitable for contact with human and lower mammal tissues without irritation, undue toxicity, or allergic reaction. They are also effective for their intended uses, as well the zwitterionic versions, where applicable, of the compound of the invention. Prodrug esters from the C-31 group of compounds are particularly preferred as pharmaceutically acceptable prodrugs.

“Prodrug esters” is a term that refers to any of several ester-forming groups. “Prodrug esters” is a term that refers to any one of several ester-forming group that can be hydrolyzed under physiological conditions. Prodrug ester group examples include acetyl and ethanoyls, pivaloyloxymethyls, acetoxymethyls, phthalidyls, methoxymethyls, indanyls, and others derived from the addition of naturally occurring or unnaturally occurring amino acid to the C-31hydroxyl group of compounds.

“The term “supporting structure” is used to describe a framework that can support a carrier or excipient. A framework capable of supporting or containing a pharmaceutically acceptable carrier/excipient. This carrier/excipient could contain one or several therapeutic agents, substances, or compounds. The support structure is usually made of metal or a multi-layered material. Support structures made of polymeric materials (including biodegradable Polymers) that can contain the therapeutic agents and substances are suitable. Nos. Nos. 6,413,272 & 5,527,337 are incorporated herein as references.”

“EMBODIMENTS”

“In one embodiment, the invention is a combination of formulas”

“”

“In an alternative embodiment of the invention, is a compound or formula.”

“”

“Preparation and use of compounds of this invention”

“The present invention’s compounds and processes will be easier to understand when they are compared with the following synthetic schemes that illustrate how the compounds can be prepared.”

“The compounds of the invention can be prepared using a variety synthetic routes.” Schema 1 shows a representative procedure.

“”

“As shown in Scheme 1, conversion of the C-42 hydroxyl of rapamycin to a trifluoromethanesulfonate or fluorosulfonate leaving group provided compound A. Displacement of the leaving group with tetrazole in the presence of a hindered, non-nucleophilic base, such as 2,6-lutidine, or, preferably, diisopropylethyl amine provided isomers B and C, which were separated and purified by flash column chromatography.”

“Synthetic Methods”

The following examples will help you understand the process of making the compounds of the invention. They are not meant to limit the scope and meaning of the invention as described in the appended claims.

“Example 1”

“42-Epi-(tetrazolyl)-rapamycin (Less Polar Isomer)”

“Example 1A”

“Example 1B”

“42-Epi-(tetrazolyl)-rapamycin (Less Polar Isomer)”

“A solution of the triflate compound from Example 1A in isopropyl acetate (0.3 mL) was treated sequentially with diisopropylethylamine (87 uL, 0.5 mmol) and 1H-tetrazole (35 mg, 0.5 mmol), and thereafter stirred for 18 hours. The mixture was divided between water (10mL) and alcohol (10mL). The organics were rinsed with brine (10mL), dried (Na2SO4) and then washed again. The organics were concentrated to form a sticky yellow liquid. This was then purified using chromatography on silica gel (3.5-2 g, 70-230 mesh), ether (30mL), hexane/ether (4:1 (10mL), 3:1 (10mL), 2:1 (10mL), 1:1 (10mL), 1:1 (10mL), ether (30mL), and hexane/acetone (1:1 (30mL). One of the isomers was found in the ether fractions. MS (ESI). m/e 966. M )?.”

“Example 2”

“42-Epi-(tetrazolyl)-rapamycin (More Polar Isomer)”

“Collection of the slower-moving band from the Chromatography column using the Hexane:acetone (1 to1) mobile phase in Example1B provided the designated compound. MS (ESI m/e966 (M )?.”).

“In Vitro Assay for Biological Activity”

“The immunosuppressant activity of the compounds of the present invention was compared to rapamycin and two rapamycin analogs: 40-epi-N-[2?-pyridone]-rapamycin and 40-epi-N-[4?-pyridone]-rapamycin, both disclosed in U.S. Pat. No. 5,527,907. Kino, T. et. al. determined the activity using the human mixed lymphocyte response (MLR). Transplantation Proceedings,XIX(5): 36-39. Suppl. 6 (1987). As shown in Table 1, the results of the assay show that the compounds of invention work as immunomodulators at nanomolar levels.

“The pharmacokinetic behavior of the Example 1 and Example 2 compound were studied following an intravenous 2.5 mg/kg dose to cynomolgus monkeys (n=3). Each compound was prepared in 2.5 mg/mL solutions in 20% ethanol:30%propylene glycol and2% cremophor E:48% dextrose,5% in water vehicle.

The intravenous 1 mL/kg dose was administered in a slow bolus (about 2 minutes) through a saphenous vein. Before dosing, blood samples were taken from the femoral veins or arteries of each animal. Blood samples were also obtained from 0.25 (IV only), 0.25 and 0.5, 1, 1,5, 2, 4, 6, 9, 12, 24 and 30 hours later. For analysis, the EDTA preserved samples were mixed thoroughly and extracted.

Sciex MacQuan was used to determine the area under the curve (AUC), measurements for Example 1, Example 2, and the internal standard. software. The calibration curves were calculated from the peak area ratio (parent drug/internal standards) using least squares linear regression. This was done by comparing the ratio to the theoretical concentration. Both compounds were linear over the standard curve (correlation >0.99), with an estimated quantitation limit (0.1). The observed blood concentration-time data were used to calculate the TMAX. To calculate pharmacokinetic parameters, blood concentration data were subject to multi-exponential curve fitting with CSTRIP. NONLIN84 was used to further define the parameters. The linear trapezoidal rule was used to calculate the area under the blood concentration-time profile from 0 to 1 hour (last measurable blood level time point). Extrapolated to infinity is the residual area, which is the final blood concentration (Ct) divided the terminal elimination rate constant(?). The residual area is the sum of the final measured blood concentration (Ct) and the terminal elimination rate constant (?). This is added to AUC0-t to create the total area under curve (AUC0-t).

FIG. “As shown in FIG. 1 and Table 2, both Example 1 compounds and Example 2 compounds had a significantly shorter terminal elimination half life (t1/2) than rapamycin. Only the compounds of the invention have sufficient efficacy (Table 1), and a shorter terminal elimination half-life (Table 2).

“Methods of Treatment.”

The invention’s compounds, not only those listed in the examples, have immunomodulatory activity in mammals (especially humans). As immunosuppressants, the compounds of the present invention are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissues such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nerves, duodenum, small-bowel, pancreatic-islet-cell, and the like; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto’s thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like. Further uses include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, lupus erythematosus, acne and alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet’s disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, and ocular pemphigus. In addition reversible obstructive airway diseases, which include conditions such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis, allergic rhinitis, and the like are targeted by compounds of this invention. Inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, and hyperproliferative vascular diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly following biologically- or mechanically-mediated vascular injury, could also be treated or prevented by the compounds of the invention.”

The compounds and drugs described herein may be used on stents coated with a polymeric substance. The stent can then be infused with the drug or compound by submerging it in a solution containing the drug. After that, dry the coated stent by drying it using an air dryer for at least 30 minutes. By using a balloon catheter, the polymer-coated drug-containing stent can be delivered to the heart. Other than stents, there are other options for introducing the drugs of the invention into the vasculature, including grafts and catheters. Other compounds and drugs can also be used to replace the drugs of this invention, including, but not limited, A-94507, SDZ RAD, and others.

The compounds herein can be combined with other pharmacological substances. Combining the compounds of the invention with pharmacological agents would be the most effective in preventing restenosis. They can be divided into the following categories: anti-proliferative, anti?platelet, anti?inflammatory, anti?thrombotic, and thrombolytic. You can further subdivide these classes. Anti-proliferative agents may also be anti-mitotic. Anti-mitotic agents are known to inhibit or alter cell division. This is because normal cell division processes don’t take place. Vinca alkaloids are one sub-class in anti-mitotic agents. Vinca alkaloids are a sub-class of anti-mitotic agents that includes paclitaxel and etoposide. Anti-mitotic alkylating agent sub-classes include tauromustine and bofumustine and anti-mitotic metabolisms such as fluorouracil and 5-bromodeoxyuridine. Anti-mitotic alkylating substances affect cell division by covalently modifying DNA,RNA, and proteins. This can inhibit DNA replication, transcription, translation, protein synthesis or combinations thereof.

Anti-platelet agents act by (1) inhibiting platelet adhesion to a surface, usually a thrombogenic one, (2) inhibiting platelet aggregation, (3) inhibiting platelet activation, or (4) combinations thereof. Platelets become active when they are transformed from a resting, quiescent state to one that undergoes a variety of morphologic changes due to contact with a thrombogenic material. These changes can include changes in platelet shape, binding to membrane receptors and the secretion small molecules and proteins such as ADP and platelet factors. Anti-platelet agents acting as inhibitors of platelet adhesion include, but not limited to: eptifibatide and tirofiban; RGD (Arg?Gly-Asp); peptides which inhibit binding to gpIIbIIIaIIIb or??3; antibodies that block binding gpIIaIIIb/?v3; anti-P-selectin antibody, anti-Electin antibodies; peptides blocking P-selectin ligandselectinselectinselectinselectinselectinselectinselectin ligandselectin ligandselectin ligandselectin ligandselectin selectin ligandselectin selectin selectin bind to their respective s, selectin selectin selectinselectinselectinselectinselectinselectinselectinselectinsselectinselectinselectinselectinselectinselectinselectinsiaseselectinselectinselectinselectinselectinselectinselectins, selectinseselectinseseselectinse, sa, sebrand factor-a, sa, s, disa, s, se, se, se, se, se, se, se, se, such as,,, se, se, s, s,, s,, s,,,, s,, s,,, cilosta,, cilosta,,,,,,,,,,,,,,,, disa, se,, se, se, cilosta,,, Disagregin, cilostazol, and other agents that inhibit ADP-mediated platelet accumulation include but are not limited.

Anti-inflammatory agents may also be used. These include prednisone and dexamethasone as well as hydrocortisone and estradiol. Non-steroidal anti-inflammatories such as acetaminophen and ibuprofen and naproxen are also examples. These agents can also inhibit the binding of cytokines and chemokines on cognate receptors in order to block pro-inflammatory signals caused by the cytokines. These agents include, but not limited to: anti-IL1, anti?IL2, anti?IL3, anti?IL4, anti?IL8, anti?IL15, anti?GM-CSF and anti?TNF antibodies.

“Thrombolytic agents” can be described as agents that degrade thrombi (clots). They can also be used to supplement other agents because the action of lysing the clot helps to disperse the platelets trapped in the fibrin matrix of the thrombus. Examples of thrombolytic agent include, but not limited to: urokinase/recombinant-urokinase; pro-urokinase/recombinant-pro-urokinase; tissue plasminogen activater or its recombinant version; and streptokinase.

“Other drugs that can be used in combination with the compounds of this invention are cytotoxic drugs, such as, for example, apoptosis inducers, such as TGF, and topoisomerase inhibitors, such as, 10-hydroxycamptothecin, irinotecan, and doxorubicin. Drugs that inhibit cell differentiation and cytostatic drugs are two other classes of drugs that may be combined with the compounds in this invention.

“Another agents that could be combined with the compounds described in this invention include anti-lipaemic agents such fenofibrate, matrix metaloproteinase inhibitors such as batimistat, antagonists to the endothelin A receptor such as darusentan and antagonists to the?v3 integrin receptor.”

The coating may contain any polymeric material that is substantially soluble in the therapeutic agent. The coating serves two purposes: to release the therapeutic agent controlled or to hold the agent until it is delivered to the lesion. The coating can be made of polymeric materials and may be hydrophilic or hydrophobic as well as biodegradable or non-biodegradable. The material for the polymeric coating can be selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyurethanes, silicones, polyorthoesters, polyanhydrides, polycarbonates, polypropylenes, polylactic acids, polyglycolic acids, polycaprolactones, polyhydroxybutyrate valerates, polyacrylamides, polyethers, and mixtures and copolymers of the foregoing. Polymeric dispersions, such as polyurethane (BAYHYDROL), etc. can be used to make coatings. Acrylic acid latex dispersions and polymeric dispersions (BAYHYDROL, etc.) can be used in conjunction with the therapeutic agents of this invention.

“Biodegradable polymers that can be used in this invention include polymers such as poly(L-lactic acid), poly(DL-lactic acid), polycaprolactone, poly(hydroxy butyrate), polyglycolide, poly(dioxanone), poly(hydroxy valerate), polyorthoester; copolymers such as poly(lactide-co-glycolide), polyhydroxy(butyrate-co-valerate), polyglycolide-co-trimethylene carbonate; polyanhydrides; polyphosphoesters; polyphosphoesterurethanes; polyamino acids; polycyanoacrylates; biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; and mixtures of the foregoing. Polymers that can be used in this invention are polyurethanes and silicones. Parylene and its derivatives; and combinations and copolymers thereof.

“Another polymer that can be used in this invention is poly(MPCw:LAMx:HPMAy:TSMAz) where w, x, y, and z represent the molar ratios of monomers used in the feed for preparing the polymer and MPC represents the unit 2-methacryoyloxyethylphosphorylcholine, LMA represents the unit lauryl methacrylate, HPMA represents the unit 2-hydroxypropyl methacrylate, and TSMA represents the unit 3-trimethoxysilylpropyl methacrylate. A drug-impregnated catheter can be used to maintain the patency of a coronary vessel that has been clogged by thrombus or atherosclerotic plaque. In-stent restenosis can be reduced by the administration of an anti-proliferative drug.

“Other treatable conditions include but are not limited to ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn’s disease and ulcerative colitis; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere’s disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow’s disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener’s granuloma and Sjogren’s syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary’s syndrome; Addison’s disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infarction); intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenesis, metastasis of carcinoma and hypobaropathy; diseases caused by histamine or leukotriene-C4 release; Behcet’s disease such as intestinal-, vasculo- or neuro-Behcet’s disease, and also Behcet’s which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. The compounds of the invention can be used to treat and prevent hepatic diseases, such as immunogenic disorders such as chronic autoimmune liver disease, primary biliary dysfunction and sclerosing.cholangitis. necrosis due to toxin, viral liver disease, shock or anoxia), non-A/nonB hepatitis and cirrhosis (such alcoholic cirrhosis), cirrhosis (such fulminant and late-onset hepatic dysfunction and?acute on-chronic? liver failure (acute or chronic liver disease), and are also useful in treating other diseases, such as cytomegalovirus infection, especially HCMV infection, sclerosing, fibrotic diseases like nephrosis and fulminant hepatic failure and late-onset hepatic failure.

“Compounds of the invention also possess FK-506 antagonistic characteristics. The present invention can be used to treat immunodepression and other disorders involving immunodepression. AIDS, cancers, fungal infections and senile dementia are all examples of immunodepression. The immunodepression to be treated may be caused by an overdose of an immunosuppressive macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-1-methylvinyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene such as FK-506 or rapamycin. Patients are more likely to overdose on such medications if they realize that they have not taken their prescribed medication as directed. This can cause serious side effects.

“The potential of the compounds of invention to treat proliferative disorders can be proven using the methods described by E. T. Bunchman, C. A. Brookshire and Yamagishi, Transplantation Proceed. Biophys. Res. Res. Invest., 87, 1867-1871 (1991). Smooth muscle proliferation, systemic swelling, cirrhosis and the liver, adult respiratory distress syndromes, idiopathic cardiovascular disease, lupus-erythematosus or other retinopathies as well as lupus erythematosus, diabetic retinalopathy or other retinopathies, psoriasis and prostatic hyperplasia are all examples of proliferative diseases. These compounds also antagonize cell responses to growth factors and have antiangiogenic qualities. They can be used to control or reverse certain types of tumors as well as fibrotic disease of the liver, kidney, and lung.

“The present invention’s aqueous liquid compositions are especially useful in the treatment and prevention autoimmune diseases, such as conical cornea, dysophia epithelialis corneae and leukoma. They also prevent rejection of corneal transplantation.

“The therapeutically effective amounts of one of these compounds may be used in the above-mentioned or other treatments in a pure or in a pharmaceutically acceptable salt or ester form. The compound can also be administered in combination with one or several pharmaceutically acceptable excipients. “Therapeutically effective amount” is a phrase that refers to the compound’s therapeutic effectiveness. The term “therapeutically effective amount” refers to a compound that is sufficient to treat certain disorders at a reasonable risk/benefit ratio. The attending physician will decide the daily dosage of the compounds and combinations of the invention. This is within the limits of sound medical judgment. The therapeutically effective dose for any patient will depend on a number of factors, including the type of disorder and severity of the condition, the activity of the specific compounds employed, the specific composition used, the time and route of administration and the rate of excretion. There may also be drugs that are combined or co-occurring with the specific compound. These factors are well known to medical professionals. It is possible to begin the dose of the compound at a lower level than necessary to achieve desired therapeutic effects and gradually increase it until you get the desired effect.

The daily average dose of the compounds described in this invention to humans or animals below the age of 10 may be between 0.01 and 10. Doses that are more suitable for oral administration may range from about 0.01 to 3 mg/kg/day. The length of the stent determines the daily dose a patient will receive for local delivery. A 15mm coronary stent might contain a drug in a dose of about 1 to 120 micrograms. The drug may be delivered over a period of several hours or even several weeks. The effective daily dose can be broken down into multiple doses if necessary. Single dose compositions may also contain sub-multiples or such amounts to meet the daily dose. Topical administration can involve doses of 0.001 to 3.3% mg/kg/day depending on the location.

“Pharmaceutical Compositions”

“The pharmaceutical compositions according to the invention consist of a compound of invention and a pharmaceutically acceptable excipient. They can be administered orally or parenterally, intravaginally or intraperitoneally. “Pharmaceutically acceptable carrier” is a term that refers to a non-toxic solid, semi-solid or liquid filler. A non-toxic solid, semisolid, or liquid filler or diluent, or encapsulating material, or formulation auxiliary, of any kind. Parenteral is a term that refers to the administration of a parenteral substance. The term “parenteral” as it is used herein refers to administration methods that include intravenous (intraarterial), intrasternal, intrasternal and subcutaneous injections, infusions, and placements such as in vasculature.

“Pharmaceutical compositions according to this invention are pharmaceutically acceptable sterile aqueous and nonaqueous solutions, suspensions, dispersions or emulsions, as well as sterile particles for reconstitution into sterile injectionable solutions or dispersions prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. You can maintain fluidity by using coating materials like lecithin or maintaining the required particle size for dispersions and using surfactants.

These compositions can also include adjuvants like preservatives and wetting agents as well as emulsifying and dispersing agents. Paraben, chlorobutanol and phenol sorbic acids can be used to prevent microorganisms from acting. You may also want to add isotonic substances such as sugars and sodium chloride. The inclusion of agents such as gelatin and aluminum monostearate that delay absorption may cause prolonged absorption of injectable pharmaceutical forms.

In some cases, to prolong the effects of the drug, it may be desirable to slow down the absorption from intramuscular or subcutaneous injections. You can do this by using a liquid suspension of crystalline and amorphous material that is not water-soluble. Rate of drug absorption is affected by the rate of dissolution. This may be dependent on crystal size and crystalline forms. Alternately, delayed absorption can be achieved by suspending or dissolving a parenterally administered drug.

“Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can vary depending on the drug-to-polymer ratio and the nature of the polymer used. Poly(orthoesters and poly(anhydrides) are two examples of biodegradable polymers. You can also make depot injectable formulations by trapping the drug in liposomes and microemulsions that are compatible with your body tissues.

The injectable formulations may be sterilized by either filtering through a bacterial-retaining screen or by adding sterilizing agents in the form sterile solid compositions that can be dissolved in sterile injection medium or sterile water just before use.

Tablets, capsules, pills, powders and granules are all viable options for oral administration. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. The dosage form of pills, capsules and tablets may contain buffering agents.

Solid compositions of the same type can also be used as fillers in hard, semi-solid, and hard-filled gelatin capsules.

The solid dosage forms for tablets, dragees or pills can be prepared using coatings and shells like enteric coatings and any other coatings that are well-known in pharmaceutical formulating. You can optionally include opacifying agents. They can also release active ingredients only or preferentially in a specific part of your intestinal tract. Polymeric substances and waxes are two examples of embedding compounds that can be used. These embedding compositions that contain a drug are suitable for use on medical devices such as stents and grafts, catheters, balloons, and other similar devices.

“Active compounds can also be micro-encapsulated, if necessary, with one or more excipients.”

Liquid dosage forms are pharmaceutically acceptable solutions, liquids, suspensions, syrups, and elixirs. The liquid dosage forms can contain active compounds in addition to other solvents, solubilizing agent and emulsifiers.

“Inert diluents are not the only options. Oral compositions can also contain adjuvants like wetting agents and emulsifying or suspending agents, sweetening and flavoring agents, and perfuming and perfuming agent.”

“Suspensions may also contain active compounds such as ethoxylated stearyl alcohols and polyoxyethylenesorbitols and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide and bentonite or mixtures thereof.”

Summary for “Medical devices that contain rapamycin analogs.”

“The widely-used compound cyclosporine (cyclosporinA) has seen a lot of use in the fields organ transplantation and immunomodulation. It has also led to a significant improvement in the success rate of transplantation procedures. Recently, several macrocyclic compounds with potent immunomodulatory properties were discovered. Okuhara et al., in European Patent Application No. Published Jun. 11 June 1986. A number of macrocyclic compounds were isolated from Streptomyces genus. These include the immunosuppressant FK-506, an immunosuppressant macrocyclic lactone with 23 members, and which was isolated from a S. tsukubaensis.”

“Other natural products, such FR900523 and FR900523, differ from FK-506 by their alkyl substituent C-21, were isolated from S. hygroscopicus yakushimnaensis. S. tsukubaensis also produced FR-900525, which differs from FK-506 by replacing a pipecolic acid moiety of the compound with a proline group. Side-effects such as nephrotoxicity and cyclosporine have been a source of concern. There is a continuing search for immunosuppressants that are more effective and safer, including an immunosupressant which is both topically and systemically ineffective (U.S. Pat. No. 5,457,111).”

“Rapamycin, a macrocyclic triene-antifungal antibiotic, is produced by Streptomyces Hygroscopicus. It was found to be particularly effective against Candida albicans in vitro as well as in vivo (C. Vezina and others, J. Antibiot. 1975, 28, 721; S. N. Sehgal et al., J. Antibiot. 1975, 28, 727; H. A. Baker et al., J. Antibiot. 1978, 31, 539; U.S. Pat. No. No. No. 3,993,749).”

“”

“Rapamycin (U.S. Patent. No. No. No. No. 4,401,653 has been proven to have antitumor activities. Rapamycin, which was discovered to have antitumor activity in 1977 in two models of experimental allergic encephalomyelitis, multiple sclerosis, and adjuvant arthritis, was also effective in suppressing the production IgE-like antibody formation (R. Martel, Can. J. Physiol. Pharmacol., 1977, 55, 48).”

“The immunosuppressive effect of rapamycin has also been revealed in FASEB 1989, 3, 3411 and its ability to prolong the survival time organ grafts of histoincompatible rodents (R. Morris Med. Sci. Res., 1989, 17, 877). M. Strauch, FASEB 1989, 3, 3411, revealed the ability of rapamycin inhibit T-cell activation. These and other biological effects are discussed in Transplantation Reviews 1992, 6, 39-87.

Rapamycin has been shown in animal models to decrease neointimal proliferation and in humans to lower the rate of restenosis. There is evidence that rapamycin has an anti-inflammatory effect. This characteristic supports its use as an agent to treat rheumatoidarthritis. Rapamycin and its analogs have been suggested to prevent restenosis, as both inflammation and cell proliferation are believed to be the main causes of the formation restenotic lesions following balloon angioplasty or stent placement.

“Mono-ester, di-ester derivatives and rapamycin (esterification at position 31 and 42) have been proven to be effective as antifungal agents (U.S. Patent. No. No. No. 4,650,803).”

“Fermentation, purification and 30-demethoxyrapamycin were described in the literature” (C. Vezina and al. J. Antibiot. (Tokyo), 1975, 28 (10), 721; S. N. Sehgal et al., J. Antibiot. (Tokyo), 1975, 28(10), 727; 1983, 36(4), 351; N. L. Pavia et al., J. Natural Products, 1991. 54(1), 167-177).

Numerous chemical modifications have been made to rapamycin. These include the preparation mono- and di-ester derivatives (WO 92/05179), 27 oximes (EPO 467606), 42-oxo analogs (U.S. Patent. No. 5,023,262); bicyclic Rapamycins (U.S. Patent. No. 5,120,725); rapamycin dimers (U.S. Pat. No. No. No. No. No. 5,177,203). Rapamycin was synthesized recently in its naturally occurring enantiomeric form (K. C. Nicolaou et. al., J. Am. Chem. Soc., 1993, 115, 4419-4420; S. L. Schreiber, J. Am. Chem. Soc., 1993, 115, 7906-7907; S. J. Danishefsky, J. Am. Chem. Soc., 1993, 115, 9345-9346.”

It is known that FKBP-12 can be bound to rapamycin (Siekierka J. J. Immunol., 1990, 144, 1418-1424; Bierer, B. E.; Schreiber, S. L.; Burakoff, S. J., Eur. J. Immunol., 1991, 21, 439-445; Fretz, H.; Albers, M. W.; Galat, A.; Standaert, R. F.; Lane, W. S.; Burakoff, S. J.; Bierer, B. E.; Schreiber, S. L., J. Am. Chem. Soc., 1991, 113, 1409-1411). Recent research has shown that the FKBP-12/rapamycin complex binds to another protein. This protein is different from calcineurin (Brown E. J.; Albers M. W. and Shin, T. B., Ichikawa K.; Keith C. T., Lane W. S. S.; Schreiber S. L. Nature 1994, 369/756; Sabatini D. M., Erdjument-Bromage H.; Lui P.

Andreas Gruntzig developed “Percutaneous transluminal Coronay Angioplasty (PTCA).” This procedure was first performed in 1970. Sep. 24, 1975 was the first time a canine had their coronary dilated. The American Heart Association presented studies demonstrating the effectiveness of PTCA at its annual meetings the next year. The first human patient was soon studied in Zurich in Switzerland. This was followed by the first American patients in San Francisco, and New York. Although this procedure was a significant change in interventional cardiology for patients suffering from obstructive or severe coronary artery disease, it did not offer long-term relief. The procedure provided temporary relief from the chest pain that is associated with vascular obstruction. Repeat procedures were frequently necessary. The new procedure was not able to be used because of the presence of restenotic lesion. Stents were developed in the 1980’s to preserve vessel integrity after angioplasty. Stenting is used in over 90% of all angioplasty procedures today. Prior to the advent of stents the incidence of restenosis was between 30% and 50% in patients who had balloon angioplasty. In-stent restenosis can result in a 70% recurrence rate for some patients. However, the angiographic restenosis rate is only 20% in de novo stents. The restenosis rate was reduced to 15% to 20% by the placement of the stent. This is the highest percentage possible with mechanical stenting. Restenosis is caused by neointimal Hyperplasia. This is distinct from atherosclerotic diseases in both time-course and histopathological appearance. Restenosis refers to the healing of damaged coronary arteries walls. Neointimal tissue can impinge significantly on the vessel lumen. Vascular brachytherapy seems to be effective against in-stent restenosis lesions. Radiation has its limitations in practicality and cost, as well as lingering concerns about safety and longevity.

Accordingly, it is hoped to decrease the rate of restenosis by at minimum 50% from its current level. The interventional device community is making a lot of effort to develop and evaluate drug-eluting devices. If they are successful, such devices would have many benefits, primarily because they would not require any auxiliary therapies (e.g., chronic oral pharmacotherapy or peri-procedural techniques) to function.

“In one aspect the present invention are disclosed compound represented by the structural formula:

“”

“Or a pharmaceutically acceptable prodrug or salt thereof.”

“Another object is the invention to provide synthetic methods for the preparation such compounds from starting material obtained by fermentation, and chemical intermediates that are useful in such synthetic processes.”

“Another object of the invention” is to provide pharmaceutical compositions that contain at least one of these compounds as active ingredients.

“Yet another object is the invention to provide a method for treating a variety disease states, including restenosis, post-transplant tissue reject, immune and autonomic dysfunction, fungal growth and cancer.”

“Another aspect of the invention is a medical device that includes a support structure with a coating on its surface, the coating comprising a therapeutic substance such as a drug. The medical devices supporting this invention are, among others, coronary stents and peripheral stents. They also include catheters, arteriovenous grafts and by-pass grafts. Drug delivery balloons are used in the vasculature. This invention is suitable for the use of drugs such as, but not limited to:

“”

“Or a pharmaceutically acceptable prodrug or salt thereof”

“”

“Or a pharmaceutically acceptable prodrug or salt thereof (hereinafter referred to as A-179578 or ABT-578).

“”

“Or a pharmaceutically acceptable prodrug or salt thereof;”

“”

“or a pharmaceutically acceptable salt or prodrug thereof (hereinafter alternatively referred to as SDZ RAD or 40-O-(2-hydroxyethyl)-rapamycin);”

“”

“Or a pharmaceutically acceptable prodrug or salt thereof (hereinafter referred to as A-94507).”

The polymeric coatings are suitable for this invention, and can include, but not limit to, any polymeric material that has the therapeutic agent, i.e. the drug, substantially soluble. The coating can be non-biodegradable, hydrophilic, biodegradable or hydrophobic. This medical device decreases restenosis in the vasculature. Direct coronary delivery of A-179578, a drug that reduces restenosis, is expected to lower the rate to around 0% to 25%.

“Definition and Definition of Terms”

“Prodrug” is a generic term for compounds that are rapidly transformed in vivo to the parent compound of the above formula. “Prodrug” is a term that refers to compounds that are quickly transformed in vivo to their parent compound, such as by hydrolysis in blood. T. Higuchi, V. Stella and others provide a detailed discussion in?Prodrugs As Novel Delivery Systems,? Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche (ed. ),?Bioreversible Carriers in Drug Design. American Pharmaceutical Association, Pergamon Press 1987. Both of these are incorporated by reference in this document.

“Pharmaceutically acceptable prodrugs” is a term that refers to prodrugs of the compound of the present invention that are suitable for contact with human and lower mammal tissues without irritation, undue toxicity, or allergic reaction. They are also effective for their intended uses, as well the zwitterionic versions, where applicable, of the compound of the invention. Prodrug esters from the C-31 group of compounds are particularly preferred as pharmaceutically acceptable prodrugs.

“Prodrug esters” is a term that refers to any of several ester-forming groups. “Prodrug esters” is a term that refers to any one of several ester-forming group that can be hydrolyzed under physiological conditions. Prodrug ester group examples include acetyl and ethanoyls, pivaloyloxymethyls, acetoxymethyls, phthalidyls, methoxymethyls, indanyls, and others derived from the addition of naturally occurring or unnaturally occurring amino acid to the C-31hydroxyl group of compounds.

“The term “supporting structure” is used to describe a framework that can support a carrier or excipient. A framework capable of supporting or containing a pharmaceutically acceptable carrier/excipient. This carrier/excipient could contain one or several therapeutic agents, substances, or compounds. The support structure is usually made of metal or a multi-layered material. Support structures made of polymeric materials (including biodegradable Polymers) that can contain the therapeutic agents and substances are suitable. Nos. Nos. 6,413,272 & 5,527,337 are incorporated herein as references.”

“EMBODIMENTS”

“In one embodiment, the invention is a combination of formulas”

“”

“In an alternative embodiment of the invention, is a compound or formula.”

“”

“Preparation and use of compounds of this invention”

“The present invention’s compounds and processes will be easier to understand when they are compared with the following synthetic schemes that illustrate how the compounds can be prepared.”

“The compounds of the invention can be prepared using a variety synthetic routes.” Schema 1 shows a representative procedure.

“”

“As shown in Scheme 1, conversion of the C-42 hydroxyl of rapamycin to a trifluoromethanesulfonate or fluorosulfonate leaving group provided compound A. Displacement of the leaving group with tetrazole in the presence of a hindered, non-nucleophilic base, such as 2,6-lutidine, or, preferably, diisopropylethyl amine provided isomers B and C, which were separated and purified by flash column chromatography.”

“Synthetic Methods”

The following examples will help you understand the process of making the compounds of the invention. They are not meant to limit the scope and meaning of the invention as described in the appended claims.

“Example 1”

“42-Epi-(tetrazolyl)-rapamycin (Less Polar Isomer)”

“Example 1A”

“Example 1B”

“42-Epi-(tetrazolyl)-rapamycin (Less Polar Isomer)”

“A solution of the triflate compound from Example 1A in isopropyl acetate (0.3 mL) was treated sequentially with diisopropylethylamine (87 uL, 0.5 mmol) and 1H-tetrazole (35 mg, 0.5 mmol), and thereafter stirred for 18 hours. The mixture was divided between water (10mL) and alcohol (10mL). The organics were rinsed with brine (10mL), dried (Na2SO4) and then washed again. The organics were concentrated to form a sticky yellow liquid. This was then purified using chromatography on silica gel (3.5-2 g, 70-230 mesh), ether (30mL), hexane/ether (4:1 (10mL), 3:1 (10mL), 2:1 (10mL), 1:1 (10mL), 1:1 (10mL), ether (30mL), and hexane/acetone (1:1 (30mL). One of the isomers was found in the ether fractions. MS (ESI). m/e 966. M )?.”

“Example 2”

“42-Epi-(tetrazolyl)-rapamycin (More Polar Isomer)”

“Collection of the slower-moving band from the Chromatography column using the Hexane:acetone (1 to1) mobile phase in Example1B provided the designated compound. MS (ESI m/e966 (M )?.”).

“In Vitro Assay for Biological Activity”

“The immunosuppressant activity of the compounds of the present invention was compared to rapamycin and two rapamycin analogs: 40-epi-N-[2?-pyridone]-rapamycin and 40-epi-N-[4?-pyridone]-rapamycin, both disclosed in U.S. Pat. No. 5,527,907. Kino, T. et. al. determined the activity using the human mixed lymphocyte response (MLR). Transplantation Proceedings,XIX(5): 36-39. Suppl. 6 (1987). As shown in Table 1, the results of the assay show that the compounds of invention work as immunomodulators at nanomolar levels.

“The pharmacokinetic behavior of the Example 1 and Example 2 compound were studied following an intravenous 2.5 mg/kg dose to cynomolgus monkeys (n=3). Each compound was prepared in 2.5 mg/mL solutions in 20% ethanol:30%propylene glycol and2% cremophor E:48% dextrose,5% in water vehicle.

The intravenous 1 mL/kg dose was administered in a slow bolus (about 2 minutes) through a saphenous vein. Before dosing, blood samples were taken from the femoral veins or arteries of each animal. Blood samples were also obtained from 0.25 (IV only), 0.25 and 0.5, 1, 1,5, 2, 4, 6, 9, 12, 24 and 30 hours later. For analysis, the EDTA preserved samples were mixed thoroughly and extracted.

Sciex MacQuan was used to determine the area under the curve (AUC), measurements for Example 1, Example 2, and the internal standard. software. The calibration curves were calculated from the peak area ratio (parent drug/internal standards) using least squares linear regression. This was done by comparing the ratio to the theoretical concentration. Both compounds were linear over the standard curve (correlation >0.99), with an estimated quantitation limit (0.1). The observed blood concentration-time data were used to calculate the TMAX. To calculate pharmacokinetic parameters, blood concentration data were subject to multi-exponential curve fitting with CSTRIP. NONLIN84 was used to further define the parameters. The linear trapezoidal rule was used to calculate the area under the blood concentration-time profile from 0 to 1 hour (last measurable blood level time point). Extrapolated to infinity is the residual area, which is the final blood concentration (Ct) divided the terminal elimination rate constant(?). The residual area is the sum of the final measured blood concentration (Ct) and the terminal elimination rate constant (?). This is added to AUC0-t to create the total area under curve (AUC0-t).

FIG. “As shown in FIG. 1 and Table 2, both Example 1 compounds and Example 2 compounds had a significantly shorter terminal elimination half life (t1/2) than rapamycin. Only the compounds of the invention have sufficient efficacy (Table 1), and a shorter terminal elimination half-life (Table 2).

“Methods of Treatment.”

The invention’s compounds, not only those listed in the examples, have immunomodulatory activity in mammals (especially humans). As immunosuppressants, the compounds of the present invention are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissues such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nerves, duodenum, small-bowel, pancreatic-islet-cell, and the like; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto’s thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like. Further uses include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, lupus erythematosus, acne and alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet’s disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, and ocular pemphigus. In addition reversible obstructive airway diseases, which include conditions such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis, allergic rhinitis, and the like are targeted by compounds of this invention. Inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, and hyperproliferative vascular diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly following biologically- or mechanically-mediated vascular injury, could also be treated or prevented by the compounds of the invention.”

The compounds and drugs described herein may be used on stents coated with a polymeric substance. The stent can then be infused with the drug or compound by submerging it in a solution containing the drug. After that, dry the coated stent by drying it using an air dryer for at least 30 minutes. By using a balloon catheter, the polymer-coated drug-containing stent can be delivered to the heart. Other than stents, there are other options for introducing the drugs of the invention into the vasculature, including grafts and catheters. Other compounds and drugs can also be used to replace the drugs of this invention, including, but not limited, A-94507, SDZ RAD, and others.

The compounds herein can be combined with other pharmacological substances. Combining the compounds of the invention with pharmacological agents would be the most effective in preventing restenosis. They can be divided into the following categories: anti-proliferative, anti?platelet, anti?inflammatory, anti?thrombotic, and thrombolytic. You can further subdivide these classes. Anti-proliferative agents may also be anti-mitotic. Anti-mitotic agents are known to inhibit or alter cell division. This is because normal cell division processes don’t take place. Vinca alkaloids are one sub-class in anti-mitotic agents. Vinca alkaloids are a sub-class of anti-mitotic agents that includes paclitaxel and etoposide. Anti-mitotic alkylating agent sub-classes include tauromustine and bofumustine and anti-mitotic metabolisms such as fluorouracil and 5-bromodeoxyuridine. Anti-mitotic alkylating substances affect cell division by covalently modifying DNA,RNA, and proteins. This can inhibit DNA replication, transcription, translation, protein synthesis or combinations thereof.

Anti-platelet agents act by (1) inhibiting platelet adhesion to a surface, usually a thrombogenic one, (2) inhibiting platelet aggregation, (3) inhibiting platelet activation, or (4) combinations thereof. Platelets become active when they are transformed from a resting, quiescent state to one that undergoes a variety of morphologic changes due to contact with a thrombogenic material. These changes can include changes in platelet shape, binding to membrane receptors and the secretion small molecules and proteins such as ADP and platelet factors. Anti-platelet agents acting as inhibitors of platelet adhesion include, but not limited to: eptifibatide and tirofiban; RGD (Arg?Gly-Asp); peptides which inhibit binding to gpIIbIIIaIIIb or??3; antibodies that block binding gpIIaIIIb/?v3; anti-P-selectin antibody, anti-Electin antibodies; peptides blocking P-selectin ligandselectinselectinselectinselectinselectinselectinselectin ligandselectin ligandselectin ligandselectin ligandselectin selectin ligandselectin selectin selectin bind to their respective s, selectin selectin selectinselectinselectinselectinselectinselectinselectinselectinsselectinselectinselectinselectinselectinselectinselectinsiaseselectinselectinselectinselectinselectinselectinselectins, selectinseselectinseseselectinse, sa, sebrand factor-a, sa, s, disa, s, se, se, se, se, se, se, se, se, such as,,, se, se, s, s,, s,, s,,,, s,, s,,, cilosta,, cilosta,,,,,,,,,,,,,,,, disa, se,, se, se, cilosta,,, Disagregin, cilostazol, and other agents that inhibit ADP-mediated platelet accumulation include but are not limited.

Anti-inflammatory agents may also be used. These include prednisone and dexamethasone as well as hydrocortisone and estradiol. Non-steroidal anti-inflammatories such as acetaminophen and ibuprofen and naproxen are also examples. These agents can also inhibit the binding of cytokines and chemokines on cognate receptors in order to block pro-inflammatory signals caused by the cytokines. These agents include, but not limited to: anti-IL1, anti?IL2, anti?IL3, anti?IL4, anti?IL8, anti?IL15, anti?GM-CSF and anti?TNF antibodies.

“Thrombolytic agents” can be described as agents that degrade thrombi (clots). They can also be used to supplement other agents because the action of lysing the clot helps to disperse the platelets trapped in the fibrin matrix of the thrombus. Examples of thrombolytic agent include, but not limited to: urokinase/recombinant-urokinase; pro-urokinase/recombinant-pro-urokinase; tissue plasminogen activater or its recombinant version; and streptokinase.

“Other drugs that can be used in combination with the compounds of this invention are cytotoxic drugs, such as, for example, apoptosis inducers, such as TGF, and topoisomerase inhibitors, such as, 10-hydroxycamptothecin, irinotecan, and doxorubicin. Drugs that inhibit cell differentiation and cytostatic drugs are two other classes of drugs that may be combined with the compounds in this invention.

“Another agents that could be combined with the compounds described in this invention include anti-lipaemic agents such fenofibrate, matrix metaloproteinase inhibitors such as batimistat, antagonists to the endothelin A receptor such as darusentan and antagonists to the?v3 integrin receptor.”

The coating may contain any polymeric material that is substantially soluble in the therapeutic agent. The coating serves two purposes: to release the therapeutic agent controlled or to hold the agent until it is delivered to the lesion. The coating can be made of polymeric materials and may be hydrophilic or hydrophobic as well as biodegradable or non-biodegradable. The material for the polymeric coating can be selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyurethanes, silicones, polyorthoesters, polyanhydrides, polycarbonates, polypropylenes, polylactic acids, polyglycolic acids, polycaprolactones, polyhydroxybutyrate valerates, polyacrylamides, polyethers, and mixtures and copolymers of the foregoing. Polymeric dispersions, such as polyurethane (BAYHYDROL), etc. can be used to make coatings. Acrylic acid latex dispersions and polymeric dispersions (BAYHYDROL, etc.) can be used in conjunction with the therapeutic agents of this invention.

“Biodegradable polymers that can be used in this invention include polymers such as poly(L-lactic acid), poly(DL-lactic acid), polycaprolactone, poly(hydroxy butyrate), polyglycolide, poly(dioxanone), poly(hydroxy valerate), polyorthoester; copolymers such as poly(lactide-co-glycolide), polyhydroxy(butyrate-co-valerate), polyglycolide-co-trimethylene carbonate; polyanhydrides; polyphosphoesters; polyphosphoesterurethanes; polyamino acids; polycyanoacrylates; biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; and mixtures of the foregoing. Polymers that can be used in this invention are polyurethanes and silicones. Parylene and its derivatives; and combinations and copolymers thereof.

“Another polymer that can be used in this invention is poly(MPCw:LAMx:HPMAy:TSMAz) where w, x, y, and z represent the molar ratios of monomers used in the feed for preparing the polymer and MPC represents the unit 2-methacryoyloxyethylphosphorylcholine, LMA represents the unit lauryl methacrylate, HPMA represents the unit 2-hydroxypropyl methacrylate, and TSMA represents the unit 3-trimethoxysilylpropyl methacrylate. A drug-impregnated catheter can be used to maintain the patency of a coronary vessel that has been clogged by thrombus or atherosclerotic plaque. In-stent restenosis can be reduced by the administration of an anti-proliferative drug.

“Other treatable conditions include but are not limited to ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn’s disease and ulcerative colitis; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere’s disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow’s disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener’s granuloma and Sjogren’s syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary’s syndrome; Addison’s disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infarction); intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenesis, metastasis of carcinoma and hypobaropathy; diseases caused by histamine or leukotriene-C4 release; Behcet’s disease such as intestinal-, vasculo- or neuro-Behcet’s disease, and also Behcet’s which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. The compounds of the invention can be used to treat and prevent hepatic diseases, such as immunogenic disorders such as chronic autoimmune liver disease, primary biliary dysfunction and sclerosing.cholangitis. necrosis due to toxin, viral liver disease, shock or anoxia), non-A/nonB hepatitis and cirrhosis (such alcoholic cirrhosis), cirrhosis (such fulminant and late-onset hepatic dysfunction and?acute on-chronic? liver failure (acute or chronic liver disease), and are also useful in treating other diseases, such as cytomegalovirus infection, especially HCMV infection, sclerosing, fibrotic diseases like nephrosis and fulminant hepatic failure and late-onset hepatic failure.

“Compounds of the invention also possess FK-506 antagonistic characteristics. The present invention can be used to treat immunodepression and other disorders involving immunodepression. AIDS, cancers, fungal infections and senile dementia are all examples of immunodepression. The immunodepression to be treated may be caused by an overdose of an immunosuppressive macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-1-methylvinyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene such as FK-506 or rapamycin. Patients are more likely to overdose on such medications if they realize that they have not taken their prescribed medication as directed. This can cause serious side effects.

“The potential of the compounds of invention to treat proliferative disorders can be proven using the methods described by E. T. Bunchman, C. A. Brookshire and Yamagishi, Transplantation Proceed. Biophys. Res. Res. Invest., 87, 1867-1871 (1991). Smooth muscle proliferation, systemic swelling, cirrhosis and the liver, adult respiratory distress syndromes, idiopathic cardiovascular disease, lupus-erythematosus or other retinopathies as well as lupus erythematosus, diabetic retinalopathy or other retinopathies, psoriasis and prostatic hyperplasia are all examples of proliferative diseases. These compounds also antagonize cell responses to growth factors and have antiangiogenic qualities. They can be used to control or reverse certain types of tumors as well as fibrotic disease of the liver, kidney, and lung.

“The present invention’s aqueous liquid compositions are especially useful in the treatment and prevention autoimmune diseases, such as conical cornea, dysophia epithelialis corneae and leukoma. They also prevent rejection of corneal transplantation.

“The therapeutically effective amounts of one of these compounds may be used in the above-mentioned or other treatments in a pure or in a pharmaceutically acceptable salt or ester form. The compound can also be administered in combination with one or several pharmaceutically acceptable excipients. “Therapeutically effective amount” is a phrase that refers to the compound’s therapeutic effectiveness. The term “therapeutically effective amount” refers to a compound that is sufficient to treat certain disorders at a reasonable risk/benefit ratio. The attending physician will decide the daily dosage of the compounds and combinations of the invention. This is within the limits of sound medical judgment. The therapeutically effective dose for any patient will depend on a number of factors, including the type of disorder and severity of the condition, the activity of the specific compounds employed, the specific composition used, the time and route of administration and the rate of excretion. There may also be drugs that are combined or co-occurring with the specific compound. These factors are well known to medical professionals. It is possible to begin the dose of the compound at a lower level than necessary to achieve desired therapeutic effects and gradually increase it until you get the desired effect.

The daily average dose of the compounds described in this invention to humans or animals below the age of 10 may be between 0.01 and 10. Doses that are more suitable for oral administration may range from about 0.01 to 3 mg/kg/day. The length of the stent determines the daily dose a patient will receive for local delivery. A 15mm coronary stent might contain a drug in a dose of about 1 to 120 micrograms. The drug may be delivered over a period of several hours or even several weeks. The effective daily dose can be broken down into multiple doses if necessary. Single dose compositions may also contain sub-multiples or such amounts to meet the daily dose. Topical administration can involve doses of 0.001 to 3.3% mg/kg/day depending on the location.

“Pharmaceutical Compositions”

“The pharmaceutical compositions according to the invention consist of a compound of invention and a pharmaceutically acceptable excipient. They can be administered orally or parenterally, intravaginally or intraperitoneally. “Pharmaceutically acceptable carrier” is a term that refers to a non-toxic solid, semi-solid or liquid filler. A non-toxic solid, semisolid, or liquid filler or diluent, or encapsulating material, or formulation auxiliary, of any kind. Parenteral is a term that refers to the administration of a parenteral substance. The term “parenteral” as it is used herein refers to administration methods that include intravenous (intraarterial), intrasternal, intrasternal and subcutaneous injections, infusions, and placements such as in vasculature.

“Pharmaceutical compositions according to this invention are pharmaceutically acceptable sterile aqueous and nonaqueous solutions, suspensions, dispersions or emulsions, as well as sterile particles for reconstitution into sterile injectionable solutions or dispersions prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. You can maintain fluidity by using coating materials like lecithin or maintaining the required particle size for dispersions and using surfactants.

These compositions can also include adjuvants like preservatives and wetting agents as well as emulsifying and dispersing agents. Paraben, chlorobutanol and phenol sorbic acids can be used to prevent microorganisms from acting. You may also want to add isotonic substances such as sugars and sodium chloride. The inclusion of agents such as gelatin and aluminum monostearate that delay absorption may cause prolonged absorption of injectable pharmaceutical forms.

In some cases, to prolong the effects of the drug, it may be desirable to slow down the absorption from intramuscular or subcutaneous injections. You can do this by using a liquid suspension of crystalline and amorphous material that is not water-soluble. Rate of drug absorption is affected by the rate of dissolution. This may be dependent on crystal size and crystalline forms. Alternately, delayed absorption can be achieved by suspending or dissolving a parenterally administered drug.

“Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can vary depending on the drug-to-polymer ratio and the nature of the polymer used. Poly(orthoesters and poly(anhydrides) are two examples of biodegradable polymers. You can also make depot injectable formulations by trapping the drug in liposomes and microemulsions that are compatible with your body tissues.

The injectable formulations may be sterilized by either filtering through a bacterial-retaining screen or by adding sterilizing agents in the form sterile solid compositions that can be dissolved in sterile injection medium or sterile water just before use.

Tablets, capsules, pills, powders and granules are all viable options for oral administration. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. The dosage form of pills, capsules and tablets may contain buffering agents.

Solid compositions of the same type can also be used as fillers in hard, semi-solid, and hard-filled gelatin capsules.

The solid dosage forms for tablets, dragees or pills can be prepared using coatings and shells like enteric coatings and any other coatings that are well-known in pharmaceutical formulating. You can optionally include opacifying agents. They can also release active ingredients only or preferentially in a specific part of your intestinal tract. Polymeric substances and waxes are two examples of embedding compounds that can be used. These embedding compositions that contain a drug are suitable for use on medical devices such as stents and grafts, catheters, balloons, and other similar devices.

“Active compounds can also be micro-encapsulated, if necessary, with one or more excipients.”

Liquid dosage forms are pharmaceutically acceptable solutions, liquids, suspensions, syrups, and elixirs. The liquid dosage forms can contain active compounds in addition to other solvents, solubilizing agent and emulsifiers.

“Inert diluents are not the only options. Oral compositions can also contain adjuvants like wetting agents and emulsifying or suspending agents, sweetening and flavoring agents, and perfuming and perfuming agent.”

“Suspensions may also contain active compounds such as ethoxylated stearyl alcohols and polyoxyethylenesorbitols and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide and bentonite or mixtures thereof.”

Click here to view the patent on Google Patents.

What is a software medical device?

The FDA can refer to software functions that include ” Software As a Medical Device” and “Software in a Medical Device(SiMD)”, which are software functions that are integral to (embedded in a) a medical device.

Section 201(h),?21 U.S.C. 321(h),(1) defines a medical device to be?an apparatus, implements, machine, contrivances, implant, in vitro regulator, or other similar or related articles, as well as a component or accessory. . . (b) is intended for diagnosis or treatment of disease or other conditions in humans or animals. (c) Is intended to alter the structure or function of human bodies or animals. To be considered a medical device, and thus subject to FDA regulation, the software must meet at least one of these criteria:

• It must be used in diagnosing and treating patients.
• It must not be designed to alter the structure or function of the body.

If your software is designed to be used by healthcare professionals to diagnose, treat, or manage patient information in hospitals, the FDA will likely consider such software to be medical devices that are subject to regulatory review.

Is Your Software a Medical Device?

FDA’s current oversight, which puts more emphasis on the functionality of the software than the platform, will ensure that FDA does not regulate medical devices with functionality that could be dangerous to patient safety. Examples of Device Software and Mobile Medical Apps FDA is focused on

• Software functions that aid patients with diagnosed mental disorders (e.g., depression, anxiety, and post-traumatic stress disorder (PTSD), etc.) by providing “Skill of the Day”, a behavioral technique, or audio messages, that the user can access when they are experiencing anxiety.
• Software functions that offer periodic reminders, motivational guidance, and educational information to patients who are recovering from addiction or smokers trying to quit;
• Software functions that use GPS location data to alert asthmatics when they are near high-risk locations (substance abusers), or to alert them of potential environmental conditions that could cause symptoms.
• Software that uses video and games to encourage patients to exercise at home.
• Software functions that prompt users to choose which herb or drug they wish to take simultaneously. They also provide information about interactions and give a summary of the type of interaction reported.
• Software functions that take into account patient characteristics, such as gender, age, and risk factors, to offer patient-specific counseling, screening, and prevention recommendations from established and well-respected authorities.
• Software functions that use a list of common symptoms and signs to give advice about when to see a doctor and what to do next.
• Software functions that help users to navigate through a questionnaire about symptoms and to make a recommendation on the best type of healthcare facility for them.
• These mobile apps allow users to make pre-specified nurse calls or emergency calls using broadband or cell phone technology.
• Apps that allow patients or caregivers to send emergency notifications to first responders via mobile phones
• Software that tracks medications and provides user-configured reminders to improve medication adherence.
• Software functions that give patients access to their health information. This includes historical trending and comparisons of vital signs (e.g. body temperature, heart rate or blood pressure).
• Software functions that display trends in personal healthcare incidents (e.g. hospitalization rates or alert notification rate)
• Software functions allow users to electronically or manually enter blood pressure data, and to share it via e-mail, track it and trend it, and upload it to an electronic or personal health record.
• Apps that offer mobile apps for tracking and reminders about oral health or tools to track users suffering from gum disease.
• Apps that offer mobile guidance and tools for prediabetes patients;
• Apps that allow users to display images and other messages on their mobile devices, which can be used by substance abusers who want to quit addictive behaviors.
• Software functions that provide drug interaction and safety information (side effects and drug interactions, active ingredient, active ingredient) in a report based upon demographic data (age and gender), current diagnosis (current medications), and clinical information (current treatment).
• Software functions that allow the surgeon to determine the best intraocular lens powers for the patient and the axis of implantation. This information is based on the surgeon’s inputs (e.g., expected surgically induced astigmatism and patient’s axial length, preoperative corneal astigmatism etc.).
• Software, usually mobile apps, converts a mobile platform into a regulated medical device.
• Software that connects with a mobile platform via a sensor or lead to measure and display electrical signals from the heart (electrocardiograph; ECG).
• Software that attaches a sensor or other tools to the mobile platform to view, record and analyze eye movements to diagnose balance disorders
• Software that collects information about potential donors and transmits it to a blood collection facility. This software determines if a donor is eligible to collect blood or other components.
• Software that connects to an existing device type in order to control its operation, function, or energy source.
• Software that alters or disables the functions of an infusion pump
• Software that controls the inflation or deflation of a blood pressure cuff
• Software that calibrates hearing aids and assesses sound intensity characteristics and electroacoustic frequency of hearing aids.

What does it mean if your software/SaaS is classified as a medical device?

SaaS founders need to be aware of the compliance risks that medical devices pose. Data breaches are one of the biggest risks. Medical devices often contain sensitive patient data, which is why they are subject to strict regulations. This data could lead to devastating consequences if it were to become unprotected. SaaS companies who develop medical devices need to take extra precautions to ensure their products are safe.

So who needs to apply for FDA clearance? The FDA defines a ?mobile medical app manufacturer? is any person or entity who initiates specifications, designs, labels, or creates a software system or application for a regulated medical device in whole or from multiple software components. This term does not include persons who exclusively distribute mobile medical apps without engaging in manufacturing functions; examples of such distributors may include the app stores.

Software As Medical Device Patenting Considerations

The good news is that investors like medical device companies which have double exclusivity obtained through FDA and US Patent and Trademark Office (USPTO) approvals. As such, the exit point for many medical device companies is an acquisition by cash rich medical public companies. This approach enables medical devices to skip the large and risky go-to-market (GTM) spend and work required to put products in the hands of consumers.

Now that we have discussed the FDA review process, we will discuss IP issues for software medical device companies. Typically, IP includes Patents, Trademarks, Copyrights, and Trade secrets. All of these topics matter and should be considered carefully. However, we will concentrate on patents to demonstrate how careless drafting and lack of planning can lead to problems, namely unplanned disclosures of your design that can then be used as prior art against your patent application.

In general, you should file patent application(s) as soon as practicable to get the earliest priority dates. This will help you when you talk to investors, FDA consultants, prototyping firms, and government agencies, among others. Compliance or other documents filed with any government agency may be considered disclosure to third parties and could make the document public. In general, disclosures to third parties or public availability of an invention trigger a one year statutory bar during which you must file your patent application. Failure to file your application within the required time frame could result in you losing your right to protect your invention.

The information from your FDA application may find its way into FDA databases, including DeNovo, PMA and 510k databases and FDA summaries of orders, decisions, and other documents on products and devices currently being evaluated by the FDA. Your detailed information may be gleaned from Freedom of Information Act requests on your application. This risk mandates that you patent your invention quickly.

When you patent your medical device invention, have a global picture of FDA regulatory framework when you draft your patent application. Be mindful of whether your software/SaaS application discusses the diagnosing and treating patients or affecting the structure or function of the body and add language to indicate that such description in the patent application relates to only one embodiment and not to other embodiments. That way you have flexibility in subsequent discussions with the FDA if you want to avoid classification of your software/SaaS/software as a medical device. In this way, if you wish to avoid FDA registration and oversight, you have the flexibility to do so.

An experienced attorney can assist you in navigating the regulatory landscape and ensure that you comply with all applicable laws. This area of law is complex and constantly changing. It is important that you seek legal advice if you have any questions about whether or not your software should be registered with FDA.

Patent PC is an intellectual property and business law firm that was built to speed startups. We have internally developed AI tools to assist our patent workflow and to guide us in navigating through government agencies. Our business and patent lawyers are experienced in software, SaaS, and medical device technology. For a flat fee, we offer legal services to startups, businesses, and intellectual property. Our lawyers do not have to track time as there is no hourly billing and no charges for calls or emails. We just focus on getting you the best legal work for your needs.

Our expertise ranges from advising established businesses on regulatory and intellectual property issues to helping startups in their early years. Our lawyers are familiar with helping entrepreneurs and fast-moving companies in need of legal advice regarding company formation, liability, equity issuing, venture financing, IP asset security, infringement resolution, litigation, and equity issuance. For a confidential consultation, contact us at 800-234-3032 or make an appointment here.